Abstract
Hajdu-Cheney syndrome (HCS) is a rare multi-system disease with autosomal dominant inheritance and skeletal involvement, resulting mostly in craniofacial dysmorphy with mid-face hypoplasia, dental anomalies, short stature, scoliosis, shortening of the digits and nail beds, acro-osteolysis and osteoporosis. We report the progression of clinical and radiographic findings in five patients with Hajdu-Cheney syndrome from two families. A custom capture array designed to capture exons and adjacent intron sequences of 230 selected genes were used for molecular analyses, and the pathogenic variants identified were confirmed by PCR and Sanger sequencing. In both families we observed age-dependent changes in the disease, with a progression of pain in older patients, a shortening of digits and nail beds on both the hands and feet, kyphoscoliosis and the persistence of Wormian bones in lambdoid sutures. Molecular analyses performed in two patients revealed that they are heterozygotes for a c.6255T>A (p.Cys2085*) variant in the NOTCH2 gene, resulting in a premature stop-codon. Bone mineral density (Z-score < -2) did not improved in a girl treated with calcium and vitamin D supplementation during childhood and bisphosphonate during adolescence. Hajdu-Cheney syndrome is a slowly progressive disease with a frequently unfavourable prognosis in elderly patients, especially for the development of dental anomalies, osteoporosis and the progression of skeletal complications requiring orthopedic surgeries.
Highlights
Hajdu-Cheney syndrome (HCS) is a rare multi-system disease with skeletal involvement and autosomal dominant inheritance, and is associated with mutations in the terminal exon 34 of the NOTCH2 gene encoding the transmembrane NOTCH2 receptor (Isidor et al, 2011; Simpson et al, 2011; Adami et al, 2016; Pittaway et al, 2018)
The results of molecular analyses demonstrated that patients P1 and P2 are heterozygotes for the novel c.6255T>A (p.Cys2085*) variant in the NOTCH2 gene resulting in a premature stop-codon
Acro-osteolysis of all distal phalanges on the hands and three distal phalanges on the feet of P1 at the age of 17 years are shown on Figure 3
Summary
Hajdu-Cheney syndrome (HCS) is a rare multi-system disease with skeletal involvement and autosomal dominant inheritance, and is associated with mutations in the terminal exon 34 of the NOTCH2 gene encoding the transmembrane NOTCH2 receptor (Isidor et al, 2011; Simpson et al, 2011; Adami et al, 2016; Pittaway et al, 2018). The disease is slowly progressive with an onset in childhood or adolescence resulting in short stature, craniofacial dysmorphism with mid-face hypoplasia, hypertelorism, bushy eyebrows, micrognathia, small mouth and dental anomalies, vertebral anomalies, scoliosis, and bowing of the long bones. We present the age-dependent progression of clinical and radiological manifestations of Hajdu-Cheney syndrome in five patients from two families Other features may develop, including hearing loss, renal cysts and cardiovascular involvement (Ramos et al, 1998; Isidor et al, 2011; Regev et al, 2019).
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