Ebook Vitiligo and other hypomelanoses of hair and skin: Part 2

(BQ) Part 2 book Vitiligo and other hypomelanoses of hair and skin presents the following contents: Hypomelanoses associated with nutritional and metabolic disorders, hypomelanosis associated with endocrine disorders, hypomelanosis secondary to irradiation and physical trauma, chemical hypomelanosis, miscellaneous hypomelanoses,....

SECTION 4 DISORDERS AFFECTING HAIR PIGMENTATION

WITHOUT AFFECTING SKIN PIGMENTATION

PREMOLAR APLASIA, HYPERHIDROSIS, AND CANITIES

PREMATURA

In 1950, Book [1] described 18 patients with a new autosomal dominant

syndrome with complete penetrance but somewhat variable expression and

characterized by bicuspid aplasia, premature whitening of the hair, and

hy-perhidrosis

Early whitening of the hair was found in all 18 cases Hair whitening began

in 14 patients before or at the age of 14 years, but onset varied from six to 23

years The whitening was uniform and never patchy The progression of

whiten-ing was usually slow, and in the older patients was always complete The scalp

hair was most constantly affected but in six of the 18 cases there was

con-spicuous whitening of axillary (five cases) and genital (six cases) hair and the

eyebrows and cilia (two cases) In 16 cases, the original hair color was specified

(seven were blond, four light brown, three dark brown, one red blond, and one

black) The hair was otherwise completely normal No depigmentation of the

skin was observed The author examined 63 members of this family and found

premature graying of the hair in seven who lacked other features of the

syn-drome All 18 patients had blue irides, but this is such a common trait in

Sweden that this observation may represent only coincidence Two-thirds of

the patients had a definite functional palmoplantar hyperhidrosis The most

striking feature was the involvement of the bicuspid teeth In nine patients, all

eight bicuspids were missing and no anlage could be detected by x-ray The

other patients were missing one to seven bicuspids In most cases, there was

a posterior displacement of the canines Deciduous teeth were present in all

cases

General health is unimpaired The pathogenesis is unknown No treatment

is available

FANCONI SYNDROME

Fanconi syndrome is vitamin-D-resistant rickets or osteomalacia with

hy-pophosphatemia, glucosuria, generalized aminoaciduria and generally chronic

acidosis, hypouricemia, and hypokalemia It may occur early (infantile form)

or later (adult form) in life

Fanconi syndrome may be idiopathic or associated with cystinosis, Lowe

syndrome, or tyrosinemia In a series of 24 patients reported by Cowie [2], 19

patients had cystinosis, four had cirrhosis and no cystinosis, and one had

neither Both groups of patients were found to have significantly fairer hair

electrospectrophotometrically than their siblings or than age-matched controls

Schneider and Seegmiller [3] noted that although these patients with

in-creased intracellular cystine often have blond hair and are significantly fairer

than their parents, they have much less tendency to sunburn than would be

expected for their degree of pigmentary dilution

461 GENETIC AND CONGENITAL DISORDERS

is characterized by acquired erythematous patches that develop atrophy, angiectasia, hypo- and hyperpigmentation, and sometimes warty keratosis [4,5] Other features include alopecia, photosensitivity, bilateral cataracts, short stat-ure, small skull, sometimes with birdlike features, and hypogonadism Life expectancy appears to be normal Premature canities is an inconstant feature

tel-of Rothmund-Thomson syndrome; it sometimes appears in adolescence and progresses rapidly

DYSTROPHIA MYOTONICA Canities occurring in the second or third decade may be seen in dystrophia myotonica [6], an entity that was first described in 1909 by Steinert [7] This rare disorder, which is inherited as an autosomal dominant disease, usually appears in the second or third decade and is characterized by myotonia, severe muscle wasting, cataracts, premature frontal baldness, and characteristic lu-gubrious physiognomy Testicular atrophy, various disorders of ovarian func-tion, and low basal metabolic rate are frequently observed Few of these patients survive beyond the sixth decade and death is often attributed to aspiration pneumonia or to cardiac conduction defects

PREMATURE AGING SYNDROMES Two of the premature aging syndromes, Werner syndrome (pangeria) and Hutchinson-Gilford syndrome (progeria), are characterized by premature gray-ing of hair

Werner Syndrome (Pangeria) Werner syndrome, which is a rare autosomal recessive disorder, was first described in 1904 in the thesis "Uber Kataract in Verbindung mit Sklerodermie" (Cataract in Combination with Scleroderma) by Otto Werner [8] Werner gave

a detailed description of four siblings with cataracts and sclerodermatous changes

as well as a senile appearance and graying beginning at about the age of 20 Males and females are equally affected The nature of the fundamental defect responsible for the disease is unknown

Pigmentary Disturbances Graying of hair is one of the earliest characteristic signs of the disease From a survey of 125 cases, Epstein et al [9] established that gray hair is first seen at about 20 years of age, while the mean age of onset is 25.3 years for

alteration of the voice, 30 years for detection of cataract formation, 33 years

for skin ulcers, and 34.2 years for diabetes mellitus Premature graying of hair

is rarely present before eight years of age

The graying generally first affects the temples and eyebrows, may require

from five to 20 years for maximal loss of pigment, and often progresses to

complete whiteness Baldness follows graying of the hair by several years

Other Clinical Features

Patients with Werner syndrome have a characteristic habitus with a

beak-shaped nose, stocky trunk with slender extremities, and short stature first

ap-parent in adolescence A weak, high-pitched voice is characteristic The skin

and subcutaneous tissues are atrophic with circumscribed hyperkeratosis

In-dolent ulcers often develop over malleoli of ankles, Achilles tendon, heels and

toes Most of the patients develop juvenile cataracts Hypogonadism and

dia-betes mellitus are frequently observed Generalized arteriosclerosis,

osteopo-rosis, calcifications of ligaments, tendons, and subcutaneous tissues may

de-velop prematurely The incidence of malignancy is increased and the life

expectancy is decreased

Diagnosis

The combination of the prematurely aged appearance, the other physical

features, the scleroderma-like skin changes, and the cataracts establish the

diagnosis [10] The other premature aging syndromes (metageria, acrogeria, total

lipodystrophy, and progeria) have a different clinical picture [11] Sclerosis of

the skin does not usually accompany Rothmund-Thomson syndrome

Obser-vation of early graying may alert the physician to other possible features

Hutchinson-Gilford Syndrome (Progeria)

This autosomal recessive disease was first described in 1886 by Hutchinson

[12] who reported a boy who had been bald since infancy and whose skin was

atrophic and wrinkled This child and another patient were subsequently

re-ported by Gilford [13], who first used the name "progeria."

Progeria is a rare condition occurring equally in both sexes The primary

defect responsible for the disease is unknown

Pigmentary Disturbances

In progeria, the hair is sparse and prematurely gray DeBusk [14] noted

that sparse, downy blond or white fuzz was present even if the original hair

was black

Other Clinical Features

Patients with this disease usually appear normal at birth During the first

year of life there is a profound failure to meet normal growth markers and

463

GENETIC AND CONGENITAL DISORDERS

464

CHAPTER 1

during the second year of life the characteristic facies (plucked-bird appearance with craniofacial disproportion, micronathia, and prominent eyes), alopecia, loss of subcutaneous fat, stiffness of joints and bones, skeletal abnormalities (pyriform thorax, coxa valga), cutaneous changes (diminution of subcutaneous fat and sclerodermatous skin), and abnormal dentition become apparent Motor and mental development is normal There is insulin resistance and increased basal metabolic rate Early death results from severe generalized arterioscle-rosis

Diagnosis

Progeria with its remarkably constant phenotypic expression can easily be distinguished from other premature aging syndromes Graying of the hair, when present, appears sooner than in Werner syndrome Cockayne syndrome differs from progeria by the presence of light sensitivity, disproportionate dwarfism, and absence of alopecia

No treatment is available

FISCH SYNDROME

Fisch [15] described a family with deafness and early, pronounced graying

of the hair Among 21 members of this family, two of the 10 who had early graying also had deafness Two other young children had only deafness and two others partial heterochromia irides Fisch observed similar cases and be-lieved this a genetically distinct syndrome Soussi Tsafir [16], arguing that none

of the 13 affected members of this family had dystopia canthorum, drew the same conclusion and distinguished this condition from Waardenburg syn-drome, which has a penetrance of 40% to 99% Other possible cases include those of Ballantyne [17] who noted that many of his patients with progressive high-tone deafness, among them a father and daughter and a brother and sister, had strikingly light blond hair and light blue eyes

KAPPA CHAIN DEFICIENCY

Bernier et al [18] reported a young girl with recurrent respiratory tions, diarrhea, white hair, extremely long white eyelashes, and very pale skin This was associated with a decreased concentration of immunoglobulins of one light chain type (kappa) Radiolabeled kappa and lamda type molecules survived equally well, suggesting that the synthesis of molecules bearing kappa chains was decreased

infec-HEREDITARY PREMATURE CANITIES

Premature graying of hair in individuals who are otherwise normal has been reported as an hereditary autosomal dominant trait Among six generations

in one family, nine individuals were involved In these cases, graying of scalp

and body hair appeared during the second decade or earlier, but did not affect

the eyebrows and eyelashes [19]

Bird-headed dwarfism is a rare autosomal recessive form of dwarfism

char-acterized by a bird-head profile, trident hands, skeletal defects, hypodontia,

and pancytopenia with hypersplenism Brown pigmentation with white

mac-ules has been reported in one Japanese infant [20] and premature senility has

been described in several patients with this disease [21] Fitch et al [21]

re-ported premature graying of scalp hair that began at age 18 in one patient

Though premature graying is most characteristic, hypo melanotic macules have

also been described

In 1974, Tay et al [22] reported such a recessive disorder in two Indian

teen-aged sisters from West Malaysia The disease, probably inherited as a

recessive autosomal trait, was characterized by microcephaly, triangular-shaped

face, prominent eyes, hypoplastic alae nasi, small pinched nose, tiny mouth

and large pegged-shaped incisors, abnormal limbs characterized by trident hands,

hypoplastic transverse palmar creases, and large big toes and stubbed short

toes One girl had a large number of cafe-au-Iait spots and depigmented lesions

on the shins, knees, extensor surfaces of the arms, and upper chest wall that

appeared at the age of nine At the same time, hairs of the scalp, eyebrows,

eyelashes, and of the limbs turned prematurely gray The skin biopsy of the

hypopigmented patches resembled vitiligo The second patient showed similar

premature canities and depigmented macules, though fewer and less extensive

In addition, these two girls had liver involvement with fatty infiltration and

hepatic cirrhosis with hypersplenism, raised serum immunoglobulins, and

hy-peraminoaciduria, mainly of taurine, beta-aminoisoleutyric acid, and glycine

As there is a striking similarity between these cases and patients with

"bird-headed dwarfism," the authors suggest that these cases may represent a variant

of the latter

TREACHER COLLINS SYNDROME, PIERRE ROBIN SYNDROME,

HALLERMAN-STREIFF SYNDROME, DOWN SYNDROME,

CHROMOSOME FIVE P·SYNDROME

Lopez et al [23] included Treacher Collins syndrome, Pierre Robin

syn-drome, and Hallerman-Streiff syndrome in the group of hereditary disorders

associated with hypomelanosis of the skin and hair Porter and Lobitz [24] also

mention fine, light-colored hair in Pierre Robin syndrome and light-colored

hair in tyrosinemia and in Down syndrome (trisomy 21) However, these are

only isolated reports

Several adult patients with chromosome five p-syndrome (cri-du-chat

syn-drome) have prematurely gray hair [25]

465 GENETIC AND CONGENITAL DISORDERS

REFERENCES

1 Book JA: Clinical and genetical studies of hyperdontia I Premolar aplasia, hyperhidrosis and canities prematura A new hereditary syndrome in man Am J Hum Genet 2:240-263, 1950

2 Cowie V: Hair colour in the infantile Fanconi syndrome Ann Hum Genet 21: 170-176, 1956

3 Schneider JA, Seegmiller JE: Cystinosis and the Fanconi syndrome, in Metabolic Basis of Inherited Disease, 3rd ed Edited by JB Stanbury et al New York, McGraw-Hill, 1972, pp 1581-1604

4 Rook A, Wells RS: Genetics in dermatology, in Textbook of Dermatology Edited by A Rook

et al London, Blackwell, 1969, pp 57-60

5 Tannhauser SJ: Werner's syndrome (progeria of the adult) and Rothmund's syndrome: two types of closely related heredofamilial atrophic dermatoses with juvenile cataracts and en- docrine features A critical study of five new cases Ann Intern Med 23:559-626, 1945

6 Touraine A: (Progres Medical 73:47, 1945) Quoted in Ebling EJ, Rook A: Premature canities,

in Textbook of Dermatology Edited by A Rook et al London, Blackwell, 1969, pp 1413-1414

7 Steinert H: Myopathologische Beitrage I Dber das klinische und anatomische Bild des skelschwunds der myotaniker Dtsch Z Nervenh 37:58-104, 1909

Mu-8 Werner 0: Dber Katarakt in Verbindung mit Sclerodermie Doctoral Dissertation, Kiel versity Kiel, Schmidt and Klaunig, 1904

Uni-9 Epstein DJ et al: Werner's syndrome Medicine (Baltimore) 45:177-221, 1966

10 Rook A: Disorders of connective tissues, in Textbook of Dermatology Edited by A Rook et al London, Blackwell, 1969, pp 1287-1288

11 Gilkes JJH et al: The premature aging syndromes Br J Dermatol 91:243-262, 1974

12 Hutchinson J: Congenital absence of hair and mammary glands Medico-Chirurg Trans 69:473,

1886 Quoted by Gilkes JJH et al: The premature aging syndromes Br J Dermatol 91:243-262,

1974

13 Gilford H: Progeria: a form of senilism Practitioner 73:188-217,1904

14 DeBusk FL: The Hutchinson-Gilford progeria syndrome J Pediatr 80:697-724, 1972

15 Fisch L: Deafness as part of an hereditary syndrome J Laryngol Otol 73:355-382, 1959

16 Soussi Tsafir J: Light-Eyed Negroes and the Klein-Waardenburg Syndrome London,

Mac-Millan, 1974

17 Ballantyne JC: Deafness London, Churchill, 1960

18 Bernier GM et al: Kappa chain deficiency Blood 40:795-805, 1972

19 Hare HJH: Premature whitening of hair J Hered 20:31-32, 1929

20 Seckel HPG: Bird-Headed Dwarfs Basel, S Karger, 1960

21 Fitch N et al: A form of bird-headed dwarfism with features of premature senility Am J Dis Child 120:260-264, 1970

22 Tay CH et al: A recessive disorder with growth and mental retardation, peculiar facies, abnormal pigmentation, hepatic cirrhosis and aminoaciduria Acta Paediatr Scand 63:777-782, 1974

23 Lopez B et al: Trastornos de la pigmentaci6n, in Actas Del VI Congresso Ibero-Latino Americano

de Dermatologia (Barcelona, Spain, 1967) Barcelona, Editorial Cientifico Medica, 1970, pp

157-179

24 Porter PS, Lobitz WC: Human hair: a genetic marker Br J Dermatol 83:225-241, 1970

25 Breg WR: Abnormalities of chromosomes 4 and 5, Endocrine and Genetic Diseases of Childhood and Adolescence Edited by 11 Gardner Philadelphia, Saunders, 1975, pp 1505-1515

26 Der Kaloustian VM et al: Prolidase deficiency: an inborn error of metabolism with major dermatological manifestations Dermatologica 164:293-304, 1982

2

Hypomelanoses Associated with

Nutritional and Metabolic Disorders

KWASHIORKOR

Kwashiorkor is a result of dietary deficiency of protein in the weaning and

early postweaning stage of childhood In underdeveloped nations it remains a

significant cause of death among children from one to four years of age

Credit for the first description of kwashiorkor is generally given to Williams

[1], who, in 1953, reported five "Gold Coast children," four of whom died The

origin of the term "kwashiorkor" is not precisely known

Kwashiorkor has been reported in every part of Africa, and also in China,

India, Malaya, Indonesia, Fiji, the Philippines, Caribbean Islands, Hungary,

Italy, and various parts of South America Henington et al [2], in 1958, reported

four cases from Louisiana The general prevalence of kwashiorkor is 0.5% to

1.5% in various community surveys [3] It is said to be much higher in primitive

cultures

Depigmentation in Kwashiorkor

Clinical Description

Depigmentation, according to Williams [1] may precede by weeks other

dermatologic features of kwashiorkor It may present in the early stages of the

disease-before the rash is well circumscribed The hypopigmentation of

kwashiorkor usually first involves the face and, after the appearance of a shiny

epidermis, resembles a background of fair skin on a red baby As the eruption

evolves over one to two days, except on the face, red raised plaques gradually

darken until they take on a shiny black appearance

Exfoliation is followed by depigmentation Enamel-plaque areas or

ulcer-ations develop to suggest the de pigmented skin is readily predisposed to

de-structive processes These depigmented macules do later repigment, often with

hyperpigmentation Lesions most typically occur on pressure points

467

468

CHAPTER 2

Banerjee and Dutta [4] noted that there may be generalized pallor with extensive hypo- and hyperpigmentation, the latter mostly in the diaper area, buttocks, back, thighs, and elbows-as opposed to the sun-exposed areas of pellagra

Dyschromic hair is a common feature of kwashiorkor Mukherjee and liffe [5] found the changes minimal in India compared to those seen in Africa, where hypochromotrichia is pronounced Others [6] reported only 13% with hair discoloration, yet Jelliffe [7] reported as high as 82% among African infants

Jel-in Jamaica In the latter, curled jet black hair is replaced by sparse dry hair varying from red-brown to gray in color

Henington et al [2] noted golden to reddish coloration at the ends of normally black hair in their four black patients There is often such minimal dilution of color-a fringe effect-and the color may be brown, red, golden, gray, or white The "signe de bandera" or "flag sign"-which is striped hair-may represent a recurrence Thinning of eyebrows or loss of the outer thirds may occur The hair also becomes dry, thin, and brittle and may be removed painlessly with little effort [8] Partial or total alopecia may result Hair pro-duction is 59 /-Lm3 per follicle in kwashiorkor vs 514 /-Lm3 for controls [9] Cystine levels are also reduced but return to normal after therapy

Histology of Depigmentation

Sims [9] compared the epidermis of 10 Zulu infants with kwashiorkor to five unaffected infants He reported decreased thickness of the epidermis and normal cell volumes and concluded there were changes in the kinetics of cell migration Desmosomes were found to be shorter than controls, and this may explain the epidermal fragility

of melanin has also been suggested Riboflavin or pantothenic acid deficiency and deficiency of sulfur or of sulfur-containing amino acids have been impli-cated [10]; this fits with the observation that cystine and glutathione as well

as other reducing enzymes affect the conversion of tyrosine to melanin by inhibiting tyrosinase and by regulating the oxidation reduction potential of melanocytes [12] That the pigment in the discolored hair behaves chromato-graphically like oxidized melanin [13], coupled with the above observation, supports the theory that lowering the SH concentration in melanocytes accel-erates the conversion of tyrosine to melanin; further oxidation of melanin to a brown or colorless product results

TABLE 111 Kwashiorkor: Associated Findings Skin

Purpura Angular stomatitis Cheilosis

Thinning, softening, ridging Xerophthalmia

Bitot's spots Blepharitis, conjunctivitis, photophobia Growth retardation

Psychic disturbances and mental retardation Muscle wasting

Edema Gastrointestinal disorders (anorexia, diarrhea) Hepatomegaly

Hypoalbuminemia Anemia

Hypovitaminosis

Leukoderma is not a primary or essential feature of kwashiorkor, the

di-agnosis of which is based on the history of malnutrition in an infant from an

endemic area plus the presence of the many clinical features noted Bands of

de pigmented or dyschromic hair may correspond to relapses and those of

re-pigmentation to treatment Other nutritional deficiency syndromes may also

be present

Treatment

Kwashiorkor responds to dietary protein and the skin is said to repigment

slowly [4]

GENERALIZED DYSCHROMIA IN A MALNOURISHED INFANT

Petrozzi [14] reported a 20-month-old black girl who presented several

months after birth with multiple episodes of infectious diarrhea associated with

febrile seizures At the age of two months, she developed asymptomatic, small,

469 HYPO- MELANOSES ASSOCIATED WITH NUTRITIONAL AND METABOLIC DISORDERS

470

CHAPTER 2

hypopigmented macules in the diaper area, upper legs, and lower abdomen During the next two months, similar lesions continued to appear on the trunk and spread to the distal extremities No inflammation preceded the hypopig-mented eruption but the father and an older sister had a history of infantile eczema

Examination revealed a generalized mottling of the skin which had ularly scattered hyperpigmented and hypopigmented macules

irreg-As poor dietary intake and recurrent diarrhea had been present in the first months of life, the author suggested that the dyschromia may result from mal-nutrition However, amino acid, copper, and vitamin B12 studies were not done

PIGMENTARY CHANGES IN THE HAIR OF PATIENTS WITH NEPHROSIS, ULCERATIVE COLITIS, OR EXTENSIVE RESECTION

As in kwashiorkor, chronic protein loss may result in pigmentary changes

of the hair [15] This can be observed in nephrosis [16] and also in malabsorption syndromes [16]

Mellinkoff [17] reported a 26-year-old Caucasian with ulcerative colitis whose hair turned red with malnutrition and returned to its normal dark brown color after he had gained weight Silverblatt and Brown [16] observed a kwash-iorkor-like syndrome with change of the hair from black to red associated with

"burning feet" in a 45-year-old black male in whom, 10 years after a gastrectomy for intractable duodenal ulcer, progressively severe diarrhea and pronounced malnutrition developed

SEVERE IRON DEFICIENCY

Tasker and Polunin [18] reported a 10-year-old aboriginal Malayan male with extremely severe iron deficiency anemia (hemoglobin level of 0.7 g per

100 ml) This boy had light brown hair, a very unusual feature among the usually dark brown-haired peoples of Malaya As the plasma protein values were grossly normal, the authors attributed the pigmentary disturbance to se-vere iron deficiency Treatment with intravenous iron oxide did not alter the hair color Clinical features of copper deficiency were not present in this patient but blood copper levels were not obtained

COPPER DEFICIENCY

Acquired copper deficiency is discussed with Menkes kinky hair syndrome (see "Copper Deficiency" in Chapter 1)

VITAMIN B12 DEFICIENCY (PERNICIOUS ANEMIA)

Pernicious anemia is associated with vitiligo in a significant number of

cases (see "Vitiligo" in Chapter 1) Premature graying is also a clinical feature

of pernicious anemia [19]

Dawber [20] found premature graying of the hair to be more frequent in

patients with pernicious anemia than in controls Among 125 patients with

pernicious anemia, 14 (11.2%) had graying of the hair before the age of 20,

compared to only three out of 132 controls (2.2%) Furthermore, early graying

of the hair (between 20 and 50 years of age) was more frequent in pernicious

anemia Thirty-eight of the 132 controls (20.8%) and 69 out of 125 patients

with pernicious anemia (55.2%) had early graying of the hair In the same group

of pernicious anemia patients, blond hair and blue eyes seemed common

A family with premature graying of the hair and pernicious anemia has

been reported One member of this family had both pernicious anemia and

premature graying of the hair Another had only pernicious anemia, and three

others only premature graying of the hair Another had diabetes mellitus and

an autoimmune hemolytic anemia in addition to premature graying of the hair

Several family members with or without premature graying had antinuclear

antibodies [21]

REFERENCES

1 Williams CD: Kwashiorkor JAMA 153:1280-1285, 1953

2 Henington VM et al: Kwashiorkor Arch Dermatol 78:157-170, 1958

3 Ebrahim GJ: The skin in malnutrition, in Essays on Tropical Dermatology Edited by J Marshall

Amsterdam, Excerpta Medica, 1972, vol 2, pp 124-128

4 Banerjee BN, Dutta AK: Malnutrition in the tropics: dermatoses in nutritional disorders, in

Clinical Tropical Dermatology Edited by 0 Canizares Oxford, Blackwell, 1975, pp 273-277

5 Mukherjee KL, Jelliffe DV: Clinical observations on kwashiorkor in Calcutta J Trop Pediatr

11 Bradfield RB, Jelliffe DB: Hair-colour changes in kwashiorkor (letter) Lancet 1:461-462, 1974

12 Lerner AB, Fitzpatrick TB: Biochemistry of melanin formation Physiol Rev 30:90-126, 1950

13 Nagchandhuri J, Platt BS: Malnutrition in African mothers, infants and young children, in

Report of the Second Inter-African [CCT A) Conference on Food and Nutrition, Gambia

Lon-don, Her Majesty's Stationery Office, 1954, p 215

14 Petrozzi JW: Unusual dyschromia in a malnourished infant Arch Dermatol103:515-519, 1971

15 Rook A: Nutritional, metabolic, and chemical influences of hair colour, in Textbook of

Der-matology Edited by A Rook et al London, Blackwell, 1969, pp 1631-1632

471 HYPO- MELANOSES ASSOCIATED WITH NUTRITIONAL AND METABOLIC DISORDERS

19 Wintrobe MM: Pernicious anemia and related macrocytic anemias, in Clinical Hematology,

6th ed Philadelphia, Lea & Febiger, 1967, pp 502-576

20 Dawber RPR: Integumentary associations of pernicious anemia Br J Dermatol 82:221-223,

1970

21 Wintrobe MM: Pernicious anemia and related macrocytic anemias, in Clinical Hematology

London, Kimpton, 1967, p 509

Hypomelanosis Associated with

Endocrine Disorders

HYPERTHYROIDISM

3

The association of vitiligo with hyperthyroidism has been discussed (see

"Vitiligo" in Chapter 1) Premature graying of hair may also accompany

hy-perthyroidism [1]

HYPOPITUITARISM

Decreased or absent skin pigmentation occurs in panhypopituitarism This

clinical finding may help distinguish primary Addison disease from secondary

Addison disease due to hypopituitarism [2] In hypopituitarism, there is an

increased sensitivity to sunburn with reduced melanin content and delayed

tanning [1] Decreased MSH and ACTH production is probably responsible

ADDISON DISEASE

The association of vitiligo and Addison disease has been discussed (see

"Vitiligo" in Chapter 1)

CUSHING SYNDROME

Brooks and Richards [3] reported depigmentation in two black women with

Cushing syndrome In both patients, depigmentation occurred on the exposed

areas (extensor surfaces of the hands and feet) but returned to normal after

adrenal surgery

The authors suggested the depigmentation may be due to suppression of

melanocyte-stimulating hormone (MSH) by high circulating levels of cortisol

But as only two cases are reported, any association must be considered tentative

473

HYPOPARATHYROIDISM, ADDISON DISEASE, AND CHRONIC MUCOCUTANEOUS CANDIDIASIS

There are several reported cases of a syndrome of hypoparathyroidism, Addison disease, chronic mucocutaneous candidiasis, and vitiligo [7,8] (See

1 Freinkel RK, Freinkel N: Dermatologic manifestations of endocrine disorders, in Dermatology

in General Medicine Edited by TB Fitzpatrick et al New York, McGraw-Hill, 1971, pp 1434-1459

2 Sheehan HL: Simmond's disease due to post-partum necrosis of the anterior pituitary Q J Med 8:277-309, 1939

3 Brooks VEH, Richards R: Depigmentation in Cushing's syndrome Arch Intern Med 117:677~80,

1966

4 Lorincz AL: Pigmentation, in Physiology and Biochemistry of the Skin Edited by S Rothman Chicago, Univ of Chicago Press, 1954, pp 515-563

5 Hamilton JB, Hubert G: Photographic nature of tanning of the human skin as shown by studies

of male hormone therapy (letter) Science 88:481, 1938

6 Edwards EA et al: Cutaneous vascular and pigmentary changes in castrate eunuchoid men Endocrinology 28:119-128, 1941

7 Fields JP et al: Hypoparathyroidism, candidiasis, alopecia and vitiligo Arch Dermatol

para-Hypomelanosis Secondary to

4

Melanocytes are vulnerable to nonspecific trauma In animals or in humans,

dark skin or hair may lose pigment in areas exposed to various types of injury

(x-rays and ionizing radiations, ultraviolet rays, thermal burns, freezing,

phys-ical traumas) (Fig 190)

X-rays have long been known to cause changes in melanin pigmentation

In animals, x-ray exposure causes depigmentation of feathers [1,2] or hair [3-6]

In humans, cutaneous depigmentation with atrophy may follow x-ray therapy

[7] Human hair color changes following x-radiation were reported just after

the turn of this century [8,9] Regrowth of white hair has been observed in

white or black children [10,11] following epilating doses of x-rays for the

treat-ment of tinea capitis

X-ray depigmentation results from a loss of functioning melanocytes Straile

[12] observed that x-ray irradiation decreases the number of melanocytes in

the hair follicles of mice Other changes included alterations of the length of

the dendrites, decrease in the transfer of pigment granules, alteration in the

distribution of melanin in the hair, and changes in the color of melanin granules

However, the mechanism by which follicular melanocytes seem to disappear

after irradiation is unknown

The epithelium target theory suggests that x-rays alter the epithelium of

the hair follicle [13]; subsequently, there is either a failure of the induction of

follicular melanogenesis or a disturbance in the regulation of the differentiation

of the secretory melanocytes at the beginning of the hair growth cycle Cohen

[14] suggested from studies of tissue culture of irradiated growing feathers

and transplant experiments that the action of x-rays is upon the

melano-blast-ectoderm relationship Chase et al [6] observed radiation effects remote

from the site of original exposure; depigmentation was delayed until the second

growth cycle after irradiation They concluded that there is an indirect effect

of x-rays on melanocytes

The melanocyte theory suggests that melanocytes are individually and

directly killed or inactivated by x-rays [13]

Still another theory is that proposed by Straile [12], who suggested a more 475

476

CHAPTER 4

FIGURE 190 Top: Clip in position on the shaved back of the rat Bottom: One month after application of the clip the hair in the previously ischemic area is white and longer than in the surrounding areas where regeneration after shearing is irregular and slow (From: Selye H: Is- chaemic depigmentation Experientia 23:524.1967 Copyright 1967 Birkhauser Verlag Used with permission.)

complicated mechanism In his view, x-ray-induced depigmentation results in part from a complete block in the differentiation of the melanoblasts, possibly related to an injury to the follicular epithelium, and also from direct or indirect destruction or inactivation of the melanocytes on an individual basis

Gamma and neutron radiation from atomic weapons also alters the melanin pigmentation, and depigmentation induced in animals by these radiations has been used for biologic radiation dosimetry [15]

Nonionizing radiation and photosensitization may lead to pigment loss; a single PUV A (psoralen plus UV A) reaction was observed to lead to depigmen-tation of an exposed square in a Dutch belted black rabbit U A Parrish, un-published observations)

Thermal burns which cause severe epidermal damage may destroy nocytes to leave a depigmented scar Freezing can be followed by cutaneous depigmentation, and, with the increased use of liquid nitrogen in dermatologic

mela-practice, this phenomenon is increasingly observed Taylor [16] observed in

black rats that hair growing from skin treated by cryotherapy lacked

pigmen-tation and also noted that in skin that survived freezing the melanocytes were

selectively destroyed This suggested the increased vulnerability of

melano-cytes to freezing

Experimental ischemia of the skin, produced by compression of a skin fold

in rubber-covered umbilical clamps for eight hours in rats [13], resulted in

long-standing depigmentation of the hair

Physical trauma also often leaves depigmentation which is most apparent

in dark-skinned patients

The reason for the increased sensitivity of melanocytes to a wide variety

of injuries is unknown The low-density, self-perpetuating melanocyte

popu-lation in the skin may be responsible Furthermore, cells are most sensitive to

trauma in mitosis and the turn-over rate of melanocytes is probably very low

6 Chase HB et al: Evidence for indirect effects of radiation of heavy ions and electrons on hair

depigmentation Ann NY Acad Sci 100:390-399, 1963

7 Ladanyi E: Nach Riintgenbestrahlung entstandene, "White Spot Disease." Hautarzt 21:328-330,

1970

8 Danysz J: De I'action du radium sur les differents tissus C R Acad Sci (Paris) 136:461-464,

1903

9 Ellinger F: Medical Radiation Biology Springfield Ill Thomas 1907 p 173

10 Hazen H: Results of repeated epilation with roentgen rays in tinea tonsurans Arch Dermatol

56:539-540, 1947

11 Zeligman I: Graying of hair following epilating doses of x-rays Arch Dermatol 66:627-628,

1952

12 Straile WE: A study of the hair follicle and its melanocytes Dev Biol10:45-70, 1964

13 Selye H: Ischemic depigmentation Experientia 23:524, 1967

14 Cohen J: The nature of the effect of x-irradiation in depigmentation Ann NY Acad Sci 100:400-412,

17 Jimbow K et al: Mitotic activity in non-neoplastic melanocytes in vivo as determined by

histochemical autoradiographic and electron microscopic studies J Cell Bio166:663-671, 1975

477 HYPOMELANOSIS SECONDARY TO IRRADIATION AND PHYSICAL TRAUMA

5

Chemical Hypomelanosis

A large number of chemical compounds induce depigmentation in humans

and in experimental animals (Fig 191, Table 112) Cutaneous chemical

depig-mentation, which often resembles vitiligo in clinical appearance, may result

from direct contact or from systemic exposure (ingestion or particularly

in-halation) to various phenol derivatives, sulfhydryl compounds, and others (Fig

192) Some of these compounds have also purportedly been found in

com-mercially available consumer products, and accidental exposures have

oc-curred historically in the course of many industrial processes Both careful

research discovery and serendipity seem to increase the growing list of known

chemical depigmenting agents There are likely important and common

de-pigmenting agents yet to be revealed

Leukoderma has been attributed to the mono benzyl ether of hydroquinone

contained in rubber-covered wire-disk trays [1,2]' adhesive tape [3,4], hat bands

[3], contraceptive diaphragms [2], rubber finger cots [3,], rubber clothing [5],

rubber aprons [3], powdered rubber condoms [6,7], rubber dolls [8], neoprene

(a synthetic rubber) [9], fabric-lined rubber gloves [10], and shoes (rubber

ce-ment) [11]

Paratertiary butyl phenol is used as an intermediate in the processing of

varnish and lacquer resins, as an ingredient in motor oil demulsifier, as a soap

antioxidant, as a plasticizer for cellulose acetate, as a rubber antioxidant, as an

intermediate in synthetic oil, and as an ingredient in insecticides, deodorants,

commercial detergents, germicidal disinfectants, writing ink, and latex

adhe-sives [12]

Paratertiary amyl phenol is used in the manufacture of oil-soluble resins,

and as a plasticizer, commercial germicide, and fumigant [12]

The germicidal phenolic detergents in Tables 113 and 114, which contain

paratertiary butyl phenols and paratertiary amylphenols, are potential

depig-menting agents

Ortho-benzyl-para-chlorophenol (chlorophene) is used widely as a

disin-fectant, cleaner, and preservative Ortho-phenylphenol is used as a germicide

and as an intermediate in the production of dyes [12]

479

TABLE 112 Chemicals Implicated

in Induction of Leukoderma in

Humans

Paratertiary butylphenol Paratertiary butylcatechol Paratertiary amylphenol Alkyl phenol

Monobenzylether of hydroquinone Hydroquinone

Dihydroxyphenylmethane Butylated hydroxy toluene Heavy metals (mercury, bismuth, zinc)

FIGURE 192 Extensive depigmentation attributed to industrial exposure to monobenzylether of

hydroquinone

481

CHEMICAL HYPOMELANOSIS

482

CHAPTER 5

TABLE 113 Germicidal Phenolic Detergents Containing

Para tertiary Amylphenolo Product

Bactophene Beaucoup Chlorocide Galahad Listophene Matar Microphene Phenocide Phenomycin Staphene i-Stroke Vesphene Tergisyl

Tri-Kem Ves-Phene Ves-Phene 0

Manufacturer Sanfax Corporation Huntington Laboratories Center Chemicals Puritan Chemical Enterprise Paint Manufacturing Huntington Laboratories Sanfax Corporation Center Chemicals Franklin Division of Purex Vestal Laboratories Vestal Laboratories Lehn and Fink Division, Sterling Drug Airwick Industries

Vestal Laboratories Vestal Laboratories

Copy-right, 1976, Donneley Publishing Corporation Used with permission

PHENOLIC COMPOUNDS

The basic structural requirements for a depigmenting phenolic compound seem to be hydroxylation of the benzene ring, particularly in the para-position, and a nonpolar side chain in the one position [13] The presence of an ether link at the 1 position increases the effective depigmenting potency [13] Many

of these phenol derivatives resemble tyrosine or dihydroxyphenylalanine in their molecular structure

Clinical Features

The leukodermas arising from chemical exposure are clinically similar Chemical exposure of as little as two weeks' duration may cause depigmen-tation, but four to six months is a more commonly cited exposure period

TABLE 114 Germicidal Phenolic Detergents Containing Paratertiary Butylphenolo Product

Bactophene Microphene O-Syl Penocide

Manufacturer Sanfax Corporation Sanfax Corporation Lehn and Fink Division, Sterling Drug Center Chemicals

Copyright, 1976, Donneley Publishing Corporation Used with mission

per-FIGURE 193 Leukomelanoderma after application of monobenzylether of hydroquinone

Contact dermatitis may precede whitening but is not necessary for development

of depigmentation Depigmentation begins as confetti-like or small, round to

oval macules which may be more or less grouped in a particular anatomic

region Predisposed sites are a function of direct occupational contact, so that

the hands, forearms, perioral skin, neck, and lower legs are among the first to

depigment Satellite lesions (Fig 193) may occur in areas not directly exposed

to the chemical In extensive cases, which certainly resemble vitiligo, genital

and perianal skin may be affected Extensive and symmetrical depigmentation

of the trunk may also occur A leukomelanoderma may result Graying of scalp

and body hair is rare Eye color is unchanged Repigmentation may occasionally

occur from the margins or from hair follicles after the chemical is withdrawn,

but more often depigmentation is permanent

Monobenzylether of Hydroquinone (MBEH)

In the late 1930s, the rubber industry began to use a phenol derivative,

monobenzylether of hydroquinone (MBEH), as an antioxidant Oliver et al first

483 CHEMICAL HYPOMELANOSIS

484

CHAPTER 5

reported in 1939 [14] depigmentation of skin occurring among factory workers exposed for several months to rubber gloves containing an antioxidant, "Agerite Alba." The leukoderma occurred mainly on the hands and half-way up the forearms, often with a sharp cut-off line corresponding to areas outlined by the heavy gauntlet type of gloves worn Other areas of the face and trunk were also involved This depigmentation was attributed to direct contact with the an-tioxidant About 50% of the workers were affected and the severity was a function of the duration of exposure Patch tests confirmed that MBEH caused the depigmentation in the affected workers McNally [15] at the same time reported the same phenomenon in 34 black employees in a tannery Leuko-derma observed at remote sites was attributed to accidental direct contact with the gloves A mild inflammatory reaction and hair loss in the depigmented macules was observed in one patient Yet, the occurrence of leukoderma in only nine of 200 workers exposed to oil droplets containing the antioxidant material suggested that exposure alone was not the sole factor required for depigmentation to occur [16]

These observations precipitated attempts to induce depigmentation with MBEH Application of MBEH to guinea-pig skin induced cutaneous depig-mentation, whereas oral feedings over five months did not [17] Later, produc-tion of depigmentation from oral feedings was observed by another group of investigators [18] who attributed the different results to a different strain of guinea pigs or to a higher dosage of MBEH

Clinically, MBEH was reported to cause pigmentary lightening in melasma [18-22], postinflammatory hyperpigmentation [22], benign acanthosis nigricans [22], idiopathic melanoderma [22], congenital eyelid melanosis [22], pigmented nevi [22,23], Riehl melanosis [24], cafe-au-Iait spots [22], generalized lentigines [22], senile lentigines [22], seborrheic keratoses [22], berloque dermatitis [22], hyperpigmented scars [21], and normally melanized skin in vitiligo patients

[22]

Monomethylether of hydroquinone (4-hydroxyanisole) is also a potent pigmenting agent [25]

de-The histology of MBEH-induced total depigmentation is identical to that

of vitiligo; the epidermis is normal except for an absence of identifiable lanocytes The dopa reaction is negative Electron microscopy reveals a total absence of melanosomes

me-Most chemical depigmenting agents appear to act by destroying cytes rather than by mere inhibition of melanin formation [26] Studies in guinea pigs have shown that MBEH inhibits melanogenesis The number and size of melanocytes is decreased The content of melanocytes and keratinocytes is diminished The effect was observed to last four weeks after application Pro-longed application would be expected to cause irreversible loss of all mela-nocytes Snell [27], like Peck and Sobatka [17], found no change in melanin content of hairs and suggested MBEH may not penetrate skin so far as the follicular melanocytes Patients bleached with MBEH generally are perma-nently depigmented but may on occasion develop perifollicular repigmenta-tion; these observations suggest that at least the potential for· perifollicular melanocyte activation may remain

melano-Hydroquinone (HQ)

Oettel [28], in 1936, noted that black-haired cats developed reversible

gray-ing of hair after six to eight weeks of hydroquinone (HQ) feedgray-ings Martin and

Ansbacher [29] noted that achromatrichia developed after four to 20 weeks of

oral HQ in mice HQ fed to guinea pigs did not cause depigmentation, whereas

subcutaneous injection resulted in depigmentation at the injection sites [18]

Workers exposed to large amounts of HQ do not develop depigmentation, but

depending on the length of exposure may develop a reddish discoloration of

hair and exposed skin, particularly on the palms and soles [30] This may result

from oxidation and polymerization of absorbed HQ [30] or from conversion of

HQ to a melanin-like product similar to that in the conjunctivae in ochronosis

[31] HQ has also been found to be a quite effective de pigmenting agent but,

unlike MBEH, it does not cause satellite depigmentation and the

depigmen-tation is usually reversible once application of HQ is discontinued (Fig 194)

Furthermore, total depigmentation has never been reported Large quantities

of HQ creams have been used in Africa for over 15 years; no reports of

vitiligo-like depigmentation have been reported despite annual sales of several million

dollars

Jimbow et al [32] found evidence of destruction of melanocytes with HQ;

there was decreased formation of melanosomes, alteration of internal structure,

increased melanosome degradation, and destruction of membranous organelles

Paratertiary Butylphenol (PTBP) and Paratertiary Amylphenol

(PTAP)

In 1962 Russian researchers [33] observed depigmentation in 23 of 52

factory workers exposed to paratertiary butylphenol (PTBP) and paratertiary

amyl phenol (PTAP) formaldehyde resin The depigmentation was symmetrical

and resembled vitiligo Three of the cases occurred after a year of exposure

Forty percent of those exposed for more than two years were depigmented The

exposure was attributed to inhalation of various phenol vapors in combination

with formaldehyde and to exposure to the resin dust

Daily injection of PTBP into black rabbits also induced graying of hair

[34,35] The observation that daily application of PTBP in propylene glycol

caused capillaritis suggested depigmentation remote to directly exposed areas

could be secondary to a generalized capillaritis [36] Subcutaneous and oral

administration also caused depigmentation in C-57 black mice [37,38]

Five housekeeping employees in a Denver hospital developed

depigmen-tation of the hands and forearms after six months' use of O-Syl, a

PTBP-con-taining detergent disinfectant [12]

Rodermund and Wieland [39] reported three men with vitiligo-like skin

changes, hepatosplenomegaly, and diffuse goiter (grade III), all of which

de-veloped after one to two years' work in a factory producing PTBP Liver function

tests showed BSP elevation and a slight increase in the SGOT and SGPT levels

Liver biopsy showed polymorphism of the hepatocytes, disintegration of the

485

CHEMICAL HYPOMELANOSIS

486

CHAPTER 5

FIGURE 194 a: Patient with melasma before treatment with hydroquinone b, c: Same patient during and after treatment The hypomelanosis is much less apparent

FIGURE 194 (Continued)

cytoplasm, and, in two of the workers, disseminated fatty degeneration In

addition, TSH levels were increased and antithyroid antibodies were present

The triad of vitiligo-like depigmentation, hepatosplenomegaly, and thyroid

struma was attributed to PTBP and suggested that an immunologic process

followed simultaneous PTBP-induced damage to cells of different organ

sys-tems Goldmann and Thiess [40] also observed thyroid struma in eight and BSP

abnormalities in nine of 12 patients with occupational PTBP-Ieukoderma

In another industrial survey [41], of 198 employees exposed to PTBP, 54

had leukoderma (in seven cases this was obvious only with Wood's light

ex-amination) Only two of those with leukoderma had been exposed less than

five years Exposure was attributed to dust and vapor and the sites of

involve-ment suggested systemic absorption The degree of leukoderma correlated with

the extent and duration of PTBP exposure None of those with leukoderma had

positive family histories or histories of associated diseases Among studies

performed-ANA, smooth muscle antibodies, thyroid antibodies, and aspartate

aminotransferase (AAT)-only the latter was abnormal more commonly in those

affected than in the 144 unaffected In the six patients with abnormal AAT

levels, all had abnormal liver histology characterized by moderate to severe

fatty changes, and one had frank cirrhosis This too suggests systemic effects

of PTBP exposure

A similar chemical, paratertiary butylcatechol (PTBC), was responsible for

depigmentation among another cluster of factory workers [42] These four

tap-487 CHEMICAL HYPOMELANOSIS

488

CHAPTER 5

pet plant workers had had a dermatitis on their upper arms prior to the pearance of depigmentation Leukoderma appeared following a few months' to four years' chemical exposure The amelanotic macules were confined to the hands and forearms in only one patient, whereas the others also had remote areas involved One worker was 75% depigmented Patch testing gave positive results in three of four patients, one of whom subsequently developed an area

ap-of depigmentation at the site ap-of patch testing

Another worker exposed to PTBC was studied It was observed that patch tests to 0.01% and 0.5% PTBC were both positive, but only with the 0.5% did depigmentation occur This developed two weeks after patch testing The same worker was also patch test-positive to PTBP but depigmentation did not occur Histologic studies show decreased melanin, a decreased number of dopa-pos-itive melanocytes, and melanophages in the dermis After three years, improve-ment was noted but some depigmentation remained Phase contrast and elec-tron microscope studies of guinea-pig ear melanocytes treated with PTBC show the changes in more detail These changes included decreased melanocyte size,

a beaded dendritic pattern, and some melanocytes rounded-up in shape; many

of these changes were reversible once PTBC was washed out PTBC exposure also caused transition from smooth melanocyte contour to irregular outlines and melanin pigmentary clumping In cell culture, half the cells were killed, but among remaining cells, no lightening occurred Thus, cell killing would appear to be the mechanism for PTBC depigmentation An alternative mech-anism for depigmentation is inhibition of tyrosine oxidation as has been ob-served in vitro [43]

In another industrial investigation in a Dutch factory, inhalation was plicated Patch testing of 16 of these workers to multiple phenol derivatives including PTBP revealed universally negative results and no depigmentation

im-at sites of applicim-ation of the testing mim-aterials Wild-type colored guinea pigs and black cats fed up to 10 months a tube feeding mixture of phenols, including PTBP, PTBC, and others did not develop hypomelanosis of hair [44a]

Depigmentation of hands and arms occurred in seven employees of a ver hospital [12] who were exposed to Vesphene, a PTAP-containing disinfec-tant PT AP was observed to cause depigmentation in the absence of an ante-cedent dermatitis In some patients and test subjects, the depigmentation disappeared in six months, whereas in others it persisted more than one year PTBP-depigmented skin lacks melanin granules and contains only occa-sional melanocytes with few melanosomes [44] In four of five patients in another series, no melanocytes were identified in the involved skin and the rare melanocytes found contained swollen mitochondria, many vacuoles, and premelanosomes with "an abacus" type of pigment distribution [44a]

Den-Occupational leukoderma from the alkylphenols has also been reported [38,45]

4-Isopropylcatechol (4-IPC)

One of the most potent depigmenting agents is 4-isopropylcatechol (4-IPC) Topical4-IPC consistently produces depigmentation of epliated and unepilated skin of black guinea pigs [46] Only rare melanocytes could be found in 4-IPC-

exposed areas The few melanocytes identified contained fewer electron-dense

melanosomes, imperfectly melanized melanosomes, vacuoles, swollen

mito-chondria, and sometimes electron-dense round or oval bodies with double

membranes Other cells resembling melanocytes without characteristic

organ-elles were observed, but could not be characterized as melanocytes, histiocytes,

or Langerhans cells; these had well-developed rough endoplasmic reticulum

and a lobate nucleus, but no Langerhans granules, premelanosomes,

melano-somes, or desmosomes Only occasional keratinocytes had melanosomes which,

in the few instances in which they were observed, appeared normal The

num-ber, morphology, and distribution of Langerhans cells were normal

Dihydroxydiphenylmethane

Depigmentation due to adhesive tape has been attributed to contact with

a natural rubber-base adhesive containing a derivative of

dihydroxydiphen-ylmethane [4]

p-Cresol

A compound in laundry ink, p-cresol, has been shown to induce permanent

hair depigmentation in CBA/J mice [47] p-Cresol appeared to be toxic to

me-lanocytes during the early anagen phase of the hair cycle Superficially the coat

appeared pigmented until the hair was parted to reveal depigmentation of 90%

of the hair, which in fact retained pigment only at the tips The area of

depig-mentation corresponded to the area of application of p-cresol

Butylated Hydroxy toluene

Vollum [48] found two black children who developed hypopigmentation

at the site of application of a polyethylene film containing an antioxidant,

butylated hydroxytoluene After four weeks one showed no signs of

repigmen-tation; the other had repigmented in eight weeks

Mechanism of Action

Bleehen et al [46] suggested seven possible mechanisms for exogenous

depigmentation with an agent such as 4-IPC:

1 Selective action on the melanocyte-as metabolic antagonists or

respi-ratory inhibitors-through formation of free radicals that disrupt melanocyte

function

2 Competitive inhibition with tyrosinase

3 Block of enzymatic oxidation of tyrosine to dopa, for example, by

re-duction of dopaquinone to an orthodihydroxyphenol compound, which may

then inhibit melanin pigmentation

489

CHEMICAL HYPOMELANOSIS

keratin-7 Reduction of melanin present in melanosomes Hydroquinone was found to inhibit the oxidation of tyrosine to dopa, but dopa oxidation itself was not inhibited [18] Others found inhibition in the conversion of dopa to melanin [49] It was also suggested that hydro quinone could function as a reducing agent [18]

The mechanism of MBEH, 4-hydroxyanisole (4-HA), and PTBP tation is not understood Denton et al [18] suggested MBEH may be converted

depigmen-to hydroquinone, which they found depigmen-to inhibit the enzymatic oxidation of rosine to dopa The hydroquinone hypothesis is not consistent with clinical experience-if hydroquinone were an intermediate step in the final pathway

ty-of MBEH depigmentation, MBEH should behave clinically as hydroquinone The mechanism must differ in order to explain the irreversible and remote depigmentation seen with MBEH but not with hydroquinone

Iijima and Watanabe [49] suggested direct tyrosinase inhibition Studies suggest various germicidal phenols may induce depigmentation by such direct inhibition of tyrosinase [50] Yet, MBEH appears to have no action in vitro on the enzymatic oxidation of tyrosine or dopa to melanin [51] Denton et al [18]

found the O2 uptake of the tyrosine-tyrosinase MBEH reaction mixtures to be greater than that of control tyrosine-tyrosinase preparations; O2 uptake of the dopa-tyrosinase reaction was also increased Although they could not relate this to the mechanism of action of MBEH, they suggested that MBEH may be converted to hydroquinone, which inhibits the formation of dopa from tyrosine

Or it may act directly as a reducing agent causing melanin reduction ening)

(light-It may be suggested that 4-HA blocks the synthesis of tyrosinase in the melanocytes If the enzyme substrate tyrosine is also an inducer of tyrosinase synthesis, then perhaps tyrosine analogs could inhibit tyrosinase synthesis by binding the inducer site [13] Supportive of this is the observation that a 10:1

molar ratio of tyrosine and 4-HA delays the appearance of 4-HA-induced pigmentation [52] Furthermore, tyrosine applied to guinea-pig ear skin causes increased pigmentation [13] However, there is no evidence in humans that tyrosine is an inducer of melanocyte tyrosinase [13]

de-An attractive variant hypothesis is that the chemical similarity of these compounds to tyrosine makes them competitive inhibitors of tyrosinase activ-ity However, the negative dopa reaction makes this untenable [13] Further-more, Riley [53] has suggested that 4-HA in vitro stimulates tyrosine oxidation Also, other possible competitive inhibitors, 4-hydroxyphenylpyruvate, adren-aline, and noradrenalin, which are all rapidly oxidized in vitro by mushroom tyrosinase, do not cause depigmentation [13]

That 4-HA may act as a tyrosinase substrate is supported by the observation

that tritiated 4-HA uptake into melanosome-rich melanocytes and distribution

of labeled compound is similar to that of dopa reaction product in control cells

These labeled granules then appear in surrounding keratinocytes [54] This

4-HA effect has been shown to be dose-dependent on cultured cells and to be

selective for melanocytes in mixed cell cultures

Similar results, according to Riley [54], have been obtained for

l-isopropyl-3,4-catechol, l-tertiary-butyl-l-isopropyl-3,4-catechol, 4-HA, and

3-tertiary-butyl-4-hydrox-yanisole These are all toxic substances, whereas the nontoxic substances

2-HA and 3-2-HA proved to be poor substrates

Thus, melanocytotoxicity results from a reaction product of tyrosinase

oxidation of a particular phenolic compound This is further supported by the

protection generally afforded by the copper-binding tyrosinase inhibitors and

by "free radical scavengers" such as ascorbate and ubiquinone [54]

A dialyzable free radical oxidation product can be formed from a mixture

of 4-HA and mushroom tyrosinase and with other nonpolar tyrosinase

sub-strates, but not with polar ones Riley [13] suggests this contributes to

diffus-ability and that greater lipid solubility may contribute to initiation of lipid

peroxidation

A third suggestion, which Denton et al [18) noted was not supported by

other studies, was that MBEH is a sylfhydryl antioxidant; it prevents sulfhydryl

oxidation so that more sulfhydryl groups are available to inhibit tyrosinase

Becker and Spencer [9] suggested an inflammatory reaction was the primary

event in chemical depigmentation-increased cell permeability occurs, MBEH

enters the melanocyte, and an antigenic substance is formed, attaches to

mel-anin granules, and enters the dermis where antibodies are produced If a certain

level of antigenic stimulation is produced, remote positive patch testing may

result The latter seems a reasonable postulation It may be that clinical or

subclinical inflammatory reaction accompanies MBEH use Membrane

disrup-tion permits MBEH to enter the melanocyte to bind with substrate to form an

antigenic complex which leaks into the dermis Antibody production could

thus be initiated against an antigenic component of normal melanocytes

It has been demonstrated that 4-HA in vitro is toxic to RNA and protein

synthesis systems, as well as to mitochondrial respiration, with secondary

inhibition of cellular capacity to manufacture melanin [53)

Possibly reduction of a quinone intermediate produces semiquinone free

radicals which diffuse out of melanosomes to initiate the chain reaction of lipid

peroxidation with resultant damage to cellular organelles and melanocyte

de-struction RBC hemolysis in vitro with these substances with or without

ty-rosinase is increased compared to unsubstituted phenol alone [53) It has been

demonstrated that tritiated 4-HA is selectively taken up by melanocytes in

tissue culture [54] and that a new electron spin resonance signal is generated

in black guinea-pig skin treated with topical 4-HA [54] This supports the

concept of new free radical formation and suggests the depigmentation results

from synthesis of diffusible free radicals

4-HA has been observed to cause membrane damage in RBC suspensions,

and also to melanocytes [53] It is not known whether this effect relates to lipid

peroxidation

Riley [13] notes that other effects of phenolic cmpounds may be relevant

491 CHEMICAL HYPOMELANOSIS

492

CHAPTER 5

4-HA was noted to produce keratinocyte pseudopods into the dermis, whereas nontoxic 2-HA and 3-HA had no, or a much slower, effect, respectively This effect is reversed once application is discontinued

The mechanism of PTBP is not understood, but it induces changes in the cresolase activity of tyrosinase [37,55] McGuire and Hinders concluded that paratertiary butylphenol depigmentation may result from competitive inhibi-tion of tyrosinase [50]

Diagnosis and Differential Diagnosis

In most cases of chemical depigmentation, except with hydroquinone, the typical clinical presentation resembles vitiligo Clusters of small round, oval,

or confetti-like depigmented macules are highly suggestive A history of posure to known depigmenting agents and industrial clustering of cases should

ex-be pursued in such incidences The distribution of lesions on exposed areas

is also suggestive Mode of spread may be helpful-a history of gradual cence of small discrete macules, rather than development of large macules with perifollicular sparing suggests chemical leukoderma For this reason a work history of those with leukoderma is essential It is also important to know whether others at work have any evidence of leukoderma

coales-Hydroquinone, however, leads to a uniform lightening over the area of application and not to focal pigmentary lightening or leukoderma

Prevention and Treatment Preventing occupational leukoderma involves constant vigilance for the offending agent Ideally, direct contact with the depigmenting agent should be avoided and adequate ventilation to prevent inhalation should be present [44] With most agents, spontaneous repigmentation may occasionally occur, but often the depigmentation persists [56] The hypermelanosis which usually accompanies chemical leukoderma is most often permanent

Topical or systemic psoralens and UV A may stimulate repigmentation The hospital orderly with depigmentation attributed to O-Syl detergent ex-posure was treated with methoxsalen applied to the dorsum of one hand, and subsequent black-light exposure Perifollicular repigmentation was observed after six treatments The left hand, which was untreated, did not repigment [57] In another case, no repigmentation was observed with similar therapy [12]

Therapeutic Use of Phenolic Depigmenting Agents Hydroquinone and monobenzylether of hydroquinone (MBEH) have been employed in the treatment of various pigmentary disorders

The only rational use of MBEH is for total removal of normal pigmentation

in patients with extensive vitiligo (Fig 195) In 18 of our patients with severe vitiligo, seven of eight who applied Benoquin (20% MBEH) once or twice a

FIGURE 195 Monobenzylether of hydroquinone Leukoderma resulting from exposure to

MBEH

day for over four months achieved complete depigmentation [58] An average

of only two to three months of therapy was required to notice any change After

completely depigmenting, two patients observed small macules of

repigmen-tation; these macules were readily erased with further applications of Benoquin

All patients who depigmented fully were very pleased with the results

Side effects of MBEH therapy are not uncommon Dermatitis, burning [59-61],

and pruritus [7] are the most frequent complaints Contact dermatitis, varying

from mild asymptomatic erythema to a painful vesicular eruption, has been

reported in 13% of treated patients; in some of these cases dermal or epidermal

hyperpigmentation resulted [22] In 3816 patch tests on 578 subjects (200

In-dians, 316 Zulus, and 62 mixed whites and blacks) with 1% to 75%

hydro-quinone or MBEH, reactions varied from erythema to vesiculation as a function

of concentration Hyperpigmentation, never depigmentation, followed [62]

Two-thirds of the 18 patients treated at the Massachusetts General Hospital

complained of burning or itching, erythema, dryness, or warm sensation One

patient developed a contact dermatitis and was unable to use Benoquin [58]

and one of the authors has since observed another such patient

Other pigmentary abnormalities, including leukomelanoderma, satellite

depigmentation (Fig 196), and hypermelanosis, may occur Hyperpigmentation

with MBEH-containing Neoprene has been reported [8], and such

hyperpig-mentary responses tend to be permanent [63] According to a study of Becker

493

CHEMICAL HYPOMELANOSIS

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CHAPTER 5

FIGURE 196 Hypomeianosis of the dorsum of the hand remote from the sites of application of monobenzyiether of hydroquinone

and Spencer [9], among 25% of patients responding to 1% to 20% MBEH plication, the response was unpredictable in extent and degree Among Japa-nese women using MBEH, a vitiligo-like leukomelanoderma developed remote from the sites of direct application [59] Development of completely depig-mented macules outside the treated area was noted in two South American patients [23] Total depigmentation was common among blacks and Asiatics but not among Caucasians [23] Curiously, in another 185 patients, neither hyper- nor hypo pigmentation was noted; this suggested possible patient misuse

ap-or careless transfer by fingers [22] was responsible fap-or the satellite tation reported by others The variation in reactions to patch testing of 43 normal black males [2], one of whom discontinued MBEH because of a disseminated eczematous eruption, confirms a spectrum of MBEH reactions Twenty-three developed inflammation at the site of MBEH application, and after four months

depigmen-26 had leukoderma Five, in fact, developed leukoderma within the time of application, and in seven the leukoderma continued to progress for six months after application Four years after application had been discontinued, nine subjects continued to be depigmented MBEH depigmentation is, however, not necessarily permanent But a few months to years may be required for repig-mentation to occur Such repigmentation may be partial or complete In two

of seven volunteers who underwent 30-day patch testing with 10% to 30% MBEH, perifollicular repigmentation was observed a month after the end of the experiment [18] Another group of Caucasians treated with MBEH did not develop leukoderma, but the test sites would not tan for several years

Other effects are rarely reported A halo nevus has been reported to develop

in an MBEH-treated patient [64J Hair loss has been observed in one case [3J While the incidence of side effects is high, these do not usually limit the proper use of Benoquin The only clinical use of MBEH is for those vitiligo patients who wish, above all, to be one color and who can accept the emotional and physical limitations of being totally amelanotic Once therapy has resulted

in hypomelanosis, irreversible depigmentation (amelanosis) should be pected to follow and remain And, after full depigmentation, the patient must

ex-be constantly aware of the possibility of sunburn and must use an effective

UVB sunscreen Attempts to repigment Benoquin-induced depigmentation with

oral psoralens have generally been unsuccessful MBEH should never be used

as a hypo pigmenting agent for melasma or postinflammatory

hyperpigmenta-tion because the end point of hypopigmentahyperpigmenta-tion cannot be reliably predicted

or controlled, and satellite depigmentation may occur

For nearly 15 years hydroquinone has been used to bleach various

hyper-melanoses Hydroquinone in 2% to 4% concentration is a useful

hypopig-menting agent for hypermelanoses of epidermal origin Pigment loss must be

considered temporary and reversible Arndt and Fitzpatrick [65] used 2% to

5% hydroquinone in 54 patients with melasma, vitiligo, idiopathic

hyperpig-mentation, postinflammatory hyperpighyperpig-mentation, and ephelides Cosmetically

acceptable results were obtained in 67% to 90% of patients treated for a month

or more Complete disappearance of hypermelanosis did not usually occur

Nevi did not respond One patient developed an equivocal leukoderma

A later report [7] showed overall improvement to be 63.5% of 93 patients

with pigmentary disorders No differences were noted in the reactivity between

blacks and Caucasians

In addition to the treatment of hypermelanoses, hydro quinone may be used

to "feather" the area of normal pigmentation into an area of vitiligo to make

the contrast less dramatic The use of such a temporary hypopigmenting agent

also leaves open the option for repigmentation should the patient decide on

such a course at a future date For effective therapy, an opaque sunscreen must

be used daily before sun exposure

In simulated use tests, 1.5% to 2% hydroquinone has been found to be

remarkably free of side effects [66] Among 98 patients with pigmentary

dis-orders, hydro quinone produced hypopigmentation in 45% and irritation and

sensitization in none Yet, hydro quinone is a mild primary irritant and may

provoke sensitivity and contact dermatitis in those previously exposed

Thirty-two percent of 93 patients using 5% hydroquinone developed erythema and

tingling at the site of application, whereas only 8% had reactions to the 2%

concentration [40] In another study, patch testing with hydroquinone revealed

essentially no reaction to a concentration of less than 3%, 11% reactivity to

3.5% hydroquinone, and 35% reactivity to 7% hydroquinone [67] The most

frequently observed adverse reaction was hyperpigmentation, either with or

without preceding erythema Increasing the concentration of hydroquinone to

10% increases its effectiveness but also its irritancy [68] Temporary brown

discoloration of the fingernails attributed to binding of hydroquinone to keratin

and oxidation may occur [40]

The combined use of hydroquinone, retinoic acid, and dexamethasone

augments the hypopigmenting effect of hydroquinone [68] Retinoic acid alone

seems to cause pigment granule dispersion in keratinocytes, interference with

pigment transfer, and accelerated pigment loss because of increased epidermal

turnover Complete depigmentation of normal skin of more than 100 adult black

males followed daily application of five to seven weeks of a mixture of 0.1%

T retinoin, 5% hydroquinone, and 0.1% dexamethasone Pigment loss was

blotchy at first and the follicles were the last to depigment Erythema and

desquamation usually preceded depigmentation, although after one month

sig-nificant hardening had occurred such that little or no irritation was present

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No satellite depigmentation occurred One to two weeks after treatment was discontinued, repigmentation from the borders and from hair follicles began and was generally complete after three to four months Biweekly exposure to

2 MEDs (minimal erythema doses) of ultraviolet radiation markedly retarded the rate of depigmentation Omission of one or two of the ingredients signifi-cantly lessened the hypopigmentary potency [68] Depigmentation seems to take a longer time and to be less satisfactory in fair-skinned individuals than

in blacks

In clinical usage, 67% to 88% of 45 patients with melasma, ephelides, and postinflammatory hyperpigmentation achieved satisfactory response None of the seven patients with senile lentigines responded to treatment

However, the long-term complications of fluorinated corticosteroid usage

on the face makes use of this combination not practicable Substitution of hydrocortisone for dexamethasone circumvents this problem but likely de-creases therapeutic responsiveness

SULFHYDRYL COMPOUNDS

Depigmentation has been found to occur with 2-mercaptoethylamine (MEA), N-(2-mercaptoethyl)-dimethylamine (MEDA), cystamine dihydrochloride, 3-mercaptopropylamine hydrochloride, and sulfanolic acid Sulfhydryl com-pounds were first observed to cause depigmentation in goldfish [69] Topical application of these compounds was later found to depigment mammalian skin [46,70]

With black guinea pigs, MEDA was found to be a more potent depigmenting agent than MEA, and sulfanilic acid, like hydroquinone, was found to induce barely perceptible hypopigmentation [71] In MEDA-treated epidermis, only rare melanocytes could be identified Those present contained many vacuoles, swollen mitochondria, and imperfectly melanized melanosomes Some small vacuoles resembled coated vesicles; larger ones containing electron-dense ma-terial resembled malformed melanosomes The depigmented skin contained some normal melanosomes similar to those in the untreated epidermis [71], a normal complement of Langerhans cells, and unidentified cells lacking des-mosomes, melanosomes, or Langerhans granules Although sulfhydryl-induced depigmentation has not been clearly documented in humans, several patients ingesting sulfhydryl-containing compounds have developed hypopigmenta-tion Depigmentation was observed in a black patient treated with thiouracil for hyperthyroidism [72] Chronic administration of BAL (2,3-dimercaptopro-panol) is said to cause graying of hair [73]

It was concluded that MEDA is a cytotoxic agent which alters or blocks the formation of melanin by tyrosinase inhibition The selective action on melanocytes suggested that thiol compounds attach to the melanocyte com-ponents by both covalent and ionic bonds, such that functional activity is disrupted These thiols may interfere directly with enzymes, including tyro-sinase, and may attach to microsomal particles thought to be templates for protein synthesis Riley [13] suggested sulfhydryl compounds may decrease the cellular capacity to inactivate a potentially harmful free radical

CINNAMIC ALDEHYDE

Several cases of perioral leukoderma simulating vitiligo from use of a

toothpaste containing cinnamic aldehyde have been observed [73a]

METALS

Mercurials have been widely used as depigmenting agents However, use

of mercurials has been banned because cutaneous absorption of mercury may

cause nephrotoxicity [67]

HYDROGEN PEROXIDE

Hydrogen peroxide is a very popular topical bleaching agent for hair

Ker-atin is irreversibly altered by oxidation of combined cysteine The cysteic acid

formed causes a significant change in the distribution of electrostatic

cross-links [74] Electron microscopy studies of bleached human scalp hair reveal

that bleaching is associated with destruction and dissolution of the melanin

granules There were no premelanosomes in bleached hair [75] There is no

evidence for a depolymerization of the melanin polymer

Benzoyl peroxide contained in antiacne preparations can also bleach hair

GUANONITROFURACIN

Cutaneous depigmentation was observed in Japan after the use of a topical

solution or ointment containing 5-nitro-2-furfurylidene aminoquaridine

(gua-nonitrofuracin) for the treatment of conjunctivitis and blepharitis One to eight

months after cessation of the therapy, depigmentation of the eyelid and

eye-lashes occurred in about 20% of the cases; in some, cutaneous depigmentation

remote from the sites of application of the compound was also observed Halo

nevi have been reported No patients had a history of preceding inflammatory

changes [76] The involved skin was normal except for the absence of melanin;

dopa reaction was negative

Absence of sweating in the leukodermatous macules has been described

and is said to precede appearance of the depigmentation This observation has

led to the hypothesis that guanonitrofuracin-induced leukoderma is

precipi-tated by some neuropathic process The eccrine sweat glands are histologically

normal

Guanonitrofuracin has been shown to interact with several components of

the melanogenesis pathways Guanonitrofuracin inhibits potato tyrosinase This

inhibition can be reversed by the addition of copper; it has been demonstrated

spectrophotometrically that guanonitrofuracin interacts with cupric sulfate

However, guanonitrofuracin does not inhibit the dopa reaction of normal

hu-man skin, and has only a 10% inhibitory effect on huhu-man melanoma tyrosinase

But according to Ito [77], since guanonitrofuracin is a competitive inhibitor of

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substrates in the dopa reaction, high concentrations of these substrates may mask an inhibitory effect of guanonitrofuracin It has also been suggested that guanonitrofuracin not only interacts with the tyrosinase copper, but also in-duces changes in the sulfhydryl metabolism of the skin so that increased sulfhy-dryl compounds are present to inhibit tyrosinase Animal experiments in which there is a slight increase in the sulfhydryl content of red blood cells support this hypothesis These changes are slow to develop and impossible to reproduce

by dopa technique None of these hypotheses, however, is totally satisfactory

sub-TRIPARANOL (MER-29)

Triparanol (MER-29), 1-[p-(~-diethylaminoethoxy)phenyl]-1-(p-tolyl)-2-(p­chlorophenyl)ethanol, a drug that principally blocks the conversion of demos-terol to cholesterol [79], was, for a short time, employed therapeutically to reduce cholesterol levels Change of hair color was one of the complications noted with use of MER-29 Achor, Winkelmann, and co-workers [80,81] re-ported loss of hair color in two males, and Minton and Bounds [82] observed

in one of 12 patients treated by MER-29 that the hair changed from dark brown

to light brown Winkelmann et a1 [81] observed two patients in whom amination of the hair shaft showed abrupt color change Alopecia, ichthyosis, and cataracts were other undesirable side effects of this drug Since MER-29

ex-is known to dex-isturb the formation of the horny layers in rat epidermex-is, it ex-is likely that the pigmentary changes are secondary to disturbed keratinization which results from interference with cholesterol synthesis [83]

The depigmentation in sites of epicutaneous testing with DNCB may be

postinfiammatory, may result from selective inhibition of melanogenesis, or

may arise from selective destruction of melanocytes The existence of DNCB

depigmentation suggests that an immunologic mechanism may cause

leuko-derma

ARSENIC

Chronic arsenical ingestion [86,87] can induce a cutaneous

leukomela-noderma which may occur without an antecedent dermatitis and may develop

several to many years after arsenical use The hyperpigmentation may be

dif-fuse, but more frequently the presence of small depigmented macules gives a

freckled or "raindrop" appearance The hypopigmented macules vary in size

from several millimeters to a few centimeters, are round to oval, usually not

confluent, and asymptomatic

Diagnosis is made by the history of therapeutic or industrial use of arsenic,

by the association of the other clinical signs of the disease, namely, loss of

hair, transverse whitish discoloration ofthe fingernails (Mees' lines), and, later,

keratotic lesions of palms and soles which can evolve into skin tumors, and

by the finding of elevated arsenic levels in urine, hair, and nails

The mechanism of the hypopigmentation is unknown

NITROGEN MUSTARD AND THIOTEPA

Boyland and Sargent [88] found intradermal injection of nitrogen mustard

to be followed by regrowth of white hair in mice Several cases of

depigmen-tation, localized to areas of topical application of thiotepa have been reported

[88a] By light and electron microscopy, melanocytes were apparently absent

in the depigmented area

CORTICOSTEROIDS

Depigmentation can follow either topical or intralesional injection of

cor-ticosteroids

Kestel [89] first reported hypopigmentation associated with the use of

cor-ticosteroid tape The tape alone (without the steroid preparation) did not

pro-duce the hypopigmentation, which was restricted to the sites of use of the

corticosteroid tape In this case, the skin remained hypopigmented for about

one week, then slowly repigmented Another patient applied flurandrenolide

tape to the side of her neck two times for 10 to 12 hours each Approximately

one month later, hypopigmentation appeared in the area of previous application

and remained unchanged for five months A 21-year-old female found herself

unable to tan in sites where triamcinolone acetonide cream had been applied

three times a day for one month Arnold et al [90] found topical depigmentation

to be fairly rapid, incomplete and reversible Amelanosis does not occur

Hypopigmentation may also complicate corticosteroid injections [91,92]

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Cutaneous depigmentation appeared four weeks after injection of 1 ml of methylprednisolone for tennis elbow [93] The complete depigmentation was postage-stamp in size and persisted at least 12 weeks after the injection De-pigmentation after injection of different corticosteroids has been noted to in-volve relatively fair-skinned as well as the dark-skinned peoples [94]

The course of the hypomelanosis induced by intralesional triamcinolone diacetate or acetonide was monitored in six black patients [95] Four months after developing hypopigmentation, two of these patients had experienced re-pigmentation while two others had shown no signs of repigmentation None had developed atrophy The inescapable conclusion was that in some cases hypopigmentation may be permanent Others [96,97] observed hypopigmen-tation several days to months after intra- or periarticular injection of cortico-steroids (triamcinolone acetonide) In these cases the hypomelanosis was gen-erally accompanied by alopecia and slight atrophy of the skin In most cases, repigmentation occurred within one year after the injections had been discon-tinued

The relative hypopigmenting potential of repeated application of several topical corticosteroid preparations was studied on guinea pigs by Arnold et al [90] Triamcinolone acetonide and betamethasone valerate 0.1% were found to

be potent depigmenting agents; desoxydecamethasone and hydrocortisone did not depigment The degree and rate of depigmentation may be a function of concentration Glick [94] suggested, and it seems reasonable, that the more potent and longer-acting corticosteroids are most likely to produce depigmen-tation

Electron microscopy suggests that the leukoderma secondary to steroid injection is related to a transfer block [98] Guinea pig studies [90] show

cortico-a decrecortico-ased number of melcortico-anocytes in the epidermis, infundibulum, cortico-and ternal root sheath The melanocytes present are swollen, have short, thick processes, and appear overloaded with melanin Arnold et al [90] noted the microscopic changes within the first several days are too limited to explain so rapid and intense a depigmentation; a mechanism other than, or in addition

ex-to, a transfer block must be involved

Cutaneous hypopigmentation must be considered one of the possible quelae of topical or intralesional steroid therapy, particularly in dark-skinned patients But considering the great frequency of usage of topical and intrale-sional corticosteroids, hypomelanosis is not commonly reported and must therefore be an unusual complication Discontinuation of the topical cortico-steroid usually results in repigmentation

eyelashes eyebrows beard and pubic hair None of the three black patients

or the two Puerto Ricans of this group was affected

All these disturbances proved reversible once butyrophenone was

discon-tinued Although the exact mechanism of this depigmentation is unknown it

seems likely that it is related to disturbances in keratinization probably induced

by an interference of the drug with cholesterol metabolism Decreased

choles-terol blood levels were found in several of these patients during the treatment

CHLOROQUINE DIPHOSPHATE

Amelanosis of hair following the administration of chloroquine was first

reported by Alving et al [100] in 1958 (Fig 197) This phenomenon occurred

in blond subjects taking 0.3 g daily Another subject developed the same changes

on a weekly dose of 0.5 g; the decreased hair color reversed spontaneously

when the dosage was reduced In three blond patients with lupus erythematosus

treated with 0.5 to 0.75 g of chloroquine diphosphate daily decreased hair

FIGURE 197 Localized

depig-mentation of hair following the

administration of chloroquine 500

mg a day This patient had light

brown hair (From: Saunders TS

et al: Decrease in human hair color

and feather pigment of fowl

fol-lowing chloroquine

diphos-phate J Invest Dermato133:87-90,

1959 Copyright, 1959, The

Wil-liams & Wilkins Co Used with

permission.)

501 CHEMICAL HYPOMELANOSIS