Clinical and Molecular Characterization of PHACES syndrome

缩写PHACES用于描述后颅窝畸形、血管瘤、动脉畸形(心血管或脑血管)、主动脉缩窄与心脏缺陷、眼睛异常以及腹部或腹部缺陷的关联。我们研究了一名患有这种神经皮肤病的罕见变异的女性患者，她表现为胸骨裂隙、脐上缝、面部、胸部和四肢的血管瘤、小颌畸形和脑血管异常。对同时患有胸骨裂和脐上缝的PHACES患者的文献回顾显示，女性有明显的偏好。结合文献中收集的胸骨裂、脐上缝和面部血管瘤病例，91%(40/44)的患者为女性。一名受影响的男性在出生后不久死亡。我们假设PHACES中的性别偏见是由一个X连锁的显性基因突变引起的，该基因在男性中通常是致命的，并对该家族中多态的雄激素受体基因进行了X-失活分析。我们记录了在未受影响的母亲中持续偏斜的X-失活(在两个独立分析中为80%/20%)和在先证者中持续的随机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的X-失活一致，这一现象记录在X连锁显性Rett综合征中。我们未来的努力将取决于确定可以进行母体X失活研究的其他PHACES家族，以及应用X染色体特异性阵列-比较基因组杂交(ARRAY-CGH)实验来寻找PHACES患者亚显微拷贝数的变化。

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.