Hajdu Cheney Syndrome; report of a novel NOTCH2 mutation and treatment with denosumab

Abstract Notch receptors play a central role in skeletal development and homeostasis. Hajdu Cheney Syndrome (HCS) is a rare disease associated with mutations of NOTCH2 that lead to the translation of a truncated, presumably stable, NOTCH2 protein. As a consequence, a gain-of-NOTCH2 function is manifested. We report a subject presenting with HCS and her child, both harboring a new heterozygous mutation in Exon 34 of NOTCH2 upstream of the PEST domain. The subject presented with osteoporosis, fractures, acroosteolysis and splenomegaly but did not have neurological complications, cardiovascular defects or polycystic kidneys. Sequencing of genomic DNA revealed a previously unreported mutation at nucleotide 6667C > T leading to a Gln2223Ter protein product in the subject and her son. Preclinical studies have demonstrated that the bone loss in HCS is secondary to enhanced osteoclastogenesis and bone resorption, and the same mechanism may operate in humans. Accordingly, the case we report was treated and responded to therapy with denosumab with an increase in bone mineral density (BMD). However, acroosteolysis progressed and was not modified by denosumab. In conclusion, we report a case of HCS associated with a novel mutation in NOTCH2 and its response to denosumab on BMD.