The spectrum of CLCN7-related osteopetrosis includes the following disorders: Infantile malignant CLCN7-related recessive osteopetrosis (ARO). Intermediate autosomal osteopetrosis (IAO). Autosomal dominant osteopetrosis type II (ADOII, Albers-Schonberg disease). Onset of ARO is in infancy; findings may include fractures; poor growth; sclerosis of the skull base (with or without choanal stenosis or hydrocephalus) resulting in optic nerve compression, facial palsy, hearing loss; absence of the bone marrow cavity resulting in severe anemia and thrombocytopenia; dental abnormalities, odontomas, risk for mandibular osteomyelitis; and hypocalcemia with tetanic seizures and secondary hyperparathyroidism. Without treatment maximal life span in ARO is ten years. Onset of IAO is in childhood; findings may include fractures after minor trauma; characteristic skeletal radiographic changes found incidentally; mild anemia; occasional visual impairment secondary to optic nerve compression. Life expectancy in IAO is usually normal. Onset of ADOII is usually late childhood or adolescence; findings may include fractures (in any long bone and/or the posterior arch of a vertebra); scoliosis; hip osteoarthritis; osteomyelitis of the mandible or septic osteitis or osteoarthritis elsewhere. Cranial nerve compression is rare.
Diagnosis of CLCN7-related osteopetrosis usually relies on 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). Molecular genetic testing of CLCN7, the only gene associated with CLCN7-related osteopetrosis, is available on a clinical basis.
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. Autosomal recessive inheritance: at conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Individuals with ARO in general only reproduce if successfully treated by HSCT. Autosomal dominant inheritance: most individuals diagnosed with autosomal dominant CLCN7-related osteopetrosis have an affected parent. The proportion of cases caused by de novo mutations is unknown. Each child of an individual with autosomal dominant CLCN7-related osteopetrosis has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk for ADOII and ARO is possible if the disease-causing mutation(s) have been identified in the family.