Case Report Severe osteoporosis and mutation in NOTCH2 gene in a woman with Hajdu–Cheney syndrome Ioannis P. Stathopoulos a, b, ⁎, George Trovas a , Kalliopi Lampropoulou-Adamidou a, b , Theodora Koromila c , Panagoula Kollia c , Nikolaos A. Papaioannou a , George Lyritis a a Laboratory for the Research of the Musculoskeletal System “Theodoros Garofalidis”, University of Athens, KAT hospital, Athens, Greece b Third Orthopaedic Department, University of Athens, KAT hospital, Athens, Greece c Laboratory of Human Genetics, Department of Genetics & Biotechnology, Faculty of Biology, University of Athens, Athens, Greece abstract article info Article history: Received 29 August 2012 Revised 18 October 2012 Accepted 19 October 2012 Available online 29 October 2012 Edited by: Rene Rizzoli Keywords: Hajdu–Cheney syndrome NOTCH2 mutation Osteoporosis Acro-osteolysis Skeletal dysplasia Hajdu–Cheney syndrome (HCS) is a rare genetic disorder characterised by acro-osteolysis, skull deformation and generalised osteoporosis. Recently, truncating mutations in the last exon of NOTCH2, a protein-coding gene, were found to be responsible. We present the case of a young woman with HCS in whom clinical and radiologic diagnosis was confirmed with DNA tests. © 2012 Elsevier Inc. All rights reserved. Introduction Hajdu–Cheney syndrome (HCS) is a rare disorder characterised by prominent skeletal dysplasia featured by craniofacial changes, dental anomalies, short stature, acro-osteolysis and generalised osteoporosis [1–3]. Although most of the reported cases are sporadic, the first case re- ports of HCS indicated that the syndrome is inheritable and the heredity pattern autosomal dominant. Recently, the genetic cause of HCS was identified to be mutations in the NOTCH2 gene, the coding gene for Notch2 receptor (Table 1) [4–6]. Notch receptors after binding to their ligands undergo changes that lead to translocation of their intracellular domain to the nucleus, thus activating the transcription of Notch target genes that have among others a dominant role in skeletal development and bone remodeling [7]. Alterations of Notch signaling are associated with developmental disorders of the skeleton, such as recessive brachydactyly, Alagille syndrome and spondylocostal dysostosis, and are also observed in osteosarcoma [7]. Here, we present the case of a young woman suffering from HCS for which we provide genetic confir- mation of the diagnosis. Patients and methods A 31-year-old woman presented in our outpatient clinic with a history of occasional back pain and multiple dental defects. She was 139 cm tall and weighed 43 kg. Upon inspection, she appeared to have many facial, head and hand abnormalities (Figs. 1 and 2A); she had small face, with telecanthus and downslated palpebral fissures, micrognathia, small mouth, thin lips, long philtrum and full cheeks. Her ears were positioned low, her neck was short, her hair was coarse and many of her fingers were thick with pseudo-clubbing. She was the first child of two healthy, non-consanguineous parents, delivered vaginally after a 37-week uncomplicated gestation. According to her mother, her development was uneventful until the age of six, when it was noticed that the child was not growing in height. She had relatively retarded puberty (at the age of fifteen), but no menstrual disorders. At the age of 16, she suffered an undisplaced forearm fracture after a fall from a 2-m height, which was treated conservatively with cast immobilisation for 6 weeks and healed well. At the age of nineteen, dental hypermobility occurred and led to the loss of six teeth. The patient's general health was good and her intelligence was normal. Both of her parents were alive. However, both suffered from arterial hypertension and her father had type II diabetes. Her 27-year-old brother had no history of medical problems. The entire family provided informed consent to undergo laboratory investigation Bone 52 (2013) 366–371 ⁎ Corresponding author at: Laboratory for the Research of Musculoskeletal System “Th. Garofalidis”, University of Athens, KAT Hospital, 10, Athinas str., Kifissia, 14561, Athens, Greece. Fax: +30 2108018122. E-mail address: ipstathopoulos@gmail.com (I.P. Stathopoulos). 8756-3282/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bone.2012.10.027 Contents lists available at SciVerse ScienceDirect Bone journal homepage: www.elsevier.com/locate/bone