Prenatal presentation of Walker\u2013Warburg syndrome with a POMT2 mutation: an extended fetal phenotype

Sara H El-Dessouky,Heba Hosny,Ahmed Ezz Elarab,Mahmoud Y Issa

doi:10.1186/s43042-020-00093-1

Abstract

BackgroundWalker–Warburg syndrome (WWS) is a rare, lethal, genetically, and clinically heterogeneous congenital muscular dystrophy resulting from defective glycosylation of α-dystroglycan (α-DG) and is associated with both cranial and ocular malformations. Prenatal detection of posterior fossa anomalies in association with hydrocephalus are nonspecific, however, an additional finding of eye anomalies are typical for WWS. The purpose of this report is to elucidate the pattern of associated malformations in a fetus with WWS born to 3rd degree consanguineously married couple. Additionally, the fetal ultrasonography revealed congenital heart disease, clenched hands, and talipes equinovarus; these findings have not been previously reported and represent an expansion of prenatal spectrum associated with WWS.Case presentationWe report on a specific sonographic pattern of congenital anomalies including hydrocephalus, agenesis of corpus callosum, and Dandy–Walker malformation. Ocular abnormalities include microphthalmia, cataract, and an echoic structure suggestive of persistent primary vitreous. Other features include congenital heart disease, unilateral multicystic kidney, and previously unreported findings of bilateral clenched hands and talipes equinovarus. The molecular analysis detected a homozygous splicing mutation, c.924-2A>C, in the POMT2 gene; this variant segregated with the phenotype.ConclusionWWS syndrome has characteristic prenatal ultrasound findings which can improve the prenatal identification of this condition and help in guiding the molecular diagnosis and counseling. The detection of bilateral clenched hands and talipes equinovarus is a novel finding that further expands the phenotypic spectrum of WWS.

Highlights

Walker–Warburg syndrome (WWS) is a rare, lethal, genetically, and clinically heterogeneous congenital muscular dystrophy resulting from defective glycosylation of α-dystroglycan (α-DG) and is associated with both cranial and ocular malformations
A combination of congenital muscular dystrophy in association with ocular, cerebellar, and cerebral anomalies in addition to myopathy is considered to be pathognomonic of a spectrum of clinically and genetically heterogeneous disorders including Walker–Warburg syndrome (WWS), Fukuyama muscular dystrophy, and muscle–eye–brain disease [3, 5]
A clinical delineation of WWS has been described by Dobyns et al [2]; aside the severe congenital muscular dystrophy with postnatal marked hypotonia and elevated levels of creatinine kinase (CK), the brain malformation is constantly present and represented by cobblestone lissencephaly, obstructive hydrocephalus, corpus callosum agenesis, and pontocerebellar hypoplasia with fourth ventricle dilatation, kinking of the brainstem and, less commonly, Dandy–Walker malformation and occipital cephalocele [5, 9, 10]

Summary

Introduction

Walker–Warburg syndrome (WWS) is a rare, lethal, genetically, and clinically heterogeneous congenital muscular dystrophy resulting from defective glycosylation of α-dystroglycan (α-DG) and is associated with both cranial and ocular malformations. A combination of congenital muscular dystrophy in association with ocular, cerebellar, and cerebral anomalies in addition to myopathy is considered to be pathognomonic of a spectrum of clinically and genetically heterogeneous disorders including Walker–Warburg syndrome (WWS), Fukuyama muscular dystrophy, and muscle–eye–brain disease [3, 5]. All these autosomal recessive disorders, grouped under the term “α-dystroglycanopathies,” result from defective glycosylation of an αdystroglycan (α-DG) that is important for the structural integrity of the muscular and neural tissue and neuronal migration [6,7,8]. There is no evident genotype-phenotype correlation, as most cases; the defective gene cannot be predicted from the clinical phenotype [1, 20,21,22]

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