Stem cell transplantation for osteopetrosis in patients beyond the age of 5 years

Abstract

Osteopetrosis (OP) is a rare disease caused by defective osteoclast differentiation or function. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment available in the infantile "malignant" form of OP. Improved clinical and genetic diagnosis of OP has seen the emergence of a cohort of patients with less severe and heterogeneous clinical presentations. This intermediate form of OP does not call for urgent intervention, but patients accumulate debilitating skeletal complications over years and decades, which are severe enough to require curative treatment and may also require intermittent transfusion of blood products. Here we present data from 7 patients with intermediate OP caused by mutations in TCIRG1 (n = 2), CLCN7 (n = 2), RANK (n = 1), SNX10 (n = 1), and CA2 (n = 1), who were transplanted between the ages of 5 to 30 years (mean, 15; median, 12). Donors were matched siblings or family (n = 4), matched unrelated (n = 2), or HLA haploidentical family donors (n = 1). Conditioning was fludarabine and treosulfan based. All 6 patients transplanted from matched donors are currently alive with a follow-up period between 1 and 8 years at time of publication (median, 4 years) and have demonstrated a significant improvement in symptoms and quality of life. Patients with intermediate OP should be considered for HSCT.

Graphical abstract

Figure 1.

Baseline and follow-up plain radiography of the left lower extremity (femur) of patient 3. (A) Before HSCT, highly increased bone density with significantly diminished radiograph transparency, “ballooning,” especially of the distal femoral diaphysis, and meta/epiphysis. Transversal intraosseous dense horizontal lines are seen. (B) About 4 years after HSCT regression/normalization of bone density, however, decreased cortical lining and even increased osseous “ballooning” is seen. (C) About 8 years after HSCT, remodeling of bone size and complete normalization of cortical thickness is seen.