Endocrine Abstracts

Background: Hajdu-Cheney syndrome (HCS) is a rare genetic skeletal disorder characterized by diverse phenotypic features, leading to delayed diagnosis. The syndrome involves significant skeletal abnormalities, including acro-osteolysis and severe osteoporosis. No definitive pharmacological treatment exists for HCS, and bisphosphonate efficacy remains uncertain due to limited studies. Here, we present a case of early-onset HCS in a preschool-aged female with severe features and her response to zoledronic acid.Case PresentationThe patient, born to healthy parents, presented with facial deformities, micrognathia, and cranial defects at birth. During the first year, she also developed hearing impairment, congenital cardiac anomalies, and developmental delay. At one year, she underwent surgery for patent ductus arteriosus (PDA) and ventricular septal defect (VSD), during which skull radiographs revealed wormian bones, initially overlooked. By age seven, the patient showed worsening skeletal deformities, including acro-osteolysis, osteoporosis, fractures, and short stature. Radiographic assessments confirmed reduced bone mineral density, while elevated serum alkaline phosphatase indicated increased bone turnover. Genetic analysis identified a de novo pathogenic duplication in exon 34 of the NOTCH2 gene (c.6426dupT, p.E2143X), confirming HCS. The patient began treatment with calcium carbonate, cholecalciferol, and annual zoledronic acid infusions. Over 4.5 years, bone mineral density (BMD) improved significantly, especially in the whole body (excluding the cranium), with a 33.7% increase. Alkaline phosphatase levels normalized within the first year, and no new fractures occurred.ConclusionThis case is the second documented occurrence of HCS linked to the c.6426dupT mutation in the NOTCH2 gene, demonstrating early onset and severe phenotype. Early recognition of HCS is essential for effective management. Zoledronic acid treatment was associated with significant BMD improvements and may help reduce osteoporosis progression and prevent fractures. Further studies are needed to confirm the long-term efficacy and safety of this approach.