Refining the clinicopathological pattern of cerebral proliferative glomeruloid vasculopathy (Fowler syndrome): report of 16 fetal cases.

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.

Molecular heterogeneity in fetal forms of type II lissencephaly.

Type II lissencephaly (type II LIS) is a group of autosomal recessive congenital muscular dystrophies (CMD) associated with defects in alpha-DG O-glycosylation, which comprises Walker-Warburg syndrome, Fukuyama cerebral and muscular dystrophy, or muscle-eye-brain disease. The most severe forms of these diseases often have a fetal presentation and lead to a pregnancy termination. We report here the first molecular study on fetal type II LIS in a series of 47 fetuses from 41 unrelated families. Sequencing of the different genes known to be involved in alpha-DG O-glycosylation allowed the molecular diagnosis in 22 families: involvement of POMT1 was demonstrated in 32% of cases, whereas POMGNT1 and POMT2 were incriminated in 15% and in 7% of cases, respectively. We found 30 different mutations in these three genes, 25 were described herein for the first time, 15 in POMT1, and five in POMT2 and POMGNT1. Despite sequencing of FKRP, FCMD, and LARGE, no definitive molecular diagnosis could be made for the other half of our cases. Preliminary results concerning genotype-phenotype correlations show that the choice of the first gene sequenced should depend on the clinical severity of the type II LIS; POMT1 and POMT2 for severest clinical picture and POMGNT1 for milder disease. The other genes, FKRP, FCMD, and LARGE, seem not to be implicated in the fetal form of CMD.