Identification of novel mutation in RANKL by whole-exome sequencing in a Thai family with osteopetrosis; a case report and review of RANKL osteopetrosis

Abstract

Background: Osteopetrosis is a rare form of skeletal dysplasia characterized by increased bone density that leads to bone marrow failure, compressive neuropathy, and skeletal dysmorphism. Molecular diagnosis is essential as it guides treatment and prognosis. We report Thai siblings with an ultra-rare form of osteopetrosis.

Methods: The older brother and the younger sister presented with chronic mandibular osteomyelitis in their 20s. Since childhood, they had visual impairment, pathological fracture, and skeletal dysmorphism. Quadruplet whole-exome sequencing was performed and confirmed with Sanger sequencing. Novel mutation in TNFSF11 (RANKL) c.842T>G, p.Phe281Cys was identified in a homozygous state in both siblings.

Results: Surgical debridement, antibiotic, and hyperbaric oxygen therapy were used and discontinued over a 6-month period with normalization of C-reactive protein. Hematopoietic stem cell transplantation candidacy was excluded by molecular diagnosis.

Conclusion: We report a novel mutation in an ultra-rare form of osteopetrosis. Our siblings manifested with a milder phenotype in comparison with nine cases previously published.

Trial registration: ClinicalTrials.gov NCT02666768.

Keywords: TNFSF11; bone; genome; osteopetrosis; skeletal dysplasia.