Overlapping Phenotypes in Osteopetrosis and Pycnodysostosis in Asian-Indians

Osteopetrosis is a disorder characterized by high bone density, hepatosplenomegaly, visual and hearing loss, and anemia. Pycnodysostosis presents with short stature, acroosteolysis, and dense bones. We, hereby, present here a family with autosomal dominant osteopetrosis and also children with recessive osteopetrosis and pycnodysostosis. The molecular confirmation was done in 3 cases. Genetic heterogeneity in clinical presentation is discussed here. Further studies will help in identifying epigenetic alterations and population-specific variants and also developing targeted therapies.

A case of autosomal dominant osteopetrosis type II with a severe bone phenotype but no amino acid converting mutation in the CLCN7 gene

Autosomal Dominant Osteopetrosis type II (ADOII), also known as Albers-Schonberg disease, is caused by mutation of the CLCN7 chloride channel gene and is characterized by reduced bone resorption. Here we report on an individual with the classic features of ADOII, who had a history of fractures from childhood, displayed high bone mass and characteristic sandwich vertebrae on x-ray. Our genetic analyses showed no amino acid converting mutation in the patients DNA but we did find evidence of haploinsufficiency of CLCN7 mRNA. An iliac crest bone sample from the patient revealed bone tissue and material abnormalities relative to normal controls based on quantitative backscattered electron imaging and histomorphometric analyses. Additionally to lamellar bone, we observed significant amounts of woven bone and mineralised cartilage, as well as an increased frequency and thickness (up to 15 microns) of cement lines. Giant osteoclasts with numerous nuclei were present. The bone mineralisation density distribution (BMDD) of the entire bone area revealed markedly increased average mineral content of the dense bone (CaMean T-score +10.1) and frequency of bone with highest mineral content (CaHigh T-score +19.6), suggesting continued mineral accumulation and lack of bone remodelling. Osteocyte lacunae sections (OLS) characteristics were unremarkable except the OLS shape which was unusually circular. Together, our findings suggest that the reduced expression of CLCN7 mRNA in osteoclasts, and possibly also osteocytes, causes poorly remodelled bone with abnormal bone matrix with high mineral content. This together with the lack of adequate bone repair mechanisms makes the material brittle and prone to fracture.