ESPE Abstracts

Background: Hajdu-Cheney syndrome (HCS) is a rare autosomal dominant condition characterized by osteoporosis, acro-osteolysis, short stature and specific craniofacial features and is caused by mutations in the NOTCH2 gene which codes for a single-pass transmembrane protein that plays a critical role in skeletal development and bone remodelling. Syringomyelia has been reported in 5 of 75 reported cases of HCS worldwide. The mechanism for this association is unknown and has not been explored. We report a 17 year old white Caucasian male who had the typical dysmorphic features of the condition, osteoporosis and multiple wedge fractures of the thoracolumbar vertebrae as well as metatarsals and metacarpals and had a pathogenic NOTCH2 mutation. He also developed a thoracic and cervical syrinx necessitating foramen magnum widening though there was no Arnold Chiari malformation or platybasia.

Objective: Postulate a mechanism for the association between HCS and syringomyelia.

Method: A literature search was undertaken to examine the relationship between NOTCH mutations and its effects on bone and the nervous system.

Results: NOTCH mutations are associated with over-activity of RANKL system and resultant osteoclast mediated osteoporosis. NOTCH signalling also plays a crucial role in enabling neural progenitors to attain sufficiently high levels of sonic hedgehog (SHH) pathway activity which in turn is needed to direct the fates of the ventral-most cells in the developing nervous system which ultimately forms the spinal cord.

Conclusion: Abnormalities in NOTCH and SHH signalling is a potential mechanism to explain the abnormalities present in bones and the nervous system in HCS. We propose that impaired NOTCH signalling is responsible for osteoporosis and the effect of impaired NOTCH on SHH pathway is a potential explanation of syringomyelia in HCS.