Hajdu-Cheney syndrome is a rare autosomal-dominant disorder characterized by severe osteoporosis, acroosteolysis of the distal phalanges, craniofacial and dental anomalies, hearing loss and renal cysts, and has recently been associated with mutations in the NOTCH2 gene, located on chromosome 1.
A 13 years old boy, affected by an unrecognized syndrome with multi-organ involvement, presented to our Pediatric ICU due to a second episode of volvulus and bowel obstruction requiring laparotomy.
Upon physical examination, severe skeletal deformities were noted, along with dysmorphic features (exophthalmos, low set ears) and short stature. His medical history was notable for hearing impairment, subaortic stenosis, polycystic kidneys and hydrocephalus (Chiarri malformation), which had previously required VP shunt insertion. Furthermore, the patient had previously undergone multiple surgeries, including abdominal surgeries (gastrostomy, Nissen funduplication, umbilical and inguinal hernia repairs), as well as a tracheostomy. While his cognition was within normal range, his multi-system involvement severely impairs his quality of life, and he is wheelchair-bound. All his eight siblings are unaffected.
The patient was seen repeatedly in numerous leading medical centers, however remained without a diagnosis.
In order to establish a molecular diagnosis, DNA was extracted from whole blood for the patient and his parents, Whole Exome Sequencing (WES) was performed, and had found the patient to harbor a de novo nonsense mutation, p.Arg2400Ter, in the NOTCH2 gene.
In conclusion, WES, while a yet imperfect diagnostic tool, may prove valuable in appropriate clinical settings, especially with the diagnosis of rare Mendelian disorders with which most clinicians are yet unfamiliar.
