A CTSK variant as a cause of intermediate autosomal recessive osteoclast poor osteopetrosis

Background Osteopetroses are rare high-bone-density disorders, classified as osteoclast-rich or -poor and as autosomal recessive or dominant, with severity ranging from neonatal to adult-onset. Autosomal recessive osteopetrosis involves variants in TCIRG1, CLCN7, OSTM1, SNX10, RANKL, RANK, SLC29A3, or few other genes. CTSK variants, encoding the osteoclast lysosomal protease cathepsin K, are classically associated with pycnodysostosis but may cause a broader skeletal spectrum. Typical pycnodysostosis features include short-limbed stature, small jaw, fragile sclerotic bones, distal acroosteolysis, delayed suture closure, clavicle dysplasia, and dental/nail anomalies; intelligence is usually normal. Biopsies, rarely performed, may show normal or low osteoclast number. Case series The index patient, aged 10, had short stature (−2.31SDS), high bone mass (BMD Z-score +4.8), and low-impact transverse femoral fractures. He had bicoronal and sagittal craniosynostosis requiring cranial vault expansion at age 6 for raised intracranial pressure, optic atrophy, and Chiari malformation type I with cervical syrinx. Additional features included scoliosis and prior vitamin D-deficiency rickets; learning was normal. Bone biopsy showed dense, irregular trabeculae without osteoblastic rim, reduced osteocytes, disorganised ossification, and no osteoclasts, fibrosis, or marrow. Gene panels for craniosynostosis and osteopetrosis were negative. Whole-genome-sequencing identified a homozygous CTSK variant (c.793T>G; p.Tyr265Asp) of uncertain significance, reclassified as likely pathogenic following segregation analysis. Both parents were heterozygous carriers and had short stature (mother −2.32SDS; father −2.53SDS) and early-onset knee osteoarthritis, without fractures. Marked variability was observed in his younger homozygous sibling, investigated after detection of the gene variant, aged 11. He had high lumbar BMD (Z-score +5.7), macrocephaly, sagittal and bilateral lambdoid craniosynostosis, mild developmental delay, normal height (0.08SDS) and no optic atrophy, scoliosis or fractures. Two heterozygous carriers had a low-normal height: one with final height −1.85SDS, normal bone mass (BMD Z-score +0.5; BMAD 0.246g/cm³), and prior vitamin D-deficiency rickets; the other with final height −1.68SDS and normal bone mass (Z-score +0.5). Two siblings were variant-negative: one had mild short stature (−1.96SDS) and one normal height (+0.31SDS); both had normal BMD (Z-score −0.3, -0.4). Conclusion We show that CTSK variants can cause osteoclast-poor ARO with craniosynostosis. Core features (high bone mass, craniosynostosis) segregated with disease, but severity varied. Some features overlap with pycnodysostosis (high bone mass, fractures, short stature), but others are atypical (craniosynostosis, optic atrophy, neurodevelopmental variability). These findings broaden the CTSK phenotype and support genomic testing and inclusion of CTSK in craniosynostosis, osteopetrosis, and bone fragility panels.