Clinical spectrum of eye malformations in four patients with Mowat–Wilson syndrome

Abstract

Mowat-Wilson syndrome (MWS) is a rare genetic syndrome characterized by a specific facial gestalt, intellectual deficiency, Hirschsprung disease and multiple congenital anomalies. Heterozygous mutations or deletions in the zinc finger E-box-binding homeobox2 gene (ZEB2) cause MWS. ZEB2 encodes for Smad-interacting protein 1, a transcriptional co-repressor involved in TGF-beta and BMP pathways and is strongly expressed in early stages of development in mice. Eye abnormalities have rarely been described in patients with this syndrome. Herein, we describe four patients (two males and two females; mean age 7 years) with MWS and eye malformations. Ocular anomalies included, iris/retinal colobomas, atrophy or absence of the optic nerve, hyphema, and deep refraction troubles, sometimes with severe visual consequences. All eye malformations were asymmetric and often unilateral and all eye segments were affected, similarly to the nine MWS cases with ophthalmological malformations previously reported (iris/chorioretinal/optic disc coloboma, optic nerve atrophy, retinal epithelium atrophy, cataract, and korectopia). In human embryo, ZEB2 is expressed in lens and neural retina. Using the present report and data from the literature, we set out to determine whether or not the presence of eye manifestations could be due to specific type or location of mutations. We concluded that the presence of eye malformations, although a rare feature in MWS, should be considered as a part of the clinical spectrum of the condition.

Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care

“…24 Strabismus is the most common finding, followed by astigmatism, with a 2.6 times higher frequency in girls. Structural anomalies are rare, with Axenfeld anomaly and coloboma the most frequent.…”

High‐throughput custom capture sequencing identifies novel mutations in coloboma‐associated genes: Mutation in DNA‐binding domain of retinoic acid receptor beta affects nuclear localization causing ocular coloboma

“…Although several genes identified in animal studies are critical for optic fissure closure during eye development, very few are known to cause coloboma in humans (Brown et al, ; Patel & Sowden, ). On the other hand, reports of human mutations are often not complemented by experimental mechanistic evidence either in animal models or in cell culture (Bourchany et al, ; Chassaing et al, ; Graham et al, ; Kahrizi et al, ; Martinez‐Garay et al, ; Ng et al, ; Patel & Sowden, ; Wenger et al, ). In many cases, studies on coloboma genetics have focused on a select number of genes, and many have included syndromic conditions with severe ocular phenotypes (e.g., severe microphthalmia and anophthalmia; Gonzalez‐Rodriguez et al, ; Guo, Dai, Huang, Liao, & Bai, ; Mihelec et al, ; Morrison et al, ; Schimmenti et al, ; Williamson & FitzPatrick, ; X. Zhang et al, ; J. Zhou et al, ).…”

A de novo triplication on 2q22.3 including the entire ZEB2 gene associated with global developmental delay, multiple congenital anomalies and behavioral abnormalities

“…MWS individuals display behavior problems including a happy affect and sociable demeanor, repetitive behaviors, pain insensitivity and a high rate of oral behaviors [ 7 ]. Eye abnormalities and craniosynostosis are rare features of this syndrome [ 8 – 10 ]. Eye abnormalities include iris/retinal colobomas, atrophy or absence of the optic nerve, hyphema, and deep refraction troubles, sometimes leading to severe visual consequences [ 8 ].…”