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

The Egyptian Journal of Radiology and Nuclear Medicine xxx (2016) xxx–xxx Contents lists available at ScienceDirect The Egyptian Journal of Radiology and Nuclear Medicine journal homepage: www.sciencedirect.com/locate/ejrnm Case Report Reversal of skeletal radiographic pathology in a case of malignant infantile osteopetrosis following hematopoietic stem cell transplantation Tamer Ahmed EL-Sobky a,⇑, Alaa El-Haddad b, Ezzat Elsobky c, Solaf M Elsayed c, Hossam Moussa Sakr d a Division of Paediatric Orthopedics, Department of Orthopaedic Surgery, Faculty of Medicine, Ain-Shams University, 11591 Abbasia, Cairo, Egypt 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 b 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 characterized 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 skeletal radiography to evaluate success of HSCT We assessed the role of skeletal radiography as a tool to evaluate 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/) Introduction Malignant infantile autosomal recessive osteopetrosis (ARO) is a rare type of skeletal dysplasia characterized by a distinct radiographic pattern of generalized increase in bone density [1] The reported incidence of ARO is 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 subsequent 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 satisfactory 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 number 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 Case Peer review under responsibility of The Egyptian Society of Radiology and Nuclear Medicine ⇑ Corresponding author E-mail addresses: tamersh@hotmail.com, tamer.ahmed@med.asu.edu.eg (T.A EL-Sobky) An 18-months-old boy was brought to our outpatient clinic with complains of delayed milestones He was first in order to a first cousin parents Birth and family history were unremarkable Clinical http://dx.doi.org/10.1016/j.ejrnm.2016.12.013 0378-603X/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/) Please cite this article in press as: EL-Sobky TA et al Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.013 T.A EL-Sobky et al / The Egyptian Journal of Radiology and Nuclear Medicine xxx (2016) xxx–xxx 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 performed 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 cyclosporine A and methotrexate for graft-versus-host disease prophylaxis He had an uneventful post-transplant period with prompt engraftment after 27 days To assess the hematopoietic performance 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 abnormalities and anemia persisted No functional limitations or recurrent 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 oneyear follow-up We analyzed the following features; bonewithin-bone appearance and homogeneity of the medullary bone, corticomedullary differentiation, diaphyseal metaphyseal modelling 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 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) Please cite this article in press as: EL-Sobky TA et al Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.013 T.A EL-Sobky et al / The Egyptian Journal of Radiology and Nuclear Medicine xxx (2016) xxx–xxx Fig 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 and its later amendments The radioclinical features of the presented 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 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 remodeling, providing mechanical support to the skeleton and mineral homeostasis Osteoclast dysfunction in ARO commonly results 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 treatment 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 skeletal manifestations of other hereditable skeletal 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 indicator of treatment responsiveness with considerable success [13–15] Please cite this article in press as: EL-Sobky TA et al Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.013 T.A EL-Sobky et al / The Egyptian Journal of Radiology and Nuclear Medicine xxx (2016) xxx–xxx Fig 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 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 abnormalities except for persistent bone-within-bone lesions in the pelvis 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 illustrated case presentation in which they reported a resolution of spine bone-within-bone appearance at the final follow-up Likewise, 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 radiographic 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 diaphyseal metaphyseal 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 consider this a shortcoming Nonetheless, we believe that one-yearly follow-up may be more suited to clinical practice and is less radiation 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 pathology 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 commonality 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 radiologic 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 hypothesis 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 Please cite this article in press as: EL-Sobky TA et al Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.013 T.A EL-Sobky et al / The Egyptian Journal of Radiology and Nuclear Medicine xxx (2016) xxx–xxx Fig 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 Please cite this article in press as: EL-Sobky TA et al Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.013 T.A EL-Sobky et al / The Egyptian Journal of Radiology and Nuclear Medicine xxx (2016) xxx–xxx Fig Hand radiographs a Pre HSCT hand radiographs showing typical bone-within-bone appearance b One-year post HSCT radiograph demonstrates complete resolution of signs, homogenous distribution of medullary bone density and restoration of corticomedullary differentiation and healing of pathologic fracture Conflict of interest The authors declare that they have no conflict of interest References [1] EL-Sobky TA, Elsobky E, Sadek I, Elsayed SM, Khattab MF A case of infantile osteopetrosis: the radioclinical features with literature update Bone Rep 2016;4:11–6 [2] Stark Z, Savarirayan R Osteopetrosis Orphanet J Rare Dis 2009;4:5 [3] Neri T, Muggeo S, Paulis M, Caldana ME, Crisafulli L, Strina D, et al Targeted gene correction in osteopetrotic-induced pluripotent stem cells for the generation of functional osteoclasts Stem Cell Rep 2015;5:558–68 [4] Bianco P Stem cells and bone: a historical perspective Bone 2015;70:2–9 [5] Abi Chahine N, Wehbe T, Rashed J, Hilal R, Elias N Autologous bone marrow derived stem cells for the treatment of multiple sclerosis Int J Stem Cells 2016;9:207–12 [6] Abdallah BM, Jafari A, Zaher W, Qiu W, Kassem M Skeletal (stromal) stem cells: an update on intracellular signalling pathways controlling osteoblast differentiation Bone 2015;70:28–36 [7] Baker N, Boyette LB, Tuan RS Characterization of bone marrow-derived mesenchymal stem cells in aging Bone 2015;70:37–47 [8] Bodle JC, Teeter SD, Hluck BH, Hardin JW, Bernacki SH, Loboa EG Age-related effects on the potency of human adipose-derived stem cells: creation and evaluation of superlots and implications for musculoskeletal tissue engineering applications Tissue Eng Part C Methods 2014;20:972–83 [9] Riminucci M, Remoli C, Robey PG, Bianco P Stem cells and bone diseases: new tools, new perspective Bone 2015;70:55–61 [10] Bodle JC, Hanson AD, Loboa EG Adipose-derived stem cells in functional bone tissue engineering: lessons from bone mechanobiology Tissue Eng Part B Rev 2011;17:195–211 [11] Mattioli-Belmonte M, Teti G, Salvatore V, Focaroli S, Orciani M, Dicarlo M, et al Stem cell origin differently affects bone tissue engineering strategies Front Physiol 2015;6:266 [12] Orchard PJ, Fasth AL, Le Rademacher J, He W, Boelens JJ, Horwitz EM, et al Hematopoietic stem cell transplantation for infantile osteopetrosis Blood 2015;126:270–6 [13] Hashemi Taheri AP, Radmard AR, Kooraki S, Behfar M, Pak N, Hamidieh AA, et al Radiologic resolution of malignant infantile osteopetrosis skeletal changes following hematopoietic stem cell transplantation Pediatr Blood Cancer 2015;62:1645–9 [14] Costelloe CM, Eftekhari F, Petropoulos D Radiography of successful bone marrow transplantation for osteopetrosis Skeletal Radiol 2007;36:S34–7 [15] Cheow HK, Steward CG, Grier DJ Imaging of malignant infantile osteopetrosis before and after bone marrow transplantation Pediatr Radiol 2001;31:869–75 [16] Langereis EJ, den Os MM, Breen C, Jones SA, Knaven OC, Mercer J, et al Progression of hip dysplasia in mucopolysaccharidosis type I Hurler after successful hematopoietic stem cell transplantation J Bone Joint Surg Am 2016;98:386–95 [17] Langereis EJ, Borgo A, Crushell E, Harmatz PR, van Hasselt PM, Jones SA, et al Treatment of hip dysplasia in patients with mucopolysaccharidosis type I after hematopoietic stem cell transplantation: results of an international consensus procedure Orphanet J Rare Dis 2013;8:155 [18] Schmidt M, Breyer S, Löbel U, Yarar S, Stücker R, Ullrich K, et al Musculoskeletal manifestations in mucopolysaccharidosis type I (Hurler syndrome) following hematopoietic stem cell transplantation Orphanet J Rare Dis 2016;11:93 [19] Yasuda E, Mackenzie WG, Ruhnke KD, Shimada T, Mason RW, Zustin J, et al Long-term follow-up of post hematopoietic stem cell transplantation for Hurler syndrome: clinical, biochemical, and pathological improvements Mol Genet Metab Rep 2015;2:65–76 [20] Yabe H, Tanaka A, Chinen Y, Kato S, Sawamoto K, Yasuda E, et al Hematopoietic stem cell transplantation for Morquio A syndrome Mol Genet Metab 2016;117:84–94 [21] Tomatsu S, Azario I, Sawamoto K, Pievani AS, Biondi A, Serafini M Neonatal cellular and gene therapies for mucopolysaccharidoses: the earlier the better? J Inherit Metab Dis 2016;39:189–202 [22] Yasuda E, Suzuki Y, Shimada T, Sawamoto K, Mackenzie WG, Theroux MC, et al Activity of daily living for Morquio A syndrome Mol Genet Metab 2016;118:111–22 [23] Tomatsu S, Sawamoto K, Alméciga-Díaz CJ, Shimada T, Bober MB, Chinen Y, et al Impact of enzyme replacement therapy and hematopoietic stem cell transplantation in patients with Morquio A syndrome Drug Des Devel Ther 2015;9:1937–53 [24] Chinen Y, Higa T, Tomatsu S, Suzuki Y, Orii T, Hyakuna N Long-term therapeutic efficacy of allogenic bone marrow transplantation in a patient with mucopolysaccharidosis IVA Mol Genet Metab Rep 2014;1:31–41 [25] Elsafadi M, Manikandan M, Atteya M, Hashmi JA, Iqbal Z, Aldahmash A, et al Characterization of cellular and molecular heterogeneity of bone marrow stromal cells Stem Cells Int 2016;2016:9378081 [26] Larsen KH, Frederiksen CM, Burns JS, Abdallah BM, Kassem M Identifying a molecular phenotype for bone marrow stromal cells with in vivo boneforming capacity J Bone Miner Res 2010;25:796–808 Please cite this article in press as: EL-Sobky TA et al Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.013 T.A EL-Sobky et al / The Egyptian Journal of Radiology and Nuclear Medicine xxx (2016) xxx–xxx [27] Zaher W, Harkness L, Jafari A, Kassem M An update of human mesenchymal stem cell biology and their clinical uses Arch Toxicol 2014;88:1069–82 [28] Kassem M, Bianco P Skeletal stem cells in space and time Cell 2015;160:17–9 [29] Worthley DL, Churchill M, Compton JT, et al Gremlin Identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential Cell 2015;160:269–84 [30] Bianco P, Robey PG Skeletal stem cells Development 2015;142:1023–7 [31] Jones EA, Giannoudis PV, Kouroupis D Bone repair with skeletal stem cells: rationale, progress to date and clinical application Ther Adv Musculoskelet Dis 2016;8:57–71 [32] Simanovsky N, Rozovsky K, Hiller N, Weintraub M, Stepensky P Extending the spectrum of radiological findings in patients with severe osteopetrosis and different genetic backgrounds Pediatr Blood Cancer 2016;63:1222–6 Please cite this article in press as: EL-Sobky TA et al Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.013