Bessières-Grattagliano B, Foliguet B, Devisme L, Loeuillet L, Marcorelles P, Bonnière M, Laquerrière A, Fallet-Bianco C, Martinovic J, Zrelli S, Leticee N, Cayol V, Etchevers H C, Vekemans M, Attie-Bitach T, Encha-Razavi F
Laboratoire d'Anatomo-Foeto-Pathologie, Institut de Puériculture et de Périnatalogie, Paris, France.
Eur J Med Genet. 2009 Nov-Dec;52(6):386-92. doi: 10.1016/j.ejmg.2009.07.006. Epub 2009 Jul 25.
Cerebral proliferative glomeruloid vasculopathy (PGV) is a severe disorder of brain angiogenesis, resulting in abnormally thickened and aberrant perforating vessels, forming glomeruloids with inclusion-bearing endothelial cells. This peculiar vascular malformation was delineated by Fowler in 1972 as a stereotyped lethal fetal phenotype associating hydranencephaly-hydrocephaly with limb deformities, called Fowler syndrome (FS) or "proliferative vasculopathy and hydranencephaly-hydrocephaly" or "encephaloclastic proliferative vasculopathy" (OMIM#225790). In PGV, the disruptive impact of vascular malformation on the developing central nervous system (CNS) is now well admitted. However, molecular mechanisms of abnormal angiogenesis involving the CNS vasculature exclusively remain unknown, as no genes have been localized nor identified to date. We observed the pathognomonic FS vascular malformation in 16 fetuses, born to eight families, four consanguineous and four non-consanguineous. A diffuse form of PGV affecting the entire CNS and resulting in classical FS in 14 cases, can be contrasted to two cases with focal forms, confined to restricted territories of the CNS. Interestingly in PGV, immunohistological response to a marker of pericytes (SMA, Smooth in PGV Muscle Actin), was drastically reduced as compared to a match control. Our studies has expanded the description of FS to additional phenotypes, that could be called Fowler-like syndromes and suggest that the pathogenesis of PGV may be related to abnormal pericyte-dependent remodelling of the CNS vasculature, during CNS angiogenesis. Gene identification will determine the molecular basis of PGV and will help to know whether the Fowler-like phenotypes are due to the same underlying molecular mechanisms.
脑增殖性肾小球样血管病（PGV）是一种严重的脑血管生成障碍性疾病，导致穿通血管异常增厚且形态异常，形成含有包涵体的内皮细胞的肾小球样结构。这种特殊的血管畸形在1972年由福勒描述为一种典型的致死性胎儿表型，伴有积水性无脑畸形 - 脑积水和肢体畸形，称为福勒综合征（FS）或“增殖性血管病和积水性无脑畸形 - 脑积水”或“脑破坏性增殖性血管病”（OMIM编号：225790）。在PGV中，血管畸形对发育中的中枢神经系统（CNS）的破坏作用现已得到充分认可。然而，仅涉及中枢神经系统脉管系统的异常血管生成的分子机制仍然未知，因为迄今为止尚未定位或鉴定出相关基因。我们在16例胎儿中观察到了特征性的FS血管畸形，这些胎儿来自8个家庭，其中4个是近亲结婚家庭，4个是非近亲结婚家庭。一种弥漫性形式的PGV影响整个中枢神经系统，14例导致典型的FS，与之形成对比的是2例局灶性形式，局限于中枢神经系统的受限区域。有趣的是，在PGV中，与匹配对照相比，对周细胞标志物（SMA，平滑肌肌动蛋白）的免疫组织学反应大幅降低。我们的研究将FS的描述扩展到了其他表型，这些表型可称为福勒样综合征，并表明PGV的发病机制可能与中枢神经系统血管生成过程中周细胞依赖性的中枢神经系统脉管系统重塑异常有关。基因鉴定将确定PGV的分子基础，并有助于了解福勒样表型是否归因于相同的潜在分子机制。
