Cathepsin K Mutation-A Subtle Clinical Presentation

Pyknodysostosis is an uncommon inherited disorder associated with consanguinity, often presenting with sclerotic bone disease, short stature, dysmorphic features, and recurrent fragility fractures at an early age.

A 34-year-old woman was evaluated for the cause of recurrent fragility fractures. She was born of a third-degree consanguineous marriage and had a twin brother who was of short stature. The index patient had a height of 141 cm, dysmorphic features including frontoparietal bossing, blue sclera with short stubby fingers and toes. Radiological evaluation revealed diffuse osteosclerosis with acro-osteolysis exclusively in the toes, apart from mid-facial hypoplasia, lack of pneumatization of the paranasal sinuses, dental abnormalities, and scoliosis. Dual-energy x-ray absorptiometry revealed increased bone mineral density. Based on the clinical features, the patient was tested for cathepsin K gene variants using next-generation sequencing and was found to be positive for a novel homozygous c.224T>C, p.Met75Thr likely pathogenic missense variant.

This patient presented at a later age than expected with recurrent fragility fractures and the diagnosis was not suspected till adulthood, owing to the subtle clinical features. Confirmation with genetic testing helped in establishing the diagnosis.

Pyknodysostosis, although uncommon, is one of the differential diagnoses for diffuse osteosclerosis presenting with recurrent fragility fractures. Next-generation sequencing in an appropriate setting may confirm the diagnosis.