RANK-dependent autosomal recessive osteopetrosis: characterisation of 5 new cases with novel mutations.

Autosomal Recessive Osteopetrosis (ARO) is a genetically heterogeneous disorder due to reduced bone resorption by osteoclasts. Most human AROs are classified as osteoclast-rich, but recently 2 subsets of osteoclast-poor ARO have been recognised as due to defects in either TNFSF11 or TNFRSF11A genes, coding the RANKL and RANK proteins, respectively. The RANKL/RANK axis drives osteoclast differentiation and also plays a role in the immune system. In fact, we have recently reported that mutations in the TNFRSF11A gene lead to osteoclast-poor osteopetrosis associated with hypogammaglobulinemia. Here we present the characterisation of 5 additional unpublished patients from 4 unrelated families in which we found 5 novel mutations in the TNFRSF11A gene, including 2 missense and 2 nonsense mutations and a single-nucleotide insertion. Immunological investigation in 3 of them showed that the previously described defect in the B cell compartment was present only in some patients and that its severity seemed to increase with age and the progression of the disease. HSCT performed in all 5 patients almost completely cured the disease even when carried out in late infancy. Hypercalcaemia was the most important post-transplant complication. Overall, our results further underline the heterogeneity of human ARO also deriving from the interplay between bone and the immune system, and highlight the prognostic and therapeutic implications of the molecular diagnosis. © 2011 American Society for Bone and Mineral Research.