reversal of skeletal radiographic pathology in a case of malignant infantile osteopetrosis following hematopoietic stem cell transplantation

Case ReportReversal of skeletal radiographic pathology in a case of malignant infantile osteopetrosis following hematopoietic stem cell transplantation a Division of Paediatric Orthopedi

Case Report

Reversal of skeletal radiographic pathology in a case of malignant

infantile osteopetrosis following hematopoietic stem cell transplantation

a Division of Paediatric Orthopedics, Department of Orthopaedic Surgery, Faculty of Medicine, Ain-Shams University, 11591 Abbasia, Cairo, Egypt

b

Department of Paediatrics, Paediatric Haematology and Oncology, National Cancer Institute, Cairo University, Cairo, Egypt

c

Division of Medical Genetics, Department of Paediatrics, Faculty of Medicine, Ain-Shams University, 11591 Abbasia, Cairo, Egypt

d

Division of Musculoskeletal Radiology, Department of Radiodiagnosis, Faculty of Medicine, Ain-Shams University, 11591 Abbasia, Cairo, Egypt

a r t i c l e i n f o

Article history:

Received 21 September 2016

Accepted 23 December 2016

Available online xxxx

Keywords:

Malignant autosomal recessive

osteopetrosis

Pediatric bone imaging

Hematopoietic stem cell transplantation

Genetic osteosclerosing dysplasias

Marble bone disease

Resolution

a b s t r a c t

Malignant infantile autosomal recessive osteopetrosis (ARO) is rare hereditable skeletal dysplasia charac-terized by a generalized osteosclerosis ARO usually runs a fatal course in early childhood if untreated Serious complications can arise from bone marrow suppression and pancytopenia Hematopoietic stem cell transplantation (HSCT) is the only available treatment option that has been demonstrated to prolong life expectancy Few publications with limited study participants have explored the employment of skele-tal radiography to evaluate success of HSCT We assessed the role of skeleskele-tal radiography as a tool to eval-uate responsiveness to HSCT in a case of ARO with favorable short-term results

Ó 2016 The Egyptian Society of Radiology and Nuclear Medicine Production and hosting by Elsevier This

is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/

4.0/)

1 Introduction

Malignant infantile autosomal recessive osteopetrosis (ARO) is a

rare type of skeletal dysplasia characterized by a distinct

radio-graphic pattern of generalized increase in bone density[1] The

reported incidence of ARO is 1 in 250,000 births[2] Autosomal

recessive osteopetrosis typically manifests in infancy In general

the prognosis is poor It usually proves fatal in early childhood if

untreated [2] The most significant complications are related to

the bone marrow suppression and bone expansion with

subse-quent cranial nerve compression [2] Experimental and clinical

research on stem cells has provided insights into regenerative

medicine in general[3–7] It has also suggested future avenues of

research for the clinical applications of musculoskeletal tissue

engineering Such clinical applications may ameliorate the adverse

impact of some skeletal disorders and offer a potential cure[8–11] Hematopoietic stem cell transplantation (HSCT) offers a satisfac-tory treatment modality for a considerable percentage of ARO Hematopoietic stem cell transplantation may affect disease outcome positively It may arrest visual impairment and reverse hematopoietic and bone manifestations, especially if instituted in the first few months of life[2,12,13] Studies that report skeletal radiographic response to HSCT in ARO are few with limited num-ber of participants [13–15] Amelioration of radiographic bone lesions after HSCT in ARO have been proposed to be important indicators of success of HSCT[13–15] Nevertheless the detailing

of these bony abnormalities and their precise response to HSCT

in ARO has been reported only once[13] The purpose of this study

is to monitor the responsiveness of skeletal radiographic pathology

to HSCT in a case of ARO on the short-term

2 Case

An 18-months-old boy was brought to our outpatient clinic with complains of delayed milestones He was first in order to a first cou-sin parents Birth and family history were unremarkable Clinical Peer review under responsibility of The Egyptian Society of Radiology and Nuclear

Medicine.

⇑ Corresponding author.

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j o u r n a l h o m e p a g e : w w w s c i e n c e d i r e c t c o m / l o c a t e / e j r n m

examination revealed macrocephaly with opened anterior fontanel,

frontal bossing, nystagmus of left eye and retromicrognathia, near

normal stature and proportions and abnormal dentition He had

small chest cavity with ptosed liver and mildly enlarged spleen

with no focal lesions on ultrasonography The blood picture

revealed moderate anemia The whole-body skeletal radiographic

survey revealed the characteristic pattern of generalized increase

in bone density associated with ARO The patient was labelled as

having ARO based on the classic history, clinical examination, and

skeletal radiographic findings Molecular analysis was not

per-formed due to constrained resources

The patient received HSCT at two years of age The graft was

prepared by deriving stem cells from the bone marrow of the

healthy HLA identical mother He received Busulfan and long

courses of cyclophosphamide conditioning regimen He received

his stem cells through a Hikman central line He received

cyclos-porine A and methotrexate for graft-versus-host disease

prophy-laxis He had an uneventful post-transplant period with prompt

engraftment after 27 days To assess the hematopoietic

perfor-mance the patient was evaluated clinically and biochemically at

regular follow-up intervals At one-year follow- up the patient’s

motor milestones normalized but he developed a proportionate short stature with remarkable dolichocephaly Dentition abnor-malities and anemia persisted No functional limitations or recur-rent infections were encountered To characterize the radiologic response to HSCT we conducted a radiographic examination of the skull, spine, pelvis and whole appendicular skeleton at one-year follow-up We analyzed the following features; bone-within-bone appearance and homogeneity of the medullary bone, corticomedullary differentiation, diaphyseal metaphyseal mod-elling of the metaphyseal ends of long bones especially distal femora, proximal tibias and humeri, increased density of skull base and periorbital bones and pathologic fractures (Figs 1–5) All radiographic bone abnormalities showed complete resolution with few exceptions The bone-within-bone appearance of the pelvis showed partial resolution while it persisted in the spine The skull base and periorbital sclerosis persisted The resolution of bone changes was highly bilateral and symmetrical We detected a greenstick fracture of the distal right radius that healed following HSCT We encountered no rachitic-like changes or signs suggestive

of osteomyelitis The study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki

Fig 1 Skull radiographs a Pre HSCT demonstrating an overall increased density of the bones of skull base and periorbital bones (arrows) with fundamental involvement of the medullary portion b One-year post HSCT radiographs demonstrating increased anteroposterior diameter of skull and macrocephaly Note persistence of diffuse bone sclerosis except for small streaks of hypodense bone (arrows).

2 T.A EL-Sobky et al / The Egyptian Journal of Radiology and Nuclear Medicine xxx (2016) xxx–xxx

and its later amendments The radioclinical features of the

pre-sented case have previously been published by some authors of

the current study[1] Since then he was lost to follow-up after

which he showed up and was scheduled for HSCT

3 Discussion

Infantile autosomal recessive osteopetrosis is caused by failure

of normal osteoclastic resorption of bone and increase in density in

medullary portions of bones with sparing of cortices Osteoclasts

are finely specialized cells, which degrade inorganic and organic

bone matrix These processes are fundamental for bone

remodel-ing, providing mechanical support to the skeleton and mineral

from abnormal function and rarely from abnormal differentiation

[2] As a consequence of medullary canal obliteration and bony expansion, serious pancytopenia, cranial nerve compression, and pathologic fractures may evolve [2] HSCT is a satisfactory treat-ment modality that has been practiced as a measure to arrest or reverse hematopoietic, skeletal and neural abnormalities occurring with ARO and hence prolong life expectancy[2,13,14] HSCT has also been employed to arrest the progression or reverse the skele-tal manifestations of other hereditable skeleskele-tal dysplasia as some subtypes of mucopolysaccharidosis with less rewarding results

[16–24] Few reports with limited study participants have explored the use of skeletal radiographic evolution following HSCT as an indica-tor of treatment responsiveness with considerable success[13–15]

Fig 2 Pelvis and lower limb radiographs Pre HSCT AP radiographs of Pelvis (a) and lower limbs (b) Note the generalized bone sclerosis with medullary canal obliteration and loss of corticomedullary differentiation The classic ‘‘bone-within-bone” appearance is detectable in the pelvis, proximal femora and both tibias at multiple locations (arrows) (c, d) One-year post HSCT radiographs Notice the generalized reduction of bone density, partial disappearance of bone-within-bone sign in the pelvis and complete disappearance from the proximal femora (c) and both femora, tibias and fibulas (d) with a significant restoration of corticomedullary differentiation.

Taheri and colleagues were the first to report a detailed description

of all skeletal radiographic features encountered in 14 ARO

patients following HSCT [13] In general Taheri and colleagues

reported a statistically significant resolution of all skeletal

abnor-malities except for persistent bone-within-bone lesions in the

pel-vis and skull base and periorbital sclerosis[13] These findings are

consistent with those reported in our case report for the same

follow-up period Although, Taheri and colleagues[13], conducted

whole-body bone surveys they did not report radiographic changes

in the tibias, hands and spine The only exception was one

illus-trated case presentation in which they reported a resolution of

spine bone-within-bone appearance at the final follow-up

Like-wise, Cheow and colleagues did not include skull radiographs in

their bone survey[15] In our study we conducted a whole-body

bone survey and detailed the whole spectrum of skeletal

radio-graphic features found in a patient with ARO before and after HSCT,

including tibias hand and spine Radiographic resolution of bone

changes has been appreciated as early as three[14,15], and six

[13], months following HSCT Nonetheless, Taheri and colleagues

[13], noticed that rachitic-like changes in the ribs, defective

dia-physeal metadia-physeal modelling of the proximal humeri, and loss

of corticomedullary differentiation exhibited delayed complete

resolution in contrast to the remainder of the skeleton In our study

a six months radiographic follow-up was not included We

con-sider this a shortcoming Nonetheless, we believe that one-yearly

follow-up may be more suited to clinical practice and is less

radi-ation hazardous The literature reports only three cases of ARO that

were followed up radiographically for more than one year after

HSCT[14,15] In these cases, the resolution of bony abnormalities

was maintained up to five[14,15], and seven[14], years post HSCT The only three relevant publications to the current topic[13–15], reported resolution of the generalized radiographic skeletal pathol-ogy post HSCT except for residual changes detected at various localized regions The previous findings are in agreement with those reported in our study The swift and satisfactory skeletal response to HSCT in contrast to the delayed hematologic response

in our patient may be attributed to the functional diversity within the human bone marrow-derived stromal stem cells [25–31] Simanovsky and colleagues[32], have explored the relationship between radiologic findings and specific genetic backgrounds in patients with ARO before HSCT They found that the various genetic types of ARO showed a high degree of radiologic common-ality in increased bone density, bone-within-bone appearance, and defective metaphyseal remodeling Nevertheless, some genetic defects such as TCIRG1 were associated with the most severe radi-ologic findings[32] The responsiveness of skeletal radiographic pathology to HSCT amongst the various genetic backgrounds in ARO patients is an eagerly awaited investigation In that regard multicenter and multidisciplinary studies are encouraged owing

to the rarity and complexity of ARO

The authors of the current study perceive plain radiographs as a simple non-invasive tool to evaluate responsiveness to HSCT in ARO

We hypothesized that skeletal radiographic examination can be dependably employed to predictor ARO patient responsiveness to HSCT This study and the previous ones lend support to this hypoth-esis The rarity of the disease may attenuate efforts to execute studies with greater patient populations Longer follow-up periods are certainly needed to consolidate the previous conclusions

Fig 3 Left femur and tibia a Pre HSCT radiograph of the left distal femur demonstrating the Erlenmeyer flask deformity which is characterized by absence of normal diaphyseal metaphyseal modelling of the distal femora with abnormal radiographic appearance of trabecular bone and alternating radiolucent metaphyseal bands (arrows) b One-year post HSCT radiograph demonstrating remodeling diaphyseal metaphyseal junction with disappearance of funneling (flask deformity), marked reduction of bone density, and a more homogenous distribution of medullary and epiphyseal (arrows) bone density c Pre HSCT of the left tibia depicting a remodeling abnormality of the proximal tibial metaphysis and classic bone-within-bone appearance (arrows) d One-year post HSCT radiograph demonstrates tibial metaphyseal remodeling and significant amelioration of bone-within-bone appearance and a more homogenous distribution of medullary bone density.

4 T.A EL-Sobky et al / The Egyptian Journal of Radiology and Nuclear Medicine xxx (2016) xxx–xxx

Fig 4 Chest and upper limb radiographs a Pre HSCT chest radiographs depicting bone-within-bone appearance of both humeri (hollow arrows) and vertebrae, failure of normal diaphyseal metaphyseal modelling of the proximal and to lesser extent the distal humeri and bony expansion of anterior ribs (solid arrows) b One-year post HSCT chest radiographs shows complete disappearance of the bone-within-bone signs and remodeling of the diaphyseal metaphyseal regions of humerus and restoration of rib morphology and density with homogenous distribution of medullary bone density and appearance of corticomedullary differentiation c Pre HSCT forearm radiograph demonstrating increased density with loss of corticomedullary differentiation, and bone-within-bone sign (arrows) d One-year post HSCT radiograph demonstrating dramatic resolution of signs.

Conflict of interest

The authors declare that they have no conflict of interest

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