Cardiac anomalies in Axenfeld-Rieger syndrome due to a novel FOXC1 mutation
Cardiac anomalies in Axenfeld-Rieger syndrome due to a novel FOXC1 mutation
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DOI：
10.1002/ajmg.a.35697
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发表时间：
2013-01-01
影响因子：
2
通讯作者：
Salvin, Jonathan
中科院分区：
文献类型：
--
作者：
Gripp, Karen W.;Hopkins, Elizabeth;Salvin, Jonathan
AxenfeldRieger综合征（ARS）是一种常染色体显性遗传病，以眼前段异常和眼外表现为特征，包括牙齿异常和脐周皮肤多余。同源盒基因PITX2或编码FOXC1的转录因子的基因内突变被鉴定出来，包含这两个基因的基因组重排也会导致ARS。4060%为分子病因。眼外异常更常见于基因内PITX2突变而不是FOXC1突变。我们报告一个21个月大的婴儿青光眼患者，由于拱形二尖瓣发育不良导致充血性心力衰竭，需要瓣膜置换术，左心室流出道和主动脉弓轻度发育不良。家族史包括4名亲属有早发性青光眼；需要手术的先天性髋关节发育不良3例；外祖母也有房间隔缺损。尽管没有牙齿或脐部异常，但在受影响的个体中存在与ARS一致的前房异常。分子检测显示先证者及其患病母亲存在一种新的FOXC1突变（c.508C>T; p.Arg170Trp）；其他家庭成员都不在。一项文献综述揭示了4例先天性心脏病与基因内FOXC1突变相关的报道，而没有一例与基因内PITX2突变相关。此前，小鼠研究显示Foxc1 （Mf1）在发育中的瓣膜和房间隔中表达，支持Foxc1突变与瓣膜异常和ASD的因果关系。三个家族成员的髋关节发育不良提示FOXC1在de Hauwere综合征股骨头发育不良中具有6p25缺失的作用。进一步的临床和分子诊断报告将阐明基因型-表型相关性。(c) 2012 Wiley期刊有限公司
AxenfeldRieger syndrome (ARS) is an autosomal dominant condition characterized by ophthalmologic anterior segment abnormalities and extraocular findings including dental anomalies and redundant periumbilical skin. Intragenic mutations in the homeobox gene PITX2 or the transcription factor encoding FOXC1 were identified, and genomic rearrangements encompassing either gene also cause ARS. A molecular etiology is identified in 4060%. Extraocular anomalies occur more often with intragenic PITX2 than FOXC1 mutations. We report on a patient with infantile glaucoma presenting at age 21 months with congestive heart failure due to a dysplastic arcade mitral valve necessitating valve replacement, and mildly hypoplastic left ventricular outflow tract and aortic arch. Family history included early onset glaucoma in four relatives; congenital hip dysplasia requiring surgery in three; and an atrial septal defect in the affected maternal grandmother. Despite the absence of dental or umbilical abnormalities, anterior chamber abnormalities consistent with ARS were present in affected individuals. Molecular testing revealed a novel FOXC1 mutation (c.508C>T; p.Arg170Trp) in the proband and his affected mother; other family members were unavailable. A literature review revealed four reports of congenital heart disease associated with intragenic FOXC1 mutations, and none with intragenic PITX2 mutations. Previously, mouse studies showed Foxc1 (Mf1) expression in the developing valves and atrial septum, supporting a causal relationship of FOXC1 mutations for valvar anomalies and ASD. Hip dysplasia in three family members suggests a role for FOXC1 in the femoral head dysplasia of de Hauwere syndrome with 6p25 deletions. Further reports of clinical and molecular diagnoses will clarify genotypephenotype correlation. (c) 2012 Wiley Periodicals, Inc.