Hajdu–Cheney syndrome, also called acroosteolysis with osteoporosis and changes in skull and mandible, arthrodentoosteodysplasia and Cheney syndrome,[1] is an extremely rare autosomal dominant congenital disorder[2][3] of the connective tissue characterized by severe and excessive bone resorption leading to osteoporosis and a wide range of other possible symptoms.

Some general characteristics of an individual with Hajdu–Cheney syndrome include bone flexibility and deformities, short stature, delayed acquisition of speech and motor skills, dolichocephalic skull, Wormian bone, small maxilla, hypoplastic frontal sinuses, basilar impression, joint laxity, bulbous finger tips and severe osteoporosis.

Early tooth loss and bone deformities, such as serpentine tibiae and fibulae, are also common in those affected.

[citation needed] Mutations within the last coding exon of NOTCH2 that remove the PEST domain and escape the nonsense-mediated mRNA decay have been shown to be the main cause of Hajdu–Cheney syndrome.

These PEST domains are removed due to the premature stop codon in the amino acid sequence.

[citation needed] One of the main methods of pinpointing a NOTCH2 mutation that leads to HCS is through whole genome sequencing.

Through sequence analysis and symptom presentation in HCS patients, this proves to be the most definitive method of diagnosis.

HCS-03 was identified as the variant that is passed through affected family members and presents symptoms throughout the lifetime of the individual.

All variants of HCS lead to the same premature termination of PEST sequences which compromise normal function of NOTCH2.