Clinical and Mutational Spectrum of Mowat–Wilson Syndrome
Introduction
In 1998, Mowat et al. [16] described a novel syndromic form of Hirschsprung disease (HSCR) associated with mental retardation, microcephaly, short stature and a facial appearance characterized by hypertelorism, pointed chin, prominent columella, broad, medial flared eyebrows and uplifted earlobes (MIM 235730). Shortly after, deletions and point mutations in the ZFHX1B gene (Fig. 1) were shown to underlie this condition [3], [21]. Further studies have demonstrated that HSCR is not an obligatory feature so that patients both with and without HSCR can be recognized by their distinctive facial gestalt [23], [25].
To date, 69 cases of MWS with nonsense or frameshift mutations, deletions or translocations have been published. No obvious genotype–phenotype correlation has been defined except for those two very large deletions [12], [26] associated with an exceptionally severe course [1], [3], [4], [8], [11], [12], [13], [17], [18], [21], [22], [23], [25], [26]. These observations led to the assumption of ZFHX1B haploinsufficiency as the underlying pathogenic mechanism in Mowat–Wilson Syndrome. Since no ZFHX1B missense mutation has yet been reported, we hypothesized that patients with atypical MWS phenotypes might harbour non-truncating ZFHX1B mutations such as the 3 bp inframe deletion described by Yoneda et al. [24] in a patient showing only late diagnosed megacolon and mild retardation with non-specific facial features.
To address the question of the full spectrum of clinical and mutational variability, we analysed 70 patients with clinical features of Mowat–Wilson Syndrome for deletions and mutations in ZFXH1B.
Section snippets
Patients
From 81 Patients referred to us with a possible clinical diagnosis of Mowat–Wilson Syndrome, 70 with sufficient phenotypic data were included in this study. Whilst unaware of their mutational status, photographs of these 70 patients were reviewed by two of the authors (C. Z. and/or A. R.). Based on the facial features, the patients were classified into three groups: 1) characteristic facial gestalt of Mowat–Wilson Syndrome; 2) facial dysmorphism partly compatible with, but not typical of,
Results
Twenty-eight of the 70 patients, two of whom were sisters, were classified as showing the characteristic facial phenotype (group 1), 15 patients, of whom one was the brother of a patient from group 1, were considered ambiguous (group 2), and 27 patients displayed a non-specific facial phenotype (group 3). Clinical details of group 1 are provided in Table 1, and representative facial photographs of patients from groups 1–3 in Fig. 2. The 15 patients in group 2 did not exhibit the typical facial
Clinical spectrum
The presence of the typical facial phenotype of Mowat–Wilson Syndrome including hypertelorism, pointed chin, prominent columella, open mouthed expression, broad, medial flared eyebrows and uplifted earlobes allowed us to predict a ZFHX1B molecular lesion in every typical case. During mid-childhood, the very specific characteristics of the eyebrows and earlobes tend to become less obvious, while later on the long and pointed chin and nose contribute to a rather distinctive facial phenotype
Acknowledgements
We thank all colleagues providing clinical information, the families for their cooperation and Brigitte Dintenfelder, Michaela Kirsch and Leonora Klassen for their excellent technical assistance.
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