Clinical and Molecular Characterization of PHACES syndrome

首字母缩略词phases用于描述后窝畸形、血管瘤、动脉异常（心脑血管）、主动脉缩窄和心脏缺陷、眼睛异常以及胸骨或腹侧缺陷的关联。我们研究了一位患有这种神经皮肤疾病的罕见变体的女性患者，她表现为胸骨裂，脐上缝，面部，胸部和四肢的血管瘤，小颌和脑血管异常。一篇文献综述了伴有胸骨裂和脐上裂的PHACES患者，发现女性有明显的偏好。结合文献中收录的胸骨裂、脐上缝和面部血管瘤病例，91%（40/44）的患者为女性。一只受感染的雄性在出生后不久死亡。我们假设PHACES的性别偏倚是由于x连锁显性基因突变导致的，该基因在男性中通常是致命的，并对该家族的多态雄激素受体位点进行了x失活分析。我们在未受影响的母亲中记录了一致的偏x失活（在两个独立分析中为80%/20%），在先证者中记录了一致的随机x失活（在独立分析中为47:53和61:39）。这些发现与有利倾斜的x失活产生正常的母体表型相一致，这是在x连锁显性Rett综合征中记录的现象。我们未来的工作将取决于确定其他可以进行母体x失活研究的PHACES家族，并应用x染色体特异性阵列-比较基因组杂交（array-CGH）实验来搜索PHACES综合征患者亚显微拷贝数变化。

The acronym PHACES is used to describe the association of Posterior fossa malformations, Hemangiomas, Arterial anomalies (cardiovascular or cerebrovascular), Coarctation of the aorta and cardiac defects, Eye abnormalities, and Sternal or ventral defects. We studied a female patient with an uncommon variant of this neurocutaneous disorder who manifested a sternal cleft, supraumbilical raphe, hemangiomas of the face, chest, and extremities, micrognathia and cerebrovascular anomalies. A literature review of PHACES patients with both sternal cleft and supraumbilical raphe revealed a marked female predilection. Taken together with cases of sternal cleft, supraumbilical raphe and facial hemangiomas compiled in the literature, 91% (40/44) of patients are female. One affected male died shortly after birth. We hypothesized that the gender bias in PHACES results from mutation in a X-linked dominant gene often lethal in males, and performed X-inactivation analysis of the polymorphic androgen receptor locus in this family. We documented consistently skewed X-inactivation (80%/20% in two independent analyses) in the unaffected mother and consistently random X-inactivation (47:53 and 61:39 in independent analyses) in the proband. These findings are consistent with favorably skewed X-inactivation producing a normal maternal phenotype, a phenomenon documented in X-linked dominant Rett syndrome. Our future efforts will depend on ascertainment of other PHACES families in whom maternal X-inactivation studies can be pursued, and application of X-chromosome specific array-comparative genomic hybridization (array-CGH) experiments to search for submicroscopic copy number changes in PHACES syndrome patients.