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CLCN7-Related Osteopetrosis.

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GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.
2007 Feb 12 [updated 2016 Jun 9].

Author information

1
CNR-IRGB, Milan Unit, Humanitas Clinical and Research Center, Rozzano, Italy
2
Universitätsklinik für Kinder- und Jugendmedizin, Ulm, Germany
3
Institut für Medizinische Genetik und Humangenetik, Charité Universitätsmedizin, Berlin, Germany

Excerpt

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-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, and hearing loss; absence of the bone marrow cavity resulting in severe anemia and thrombocytopenia; dental abnormalities, odontomas, and 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, and 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, and osteomyelitis of the mandible or septic osteitis or osteoarthritis elsewhere. Cranial nerve compression is rare.

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: ARO. Calcium supplementation for hypocalcemic convulsions; management of calcium homeostasis per individual 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, and 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. In general, individuals with ARO 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 pathogenic variants is unknown. Each child of an individual with autosomal dominant CLCN7-related osteopetrosis has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk for ADOII and ARO is possible if the pathogenic variant(s) have been identified in the family.

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