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Endocrine Abstracts (2019) 63 P467 | DOI: 10.1530/endoabs.63.P467

ECE2019 Poster Presentations Calcium and Bone 2 (59 abstracts)

Discovery of a novel NOTCH2 mutation causing Hajdu Cheney Syndrome in a kindred with remarkable phenotypic diversity

Zoe Efstathiadou 1 , Charilaos Kostoulas 2 , Stergios Polyzos 3 , Fani Kalograni 1 , Sotirios Tirkalas 1 , Fotini Adamidou 1 , Ioannis Georgiou 2 & Marina Kita 1

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1Department of Endocrinology, ‘Hippokration’ General Hospital of Thessaloniki, Thessaloniki, Greece; 2University of Ioannina, School of Health Sciences, Faculty of Medicine, Laboratory of Medical Genetics in Clinical Practice, Ioannina, Greece; 3Aristotle University of Thessaloniki, School of Medicine, Faculty of Clinical Pharmacology, Thessaloniki, Greece.


Introduction: Hajdu Cheney Syndrome (HCS) is a rare genetic autosomal dominant disorder affecting multiple organ systems, characterized by distinctive facial features, acroosteolysis and severe osteoporosis. In a limited number of cases, the disease appears in association with polycystic kidney disease (PKD) or Crohn’s disease (CD). Splenomegaly has also been reported. Heterozygous gain-of-function mutations in NOTCH2 gene have been confirmed to be the cause of HCS. Treatment with bisphosphonates or denosumab is reported to result in bone mineral density (BMD) increase.

Objective: We report a novel mutation in exon 34 of NOTCH2 gene, in a Greek pedigree, with diverse phenotype among members.

Description of the pedigree: The mother is a 48-year-old woman, with typical facial characteristics of HCS and a history of a T12 vertebral fracture, after parturition of her first male child, at 21 years of age, who presents with acroosteolysis and low BMD, but no further clinical fractures despite two subsequent pregnancies and the lack of antiosteoporotic treatment. The first male offspring is a 29-year-old male with severe osteoporosis and multiple morphological vertebral fractures. At age 25, he received a two-year treatment with teriparatide, with no improvement in BMD, but no incident fractures. Her second offspring passed away at the age of 10 months due to cystic fibrosis. The third offspring is a 21-year-old female with HCS clinical characteristics and vertebral fractures since 10 years of age. She received disodium pamidronate (during childhood) for 2 years. At 17 years of age, she developed severe CD, with functional hypothalamic hypogonadism and recurrent multiple vertebral fractures. She is on hormone replacement therapy and has received two courses of yearly zoledronic acid, with stabilization of BMD and no further incident fractures. None of the subjects had splenomegaly or renal defects on ultrasound examination.

Genetic testing: Heterozygous c.6758G>A (NM_008163.1) nonsense mutation, leading to a Trp2253Ter protein. This mutation has been classified (SCV000620308), however, this is the first report in association with HCS.

Conclusions: 1) Bone involvement can present with diverse severity in different members of the same pedigree, ranging from low BMD to multiple fragility fractures.

2) Antiresorptive therapy may be more rational than osteoanabolic therapy, since increased osteoclastogenesis is the primary pathophysiological mechanism; however, it remains to be definitely shown.

3) Apart from the characteristic bone manifestations, pulmonary disease and CD were diagnosed in different members of the family, indicating the significant role of NOTCH2 signaling pathway in different tissues.

Volume 63

21st European Congress of Endocrinology

Lyon, France
18 May 2019 - 21 May 2019

European Society of Endocrinology 

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