CLCN7-Related Osteopetrosis

Clinical characteristics The spectrum of CLCN7-related osteopetrosis includes infantile malignant CLCN7-related recessive osteopetrosis (ARO), intermediate autosomal osteopetrosis (IAO), and autosomal dominant osteopetrosis type II (ADOII, Albers-Schonberg disease). Diagnosis/testing CLCN7-related osteopetrosis is suspected with identification of radiographic changes that are pathognomonic in ARO (generalized osteosclerosis, club-shaped long bones, osteosclerosis of the skull base, bone-within-bone appearance) and characteristic in ADOII (osteosclerosis of the spine ["sandwich vertebra" appearance], bone-within-bone appearance [mainly iliac wings], Erlenmeyer-shaped femoral metaphysis, mild osteosclerosis of the skull base, transverse bands of osteosclerosis in long bones). Identification of pathogenic variants in CLCN7 establishes the diagnosis. Management Treatment of manifestations: Prevention of primary manifestations: ARO. Hematopoietic stem cell transplantation (HSCT) can be curative; however, cranial nerve dysfunction is usually irreversible, and progressive neurologic sequelae occur in children with the neuronopathic form even after successful HSCT. Prevention of secondary complications: Surveillance: ARO. Complete blood count and ophthalmologic examination at least once a year; follow up per the transplantation center following HSCT. Agents/circumstances to avoid: ADOII. Activities with high fracture risk. Genetic counseling ARO is inherited in an autosomal recessive manner; ADOII is inherited in an autosomal dominant manner; about 40% of IAO is inherited in an autosomal recessive manner and about 60% in an autosomal dominant manner. Prenatal diagnosis for pregnancies at increased risk for ADOII and ARO is possible if the pathogenic variant(s) have been identified in the family.