Clinical and Molecular Characterization of PHACES syndrome

首字母缩略词PHACES用于描述后颅窝畸形、血管瘤、动脉异常（心血管或脑血管）、主动脉缩窄和心脏缺陷、眼异常以及胸骨或腹侧缺陷的相关性。我们研究了一名女性患者与一种罕见的变异，这种神经皮肤疾病谁表现出胸骨裂，脐上缝，血管瘤的脸，胸部和四肢，小颌和脑血管异常。一项关于胸骨裂和脐上缝的PHACES患者的文献综述显示了明显的女性偏好。结合文献中胸骨裂、脐上缝和面部血管瘤的病例，91%（40/44）的患者为女性。 一名受影响的男性在出生后不久死亡。我们假设PHACES的性别偏见是由一个X连锁显性基因突变引起的，该基因在男性中通常是致命的，并对该家族的多态性雄激素受体基因座进行了X失活分析。 我们在未受影响的母亲中记录了一致的偏斜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）。这些发现与产生正常母体表型的有利偏斜X-失活一致，这是X连锁显性Rett综合征中记录的现象。我们未来的努力将取决于确定其他PHACES家庭中，母亲X-失活研究可以追求，和应用X染色体特异性阵列比较基因组杂交（阵列CGH）实验，以寻找亚显微拷贝数的变化PHACES综合征患者。

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.