Genetic study of eight Egyptian patients with pycnodysostosis: identification of novel CTSK mutations and founder effect

Summary This is the first Egyptian study with detailed clinical and orodental evaluation of eight patients with pycnodysostosis and identification of four mutations in CTSK gene with two novel ones and a founder effect. Introduction Pycnodysostosis is a rare autosomal recessive skeletal dysplasia due to mutations in the CTSK gene encoding for cathepsin K, a lysosomal cysteine protease. Methods We report on the clinical, orodental, radiological, and molecular findings of eight patients, from seven unrelated Egyptian families with pycnodysostosis. Results All patients were offspring of consanguineous parents and presented with the typical clinical picture of the disorder including short stature, delayed closure of fontanels, hypoplastic premaxilla, obtuse mandibular angle, and drum stick terminal phalanges with dysplastic nails. Their radiological findings showed increased bone density, acro-osteolysis, and open cranial sutures. Mutational analysis of CTSK gene revealed four distinct homozygous missense mutations including two novel ones, c.164A>C (p. K55T) and c.433G>A (p.V145M). The c.164A>C (p. K55T) mutation was recurrent in three unrelated patients who also shared similar haplotype, suggesting a founder effect. Conclusion Our findings expand the mutational spectrum of CTSK gene and emphasize the importance of full clinical examination of all body systems including thorough orodental evaluation in patients with pycnodysostosis.