Autosomal dominant osteopetrosis: Clinical severity and natural history of 94 subjects with a chloride channel 7 gene mutation
Autosomal dominant osteopetrosis: Clinical severity and natural history of 94 subjects with a chloride channel 7 gene mutation
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DOI：
10.1210/jc.2006-1986
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发表时间：
2007-03-01
影响因子：
5.8
通讯作者：
Econs, Michael J.
中科院分区：
文献类型：
--
作者：
Waguespack, Steven G.;Hui, Siu L.;Econs, Michael J.
背景：常染色体显性骨硬化症（ADO）是一种由氯离子通道7（C1 CN 7）基因杂合突变引起的硬化性骨病。这种疾病的临床表现还没有得到很好的特点，因为发现的遗传基础ADO.Objectives：主要目的是提高我们的理解ADO的临床特点和研究的自然历史的疾病在最大系列的病人报告日期。设计和设置：这项研究主要是一项回顾性横断面分析的个人与C1 CN 7突变，进行了为期4年的时间在三级转诊中心和通过家庭团聚。还研究了受试者子集的纵向数据。患者和干预措施：我们研究了来自11个ADO家系的311名受试者，其中包括62名ADO患者（根据X光片和/或生化检查，具有经典临床表型的患者），32名未受影响的基因携带者（具有基因突变但没有放射学和/或生化表型的受试者），以及217名没有携带C1 CN 7基因突变的对照。临床数据收集通过患者的访谈和检查，医疗记录，和/或自我报告的问卷调查，完成了所有subjects.Main结果的措施：骨折，骨髓炎，视力下降，骨髓衰竭的患病率进行了测定。临床表现的差异进行了分析，根据受影响与载体状态，年龄和潜在的genotype.Results：百分之九十二的ADO受试者至少有一个后遗症的疾病。基因携带者并没有增加疾病表现的风险，尽管他们被发现有显着增加骨密度（P < 0.05）。与对照组相比，ADO受试者骨折（84 vs. 36%; P < 0.0001）和骨髓炎（16 vs. 0.9%; P < 0.0001）的患病率显著增加。仅在ADO受试者中发现严重骨折（定义为任何类型的骨折≥ 10处和/或髋关节/股骨骨折超过1处），骨髓炎通常发生在老年人的上颌骨或下颌骨。视力丧失，通常在儿童期发病，和骨髓衰竭分别发生在19%和3%的ADO受试者中。成人更可能表现出ADO临床特征，但不能得出明确的基因型-表型关系。纵向数据表明，ADO的临床表型随时间推移而变化。结论：ADO引起的CLCN 7基因突变是一种常见的症状性疾病表现为骨折，骨髓炎，视力丧失，偶尔骨髓衰竭的高比率。ADO的后遗症早在婴儿期就可以发现，但随着时间的推移似乎会恶化。骨折是ADO最常见的后果，尽管可能发生其他更严重的疾病表现，但不应与隐性形式的骨硬化症混淆，特别是在儿童早期发现时。
Context: Autosomal dominant osteopetrosis (ADO) is a sclerosing bone disorder caused by heterozygous mutations in the chloride channel 7 (C1CN7) gene. The clinical manifestations of this disease have not been well characterized since the discovery of the genetic basis of ADO.Objectives: The primary objectives were to improve our understanding of ADO clinical characteristics and to study the natural history of the disease in the largest series of patients reported to date.Design and Setting: This study was primarily a retrospective cross-sectional analysis of individuals with a C1CN7 mutation that was conducted over a 4-yr period at a tertiary referral center and through family reunions. Longitudinal data on a subset of subjects were also studied.Patients and Interventions: We studied 311 subjects from 11 ADO families, including 62 individuals with ADO (patients with the classic clinical phenotype based on radiographs and/or biochemistries), 32 unaffected gene carriers (subjects with the gene mutation but no radiographic and/or biochemical phenotype), and 217 controls who did not harbor a C1CN7 gene mutation. Clinical data were collected through patient interviews and examinations, medical records, and/ or self-reported responses on a questionnaire that was completed by all subjects.Main Outcome Measures: The prevalence of fracture, osteomyelitis, visual loss, and bone marrow failure was determined. Differences in clinical manifestations were analyzed according to affected vs. carrier status, age, and underlying genotype.Results: Ninety-two percent of ADO subjects had at least one sequela of the disease. Gene carriers did not have an increased risk of disease manifestations, although they were found to have significant increases in bone mineral density (P < 0.05). Compared with controls, subjects with ADO had a significantly increased prevalence of fracture (84 vs. 36%; P < 0.0001) and osteomyelitis (16 vs. 0.9%; P < 0.0001). Severe fractures (defined as >= 10 fractures of any type and/ or greater than one hip/femur fracture) were identified only in ADO subjects, and osteomyelitis typically occurred in the maxilla or mandible in older adults. Visual loss, which typically had its onset in childhood, and bone marrow failure occurred in 19 and 3% of ADO subjects, respectively. Adults were more likely to manifest an ADO clinical characteristic, but no definitive genotype-phenotype relationship could be concluded. Longitudinal data suggest that the ADO clinical phenotype worsens over time.Conclusions: ADO caused by mutations in the CLCN7 gene is a frequently symptomatic disease manifested by a high rate of fracture, osteomyelitis, visual loss, and occasional bone marrow failure. The sequelae of ADO, which can be identified as early as infancy, appear to worsen over time. Fracture is the most prevalent consequence of ADO, although other more severe manifestations of disease can occur and should not be confused with recessive forms of osteopetrosis, particularly when identified in early childhood.