Ebook Hurwitz clinical pediatric dermatology A textbook of skin disorders of childhood and adolescence (5th edition) Part 2

(BQ) Part 2 book Hurwitz clinical pediatric dermatology A textbook of skin disorders of childhood and adolescence presentation of content: Disorders of pigmentation, vascular vascular disorders of infancy and childhood, bullous disorders of childhood, viral diseases of the skin, skin disorders caused by fungi,...and other contents.

Disorders of decreased pigmentation may be classified as:

1 Genetic or developmentally controlled disorders, in which tation tends to be abnormal from birth or early infancy

pigmen-2 Disorders associated with depigmentation or loss of previously existing melanin

Genetic disorders of decreased pigmentation include tuberous sclerosis, piebaldism, Waardenburg syndrome (WS), and albinism Acquired disorders of decreased pigmentation include vitiligo, postin-flammatory hypopigmentation, pityriasis alba, and tinea versicolor Hypopigmentary disorders may be further divided into patterned and unpatterned groups Patterned forms of decreased pigmentation include pityriasis alba, cutaneous T-cell lymphoma, tinea versicolor, postinflammatory hypopigmentation, leprosy, pinta, tuberous sclero-sis, pigmentary mosaicism, vitiligo, piebaldism, and the Waardenburg and Vogt–Koyanagi syndromes Unpatterned decreases in pigmenta-tion may be seen in albinism, phenylketonuria, and the silvery hair syndromes

VITILIGO

Vitiligo, an acquired form of patterned loss of pigmentation, is a genic, multifactorial disorder that involves at least 16 susceptibility genes,10,11 encoding a variety of proteins involved in regulation of the immune system and tyrosinase, the principal vitiligo autoimmune antigen Melanocytes are destroyed by antigen-specific cytotoxic T cells, resulting in patchy depigmentation Both lesional and nonle-sional skin show up regulation of markers of heightened innate immunity, although only lesional skin shows suppression or absence

poly-of melanocyte-specific genes.12 Autoantibodies that can destroy nocytes have been detected in serum samples of patients with vitiligo, further emphasizing that alterations are not limited to lesional skin.Vitiligo affects approximately 1% of the population.13 Although rarely congenital, its onset in about half of affected patients is before the age of 20 years and in one-quarter before 8 years of age.14–16 The disorder has a prevalence of 7% to 12% among first-degree relatives, 6% among siblings, and 23% among monozygotic twins,17 but a recent study suggested a family history of vitiligo in approximately 30% of patients.18 Relative to postpubertal onset (after 12 years of age), prepubertal onset is associated with a greater likelihood of a family history of vitiligo and a personal history of atopic dermatitis.18Autoimmune disorders are seen with significantly increased incidence

mela-in immediate family members of affected mela-individuals, most commonly vitiligo itself,14 but other autoimmune disorders (particularly hypothy-roidism and alopecia areata) occasionally occur in pediatric patients with vitiligo.19–21 Thyroid autoimmune antibodies have been described

in 11% of patients.19,22The location, size, and shape of individual lesions vary considerably, yet the overall picture is characteristic Lesions usually appear as par-tially or completely depigmented ivory-white macules or patches, usually with well-defined, sometimes hyperpigmented, convex bor-ders23 (Figs 11-2 through 11-7) They tend to have an oval or linear contour and range in size from several millimeters to large patches Rarely, extensive or near-total depigmentation of the body (universal

Although chiefly of cosmetic significance, disorders of pigmentation

are among the most conspicuous and thus can have profound

psycho-social implications for pediatric patients The most important

pig-ments in skin are melanin, reduced and oxygenated hemoglobin, and

carotene Melanin is a pigment produced by melanocytes, specialized

dendritic cells derived from the neural crest that migrate to the basal

layer of the epidermis during embryogenesis Melanocytes synthesize

and package melanin within discrete membrane-bound organelles

called melanosomes, which are then transferred via melanocytic

den-drites to surrounding keratinocytes of epidermis and hair follicles;

on average, there is one melanocyte to every 36 surrounding

keratinocytes.1–4 Variations in skin color among different individuals

reflect the number and size of mature melanosomes, not the number

of melanocytes

Four stages of melanosome maturation have been described and

can be distinguished by ultrastructural examination:

1 Membrane vesicles that contain no visible pigment (stage I or

premelanosomes)

2 More elongated vesicles with an ordered internal membrane but

no pigment (stage II melanosome)

3 The presence of melanin on ordered internal fibers (stage III

melanosome)

4 Structures so full of melanin that the luminal structures cannot be

seen (mature or stage IV melanosomes)

Darkly pigmented individuals have more numerous, larger, singly

dispersed melanosomes, whereas individuals with light pigmentation

have fewer, smaller melanosomes that are aggregated into complexes

and are more rapidly degraded.5 The presence of melanin in the

epi-dermis helps protect against ultraviolet (UV) radiation and associated

cutaneous damage, including pigmented nevi,6 actinic damage, and

cutaneous neoplasia Red hair color, usually associated with an

inabil-ity to tan, increases the risk of developing melanoma fourfold and has

been associated with polymorphisms in the melanocortin receptor 1

(MCR1).7

Melanin exists in two forms in human skin: brown-black eumelanin

and yellow-red pheomelanin Melanin biosynthesis is primarily

regu-lated by tyrosinase, a copper-dependent enzyme that allows the initial

conversion of tyrosine to dihydroxyphenylalanine (DOPA) Eumelanin

synthesis involves increased levels of tyrosinase activity and

addi-tional melanogenic enzymes such as tyrosinase-related protein

(TRYP)-1 and TRYP-2/dopachrome tautomerase, both regulators of

distal steps in the pathway to melanin and/or stabilizers of tyrosinase

Pheomelanin synthesis, however, involves the addition of a cysteinyl

group that accounts for the yellow-red color and is associated with

reduced tyrosinase activity and absence of TRYP-1, TRYP-2, and a

protein called pink-eyed dilution (P) protein

The ratio of eumelanin to pheomelanin, as well as the total content

of melanin, is higher in skin types V–VI (the darkest skin colors) than

in skin types I and II (the lightest skin colors, most prone to burning

with UV light exposure) Pheomelanin levels tend to be greatest in

individuals with bright red hair, whereas eumelanin is the

predomi-nant pigment in individuals with brown or black hair.8

In all races the dorsal and extensor surfaces are relatively

hyperpig-mented, and the ventral surfaces are less pigmented This is most

evident in races with darker skin (African-Americans, Hispanics, and

Asians) The separation of the dorsal and ventral pigmentation is most

conspicuous on the extremities (Voigt–Futcher lines) (Fig 11-1).9 This

differentiation of dorsal and ventral pigmentation is present from

infancy and persists throughout adulthood Approximately 75% of

11  •  Disorders of Pigmentation

246

shins (see Fig 11-3) Approximately 12% of patients show white hairs (leukotrichia or poliosis) (Fig 11-8) Vitiligo has been divided into several subtypes based on the distribution of lesions In descending order of incidence in pediatric patients, these include generalized, focal, segmental, acrofacial, mucosal, and universal Patients with vitiligo, especially those with prepubertal onset,18 commonly show halo nevi,24 pigmented nevi surrounded by a zone of depigmentation (Fig 11-9) (see Chapter 9, Fig 9-26) The discovery of a halo nevus

or total vitiligo) occurs (see Fig 11-4) Although usually considered

to be a bilateral disorder, vitiligo may be asymmetric; segmental

viti-ligo, in which the depigmentation is confined to a localized, usually

unilateral area, occurs more often in children than in adults (see Fig

11-5) In 75% of affected individuals the first lesions occur as

depig-mented spots on exposed areas such as the dorsal surfaces of the

hands, face, and neck Other sites of predilection include the body folds

(the axillae and groin), body orifices (the eyes, nostrils, mouth, navel,

areolae, genitalia, and perianal regions (see Figs 11-6 and 11-7), and

areas over bony prominences such as the elbows, knees, knuckles, and

Figure 11-1 Voigt–Futcher  line.  This  persistent  line  of  demarcation 

Figure 11-4 Vitiligo. Extensive depigmentation in this 13-year-old girl. Virtually  all  of  her  skin  was  depigmented,  except  for  the  pigmented areas  on  the  back.  After  years  of  unsuccessfully  trying  to  stimulate repigmentation, at 16 years of age this girl and her parents elected to initiate 20% monobenzyl ether of hydroquinone. 

of trauma in triggering new lesions.26 Other individuals associate the onset of vitiligo with periods of severe physical or emotional trauma.Ordinarily the diagnosis of vitiligo is not difficult, especially when there is symmetric depigmentation about the eyes, nostrils, mouth, nipples, umbilicus, or genitalia In fair-skinned individuals it may be difficult to differentiate areas of vitiligo from the adjacent normal skin

In such cases examination under Wood light in a darkened room may help delineate a contrast between normal and depigmented skin When the diagnosis is in doubt, the distribution of lesions, the age

at onset, the presence of a convex hyperpigmented border, and the characteristic sites of predilection may help establish the correct diagnosis

Lesions of postinflammatory hypopigmentation are mented, not depigmented, and patients usually provide a history of previous localized inflammation However, it is not uncommon to see residual depigmentation in severe atopic dermatitis, especially in darker skinned patients and involving the wrists, hands, ankles, and feet Nevus depigmentosus tends to be a well-defined, usually

Figure 11-9 Vitiligo.  Halo  nevi  are  commonly  seen  in  children  with vitiligo and can partially or fully clear the nevus. Any patient with a halo nevus  should  be  completely  examined  for  the  possibility  of  vitiligo elsewhere. The mechanism of clearance of pigmentation in vitiligo and halo nevi is thought to be the same. 

11  •  Disorders of Pigmentation

248

hair follicles, such as the dorsal surfaces of the fingers, hands, feet, and the volar aspect of the wrists, do not respond as well as other areas.Quality-of-life studies have shown that children with vitiligo have impaired social development as young adults, stressing the impor-tance of intervention.30 Risk factors associated with the highest risk for quality-of-life impairment are age (15 to 17 years), location (face and legs), and greater extent of involvement.31 In one study, anxiety was observed in 42% of caregivers of children with vitiligo, even higher than that in caregivers of children with atopic dermatitis or psoriasis, and was correlated with poor quality-of-life scores in the children.32 Patients with vitiligo and their families can find support through the National Vitiligo Foundation (www.vitiligofoundation.org

or www.nvfi.org)

Full repigmentation is challenging, especially in children with more extensive involvement and when vitiligo involves more recalcitrant areas At least partial repigmentation can often be accomplished

by the twice-daily application of mid-strength to potent topical costeroids or topical calcineurin inhibitors (tacrolimus ointment, pimecrolimus cream).33,34 The skin of the head and neck responds best

corti-to both of these treatment modalities Overall, 40% corti-to 90% of pediatric patients show a response to these treatments, although moderate to high potency steroids can theoretically be associated with systemic absorption, especially if applied over large body-surface areas or on the head and neck continuously.21,35,36 Application of a topical calci-neurin inhibitor, especially for facial vitiligo, eliminates the risk of cutaneous atrophy and ocular toxicity carried by application of topical corticosteroids However, hyperpigmentation in sun-exposed areas has been described after use of tacrolimus ointment.37 Although topical anti-inflammatory therapy has been standard, one study described good to excellent repigmentation in 65% of 400 children treated with minipulses of oral methylprednisolone on 2 consecutive days weekly and fluticasone ointment twice daily.38 Topical application

of vitamin D3 analogues (calcipotriene, calcipotriol) has also been used but has the potential to be more irritating

The repigmentation of lesional skin can be stimulated most tively by exposure to UV light, generally in combination with topically applied anti-inflammatory medications or vitamin D3 analogues Avoidance of burning with phototherapy is important, because cuta-neous burning can lead to further depigmentation via the Koebner phenomenon Most commonly narrow-band (nb) UVB is utilized, because it has been shown to be as effective as psoralen and UVA (PUVA) therapy,39–41 which is now rarely used in children because of its toxicity nbUVB phototherapy is largely reserved for older pediatric patients who are highly motivated and completely informed about their chances for improvement with these therapies Treatment is tra-ditionally 2 to 3 times weekly, beginning at a relatively low dose and increasing by about 20% each treatment until slight erythema is reached Should there not be a good response within 6 months, nbUVB can be stopped.42 The 308-nm monochromatic excimer laser (in the UVB range) is a painless therapy for more localized lesions.43 The best responses to excimer laser are at sites that also respond best to nbUVB, with the dorsal aspect of the hands and feet, genital area, and supra-pubic area the most difficult sites to repigment.44 In one study of chronic stable vitiligo, more than 50% of patients showed more than 75% repigmentation.45 Responses to the excimer laser may be improved by concurrently using anti-inflammatory therapy.46 Treat-ment with the combination of topical tacalcitol (vitamin D derivative) and excimer laser for 12 sessions (over 12 weeks) was significantly more effective than the excimer laser treatments alone.47 The use of antioxidants, particularly pseudocatalase, has been based on the dem-onstration of decreased enzymatic and nonenzymatic oxidants in the skin of patients with vitiligo.48 Although in one retrospective uncon-trolled study, twice-daily full-body application of pseudocatalase cream coupled with daily low-dose nbUVB stopped vitiligo progression and led to more than 75% repigmentation in 93% of treated chil-dren,49 most experience with pseudocatalase cream has been disap-pointing Oral antioxidants for vitiligo are under investigation.Surgical modalities are based on the autologous grafting of nonle-sional epidermis or cultured melanocytes from healthy skin sites to depigmented areas that have been deepithelialized by ablative proce-dures.50,51 Chinese cupping has recently been shown to be a technique

effec-to induce blisters for capturing donor melanocytes.52 Grafting has

hypopigmented patch that may be present at birth or appear during

infancy as normal pigmentation increases but is subsequently stable

(see Fig 11-22) Pityriasis alba is a hypopigmentary disorder and may

be further differentiated by its common distribution on the face, upper

arms, neck, and shoulders and its occasional fine adherent scale (see

Chapter 3, Fig 3-33) Lesions of tinea versicolor may be differentiated

by their discrete or confluent small, round hypopigmented macules;

their fine scales; and their typical distribution on the trunk, neck,

upper arms, or particularly in pediatric patients, the face (see Chapter

17, Figs 17-33 and 17-34) The demonstration of hyphae on

micro-scopic examination of epidermal scrapings is confirmatory (see Fig

17-36) The diagnosis of cutaneous T-cell lymphoma of the

hypopig-mented type should be considered in adolescents with more extensive

hypopigmented macules resembling pityriasis alba (see Chapter 10,

Fig 10-21).27

The presence of a white forelock and the pattern of depigmentation

suggest a diagnosis of piebaldism or WS (see Figs 11-17 and 11-19)

Most individuals with WS show characteristic facial features The

diagnosis of albinism (see Oculocutaneous Albinism section) may be

established by its presence at birth and by the facts that normal eye

color is retained in vitiligo (but not in albinism); in addition, hair on

glabrous skin in the patient with vitiligo, in contrast to that in the

patient with albinism, often retains most of its pigment (see Fig

11-11) Adolescents with GM3 synthase deficiency progressively

develop depigmented patches as well as acral lentigines.28 The hy

-popigmented macules of tuberous sclerosis (see Fig 11-21, A) usually

lack the characteristic milk-white appearance of lesions of vitiligo, are

present at birth or during the first years of life, do not change with

age, and have a normal number of melanocytes (with reduction in size

of melanosomes and melanin granules within them) in contrast to the

absence or decrease in number of melanocytes in patients with

vitiligo

The course of vitiligo is variable Long periods of quiescence may be

interrupted by periods of extension or partial improvement Complete

spontaneous repigmentation is very rare, and in one study, more than

50% repigmentation occurred in only 2.4% of patients over 6

months.29 At least partial repigmentation is more likely in children

with lesions of recent onset and during the summer months because

of increased exposure to UV light Loss of pigmentation in lesions that

have at least partially repigmented is common in temperate climates

during the winter months The repigmentation process proceeds

slowly, although children tend to respond with more permanent and

complete repigmentation than adults Repigmentation most

com-monly appears as small, freckle-like spots of repigmentation, reflecting

the migration of melanocytes from the hair follicle (Fig 11-10) As

such, the chance of repigmentation in a site is greater if pigmentation

of regional hairs is retained Diffuse repigmentation of lesions or

repigmentation from the margins has also been described The

prefer-ential tendency to repigment the face and neck versus other body sites

has been attributed to the high density of hair follicles at these sites,

as well as exposure to UV light In contrast, sites lacking or poor in

Figure 11-10 Vitiligo. Note the perifollicular pattern of repigmentation. 

11  •  Disorders of Pigmentation 249

McKusick–Breen syndrome) is characterized by oculocutaneous nism (OCA), microphthalmos, spasticity, and mental retardation.71Although albinism associated with immunodeficiency is primarily seen in the silvery hair syndromes (especially Chédiak–Higashi and Griscelli type 2), immunodeficiency is a feature of OCA associated with

albi-short stature (owing to mutations in LAMTOR2)72 and in Hermansky–Pudlak syndrome (HPS) types 2 and 9, all related to the requirement for secretion of lysosomes and cytosolic granules for cytotoxic T- and natural killer cell function, antigen presentation to T cells, and neu-trophil antimicrobial activity.73

Nonsyndromic Oculocutaneous Albinism

Nonsyndromic oculocutaneous albinism (OCA) en compasses seven subtypes (Table 11-1) with decreased or absent melanin biosynthesis

in the melanocytes of the skin, hair follicles, and eyes.74,75OCA affects 1 in 17,000 persons in the United States The highest prevalence (as high as 1% of the population) occurs in the indigenous Cuna tribe on the San Blas Islands off the coast of Panama Affected

Cuna children have been called moon children because they have

marked photosensitivity and photophobia and prefer to go outdoors only at night In some African tribes, the frequency is 1:1500 OCA is characterized by varying degrees of unpatterned reduction of pigment

in the skin and hair, translucent irides, hypopigmented ocular fundi, and an associated nystagmus Melanocytes and melanosomes are present in the affected skin and hair in normal numbers but fail to produce normal amounts of melanin Regardless of subtype, affected individuals require vigorous sun protection of the skin and eyes and are at risk of adverse psychosocial effects because of the cosmetic aspects of albinism, especially in children from darker-skinned back-grounds In addition to the stigma and potential social isolation, affected individuals in Africa have been maimed or killed because of the myths associated with albinism (contagion, body parts with magical and medicinal powers, intercourse with an affected woman will cure human immunodeficiency virus [HIV] infection).76

In the past, albinism was divided into tyrosinase-negative and tyrosinase-positive forms based on the ability (tyrosinase-positive) or inability (tyrosinase-negative) of plucked hair to become pigmented in the presence of tyrosine or DOPA Tyrosinase-negative albinism, now

called type I albinism (OCA1), results from absence (OCA1A) or partial

reduction of the activity (OCA1B) of tyrosinase, the critical enzyme in melanin formation (see Table 11-1).77 The underlying genetic bases for most forms of tyrosinase-positive albinism are also known Type II albinism (OCA2) results from the absence of P protein,78 OCA3 from absence of TRYP1,79,80 and OCA4 from mutations in membrane-associated transporter protein (MATP).81 Types OCA5–7 have been only been described in one to a few families (see Table 11-1).82–85Individuals with OCA1A are unable to produce melanin at all and show white skin, white hair, and blue irides regardless of familial skin coloration.86 Hair may show a slight yellow tint with advanc-ing age because of denaturation of hair keratins Similarly, ocular abnormalities are most severe with OCA1A Eye findings include photophobia (with squinting), nystagmus (which typically develops

at 6 to 8 weeks of age), strabismus, and decreased visual acuity; patients with OCA1A are often legally blind The optic fibers are misrouted, resulting in monocular vision, which is usually not altered

by surgical correction of the nystagmus or strabismus.87,88 Although neurologic development is otherwise generally normal, an increased risk of attention-deficit/hyperactivity disorder (ADHD) has also been described.89 Actinic damage (cutaneous atrophy, telangiectasia and wrinkling, actinic cheilitis, actinic keratoses) and malignant skin tumors (especially squamous cell carcinoma and nodular basal cell carcinoma but also melanoma) are almost always seen in affected young adults90 but may present during childhood if the skin and eyes are not protected

Patients with OCA1B have been divided into different phenotypic subgroups (see Table 11-1) that occur because of differences in degree

of tyrosinase activity and the localization within the TYR gene of the

mutation In the yellow mutant form, the hair turns yellow in the first few years and a golden blond to light brown by the end of the second decade Patients with platinum OCA develop small amounts of pigment with a metallic tinge in late childhood Those with minimal-pigment OCA show darkening of the eyes with time, but the skin

been demonstrated to lead to at least 75% repigmentation in 30% to

90% of patients and is most successful for more localized lesions.53,54

Although minigrafting with or without UV light exposure has shown

success, especially in patients with facial grafts and with segmental

and limited subtypes,55,56 these approaches are time-consuming,

costly, and can result in recurrence of vitiligo (including at the donor

site), scarring, infection, and keloids in at-risk patients; grafting should

only be considered for stable vitiligo in selected adolescents at sites that

are resistant to medical treatment

When treatment is unsatisfactory, lesions can be hidden by the use

of camouflage therapy,57 which has been shown to improve the quality

of life in children with vitiligo.58 Camouflage can be achieved most

effectively with cosmetics (e.g., Cover FX, Dermablend, or Covermark),

but aniline dye stains, such as Vitadye (Elder) and quick-tan

prepara-tions59 have also been used

In those few recalcitrant cases in which vitiligo has progressed to

such an extent that more than 50% of the body is involved

(particu-larly in those persons in whom only a few islands of normal skin

remain), an attempt at depigmentation with 20% monobenzyl ether

of hydroquinone (Benoquin) may be considered Such patients should

be reminded that the depigmentation is permanent, requiring lifelong

vigilant use of sun protection Owing to the permanence of

depigmen-tation therapy, this treatment is not generally offered to preadolescent

patients

VOGT–KOYANAGI–HARADA SYNDROME

Vogt–Koyanagi–Harada syndrome is a rare autoimmune disorder

characterized by bilateral granulomatous uveitis, alopecia, vitiligo,

poliosis, dysacousia (in which certain sounds produce discomfort),

deafness, and sometimes meningeal irritation or encephalitic

symp-toms.60 Usually seen in adults in the third and fourth decades of life,61

the disorder also occurs in children and adolescents.62,63

The bilateral uveitis occurs in all patients and generally takes a year

or more to clear The uveitis is often accompanied by choroiditis and

optic neuritis As the uveitis begins to subside, poliosis (in 80% to

90%), usually bilateral vitiligo (in 50% to 60%), alopecia (in 50%),

and temporary auditory impairment develop A prodromal febrile

episode with lymphocytosis, encephalitic or meningeal symptoms,

and increased pressure of the cerebrospinal fluid may precede the

bilateral uveitis The poliosis may be limited to the eyebrows and

eye-lashes or may also involve the scalp and body hair The pigmentary

changes, which generally appear 3 weeks to 3 months after the

onset of the uveitis, tend to be permanent Although most patients

show some recovery of visual acuity, the majority of children and

adolescents have a residual visual defect related to the development of

cataracts, glaucoma, choroidal neovascularization, and subretinal

fibrosis.64

Early and aggressive systemic corticosteroids are the primary

inter-vention, but refractory cases may respond to cyclosporine,

methotrex-ate, or tumor necrosis factor (TNF) inhibitors.65,66

ALEZZANDRINI SYNDROME

Alezzandrini syndrome is a rare disorder of unknown origin primarily

seen in adolescents and young adults Possibly related to Vogt–

Koyanagi–Harada syndrome, it is characterized by unilateral

degen-erative retinitis with visual impairment followed after an interval of

months or years by bilateral deafness and unilateral vitiligo and

polio-sis, which appear on the side of the retinitis.67,68

OCULOCUTANEOUS ALBINISM

Albinism is a group of inherited disorders of melanin synthesis

mani-fested by a congenital decrease of pigmentation of the skin, hair, and

eyes.69,70 Although some classifications include nonsyndromic and

syndromic (e.g., silvery hair and Hermansky–Pudlak syndromes)

forms, the pigmentary changes are very different among these

disor-ders Most albinism is oculocutaneous, but affected individuals may

have ocular albinism, usually an X-linked recessive form caused by

mutation in OA1/GPR143, with the abnormal pigmentation limited

to the eye An oculocerebral syndrome with hypopigmentation (Cross–

11  •  Disorders of Pigmentation

250

and pigmented nevi usually develop at sun-exposed sites (Fig 11-12) These individuals can also have problems with their eyes and an increased risk of cutaneous malignancy, but significantly less than that seen in individuals with tyrosinase-negative albinism Although the degree of pigment dilution in affected individuals is variable, the diagnosis is usually easily established in those who have striking pigment loss or relative pigment dilution when compared with unaf-fected siblings or parents Some patients with OCA2 have red hair, which has been shown to result from concomitant mutations in the melanocortin 1 receptor.91 OCA2 has also been described in approximately 1% of patients with Angelman syndrome or Prader–Willi syndrome, disorders that result from deletion of the long arm of

chromosome 15, the site of the P gene Prader–Willi syndrome results

remains without pigmentation Individuals with

temperature-sensitive OCA1B are born with white skin and hair and blue eyes

Usually during the second decade of life, however, areas with lower

temperature (especially hair at acral sites on the upper and lower

extremities) are able to produce melanin, because the tyrosinase

activ-ity is only inactivated above 35 °C This interesting phenotype is

shared with that of the Siamese cat, a breed that also results from

temperature-sensitive tyrosinase activity

The OCA2 type of albinism, which includes tyrosinase-positive

albi-nism and Brown OCA, is the most common form and is usually the

type that occurs in African-American individuals (Fig 11-11) The

phenotype may vary from a slight to moderate decrease in

pigmenta-tion of the skin, hair, and eyes With time, however, dark lentigines

Figure 11-11 Albinism. This African-American girl has type II albinism 

(mutations in P gene) with light skin and yellow hair. 

Figure 11-12 In type II albinism, pigmentation can develop with time, including in pigmented nevi. 

Type Percentage of   Patients Worldwide Mutation Function of Affected Gene Comments

negative

Critical enzyme in melanin formation 1:40,000; most severe cutaneous and 

ocular defects; highest risk of skin cancer; most common type in Caucasians

hair); platinum (metallic tinge); minimal pigment (only eyes darken)

(Rufous) 3% TRYP1 Catalyzes oxidation of 5, 6-dihydroxyindole-2-carboxylic acid 

monomers into melanin and stabilizes TYR so it can leave endoplasmic reticulum for incorporation into melanosomes

1:8500 Africans; reddish-bronze color to skin and hair

mutations misroute TYR

Rare (whites); 1:, 000 Japanese (27% 

of OCA in Japan); resembles OCA2

melanosome maturation and melanin biosynthesis

Heterogeneous extent of pigmentation

Table 11-1  Forms of Oculocutaneous Albinism

MATP, Membrane-associated transporter protein; OCA, oculocutaneous albinism; P protein, pink-eyed dilution protein; TS, temperature-sensitive;

TYR, tyrosinase; TRYP1, tyrosinase-related protein 1.

11  •  Disorders of Pigmentation 251

Special precautions and sometimes platelet transfusions must be given

to avoid excessive bleeding after minor trauma or dental surgery.The diffuse pigmentary features of the skin and eyes of individuals with HPS include pigmentary dilution of the skin and often the irides with hair that has a peculiar sheen, although not as silvery as in Chédiak–Higashi syndrome (CHS), another syndrome of lysosome-related organelles The degree of generalized pigment loss is quite variable in intensity, ranging from white skin to brown and light to brown eyes Ocular pigmentation generally correlates with cutaneous pigmentation Ocular findings include nystagmus, photophobia, and decreased visual acuity Extensive ecchymoses are a common clinical manifestation (Fig 11-13) The bleeding diathesis also commonly manifests as epistaxis and menometrorrhagia Patients with both HPS and systemic lupus erythematosus have been described.102 The life-threatening complications of HPS, other than the bleeding diathesis, have been described in certain subtypes and are unusual in most affected children These include granulomatous colitis (including two patients with cutaneous granulomatous disease that resembled meta-static Crohn disease),103,104 progressive pulmonary fibrosis,105 and less

from deletion of the paternal chromosome at 15q and is characterized

by hyperphagia with obesity, hypogonadism, and mental retardation

In contrast, Angelman syndrome results from deletion of the

mater-nal chromosome at 15q and is characterized by microcephaly, severe

mental retardation, ataxia, and inappropriate laughter Pigment

dilu-tion occurs when both copies of the P gene are mutated or deleted

Interestingly, duplication of the 15q chromosomal region has been

associated with generalized skin hyperpigmentation.92

Rufous OCA or OCA3 presents as “ginger” red hair, a reddish-bronze

color of skin, and blue or sometimes brown irides This form may be

underreported, because the decrease in pigmentation is slight and

may be undetectable in lighter skinned patients OCA4 is now

consid-ered one of the most common forms in Japan,93 and affected

individu-als resemble patients with OCA2.81

Patients with albinism should be monitored by an ophthalmologist

in addition to the dermatologist Glasses may help the poor vision, and

contact lenses and tinted glasses may ameliorate the photophobia

Nystagmus may be helped by surgery of the eye muscles or contact

lenses; eye patching may be needed for the strabismus High-contrast

written material, large-type textbooks and computers that can enlarge

text are all helpful for patients with poor visual acuity Early actinic

changes, keratoses, basal cell tumors, and particularly squamous cell

carcinomas are common; the risk of melanoma (often amelanotic)94

is also increased, even in children and adolescents Thus individuals

with cutaneous albinism must learn to avoid sunlight exposure, to

wear sunglasses, and to use protective clothing and sunscreen

prepa-rations on exposed surfaces The National Organization for Albinism

and Hypopigmentation (NOAH) is a national support group for

patients and their families (www.albinism.org)

HERMANSKY–PUDLAK SYNDROME

Hermansky–Pudlak syndrome (HPS) is a group of at least 9

autoso-mal recessive disorders (HPS1–9) characterized by pigment dilution,

a hemorrhagic diathesis secondary to a platelet storage pool defect,

and ceroid-lipofuscin depositions within the reticuloendothelial

system, oral and intestinal mucosae, lung, and urine.95–97 HPS is a

disorder of biogenesis of melanosomes and other lysosome-related

organelles98–100 including platelet dense granules (Table 11-2), and all

of the mutations found are in genes encoding components of protein

complexes (e.g., BLOC-1, BLOC-2, BLOC-3, and AP-3) that regulate

vesicle trafficking in these organelle systems.101 HPS is most

com-monly seen in Hispanics from Puerto Rico (1:1800 to 1:400 persons;

HPS-1 and sometimes HPS-3), in persons of Dutch origin, and in East

Indians from Madras The platelet defect in patients with HPS does not

produce a severe problem in children Its expression, however, can be

aggravated by ingestion of aspirin and other prostaglandin blockers

Type Mutation Underlying Cause Findings Associated with the Cutaneous   Pigment Dilution

Nystagmus, decreased visual acuity; prolonged bleeding; pulmonary fibrosis; granulomatous colitis (up to 1 of patients)

HPS-2 AP3B1 AP3B1 encodes a subunit of AP-3, which mediates protein 

trafficking into transport vesicles of the lysosome (and is thus also involved in immune function)

Nystagmus, decreased visual acuity; prolonged bleeding; neutropenia; recurrent bacterial and viral infections; conductive hearing loss

Nystagmus, decreased visual acuity; prolonged bleeding

manifestationsOthers Subunits of BLOC-1 (MUTED; CNO; KXD1) and component of 

other subunits (AP3D of AP-3; VPS33A, RABGGTA)

Table 11-2  Clinical Features of Hermansky–Pudlak Syndrome

BLOC, Biogenesis of lysosome-related organelles complex; DTNBP1, dystrobrevin binding protein 1.

Figure 11-13 Hermansky–Pudlak  syndrome.  The  legs  of  this  baby show both the pigmentary abnormality and extensive ecchymoses as 

a sign of the bleeding diathesis. 

11  •  Disorders of Pigmentation

252

pneumococcus The skin infections are primarily pyodermas, but infections with these organisms that result in deeper ulcerations resembling pyoderma gangrenosum have been reported

Approximately 50% to 85% of patients with CHS undergo an erated” lymphohistiocytic phase during the first decade of life, char-acterized by widespread visceral tissue infiltration with lymphoid and histiocytic cells that are sometimes atypical in appearance.113,114Hepatosplenomegaly, lymphadenopathy, pancytopenia, jaundice, a leukemia-like gingivitis, and pseudomembranous sloughing of the buccal mucosa are associated features The thrombocytopenia, plate-let dysfunction, and depletion of coagulation factors may lead to pete-chiae, bruising, and gingival bleeding Granulocytopenia and anemia are found in 90% of patients during the accelerated phase Neurologic manifestations may range from seizures to cranial nerve palsy to loss

“accel-of consciousness Viral infection, particularly from Epstein–Barr virus (EBV) infection, has been implicated in causing the accelerated lym-phohistiocytic phase The pigmentary changes that help to distinguish the CHS-related accelerated phase must be distinguished from autoim-mune hemophagic syndromes and familial hemophagocytic lympho-histiocytosis (genetic defects in the cytolytic granule-dependent exocytosis pathway such as perforin) Neutropenia is common, and neutrophils are deficient in chemotactic and bactericidal capability Selective deficiency of natural killer (NK) cells is characteristic These immune abnormalities have been thought to cause the increased sus-ceptibility to infections and the lymphohistiocytic phase

Patients who survive into early adulthood may develop progressive neurologic deterioration, particularly with clumsiness, abnormal gait, paresthesias, and dysesthesias Peripheral and cranial neuropathies and occasionally a form of spinocerebellar degeneration may occur

CHS results from biallelic mutations in LYST, a lysosomal transport

protein that regulates the fusion of primary lysosome-like structures The skin pigmentary disorder has been attributed to the inability of melanosomal fusion and transfer to keratinocytes, leading to giant melanosomes within melanocytes Giant granules are found in circu-lating leukocytes, melanocytes of skin and hair, renal tubular epithe-lial cells, central nervous system (CNS) neurons, and other tissues In the hair shaft, these giant melanosomes are smaller than those of GS and regularly spaced (Fig 11-15, A) The giant granules within phagocytic cells of affected children cannot discharge their lysosomal and peroxidative enzymes into phagocytic vacuoles Of note, patients with leukemia may show granules that resemble those of CHS in leukocytes

The mean age of death for patients with CHS without immune reconstitution is 6 years of age Fatality usually results from over-whelming infection or hemorrhage during the accelerated phase Approximately 10% to 15% of affected patients have a milder clinical phenotype and survive into adulthood but tend to develop the progres-sive neurologic dysfunction.115 For all of the silvery hair syndromes, early bone marrow or stem-cell transplantation is the treatment of choice for patients with a human leukocyte antigen (HLA) match Bone marrow transplantation reverses the immunodeficiency and prevents the often-fatal accelerated phase but has no effect on pigmen-tation or on neurologic deterioration Otherwise, management of the disorder is largely supportive Antibiotics help to control the recurrent infections, and immunoglobulin or immunosuppressive agents have been administered in an attempt to control the lymphohistiocytic or hemophagocytic phases Splenectomy has been advocated in patients with the accelerated phase unresponsive to other forms of therapy

commonly, cardiomyopathy and renal failure Immunodeficiency is a

features of HPS-2 and the newest described form, HPS-9, which to

date has not been associated with a bleeding diathesis.106,107 The life

expectancy is 30 to 50 years of age Glasses or contact lenses can help

to correct the refractive errors The bleeding from skin wounds may

be stopped with thrombin-soaked Gelfoam, and desmopressin (DDAVP)

has been administered for tooth extraction and other invasive

proce-dures Transfusions of platelets or erythrocytes are occasionally

required The pulmonary fibrosis and enterocolitis are most

com-monly seen in HPS-1 and are often recalcitrant to therapy; infliximab

is sometimes helpful.108 Gene testing is available for mutations of

HPS1 and HSP3.

Phenylketonuria

Phenylketonuria results from deficiency in phenylalanine

hydroxy-lase, the enzyme that converts phenylalanine to tyrosine Although

rarely an issue because of widespread perinatal Guthrie testing,

untreated patients with phenylketonuria may develop generalized

hypopigmentation of the hair, skin, and/or eyes in comparison with

family members, related to the deficiency of tyrosine, the substrate for

melanin Neurologic features predominate (mental retardation,

sei-zures, hyperreflexia), but patients may also show dermatitis and rarely,

focal morphea-like skin lesions (see Chapter 22) Treatment is by

avoidance of dietary phenylalanine

SILVERY HAIR SYNDROMES

Three syndromes, CHS, Griscelli syndrome (GS), and Elejalde

syn-drome (probably a subset of GS), are autosomal recessive disorders

characterized by an early silvery sheen to the hair, relative pigmentary

dilution of skin with a grayish coloration, and in some patients ocular

hypopigmentation.97

Chédiak–Higashi Syndrome

Patients with Chédiak–Higashi syndrome (CHS) usually have a

char-acteristic silvery sheen to the hair and skin, with a skin color that may

appear lighter than that of other family members.109,110 In affected

individuals of family backgrounds of darker skin, however, the skin of

acral, sun-exposed areas (ears, nose) may become intensely

hyperpig-mented (Fig 11-14) or show only speckled hypopigmentation.111,112

Decreased iris pigmentation results in an increased red reflex and

pho-tophobia Strabismus and nystagmus are common, but visual acuity

is usually normal Inflammation and ulceration of the oral mucosa,

especially of the gingivae, have been described

The immunodeficiency of patients with CHS leads to infectious

epi-sodes These episodes are associated with fever and predominantly

involve the skin, lungs, and upper respiratory tract The most common

organisms found are Staphylococcus aureus, Streptococcus pyogenes and

con-tooncogene, which encodes a cell-surface receptor for the stem-cell/mast cell growth factor130; deletions in SNAI2/SLUG (encoding snail

homolog of 2), a transcription factor, have also been described.131 The clinical manifestations of piebaldism may be explained by the resul-tant defective migration of melanoblasts from the neural crest to the ventral midline and a defect in the differentiation of melanoblasts to melanocytes The distinctive patterns of hypopigmentation or depig-mentation usually persist unchanged throughout life, but affected individuals with progressive depigmentation,132 response to UV light and partial repigmentation,133,134 or forelock regression during infancy135 have occasionally been described The white forelock, with

a depigmented triangular patch of the scalp and forehead (widest at the forehead with the apex pointing backward) occurs in 80% to 90%

of individuals with piebaldism (Fig 11-17) Depigmented areas on the forehead often include the whole or inner portions of the eyebrows and eyelashes and extend to the root of the nose Hypopigmented or depigmented areas have also been noted commonly on the chin, ante-rior neck, anterior portion of the trunk and abdomen, and on the anterior and posterior aspects of the mid-arm to the wrist and the mid-thigh to mid-calf Typical of the lesions of piebaldism are islands

of normal and increased pigmentation within the hypomelanotic areas and sometimes hyperpigmented borders (Fig 11-18) Intertrigi-nous freckling and multiple café-au-lait (CAL) macules may occasion-ally be noted in patients and do not reflect the concurrence of piebaldism and neurofibromatosis (NF) 1 or Legius syndrome.136,137The depigmentation of piebaldism can be differentiated from that of vitiligo by the usual presence at birth, lack of convex borders, and

Griscelli Syndrome

Three subsets of patients with Griscelli syndrome (GS) have been

described based on clinical manifestations and underlying gene

defects Two of these subsets are caused by mutations in genes close

to each other on chromosome 15q21, myosin Va (type 1) and RAB27A

(type 2) Myosin Va encodes a protein that binds organelles such as

melanosomes to actin RAB27A is a guanosine triphosphate

(GTP)-binding protein involved in the movement of melanosomes

Melano-cytes are unable to transfer melanosomes to epidermal cells, and

ultrastructural examination of skin biopsies reveals accumulation of

melanosomes in melanocytes but few in surrounding keratinocytes

Patients who have uncontrolled activation of T lymphocytes

and macrophages (hemophagocytic syndrome) and immune deficits

(especially reduction in T-cell cytotoxicity and cytolytic granule

exo-cytosis) have mutations in RAB27A,116 whereas those patients with

neurologic problems and without immune abnormalities or

hemo-phagocytosis tend to have myosin Va mutations.117 Elejalde syndrome

(neuroectodermal melanolysosomal disease), characterized by similar

abnormal pigmentation in the skin and hair and severe neurologic

dysfunction (seizures, severe hypotonia, ocular abnormalities, and

mental retardation) but no immunodeficiency or

hemophagocyto-sis118,119 is now considered a subset of GS type 1.120 Rare patients with

neurologic abnormalities with or without hemophagocytosis have

shown a RAB27A mutation.118,121 Type 3 GS shows a phenotype

restricted to the pigmentary defects and results either from mutation

in the gene that encodes melanophilin (MLPH) or from a deletion in

the F-exon of myosin Va.122–124

Patients with GS, especially GS type 2, may be difficult to distinguish

clinically from patients with CHS, because the silver-gray hair and

skin color (Fig 11-16), recurrent episodes of fever with or without

infection, increasing hepatosplenomegaly owing to lymphohistiocytic

infiltration, and progressive neurologic deterioration may be part of

the clinical spectrum of both disorders.125 In contrast to CHS, the

lymphohistiocytic infiltration tends to occur in the first year of life

Blood smears show pancytopenia, but in contrast to the patients

with CHS, no leukocyte inclusions Microscopic examination of hair

shows clumping of pigment in the hair shaft similar to that of CHS

but with larger, more irregularly spaced macromelanosomes (see

Fig 11-15, B)

Intervention is similar to that of CHS, primarily through

hemato-poietic stem-cell transplantation Given the lack of success of

trans-plantation in patients with mutations in myosin Va,126 restriction of

transplantation to patients with RAB27A mutations has been

11  •  Disorders of Pigmentation

254

predilection for ventral surfaces in contrast to the predilection on

exposed areas, body orifices, areas of trauma, and intertriginous

regions in vitiligo The typical facial characteristics of type I WS are

not seen in patients with piebaldism, although sensorineural deafness

has rarely been described in piebaldism.138 Biallelic homozygous

muta-tions in c-KIT have been described from affected consanguineous

parents; affected neonates show generalized depigmentation of the

skin and hair, blue irides, and profound sensorineural deafness.139

Incomplete penetrance has been described (e.g., a parent without

evi-dence of piebaldism who has children with piebaldism and shares the

c-KIT mutations).140

Treatment consists of cosmetic masking of areas of leukoderma59

and vigorous sun protection In the rare patients who show increased

pigmentation after UV exposure, phototherapy may be considered

Reepithelialization by grafting from suction blisters and autologous

cultured or noncultured epidermis, with or without laser, has provided

permanent repigmentation.141,142

WAARDENBURG SYNDROME

Waardenburg syndrome (WS) is a heterogenous group of autosomal

dominant disorders characterized by heterochromia irides, a white

forelock, cutaneous depigmentation, and in many patients, congenital

sensorineural deafness.143,144 WS reportedly accounts for 2% to 5% of

cases of congenital deafness.145 Four major subtypes of WS have been

described (Tables 11-3 and 11-4) Individuals with type I WS, the most

common form, have characteristic facial features including a broad

nasal root and lateral displacement of the medial canthi and lacrimal

puncta of the lower eyelids (dystopia canthorum) (Fig 11-19) For

clinical diagnosis, an individual must have two major criteria or one

major plus two minor criteria to be considered affected (see Table

11-3) Dystopia canthorum can be confirmed by a W index of greater

than 1.95 (see Table 11-3).144 Congenital, usually nonprogressive,

sensorineural hearing loss occurs in 47% to 58% of affected

individu-als, whereas the white forelock and cutaneous depigmentation occur

in approximately 45% and 30%, respectively The white forelock may

be present at birth, may appear later (typically during teenage years),

or may become pigmented with time The heterochromic irides and/

or hypoplastic (often brilliant) blue eyes (Fig 11-20) are less common

than the hair or skin depigmentation Type I WS results from

loss-of-function mutations in PAX3, a gene critical for both melanocyte

migration and facial embryogenesis.146,147 Spina bifida has been

described in several affected families, leading to the firm

recommenda-tion for folate supplementarecommenda-tion during pregnancy

Type II WS is a heterogeneous group of disorders that commonly

shows the iris pigmentary changes (almost all patients, particularly

the blue irides) and deafness (80%) of WS type I but not the facial

Figure 11-18 

Piebaldism. Note the sharply demarcated areas of depig-

mentation with the islands of normal pigmentation within the depig-mented areas. 

characteristics.148 Mutations in the microphthalmia-associated

tran-scription factor (MITF) gene have been described in 15% to 21% of

patients with type II WS.149 Tietze syndrome, also linked to MITF

mutations on one allele, was originally characterized by generalized, albino-like pigmentary deficiency and hearing loss but no iris hetero-chromia; subsequent studies have shown clinical variability within

families with heterozygous MITF mutations, ranging from a

general-ized decrease in pigmentation to patchy loss to no cutaneous tations in association with profound hearing loss and blue irides.148Patients with WS2 may have strabismus Freckling in sun-exposed areas without depigmentation is common, especially among patients

manifes-of Asian descent.148,149 Other patients with type II WS have mutations

in SOX10 (≈15%, encoding sex-determining region Y [SRY]-box10) or SNAI2/SLUG (as in piebaldism), transcription factors critical for the

Disorder Inheritance Gene Other Comments

canthorum

risk of hearing loss; iris heterochromia

risk of hearing loss; iris heterochromia

risk of hearing loss; iris heterochromia

risk of hearing loss; iris heterochromia

risk of hearing loss; iris heterochromia

nervous system and peripheral nerve abnormalities

Major Criteria Minor Criteria

White forelock, hair depigmentationPigmentary abnormality of the irisDystopia canthorum, W index* >1.95Congenital sensorineural hearing lossAffected first-degree relative

Skin depigmentationSynophrys/medial eyebrow flare

High/broad nasal rootHypoplastic alae nasiGray hair before 30 years old

Table 11-3  Diagnostic Criteria for Type I 

Waardenburg Syndrome

*W index: The measurements necessary to calculate the W index (in mm) are as follows: the inner canthal distance (a), the interpupillary distance (b), and the outer canthal distance (c)

Calculate X = (2a − 0.2119c + 3.909)/c

Calculate Y = (2a − 0.2479b + 3.909)/b

Calculate W = X + Y + a/b

WS, Waardenburg syndrome.

11  •  Disorders of Pigmentation 255

TSC2 (encoding tuberin; approximately 60% of patients); gene

muta-tions have not been discovered in 10% to 25% of affected individuals Tuberin and hamartin form a complex that suppresses cell growth through regulation of several signaling pathways, most importantly the mammalian target-of-rapamycin (mTOR) pathway signaling through switching Rheb from an active (GTP-bound) to inactive (gua-nosine diphosphate [GDP]-bound) state.162 In general, patients with

mutations in TSC1 have milder disease.164 The disorder is ized by the development of hamartomas of the skin, brain, eye, heart, kidneys, lungs, and bone (Box 11-1).162 A variety of cutaneous fea-tures, including hypopigmented macules, angiofibromas, fibrous tumors, and periungual and gingival fibromas, may be seen.Three or more hypopigmented macules (white spots) of TSC are seen in 97% of patients at birth or shortly thereafter, although the appearance of additional lesions as late as 6 years of age has been described.165 Once present, the hypopigmented macules tend to be persistent and stable in shape and relative size but may become less apparent during adulthood Wood lamp examination in a completely darkened room may be useful in accentuating the macules in fair-skinned children The white spots most commonly occur on the trunk, but hypopigmented tufts of scalp or eyelash hair meet the criterion for

character-a hypopigmented mcharacter-acule They rcharacter-ange in size from character-a millimeter to several centimeters and number from a few to more than 75; 18% to 20% of individuals with TSC have 1 or 2 hypopigmented macules The hypopigmented macules (Fig 11-21) are often round (“thumbprint”), confetti-like hypopigmented macules (particularly over the pretibial areas), and oval or linear, but a lance-ovate shape (“ash leaf spots”) is commonly described and is unusual in other disorders of localized decreased skin pigmentation such as nevus depigmentosus and viti-ligo Lesions of vitiligo tend to be depigmented and show a bright white coloration with Wood lamp examination The hypopigmented white spots of TSC are most difficult to distinguish from nevus depigmento-

sus (also called nevus achromicus; Fig 11-22), which occurs in 1.6%

to 4.7% of children,166,167 suggesting that the majority of young dren with a white spot do not have TSC Nevus depigmentosus may be present at birth or appear during early infancy as normal pigmenta-tion increases and then persist Despite its name, most nevus depigmentosus lesions are hypopigmented, not depigmented Most individuals will have a solitary lesion of nevus depigmentosus, but multiple lesions and segmental forms of nevus depigmentosus have been described Nevus depigmentosus and the hypomelanotic macules of TSC must also be distinguished from nevus anemicus, a developmental anomaly characterized by a circumscribed round or oval patch of pale or mottled skin168 (see Chapter 12, Fig 12-60)

Major Features

Hypopigmented macules ≥5mm across (≥3)Angiofibromas (>3) or fibrous cephalic plaqueShagreen patch (connective tissue nevus)Ungual fibromas (≥2)

Cortical dysplasiasSubependymal nodulesSubependymal giant-cell astrocytomaCardiac rhabdomyoma

Multiple retinal hamartomasAngiomyolipomas (≥2)LymphangioleiomyomatosisMinor features

“Confetti” skin lesionsIntraoral fibromas (>2)Dental enamel pits (>3)Multiple renal cystsNonrenal hamartomasRetinal achromic patch

migration and development of neural-crest cells Type III WS is an

extreme presentation of type I WS with musculoskeletal abnormalities

and rarely associated neural-tube defects.150 Some but not all patients

with type III WS have homozygous mutations in PAX3 Type IV WS

includes the pigmentary defects and sensorineural deafness in

associa-tion with absence of enteric ganglia in the distal part of the intestine

(Hirschsprung disease); presentation with chronic constipation

begin-ning in the neonatal period is not unusual.151,152 Facies are normal

Mutations have been described in three genes: EDN3, EDNRB, and

SOX10, encoding endothelin 3,153 endothelin B receptor,154 and Sox

10, respectively.155 Patients with Sox 10 mutations may also have

severe hypotonicity with CNS and peripheral-nerve abnormalities

because of the important role of Sox 10 in glial cell development.156

All of the forms of WS show marked variability of clinical

character-istics, even within families and in monozygotic twins,157 and subtle

features may be seen, especially in WS1 The white forelock may be a

feature of several other genetic and acquired disorders, but most

com-monly piebaldism.158 Iris heterochromia has also been described in

HPS.159

TUBEROUS SCLEROSIS COMPLEX

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder

with variable expressivity that occurs in as many as 1 in 6000 to 1 in

10,000 persons.160–163 Up to 70% of patients are thought to have new

mutations The disorder results from mutation in one of two different

genes, TSC1 (encoding hamartin; approximately 20% of patients) and

11  •  Disorders of Pigmentation

256

extensively on the face (Fig 11-23) The upper lip is relatively spared, except immediately below the nose The angiofibromas in affected ado-lescents may be masked by or misdiagnosed as acne Their distribution

is usually symmetrical but may be asymmetrical, especially in patients with a mosaic form of TSC.169

Large fibrotic plaques or nodules may occur on the forehead (fibrous cephalic plaque; Fig 11-24), cheeks, or scalp in 25% of patients and are often present at birth In 14% to 20% of patients, collagenomas also develop on the trunk, especially in the lumbosacral area, and

most commonly during later childhood (shagreen patches or peau de chagrin lesions) (Fig 11-25) They may be solitary or multiple and vary from smaller than 1 cm to palm-sized Collagenomas are usually slightly raised with focal depression at follicular openings, leading to comparison with pigskin, elephant skin, orange peel, or gooseflesh Fibromas under or around the nails of the fingers and especially the

toes (ungual fibromas, sometimes called Koenen tumor; Fig 11-26, A) and on the gums and other intraoral sites (intraoral fibromas) are also considered pathognomonic (Fig 11-26, B) Seen in up to 80% of patients,170 these fibromas do not tend to appear until after puberty but may be the only sign of TSC.171

Confetti-like hypopigmented macules have been noted in 6% of patients with multiple endocrine neoplasia (MEN) type 1172 and mul-tiple angiofibromas in 43% to 88% of adolescents and adults with MEN1.172,173 Facial angiofibromas in patients with MEN1 tend to be fewer in number than in patients with TSC, may involve the upper lip

or vermilion border, and fail to cluster in the nasolabial folds lagenomas have been observed in 72% of patients with MEN1.172

Col-Cutaneous angiofibromas (adenoma sebaceum), which are

hamar-tomas composed of fibrous and vascular tissue, appear in 75% of

cases They typically develop between 2 and 6 years of age and

con-tinue to increase in number thereafter but have been described at birth

or as late as the mid-20s These lesions characteristically are 1- to

4-mm, pink to red, dome-shaped papules with a smooth surface They

occur on the nasolabial folds, cheeks, and chin and sometimes more

Figure 11-21 Tuberous  sclerosis.  (A)  Several  lance-ovate  (“ash-leaf”) 

and  “thumbprint”  white  macules  are  noted  on  this  infant’s  back.   

(B) Confetti-like macules on the lower extremities in a 13-year-old boy. 

A

B

Figure 11-22 Nevus  depigmentosus.  Well-demarcated  patch  of 

hypopigmentation  that  tends  to  be  round  or  oval  in  configuration. 

Nevus depigmentosus, also known as nevus achromicus, may be noted 

at birth or may become apparent during infancy. 

Figure 11-23 Tuberous  sclerosis.  Facial  angiofibromas  (adenoma sebaceum) are typically 1- to 4-mm, skin-colored to red, dome-shaped papules with a smooth surface. The facial angiofibromas largely involve the cheeks and nose with relative sparing of the upper lip. 

Figure 11-24 Tuberous sclerosis. The fibrous cephalic plaque may be present at birth and, together with the hypopigmented macules, may allow a definitive diagnosis of tuberous sclerosis. 

11  •  Disorders of Pigmentation 257

papules is common in normal adults and may begin during cence; they resemble angiofibromas and have recently been shown to have activated mTOR signaling as well.177

adoles-The systemic lesions of TSC may produce severe symptoms and sibly death Seizures, seen in 80% to 90% of patients with TSC, may begin as infantile spasms in which sudden repetitive myoclonic con-tractions of most of the body musculature are combined with flexion, extension, opisthotonos, and tremors By 2 or 3 years of age, focal or generalized seizures and mental retardation may become evident Extensive CNS involvement leads to hypsarrhythmia (salaam seizures) with electroencephalographic findings of multifocal high-voltage spikes and slow chaotic waves Later in life the seizure pattern may

pos-change to a petit mal variety, and in less severe cases generalized or

focal motor seizures may develop

Retardation may be mild or severe and appears in 62% of affected individuals The severity of mental retardation correlates well with the age of seizure onset In approximately 90% of patients with TSC, the brain shows areas of cortical dysplasia (including cortical “tubers” and white-matter migrational abnormalities) These areas of cortical dysplasia can calcify and be visible on skull radiographs as curvilinear opacities Periventricular or subependymal nodules may be seen by computed tomography (CT) or magnetic resonance imaging (MRI) scanning before calcification occurs.178,179 Subependymal nodules are not malignant but may enlarge to cause obstructive hydrocephalus

By the end of the first decade of life, 80% of patients show renal involvement Renal hamartomas (angiomyolipomas) occur in about 70% of patients, and larger ones may lead to hemorrhage; of note, angiomyolipomas may be found in other organs as well, and having

at least two angiomyolipoma without organ specificity is a major nostic feature With advancing age, 20% to 30% of patients develop multiple bilateral renal cysts resembling those of polycystic kidney

diag-disease These cysts can occur in individuals with TSC1 or TSC2

muta-tions, but a subset of individuals with aggressive renal cysts have

deletions involving both TSC2 and the contiguous polycystic kidney disease (PKD1) genes.180 Abdominal ultrasound or scans are able to detect renal hamartomas or cysts in asymptomatic patients Cardiac rhabdomyomas are most commonly present in the ventricles prena-tally or in infancy and tend to regress spontaneously.181 Although usually asymptomatic, rhabdomyomas may be associated with con-gestive heart failure, murmurs, cyanosis, arrhythmias, and sudden death, particularly during the first year of life Two-dimensional echo-cardiography is a noninvasive technique that allows detection of asymptomatic cardiac rhabdomyomas

The eyes may have characteristic retinal lesions (gliomas) referred

to as phakomas These retinal hamartomas have been described in 30%

to 50% of patients Funduscopy may show one of two types of lesions: multiple, raised, mulberry-like lesions on or adjacent to the optic nerve head; or flat, disk-like lesions in the periphery of the retina Pulmo-nary lymphangioleiomyomatosis occurs overall in 2.3% of individuals with TSC, particularly in women between the ages of 20 and 40 years.182 Affected individuals experience shortness of breath, hemop-tysis, or pneumothorax and show diffuse interstitial infiltrates with cystic changes by CT examination About 85% of patients with TSC have osseous manifestations with the bones, particularly those of the hands and feet, demonstrating cysts and periosteal thickenings At least three dental pits (seen as punctate, round or oval, 1- to 2-mm randomly arranged enamel defects), particularly in the permanent teeth, are another marker of TSC and may be visualized better with use of dental disclosing solution

The diagnosis of TSC may be difficult, because many affected viduals have subtle manifestations However, the appearance of char-acteristic skin lesions in children with seizures, retardation, or both should establish a diagnosis of TSC (see Box 11-1).163,183 Diagnosis depends on the cutaneous manifestations, family history (with careful clinical and sometimes imaging examination of family members), MRI

indi-of the brain, renal ultrasound, cardiac echocardiography in infants and young children, and in some cases ophthalmologic examination and chest radiography for honeycombing of the lungs

The prognosis of TSC depends on the severity of the disorder and the presence of neurologic involvement.184 The leading causes of pre-mature death, status epilepticus and bronchopneumonia, are related

to the associated neurologic issues Seizures can be controlled by

Patients with MEN1 are at high risk for the development of

parathy-roid, pituitary, pancreatic, and duodenal tumors.174 Multiple facial

angiofibromas with onset during adulthood have also been noted in

patients with Birt–Hogg–Dube syndrome,175 but facial

fibrofolliculo-mas or trichodiscofibrofolliculo-mas are more typical Multiple biopsy-proven

angiofibromas without other signs and with negative molecular

testing have been described.176 Having one to a few facial fibrous

11  •  Disorders of Pigmentation

258

of postinflammatory leukoderma Postinflammatory tion is generally self-limiting, clearing after months to years It often becomes cosmetically obvious in individuals with darker skin, particularly during summer months, because the preferential darken-ing with UV light exposure of surrounding skin accentuates the hypopigmentation

Although the pathophysiology of postinflammatory tion is unclear, it is postulated that the hypopigmentation is caused when keratinocytes injured by the inflammatory process are tempo-rarily unable to accept melanosomes from the melanocyte dendrites

hypopigmenta-No therapy is effective, but the condition tends to improve with time.Pityriasis alba (see Chapter 3) is a common cutaneous disorder characterized by asymptomatic, sometimes scaly hypopigmented patches on the face, neck, upper trunk, arms, shoulders, and at times the lower aspect of the trunk and extremities of children and young adults (see Fig 3-33) Seen predominantly in children 3 to 16 years

of age, individual lesions vary from 1 to several centimeters in eter and have sharply delineated margins and a fine, branny scale Although the cause is unknown, this disorder appears to represent

diam-a nonspecific dermdiam-atitis Postinfldiam-ammdiam-atory hypopigmentdiam-ation is commonly seen in children with atopic dermatitis, psoriasis (see

Fig 4-15, A), pityriasis lichenoides, and contact dermatitis; in the

latter the pattern of the hypopigmentation may provide the clue to the contactant.200

Tinea versicolor (pityriasis versicolor; see Chapter 17) is a common condition often found on the upper part of the trunk and neck of young adults Caused by overgrowth of a yeast that normally inhabits

skin, Pityrosporum orbiculare (Malassezia furfur), the condition is

char-acterized by small, either hypopigmented or occasionally mented macules, particularly on the trunk and upper arms The round, individual lesions often coalesce Facial involvement is more common in affected children than in older individuals The hypopig-mentation results from the production of azelaic acid, which inhibits tyrosinase; the hyperpigmentation is postinflammatory (see Figs 17-33 through 17-34)

hyperpig-Sarcoidosis (see Chapter 25) is a granulomatous disorder of unknown origin with widespread manifestations involving the skin and many of the internal organs In addition to the characteristic yellowish brown, flesh-colored, pink, red, and reddish brown to black

or blue lesions, subcutaneous nodules, and infiltrated plaques, the spectrum of sarcoidal skin lesions includes hypomelanotic macules and papules Measuring up to 1.5 cm in diameter, these hypopig-mented lesions reveal sarcoid-type granulomas on cutaneous biopsy.Leprosy (Hansen disease; see Chapter 14), a chronic infection in

which the acid-fast bacillus Mycobacterium leprae has a special

predi-lection for the skin and nervous system, can be divided into several

types depending on the patient’s cellular immune response to M leprae Tuberculoid leprosy shows characteristic well-defined anes-

thetic hypopigmented lesions and thickened and palpable peripheral nerves Lepromatous leprosy, in contrast, more commonly shows nodules or diffuse infiltrates, especially on the eyebrows and ears, resulting in a leonine facies A granulomatous infiltrate on micro-scopic examination of cutaneous lesions and particularly in the lep-

romatous lesions, demonstration of M leprae on cutaneous smear or

biopsy specimen generally confirm the diagnosis

Pinta (see Chapter 14) is a treponemal infection caused by nema carateum Seen almost exclusively among the dark-skinned popu-

Trepo-lation of Cuba and Central and South America, the disorder is commonly found in children of parents afflicted with this disorder The cutaneous manifestations may be divided into primary, secondary, and tertiary stages The late dyschromic stage takes several more years to develop These lesions have an insidious onset and usually appear during adolescence or young adulthood They consist of slate-blue hyperpigmented lesions that after a period of years become wide-spread and are replaced by depigmented macules resembling those seen in patients with vitiligo Located chiefly on the face, waist, and areas close to bony prominences (elbows, knees, ankles, wrists, and the dorsal aspect of the hands), these depigmented lesions of pinta can

be differentiated from those of other depigmented disorders by the presence of pigmented lesions, histologic examination of lesional

specimens, identification of antibodies directed against T carateum by

serologic testing, and darkfield examination

anticonvulsant therapy in many patients, and prevention of seizures

early in life has been shown to lower the risk of developmental delay

and retardation With routine MRI evaluations and the availability of

microscopic surgery for neoplastic brain lesions, patients are

surviv-ing longer and have a better quality of life Neurosurgical intervention

may be required in patients with signs of increased intracranial

pres-sure such as visual disturbances, papilledema, vomiting, or

head-aches Sun protection is important for patients, not just at the sites of

the hypopigmented macules, but also to prevent facial angiofibromas,

which show second-hit mutations in TSC genes with a UV-signature

mutation that is not seen in TSC germline mutations, in 50% of

patients.185

The facial angiofibromas may be a cosmetic problem that responds

to cryosurgical, surgical, or laser therapy.186 However, a meta-analysis

of 16 reports noted improvement in 94% of 84 patients with use of a

variety of formulations of compounded topical rapamycin (ointment,

gel, solution, cream; there is no commercially available formulation)

with concentrations from 0.003% to 1%).187–190 Recent-onset fibrous

angiofibromas respond best, and topical rapamycin has also been used

for maintenance after laser or surgical therapy Local irritation is

unusual but has been described with the use of rapamycin solution

Topical rapamycin has also led to improvement in early ungual

fibro-mas.191 Mammalian TOR inhibitors such as rapamycin and

everoli-mus cause regression of astrocytomas, renal angiomyolipomas, and

pulmonary lymphangioleiomyomas, as well as facial

angiofibro-mas.192,193 The Tuberous Sclerosis Alliance (at www.tsalliance.org)

and the Tuberous Sclerosis Association (of the United Kingdom, at

www.tuberous-sclerosis.org) are among the groups that offer support

for patients with TSC

CHEMICALLY INDUCED DEPIGMENTATION

A number of chemical agents are known to cause depigmentation

after topical exposure Among these compounds are the rubber

antioxidant monobenzyl ether of hydroquinone, hydroquinone

pho-tographic developer, sulfhydryl compounds, azo dyes,

diphenylcyclo-propenone, phenolic germicidal agents (paratertiary butylphenol and

amylphenol), hydroxyanisole, and 4-tertiary butyl catechol (an

addi-tive to polyethylene film) The biochemical mechanism by which

phe-nolic chemicals induce such hypopigmentation appears to be the

competitive inhibition of tyrosinase or the release of toxic metabolites

that produce injury to the melanocytes Depigmentation has also

occurred after topical exposure to paraphenylenediamine,194

injec-tions of triamcinolone, and in the periorbital area after injection

of botulinum A toxin.195 Oral ingestion of chloroquine,196 arsenic,

STI571 (imatinib),197 and dasatinib198 have also led to

depigmenta-tion A progressive generalized decrease in pigmentation has been

reported after drug reaction to sulfonamide.199

IDIOPATHIC GUTTATE HYPOMELANOSIS

Idiopathic guttate hypomelanosis is a common disorder of adults, and

its incidence increases with increasing age It occasionally occurs in

children and is more common in female individuals, although the

latter may represent reporting bias More striking in individuals with

darker pigmentation, the lesions of idiopathic guttate hypomelanosis

are characteristically 0.5- to 6-mm sharply defined, porcelain white

macules They are asymptomatic and once present do not tend to

change The macules most commonly occur on the extensor forearms

and on the shins The diagnosis is usually made clinically, and no

treatment is effective The underlying cause is unknown, although

sun exposure is thought to be a trigger

POSTINFLAMMATORY HYPOPIGMENTATION

Postinflammatory hypopigmentation (or leukoderma) may be

associ-ated with a wide variety of inflammatory dermatoses or infections

This relative pigmentary deficiency may be noted after involution of

certain inflammatory skin disorders, particularly burns, bullous

dis-orders, infections, eczematous or psoriatic lesions, and pityriasis rosea

(see Fig 3-17) In the inflammatory dermatoses the intensity of the

inflammatory reaction may bear little relationship to the development

11  •  Disorders of Pigmentation 259

hyperpigmentation of disorders like dyskeratosis congenita (see Chapter 7), Rothmund–Thomson (see Chapter 19) and Kindler (see Chapter 13) syndromes The differential diagnosis of these dyschro-matoses includes other disorders with more of a macular pigmenta-tion (such as xeroderma pigmentosum (see Chapter 19), Kitamura reticulate acropigmentation, and dyschromic amyloidosis (Table11-5) Keratin disorders with hyperpigmentation also tend to have

a more net-like reticulated pigmentation (e.g., EB simplex with mottled pigmentation [see Chapter 13], Dowling–Degos disease, Naegeli–Franceschetti–Jadassohn syndrome and dermatopathia pigmentosa reticularis)

DSH is an autosomal dominant disorder characterized by pinpoint

to pea-sized hyperpigmented and hypopigmented macules on the dorsal aspects of the distal extremities and face.201 Lesions first appear

Disorders of Both Hypopigmentation 

and Hyperpigmentation

DYSCHROMATOSES

Two major forms of dyschromatoses have been described:

dyschro-matosis symmetrica hereditaria (DSH; reticulate acropigmentation of

Dohi) and dyschromatosis universalis hereditaria (DUH), both of

which are seen most commonly in Japanese and Chinese individuals

(in about 2 per 100,000 individuals) These disorders show only

pig-mentary manifestations and affected individuals are almost always

otherwise healthy The reticulate hyperpigmentation of these

disor-ders tends to appear more spotty than the more net-like reticulated

dyschromica

Blaschko, resembling incontinentia pigmentiX-linked reticulate 

hyperpigmentation XL XL form: failure to thrive, developmental delay, seizures, hemiplegia, colitis, 

gastroesophageal reflux, inguinal hernia, urethral stricture, dental anomalies, hypohidrosis, photophobia, corneal clouding, skeletal changes

XL form: often no amyloid in biopsies  

No acantholysisMore generalized reticulated pigmentation in  EBS with mottled 

pigmentation (KRT5 

mutations; see Ch. 13)Familial progressive 

hyperpigmentation 

and hypopigmentation

infancy; increase in number with time

Face, neck, trunk, limbs with reticulate hyperpigmentation as well as diffuse background hyperpigmentation; café-au-lait macules and freckling; sometimes larger hypopigmented macules

Called familial progressive hyperpigmentation if 

no hypopigmentation; distinguish from NF1 and Legius syndromeDyschromatosis 

symmetrica hereditaria

childhood

Hyperpigmented and hypopigmented small macules on dorsum of hands and feetDyschromatosis 

universalis hereditaria AD ABCB6 First months of life (starts on trunk) Generalized pigmented macules; may involve palms and soles, oral mucosa, and 

nails (dystrophy with pterygium)Galli–Galli disease AD Keratin 5 Early adolescence Reticulate pigmentation of flexures Moderate to severe 

suprabasal acantholysis 

in biopsies

decade Acral reticular pigmentation with subtle atrophy, palmar pits, and rete ridge breaksDyskeratosis congenita 

(see Ch. 7) Esp. XL Esp. DKC1 Late childhood Net-like pigmentation, esp. in sun-exposed areas, often poikilodermatous; associated 

with mucosal leukokeratosis, nail dystrophy, risk of bone marrow failure, mucosal squamous cell carcinomas

pigmentosa reticularis AD KRT14 Pigmentation primarily truncal distribution; nonscarring alopecia; palmoplantar 

keratoderma, absence of dermatoglyphics, onychodystrophy, hypohidrosis

Table 11-5  Disorders with Reticulate Hyperpigmentation (and Sometimes Hypopigmentation)

AD, Autosomal dominant; ADAM10, a disintegrin and metalloproteinase domain-containing protein 10; ADAR1, adenosine deaminase acting on RNA 1;

AR, autosomal recessive; DCK1, dyskerin; EBS, epidermolysis bullosa simplex; Esp., especially; KITLG, KIT ligand; KRT, keratin; NF, neurofibromatosis;

POFUT1, protein O-fucosyltransferase 1; POGLUT1, protein O-glucosyltransferase 1; XL, X-linked.

11  •  Disorders of Pigmentation

260

Figure 11-27 Dyschromatosis  universalis  hereditaria.  Reticulated 

hyperpigmented and hypopigmented macules of various shapes and 

sizes on the trunk. (Courtesy of Drs S Worobec and S Reddy.)

during infancy or early childhood, commonly spread until

adoles-cence, and persist lifelong Neurologic disease has been described in

the minority of patients.202,203 Molecular studies have uncovered

mutations in ribonucleic acid (RNA)-specific adenosine deaminase

(ADAR1, also called DSRAD).204–207 Reticulate acropigmentation of

Kitamura is another autosomal dominant disorder characterized by

reticulated or lentiginous hyperpigmentation localized primarily to

the dorsal areas of the hands and feet It is caused by mutations in

ADAM10.208 The lesions have their onset is during childhood and tend

to be more atrophic than those of DSH Pits on the palms, soles, and

dorsal surface of the fingers and toes are associated.209 DSH has

recently been treated with miniature punch grafting and excimer light

therapy.210

DUH is an autosomal dominant disorder (rarely recessive) in which

patients show hyperpigmented and hypopigmented macules of

various shapes and sizes with a mottled appearance (Fig 11-27) In

DUH skin lesions appear within the first months of life, predominantly

on the trunk, and subsequently generalize, including the palms and

soles in some cases The oral mucosa may be involved, and nails may

show dystrophy with pterygium formation The numbers of

melano-somes is normal, and the disorder presumably reflects increased

melanocyte activity DUH is caused by mutations in ABCB6.211

Dys-chromatoses resembling DUH may also be caused by heterozygous

mutations in KITLG, encoding KIT ligand (familial progressive

hyper-pigmentation and hypohyper-pigmentation)212 or SASH1 (SAM and SH3

domain-containing protein 1), a tumor suppressor gene.213,214 SASH1

mutations on both alleles lead to the reticulate hypopigmentation and

hyperpigmentation in association with alopecia, palmoplantar

kera-toderma, nail dystrophy, dental anomalies, skin ulcers, and recurrent

squamous cell carcinoma.215 The hyperpigmented lesions of DUH

have been treated with Q-switched alexandrite laser.216

Reticulated hyperpigmentation is also seen in X-linked reticulate

pigmentary disorder (also called Partington syndrome or familial

cutaneous amyloidosis).217 Affected boys show generalized reticulate

hyperpigmentation in association with xerosis, failure to thrive,

devel-opmental delay, seizures, hemiplegia, colitis, gastroesophageal reflux,

inguinal hernia, and urethral stricture Dental anomalies,

hypohidro-sis, photophobia, and corneal clouding are also seen Skeletal changes

may include delayed bone age and shortened metacarpals The

amyloid found in skin biopsies of some affected adults has not been

demonstrated in the skin of affected children Pigmentation

distrib-uted along the lines of Blaschko in female carriers resembles the

pig-mented streaks and whorls of incontinentia pigmenti Familial

dyschromic amyloidosis with only the pigmentary abnormalities may

be inherited in an autosomal dominant manner with incomplete

pen-etrance.218,219 The underlying genetic cause of these familial

cutane-ous amyloidoses is unknown

Dowling–Degos disease and its acantholytic variant Galli–Galli disease are both autosomal dominant disorders usually caused by mutations in keratin 5.220 Reticulated hyperpigmentation is localized

to the intertriginous areas, primarily the axillae and the inguinal folds Comedonal lesions and pitted acneiform facial scars are associated.221

A more generalized form of Dowling–Degos disease has also been associated with mutations that affect glycoprotein synthesis, protein O-fucosyltransferase 1 and protein O-glucosyltransferase 1.222,223Naegeli–Franceschetti–Jadassohn syndrome and dermatopathia pig-mentosa reticularis are autosomal dominant disorders with reticulate hyperpigmentation, palmoplantar keratoderma, absence of dermato-glyphics, onychodystrophy, and decreased sweating with lifelong heat intolerance Both disorders result from heterozygous nonsense or frameshift mutations in keratin 14 that increase the susceptibility of keratinocytes to apoptosis.224,225 In Naegeli–Franceschetti–Jadassohn syndrome, the reticulated hyperpigmentation is present during the first 2 years of life and primarily involves the abdomen, perioral, and periocular areas.226 The pigmentation commonly fades during adoles-cence and may disappear altogether Dental abnormalities are associ-ated The pigmentation in dermatopathia pigmentosa reticularis is primarily in a truncal distribution and is associated with nonscarring alopecia.227

The hyperpigmentation in all of these disorders is nonpalpable in contrast to the hyperpigmented papules and plaques of confluent and reticulated papillomatosis of Gougerot and Carteaud, an asymptom-atic disorder of hyperkeratotic hyperpigmented papules in a reticu-lated pattern.228 Seen primarily in adolescents and young adults, this disorder usually occurs on the upper anterior trunk, often in individuals with acanthosis nigricans (see Chapter 23, Figs 23-26 through 23-28)

POIKILODERMA

The term poikiloderma (poikiloderma atrophicans vasculare) is used to

describe a triad of telangiectasia, atrophy, and reticulated dyschromia (hyperpigmentation and hypopigmentation) The disorder may be seen in patients with poikiloderma congenitale (Rothmund–Thomson syndrome), xeroderma pigmentosum, Bloom syndrome (see Chapter 19), dyskeratosis congenita (see Chapter 7), juvenile dermatomyositis (see Chapter 22), and cutaneous T-cell lymphoma (see Chapter 10) Actinic, thermal (see Erythema Ab Igne section, Chapter 20), and radiation damage can also leave poikilodermatous changes Histo-pathologic examination of areas of poikiloderma reveals varying degrees of epidermal hyperkeratosis and atrophy, hydropic degenera-tion of the basal layer, varying numbers of pigment-laden melano-phages, and a lymphocytic band-like or perivascular infiltration in the dermis Management consists of early recognition, avoidance of sun exposure, and the use of protective clothing and topical sunscreen preparations in an attempt to arrest progression of the dermatosis

INCONTINENTIA PIGMENTI

Incontinentia pigmenti (Bloch–Sulzberger syndrome) is an X-linked disorder that predominantly affects the skin, teeth, CNS, and eyes.229–231 The disorder results from mutations in nuclear factor-kappa B (NF-κB) essential modulator (NEMO; IKBKG), a gene local-ized to the X chromosome In approximately 80% of patients, the

mutation is a rearrangement in the NEMO gene that eliminates its

activity.232,233 Less commonly, affected girls (often with milder disease)

have a missense mutation in the NEMO gene, particularly involving

exon 10; these girls are at risk of having a son with hypohidrotic

ectodermal dysplasia with immunodeficiency (see Chapter 7) De novo

mutations occur in 65% of patients.234 The mutation in NEMO

pre-vents the activation of NF-κB, which is a regulator of cell proliferation, inflammation, and TNF-α-induced apoptosis Approximately 97% of patients are female, suggesting that the disorder is lethal to affected hemizygous male individuals.235 Male patients with Klinefelter syn-drome (XXY genotype) or with incontinentia pigmenti as a mosaic condition have been described.236–240 Affected girls show functional mosaicism because of the random inactivation early in embryologic development of one of the X chromosomes (lyonization) As such, the cutaneous lesions of incontinentia pigmenti tend to follow lines of

11  •  Disorders of Pigmentation 261

dermis, and absence of hair follicles and sweat glands, allowing nosis in older individuals.246

diag-Cicatricial alopecia is seen in 38% to 66% of patients (Fig 11-32)

It occurs most often near the vertex and does not necessarily relate to the previous presence of lesions at the site Nail dystrophy is present

in 7% to 51% of affected individuals In addition, painful white verrucous or keratotic subungual tumors are seen in up to 10%, usually during the second or third decades of life247 and rarely lead

grayish-to squamous cell carcinomas.248 Lytic defects on roentgenographic examination of the distal phalanges may be seen as well

Noncutaneous manifestations occur in a high percentage of patients with incontinentia pigmenti Some 70% to 95% of patients show

Blaschko, representing the clonal outgrowth of cells that express the

affected allele The variable severity and expression of clinical

involve-ment in the eyes and brain reflect the random activation of the affected

X allele in these tissues

The disorder generally appears at birth or shortly thereafter (90%

of patients have cutaneous lesions within the first 2 weeks of life; 96%

have their onset before the age of 6 weeks) Although the cutaneous

lesions have four distinct phases, their sequence is irregular and

over-lapping of stages is common (Box 11-2)

The first phase of incontinentia pigmenti begins with inflammatory

vesicles or pustules that develop in crops over the trunk and

extremi-ties, often persisting for months These may range from largely papular

with scattered vesicles to pustules (Fig 11-28) Biopsy of a blister

during this vesicular stage reveals epidermal vesicles filled with

eosino-phils, and 74% of affected neonates show eosinophilia (from 18% to

89%) The vesicles clear spontaneously through cellular apoptosis and

repopulation by continuous normal keratinocytes However, the

vesic-ular phase may be reactivated focally, especially in infants after

infec-tion, immunizainfec-tion, or physical trauma; less commonly erythematous

whorls without vesiculation may occur in older individuals.241,242

In 70% of patients, the vesicular stage is followed by a verrucous

phase characterized by irregular, linearly arrayed warty papules on

one or more extremities and often on the hands and feet (Fig 11-29)

This stage resolves spontaneously, usually within a period of up

to 2 years

During or shortly after this verrucous stage, the highly

characteris-tic pigmentary phase occurs in approximately 80% of patients Lesions

typically are thin bands of slate-brown to blue-gray coloration

arranged in lines and swirls on the extremities and trunk (Fig 11-29)

These pigmentary bands may coalesce in areas and more closely

resemble Chinese writing figures than linear streaks or whorls When

more linear, they must be distinguished from X-linked macular

amy-loidosis in carrier females.243,244 Occasionally, these bands appear

pur-puric at onset (Fig 11-30), and this appearance has raised the question

of child abuse.245 These pigmentary lesions progress until the patient’s

second year of life, then stabilize and persist for years By adolescence

they gradually fade and disappear in two-thirds of affected

individu-als Biopsy sections from lesional skin show incontinence of pigment

during this phase, leading to the name incontinentia pigmenti Although

the pigmentary changes were originally considered to be a

postinflam-matory phenomenon secondary to the vesiculobullous or verrucous

stages, the pigment fails to follow the pattern, shape, or location of the

vesicular or verrucous lesions

A fourth phase is characterized by persistent atrophic streaks that

are often hypopigmented (Fig 11-31) Most commonly noted on the

arms, thighs, trunk, and particularly the calves of affected individuals,

these affected areas show diminished hair, eccrine glands, and sweat

pores These streaks are often subtle and may be accentuated by

viewing with side lighting or by Wood lamp examination Skin biopsy

shows characteristic changes with scattered apoptotic cells, thickened

Figure 11-28 Incontinentia pigmenti. (A) The lesions of incontinentia 

pigmenti tend to follow a curvilinear pattern along lines of Blaschko, lines of the embryological development of ectoderm, as a manifesta-tion of functional mosaicism (i.e., the X chromosome with the mutation 

in the NEMO gene is the activated X chromosome in the skin at these 

sites). The lesions of the vesicular phase may range from largely papular with a minor vesicular component to vesiculopustular as shown here 

and occasionally to bullous. (B) Sometimes the lesions of incontinentia 

pigmenti do not show a linear pattern. Note the residual inflammation and scaling as the vesicular lesions clear. 

11  •  Disorders of Pigmentation

262

immunodeficiency (see Chapter 7) have mutations in NEMO that

decrease its function but do not eliminate it

Up to 30% of patients with incontinentia pigmenti demonstrate involvement of the CNS, most commonly seizures.251,252 These seizures have been attributed to acute microvascular hemorrhagic infarcts,253although recurrent stroke has also been described.254 Many such neo-nates are mistakenly thought to have neonatal herpes simplex infec-tion because of the presence of vesiculopustular lesions and seizures Overall, 7.5% have severe neurologic abnormalities including con-tinuing seizures, retardation, and/or spastic abnormalities.231 Seizures during the first week of life have been associated with the worst prog-nosis for normal development Learning disabilities are common.255Ophthalmic changes are present in 37% of patients; 18% have strabismus, and an equal number demonstrate more serious eye involvement (cataracts, optic atrophy, or retinal neovascularization or detachment) Bilateral blindness has been described in 4% to 8% of individuals with incontinentia pigmenti Occasionally, cardiac anom-alies and skeletal malformations (such as microcephaly, syndactyly, supernumerary ribs, hemiatrophy, or shortening of the arms or legs) may occur

dental anomalies (delayed dentition, partial anodontia, pegged or

conical teeth)249,250 (Fig 11-33) reminiscent of those in boys with

hypohidrotic ectodermal dysplasia (see Chapter 7) Ectodysplasin

(which is usually mutated in boys with hypohidrotic ectodermal

dys-plasia), the ectodysplasin receptor, and NEMO all participate in

NF-κB signaling, providing an explanation for these shared phenotypic

features In fact, boys with a form of ectodermal dysplasia with

Figure 11-32 Incontinentia  pigmenti.  Cicatricial  alopecia  most  monly appears near the vertex and does not necessarily relate to the previous presence of lesions at the site. 

com-11  •  Disorders of Pigmentation 263

The characteristic cutaneous lesions of incontinentia pigmenti

allow early diagnosis and investigation for associated ocular and

neu-rologic abnormalities No special therapy is required for the skin

lesions of incontinentia pigmenti, because they tend to clear

sponta-neously, but regular ophthalmologic evaluations are important.256 If

retinal involvement is discovered, early intervention with laser,

cryo-therapy, or intravitreal bevacizumab should be initiated.257 If seizures

or evidence of developmental delay appear, neurologic consultation is

appropriate High-dose glucocorticoids in the neonatal period have

helped to control seizures recalcitrant to antiepileptics.258 Dental

eval-uation by 2 years of age will allow investigation of missing or

mis-shapen secondary teeth; prostheses can be made in patients with

significant dental abnormalities

Obtaining a history of cutaneous disorders during the neonatal and

infantile periods and careful physical examination of mothers who

may be carriers is important for genetic counseling A mother of an

affected individual who shows subtle manifestations is at increased

risk for having another affected daughter (50% probability in

daugh-ters) and aborting a male fetus (50% probability in sons) Affected

mothers may show subtle signs, most commonly hypopigmented,

atrophic, hairless streaks along Blaschko lines (sometimes seen best by

side lighting)259 and sometimes a patch of cicatricial alopecia,260

conical incisor, or nail dystrophy.261 Sometimes carrier mothers show

no signs, despite a history of a previous blistering disorder in the

neonatal period Prenatal diagnosis is possible, and preimplantation

genetic diagnosis has been performed.262 Treatment with topical

cor-ticosteroids263 or tacrolimus264 may halt the progression of the

vesicu-lar phase, although lesions ultimately clear spontaneously The retinal

neovascularization may regress with laser photocoagulation,265 and

preliminary studies of vascular endothelial growth factor (VEGF)

inhibitors appear promising.266 The Incontinentia Pigmenti

Inter-national Foundation provides education and support (http://www

.ipif.org/)

PIGMENTARY MOSAICISM

The term pigmentary mosaicism is preferred for this heterogeneous

group of disorders that includes hypomelanosis of Ito (incontinentia

pigmenti achromians), linear and whorled nevoid hypermelanosis,267

and the segmental form of nevus depigmentosus,268 which is

charac-terized by patterned streaks of hypopigmentation and/or

hyperpig-mentation (Figs 11-34 and 11-35) The linear streaks and whorls

tend to follow lines of mosaicism,269 particularly the lines of Blaschko

(lines of ectodermal embryologic development), or a phylloid pattern

of mosaic distribution.270,271 Both hypopigmented and

hyperpig-mented streaks may be seen in the same individual

11  •  Disorders of Pigmentation

264

in males than females, and affected individuals tend to be otherwise healthy The first change generally appears as a brown pigmentation, most commonly on the chest, back, or upper arm, that expands to 10

to 15 cm in diameter (about the size of a hand or larger) (Fig 11-36) The outline is irregular and sometimes surrounded by islands of blotchy pigmentation Although characteristically seen unilaterally

on the upper half of the trunk, especially around the shoulder, it has also been reported in other areas on the trunk, forehead, cheeks, supraclavicular region, abdomen, forearm, wrist, buttocks, and shins and may be bilateral.280,281 After a period of time (often 1 or 2 years), coarse terminal hairs appear in the region of, but not necessarily coin-ciding with, the pigmented area (Fig 11-37) The intensity of pigmen-tation may fade somewhat as the patient becomes older, but the hyperpigmentation and hypertrichosis tend to persist for life.The etiology of Becker nevus is unknown, but a localized increase

in androgen receptor sensitivity may explain the time of onset and clinical features seen in most individuals with this disorder.282 Reports

of familial cases283 raise the question of a genetic influence in some patients, and the occasional association of significantly increased smooth muscle suggests that Becker nevus and smooth muscle hamartoma may perhaps represent two poles of the same hamarto-matous change Although most Becker nevi occur without other pathologic findings, association with a variety of other abnormalities (such as unilateral breast and areolar hypoplasia, focal acne, pectus

The pigmentary mosaicism reflects gene mosaicism of affected

areas These mosaic conditions do not tend to be hereditary, although

familial cases have rarely been reported.272 Gross chromosomal

abnor-malities have been described in 60% of affected pediatric patients with

more extensive pigmentary mosaicism and/or associated

noncutane-ous abnormalities when peripheral blood leukocytes and cultured

fibroblasts or keratinocytes are evaluated.273–275 In another study, an

unselected patient population with pigment mosaicism showed an

incidence of associated abnormalities (particularly of the bones, eyes,

and/or CNS) in 30% of patients.276 The majority of patients, however,

do not have widespread involvement with pigmentary mosaicism and

show no other problems by history and examination; these children

require no further investigation

The streaks of hypopigmentation or hyperpigmentation along

Blaschko lines of embryologic development must be distinguished

from the hypopigmented or hyperpigmented streaks of incontinentia

pigmenti The term incontinentia pigmenti achromians for the streaks of

hypopigmentation has been abandoned to avoid confusion, because

incontinentia pigmenti is unrelated The lack of preceding vesicular

or verrucous lesions of incontinentia pigmenti and the finding of

increased melanin deposition at the basal cell layer in hyperpigmented

streaks of pigment mosaicism (linear and whorled hypermelanosis)

rather than the pigment incontinence of incontinentia pigmenti help

to distinguish these disorders.277 Epidermal nevi may present as flat

brown streaks but more commonly are hyperkeratotic (see Chapter 9)

Disorders of Hyperpigmentation

Pigmented nevi are among the most common hyperpigmented lesions

and are reviewed in Chapter 9, as are streaks of pigmentation

involv-ing the nails (longitudinal melanonychia; see Chapter 7) Treatment

of hyperpigmented lesions with topical agents has generally been

unsuccessful Sun protection is a critical aspect of management in

preventing darkening Lasers have been used to treat a variety of

hyperpigmented disorders in children,278 in particular CAL macules,

nevus of Ota, and other forms of dermal melanocytosis, Becker nevi,

and tattoos Several therapeutic sessions are required, and results are

rarely permanent

EPIDERMAL MELANOCYTE LESIONS

Freckles

Freckles (ephelides) are light brown, well-circumscribed macules,

usually smaller than 3 mm in diameter, that appear in childhood,

especially between 2 and 4 years of age and tend to fade during the

winter and adult life Their presence correlates with fair skin, red hair,

and an increased risk of developing melanoma.279 Freckles are most

common on the sun-exposed areas of the face (especially the nose and

cheeks), shoulders, and upper back

Freckles become darker and more confluent after UV light exposure

in the sunburn spectrum (290 to 320 nm) as well as in the long-

wave UV (UVA) range (320 to 400 nm) UVA light is not blocked

by window glass and sunscreen agents that filter out only the sunburn

spectrum They often become smaller, lighter, and fewer during

the winter months Histopathologic features of ephelides include

increased melanin pigmentation of the basal layer without an increase

in the number of melanocytes or elongation of the epidermal rete

ridges

Freckles bear cosmetic but no systemic significance Treatment

includes avoidance of sun exposure and appropriate covering makeup

Use of “full-spectrum” sunscreens that provide protection against

both UVA and UVB light (e.g., with avobenzone or titanium dioxide)

are more protective than sunscreens that only provide UVB protection

When desired, although seldom necessary, gentle chemical peels or

laser may remove the superficial pigmentation and make many of the

freckles less conspicuous

Becker Nevus

Becker nevus (Becker melanosis), an irregular macular

hyperpigmen-tation with hypertrichosis, is sometimes congenital, but more

com-monly starts during early adolescence It occurs much more comcom-monly

Figure 11-36 Becker  nevus.  This  light  brown,  irregularly  bordered patch without hypertrichosis was recently noticed on the axillary area and shoulder of this 12-year-old boy. 

Figure 11-37 tion on the back with associated coarse terminal hairs. These lesions usually appear during late childhood or early adolescence on the upper trunk. 

Becker nevus. Large patch of grayish-brown pigmenta-11  •  Disorders of Pigmentation 265

childhood Lentigines occur on the centrofacial area, lips, oral mucosae, buttocks, elbows, palms, and soles, and affected individuals are otherwise healthy

Localized or extensive lentiginosis may also be a component of a multisystem disorder Although they may occur in children without medical problems, lentigines of the penis are characteristic of Bannayan–Zonana (Bannayan–Zonana–Ruvalcaba) syndrome, an

autosomal dominant disorder that results from mutations in the PTEN

gene and is allelic with Cowden syndrome (Fig 11-40) (see Chapter 9) Other major features are macrocephaly and lipomas Lentigines of the hands, feet, and buccal mucosa may also be a feature of Cronkhite–Canada syndrome, in which nail dystrophy, hair loss, and intestinal polyposis are other characteristics Centrofacial lentiginosis (also

called centrofacial neurodysraphic lentiginosis or Touraine syndrome) is an

autosomal dominant process in which lentigines are first noted in the

carinatum, limb asymmetry, and spina bifida)284,285 has been called

Becker nevus syndrome.283,286

Histopathologic features reveal epidermal thickening, elongation of

the rete ridges, and hyperpigmentation of the basal layer with

increased melanocytes.282 Malignant transformation does not occur

Treatment of this disorder is purely cosmetic and is generally

discour-aged Laser therapy or excision usually does not improve the

appear-ance The hypertrichosis may be treated with laser depilation287 (see

Chapter 7)

Lentigines

Lentigines are small, tan, dark brown, or black flat, oval, or circular,

sharply circumscribed lesions that usually appear in childhood and

may increase in number until adult life These may occur on

sun-exposed areas (especially the face and dorsal aspect of the hands) as

“lentigo simplex.” Lentigines usually measure 3 to 15 mm in diameter

and may occur on any mucocutaneous surface (Fig 11-38) including

the lips or conjunctivae The pigmentation is uniform and darker than

that seen in ephelides (freckles) and CAL macules, and the color is

unaffected by exposure to sunlight Lentigines are typically larger

than freckles and smaller than a typical CAL macule and can be

dis-tinguished from freckles and CAL macules histologically.288 Multiple

facial lentigines can be an early sign of xeroderma pigmentosum,

especially in association with a history of sun burning after limited

sun exposure Lentigines have rarely been described after use of topical

tacrolimus.289,290

Lentigines that appear early in life may fade or disappear; those

appearing later in life tend to be permanent Treatment other than for

cosmetic purposes is ordinarily not indicated When desired, however,

excision by a small punch biopsy, cryosurgery, or laser may be

benefi-cial Interestingly, a patient with multiple lentigines shows marked

lightening when treated with STI571 (imatinib) for familial

gastroin-testinal stromal tumor syndrome.291

Patients with speckled lentiginous nevus or segmental lentiginosis

show patches of lentigines, usually overlying a slight increase in

cuta-neous pigmentation (Fig 11-39) Eruptive, agminated Spitz nevi may

be seen within a segmental lentiginosis.292 Eruptive lentiginosis is a

disorder characterized by a widespread eruption of several hundred

lentigines that may develop over a few months or years, usually in

adolescents or young adults, without systemic manifestations

Inher-ited patterned lentiginosis is an autosomal dominant disorder of

dark-skinned individuals with the onset of lentiginosis during early

Figure 11-38 

Lentigines. This girl showed hundreds of lentigines, par-ticularly  on  the  face  and  extensor  surfaces  of  the  extremities.  These 

sharply  demarcated  macules  tend  to  be  larger  than  a  freckle  but 

Speckled lentiginous nevus. This large patch of lentigi-Figure 11-40 Bannayan–Zonana–Ruvalcaba  syndrome.  Lentigines  of the  penis  are  characteristic  of  Bannayan–Zonana–Ruvalcaba  syn-drome, an autosomal dominant disorder that also commonly features macrocephaly and lipomas. 

11  •  Disorders of Pigmentation

266

described.294,299 Sertoli cell tumors can occur prepubertally and may present with gynecomastia.300 However, most cancers occur during adulthood301 with an 81% to 94% lifetime cumulative risk for all cancers (18-fold that of the general population) and an almost 70% risk for gastrointestinal cancer

In the past, therapeutic management focused on relief of symptoms and recurrent resections with the risk of malabsorption The recom-mendation now is to remove polyps if technically feasible (especially

if larger than 5 mm).302,303 Guidelines for initiating screening for polyps vary Some suggest initially screening at 8 to 10 years with esophagogastroduodenoscopy (EGD) or capsule endoscopy and if these are negative, colonoscopy at age 18 unless a concern arises In

a case series of 14 children, however, the median age of polyp tion was 5 years,300 leading to the suggestion that initial screening occur at 4 to 5 years of age Sertoli cell tumors should be sought prepubertally, but yearly evaluation of other organs at risk of malig-nancy (breast, thyroid gland, pancreas, uterus, and ovaries) should begin by the end of adolescence The lentigines of Peutz–Jeghers syn-drome have responded to laser304 and intense pulsed light305 therapies, although the lentigines not uncommonly recur.306

detec-Laugier–Hunziker syndrome is a benign pigmentary disorder that manifests as macular hyperpigmentation of the lips and buccal mucosa Many patients also show long pigmented bands of the nails (melanonychia striata), but the visceral manifestations of Peutz–Jeghers syndrome are absent.306,307

Carney Complex

Carney complex comprises an autosomal dominant disorder that tures the pigmentary abnormalities of lentigines, epithelioid blue nevi, and pigmented schwannomas.308 Nevi, atrial myxoma, and neurofi-broma ephelides (NAME)309 and lentigines, atrial myxoma, and blue nevi (LAMB)310 syndromes are included in Carney complex.311–314Most cases are sporadic The group of disorders is considered a form

fea-of MEN, in that endocrine abnormalities and tumors are common features, especially pituitary adenomas, ovarian tumors,315 testicular (Sertoli cell) tumors, and pigmented nodular adrenocortical disease.316Skin manifestations are seen in 80% of patients, most commonly lentigines that typically fade during adulthood in 70% to 75% of patients The lentigines tend to appear peripubertally and most com-monly involve the center of the face, especially the vermilion border

of the lips, (leading to the misdiagnosis of Peutz–Jeghers syndrome,317

as well as the conjunctivae and occasionally the intraoral area Peutz–Jeghers and Carney syndromes share several other features including the occurrence of gynecomastia and growth acceleration, as well as Sertoli cell tumors and tumors of the breast and thyroid The blue nevi, including epithelioid blue nevi, occur in 40% of Carney complex patients They tend to be multiple, most commonly on the face, trunk and extremities, and characteristically are dome-shaped dark blue papules The majority of epithelioid blue nevi in children are associ-ated with Carney complex, but this form of blue nevus has also been described in children without other features of the syndrome.318 The lentigines and blue nevi are often accompanied by CAL spots Multiple cutaneous myxomas occur in 30% to 55% of studied patients and are most commonly seen on the eyelids, ears, nipples, and external geni-talia They are usually diagnosed during the late teen years but can occur as early as infancy.319,320 Patients often show myxomas of the oropharynx, heart, and breast and may develop other neoplasia of mesenchymal and neural-crest origin The typical psammomatous melanotic schwannomas occur in 10% of affected individuals and may involve the skin, posterior spinal nerve roots, gastrointestinal tract, and bone Biopsies of the blue nevi and schwannomas show characteristic histologic features.321 Patients have been described both with predominantly cutaneous features322 and without cutaneous lentigines The most common endocrine tumors or overactivity include primary pigmented nodular adrenocortical disease (25% of patients), growth hormone-producing pituitary adenoma (10% of patients), large cell calcifying Sertoli cell tumor, and thyroid adenoma (up to 75% of patients) Development of carcinoma is rare

Mutations in the protein kinase A type I-α regulatory subunit

(PRKAR1A)323 occur in approximately 57% of patients An additional 20% of families with Carney complex show linkage to 2p16 (gene not yet identified) and have a milder phenotype with later onset

first year of life, particularly on the nose and cheeks Patients with

centrofacial lentiginosis may have associated mental retardation,

con-genital mitral valve stenosis, seizures, sacral hypertrichosis,

coales-cence of the eyebrows, high-arched palate, absent upper middle

incisors, bony abnormalities, defective fusion of the neural tube

(dys-raphia), psychiatric disorders, dwarfism, and endocrine dysfunction

The major lentiginous syndromes are Peutz–Jeghers syndrome,

multiple lentiginosis/lentigines, electrocardiographic abnormalities,

ocular hypertelorism, pulmonic stenosis, abnormal genitalia,

retarda-tion of growth, and sensorineural deafness (LEOPARD) syndrome, and

Carney complex

Peutz–Jeghers Syndrome

The prevalence of this autosomal dominant disorder of

mucocutane-ous lentiginmucocutane-ous macules and multiple hamartomatmucocutane-ous intestinal

polyps is approximately 1 in 100,000 individuals.293 Mutations in the

serine-threonine kinase STK11/LKB1 gene have been found in 70%

of familial cases and up to 67% of sporadic cases.293,294

Characteristic bluish-brown to black spots, often apparent at birth

or in early infancy, represent the cutaneous marker of this syndrome

These discrete, flat pigmented lesions are irregularly oval and usually

measure less than 5 mm in diameter They are most commonly seen

on the lips (Fig 11-41), buccal mucosa, nasal and periorbital regions,

elbows, dorsal aspects of the fingers and toes, palms, soles, and

peri-umbilical, perianal, and labial regions; occasionally the gums and

hard palate and on rare occasions, even the tongue may be involved

An umbilical lentigo has recently been described at birth in an affected

neonate.295 The pigmented lesions on the skin and lips often fade after

puberty; those on the buccal mucosa, palate, and tongue, however,

persist

The hamartomatous gastrointestinal polyps seen in this disorder

may be found from the stomach to the anal canal, although the small

bowel represents the most commonly involved portion of the intestinal

tract Polyps vary from minute pinhead lesions to those measuring

several centimeters in diameter They may occur in early childhood,

with one study showing a median age of presentation of 5 years; 50%

of patients have symptoms in the first 2 decades of life, including

abdominal pain, melena, or intussusception.296 The most common

symptom, recurrent attacks of colicky abdominal pain, is thought

to result from recurring transient episodes of incomplete

intussus-ception A recent prospective multicenter study found a 15% risk of

cumulative intussusception by age 10 years and 50% by age 20.297

Hematemesis, although less common, may occur owing to

involve-ment of the stomach, duodenum, or upper jejunum Polyps of the

nasal mucosae and gallbladder have occasionally been described, and

rarely polyps involve the respiratory and urogenital tracts.298

Although the polyps of Peutz–Jeghers syndrome are generally

benign, adenocarcinomas of the gastrointestinal tract (stomach,

small intestine, colorectum, pancreas, and biliary tract), breast and

uterine cervical carcinomas, and gonadal sex tumors (Sertoli cell

tumors of the testis and sex-cord tumors of the ovary) have been

Figure 11-41 Peutz–Jeghers syndrome. Characteristic bluish-brown to 

black spots were first noted in early childhood on the lips of this boy 

who later developed hamartomatous gastrointestinal polyps. 

11  •  Disorders of Pigmentation 267

plastic ovaries, and delayed puberty The hearing loss of LEOPARD syndrome is congenital and neurosensory and can be detected by early auditory evoked potentials

on the body A recent study suggested that neonatal blue-light therapy increases CAL spots in preschool children.337

photo-The CAL spots of McCune–Albright syndrome are seen in mately 50% of patients They tend to be present during infancy or early childhood, with a predilection for areas with particularly bony prominences (the forehead, nuchal area, thorax, sacral areas, and buttocks) However, CAL spots may be seen elsewhere, including on the oral mucosae.338 They are commonly unilateral, stopping abruptly

approxi-at the midline and following a dermapproxi-atomal distribution They tend to have irregularly jagged or serrated borders (described as resembling the coast of Maine, in contrast to the smooth-bordered CAL spots of

NF, which have been compared to the coast of California) The McCune–Albright syndrome in its complete form is a triad character-ized by CAL spots, polyostotic fibrous dysplasia, and endocrine dys-function, often manifesting as precocious puberty (see Chapter 23, Fig 23-23) McCune–Albright syndrome is a mosaic disorder result-

ing from activating mutations in GNAS, but next-generation

sequenc-ing techniques enable detection of the low-abundance mutations in blood samples.339

CAL spots are increased in number in Russell–Silver syndrome,340 a disorder that also features short stature, musculoskeletal abnormali-ties, craniofacial dysmorphism, and genitourinary malformations, as well as in multiple lentigines/LEOPARD syndrome (see Multiple Lentigines/LEOPARD Syndrome section and Fig 11-42) Johnson–McMillin syndrome is an autosomal dominant disorder in which fami-lies show truncal CAL spots in association with facial nerve palsy and mild developmental delay.341 Other disorders with increased numbers

of CAL spots are ring chromosomes (chromosomes 7, 11, 12, 15, 17, 22), Cowden and Fanconi syndromes, TSC, and piebaldism

Multiple Lentigines/LEOPARD Syndrome

Multiple lentiginoses/LEOPARD syndrome (also called Noonan

syn-drome with multiple lentigines [NSML]) comprises a spectrum of patients

who show manifestations ranging from generalized lentigines alone

to the complete syndrome that characteristically shows lentigines,

electrocardiographic abnormalities, ocular hypertelorism, pulmonic

stenosis, abnormal genitalia, retardation of growth, and

sensorineu-ral deafness.324–327

Affected individuals typically are thin; show an elongated,

mar-fanoid facies; and have CAL macules admixed within the myriad of

lentigines (Fig 11-42) The disorder is within the spectrum of

“RASopathies,” and mutations in PTPN11 have been found in 90%

patients; genotyping may be required to confirm the diagnosis Rarely,

affected individuals have mutations in RAF1 (3%), BRAF, or

MAP2K1.328–331 Variable expressivity is seen within families, so that

some affected individuals show only the multiple lentigines, whereas

others show a variety of the visceral manifestations Nevertheless, the

underlying mutation of a family with multiple lentigines without

other features maps to chromosome 6q, a site that is distinct from

PTPN11 and RAF1.332

The dark, 1- to 5-mm lentigines that define the syndrome often first

appear at 4 to 5 years of age but then increase dramatically (to

thou-sands of lentigines) by puberty The cutaneous lesions tend to be

con-centrated on the neck and upper trunk, but they may also appear on

the skin of the face and scalp, arms, palms, soles, and genitalia The

lentigines characteristically spare the mucosa Occasionally formes

frustes of this disorder occur, in which the characteristic lentigines are

absent In most patients, the CAL macules are present before the onset

of the lentigines, leading to consideration of the alternative diagnosis

of NF type 1 or its allelic variant with CAL spots and pulmonary valve

stenosis, Watson syndrome

Cardiac abnormalities occur in about 85% of affected individuals—

mostly hypertrophic cardiomyopathy (up to 75%), which usually

appears during infancy and subsequently progresses Pulmonary

valve stenosis and conduction defects have been described in 10% and

7% of patients, respectively.330 Skeletal aberrations may include

retar-dation of growth (below the 25th percentile), hypertelorism, an

elon-gated facies, pectus deformities (carinatum or excavatum), dorsal

kyphosis, winged scapulae, and prognathism Endocrine disorders

include gonadal hypoplasia, hypospadias, undescended testes,

hypo-Figure 11-42 Multiple  lentiginosis/LEOPARD  syndrome.  Myriad  of 

lentigines  with  scattered  café-au-lait  macules  overlying  generalized 

hyperpigmentation  in  this  adolescent  with  only  cutaneous  changes.   

In  some  individuals,  the  pigmentary  changes  are  associated  with  a 

11  •  Disorders of Pigmentation

268

extensive in pediatric patients (especially vestibular and cranial schwannomas, cranial meningiomas, and spinal cord tumors) Overall, 75% of affected children develop hearing loss Removal of vestibular schwannomas does not preserve hearing, although early detection and smaller tumors are associated with a better prognosis Visual impairment owing to cataracts and amblyopia occurs in 83%

of affected children Treatment is primarily surgical Auditory stem implants may partially restore hearing.356

brain-Although NF1 is best known because of Joseph Merrick, the famed

“Elephant Man” of the 1800s, he is now thought to have had Proteus syndrome, a disorder characterized by segmental overgrowth with asymmetry, macrocephaly, lipomas, linear verrucous epidermal nevi, and vascular malformations (see Chapter 12) The diagnostic criteria for NF1 (Box 11-4) have not been modified since 1988 and thus do not yet include having a pathogenic mutation in neurofibromin These criteria are of limited value for young children who typically show only multiple CAL spots and in 50% of cases have no affected first-degree family member As such, the diagnostic criterion of six or more CAL spots of greater than 5 mm in diameter prepubertally and more than 15 mm postpubertally probably indicates the presence of NF1 (Fig 11-44)357 but is not definitively diagnostic About 95% of patients with NF1 meet these criteria by 8 years of age, and all meet it by age

20 years There is marked variability in the overall severity and gression of NF It can cause serious problems and even death in the newborn, or it may produce only mild or insignificant problems during the lifetime of the affected individual

pro-Cutaneous Manifestations of Neurofibromatosis Type 1 CAL spots

and dermal and plexiform neurofibromas are the characteristic neous findings of pediatric NF1 The severity of cutaneous involve-ment is not indicative of the extent of disease in other organs In fact,

cuta-Not uncommonly, infants may show what appears to be a CAL, but

sometimes years later the CAL develops tiny more darkly

hyperpig-mented macules or papules This lesion is called nevus spilus (see

Chapter 9), and biopsy of the more darkly pigmented lesions will show

typical features of pigmented nevi (see Fig 9-28) Individuals with red

hair or with parents of markedly different skin pigmentation may

show hyperpigmented macules that resemble CAL spots They can be

differentiated by their often irregular shape, tendency to be less well

defined than the CAL spots of NF, and the paler coloration of the

hyperpigmentation Observation of these CAL-like macules during the

first 5 to 6 years of life should be performed, and annual

ophthalmo-logic evaluations should be considered to be convinced that the

macules merely represent a pigment variation Lichen aureus, a form

of pigmented purpuric eruption, can also be confused with a CAL but

tends to show pinpoint petechiae and purpura on a hyperpigmented

base342 (see Chapter 12)

Neurofibromatosis

Neurofibromatosis (NF) is an autosomal dominant disorder

character-ized by an increased propensity toward the development of tumors,

particularly of the nerve sheath.343–345 NF encompasses three distinct

disorders: NF type 1 (NF1; von Recklinghausen disease), NF type 2

(NF2; bilateral acoustic or central NF),346 and schwannomatosis

The latter is characterized by painful peripheral (nonvestibular,

non-dermal) schwannomas and is largely diagnosed in adults.347 More

than 90% of cases of NF are NF1, which occurs in approximately 1

in 3000 births.348–351 NF2 occurs in 1 in 25,000 to 40,000

individu-als, and its diagnosis during childhood is unusual Both disorders

show variable expressivity; NF1 shows an approximately 50% rate of

new mutations, whereas two-thirds of children with NF2 have an

affected parent Patients with NF1 have mutations in neurofibromin,

a large gene that encodes a large GTPase-activating cytoplasmic

protein that negatively regulates Ras activation.345 The gene mutated

in NF2, merlin or schwannomin, encodes a cytoskeletal protein that

inhibits a serine/threonine kinase PAK1, which is essential for Ras

transformation.352

The cutaneous manifestations of NF1 are of major importance, and

thus most discussion of NF in this chapter will focus on NF1 However,

skin tumors are an important diagnostic clue for patients with NF2

and are often present months to years before other features These

tumors, predominantly schwannomas or neurofibromas, are the

pre-senting sign in 27% of individuals with NF2 and eventually occur in

59% of patients.353,354 A higher number of skin tumors has been

cor-related with a worse prognosis CAL spots are found in 33% of

indi-viduals with NF2, but only 2% have six or more CAL spots Although

NF2 is commonly considered a disorder of adults, approximately 15%

of patients with NF2 are diagnosed before 18 years of age,355 and

onset during childhood predicts a worse prognosis The major criteria

for NF2 are shown in Box 11-3 NF2 in children most commonly

presents with hearing impairment (one-third of children) or

cranial-nerve dysfunction (one-third of children) Tumor load is often

Modified from Mulvihill JJ, Parry DM, Sherman JL, et al NIH conference

Neurofibromatosis 1 (Recklinghausen disease) and neurofibromatosis 2 (bilateral

acoustic neurofibromatosis): an update Ann Intern Med 1990;113(1):39–52; and

Nunes F, MacCollin M Neurofibromatosis 2 in the pediatric population J Child

MRI, Magnetic resonance imaging; NF, neurofibromatosis

Box 11-4 Diagnostic Criteria for Neurofibromatosis

An affected first-degree relative

*Given the recognition that Legius syndrome is distinct from neurofibromatosis type 1 (NF1) clinically and genetically but shares two of the major features, experts on NF1 have recently suggested that having the cutaneous pigmentary lesions alone (café-au-lait spots and freckling) is insufficient for a definitive diagnosis of NF1.

Figure 11-44 Neurofibromatosis type 1 (NF1). The presence of six or more café-au-lait (CAL) spots larger than 0.5 cm in diameter in children and  1.5 cm  in  adolescents  suggests  the  possibility  of  NF1,  although having CAL spots alone does not allow for definitive diagnosis. 

11  •  Disorders of Pigmentation 269

adults.365 They are soft in consistency, may range in size from a limeter to several centimeters in diameter, and often have an overlying violaceous, pink, or blue hue (Fig 11-46) They may be sessile or pedunculated With pressure from a finger, dermal neurofibromas

mil-may be invaginated, a sign called buttonholing “Pseudoatrophic

macules” and “red-blue macules” are unusual variants of dermal rofibromas that show replacement of dermal collagen with neural tissue and thick-walled blood vessels in the superficial dermis overly-ing the neurofibroma, respectively By adulthood, dermal neurofibro-mas may number from a few to hundreds, with a progressive increase

neu-in size and number as the patient becomes older Neurofibromas may occur anywhere on the body with no specific site of predilection Not uncommonly, patients complain of itchiness at the site of a dermal neurofibroma, perhaps related to the presence of mast cells

Plexiform neurofibromas may be superficial or deep and occur in approximately 25% of children.366,367 They often are oriented along the length of a nerve and involve several fascicles They may be barely palpable, may be quite firm, or may become huge with a “bag of worms” consistency Plexiform neurofibromas not uncommonly are present at birth and have a predilection to involve the extremities Commonly, a large CAL spot, often with irregular borders, overlies the plexiform neurofibroma (Fig 11-47); hypertrichosis maybe associated

as well (Fig 11-48) Underlying soft-tissue and bone hypertrophy (Fig.11-49) or bone erosion may be seen Plexiform neurofibromas may at times cause pain, muscle weakness, atrophy, or slight sensory loss Given the hyperpigmentation and associated hypertrichosis, a plexi-form neurofibroma may be confused with a congenital nevus, Becker nevus, or smooth muscle hamartoma Orbital plexiform neurofibro-mas present with eyelid swelling and ptosis,368 leading to amblyopia in 62% of affected children.369 Isolated plexiform neurofibromas have been described in patients without NF1, although the possibility of mosaicism should be considered (Fig 11-50)

Although a benign course for neurofibromas is usual, malignant peripheral nerve sheath tumors (MPNSTs) occur in 8% to 13% of affected individuals, peak in their occurrence during the second and third decades of life, and are the primary cause of early mortality MPNSTs have been attributed to the occurrence of a second mutation within tumor cells, commonly a p53 mutation.370 Malignant degen-eration may be heralded by rapid enlargement, pain, change in texture, and neurologic deficit Positron emission tomography (PET)-

CT imaging of MPNSTs can distinguish benign neurofibromas from MPNSTs

Two other skin changes in NF1 are juvenile xanthogranulomas (JXGs) and nevus anemicus JXGs are discussed in Chapter 10, and these yellow dome-shaped papules (Fig 11-51) are found overall in up

to 37% of affected children with a mean age of onset of 24 months

of age.366,371,372 Most children have more than one JXG (mean ≈3), and 90% clear by a mean age of 47 months Nevus anemicus tends to be

Figure 11-45 Neurofibromatosis type 1 (NF1). Axillary freckling (Crowe 

sign) is present in 20% to 50% of individuals with NF1 and commonly 

appears between 3 and 5 years of age. Although the presence of both 

axillary  freckling  and  multiple  café-au-lait  spots  currently  allows  a 

definitive  diagnosis  of  NF1,  these  features  are  also  seen  in  Legius 

syndrome. 

Figure 11-46 Neurofibromatosis  type  1.  Dermal  and  subcutaneous neurofibromas  are  rarely  found  before  adolescence.  These  tumors, which originate from Schwann cells, increase in number progressively thereafter. 

the number of CAL spots has recently been shown to be a function of

germline sequence variants of other genes involved in pigment

biology.358

CAL spots may occur anywhere on the body They may be present

at birth but often first appear during the first few months They

con-tinue to increase in size and number during the first decade, especially

the first 2 years of life CAL spots in NF1 tend to have a greater

mela-nocyte density and increased fibroblast secretion of stem-cell factor

than CAL spots without associated NF1.359 Large CAL spots may be a

sign of an underlying plexiform neurofibroma

Another form of pigmentation, termed axillary freckling (Crowe

sign), also serves as a valuable diagnostic aid in the early recognition

of NF (Fig 11-45).360 Axillary freckling appears as multiple 1- to

4-mm CAL spots in the axillary vault These most commonly appear

between 3 and 5 years of age Lack of sun exposure in this area

pre-vents confusion with true freckles These freckles are also commonly

seen in the inguinal region and may be more generalized Overall

almost 90% of affected children have intertriginous freckling by 7

years of age

Multiple CAL spots and axillary and/or inguinal freckling are

fea-tures of Legius syndrome (sometimes called NF type 1-like syndrome),

which results from mutations in SPRED1 SPRED1 interacts directly

with Ras and is involved in its function Although the clinical features

during childhood generally do not allow Legius syndrome to be

distin-guished from NF1, distinction is important prognostically, because

Legius syndrome has been associated with macrocephaly and

learn-ing disabilities but not with the cutaneous or plexiform

neurofibro-mas, NF1 osseous lesions, or symptomatic optic-pathway gliomas.361

Almost 2% of individuals with a previous diagnosis of NF1 are now

thought to have Legius syndrome Although CAL spots and freckling

have been distinct criteria that, if both present, allow the definitive

diagnosis of NF1, the discovery that Legius syndrome presents with

these two criteria has led to the suggestion that multiple CAL spots and

freckling be combined into a single criterion for diagnosis.362

NF1 is also characterized by dermal or subcutaneous neurofibromas

that represent tumors primarily comprised of Schwann cells, mast

cells, and fibroblasts The Schwann cell has been shown to be the cell

of origin, in which loss of the normal neurofibromin allele leads to

uncontrolled growth in the setting of NF1 (loss of

heterozygos-ity).363,364 The dermal and subcutaneous neurofibromas usually occur

in late childhood or adolescence; thus they are generally not found in

affected children Their appearance is commonly associated with

puberty and pregnancy, and they have been noted in 84% of affected

11  •  Disorders of Pigmentation

270

The ocular manifestations of NF1 include plexiform neurofibromas, Lisch nodules, optic gliomas, and the recently recognized choroidal nodules Lisch nodules are asymptomatic yellowish-brown melano-cytic hamartomas on the iris that cause no problem with vision These Lisch nodules are found in more than 90% of affected adults but in only 43% of children under 12 years of age They are best detected by slit-lamp examination, although larger ones may be seen without magnification as beige spots on a dark iris or darker spots on a light iris Their presence virtually ensures the diagnosis of NF1, but their absence does not discount the diagnosis Choroidal nodules are detect-able in 71% to 79% of children with NF1 by near-infrared reflec-tance,379,380 suggesting that they may be a better criterion for diagnosis

in young children.381 Optic gliomas occur in approximately 15% of children with NF1 and are more indolent than optic gliomas in

present at birth or infancy and has been described in 9% of children

with NF373 and 35% of those under 2 years of age.372 These skin signs

may add to the suspicion of NF1 in an infant (nevus anemicus) or

young child (JXG) with only CAL spots and may become new

criteria

Systemic Manifestations of Neurofibromatosis Other than the CAL

spots, learning disability is the most common manifestation of NF1 in

children.374,375 Learning disability, which occurs in 30% to 70% of

affected children, includes nonverbal and verbal disability as well as

attention-deficit/hyperactivity disorder, which can lead to the poor

development of social skills.376 Diagnostic criteria for autism spectrum

disorders have been found in 30% of children with NF1.377 Another

common sign is the occurrence of enhanced intensity of T2 signals in

brain MRI examinations in the basal ganglia, brainstem, internal

capsule, and cerebellum (unidentified bright objects) (43% to 93%).378

11  •  Disorders of Pigmentation 271

routine baseline MRIs are not necessary, imaging should be performed

if abnormalities are found on ophthalmologic evaluation or in the face

of signs of a problematic optic glioma.384 Spontaneous regression of optic gliomas may occur.385

Brain tumors may lead to neurologic abnormalities Other than optic pathway gliomas, brainstem gliomas (pilocytic astrocytomas) are the most common intracranial neoplasms386 but usually behave less aggressively than histologically identical tumors patients who do not have NF1 Owing to the indolent nature of these tumors, conser-vative management with close follow-up monitoring is recommended

A total of 23% of meningiomas have been noted in individuals with NF1.387 More severe developmental delay occurs in only 5% of patients and has been associated with total deletion of the neurofibromin gene388; these patients also have facial dysmorphism and large numbers of neurofibromas

Skeletal manifestations are most commonly bone dysplasias, pectus deformity, and scoliosis Even without osseous abnormalities, children and adolescents with NF1 have decreased bone mineral density.389Although not among the diagnostic criteria, spinal deformities, par-ticularly scoliosis or kyphosis, may occur in at least 10% of patients, and pectus deformities occur in approximately 24% of patients.390,391The dystrophic form of scoliosis almost always develops before 10 years of age and then progresses, usually involving the lower cervical and upper thoracic spine, and is associated with dysplastic changes of the vertebral bodies Tibial dysplasia (congenital bowing), pathogno-monic for NF1, presents as anteromedial bowing of the tibia (Fig.11-53), usually during the first year of life and has been described in about 1% to 4% of affected children The cortex of the bone is thinned,

individuals without NF1 Precocious puberty has been described in up

to 40% of patients with gliomas of the posterior chiasm and

hypotha-lamic areas (Fig 11-52).382 Overall, only 33% of patients with optic

gliomas develop symptoms or signs such as decreased visual acuity or

visual-field defects, proptosis, strabismus, and/or optic-nerve pallor A

total of 35% of those with symptomatic optic gliomas eventually

require treatment, specifically for their progressive loss of vision, gross

disfigurement (e.g., from proptosis), or poor weight gain with

dience-phalic syndrome Chemotherapy with carboplatin and vincristine is

the treatment of choice Surgical resection is used for cosmetic

pallia-tion, and radiation therapy is avoided because of the risk of second

malignancy treatment.383,384 Progression in optic gliomas usually

occurs by 6 to 7 years of age, suggesting that annual eye examinations

can thereafter be spaced to every 2 years until adulthood Although

11  •  Disorders of Pigmentation

272

Individuals with mosaic forms of NF1 who also have germ-line involvement (more common with mosaic-generalized NF1) may have offspring with full NF1 with an up to 50% probability with each preg-nancy A national support group, the National Neurofibromatosis Foundation (www.nfnetwork.org and www.ctf.org), offers patient information and support

ERYTHEMA DYSCHROMICUM PERSTANS

Erythema dyschromicum perstans (ashy dermatosis) is an acquired chronic, progressive bluish to ash-gray hyperpigmentation that can affect individuals of both sexes from childhood through adulthood Although more common in darker-skinned individuals, several light-skinned affected children have been described.411,412 The cause of ery-thema dyschromicum perstans remains unknown Lesions usually begin as slate-gray macules (Fig 11-54) but occasionally show a tran-sient, slightly raised erythematous border Generally seen on the trunk and upper limbs, lesions may also occur on other areas, with the exception of the scalp, mucous membranes, palms, and soles Lesions vary from a few millimeters to many centimeters in diameter and often cover extensive areas Lesions are usually distinct but can be conflu-ent Multiple linear lesions of erythema dyschromicum perstans have been described that follow the lines of Blaschko,413 and lesions may be unilateral.414

This disorder must be differentiated from the postinflammatory hyperpigmented lesions of tinea versicolor, pityriasis rosea, and fixed-drug eruption, which usually show brown rather than grayish pig-mentation Idiopathic eruptive macular pigmentation is differentiated

by the development of brown (rather than grayish) nonconfluent macules of the trunk, neck, and proximal extremities; the absence of preceding inflammation; the lack of exposure to a medication; and basal cell hyperpigmentation without damage to the keratinocytes and without dermal mast cells in biopsy sections Histologic features

of erythema dyschromicum perstans depend on the stage of the lesion Older lesions show pigment incontinence, but early lesions may show hydropic degeneration of epidermal cells and a lichenoid infil-trate of lymphocytes

and the medulla is sclerotic.392 Fractures may occur at the site, leading

to pseudoarthrosis Sphenoid wing dysplasia occurs in 3% to 7% of

children with NF1 and may manifest as pulsating exophthalmos

Non-ossifying fibromas have also been described in association with

mul-tiple CAL spots (Jaffe–Campanacci syndrome); this group of patients

has a high risk of recurrent fractures and significant resultant

defor-mity and disability.393

Other features of NF1 that may be seen during childhood are short

stature (10%), frequent headaches (30% to 40%), macrocephaly

(24%), and rarely hypertension (1%) Short stature most often occurs

without evidence of neuroendocrine problems.394,395 The

macroceph-aly is usually not associated with hydrocephalus, although aqueductal

stenosis has rarely been reported In children, hypertension usually

relates to renal artery stenosis, a form of NF1 vasculopathy396; in

adults with hypertension and NF1, pheochromocytoma should be

suspected Stenosis or occlusion of several other arteries may occur,

leading to cerebral vascular accidents, aneurysms, and even sudden

cardiac death.397,398 Small telangiectatic vessels often form around the

stenotic area of the cerebral arteries, leading to a “puff of smoke”

(moyamoya) on cerebral angiography Watson syndrome is an allelic

variant of NF 1 with associated pulmonic stenosis, and NF1-Noonan

syndrome combines the features of Noonan syndrome (ocular

hyper-telorism, low-set ears, downslanting palpebral fissures, webbed neck,

and pulmonic stenosis) with NF1, usually with mutations in

neurofi-bromin but not PTPN11, the gene usually associated with Noonan

syndrome

NF1 is associated with a 5% lifetime risk of developing malignancy

In addition to the development of MPNSTs, nonlymphocytic

leuke-mias, rhabdomyosarcoma, and lymphoma are described with

in-creased incidence in affected children Although JXGs have been

described in association with juvenile chronic myelogenous leukemia,

few patients with NF1 and JXGs have leukemia.399

Therapy of Neurofibromatosis Type 1 The current management for

most children with NF1 is anticipatory guidance, genetic counseling,

and surveillance for potential complications If available, referral to a

multidisciplinary clinic that specializes in seeing individuals with NF1

is optimal Baseline screening tests, except for ophthalmologic

exami-nations, are not recommended Monitoring and early intervention for

learning disabilities is important Complete physical examinations

should be performed at least twice yearly, including measurements of

height, weight, head circumference, and blood pressure; careful

palpa-tion for tumors; and assessment for scoliosis or other bony deformities

Methylphenidate has been shown to be helpful for the attention-deficit

issues in children with NF1.400

Dermal neurofibromas may be excised, but plexiform neurofibromas

usually cannot be removed in their entirety.401 Surgical debulking may

be undertaken for tumors that are disfiguring, interfere with function,

or are subject to irritation, trauma, or infection Mitogen-activated

protein kinase kinase (MEK) inhibition has been shown to decrease

both neurofibroma and MPNST size and prolong survival in

preclini-cal studies402; decreased tumor size was noted in all 11 children

treated with selumetinib, a MEK1/2 inhibitor.403 Mast cells appear to

play a critical role in the initiation and progression of plexiform

neu-rofibromas, and imatinib has led to an at least 20% decrease in tumor

size within 6 months in 26% of patients.404,405 Treatment with

siroli-mus (mTOR inhibitor) improved pain associated with pediatric

plexi-form neurofibromas but caused no shrinkage.406

Genetic counseling is another important aspect of treatment,

because there is a 50% chance of transmitting NF with each

preg-nancy Mutations can be found by multistep mutation detection in

more than 95% of individuals with NF1.345,407 Mosaicism with

postzy-gotic mutation in neurofibromin, however, is not uncommon.408,409

Affected patients may show mosaic-generalized NF1, which is

indis-tinguishable clinically from germ-line mutations with generalized

manifestations or localized NF1 Patients with

mosaic-localized or “segmental NF1” show typical features of NF1 limited to

a specific body segment Although CAL spots are the most common

manifestation of segmental NF1 in children, other cutaneous

mani-festations (freckling, dermal and plexiform neurofibromas) or

noncu-taneous manifestations (pseudoarthrosis, sphenoid wing dysplasia,

optic glioma, Lisch nodules) in the localized area may also occur.410

Figure 11-54 Erythema  dyschromicum  perstans.  Oval  slate-gray macules, all oriented along the same axis, on the trunk of this otherwise healthy  boy.  In  children  with  erythema  dyschromicum  perstans,  the hyperpigmented macules often clear spontaneously after years. 

11  •  Disorders of Pigmentation 273

neither pregnant nor taking oral contraceptives Occasionally it may also appear in patients of both sexes taking phenytoin (Dilantin) or its derivatives Overall 10% of affected individuals are male Once melasma has developed, it tends to persist for a long time, and treat-ment is generally not very satisfactory Melasma of pregnancy usu-ally clears within a few months after delivery only to recur with subsequent pregnancies Oral contraceptive-induced melasma may persist for up to 5 years after discontinuation of the medication.Because sun exposure tends to trigger and intensify this hyperpig-mentation, the disorder characteristically becomes more prominent in the summer months.421 Both UVA and visible light have been impli-cated, emphasizing the need for physical sunscreen use and use of sun-protective clothing In addition, treatment of melasma consists of discontinuation of potentially responsible medications and the use

of bleaching agents.418,419 Topically applied hydroquinones have been the gold standard of treatment, but their safety has recently been questioned, leading to the search for alternatives Hydroquinones inhibit tyrosinase and are most effective when compounded with tretinoin (0.05% to 0.1%) and mild topical steroids Twice-daily appli-cation of azelaic acid 15% to 20% is less efficacious but causes less irritation.422 Other topical agents that have been used are tranexamic acid (also used orally), kojic acid, plant extracts (such

as licorice or orchid extracts, soy, arbutin, and silymarin), ascorbic acid, N-acetylglucosamine, and niacinamide.419 Chemical peels (e.g., with tretinoin or trichloroacetic acid) and laser therapy, especially with Q-switched neodymium:yttrium-aluminum-garnet (Nd:YAG), may also be helpful These preparations often require 3 to 4 months before a therapeutic effect is achieved Concurrent sun protection is critical to prevent further hyperpigmentation in patients using hydro-quinones Because continuous use of hydroquinone bleaching creams

or lotions can result in excessive pigmentary loss or ochronosis-like hyperpigmentation, once the desired degree of depigmentation is achieved, hydroquinone therapy should be discontinued

METABOLIC CAUSES OF HYPERPIGMENTATION

Cutaneous changes often are helpful in the diagnosis of several crine disorders, including Addison disease (see Figs 23-6, and 23-7), hyperthyroidism (see Fig 23-2), hypothyroidism, acromegaly, and Cushing syndrome (see Chapter 23) More than two-thirds of patients with chronic hepatic disease (cirrhosis or prolonged bile-duct obstruc-tion) also have some degree of cutaneous hyperpigmentation Of these, diffuse darkening of the skin is perhaps the most common Blotchy areas of brown hyperpigmentation occasionally may be seen, and accentuation of normal freckling and areolar hyperpigmentation may appear Progressive, diffuse blotchy hyperpigmentation in addi-tion to hair lightening has been described with cobalamin (vitamin

endo-B12) deficiency from homozygous mutations in ABCD4, which encodes

a transporter involved in processing cobalamin.423 Polycystic kidney disease and other chronic renal disease may be accompanied by diffuse yellowish-brown skin discoloration, especially on the face and hands Although urinary chromogens and carotenemia may be present, melanin pigmentation also has been implicated

hemojuv-is seen in almost every patient with hemochromatoshemojuv-is and in tion with abdominal pain, is often the presenting sign The increased pigmentation is produced by melanin and not by the deposition of iron

conjunc-in the skconjunc-in It appears conjunc-initially conjunc-in the exposed areas before it becomes diffuse and is most intense in the skin of the face, arms, body folds, and genitalia Mucous membranes (the gums, palate, and buccal mucosa) and sometimes the conjunctivae are involved in 15% to 20%

of affected persons The skin is soft, dry, thin, shiny, and of fine texture Spider angiomas are present in 60% to 80% of affected individuals, and palmar erythema is common Facial, axillary, thoracic, and pubic

The dermatosis is asymptomatic but chronic There are frequent

exacerbations with extension into previously uninvolved areas There

is no known effective therapy, but most cases in children clear

spon-taneously within a few years.411,415

POSTINFLAMMATORY HYPERPIGMENTATION

Post-inflammatory hyperpigmentation is one of the most common

causes of hyperpigmentation, and is characterized by an increase in

melanin formation following cutaneous inflammation.416,417 Ordinary

post-inflammatory hyperpigmentation is of relatively short duration

and tends to persist for several months after the original cause has

subsided Examples include the pigmentation following physical

trauma, friction, primary irritants, eczematous eruptions, lichen

simplex chronicus, acne vulgaris and dermatoses such as pityriasis

rosea, psoriasis, fixed drug eruptions, photodermatitis, and pyoderma

Individuals with dark complexions and those who tan easily following

UV light exposure show the greatest degree and longest persistence of

this form of post-inflammatory hyperpigmentation In cases in which

the dermal–epidermal junction and basal layer become disrupted

(lupus erythematosus, lichen planus, lichenoid drug eruptions)

melanin incontinence occurs (Figs 4-43 and 4-51) The melanin

tends to drop from its normal epidermal position and passes into

mela-nophages of the dermis, leading to more pronounced and persistent

discoloration If areas of postinflammatory hyperpigmentation can be

protected from further UV light exposure, fading gradually occurs over

a period of months to years Most patients do not respond to topical

agents or resurfacing procedures as well as patients with melasma (see

below).418,419 Topical anti-inflammatory medications are appropriate

if inflammation is ongoing

Retention Hyperkeratosis

Because melanin is transferred to epidermal cells, thickened epidermis

often appears hyperpigmented Focal patches of hyperpigmentation

and mild skin thickening are not uncommonly seen at fold areas (such

as the ankle) and on the neck and represent retention hyperkeratosis

(sometimes called scurf) (Fig 11-55) These persistent patches can be

removed easily by gently scrubbing with an alcohol pad

MELASMA

Melasma is a term applied to a patchy dark-brown to black

hyperpig-mentation located primarily on the cheeks, the forehead, and

occa-sionally the temples, upper lip, and neck.417,420 Seen in up to 20% of

women, including adolescents, who take anovulatory drugs or who

are pregnant, this disorder has been termed the mask of pregnancy

Typical melasma also can occur in males and in females who are

Figure 11-55 Retention  hyperkeratosis.  Persistent  focal  patches  of 

hyperpigmentation  and  mild  skin  thickening,  especially  on  the  neck 

and near joints represent retained scale and can be removed easily by 

gently scrubbing with an alcohol pad. Parents often erroneously con-sider this a sign of inadequate cleansing. 

11  •  Disorders of Pigmentation

274

Argyria occurs after long-term ingestion or excessive application of silver preparations and presents as localized or widespread bluish-gray

or slate-colored discoloration of the skin produced by the deposition

of silver within the dermis The condition is more pronounced on exposed parts of the body—namely the face, forearms, and hands—but may also occur in the sclerae, oral mucous membranes, and lunulae of the nails Argyria has been increasingly described because

of the promotion of colloidal silver-based products for their stimulant, antimicrobial, and anti-inflammatory properties The anti-microbial properties are proportional to the bioactive silver ion released and its availability to interact with bacterial or fungal cell membranes.433 These “health food” products deliver primarily inactive metallic silver, not the antimicrobial ionized form Colloidal silver and silver sulfadiazine cream, for example, have high levels of silver release with relatively low levels of ionized silver.434 Ionized silver dressings have more recently been introduced for wound care433; they occasion-ally cause local dermal argyria435 but show very low local silver levels

immuno-On the other hand, temporary superficial silver staining of the stratum corneum is a common side effect of these dressings An adolescent girl with osteosarcoma who had limb salvage and placement of a silver-coated megaprosthesis developed intense blue-gray pigmentation along the surgical incision line 1 year after surgery from slow release

of the silver.436Cases with more extensive hyperpigmentation have been described after chronic ingestion of silver-containing water437 or colloidal silver438 or widespread topical application of silver sulfadiazine439,440

or colloidal silver Localized staining can be seen periorbitally and

on the eyes from ophthalmic preparations containing silver at puncture sites441,442 or after exposure to silver earrings443,444 but most commonly is now reported at burn or wound sites after use of silver sulfadiazine or colloidal silver when used as antibacterial agents, for example, for patients with burns or epidermolysis bullosa.440,445The diagnosis of argyria is based on clinical examination and history of exposure and may be confirmed by cutaneous biopsy

acu-of affected areas, which shows fine, small round refractive silver granules throughout the dermis, especially around eccrine glands Increased amounts of melanin may be seen in the basal layer of the epidermis and also within macrophages in the upper dermis Treatment of argyria depends on recognition of the disorder, discon-tinuation of the use of the silver-containing preparation, and avoid-ance of sunlight exposure The dermal hyperpigmentation is usually irreversible

Chrysiasis (gold-induced hyperpigmentation) is a rare cutaneous disorder induced by the administration of gold salts followed by expo-sure to UV light.446,447 The pigmentation is bluish gray or purplish and

is similar to that seen in argyria except that the hyperpigmentation is more prominent around the eyes, is limited to areas of sunlight expo-sure, and does not affect the sclerae and oral mucous membranes Hyperpigmentation may develop after treatment with a Q-switched laser after systemic gold treatment.448 Other cutaneous manifestations are seen in up to 20% of individuals on gold therapy, which is most commonly administered for rheumatoid arthritis These include mor-billiform, eczematous, urticarial, bullous, purpuric, lichen planus-like, and pityriasis rosea-like eruptions The histopathologic features of gold-induced hyperpigmentation consist of small, black, round or oval, irregularly shaped gold particles located in a perivascular distri-bution and in dermal histiocytes

Chronic exposure to mercury systemically may result in acrodynia (pink disease), a disorder of infants and young children characterized

by leg cramps; headaches; hypertension; excessive perspiration; itching; swelling; redness and peeling of the hands, feet, and nose; weakness of the pectoral and pelvic girdles; and nerve dysfunction in the lower extremities However, exposure to topically applied mercury may lead to slate-gray pigmentation in areas of topical application The discoloration is exaggerated in the areas of skin folds and is permanent.449

DRUG-INDUCED HYPERPIGMENTATION

Hyperpigmentation may be induced by chronic exposure to tion and tends to be worsened by sun exposure The diagnosis of a drug eruption is based almost entirely on history and physical

medica-hairs are scant or absent Cardiomyopathy, evidence of hypogonadism,

and reduced glucose tolerance are seen by young adulthood The

hepatic cirrhosis characteristic of adult-onset hemochromatosis,

however, is less clinically relevant in type 2 hemochromatosis, and

icterus is unusual.426

Secondary hemochromatosis (hemosiderosis) with associated

hyperpigmentation may be seen in patients with anemia who receive

numerous blood transfusions In such instances visceral fibrosis is

unusual, diabetes mellitus is uncommon, and hypogonadism is not

present

The diagnosis of metabolic hemochromatosis is suggested by the

presence of cutaneous hyperpigmentation in patients with hepatic

cirrhosis and a history of diabetes mellitus Elevated levels of serum

ferritin and transferrin saturation confirm the diagnosis.427 The

dem-onstration of parenchymal iron distribution by skin, liver, and gastric

biopsies and the presence of hemosiderin in urinary sediment are

helpful Skin biopsies show increased melanin in the basal layer and

deposition of iron in the upper cutis (especially in macrophages,

endo-thelial cells of capillaries, and the propria of eccrine glands)

The clinical course of untreated hemochromatosis is characterized

by tissue destruction, malfunction of involved organs, and eventual

death Symptomatic treatment of the diabetes, liver dysfunction, and

cardiac symptoms and quarterly phlebotomies, when initiated early,

commonly result in clinical and pathologic improvement Dietary

restriction of iron is impractical, and chelating agents to date have

been of little value

Ochronosis

Alkaptonuria (ochronosis) is an inborn error of tyrosine metabolism

in which homogentisic acid, an intermediate product in the

meta-bolism of phenylalanine and tyrosine, accumulates in the tissues

and is excreted in the urine because of a lack of homogentisic acid

oxidase This autosomal recessive disorder usually first becomes

mani-fest in the third decade with scleral blue-black pigmentation (Osler

sign) Affected children rarely show Osler sign, and the characteristic

dark urine is usually not noted because the color change only occurs

with sitting for 1 to 2 h, especially in an alkaline environment.428,429

Dark urine in the diaper may be the first sign in infants Skin

pig-mentation first becomes visible around the fourth decade of life,

espe-cially on ear cartilage, eyelids and other facial areas, intertriginous

areas, and over tendons Nails may be stained brown Around this

time, the ochronotic arthropathy from pigment deposition also starts

to develop and involves the weight-bearing joints (spine, knees)

most commonly The mean age of joint replacement is 55 years,

of development of renal stones 64 years, of cardiac valve

involve-ment 54 years, and of coronary artery calcification 59 years The

diagnosis can be confirmed by alkalinizing the urine (e.g., with

sodium hydroxide), which leads to the typical black color; the

homogentisic acid is detected by enzymatic spectrophotometry or

gas liquid chromatography Treatment with ascorbic acid twice daily

may reduce the connective tissue damage, and affected children have

also been placed on a low-protein diet Nitisinone therapy may

decrease homogentisic acid production.430 Endogenous ochronosis

has recently been improved by erbium-doped YAG laser resurfacing

and deep focal point treatment to remove areas of residual deep

pigment.431

Exogenous ochronosis is clinically and histologically similar to its

endogenous counterpart but is not hereditary and has no internal

manifestations The condition usually occurs in African-American

patients from exposure to hydroquinones and is characterized by

asymptomatic hyperpigmentation of the face, neck, back, and

exten-sor surfaces of the extremities Less commonly, exogenous ochronosis

has been described after exposure to antimalarials or products

con-taining resorcinol, phenol, mercury, or picric acid.432

HYPERPIGMENTATION CAUSED BY HEAVY METALS

The systemic absorption of chemicals can also cause discoloration of

the skin Although the incidence of hyperpigmentation owing to

exog-enous heavy metals has decreased in recent years, limited exposure to

such preparations still occurs, and metallic hyperpigmentation may

still be seen in children as well as adults

11  •  Disorders of Pigmentation 275

examination The main drugs implicated in causing skin pigmentation

are nonsteroidal anti-inflammatory drugs, minocycline,

antimalari-als,450 amiodarone, diltiazem,451 cytotoxic drugs, heavy metals (see

Hyperpigmentation Caused by Heavy Metals section), clofazimine,

imipramine,452,453 and chlorpromazine Clinical features are variable

according to the triggering molecule and have a large range of

pat-terns and shades Bluish-gray discoloration is most common and

espe-cially prominent at sites of exposure to UV light The condition is most

commonly seen in the pediatric population in adolescents who have

been taking minocycline for acne, with the blue discoloration usually

notable at sites of acne scarring and on the oral mucosae and shins

(Fig 11-56).454 Three subgroups have been described based on clinical

appearance and histopathologic correlates: type I (blue-gray

pigmen-tation in scars); type II (blue-gray pigmenpigmen-tation in previously normal

skin, especially of the shins); and type III (brown discoloration at

sun-exposed sites).455 Biopsy specimens tend to show pigmentation

within dermal macrophages, often localized to vessels and adnexal

structures Treatment involves interruption of therapy and sun

avoidance, although laser, particularly the alexandrite 755 nm laser,

may be useful.456,457 These measures are often followed by fading of

lesions, but pigmentation may persist for a long time or even be

permanent.458

The plaques of fixed drug eruptions are circumscribed, usually

round or oval, often edematous and sometimes bullous, usually

pruritic, and reddish-purple Drug-induced hyperpigmentation tends

to recur in the same location after the readministration of certain

drugs, particularly sulfonamides, tetracyclines, acetaminophen,

phe-nolphthalein, barbiturate derivatives, and antineoplastic agents such

as cyclophosphamide Histopathologic examination of lesions of the

hyperpigmented phase of fixed drug eruptions reveals an increase in

the amount of melanin in the basal layer of the epidermis and within

macrophages of the upper dermis and is helpful in confirming the

diagnosis

Carotenemia

Carotenemia (sometimes called carotenoderma) is a yellowish-orange

discoloration of skin caused by the ingestion of excessive quantities of

carotene-containing foods, particularly carrots, squash, pumpkin,

yellow turnips, sweet potatoes, peaches, apricots, papayas, mangos,

egg yolk, and even green beans.459–461 The condition is seen primarily

in infants and occasionally in older children and adults.462 The color

is most prominent on the palms and soles, in the nasolabial grooves,

on the forehead, chin, upper eyelids, postauricular areas, and anterior

axillary folds, and over areas of pressure such as the elbows, knees,

knuckles, and ankles (see Fig 23-3) Lack of involvement of the

sclerae and mucous membranes coupled with the absence of pruritus

and lack of color change in the urine or stool helps rule out the

pres-ence of hepatic or biliary jaundice Lycopene, a red-colored carotenoid

pigment found in fruits and vegetables, especially ripened tomatoes,

beets, chili beans, and various fruits and berries, may cause a

reddish-yellow discoloration of the skin (lycopenemia)

Carotenemia is a benign disorder in infants, and no intervention

is required Rarely carotenemia may be a sign of systemic disease,

especially hypothyroidism, weight-loss diets or anorexia, or diabetes

The diagnosis of carotenemia is confirmed by the presence of high

carotene levels in the presence of normal serum bilirubin If the

col-oration is problematic, reduction of dietary intake of

carotene-containing foods to normal levels or correction of the underlying

disorder usually results in gradual improvement within 4 to 6 weeks

Rarely children will show a genetic defect in the metabolism of

carot-enoids that is more recalcitrant to dietary intervention.463,464

DERMAL MELANOCYTOSES

Mongolian Spots

Mongolian spots are flat, deep brown to slate gray or blue-black, often

poorly circumscribed, large macular lesions generally located over the

lumbosacral areas, buttocks (Fig 11-57), and occasionally the lower

limbs, back, flanks, and shoulders of normal infants They are seen in

75% to 90% of individuals of African descent and Native-American

babies; 62% to 86% of Asians465–468; 70% of the Hispanic population,

11  •  Disorders of Pigmentation

276

melanocytosis alone is a much more common finding, which can progress and then recede with advancing age In a study of Chinese children, only 4% to 5% were found to have scleral melanocytosis during the first year of life, but that number increased to 45% by 6 years of age with 78% of cases bilateral478; only 12% of the children continued to show evidence of scleral melanocytosis by 18 years

of age

The nevus of Ito (nevus fuscoceruleus acromiodeltoideus) has the same features as the nevus of Ota except that the pigmentary changes tend to involve the shoulder (Fig 11-59), supraclavicular areas, sides

of the neck, and upper arm, scapulae, and deltoid regions It may occur alone or may be seen in conjunction with the nevus of Ota.Similar to Mongolian spots, biopsy sections of the nevus of Ota and nevus of Ito show elongated dendritic melanocytes scattered among the collagen bundles The melanocytes, however, often appear to be situated somewhat higher in the dermis than those seen in ordinary Mongolian spots

Although these lesions do not disappear spontaneously, changes

in color may occur Darkening of lesions has been noted during and after puberty These disorders are generally benign However, glau-coma has been described in 10%479 and melanoma, most commonly

of the eye (choroid, orbit, iris, ciliary body, and/or optic nerve), but also of the skin, brain and meninges, has rarely been reported.479–483Long-term dermatologic and ophthalmologic follow-up monitoring is needed

Laser therapy may improve the appearance of nevus of Ota, cially the Q-switched alexandrite laser and fractionated Nd:YAG.484,485

espe-and 10% of Caucasian infants Mongolian spots are present at birth,

tend to fade during the first 2 to 3 years of life, and only occasionally

persist into adulthood Extrasacral location, multiple Mongolian spots,

large size (>10 cm in diameter), and darker color are associated with

persistence beyond 1 year

Mongolian spots may be single (≈50% of babies) or multiple and

vary from a few millimeters to 10 cm or more in diameter They

rep-resent collections of spindle-shaped melanocytes located deep in the

dermis, probably as the result of arrest during their embryonal

migra-tion from the neural crest to the epidermis The slate blue to blue-black

color depends on the Tyndall effect (a phenomenon in which light

passing through a turbid medium such as the skin is scattered as it

strikes particles of melanin) Long-wavelength light rays (red, orange,

and yellow) tend to be less scattered and therefore continue to pass

downward into the lower levels of the skin; colors of shorter

wave-lengths (blue, indigo, and violet) are scattered to the side and

back-ward to the skin surface, thus creating the blue-black or slate-gray

discoloration

Because Mongolian spots are benign, therapy is unnecessary

However, large and numerous Mongolian spots may be seen in

lyso-somal storage disorders, among them GM1 gangliosidosis type 1,

Hunter syndrome, and Hurler syndrome.469–473 In these children, the

Mongolian spots often fade but not until at least the second decade of

life.473 Large and extensive Mongolian spots can be seen with

phako-matosis pigmentovascularis and phakophako-matosis pigmentopigmentalis,

on association with vascular malformations, and other pigmented

lesions, respectively.474

Nevus of Ota and Nevus of Ito

The nevus of Ota (nevus fuscoceruleus ophthalmomaxillaris)

repre-sents a usually unilateral, irregularly patchy, blue to bluish-gray to

brown discoloration of the skin of the face supplied by the first and

second divisions of the trigeminal nerve.475,476 It typically involves the

periorbital region, the temple, the forehead, the malar area, and the

nose (Fig 11-58) About two-thirds of patients with this disorder have

a patchy bluish discoloration of the sclera of the ipsilateral eye (see

Fig 11-58) and occasionally, the conjunctiva, cornea, and retina

Palatal involvement has been described in up to 18% of affected

indi-viduals.477 In about 5% of cases the nevus of Ota is bilateral rather

than unilateral, and in rare instances the lips, pharynx, and nasal

mucosa are similarly affected

Although most commonly seen in Asians, nevus of Ota is not

uncommonly seen in persons of African descent Unlike Mongolian

spots, which tend to disappear with time, the cutaneous coloration of

nevus of Ota generally persists and often shows a speckled rather than

a uniform discoloration Approximately 50% of lesions are congenital;

the remainder usually appear during the second decade of life Scleral

Figure 11-57 

Mongolian spots. Large blue-gray patches over the lum-bosacral area and buttocks of an African-American baby. These spots 

often fade or clear within the first few years of life. 

Figure 11-58 Nevus  of  Ota.  Unilateral,  irregularly  patchy, 

brownish-gray  discoloration  of  the  sclera  (A)  and  periorbital  region  (B)  in  an 

African-American boy. 

A

B

11  •  Disorders of Pigmentation 277

considered, the common blue nevus can be differentiated from it by the presence of normal skin markings over the lesion, in contrast to the loss of such markings in lesions of malignant melanoma, the homogeneity of coloration and the smooth borders on routine exami-nation, and the presence of a bluish-gray homogeneous lesion by dermoscopic evaluation.495

Cellular blue nevi tend to be larger and generally measure more than 1 cm in diameter They are usually located on the scalp, buttocks, sacrococcygeal areas, and occasionally the dorsal aspect of the hands and feet The plaque-type variant of blue nevus is a subset that is present at birth or develops during early childhood, occurs most com-monly on the scalp, and may enlarge during puberty The cellular blue nevus carries a higher risk of malignant transformation than the common blue nevus, but malignant transformation is still rare Malig-nant blue nevi are locally aggressive but spread to regional lymph nodes in about 5% of individuals

The classification of other forms of blue nevi is controversial.496Blue nevi may be hypochromic (sclerotic, hypomelanotic, and amela-notic forms), eruptive (particularly after sunburn on the upper central chest, shoulders, and “V” of the neck), or targetoid (preferentially on the back of the hands or feet, leading to a misdiagnosis of melanoma) Many show clinical and histologic features of more than one form, particularly combinations of variants of blue nevi with common and/

or Spitz nevi (see Chapter 9) The deep penetrating nevus (usually has its onset after the first decade of life), epithelioid blue nevus (most commonly seen in individuals with Carney complex), and pigmented epithelioid melanocytoma show features of both blue nevi (intrader-mal location, pigmentation) and Spitz nevi (epithelioid morphol-ogy).497 Molecular studies are likely to refine classification GNAQ is

mutated in about 83% of blue nevi.492 However, deep penetrating nevi

show HRAS mutations as seen in Spitz nevi rather than GNAQ or GNA11 mutations,498 suggesting reclassification of deep penetrating nevi with Spitz nevi

Benign-appearing blue nevi do not require excision If the diagnosis

is in question, biopsy can be performed Histopathologic examination

of common blue nevi reveals greatly elongated spindle-shaped nocytes, mainly in the middle and lower thirds of the dermis, which results in the blue coloration In addition to spindle-shaped melano-cytes, cellular blue nevi also have nodular islands of melanocytes

mela-The complete list of 498 references for this chapter is available online

find-Figure 11-59 Nevus of Ito. Blue patch on the shoulder.  Figure 11-60 Blue nevus. Acquired navy blue papule on a girl’s nose. 

Multiple sessions are required, but resultant scarring is rare One

com-plication in individuals with darker skin types is postinflammatory

hypopigmentation; vigorous sun protection is imperative, and

pre-treatment with hydroquinone is sometimes used Involvement on the

zygomatic arch or frontal forehead regions responds better than

peri-orbital pigmentation.486–488 Cosmetic cover-up may also be used

Nevus of Ota and nevus of Ito may be seen in association with

vascular malformations (nevus flammeus or cutis marmorata

telan-giectatica congenita most commonly) in a disorder called phakomatosis

pigmentovascularis (see Chapter 12).489 The condition may be

associ-ated with Sturge–Weber syndrome or Klippel–Trénaunay syndrome

when the nevus flammeus is on the forehead or limbs, respectively

Occasionally, a nevus spilus is seen in association as well.490 Sturge–

Weber syndrome has been shown to result from somatic

muta-tions in GNAQ491 and Klippel–Trénaunay syndrome in PI3KCA

(phosphoinositide-3-kinase, catalytic, alpha), suggesting that these

mutations, when occuring in melanocytes, may cause nevus of Ota or

nevus of Ito.491,492

BLUE NEVI

Blue nevi are a heterogeneous group of congenital and more often

acquired melanocytic tumors.493 Most often seen are common blue

nevi and cellular blue nevi, although there may be histologic overlap

between these types.494 The nevi appear blue-gray clinically because

of the deep (dermal) location of the melanin pigment and the Tyndall

effect (selective absorption of longer wavelength components of light

by melanin with reflection of the shorter blue components) Blue nevi

are thought to result from the arrested embryonal migration of

mela-nocytes bound for the dermal–epidermal junction It is thus possible

that the blue nevi, Mongolian spots, and the nevi of Ota and Ito are

closely related and possibly represent different stages of the same

physiologic process

The common blue nevus (also called the classic or dendritic blue

nevus) presents as a small, round or oval, dark blue or bluish-black,

smooth-surfaced, sharply circumscribed, slightly elevated

dome-shaped papule, nodule, or plaque (Fig 11-60) Most common blue

nevi range from 2 or 3 mm to 10 mm (<1 cm) in diameter Although

usually single, they may be multiple Lesions may be present at birth

but may appear at any age Although common blue nevi may occur

on any part of the body, areas of predilection include the buttocks,

dorsal aspect of the hands and feet, scalp, and the extensor surfaces

of the forearms They also may occur on the face, bulbar conjunctiva,

mucous membranes, and the hard and soft palates

Once a common blue nevus appears, it usually remains static and

persists throughout life Although fading of color and some degree of

flattening may occur with time, malignant degeneration of this form

of blue nevus is rare When a diagnosis of malignant melanoma is

11  •  Disorders of Pigmentation

278

dations of the 2012 International Tuberous Sclerosis Complex Consensus ference Pediatr Neurol 2013;49(4):255–65.

Con-231 Scheuerle A, Nelson DL Incontinentia pigmenti In: Pagon RA, Bird TC, Dolan

CR, et al., editors GeneReviews [Internet] Seattle: University of Washington; 1993–1999 June 8 [updated January 28, 2008].

343 Williams VC, Lucas J, Babcock MA, et al Neurofibromatosis type 1 revisited Pediatrics 2009;123:124–33.

496 Barnhill RL, Cerroni L, Cook M, et al State of the art, nomenclature, and points

of consensus and controversy concerning benign melanocytic lesions: outcome

of an international workshop Adv Anat Pathol 2010;17:73–90.

96 Dessinioti C, Stratigos AJ, Rigopoulos D, et al A review of genetic disorders of

hypopigmentation: lessons learned from the biology of melanocytes Exp

Der-matol 2009;18:741–9.

110 Kaplan J, De Domenico I, Ward DM Chédiak-Higashi syndrome Curr Opin

Hematol 2008;15:22–9.

129 Oiso N, Fukai K, Kawada A, et al Piebaldism J Dermatol 2013;40(5):330–5.

163 Northrup H, Krueger DA Tuberous sclerosis complex diagnostic criteria

update: recommendations of the 2012 International Tuberous Sclerosis

Complex Consensus Conference Pediatr Neurol 2013;49(4):243–54.

183 Krueger DA, Northrup H, International Tuberous Sclerosis Complex Consensus

Group Tuberous sclerosis complex surveillance and management:

recommen-11  •  Disorders of Pigmentation 278.e1

References

1 Hearing VJ The melanosome: the perfect model for cellular responses to the

environment Pigment Cell Res 2000;13(Suppl 8):23–34.

2 Marks MS, Seabra MC The melanosome: membrane dynamics in black and

white Nat Rev Mol Cell Biol 2001;2(10):738–48.

3 Minwalla L, Zhao Y, Le Poole IC, et al Keratinocytes play a role in regulating

distribution patterns of recipient melanosomes in vitro J Invest Dermatol

2001;117(2):341–7.

4 Seiberg M, Paine C, Sharlow E, et al Inhibition of melanosome transfer results

in skin lightening J Invest Dermatol 2000;115(2):162–7.

5 Sturm RA, Box NF, Ramsay M Human pigmentation genetics: the difference is

only skin deep Bioessays 1998;20(9):712–21.

6 Dulon M, Weichenthal M, Blettner M, et al Sun exposure and number of nevi

in 5- to 6-year-old European children J Clin Epidemiol 2002;55(11):

1075–81.

7 Garbe C, Buttner R, Weiss J, et al Risk factors for developing cutaneous

mela-noma and criteria for identifying persons at risk: multicenter case-control study

of the Central Malignant Melanoma Registry of the German Dermatological

Society J Invest Dermatol 1994;102(5):695–9.

8 Schaffer JV, Bolognia JL The melanocortin-1 receptor: red hair and beyond

Arch Dermatol 2001;137(11):1477–85.

9 Laude TA Approach to dermatologic disorders in black children Semin

Der-matol 1995;14(1):15–20.

10 Jin Y, Birlea SA, Fain PR, et al Variant of TYR and autoimmunity susceptibility

loci in generalized vitiligo N Engl J Med 2010;362(18):1686–97.

11 Quan C, Ren YQ, Xiang LH, et al Genome-wide association study for vitiligo

identifies susceptibility loci at 6q27 and the MHC Nat Genet 2010;42(7):

614–18.

12 Yu R, Broady R, Huang Y, et al Transcriptome analysis reveals markers of

aberrantly activated innate immunity in vitiligo lesional and non-lesional skin

PLoS ONE 2012;7(12):e51040.

13 Krüger C, Schallreuter KU A review of the worldwide prevalence of vitiligo in

children/adolescents and adults Int J Dermatol 2012;51(10):1206–12.

14 Castanet J, Ortonne JR Pathophysiology of vitiligo Clin Dermatol 1997;

17 Alkhateeb A, Fain PR, Thody A, et al Epidemiology of vitiligo and associated

autoimmune diseases in Caucasian probands and their families Pigment Cell

Res 2003;16(3):208–14.

18 Ezzedine K, Diallo A, Léauté-Labrèze C, et al Pre- vs post-pubertal onset of

vitiligo: multivariate analysis indicates atopic diathesis association in

pre-pubertal onset vitiligo Br J Dermatol 2012;167(3):490–5.

19 Handa S, Dogra S Epidemiology of childhood vitiligo: a study of 625 patients

from north India Pediatr Dermatol 2003;20(3):207–10.

20 Fernandes NC, Campos MM Childhood vitiligo and thyroid disease An Bras

Dermatol 2009;84:200–2.

21 Kwinter J, Pelletier J, Khambalia A, et al High-potency steroid use in children

with vitiligo: a retrospective study J Am Acad Dermatol 2007;56:236–41.

22 Afsar FS, Isleten F Prevalence of thyroid function test abnormalities and

thyroid autoantibodies in children with vitiligo Indian J Endocrinol Metab

2013;17(6):1096–9.

23 Silverberg NB Pediatric vitiligo Pediatr Clin North Am 2014;61(2):347–66.

24 Stierman SC, Tierney EP, Shwayder TA Halo congenital nevocellular nevi

asso-ciated with extralesional vitiligo: a case series with review of the literature

Pediatr Dermatol 2009;26:414–24.

25 Patrizi A, Bentivogli M, Raone B, et al Association of halo nevus/i and vitiligo

in childhood: a retrospective observational study J Eur Acad Dermatol Venereol

2013;27(2):e148–52.

26 Gauthier Y, Cario-Andre M, Lepreux S, et al Melanocyte detachment after skin

friction in nonlesional skin of patients with generalized vitiligo Br J Dermatol

2003;148(1):95–101.

27 Wain EM, Orchard GE, Whittaker SJ, et al Outcome in 34 patients with

juvenile-onset mycosis fungoides: a clinical, immunophenotypic, and

molecu-lar study Cancer 2003;98(10):2282–90.

28 Wang H, Bright A, Xin B, et al Cutaneous dyspigmentation in patients with

ganglioside GM3 synthase deficiency Am J Med Genet A 2013;161A(4):

875–9.

29 Ho N, Pope E, Weinstein M, et al A double-blind, randomized,

placebo-controlled trial of topical tacrolimus 0.1% vs clobetasol propionate 0.05% in

childhood vitiligo Br J Dermatol 2011;165(3):626–32.

30 Linthorst Homan MW, de Korte J, Grootenhuis MA, et al Impact of childhood

vitiligo on adult life Br J Dermatol 2008;159:915–20.

31 Silverberg JI, Silverberg NB Quality of life impairment in children and

adoles-cents with vitiligo Pediatr Dermatol 2014;31(3):309–18.

32 Manzoni AP, Weber MB, Nagatomi AR, et al Assessing depression and anxiety

in the caregivers of pediatric patients with chronic skin disorders An Bras

Dermatol 2013;88(6):894–9.

33 Isenstein AL, Morrell DS, Burkhart CN Vitiligo: treatment approach in

chil-dren Pediatr Ann 2009;38:339–44.

34 Lotti T, Berti S, Moretti S Vitiligo therapy Expert Opin Pharmacother

2009;10:2779–85.

35 Cockayne SE, Messenger AG, Gawkrodger DJ Vitiligo treated with topical ticosteroids: children with head and neck involvement respond well J Am Acad Dermatol 2002;46(6):964–5.

cor-36 Silverberg NB, Lin R, Farley-Li J, et al Tacrolimus ointment promotes mentation of vitiligo in children: a review of 57 cases J Am Acad Dermatol 2004;51(5):760–6.

repig-37 Sahni K, Gupta V, Khanna N Hyperpigmentation in photo exposed patches of vitiligo following tacrolimus therapy Indian Dermatol Online J 2014;5(2): 164–6.

38 Majid I, Masood Q, Hassan I, et al Childhood vitiligo: response to nisolone oral minipulse therapy and topical fluticasone combination Indian J Dermatol 2009;54:124–7.

methylpred-39 Njoo MD, Bos JD, Westerhof W Treatment of generalized vitiligo in children with narrow-band (TL-01) UVB radiation therapy J Am Acad Dermatol 2000;42(2 Pt 1):245–53.

40 Scherschun L, Kim JJ, Lim HW Narrow-band ultraviolet B is a useful and tolerated treatment for vitiligo J Am Acad Dermatol 2001;44(6):999–1003.

well-41 Ersoy-Evans S, Altaykan A, Sahin S, et al Phototherapy in childhood Pediatr Dermatol 2008;25:599–605.

42 Percivalle S1, Piccinno R, Caccialanza M, et al Narrowband ultraviolet B totherapy in childhood vitiligo: evaluation of results in 28 patients Pediatr Dermatol 2012;29(2):160–5.

pho-43 Cho S, Zheng Z, Park YK, et al The 308-nm excimer laser: a promising device for the treatment of childhood vitiligo Photodermatol Photoimmunol Pho- tomed 2011;27(1):24–9.

44 Hofer A, Hassan AS, Legat FJ, et al The efficacy of excimer laser (308 nm) for vitiligo at different body sites J Eur Acad Dermatol Venereol 2006;20: 558–64.

45 Baltas E, Csoma Z, Ignacz F, et al Treatment of vitiligo with the 308-nm xenon chloride excimer laser Arch Dermatol 2002;138(12):1619–20.

46 Hui-Lan Y, Xiao-Yan H, Jian-Yong F, et al Combination of 308-nm excimer laser with topical pimecrolimus for the treatment of childhood vitiligo Pediatr Dermatol 2009;26:354–6.

47 Hadi S, Tinio P, Al-Ghaithi K, et al Treatment of vitiligo using the 308-nm excimer laser Photomed Laser Surg 2006;24:354–7.

48 Lotti T, Berti S, Moretti S Vitiligo therapy Expert Opin Pharmacother 2009;10:2779–85.

49 Schallreuter KU, Kruger C, Wurfel BA, et al From basic research to the bedside: efficacy of topical treatment with pseudocatalase PC-KUS in 71 children with vitiligo Int J Dermatol 2008;47:743–53.

50 Lee KJ, Lee JH, Lee DY Successful treatment of vitiligo in a 6-year-old child by topical anaesthesia and epidermal grafting J Eur Acad Dermatol Venereol 2009;23:859–60.

51 Mulekar SV, Al Eisa A, Delvi MB, et al Childhood vitiligo: a long-term study of localized vitiligo treated by noncultured cellular grafting Pediatr Dermatol 2009;27(2):132–6.

52 Awad SS Chinese cupping: a simple method to obtain epithelial grafts for the management of resistant localized vitiligo Dermatol Surg 2008;34: 1186–93.

53 Gupta S, Kumar B Epidermal grafting for vitiligo in adolescents Pediatr matol 2002;19(2):159–62.

Der-54 Mulekar SV Melanocyte-keratinocyte cell transplantation for stable vitiligo Int

J Dermatol 2003;42(2):132–6.

55 Kato H, Furuhashi T, Ito E, et al Efficacy of 1-mm minigrafts in treating vitiligo depends on patient age, disease site and vitiligo subtype J Dermatol 2011; 38(12):1140–5.

56 Matsuzaki K, Kumagai N Treatment of vitiligo with autologous cultured tinocytes in 27 cases Eur J Plast Surg 2013;36:651–6.

kera-57 Padilla-España L, del Boz J, Ramírez-López MB, et al Camouflage therapy shop for pediatric dermatology patients: a review of 6 cases Actas Dermosifil- iogr 2014;105(5):510–14.

work-58 Ramien ML, Ondrejchak S, Gendron R, et al Quality of life in pediatric patients before and after cosmetic camouflage of visible skin conditions J Am Acad Dermatol 2014;71(5):935–40.

59 Suga Y, Ikejima A, Matsuba S, Ogawa H Medical pearl: DHA application for camouflaging segmental vitiligo and piebald lesions J Am Acad Dermatol 2002;47(3):436–8.

60 Sakata VM, da Silva FT, Hirata CE, et al Diagnosis and classification of Koyanagi-Harada disease Autoimmun Rev 2014;13(4–5):550–5.

Vogt-61 Read RW, Rechodouni A, Butani N, et al Complications and prognostic factors

in Vogt-Koyanagi-Harada disease Am J Ophthalmol 2001;131(5):599–606.

62 Tian’en Z, Libin D, Yushu T Vogt-Koyanagi-Harada syndrome: report of a nile case J Dermatol 2003;30(7):570–1.

juve-63 Rathinam SR, Vijayalakshmi R, Namperumalsamy R, et al Harada syndrome in children Ocul Immunol Inflamm 1998;6(3):155–61.

Vogt-Koyanagi-64 Tabbara KF, Chavis PS, Freeman WR Vogt-Koyanagi-Harada syndrome in children compared to adults Acta Ophthalmol Scand 1998;76(6):723–6.

65 Jeroudi A, Angeles-Han ST, Yeh S Efficacy of adalimumab for pediatric Vogt-Koyanagi-Harada syndrome Ophthalmic Surg Lasers Imaging Retina 2014;45(4):332–4.

66 Khalifa YM, Bailony MR, Acharya NR Treatment of pediatric Harada syndrome with infliximab Ocul Immunol Inflamm 2010;18(3): 218–22.

Vogt-Koyanagi-67 Gupta M, Pande D, Lehl SS, et al Alezzandrini syndrome BMJ Case Rep 2011;2011.

11  •  Disorders of Pigmentation

278.e2

68 Andrade A, Pithon M Alezzandrini syndrome: report of a sixth clinical case

Dermatology 2011;222(1):8–9.

69 Oetting WS Albinism Curr Opin Pediatr 1999;11(6):565–71.

70 Gronskov K, Ek J, Brondum-Nielsen K Oculocutaneous albinism Orphanet J

Rare Dis 2007;2:43.

71 Cross HE, McKusick VA, Breen W A new oculocerebral syndrome with

hypopig-mentation J Pediatr 1967;70(3):398–406.

72 Bohn G, Allroth A, Brandes G, et al A novel human primary immunodeficiency

syndrome caused by deficiency of the endosomal adaptor protein p14 Nat Med

2007;13(1):38–45.

73 Dotta L, Parolini S, Prandini A Clinical, laboratory and molecular signs of

immunodeficiency in patients with partial oculo-cutaneous albinism Orphanet

J Rare Dis 2013;8:168.

74 Grønskov K, Brøndum-Nielsen K, Lorenz B, et al Clinical utility gene card for:

oculocutaneous albinism Eur J Hum Genet 2014;22(8).

75 Montoliu L, Grønskov K, Wei AH, et al Increasing the complexity: new

genes and new types of albinism Pigment Cell Melanoma Res 2014;27(1):

11–18.

76 Ladizinski B, Cruz-Inigo AE, Sethi A The genocide of individuals with albinism

in Africa Arch Dermatol 2012;148(10):1151.

77 Toyofuku K, Wada I, Spritz RA, Hearing VJ The molecular basis of

oculocuta-neous albinism type 1 (OCA1): Sorting failure and degradation of mutant

tyrosinases results in a lack of pigmentation Biochem J 2001;355(Pt 2):

259–69.

78 Brilliant MH The mouse p (pink-eyed dilution) and human P genes,

oculocu-taneous albinism type 2 (OCA2), and melanosomal pH Pigment Cell Res

2001;14(2):86–93.

79 Sarangarajan R, Boissy RE TYRPl and oculocutaneous albinism type 3

Pigment Cell Res 2001;14(6):437–44.

80 Manga R, Kromberg JG, Box NF, et al Rufous oculocutaneous albinism in

southern African blacks is caused by mutations in the TYRP1 gene Am J Hum

Genet 1997;61(5):1095–101.

81 Newton JM, Cohen-Barak O, Hagiwara N, et al Mutations in the human

ortho-logue of the mouse underwhite gene (uw) underlie a new form of

oculocutane-ous albinism, OCA4 Am J Hum Genet 2001;69(5):981–8.

82 Kausar T, Bhatti MA, Ali M, et al OCA5, a novel locus for non-syndromic

oculocutaneous albinism, maps to chromosome 4q24 Clin Genet 2013;84:

91–3.

83 Wei AH, Zang DJ, Zhang Z, et al Exome sequencing identifies SLC24A5 as a

candidate gene for nonsyndromic oculocutaneous albinism J Invest Dermatol

2013;133:1834–40.

84 Morice-Picard F, Lasseaux E, Francois S, et al SLC24A5 mutations are

associ-ated with non-syndromic oculocutaneous albinism J Invest Dermatol

2014;134(2):568–71.

85 Grønskov K, Dooley CM, Ostergaard E, et al Mutations in c10orf11, a

melanocyte-differentiation gene, cause autosomal-recessive albinism Am J

Hum Genet 2013;92:415–21.

86 King RA, Pietsch J, Fryer JR, et al Tyrosinase gene mutations in

oculocutane-ous albinism 1 (OCA1): definition of the phenotype Hum Genet 2003;

113(6):502–13.

87 Russell-Eggitt I Albinism Ophthalmol Clin North Am 2001;14(3):533–46.

88 Summers CG Albinism: classification, clinical characteristics, and recent

find-ings Optom Vis Sci 2009;86:659–62.

89 Kutzbach BR, Summers CG, Holleschau AM, et al Neurodevelopment in

chil-dren with albinism Ophthalmology 2008;115:1805–8, e1801–2.

90 Kiprono SK, Chaula BM, Beltraminelli H Histological review of skin cancers in

African albinos: a 10-year retrospective review BMC Cancer 2014;14:157.

91 King RA, Willaert RK, Schmidt RM, et al MC1R mutations modify the classic

phenotype of oculocutaneous albinism type 2 (OCA2) Am J Hum Genet 2003;

73(3):638–45.

92 Akahoshi K, Fukai K, Kato A, et al Duplication of 15q11.2-q14, including the

P gene, in a woman with generalized skin hyperpigmentation Am J Med Genet

2001;104(4):299–302.

93 Inagaki K, Suzuki T, Shimizu H, et al Oculocutaneous albinism type 4 is one

of the most common types of albinism in Japan Am J Hum Genet 2004;

74(3):466–71.

94 Terenziani M, Spreafico F, Serra A, et al Amelanotic melanoma in a child with

oculocutaneous albinism Med Pediatr Oncol 2003;41(2):179–80.

95 Huizing M, Gahl WA Disorders of vesicles of lysosomal lineage: the

Hermansky-Pudlak syndromes Curr Mol Med 2002;2(5):451–67.

96 Dessinioti C, Stratigos AJ, Rigopoulos D, et al A review of genetic disorders of

hypopigmentation: lessons learned from the biology of melanocytes Exp

Der-matol 2009;18:741–9.

97 Huizing M, Helip-Wooley A, Westbroek W, et al Disorders of lysosome-related

organelle biogenesis: clinical and molecular genetics Annu Rev Genomics

Hum Genet 2008;9:359–86.

98 Li W, Zhang Q, Oiso N, et al Hermansky-Pudlak syndrome type 7 (HPS-7)

results from mutant dysbindin, a member of the biogenesis of lysosome-related

organelles complex 1 (BLOC-1) Nat Genet 2003;35(1):84–9.

99 Huizing M, Hess R, Dorward H, et al Cellular, molecular and clinical

charac-terization of patients with Hermansky-Pudlak syndrome type 5 Traffic

2004;5(9):711–22.

100 Morgan NV, Pasha S, Johnson CA, et al A germline mutation in BLOC1S3/

reduced pigmentation causes a novel variant of Hermansky-Pudlak syndrome

(HPS8) Am J Hum Genet 2006;78:160–6.

101 Wei AH, Li W Hermansky-Pudlak syndrome: pigmentary and non-pigmentary defects and their pathogenesis Pigment Cell Melanoma Res 2013;26(2): 176–92.

102 Mitsui H, Komine M, Watanabe T, et al Does Hermansky-Pudlak syndrome predispose to systemic lupus erythematosus? Br J Dermatol 2002;146(5): 908–11.

103 Mahadeo R, Markowitz J, Fisher S, Daum F Hermansky-Pudlak syndrome with granulomatous colitis in children J Pediatr 1991;118(6):904–6.

104 Salvaggio HL, Graeber KE, Clarke LE, et al Mucocutaneous granulomatous disease in a patient with Hermansky-Pudlak syndrome JAMA Dermatol 2014;150(10):1083–7.

105 Harada T, Ishimatsu Y, Nakashima S, et al An autopsy case of Pudlak syndrome: a case report and review of the literature on treatment Intern Med 2014;53(23):2705–9.

Hermansky-106 Cullinane AR, Curry JA, Carmona-Rivera C, et al A BLOC-1 mutation screen reveals that PLDN is mutated in Hermansky-Pudlak syndrome type 9 Am J

Hum Genet 2011;88(6):778–87.

107 Badolato R, Prandini A, Caracciolo S, et al Exome sequencing reveals a pallidin mutation in a Hermansky-Pudlak-like primary immunodeficiency syndrome Blood 2012;119(13):3185–7.

108 Mora AJ, Wolfsohn DM The management of gastrointestinal disease in Hermansky-Pudlak syndrome J Clin Gastroenterol 2011;45(8):700–2.

109 Ward DM, Shiflett SL, Kaplan J Chédiak-Higashi syndrome: a clinical and molecular view of a rare lysosomal storage disorder Curr Mol Med 2002; 2(5):469–77.

110 Kaplan J, De Domenico I, Ward DM Chédiak-Higashi syndrome Curr Opin Hematol 2008;15:22–9.

111 Anderson LL, Paller AS, Malpass D, et al Chédiak-Higashi syndrome in a black child Pediatr Dermatol 1992;9(1):31–6.

112 Al-Khenaizan S Hyperpigmentation in Chédiak-Higashi syndrome J Am Acad Dermatol 2003;49(5 Suppl.):S244–6.

113 Ahluwalia J, Pattari S, Trehan A, et al Accelerated phase at initial tion: an uncommon occurrence in Chédiak-Higashi syndrome Pediatr Hematol Oncol 2003;20(7):563–7.

presenta-114 Nagai K, Ochi F, Terui K, et al Clinical characteristics and outcomes of Chédiak-Higashi syndrome: a nationwide survey of Japan Pediatr Blood Cancer 2013;60(10):1582–6.

115 Karim MA, Suzuki K, Fukai K, et al Apparent genotype-phenotype correlation

in childhood, adolescent, and adult Chédiak-Higashi syndrome Am J Med Genet 2002;108(1):16–22.

116 Menasche G, Pastural E, Feldmann J, et al Mutations in RAB27A cause

Gris-celli syndrome associated with haemophagocytic syndrome Nat Genet 2000; 25(2):173–6.

117 Sanal O, Ersoy F, Tezcan I, et al Griscelli disease: genotype-phenotype tion in an array of clinical heterogeneity J Clin Immunol 2002;22(4): 237–43.

correla-118 Anikster Y, Huizing M, Anderson PD, et al Evidence that Griscelli syndrome

with neurological involvement is caused by mutations in RAB27A, not MY05A

Am J Hum Genet 2002;71(2):407–14.

119 Duran-McKinster C, Rodriguez-Jurado R, Ridaura C, et al Elejalde syndrome-A melanolysosomal neurocutaneous syndrome: clinical and morphological find- ings in 7 patients Arch Dermatol 1999;135(2):182–6.

120 Sanal O, Yel L, Kucukali T, et al An allelic variant of Griscelli disease: tion with severe hypotonia, mental-motor retardation, and hypopigmentation consistent with Elejalde syndrome (neuroectodermal melanolysosomal disor- der) J Neurol 2000;247(7):570–2.

presenta-121 Aksu G, Kutukculer N, Genel F, et al Griscelli syndrome without cytosis in an eleven-year-old girl expanding the phenotypic spectrum of

hemophago-RAB27A mutations in humans Am J Med Genet 2003;116A(4):329–33.

122 Menasche G, Ho CH, Sanal O, et al Griscelli syndrome restricted to

hypopig-mentation results from a melanophilin defect (GS3) or a MY05A F-exon

dele-tion (GS1) J Clin Invest 2003;112(3):450–6.

123 Kaur S, Jindal N, Dayal S, et al A rare pigmentary disorder in two non-identical siblings: Griscelli syndrome-type 3 Dermatol Online J 2014;20(7).

124 Westbroek W, Klar A, Cullinane AR Cellular and clinical report of new Griscelli syndrome type III cases Pigment Cell Melanoma Res 2012;25(1): 47–56.

125 Mancini AJ, Chan LS, Paller AS Partial albinism with immunodeficiency: Griscelli syndrome Report of a case and review of the literature J Am Acad Dermatol 1998;38(2 Pt 2):295–300.

126 Schuster F, Stachel DK, Schmid I, et al Griscelli syndrome: report of the first

peripheral blood stem cell transplant and the role of mutations in the RAB27A

gene as an indication for BMT Bone Marrow Transplant 2001;28(4): 409–12.

127 Hamidieh AA, Pourpak Z, Yari K, et al Hematopoietic stem cell transplantation with a reduced-intensity conditioning regimen in pediatric patients with Gris- celli syndrome type 2 Pediatr Transplant 2013;17(5):487–91.

128 Ward KA, Moss C, Sanders DS Human piebaldism: relationship between

phe-notype and site of KIT gene mutation Br J Dermatol 1995;132(6):929–35.

129 Oiso N, Fukai K, Kawada A, et al Piebaldism J Dermatol 2013;40(5):330–5.

130 Spritz RA Molecular basis of human piebaldism J Invest Dermatol 1994; 103(5 Suppl.):137S–140S.

131 Sanchez-Martin M, Perez-Losada J, Rodriguez-Garcia A, et al Deletion of the

SLUG (SNAI2) gene results in human piebaldism Am J Med Genet

2003;122A(2):125–32.

11  •  Disorders of Pigmentation 278.e3

132 Richards KA, Fukai K, Oiso N, Paller AS A novel KIT mutation results in

pie-baldism with progressive depigmentation J Am Acad Dermatol 2001;44(2):

288–92.

133 Murakami T, Fukai K, Oiso N, et al New KIT mutations in patients with

piebald-ism J Dermatol Sci 2004;35(1):29–33.

134 Makino T, Yanagihara M, Oiso N, et al Repigmentation of the epidermis around

the acrosyringium in piebald skin: an ultrastructural examination Br J

Derma-tol 2013;168(4):910–12.

135 Matsunaga H, Tanioka M, Utani A, et al Familial case of piebaldism with

regression of white forelock Clin Exp Dermatol 2008;33:511–12.

136 Stevens CA, Chiang PW, Messiaen LM Café-au-lait macules and intertriginous

freckling in piebaldism: clinical overlap with neurofibromatosis type 1 and

Legius syndrome Am J Med Genet A 2012;158A(5):1195–9.

137 Spritz R Misdiagnosis of “neurofibromatosis” in patients with piebaldism

Dermatol Online J 2011;17(11):13.

138 Spritz RA, Beighton P Piebaldism with deafness: molecular evidence for an

expanded syndrome Am J Med Genet 1998;75(1):101–3.

139 Kilsby AJ, Cruwys M, Kukendrajah C, et al Homozygosity for piebaldism with

a proven KIT mutation resulting in depigmentation of the skin and hair,

deaf-ness, developmental delay and autism spectrum disorder Clin Dysmorphol

2013;22(2):64–7.

140 Narita T, Oiso N, Fukai K, et al Two children with a mild or moderate

piebald-ism phenotype and a father without leukoderma in a family with the same

recurrent missense mutation in the kinase domain of KIT J Dermatol

2011;21(3):446–7.

141 Guerra L, Primavera G, Raskovic D, et al Permanent repigmentation of

pie-baldism by erbium:YAG laser and autologous cultured epidermis Br J Dermatol

2004;150(4):715–21.

142 Garg T, Khaitan BK, Manchanda Y Autologous punch grafting for

repigmenta-tion in piebaldism J Dermatol 2003;30(11):849–50.

143 Cambiaghi S, Cavalli R, Legnani C, Gelmetti C What syndrome is this?

Waardenburg syndrome Pediatr Dermatol 1998;15(3):235–7.

144 Milunsky JM Waardenburg syndrome type I In: Pagon RA, Bird TC, Dolan CR,

et al., editors GeneReviews [Internet] Seattle: University of Washington;

1993–2001 Jul 30 [updated August 4, 2009].

145 Nayak CS, Isaacson G Worldwide distribution of Waardenburg syndrome Ann

Otol Rhinol Laryngol 2003;112(9 Pt 1):817–20.

146 Wollnik B, Tukel T, Uyguner O, et al Homozygous and heterozygous

inheri-tance of PAX3 mutations causes different types of Waardenburg syndrome

Am J Med Genet 2003;122A(1):42–5.

147 Pingault V, Ente D, Dastot-Le Moal F, et al Review and update of mutations

causing Waardenburg syndrome Hum Mutat 2010;31:391–406.

148 Léger S, Balguerie X, Goldenberg A, et al Novel and recurrent non-

truncating mutations of the MITF basic domain: genotypic and phenotypic

variations in Waardenburg and Tietz syndromes Eur J Hum Genet 2012;

20(5):584–7.

149 Yang S, Dai P, Liu X, et al Genetic and phenotypic heterogeneity in

Chinese patients with Waardenburg syndrome type II PLoS ONE 2013;8(10):

e77149.

150 Nye JS, Balkin N, Lucas H, et al Myelomeningocele and Waardenburg

syn-drome (type 3) in patients with interstitial deletions of 2q35 and the RAX3

gene: possible digenic inheritance of a neural tube defect Am J Med Genet

1998;75(4):401–8.

151 Viñuela A, Morín M, Villamar M, et al Genetic and phenotypic heterogeneity

in two novel cases of Waardenburg syndrome type IV Am J Med Genet

2009;149A(10):2296–302.

152 Arimoto Y, Namba K, Nakano A, et al Chronic constipation recognized as a

sign of a SOX10 mutation in a patient with Waardenburg syndrome Gene

2014;540(2):258–62.

153 Hofstra RM, Osinga J, Tan-Sindhunata G, et al A homozygous mutation in

the endothelin-3 gene associated with a combined Waardenburg type 2 and

Hirschsprung phenotype (Shah-Waardenburg syndrome) Nat Genet 1996;

12(4):445–7.

154 Boardman JR, Syrris R, Holder SE, et al A novel mutation in the endothelin B

receptor gene in a patient with Shah-Waardenburg syndrome and Down

syn-drome J Med Genet 2001;38(9):646–7.

155 Pingault V, Girard M, Bondurand N, et al SOX10 mutations in chronic

intesti-nal pseudo-obstruction suggest a complex physiopathological mechanism

Hum Genet 2002;111(2):198–206.

156 Inoue K, Shilo K, Boerkoel CF, et al Congenital hypomyelinating neuropathy,

central dysmyelination, and Waardenburg-Hirschsprung disease: phenotypes

linked by SOX10 mutation Ann Neurol 2002;52(6):836–42.

157 Suyugul Z, Tuysuz B, Tukenmez F, et al Waardenburg syndrome: variable

phe-notypic expression in monozygotic twins Clin Dysmorphol 1998;7(1):77–8.

158 Sleiman R, Kurban M, Succaria F, et al Poliosis circumscripta: overview and

underlying causes J Am Acad Dermatol 2013;69(4):625–33.

159 Radke P, Schimmenti LA, Schoonveld C, et al The unique association of iris

heterochromia with Hermansky-Pudlak syndrome J AAPOS 2013;17(5):

542–4.

160 DiMario FJ Jr, Sahin M, Ebrahimi-Fakhari D Tuberous sclerosis complex

Pediatr Clin North Am 2015;62(3):633–48.

161 Osborne JR, Fryer A, Webb D Epidemiology of tuberous sclerosis Ann NY Acad

164 Dabora SL, Jozwiak S, Franz DN, et al Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2 compared with TSC1, disease in multiple organs Am J Hum Genet 2001;68(1):64–80.

165 Teng JM, Cowen EW, Wataya-Kaneda M, et al Dermatologic and dental aspects

of the 2012 International Tuberous Sclerosis Complex Consensus Statements JAMA Dermatol 2014;150(10):1095–101.

166 Karabiber H, Sasmaz S, Turanli G, et al Prevalence of hypopigmented maculae and café-au-lait spots in idiopathic epileptic and healthy children J Child Neurol 2002;17(1):57–9.

167 Vanderhooft SL, Francis JS, Pagon RA, et al Prevalence of hypopigmented macules in a healthy population J Pediatr 1996;129(3):355–61.

168 Ahkami RN, Schwartz RA Nevus anemicus Dermatology 1999;198(4): 327–9.

169 Trauner MA, Ruben BS, Lynch PJ Segmental tuberous sclerosis presenting as unilateral facial angiofibromas J Am Acad Dermatol 2003;49(2 Suppl.): S164–6.

170 Aldrich CS, Hong CH, Groves L, et al Acral lesions in tuberous sclerosis complex: insights into pathogenesis J Am Acad Dermatol 2010;63(2): 244–51.

171 Quist SR, Franke I, Sutter C, et al Periungual fibroma (Koenen tumors) as isolated sign of tuberous sclerosis complex with tuberous sclerosis complex 1 germline mutation J Am Acad Dermatol 2010;62:159–61.

172 Darling TN, Skarulis MC, Steinberg SM, et al Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1 Arch Der- matol 1997;133(7):853–7.

173 Sakurai A, Matsumoto K, Ikeo Y, et al Frequency of facial angiofibromas in Japanese patients with multiple endocrine neoplasia type 1 Endocr J 2000; 47(5):569–73.

174 Agarwal SK, Lee Burns A, Sukhodolets KE, et al Molecular pathology of the

MEN1 gene Ann NY Acad Sci 2004;1014:189–98.

175 Schaffer JV, Gohara MA, McNiff JM, et al Multiple facial angiofibromas: a neous manifestation of Birt-Hogg-Dube syndrome J Am Acad Dermatol 2005;53:S108–11.

cuta-176 Hunter AG, Nezarati MM, Velsher L Absence of signs of systemic involvement

in four patients with bilateral multiple facial angiofibromas Am J Med Genet

A 2010;152A:657–64.

177 Chan JY, Wang KH, Fang CL Fibrous papule of the face, similar to tuberous sclerosis complex-associated angiofibroma, shows activation of the mamma- lian target of rapamycin pathway: evidence for a novel therapeutic strategy? PLoS ONE 2014;9(2):e89467.

178 Christophe C, Sekhara T, Rypens F, et al MRI spectrum of cortical tions in tuberous sclerosis complex Brain Dev 2000;22(8):487–93.

malforma-179 Torres OA, Roach ES, Delgado MR, et al Early diagnosis of subependymal giant cell astrocytoma in patients with tuberous sclerosis J Child Neurol 1998; 13(4):173–7.

180 Brook-Carter PT, Peral B, Ward CJ, et al Deletion of the TSC2 and PKD1 genes

associated with severe infantile polycystic kidney disease-A contiguous gene syndrome Nat Genet 1994;8(4):328–32.

181 Harding CO, Pagon RA Incidence of tuberous sclerosis in patients with cardiac rhabdomyoma Am J Med Genet 1990;37(4):443–6.

182 Hohman DW, Noghrehkar D, Ratnayake S Lymphangioleiomyomatosis: a review Eur J Intern Med 2008;19:319–24.

183 Krueger DA, Northrup H, International Tuberous Sclerosis Complex Consensus Group Tuberous sclerosis complex surveillance and management: recommen- dations of the 2012 International Tuberous Sclerosis Complex Consensus Con- ference Pediatr Neurol 2013;49(4):255–65.

184 Webb DW, Fryer AE, Osborne JR Morbidity associated with tuberous sclerosis:

a population study Dev Med Child Neurol 1996;38(2):146–55.

185 Tyburczy ME, Wang JA, Li S, et al Sun exposure causes somatic second-hit mutations and angiofibroma development in tuberous sclerosis complex Hum Mol Genet 2014;23(8):2023–9.

186 Papadavid E, Markey A, Bellaney G, Walker NP Carbon dioxide and pulsed dye laser treatment of angiofibromas in 29 patients with tuberous sclerosis Br J Dermatol 2002;147(2):337–42.

187 Haemel AK, O’Brian AL, Teng JM Topical rapamycin: a novel approach to facial angiofibromas in tuberous sclerosis Arch Dermatol 2010;146(7):715–18.

188 Balestri R, Neri I, Patrizi A, et al Analysis of current data on the use of topical rapamycin in the treatment of facial angiofibromas in tuberous sclerosis complex J Eur Acad Dermatol Venereol 2015;29(1):14–20.

189 Koenig MK, Hebert AA, Roberson J, et al Topical rapamycin therapy to alleviate the cutaneous manifestations of tuberous sclerosis complex: a double-blind, randomized, controlled trial to evaluate the safety and efficacy of topically applied rapamycin Drugs R D 2012;12(3):121–6.

190 Tanaka M, Wataya-Kaneda M, Nakamura A, et al First left-right comparative study of topical rapamycin vs vehicle for facial angiofibromas in patients with tuberous sclerosis complex Br J Dermatol 2013;169(6):1314–18.

191 Muzic JG, Kindle SA, Tollefson MM Successful treatment of subungual mas of tuberous sclerosis with topical rapamycin JAMA Dermatol 2014;150(9):1024–5.

fibro-192 Hofbauer GF, Marcollo-Pini A, Corsenca A, et al The mTOR inhibitor cin significantly improves facial angiofibroma lesions in a patient with tuberous sclerosis Br J Dermatol 2008;159:473–5.

rapamy-11  •  Disorders of Pigmentation

278.e4

193 Tarasewicz A, Debska-Slizien A, Konopa J, et al Rapamycin as a therapy of

choice after renal transplantation in a patient with tuberous sclerosis complex

Transplant Proc 2009;41:3677–82.

194 Korsaga-Somé N, Barro-Traoré F, Andonaba JB, et al Vitiligoid achromia after

temporary tattooing Int J Dermatol 2012;51(Suppl 1):54–6, 60–2.

195 Roehm PC, Perry JD, Girkin CA, Miller NR Prevalence of periocular

depigmen-tation after repeated botulinum toxin A injections in African American

patients J Neuroophthalmol 1999;19(1):7–9.

196 Selvaag E Chloroquine-induced vitiligo-like depigmentation Ann Trop

Paedi-atr 1997;17(1):45–8.

197 Raanani R, Goldman JM, Ben-Bassat I Challenges in oncology Case 3

Depig-mentation in a chronic myeloid leukemia patient treated with STI-571 J Clin

Oncol 2002;20(3):869–70.

198 Brazzelli V, Grasso V, Barbaccia V, et al Hair depigmentation and vitiligo-like

lesions in a leukaemic paediatric patient during chemotherapy with dasatinib

Acta Derm Venereol 2012;92(2):218–19.

199 Martinez-Ruiz E, Ortega C, Calduch L, et al Generalized cutaneous

depigmen-tation following sulfamide-induced drug eruption Dermatology 2000;201(3):

252–4.

200 Gordon S, LaTorre A, Witman P Persistent pediatric contact leukoderma after

exposure to butterfly electrocardiogram back pad: a report of three cases

Pediatr Dermatol 2013;30(6):e169–71.

201 Oyama M, Shimizu H, Ohata Y, et al Dyschromatosis symmetrica hereditaria

(reticulate acropigmentation of Dohi): report of a Japanese family with the

condition and a literature review of 185 cases Br J Dermatol 1999;140(3):

491–6.

202 Kondo T, Suzuki T, Ito S, et al Dyschromatosis symmetrica hereditaria

associ-ated with neurological disorders J Dermatol 2008;35:662–6.

203 Kaliyadan F, Vinayan KP, Fernandes B, et al Acral dyschromatosis with

devel-opmental regression and dystonia in a seven-year-old child: dyschromatosis

symmetrica hereditaria variant or a new syndrome? Indian J Dermatol

Vene-reol Leprol 2009;75:412–14.

204 Suzuki N, Suzuki T, Inagaki K, et al Mutation analysis of the ADAR1 gene in

dyschromatosis symmetrica hereditaria and genetic differentiation from both

dyschromatosis universalis hereditaria and acropigmentatio reticularis

J Invest Dermatol 2005;124:1186–92.

205 Li M, Yang L, Li C, et al Mutational spectrum of the ADAR1 gene in

dyschromatosis symmetrica hereditaria Arch Dermatol Res 2010;302(6):

469–76.

206 Miyamura Y, Suzuki X, Kono M, et al Mutations of the RNA-specific adenosine

deaminase gene (DSRAD) are involved in dyschromatosis symmetrica

heredi-taria Am J Hum Genet 2003;73(3):693–9.

207 He PP, He CD, Cui Y, et al Refined localization of dyschromatosis symmetrica

hereditaria gene to a 9.4-cM region at 1 q21–q22 and a literature review of

136 cases reported in China Br J Dermatol 2004;150(4):633–9.

208 Kono M, Sugiura K, Suganuma M, et al Whole-exome sequencing identifies

ADAM10 mutations as a cause of reticulate acropigmentation of Kitamura,

a clinical entity distinct from Dowling-Degos disease Hum Mol Genet

2013;22:3524–33.

209 Schnur RE, Heymann WR Reticulate hyperpigmentation Semin Cutan Med

Surg 1997;16(1):72–80.

210 Kawakami T, Otaguchi R, Kyoya M, et al Patient with dyschromatosis

sym-metrica hereditaria treated with miniature punch grafting, followed by excimer

light therapy J Dermatol 2013;40(9):771–2.

211 Zhang C, Li D, Zhang J, et al Mutations in ABCB6 cause dyschromatosis

uni-versalis hereditaria J Invest Dermatol 2013;133(9):2221–8.

212 Amyere M, Vogt T, Hoo J, et al KITLG mutations cause familial progressive

hyper- and hypopigmentation J Invest Dermatol 2011;131(6):1234–9.

213 Xing QH, Wang MT, Chen XD, et al A gene locus responsible for

dyschromato-sis symmetrica hereditaria (DSH) maps to chromosome 6q24.2-q25.2 Am J

Hum Genet 2003;73(2):377–82.

214 Zhou D, Wei Z, Deng S, et al SASH1 regulates melanocyte transepithelial

migration through a novel Gαs-SASH1-IQGAP1-E-Cadherin dependent

pathway Cell Signal 2013;25(6):1526–38.

215 Courcet JB, Elalaoui SC, Duplomb L, et al Autosomal recessive SASH1 variants

associated with a new genodermatosis with pigmentation defects,

palmoplan-tar keratoderma and skin carcinoma Eur J Hum Genet 2015;23(7):

957–62.

216 Nogita T, Mitsuhashi Y, Takeo C, et al Removal of facial and labial lentigines in

dyschromatosis universalis hereditaria with a Q-switched alexandrite laser

J Am Acad Dermatol 2011;65(2):e61–3.

217 Ades LC, Rogers M, Sillence DO An X-linked reticulate pigmentary disorder

with systemic manifestations: report of a second family Pediatr Dermatol

1993;10(4):344–51.

218 Urabe K, Hori Y Dyschromatosis Semin Cutan Med Surg 1997;16(1):81–5.

219 Garg T, Chander R, Jabeen M, et al Amyloidosis cutis dyschromica: a rare

pigmentary disorder J Cutan Pathol 2011;38(10):823–6.

220 Wu YH, Lin YC Generalized Dowling-Degos disease J Am Acad Dermatol

2007;57:327–34.

221 Kim YC, Davis MD, Schanbacher CF, Su WR Dowling-Degos disease (reticulate

pigmented anomaly of the flexures): a clinical and histopathologic study of 6

cases J Am Acad Dermatol 1999;40(3):462–7.

222 Li M, Cheng R, Liang J, et al Mutations in POFUT1, encoding protein

O-fucosyltransferase 1, cause generalized Dowling-Degos disease Am J Hum

Genet 2013;92:895–903.

223 Basmanav FB, Oprisoreanu AM, Pasternack SM, et al Mutations in POGLUT1,

encoding protein O-glucosyltransferase 1, cause autosomal dominant Degos disease Am J Hum Genet 2014;94:135–43.

Dowling-224 Lugassy J, McGrath JA, Itin P, et al KRT14 haploinsufficiency results in

increased susceptibility of keratinocytes to TNF-alpha-induced apoptosis and causes Naegeli-Franceschetti-Jadassohn syndrome J Invest Dermatol 2008;128:1517–24.

225 Lugassy J, Itin P, Ishida-Yamamoto A, et al Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal

dysplasias caused by dominant mutations in KRT14 Am J Hum Genet

2006;79:724–30.

226 Sprecher E, Itin P, Whittock NV, et al Refined mapping of Jadassohn syndrome to a 6 cM interval on chromosome 17q11.2-q21 and investigation of candidate genes J Invest Dermatol 2002;119(3):692–8.

Naegeli-Franceschetti-227 Itin PH, Lautenschlager S Genodermatosis with reticulate, patchy and mottled pigmentation of the neck: a clue to rare dermatologic disorders Dermatology 1998;197(3):281–90.

228 Barnette DJ Jr, Yeager JK A progressive asymptomatic hyperpigmented papular eruption: confluent and reticulated papillomatosis (CRP) of Gougerot and Car- teaud Arch Dermatol 1993;129(12):1608–9, 1611–2.

229 Berlin AL, Paller AS, Chan LS Incontinentia pigmenti: a review and update

on the molecular basis of pathophysiology J Am Acad Dermatol 2002;47(2): 169–87, quiz 188–90.

230 Hadj-Rabia S, Froidevaux D, Bodak N, et al Clinical study of 40 cases of tinentia pigmenti Arch Dermatol 2003;139(9):1163–70.

incon-231 Scheuerle A, Nelson DL Incontinentia pigmenti In: Pagon RA, Bird TC, Dolan

CR, et al., editors GeneReviews [Internet] Seattle: University of Washington; 1993–1999 June 8 [updated January 28, 2008].

232 Smahi A, Courtois G, Vabres R, et al Genomic rearrangement in NEMO

impairs NF-kappaB activation and is a cause of incontinentia pigmenti The International Incontinentia Pigmenti (IP) Consortium Nature 2000; 405(6785):466–72.

233 Fusco F, Bardaro T, Fimiani G, et al Molecular analysis of the genetic defect in

a large cohort of IP patients and identification of novel NEMO mutations

inter-fering with NF-kappaB activation Hum Mol Genet 2004;13(16):1763–73.

234 Minić S, Trpinac D, Obradović M Incontinentia pigmenti diagnostic criteria update Hum Mutat 2014;35(2):165–77.

235 Dufke A, Vollmer B, Kendziorra H, et al Hydrops fetalis in three male fetuses

of a female with incontinentia pigmenti Prenat Diagn 2001;21(12): 1019–21.

236 Prendiville JS, Gorski JL, Stein CK, Esterly NB Incontinentia pigmenti in a male infant with Klinefelter syndrome J Am Acad Dermatol 1989;20(5 Pt 2):937–40.

237 Kenwrick S, Woffendin H, Jakins T, et al Survival of male patients with incontinentia pigmenti carrying a lethal mutation can be explained by somatic mosaicism or Klinefelter syndrome Am J Hum Genet 2001;69(6): 1210–17.

238 Pacheco TR, Levy M, Collyer JC, et al Incontinentia pigmenti in male patients

J Am Acad Dermatol 2006;55:251–5.

239 Ardelean D, Pope E Incontinentia pigmenti in boys: a series and review of the literature Pediatr Dermatol 2006;23:523–7.

240 Fusco F, Fimiani G, Tadini G, et al Clinical diagnosis of incontinentia pigmenti

in a cohort of male patients J Am Acad Dermatol 2007;56:264–7.

241 Darne S, Carmichael AJ Isolated recurrence of vesicobullous incontinentia pigmenti in a schoolgirl Br J Dermatol 2007;156:600–2.

242 Alikhan A, Lee AD, Swing D, et al Vaccination as a probable cause of nentia pigmenti reactivation Pediatr Dermatol 2010;27:62–4.

243 Wu JJ, Su YN, Hsiao CH, et al Macular amyloidosis presenting in an nentia pigmenti-like pattern with subepidermal blister formation J Eur Acad Dermatol Venereol 2008;22:635–7.

inconti-244 Pezzani L, Brena M, Callea M, et al X-linked reticulate pigmentary disorder with systemic manifestations: a new family and review of the literature Am J Med Genet A 2013;161A(6):1414–20.

245 Ciarallo L, Paller AS Two cases of incontinentia pigmenti simulating child abuse Pediatrics 1997;100(4):E6.

246 Fraitag S, Rimella A, de Prost Y, et al Skin biopsy is helpful for the diagnosis of incontinentia pigmenti at late stage (IV): a series of 26 cutaneous biopsies

J Cutan Pathol 2009;36:966–71.

247 Montes CM, Maize JC, Guerry-Force ML Incontinentia pigmenti with painful subungual tumors: a two-generation study J Am Acad Dermatol 2004; 50(2 Suppl.):S45–52.

248 Pena ZG, Brewer JD Multiple subungual squamous cell carcinomas in a patient with incontinentia pigmenti Dermatol Surg 2014;40(10):1159–61.

249 Minić S, Trpinac D, Gabriel H, et al Dental and oral anomalies in incontinentia pigmenti: a systematic review Clin Oral Investig 2013;17(1):1–8.

250 Bergendal B Orodental manifestations in ectodermal dysplasia-a review Am J Med Genet A 2014;164A(10):2465–71.

251 Minić S, Trpinac D, Obradović M Systematic review of central nervous system anomalies in incontinentia pigmenti Orphanet J Rare Dis 2013;8:25.

252 Meuwissen ME, Mancini GM Neurological findings in incontinentia pigmenti;

a review Eur J Med Genet 2012;55(5):323–31.

253 Hennel SJ, Ekert PG, Volpe JJ, Inder TE Insights into the pathogenesis of bral lesions in incontinentia pigmenti Pediatr Neurol 2003;29(2):148–50.

cere-254 Cartwright MS, White DL, Miller LM, et al Recurrent stroke in a child with incontinentia pigmenti J Child Neurol 2009;24:603–5.

11  •  Disorders of Pigmentation 278.e5

255 Pizzamiglio MR, Piccardi L, Bianchini F, et al Incontinentia pigmenti: learning

disabilities are a fundamental hallmark of the disease PLoS ONE 2014;

9(1):e87771.

256 Wong GA, Willoughby CE, Parslew R, Kaye SB The importance of screening

for sight-threatening retinopathy in incontinentia pigmenti Pediatr Dermatol

2004;21(3):242–5.

257 Shah PK, Bachu S, Narendran V, et al Intravitreal bevacizumab for

incontinentia pigmenti J Pediatr Ophthalmol Strabismus 2013;50:Online

e52–4.

258 Wolf DS, Golden WC, Hoover-Fong J, et al High-dose glucocorticoid therapy in

the management of seizures in neonatal incontinentia pigmenti: a case report

J Child Neurol 2015;30(1):100–6.

259 Hadj-Rabia S, Rimella A, Smahi A, et al Clinical and histological features of

incontinentia pigmenti in adults with nuclear factor-κB essential modulator

gene mutations J Am Acad Dermatol 2011;64(3):508–15.

260 Chan YC, Happle R, Giam YC Whorled scarring alopecia: a rare phenomenon

in incontinentia pigmenti? J Am Acad Dermatol 2003;49(5):929–31.

261 Nicolaou N, Graham-Brown RA Nail dystrophy, an unusual presentation of

incontinentia pigmenti Br J Dermatol 2003;149(6):1286–8.

262 Pettigrew R, Kuo HC, Scriven R, et al A pregnancy following PGD for X-linked

dominant [correction of X-linked autosomal dominant] incontinentia pigmenti

(Bloch-Sulzberger syndrome): case report Hum Reprod 2000;15(12):

2650–2.

263 Kaya TI, Tursen U, Ikizoglu G Therapeutic use of topical corticosteroids in the

vesiculobullous lesions of incontinentia pigmenti Clin Exp Dermatol

2009;34:e611–13.

264 Jessup CJ, Morgan SC, Cohen LM, et al Incontinentia pigmenti: treatment of

IP with topical tacrolimus J Drugs Dermatol 2009;8:944–6.

265 Ranchod TM, Trese MT Regression of retinal neovascularization after laser

photocoagulation in incontinentia pigmenti Retina 2010;30(4):708–9.

266 Lin KL, Hirose T, Kroll AJ, et al Prospects for treatment of pediatric vitreoretinal

diseases with vascular endothelial growth factor inhibition Semin Ophthalmol

269 Happle R Mosaicism in human skin: understanding the patterns and

mecha-nisms Arch Dermatol 1993;129(11):1460–70.

270 Gonzalez-Ensenat MA, Vicente A, Poo P, et al Phylloid hypomelanosis and

mosaic partial trisomy 13: two cases that provide further evidence of a distinct

clinicogenetic entity Arch Dermatol 2009;145:576–8.

271 Dhar SU, Robbins-Furman P, Levy ML, et al Tetrasomy 13q mosaicism

associ-ated with phylloid hypomelanosis and precocious puberty Am J Med Genet A

2009;149A:993–6.

272 Akiyama M, Aranami A, Sasaki Y, et al Familial linear and whorled nevoid

hypermelanosis J Am Acad Dermatol 1994;30(5 Pt 2):831–3.

273 Sybert VR Hypomelanosis of Ito: a description, not a diagnosis J Invest

Der-matol 1994;103(5 Suppl.):141S–143S.

274 Taibjee SM, Hall D, Balderson D, et al Keratinocyte cytogenetics in 10 patients

with pigmentary mosaicism: identification of one case of trisomy 20 mosaicism

confined to keratinocytes Clin Exp Dermatol 2009;34:823–9.

275 Lipsker D, Flory E, Wiesel ML, et al Between light and dark, the chimera comes

out Arch Dermatol 2008;144:327–30.

276 Nehal KS, PeBenito R, Orlow SJ Analysis of 54 cases of hypopigmentation and

hyperpigmentation along the lines of Blaschko Arch Dermatol 1996;

132(10):1167–70.

277 Delaporte E, Janin A, Blondel V, et al Linear and whorled nevoid

hypermelano-sis versus incontinentia pigmenti: is pigmentary incontinence really a

distinc-tive feature? Dermatology 1996;192(1):70–2.

278 Carpo BG, Grevelink JM, Grevelink SV Laser treatment of pigmented lesions in

children Semin Cutan Med Surg 1999;18(3):233–43.

279 Bastiaens M, ter Huurne J, Gruis N, et al The melanocortin-1-receptor gene is

the major freckle gene Hum Mol Genet 2001;10(16):1701–8.

280 Grim KD, Wasko CA Symmetrical bilateral Becker melanosis: a rare

presenta-tion Dermatol Online J 2009;15:1.

281 Khatami A, Seradj MH, Gorouhi F, et al Giant bilateral Becker nevus: a rare

presentation Pediatr Dermatol 2008;25:47–51.

282 Kim YJ, Han JH, Kang HY, et al Androgen receptor overexpression in Becker

nevus: histopathologic and immunohistochemical analysis J Cutan Pathol

2008;35:1121–6.

283 Angelo C, Grosso MG, Stella R, et al Becker’s nevus syndrome Cutis

2001;68(2):123–4.

284 Sharma R, Mishra A Becker’s naevus with ipsilateral areolar hypoplasia in

three males Br J Dermatol 1997;136(3):471–2.

285 Santos-Juanes J, Galache C, Curto JR, et al Acneiform lesions in Becker’s nevus

and breast hypoplasia Int J Dermatol 2002;41(10):699–700.

286 Happle R, Koopman RJ Becker nevus syndrome Am J Med Genet

1997;68(3):357–61.

287 Lapidoth M1, Adatto M, Cohen S, et al Hypertrichosis in Becker’s nevus:

effec-tive low-fluence laser hair removal Lasers Med Sci 2014;29(1):191–3.

288 Okulicz JF, Schwartz RA, Jozwiak S Lentigo Cutis 2001;67(5):367–70.

289 Hickey JR, Robson A, Barker JN, et al Does topical tacrolimus induce lentigines

in children with atopic dermatitis? A report of three cases Br J Dermatol

2005;152(1):152–4.

290 Castelo-Soccio L, Di Marcantonio D, Shah P, et al Induced lentiginosis with use

of topical calcineurin inhibitors Arch Dermatol 2012;148(6):766–8.

291 Campbell T, Felsten L, Moore J Disappearance of lentigines in a patient ing imatinib treatment for familial gastrointestinal stromal tumor syndrome Arch Dermatol 2009;145:1313–16.

receiv-292 Betti R, Inselvini E, Palvarini M, Crosti C Agminated intradermal Spitz nevi arising on an unusual speckled lentiginous nevus with localized lentiginosis: a continuum? Am J Dermatopathol 1997;19(5):524–7.

293 Kopacova M, Tacheci I, Rejchrt S, et al Peutz-Jeghers syndrome: diagnostic and therapeutic approach World J Gastroenterol 2009;15:5397–408.

294 Olschwang S, Boisson C, Thomas G Peutz-Jeghers families unlinked to STK11/ LKB1 gene mutations are highly predisposed to primitive biliary adenocarci-

noma J Med Genet 2001;38(6):356–60.

295 Morrison PT, Donnelly DE, Morrison PJ Umbilical pigmentation in Jeghers syndrome Clin Dysmorphol 2014;23(3):114–15.

Peutz-296 Cunningham JD, Vine AJ, Karch L, Aisenberg J The role of laparoscopy in the management of intussusception in the Peutz-Jeghers syndrome: case report and review of the literature Surg Laparosc Endosc 1998;8(1):17–20.

297 van Lier MG, Mathus-Vliegen EM, Wagner A, et al High cumulative risk of intussusception in patients with Peutz-Jeghers syndrome: time to update sur- veillance guidelines? Am J Gastroenterol 2011;106:940–5.

298 Vogel T, Schumacher V, Saleh A, et al Extraintestinal polyps in Peutz-Jeghers syndrome: presentation of four cases and review of the literature Deutsche Peutz-Jeghers-Studiengruppe Int J Colorectal Dis 2000;15(2):118–23.

299 Alikasifoglu A, Gonc EN, Akcoren Z, et al Feminizing Sertoli cell tumor ated with Peutz-Jeghers syndrome J Pediatr Endocrinol Metab 2002;15(4): 449–52.

associ-300 Goldstein SA, Hoffenberg EJ Peutz-Jegher syndrome in childhood: need for updated recommendations? J Pediatr Gastroenterol Nutr 2013;56(2): 191–5.

301 Hemminki A The molecular basis and clinical aspects of Peutz-Jeghers drome Cell Mol Life Sci 1999;55(5):735–50.

syn-302 Barnard J Screening and surveillance recommendations for pediatric testinal polyposis syndromes J Pediatr Gastroenterol Nutr 2009;48(Suppl 2):S75–8.

gastroin-303 Vidal I, Podevin G, Piloquet H, et al Follow-up and surgical management of Peutz-Jeghers syndrome in children J Pediatr Gastroenterol Nutr 2009;48: 419–25.

304 Kato S, Takeyama J, Tanita Y, Ebina K Ruby laser therapy for labial lentigines

in Peutz-Jeghers syndrome Eur J Pediatr 1998;157(8):622–4.

305 Remington BK, Remington TK Treatment of facial lentigines in Peutz-Jeghers syndrome with an intense pulsed light source Dermatol Surg 2002;28(11): 1079–81.

306 Lema B, Najarian DJ, Lee M, et al JAAD grand rounds quiz: numerous pigmented macules of the oral mucosa J Am Acad Dermatol 2010;62(1): 171–3.

hyper-307 Mignogna MD, Lo Muzio L, Ruoppo E, et al Oral manifestations of idiopathic lenticular mucocutaneous pigmentation (Laugier-Hunziker syndrome): a clinical, histopathological and ultrastructural review of 12 cases Oral Dis 1999;5(1):80–6.

308 Salpea P, Stratakis CA Carney complex and McCune Albright syndrome: an overview of clinical manifestations and human molecular genetics Mol Cell Endocrinol 2014;386(1–2):85–91.

309 Koopman RJ, Happle R Autosomal dominant transmission of the NAME drome (nevi, atrial myxoma, mucinosis of the skin and endocrine overactivity) Hum Genet 1991;86(3):300–4.

syn-310 Rhodes AR, Silverman RA, Harrist TJ, Perez-Atayde AR Mucocutaneous tigines, cardiomucocutaneous myxomas, and multiple blue nevi: the “LAMB” syndrome J Am Acad Dermatol 1984;10(1):72–82.

len-311 Stratakis CA, Horvath A Carney complex In: Pagon RA, Bird TC, Dolan CR,

et al., editors GeneReviews [Internet] Seattle: University of Washington; 1993 [updated January 10, 2008].

312 Horvath A, Stratakis CA Carney complex and lentiginosis Pigment Cell noma Res 2009;22:580–7.

Mela-313 Boikos SA, Stratakis CA Carney complex: pathology and molecular genetics Neuroendocrinology 2006;83:189–99.

314 Mateus C, Palangie A, Franck N, et al Heterogeneity of skin manifestations in patients with Carney complex J Am Acad Dermatol 2008;59:801–10.

315 Stratakis CA, Papageorgiou T, Premkumar A, et al Ovarian lesions in Carney complex: clinical genetics and possible predisposition to malignancy J Clin Endocrinol Metab 2000;85(11):4359–66.

316 Stratakis CA, Carney JA, Kirschner LS, et al Synaptophysin immunoreactivity

in primary pigmented nodular adrenocortical disease: neuroendocrine ties of tumors associated with Carney complex J Clin Endocrinol Metab 1999;84(3):1122–8.

proper-317 Richey JD, Bradish JR, Lacy SR, et al Carney syndrome in a patient previously considered to have Peutz-Jeghers syndrome J Am Acad Dermatol 2014; 70(2):e44–6.

318 O’Grady TC, Barr RJ, Billman G, Cunningham BB Epithelioid blue nevus ring in children with no evidence of Carney complex Am J Dermatopathol 1999;21(5):483–6.

occur-319 Briassoulis G, Quezado M, Lee CC, et al Myxoma of the ear lobe in a old girl with Carney complex J Cutan Pathol 2012;39(1):68–71.

23-month-320 Martí N, Jordá E, Monteagudo C, et al Multiple cutaneous angiomyxomas in a child Pediatr Dermatol 2011;28(4):462–4.

11  •  Disorders of Pigmentation

278.e6

321 Carney JA, Stratakis CA Epithelioid blue nevus and psammomatous melanotic

schwannoma: the unusual pigmented skin tumors of the Carney complex

Semin Diagn Pathol 1998;15(3):216–24.

322 Armstrong DK, Irvine AD, Handley JM, et al Carney complex: report of a

kindred with predominantly cutaneous manifestations Br J Dermatol

1997;136(4):578–82.

323 Kirschner LS, Carney JA, Pack SD, et al Mutations of the gene encoding the

protein kinase A type 1-alpha regulatory subunit in patients with the Carney

complex Nat Genet 2000;26(1):89–92.

324 Coppin BD, Temple IK Multiple lentigines syndrome (LEOPARD syndrome or

progressive cardiomyopathic lentiginosis) J Med Genet 1997;34(7):582–6.

325 Arnsmeier SL, Paller AS Pigmentary anomalies in the multiple lentigines

syn-drome: is it distinct from LEOPARD syndrome? Pediatr Dermatol 1996;13(2):

100–4.

326 Staub J, Behnecke A, Leverkus M Delayed primary diagnosis of LEOPARD

syn-drome type 1 J Am Acad Dermatol 2013;68(2):e58–60.

327 Santoro C, Pacileo G, Limongelli G, et al LEOPARD syndrome: clinical

dilemmas in differential diagnosis of RASopathies BMC Med Genet 2014;

15:44.

328 Gelb BD, Tartaglia M LEOPARD syndrome In: Pagon RA, Bird TC, Dolan CR,

et al., editors GeneReviews [Internet] Seattle: University of Washington; 1993

[November 30, 2007].

329 Digilio MC, Conti E, Sarkozy A, et al Grouping of multiple-lentigines/LEOPARD

and Noonan syndromes on the PTPN11 gene Am J Hum Genet 2002;71(2):

389–94.

330 Sarkozy A, Conti E, Digilio MC, et al Clinical and molecular analysis of 30

patients with multiple lentigines LEOPARD syndrome J Med Genet

2004;41(5):e68.

331 Nishi E, Mizuno S, Nanjo Y, et al A novel heterozygous MAP2K1 mutation in

a patient with Noonan syndrome with multiple lentigines Am J Med Genet A

2015;167(2):407–11.

332 Pacheco TR, Oreskovich N, Fain P Genetic heterogeneity in the multiple

lentigines/LEOPARD/Noonan syndromes Am J Med Genet A 2004;127A:

324–6.

333 Sigg C, Pelloni F, Schnyder UW Frequency of congenital nevi, nevi spili and

café-au-lait spots and their relation to nevus count and skin complexion in 939

children Dermatologica 1990;180(3):118–23.

334 Tekin M, Bodurtha JN, Riccardi VM Café-au-lait spots: the pediatrician’s

per-spective Pediatr Rev 2001;22(3):82–90.

335 Landau M, Krafchik BR The diagnostic value of café-au-lait macules J Am

Acad Dermatol 1999;40(6 Pt 1):877–90, quiz 891–2.

336 McLean DI, Gallagher RR “Sunburn” freckles, café-au-lait macules, and other

pigmented lesions of schoolchildren: the Vancouver Mole Study J Am Acad

Dermatol 1995;32(4):565–70.

337 Wintermeier K, von Poblotzki M, Genzel-Boroviczény O, et al Neonatal blue

light phototherapy increases café-au-lait macules in preschool children Eur J

Pediatr 2014;173(11):1519–25.

338 Pichard DC, Boyce AM, Collins MT, et al Oral pigmentation in

McCune-Albright syndrome JAMA Dermatol 2014;150(7):760–3.

339 Narumi S, Matsuo K, Ishii T, et al Quantitative and sensitive detection of GNAS

mutations causing McCune-Albright syndrome with next generation

sequenc-ing PLoS ONE 2013;8(3):e60525.

340 Perkins RM, Hoang-Xuan MT The Russell-Silver syndrome: a case report and

brief review of the literature Pediatr Dermatol 2002;19(6):546–9.

341 Hennekam RC, Holtus FJ Johnson-McMillin syndrome: report of another

family Am J Med Genet 1993;47(5):714–16.

342 Torrelo A, Requena C, Mediero IG, Zambrano A Schamberg’s purpura in

chil-dren: a review of 13 cases J Am Acad Dermatol 2003;48(1):31–3.

343 Williams VC, Lucas J, Babcock MA, et al Neurofibromatosis type 1 revisited

Pediatrics 2009;123:124–33.

344 Boyd KP, Korf BR, Theos A Neurofibromatosis type 1 J Am Acad Dermatol

2009;61:1–14, quiz 15–6.

345 Hirbe AC, Gutmann DH Neurofibromatosis type 1: a multidisciplinary

approach to care Lancet Neurol 2014;13(8):834–43.

346 Mulvihill JJ, Parry DM, Sherman JL, et al NIH conference: neurofibromatosis

1 (Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic

neuro-fibromatosis) An update Ann Intern Med 1990;113(1):39–52.

347 Lu-Emerson C, Plotkin SR The neurofibromatoses Part 2 NF2 and

schwanno-matosis Rev Neurol Dis 2009;6:E81–6.

348 North KN Neurofibromatosis 1 in childhood Semin Pediatr Neurol 1998;

351 Friedman JM Neurofibromatosis 1: clinical manifestations and diagnostic

cri-teria J Child Neurol 2002;17(8):548–54.

352 Hirokawa Y, Tikoo A, Huynh J, et al A clue to the therapy of neurofibromatosis

type 2: NF2/merlin is a PAK1 inhibitor Cancer J 2004;10(1):20–6.

353 Mautner VF, Lindenau M, Baser ME, et al Skin abnormalities in

neurofibroma-tosis 2 Arch Dermatol 1997;133(12):1539–43.

354 MacCollin M, Mautner VF The diagnosis and management of

neurofibromato-sis 2 in childhood Semin Pediatr Neurol 1998;5(4):243–52.

355 Nunes F, MacCollin M Neurofibromatosis 2 in the pediatric population J Child

Neurol 2003;18(10):718–24.

356 Seki Y, Umezu H, Usui M, et al Restoration of hearing with an auditory stem implant in a patient with neurofibromatosis type 2: case report Neurol Med Chir (Tokyo) 2000;40(10):524–7.

brain-357 Crowe FW, Schull WJ Diagnostic importance of the café-au-lait spot in fibromatosis Arch Intern Med 1963;91:758–66.

neuro-358 Pemov A, Sung H, Hyland PL, et al Genetic modifiers of neurofibromatosis type 1-associated café-au-lait macule count identified using multi-platform analysis PLoS Genet 2014;10(10):e1004575.

359 De Schepper S, Boucneau J, Vander Haeghen Y, et al Café-au-lait spots in rofibromatosis type 1 and in healthy control individuals: hyperpigmentation of

neu-a different kind? Arch Dermneu-atol Res 2006;297:439–49.

360 Crowe FW Axillary freckling as a diagnostic aid in neurofibromatosis Ann Intern Med 1962;61:1142–3.

361 Messiaen L, Yao S, Brems H, et al Clinical and mutational spectrum of fibromatosis type 1-like syndrome JAMA 2009;302:2111–18.

neuro-362 Stevenson D, Viskochil D Pigmentary findings in neurofibromatosis type 1-like syndrome (Legius syndrome): potential diagnostic dilemmas JAMA 2009; 302:2150–1.

363 Yang FC, Ingram DA, Chen S, et al Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for NF1+/− mast cells J Clin Invest 2003;112(12):1851–61.

364 Viskochil DH It takes two to tango: mast cell and Schwann cell interactions in neurofibromas J Clin Invest 2003;112(12):1791–3.

365 Khosrotehrani K, Bastuji-Garin S, Zeller J, et al Clinical risk factors for ity in patients with neurofibromatosis 1: a cohort study of 378 patients Arch Dermatol 2003;139(2):187–91.

mortal-366 Sbidian E, Hadj-Rabia S, Riccardi VM, et al Clinical characteristics predicting internal neurofibromas in 357 children with neurofibromatosis-1: results from

a cross-sectional study Orphanet J Rare Dis 2012;7:62.

367 Korf BR Plexiform neurofibromas Am J Med Genet 1999;89(1):31–7.

368 Cassiman C, Legius E, Spileers W, et al Ophthalmological assessment of dren with neurofibromatosis type 1 Eur J Pediatr 2013;172(10):1327–33.

chil-369 Avery RA, Dombi E, Hutcheson KA, et al Visual outcomes in children with neurofibromatosis type 1 and orbitotemporal plexiform neurofibromas Am J Ophthalmol 2013;155(6):1089–94.

370 Dasgupta B, Gutmann DH Neurofibromatosis 1: closing the GAP between mice

and men Curr Opin Genet Dev 2003;13(1):20–7.

371 Fenot M, Stalder JF, Barbarot S Juvenile xanthogranulomas are highly lent but transient in young children with neurofibromatosis type 1 J Am Acad Dermatol 2014;71(2):389–90.

preva-372 Ferrari F, Masurel A, Olivier-Faivre L, et al Juvenile xanthogranuloma and nevus anemicus in the diagnosis of neurofibromatosis type 1 JAMA Dermatol 2014;150(1):42–6.

373 Tadini G, Brena M, Pezzani L, et al Anemic nevus in neurofibromatosis type 1 Dermatology 2013;226(2):115–18.

374 Cutting LE, Koth CW, Denckla MB How children with neurofibromatosis type

1 differ from “typical” learning disabled clinic attenders: nonverbal learning disabilities revisited Dev Neuropsychol 2000;17(1):29–47.

375 Koth CW, Cutting LE, Denckla MB The association of neurofibromatosis type

1 and attention deficit hyperactivity disorder Neuropsychol Dev Cogn Sect C Child Neuropsychol 2000;6(3):185–94.

376 Barton B, North K Social skills of children with neurofibromatosis type 1 Dev Med Child Neurol 2004;46(8):553–63.

377 Garg S, Green J, Leadbitter K, et al Neurofibromatosis type 1 and autism trum disorder Pediatrics 2013;132(6):e1642–8.

spec-378 Hyman SL, Gill DS, Shores EA, et al Natural history of cognitive deficits and their relationship to MRI T2-hyperintensities in NF1 Neurology 2003;60(7): 1139–45.

379 Viola F, Villani E, Natacci F, et al Choroidal abnormalities detected by infrared reflectance imaging as a new diagnostic criterion for neurofibromato- sis 1 Ophthalmology 2012;119(2):369–75.

near-380 Goktas S, Sakarya Y, Ozcimen M, et al Frequency of choroidal abnormalities

in pediatric patients with neurofibromatosis type 1 J Pediatr Ophthalmol bismus 2014;51(4):204–8.

Stra-381 Tadini G, Milani D, Menni F, et al Is it time to change the neurofibromatosis 1 diagnostic criteria? Eur J Intern Med 2014;25(6):506–10.

382 Habiby R, Silverman B, Listernick R, Charrow J Precocious puberty in children with neurofibromatosis type 1 J Pediatr 1995;126(3):364–7.

383 Laithier V, Grill J, Le Deley MC, et al Progression-free survival in children with optic pathway tumors: dependence on age and the quality of the response to chemotherapy Results of the first French prospective study for the French Society of Pediatric Oncology J Clin Oncol 2003;21(24):4572–8.

384 King A, Listernick R, Charrow J, et al Optic pathway gliomas in tosis type 1: the effect of presenting symptoms on outcome Am J Med Genet 2003;122A(2):95–9.

neurofibroma-385 Astrup J Natural history and clinical management of optic pathway glioma

Br J Neurosurg 2003;17(4):327–35.

386 Rosser T, Packer RJ Intracranial neoplasms in children with neurofibromatosis

1 J Child Neurol 2002;17(8):630–7.

387 Turgut M, Ozcan OE, Bertan V Meningiomas in childhood and adolescence:

a report of 13 cases and review of the literature Br J Neurosurg 1997;11(6):501–7.

388 Wu BL, Austin MA, Schneider GH, et al Deletion of the entire NF1 gene

detected by the FISH: four deletion patients associated with severe tions Am J Med Genet 1995;59(4):528–35.