Multiple osteochondromas following irradiation‐containing conditioning in severe combined immunodeficiency

Osteochondroma (exostosis) is identified in 1–3% of the population as a slow-growing solitary cartilage-capped bony protuberance, typically arising from long bone diametaphysis (Kitsoulis et al, 2008). Multiple osteochondromas are found in some families as a hereditary autosomal dominant condition. Irradiation for malignancies or total body irradiation (TBI) prior to bone marrow transplantation (BMT) are associated with neurological dysfunction, cataracts, growth and dental abnormalities, pulmonary disease, hypothyroidism, gonadal dysfunction and secondary malignancies or benign tumours, including osteochondromas (Faraci et al, 2005; Shido et al, 2012). Severe combined immune deficiency (SCID) is a heterogeneous group of inherited profound T lineage defects resulting in increased susceptibility to infections or immune dysregulation. SCID often leads to death in infancy unless treated by allogeneic BMT. Various conditioning regimens, with or without TBI have been given to patients with SCID to facilitate donor engraftment (Filipovich et al, 1992; Dror et al, 1993; Grunebaum et al, 2006). Recently, the European Blood and Marrow Transplantation group also suggested TBI for reduced intensity transplantations (Bacigalupo, 2004). There has been a single report of osteochondromas developing in four SCID patients, which lacked detailed radiological and long-term outcome descriptions (Chou et al, 1996), hence it is not known whether SCID patients are also prone to the development of osteochondromas. Here we describe two additional SCID patients who developed multiple osteochondromas after TBI conditioning. Patient 1 presented with exfoliative dermatitis, lymphadenopathy, hepatosplenomegaly, failure to thrive and Pneumocystis Jiroveci pneumonia. He was diagnosed with SCID and Omenn syndrome. There were no mutations in genes known to cause SCID associated with increased irradiation sensitivity. The patient received BMT at 13 months of age following busulfan and cyclophosphamide conditioning. He required a second BMT 3 months later, which was accomplished with stored bone marrow from the original donor following cyclophosphamide and TBI (200 cGy × 2/d for 3 consecutive d). A skeletal survey, performed 9 years after BMT for short stature (<3rd percentile), revealed multiple bony outgrowths of the right iliac bone, proximal and distal femurs, fibula (not shown), proximal metaphysis of the right humerus (Fig 1A) and distal metaphysis of the radius (Fig 1B). There were also irregularities and linear sclerosis of the tibial, metatarsal, radial and ulnar metaphyses. A repeat skeletal survey 12 years after BMT showed continued growth of the bony lesions as well as a new osteochondroma at the left iliac crest (Fig 1C). Patient 2 presented with progressive respiratory difficulties, oral thrush, failure to thrive and Pneumocystis Jiroveci pneumonia. He was diagnosed at 8 months of age as suffering from SCID due to an IL2RG defect. Four months later, the patient received BMT following busulfan and cyclophosphamide conditioning. Because of engraftment failure the patient received a second BMT at 19 months of age with stored bone marrow from the original donor following cyclophosphamide and TBI conditioning. A right distal ulnar bone growth was noticed 7 years after the second BMT, which caused significant parental and patient anxiety. Radiograph demonstrated an osteochondroma arising from the anteromedial aspect of the distal right ulnar diametaphysis (Fig 2A), which was not present in a radiograph of the ulna performed at 2 years of age. There was also shortening of the ulna with broadening and down-sloping of the distal articular surface as well as enlargement of the distal epiphysis. Computerised tomography scan of the chest performed 1 year later revealed another osteochondroma at the superior-medial aspect of the scapula (Fig 2B). A year later, radiographs identified additional small osteochondromas at the distal metaphysis of the 2nd metacarpal as well as the 2nd and 3rd proximal phalanges of the right hand (not shown). The patient and family continue to be concerned about the aesthetic implications of the bone growths. Both patients are clinically well, have complete donor engraftment and normal immune function. Osteochondromas were not detected in other patient's family members, nor were they found in additional 26 patients with SCID who received BMT following similar busulphan and cyclophosphamide conditioning but without TBI at the Hospital for Sick Children, Toronto, Ontario (Fisher's exact test; P = 0·003). In contrast to previous reports of osteochondromas in patients who typically had multiple courses of chemo- and radio- therapy (Faraci et al, 2009; Shido et al, 2012), the patients described here received 400 mg/kg cyclophosphamide and 16 mg/kg busulfan. Also, while the former patients often suffered from abnormalities in genes responsible for uncontrolled cell growth, this is not the case in our patients. Moreover, our patients had no other known factors predisposing for bone overgrowth, such as familial osteochondromas or mutations in genes associated with irradiation sensitivity. Taken together, our findings implicate TBI as a major cause for osteochondromas development in SCID patients, possibly because of damage to the periosteal bone cuff that surrounds the epiphyseal plate during early life (Bovée et al, 2010). The optimal skeletal surveillance of children who receive TBI at early age for SCID or other indications is not known. The osteochondromas in our patients were first identified 7 and 9 years after TBI and new tumours were detected during subsequent years. Our patients were managed conservatively with thorough evaluations for pain, neurovascular damage and articular malfunction as well as a repeat of skeletal survey in one patient. Yet, there are significant aesthetic and potential functional implications arising from osteochondromas. Moreover, malignant transformations have been reported in 1–5% of osteochondromas (Bovée et al, 2010). Thus, studies with larger number and longer follow-up of patients SCID and possibly other non-malignant conditions who receive TBI are required to determine the role of preemptive skeletal imaging and/or lesion biopsies. In the meantime it is important to counsel families of infants receiving TBI prior to BMT regarding the potential development of multiple osteochondromas. In conclusion, our study shows that immature bones of SCID patients who receive TBI prior to BMT are prone to the development of osteochondromas. Our observation also suggests the need to revise TBI-containing protocols for patients with SCID and possibly other infants with malignant and non-malignant conditions. This work was supported in part by the Jeffrey Modell Foundation, by the Canadian Centre for Primary Immunodeficiency, and by the Donald and Audrey Campbell Chair of Immunology (CMR). EG, CMR and MG made substantial contributions to conception and design of the study. EG, CMR, AD, DM, VHDK, LMF and MG performed the study. EG, CMR and MG analysed the data. All authors contributed to writing and reviewing the manuscript.

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