Genotype and phenotypic spectrum of pycnodysostosis: report of a case harboring two novel CTSK variants and literature review

Background Pycnodysostosis is an extremely rare inherited skeletal dysplasia with incidence of about 1 to 1.7 per million neonates. We reported a patient with pycnodysostosis, who had typical craniofacial deformity, short stature and recurrent limb fracture history. Literature was comprehensively reviewed to summarize the phenotype and genotypes of pycnodysostosis. Methods The patient underwent detailed physical and imaging examination. Bone mineral density and serum bone turnover biomarkers were measured. CTSK variants were detected by whole-exome sequencing and confirmed by sanger sequencing. A literature review was conducted for studies or case reports of pycnodysostosis confirmed by molecular diagnosis from 1996 to 2025 on PubMed, Google Scholar and Web of Science databases. Results The patient had very high bone mineral density at lumbar spine and proximal hip, with open anterior fontanelle, “sandwich-like” vertebral bodies, thickened cortical bone of limbs in X ray films. Novel heterozygous variants of c·653del (p.A218Efs*18) and c·581 G > T (p.G194V) in CTSK were identified. Literature review in 386 patients from 283 unrelated families showed that short stature (99%), osteosclerosis (99%) and brachydactyly (98%) were the most common manifestations of pycnodysostosis. 90 different mutations were identified and the most common mutation in CTSK were missense and frameshift mutations, accounting for 55.6% and 20.0% respectively. Residues Gly146, Arg241 and Ala277 of Cathepsin K were hotspot variants for pycnodysostosis. Conclusion: This study identified two novel variants in CTSK gene which may contribute to pycnodysostosis, and an updated comprehensive review of genotype and phenotypic spectrum of pycnodysostosis was conducted, providing important reference for the diagnosis of this extremely rare disease.