DISEASE CHARACTERISTICS:
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-Schönberg 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/TESTING:
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.
MANAGEMENT:
Treatment of manifestations: ARO: calcium supplementation for hypocalcemic convulsions; management of calcium homeostasis per the patient's needs; erythrocyte or platelet transfusions as needed; antibiotics for leukocytopenia; immunoglobulins for hypogammaglobulinemia; surgical decompression of the optic nerve; treatment of fractures by an experienced orthopedist; dental care with attention to tooth eruption, ankylosis, abscesses, cysts, fistulas. ADOII: orthopedic treatment for fractures and arthritis with attention to potential post-surgical complications (delayed union or non-union of fractures, infection); fractures near joints may require total joint arthroplasty. 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: ARO: Restricted intake of calcium and vitamin D just before, during, and following HSCT to prevent hypercalcemia. ADOII: Good routine dental care and oral hygiene to help prevent osteomyelitis of the mandible. 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. 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.
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