EXTENSIVE CLINICAL EXPERIENCE Autosomal Dominant Osteopetrosis: Clinical Severity and Natural History of 94 Subjects with a Chloride Channel 7 Gene Mutation

摘要: Context: Autosomal dominant osteopetrosis (ADO) is a sclerosing bone disorder caused by heterozygous mutations in the chloride channel 7 (ClCN7) gene. The clinical manifestations of this disease have not been well characterized since discovery genetic basis ADO. Objectives: primary objectives were to improve our understanding ADO characteristics and study natural history largest series patients reported date. Design Setting: This was primarily retrospective crosssectional analysis individuals with ClCN7 mutation that conducted over 4-yr period at tertiary referral center through family reunions. Longitudinal data on subset subjects also studied. Patients Interventions: We studied 311 from 11 families, including 62 (patients classic phenotype based radiographs and/or biochemistries), 32 unaffected gene carriers (subjects but no radiographicand/orbiochemicalphenotype),and217controlswhodid harbor mutation. Clinical collected patient interviews examinations, medical records, self-reported responses questionnaire completed all subjects. Main Outcome Measures: prevalence fracture, osteomyelitis, visual loss, marrow failure determined. Differences analyzed according affected vs. carrier status, age, underlying genotype. Results:Ninety-twopercentofADOsubjectshadatleastonesequela disease. Gene did an increased risk manifestations, although they found significant increases mineral density (P 0.05). Compared controls, had significantly fracture (84 36%; P 0.0001) osteomyelitis (16 0.9%; 0.0001). Severe fractures (defined as 10 any type greater than one hip/femur fracture) identified only subjects, typically occurred maxilla or mandible older adults. Visual which its onset childhood, 19 3% respectively. Adults more likely manifest characteristic, definitive genotype-phenotype relationship could be concluded. suggest worsens time. Conclusions: CLCN7 frequently symptomatic manifested high rate occasional failure. sequelae ADO, can early infancy, appear worsen Fracture most prevalent consequence other severe occur should confused recessive forms osteopetrosis, particularly when childhood. (J Clin Endocrinol Metab 92: 771–778, 2007)