Pycnodysostosis: a case series of eight Saudi patients with cathepsin K gene mutation and a literature review

Abstract

Pycnodysostosis, a rare osteopetrosis subtype, is mainly caused by homozygous or compound heterozygous biallelic pathogenic mutation of the cathepsin K (CTSK) gene. The cohort included eight patients (four males and four females) with a mean current age of 13 years (SD ± 3.6) and a mean age at diagnosis of 5 years (SD ± 2). All patients had a positive family history of pycnodysostosis and were born to consanguineous parents. Genetic analysis revealed that all individuals carried the same mutation: NM_000396.3(CTSK):c.244-29A>G. Clinically, they exhibited characteristic craniofacial features and skeletal deformities consistent with the diagnosis. Bone fractures were reported in 7 out of 8 patients, highlighting a significant clinical burden. All affected individuals received growth hormone therapy(GHT), though response to treatment varied among the group. These findings emphasize the importance of early genetic screening, particularly in families with a known history of pycnodysostosis, to enable timely diagnosis and intervention. Although pycnodysostosis is typically described as a nonprogressive skeletal dysplasia, the presence of complications such as osteomyelitis and recurrent fractures may contribute to a more complex and progressive clinical course in some patients.

Keywords: CTSK gene; bone fracture; osteomyelitis; osteopetrosis; skeletal deformities.

Figure 1

Skeletal X-ray of a male patient done at 11-year-old (Case 6) revealing moderate diffuse increased density of the skeletal bones with persistent open skull sutures, and widenings most prominent of the posterior sagittal and lambdoid sutures, anterior fontanelle, and straight mandible angles with abnormal teeth are noted (a, b). Irregularity at the posterior elements of the C2, C3 are seen (b). Spondylolysis /grade 1 spondylolisthesis of L5-S1 (c). Mild to moderately hypoplastic bilateral acetabulae are noted, with 8 mm lateral uncoverage of the right femur head, 12 mm lateral uncoverage of the left femur head seen (d). Prominent tufts resorptions /distal acro-osteolysis of bilateral feet and hands distal phalanges are noted (e, f). Overall Sclerosis and dysplastic skeletal features are compatible with Pycnodysostosis.

Figure 2

Skeletal X-ray of a male patient done at 8-year-old (Case 8) revealing multiple wormian bones identified in the skull with straightening of the mandibular angle (a, b). There are mild-to-moderate resorption of the distal phalanges of the hands and feet on both sides (c–e). Findings are consistent with Pycnodysostosis.

Figure 3

CDC Growth chart of a male patient (Case 8). At the presentation (aged 11 years old), his height measured 122 cm (SDS: -3.38, centile: 0.04). At his last visit (aged 16 years old), his height was recorded as 146.5 cm (SDS: -3.61, centile: 0.02). He is currently undergoing growth hormone therapy at a dose of 0.03 mg/kg/day.