Mowat–Wilson Syndrome

A syndrome of multiple congenital anomalies and intellectual disability due to ZEB2 haploinsufficiency (2q22.3), with a recognisable face, epilepsy, Hirschsprung disease, congenital heart disease, urogenital and corpus callosum abnormalities; almost always de novo.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Clinical Delineation

Mowat–Wilson syndrome (MWS) was delineated in 1998 by David Mowat and colleagues in Sydney, Australia, on the basis of six children with a distinctive face, intellectual disability, microcephaly and short stature. Four had neonatal Hirschsprung disease, a fifth was diagnosed at 3 years because of severe chronic constipation, and the sixth had chronic constipation without demonstrated aganglionosis. One child carried an interstitial deletion del(2)(q21q23), and the authors noted the similarity to a patient described by Lurie and colleagues with Hirschsprung disease and del(2)(q22q23). Since all cases were isolated, they proposed two hypotheses: a contiguous gene syndrome or a single-gene dominant disorder, with a Hirschsprung disease locus at 2q22-q23. In the same paper, they distinguished the condition from Goldberg–Shprintzen syndrome, then considered autosomal recessive [15].

1.2. Molecular Discovery

In 2001, two groups independently identified the gene. Wakamatsu and colleagues showed that variants in SIP1 (Smad-interacting protein 1) cause a form of Hirschsprung disease with intellectual disability, microcephaly and a distinctive face; the gene lay within the deleted segment at 2q22 and was disrupted by a de novo translocation t(2;13)(q22;q22) [16]. Cacheux and colleagues characterised another de novo translocation breakpoint at 2q22 that disrupted SIP1 and identified heterozygous frameshift variants causing premature protein truncation in four unrelated patients; they proposed that protein deficiency altered the TGF-β/BMP/Smad pathway (transforming growth factor beta and bone morphogenetic protein), consistent with the enteric nervous system defect [17]. The protein had been identified in 1999 by Verschueren and colleagues, using yeast two-hybrid screening, as a transcriptional repressor with zinc fingers and a homeodomain that interacts with the MH2 domain of receptor-regulated Smads and binds 5'-CACCT sequences [18].

In 2002, Zweier and colleagues showed that the condition, with or without Hirschsprung disease, constitutes a recognisable entity of multiple congenital anomalies and intellectual disability caused by variants in the gene then designated ZFHX1B, and proposed the eponym “Mowat–Wilson syndrome” [6, 19]. This was followed by reviews by Mowat, Wilson and Goossens in 2003, the first American series by Adam and colleagues in 2006 (12 patients diagnosed over two years, when most previous publications had come from Northern Europe and Australia), and the review by Garavelli and Mainardi in 2007, which counted 171 published patients [20–22]. In 2008, Engenheiro and colleagues, in a Portuguese–Danish collaboration, counted 115 different variants in 161 individuals and described two patients diagnosed only after disruption of ZEB2 had been identified at a balanced translocation breakpoint and by an interstitial microdeletion, prompting them to ask whether the syndrome was underdiagnosed [23].

The following decade brought systematic studies of Italian and international cohorts: age-related facial evolution in 19 Italian patients [24], neuroimaging in 54 patients [9], phenotype and genotype in 87 patients with care recommendations [6], syndrome-specific growth charts [25], the longitudinal electroclinical history of epilepsy [26], and the DNA methylation signature [8]. GeneReviews, first published in 2007, underwent full updates in 2013, 2019 and 2025 and revisions in 2026 [1].

1.3. Nomenclature and Definition of the Entities

The gene is now designated ZEB2; the names ZFHX1B, SIP1 and SMADIP1 appear in older literature and refer to the same gene (HGNC:14881) [4]. Orphanet classifies MWS as a malformation syndrome with the main code ORPHA:2152 and defines it as a rare multiple congenital anomaly syndrome characterised by a distinctive facial phenotype, intellectual disability, epilepsy, Hirschsprung disease and variable congenital malformations; this code encompasses two aetiological subtypes, ORPHA:261552 (due to a ZEB2 point variant) and ORPHA:261537 (due to 2q22 monosomy), both associated with OMIM #235730 [7].

The term “classic MWS”, adopted by GeneReviews, applies to ZEB2 haploinsufficiency due to gene deletion (including 2q22.3 deletions of variable size), protein-truncating variants (nonsense and frameshift) or chromosomal rearrangements disrupting the gene, with the characteristic face and moderate to severe intellectual disability [1]. At one end of the spectrum are missense variants, some splicing variants and truncating variants in the penultimate exon that preserve most functional domains; these produce milder presentations, with more subtle suggestive facial features, or even apparently non-syndromic intellectual disability with or without epilepsy. Their inclusion within the diagnosis of MWS is discussed case by case [1, 6, 27].

1.4. Scope and Cross-References

This article covers classic MWS, contiguous deletions including ZEB2, and the milder allelic spectrum. Isolated Hirschsprung disease and its general syndromic differential diagnosis, as well as agenesis of the corpus callosum as a finding, with its chromosomal and monogenic causes and prenatal diagnosis, form the background; the aspects of these manifestations specific to MWS are addressed here.

2. Molecular Genetics and Pathophysiology

2.1. The ZEB2 Gene and Protein

ZEB2 is located at 2q22.3 and encodes the ZEB2 protein (zinc finger E-box-binding homeobox 2), a member of the ΔEF1/Zfh-1 family of “two-handed” zinc finger and homeodomain transcription factors [1, 17]. The gene has 10 exons; exon 1 is non-coding, and the coding region spans exons 2 to 10 [1, 28]. The MANE Select transcript is NM_014795.4 (protein NP_055610.1); the 2011 Clinical Utility Gene Card used version NM_014795.2, with a protein of 1214 amino acids [2, 5]. The protein has six described domains: the N-terminal zinc finger cluster (N-ZF), the binding domain for SMAD proteins, intracellular effectors of the TGF-β pathway (SBD), the homeodomain (HD), the interaction domain for the CtBP corepressor, C-terminal binding protein (CID), the C-terminal zinc finger cluster (C-ZF), and, at the N-terminus, an interaction motif for the NuRD chromatin-remodelling complex (nucleosome remodeling and deacetylase) [6, 28]. Exon 8 encodes approximately 60% of the protein, including the last zinc finger of N-ZF, SBD, HD and CID [28].

ZEB2 is a nuclear transcriptional repressor. The two zinc finger clusters bind E-box-like sequences (5'-CACCT-3') in the promoters of target genes, which include E-cadherin (CDH1). Interaction with activated SMADs, through their MH2 domain, modulates TGF-β/BMP signalling [4, 18]. The gene is widely expressed in the mouse embryo and plays a central role in the neural crest; homozygous Zeb2-null mice die during development because of neural crest abnormalities [1, 29].

2.2. Molecular Mechanism

Classic MWS results from haploinsufficiency. The vast majority of alterations are whole-gene deletions or nonsense and frameshift variants, and by 2007 more than 100 variants had been counted, almost all of these types, with atypical phenotypes associated with missense or splicing variants [30]. Multimegabase deletions removing ZEB2 and adjacent genes produce the same classic phenotype as truncating variants, arguing against a dominant-negative effect as the main mechanism [1, 6]. The idea that all truncating alleles are eliminated by nonsense-mediated mRNA decay (NMD) has not been demonstrated: in two Turkish patients with truncating indels, total and allele-specific RT-qPCR in blood showed no decay of the mutant transcripts, even with premature termination codons at the N-terminus [31]. The authors propose that the phenotype results from the absence of functional domains in the truncated protein; other groups have suggested a dominant-negative effect [9, 31]. A 2026 analysis of ClinVar variants, published as a non-peer-reviewed preprint, found no significant difference between truncating variants near the N-terminus and those near the C-terminus [32].

2.3. Tissue Pathophysiology

Reduced repressor dosage leaves target genes unrepressed in the neural crest and central nervous system (CNS). This results in neurocristopathic features at the cephalic, cardiac and vagal levels (face, outflow tract and pulmonary artery defects, Hirschsprung disease), together with corpus callosum dysgenesis and intellectual disability [4]. In the enteric nervous system, Zeb2 interacts genetically with Sox10 [33]. In the mouse cerebral cortex, Zeb2 is required for cortical interneuron differentiation and directed migration. This role in the GABAergic network underpins the hypothesis of an inhibitory imbalance in MWS epilepsy [1, 26, 34].

Human cellular models have begun to be studied: neural progenitors derived from patients' induced pluripotent stem cells (iPSCs) show transcriptional alterations in the neuroepithelium-to-radial-glia transition and lineage specification, dysregulation of cytoskeletal, extracellular matrix and motility genes, and increased motility of progenitors and early neurons [35]. In a 2026 murine model, conditional inactivation of Zeb2 in ureteric mesenchyme prevented formation of the ureteric smooth muscle layer and caused hydroureter and hydronephrosis, a proposed mechanism for the congenital kidney and urinary tract abnormalities of MWS [36]. The brown-to-red hair colour of many patients is associated with lower eumelanin and higher pheomelanin content, and melanocytes with mutant ZEB2 express less SLC45A2 [37]. These data are preclinical or translational and have not, to date, altered clinical management.

2.4. Variant Spectrum

All alterations described in classic MWS are heterozygous. The distribution of variant types depends on the source and counting method (systematically tested cohort, literature compilation or variant database data), as summarised in the following table.

The most frequent variant in the 2024 review is NM_014795.4:c.2083C>T p.(Arg695Ter), in exon 8, which affects the homeodomain and was found in 11% of the 298 patients [5, 28]. Frameshift variants occur in nine of the ten exons, except exon 1 [28]. In ClinVar in 2026, there were 301 ZEB2 variants classified as pathogenic or likely pathogenic or with conflicting classifications; more than 4% of pathogenic variants and more than 10% of likely pathogenic or conflicting variants were intronic or splice-site variants, and the density of pathogenic variants per amino acid was highest in the C-ZF zinc finger designated type 6 [32]. In 2023, there were also 290 missense variants classified as variants of uncertain significance (VUS) in ClinVar [8]. Alterations that escape standard methods have been described: a de novo Alu insertion in exon 8, recognised only through manual inspection of genome alignments and confirmed by long-read sequencing [38]; balanced translocations disrupting the gene [16, 23]; and a large intragenic multiexon deletion recurring in siblings [39]. The sources consulted describe no founder variants.

2.5. Normalised Reference Variants

The cited variants were normalised according to Human Genome Variation Society (HGVS) nomenclature in VariantValidator using the MANE Select transcript NM_014795.4 (GRCh38), and classifications are from ClinVar [5, 40].

2.6. Genotype–Phenotype Correlations

Deletions and truncating variants are associated with the typical face, and deletion size and breakpoints show no clear correlation with the phenotype, except for very large deletions (>5 Mb) including several adjacent genes [1]. In the cohort of 87 patients, Ivanovski and colleagues grouped genotypes into three categories: whole-gene deletion, intragenic variants with no protein synthesis or rapid degradation, and intragenic variants with synthesis of a defective protein. The few significant correlations compared complete deletion with the other categories: multimegabase deletions (which may include other genes and non-coding transcripts, such as antisense transcripts in the 5' region of ZEB2) were associated with a greater delay in the age at sitting and speech onset, and complete deletion appeared to be associated with more heart defects, with small numbers [6]. In the Chinese series of 22 patients, the four with chromosomal deletions including ZEB2 were the most severely affected [41].

In the neuroimaging study of 54 patients, genotypes were grouped into A (complete allele deletion, n=7), B (predicted absence of protein, n=40) and C (defective protein, n=7). Complete agenesis of the corpus callosum was more frequent in group C (6/7; 71.4%) than in groups A and B combined (19.1%; p=0.0095). Group C nevertheless achieved motor milestones earlier (sitting at a mean of 17.1 months, compared with 20.0 months in group B and 24 months in A; walking at 44.7, 49.8 and 80 months, respectively) and had no cases of drug-resistant epilepsy, compared with 3/6 in A and 8/27 in B. At least 60% of patients with complete deletion had no speech [9]. GeneReviews adds that whole-gene deletion is associated with earlier epilepsy onset and a higher risk of multidrug resistance than alterations allowing production of a defective protein [1].

There are exceptions: patient P23, with a frameshift affecting only part of C-ZF, had mild to moderate intellectual disability; in HEK293T cells, the mutant protein localised to the nucleus and retained some ability to repress the E-cadherin promoter (preliminary data). Patient P34, who was very mildly affected, had a splicing defect altering only the N-terminal portion and abolishing the NuRD interaction motif. Since some mildly affected patients have variants abolishing function, the authors suggest genetic or environmental cofactors [6].

2.7. Mild Allelic Spectrum and Allelic Disorders

Missense, splicing or in-frame variants account for less than 5% of all published cases and less than 2% of classic MWS cases [1]. Ghoumid and colleagues described three missense variants in C-ZF, a highly conserved domain: p.(Tyr1055Cys), p.(Ser1071Pro) and p.(His1045Arg). The patients had an MWS face and moderate intellectual disability, without microcephaly, heart disease or Hirschsprung disease. In vitro, the variants prevented binding to and repression of the E-cadherin promoter, and rescue in zebrafish embryos with knockdown was variable and tracked clinical severity, indicating hypomorphic alleles with partial loss of function [27]. The spectrum extends to subtle features, including non-syndromic intellectual disability and epilepsy without malformations or recognisable dysmorphism, particularly with missense variants in C-ZF [1, 42]. One patient with a splicing variant had mild intellectual disability (full-scale intelligence quotient of 52), spoke in complete sentences and had subtle non-classic dysmorphism, choreoathetosis, hyperreflexia and distal dystonia [1, 43]. Truncating variants in the penultimate exon preserving most functional domains may cause apparently non-syndromic intellectual disability without the MWS face, according to a personal observation by one of the GeneReviews authors [1]. Therefore, a ZEB2 variant found on exome sequencing in a child without the classic gestalt should not be automatically dismissed [4].

2.8. Penetrance, Expressivity and Modifiers

Non-mosaic ZEB2 variants have complete penetrance, with variable expressivity [2]. Hirschsprung disease is the manifestation with the most variable expressivity: short and long segments occur in both sexes, with a predominance in boys [6]. The sources consulted identify no validated genetic modifiers. Parents with somatic and gonadal mosaicism may have mild or minimal manifestations [1].

3. Clinical Spectrum and Manifestations by System

3.1. Sources of Frequencies and Denominators

The main source of frequencies is the study by Ivanovski and colleagues (2018): 87 molecularly confirmed patients, aged 6 months to 36 years (mean age at last assessment of 9 years and 10 months), from four continents and predominantly European, with an M:F ratio of 45:42. The authors added patients from the literature, excluding missense variants, for a total of more than 340 individuals [6]. Textbooks and GeneReviews reproduce figures from this table with different denominators: Smith mainly cites the percentages from the cohort of 87 (for example, Hirschsprung disease 30.6%), whereas GeneReviews cites those from the combined total (44%) [1, 3]. The following table reproduces the original study with the denominators; unless otherwise stated, frequencies cited below refer to the combined total.

The text of the same article reports heart disease in 52/86 (60.5%) and constipation in 43.5%, a minimal internal discrepancy relative to the table [6]. GeneReviews gives 5% for pyloric stenosis in the text and 7% in the table; the value of 7.4% corresponds to the combined total in the original study [1, 6]. According to the authors, the difference between the frequency of Hirschsprung disease in the cohort (30.6%) and in the literature (48.8%) reflects current diagnosis based on facial gestalt rather than aganglionosis; Hirschsprung disease may be underestimated in the cohort because many patients with severe constipation did not undergo rectal biopsy [6]. Other series confirm the order of magnitude: a systematic review of 52 articles (256 patients) found Hirschsprung disease in 111 (43.4%) [44], and national series include 19 Italian [24], 12 American [21], 28 Polish [45], 22 Chinese [41] and 10 Turkish patients [39].

3.2. Facial Appearance and Its Evolution with Age

The face is the most specific finding and changes with age, making diagnosis easier in older children [1, 24]. The French National Diagnosis and Care Protocol (PNDS) estimates that close to 90% of patients have a suggestive facial dysmorphism of variable expression, without stating the source series, and adds enophthalmos, a short philtrum and an elongated face to the list [10]; in the cohort of 87 patients with a confirmed ZEB2 alteration, all had the distinctive face, which also reflects recruitment based on the classic phenotype [6]. In infancy, the earlobes are uplifted, with a central depression resembling orecchiette pasta or a red blood cell; the eyebrows are broad, with medial flaring and central sparseness; the skull is rounded, the hair fine and sparse, the anterior neck appears “swollen”, and there is excess nuchal skin [3, 6]. In childhood, the face is square, with a high forehead, frontal bossing, epicanthal folds, hypertelorism, telecanthus, large deep-set eyes, strabismus, a broad nasal root, a rounded nasal tip, a prominent low-hanging columella, an open mouth with an “M”-shaped upper lip (full centrally and thin laterally), thick or everted lower lip vermilion, and a prominent triangular chin; smiling is frequent [1, 3, 6]. At school age the face lengthens and the mandible becomes prominent. From adolescence, the eyebrows become denser and horizontal, the nasal profile more convex, the nasal tip lengthens and hangs over the philtrum (which appears short), and the chin becomes long, pointed or “chisel-shaped”, with prognathism [3, 6]. The uplifted earlobes persist; only the central depression becomes less distinct in adulthood, making this sign useful at any age [1, 6].

In the cohort of 87, each patient had a mean of 15.8 of the 26 facial features assessed; two had 25 of the 26, and the three most frequent features (uplifted earlobes, rounded nasal tip and prominent columella) coexisted in 40 patients [6]. The figures in Smith (Fig. 1 A–D and Fig. 2 A–C, the same individual at 3, 14 and 31 years) and Figure 1 of GeneReviews (an individual from 1 month to 21 years) show this evolution [1, 3]. Bifid uvula, submucous or hard palate cleft, and unicoronal craniosynostosis occur rarely [1]. Many patients have brown-to-red hair [37].

3.3. Growth

Birth weight and length are usually normal. In the cohort of 87, mean gestational age was 39 weeks (33–43); mean birth weight was 3408 g in boys and 3110 g in girls, and head circumference (HC) was 33.5 cm and 32.6 cm, with mean percentiles of 27 and 31 [6]. Microcephaly (HC ≤ −2 standard deviations) is sometimes present at birth but is more often acquired. Short stature develops over time: 7/29 (24.1%) from 0 to 6 years, 8/25 (32%) from 6 to 12 years, and 16/25 (64%) after 12 years; 68/80 (85%) had height below the 50th percentile. Adult height was 155–185 cm in men (n=9; mean 165.1 cm) and 146–155 cm in women (n=2; mean 150.5 cm). Weight was below the 3rd percentile in 25/76, and build is slender with normal proportions [1, 6].

Sex-specific growth charts from 0 to 16 years were constructed from 2865 measurements in 99 patients of 20 nationalities (including 3 from Portugal and 1 from Brazil), born between 1986 and 2016, none treated with growth hormone [25]. Length decelerates from 2 months, and the slope falls significantly after 7 years in boys and 11 years in girls, without an evident pubertal growth spurt; at 9 years, mean height was 121 cm in boys (below the 3rd percentile) and 123.8 cm in girls (3rd–5th percentile). At 16 years, mean weight was 48 kg in boys and 39 kg in girls, and body mass index (BMI) was 17.2 and 17.1 kg/m², compared with 20.5 kg/m² in the reference population. HC lies between the 3rd and 25th percentiles in the first months, decreases significantly between 1 and 3 years, and at 3 years was 47 cm in boys and 46 cm in girls (approximately −2 standard deviations); not all patients are microcephalic, and many have HC between the 3rd and 10th percentiles. Intrauterine growth restriction is not consistent. The authors acknowledge a small absolute number and lower precision in adolescence [25]. The French PNDS reproduces these charts in an appendix, by sex (length and height, weight and HC), and recommends plotting measurements on them or on the charts in the child health record; when the growth curve falters, it advises investigating the cause [10].

3.4. Neurodevelopment, Motor Skills and Communication

In the classic form, all patients have moderate to severe intellectual disability; intelligence quotient has rarely been formally measured [1]. Hypotonia in the early years was recorded in 79.1% and may evolve into spasticity in adolescence or adulthood, with contractures, reduced weight-bearing, low bone mineral density and fractures [1, 6]. Mean age at unsupported sitting was 17.4 months and at walking 3 years and 9 months (16 months to 11 years); 33/86 (38.3%) were not walking independently at the last assessment, which included young children [6]. Gait is broad-based and ataxic, with raised arms and flexed elbows, in a posture resembling that of Angelman syndrome. Fine motor development is delayed, and most patients over 20 years need help with dressing and activities of daily living [1, 6].

Speech rarely extends beyond a few words, with a mean onset at 4 years; 58/86 (67.4%) had no speech, 10 of whom were under 4 years [6]. In the American series of 12 patients, speech was severely impaired or absent in all those over 1 year, with relatively preserved receptive language [21]. Comprehension exceeds expression, and most use augmentative and alternative communication (AAC); GeneReviews notes that sign language and communication boards have had limited success [1, 6]. In 22 Chinese patients, performance in cognitive play and social communication was better than in receptive and expressive language, and in receptive language they understood more nouns than adjectives and verbs [41]. Patients with variants allowing production of a defective protein acquire walking and their first words earlier (section 2.6) [9].

3.5. Epilepsy

Epilepsy is the neurological manifestation with the greatest impact on prognosis. It affects 78.5% in the combined total and 73/87 (83.9%) in the Ivanovski cohort, with a mean onset at 27.5 months (1 month to 11 years); seizures were triggered by fever in 45%, were focal in 72.1%, generalised in 50.8% and focal with secondary generalisation in 40%, and drug resistance reached 25.9% [6]. In Garavelli's MRI cohort, 45/49 (91.8%) had epilepsy, with a mean onset at 29.7 months (3 months to 10 years) and febrile seizures in 24/43 (55.8%) [9]. The first seizure is often focal and associated with fever [1]. The Oxford Desk Reference includes ZEB2 among epilepsy genes with onset after the first year of life [46].

The Italian longitudinal study by Ricci and colleagues followed 40 individuals in three age groups (0–4, 5–12 and over 13 years). Epilepsy was present in 36/40, including all 35 over 5 years. Focal seizures were present at onset in 35/36, with a mean age at onset of 3.4 ± 2.3 years, and persisted, less frequently, in 7/22 after 13 years. Atypical absences developed in 22/36, with a mean onset at 7.2 ± 0.9 years, never before 6 or after 16 years. Interictal abnormalities during sleep increased at school age (p=0.002) and decreased in adolescence (p=0.008). Electrical status epilepticus during sleep (ESES) was found in 14/36 (39%), beginning between 5 and 13 years in 13 of the 14. The seven focal seizures recorded on video-electroencephalography (EEG) were prolonged, and visible clinical signs were preceded by prolonged electrical or subtle seizures, with erratic head and eye orientation. Epilepsy usually improved in adolescence and adulthood [26].

EEG findings depend on age: mild slowing or a normal tracing at presentation; subsequently, diffuse irregular spike-and-wave discharges with frontal predominance, sometimes asymmetric, accentuated during slow-wave sleep up to a continuous or near-continuous spike-and-wave pattern [1, 47]. ESES may worsen behaviour, motor function and cognition, and should be sought in the presence of cognitive or motor regression, including new-onset ataxia or dyspraxia [1, 47]. Epileptic activity does not correlate with brain malformations, suggesting a genetic origin of the epilepsy [6, 9].

In a hospital series of 31 Chinese children with MWS and epilepsy (Beijing, June 2020 to December 2024), median onset was at 25.5 months (1–113); 18/31 (58.1%) began with febrile seizures, all had focal seizures, 16/31 (51.6%) had atypical presentations, 12/31 (38.7%) had seizures with gastrointestinal symptoms, and 10/31 (32.3%) had convulsive status epilepticus. EEG evolved from posterior to multifocal or anterior discharges, increasing during sleep [48]. Seizure surveillance should continue even after long periods of control: a 45-year-old man with MWS developed drug-resistant status epilepticus after 26 seizure-free years, with a focal lesion in the left thalamic pulvinar on MRI [49].

3.6. Neuroimaging

MRI was abnormal in 96% of the 54 patients in the study by Garavelli and colleagues. Corpus callosum abnormalities were present in 43/54 (79.6%): complete agenesis in 14 (25.9%), partial agenesis in 9 (16.7%), and hypoplasia or a thin corpus callosum in 20 (37%); typical agenesis leaves a frontal remnant, with an absent splenium and preserved genu. Other findings included bilateral hippocampal abnormalities, mainly malrotation, in 42 (77.8%); dilatation of the temporal horn in 32 (59.3%) and lateral ventricles in 21 (38.9%); reduced white matter thickness in 22 (40.7%) and focal signal changes in 12 (22.2%); enlarged basal ganglia in 3 (5.6%); cerebellar hypoplasia in 2; and, in one patient each, polymicrogyria, periventricular heterotopia, focal cortical dysplasia, Chiari 1 malformation, absent vermis, small vermis, macrocerebellum and a CNS tumour [9]. Figure 2 of the article illustrates these findings (https://pmc.ncbi.nlm.nih.gov/articles/PMC5438871/figure/fig2/) [9].

GeneReviews reports CNS abnormalities in approximately half of patients who underwent imaging, and earlier studies reported corpus callosum abnormalities in 46% [1, 9]. The difference from Garavelli's 79.6% is due, at least in part, to the inclusion of hypoplasia and a thin corpus callosum, which the 2017 series recorded more frequently than earlier literature with detailed MRI (37.0% versus 23.2%), as well as partial agenesis (16.7% versus 1.8%) [9]. Smith gives 80% for complete or partial agenesis, but in the original study complete or partial agenesis corresponds to 23/54 (42.6%), and 80% refers to any corpus callosum abnormality [3, 9].

3.7. Sleep, Behaviour and Continence

Sleep disturbances affect approximately half of patients, with frequent nocturnal waking and early waking [1]. On the SDSC (Sleep Disturbance Scale for Children) administered to 35 individuals, 53% scored in the borderline range and 44% in the clinical range on at least one subscale, and 91% were at least in the borderline range for sleep–wake transition disorders; the total score was associated with behavioural problems [50]. In 16 individuals aged 16 months to 25 years studied by video-polysomnography in Bologna, total sleep time was reduced, wake after sleep onset and the arousal index were increased, and background EEG activity during sleep was slow, with a paucity of physiological graphoelements; after 7 years, anterior-predominant spike-and-wave activity was markedly activated by sleep, becoming subcontinuous or continuous [51].

The behavioural phenotype includes a happy disposition, frequent laughter and sociable affection. In the cohort of 87, more than 60% mouthed or chewed objects or body parts, had reduced pain responsiveness (42/65), and had bruxism; between 30 and 50% laughed for no apparent reason, manipulated objects, showed disproportionate happiness, switched lights on and off (more often boys), had rapid mood changes, stood very close to others, or ate non-food substances (pica) [6]. Reduced pain responsiveness is attributed to diminished nociceptive responsiveness rather than solely to communication difficulties, and has practical consequences: fever without an apparent focus should prompt a search for otitis media or another infection [1, 6]. In a comparison of 61 individuals with an epidemiological sample of intellectual disability from other causes, using the Developmental Behaviour Checklist (DBC), oral and repetitive behaviours and reduced pain responsiveness were more frequent; more than 30% had a clinically significant behavioural or emotional disturbance, a level similar to that in intellectual disability from other causes [52].

Incontinence is almost universal. In a survey of 47 individuals (26 children aged 4–12 years, 13 adolescents and 8 adults, recruited through support groups), 97.7% had at least one type of incontinence: nocturnal enuresis in 74.4%, daytime urinary incontinence in 76.2% and faecal incontinence in 81.4%. The proportion with DBC scores above the cut-off was 46.2% in children, 25% in adolescents and 37.5% in adults, and the ability to urinate in the toilet improved with age [53]. Treatment of constipation may improve urinary incontinence [1].

3.8. Heart and Great Vessels

Congenital heart disease affects 58.1% in the combined total. In the cohort of 87, the most frequent defects (each in more than 25% of patients with heart disease) were patent ductus arteriosus, ventricular septal defect (VSD) and atrial septal defect (ASD); pulmonary stenosis affected almost 20% and aortic coarctation more than 10%. Bicuspid aortic valve, aortic stenosis, tetralogy of Fallot, pulmonary artery sling, proximal pulmonary branch stenosis, mitral prolapse and pulmonary atresia occurred at frequencies below 10% [6]. The American series of 12 patients recorded heart disease in 75%, mainly involving the pulmonary arteries and valves [21]. Pulmonary artery sling, with or without tracheal stenosis, occurred in 3.4% in the combined total, compared with approximately 1 in 17,000 school-age children (0.006%) in the general population; MWS should be considered when a sling occurs in a child with developmental impairment or dysmorphism [1, 6]. Shone complex, interrupted aortic arch, congenital tracheal stenosis, and a case of single ventricle with hypoplastic left heart and left pulmonary artery sling have been described (section 10) [3, 28, 54, 55].

3.9. Gastrointestinal Tract and Hirschsprung Disease

MWS was initially described as a syndromic form of Hirschsprung disease, but only 44.2% of patients have biopsy-proven aganglionosis; chronic constipation without documented Hirschsprung disease affects a further 29%, and the two combined exceed 72% in the cohort of 87 [1, 6]. Whether this constipation represents ultrashort-segment Hirschsprung disease or another partial ganglionic defect is unknown; a supernumerary submucosal smooth muscle layer is more frequent than in the general population, with or without Hirschsprung disease, and its clinical significance is uncertain [1, 56]. Constipation worsens with age because of inadequate fluid intake, a low-fibre diet and reduced caregiver monitoring of bowel movements [1, 53].

The extent of aganglionosis tends to be greater than in non-syndromic Hirschsprung disease. In the systematic review of 256 patients, the rectosigmoid form accounted for 66.7% of cases with a described phenotype, a lower proportion than expected in Hirschsprung disease overall [44]. In a Robert-Debré series (Paris, 2003–2018) of 23 patients with MWS, 10 (43%) had Hirschsprung disease: rectosigmoid in 2, extending to the splenic flexure in 3, to the hepatic flexure in 2, and total colonic in 3 [57]. Large ZEB2 deletions tend to be associated with longer-segment aganglionosis [3]. Surgical and functional outcomes are worse than in the isolated form, with prolonged parenteral nutrition and recurrent enterocolitis, possibly because of a generalised motility disorder involving the upper gastrointestinal tract [1, 58]; data from surgical series are presented in section 7.4. Recurrent vomiting occurred in 14/77 (18.2%), pyloric stenosis in 7.4%, and dysphagia is rare [1, 6]. A Chinese series of 35 patients recorded intestinal symptoms in 86%, constipation in 69%, Hirschsprung disease in 17% and feeding difficulties in 4/9 (44.4%), with exploratory findings of altered plasma neurotransmitters in 6 patients [59]. Intestinal pseudo-obstruction with recurrent transient small-bowel intussusceptions and cholestasis with biliary atresia have been described [3, 60].

3.10. Kidneys, Genital Tract and Puberty

Renal abnormalities affect 25.3% (mainly vesicoureteric reflux and hydronephrosis; less often duplex kidney, pelvic kidney or multicystic dysplastic kidney) [1, 6]. In the cohort of 87, urogenital abnormalities were present in 49/80 (61.3%) [6]. In boys, hypospadias affects 59.7% and cryptorchidism 41.5%; less frequent findings include bifid scrotum, webbed penis or chordee, micropenis, hooded prepuce, macro-orchidism and hydrocele. A vaginal septum has been described in girls [1, 3, 6, 39]. Puberty data are scarce: one girl had menarche at 15 years and irregular menstruation, one boy had normal puberty and another a mild delay; in the experience of the GeneReviews authors, most adults undergo typical puberty [1, 21]. Growth charts show no pubertal growth spurt [25].

3.11. Eyes, Ears, Teeth, Skin and Hair

Strabismus is the most common ocular finding (56.8% in the cohort of 87); astigmatism, more frequent in girls (F:M 2.6:1; p=0.031), and myopia are frequent, and nystagmus, present in some infants, often resolves [1, 6]. Approximately 10% have structural or optic nerve abnormalities: microphthalmia, iris or retinal coloboma (which may suggest CHARGE), Axenfeld anomaly or posterior embryotoxon, ptosis, congenital or acquired cataract, retinal aplasia or pigment epithelial atrophy, optic nerve hypoplasia or atrophy, heterochromia, and dark pigment clumps in blue irides [1, 3, 61]. Acquired progressive anterior iris synechiae have been described in one patient and, in a 3-year-old boy, posterior embryotoxon with suspected congenital glaucoma, a cup-to-disc ratio of 0.5 and halving of visual evoked potential amplitude in one eye [62, 63].

Recurrent otitis media affects 34.6% and may cause conductive hearing loss, present in 9/77 (11.6%); sensorineural hearing loss is rare (4/77; 5.2%) [6]. Dental abnormalities are frequent: spaced teeth in 50%, delayed eruption in 47.7%, malpositioned teeth in 34.3% and crowding in 26.4%, in addition to dental malformations, gingival hypertrophy and bruxism [1, 6]. In the skin, hyperpigmentation (12/79; 15.2%), depigmentation (10/78; 12.8%) and accessory nipples (8/80; 10%) are the most commonly recorded findings [6]. A 16-year-old girl with a de novo frameshift had extensive cutis tricolor-type pigmentary mosaicism, overlapping that of Ruggieri–Happle syndrome, with bilateral microphthalmia, optic nerve hypoplasia, coloboma, a short corpus callosum and inferior vermian hypoplasia [64].

3.12. Skeleton

The most common findings are long, slender, tapering fingers, with prominent interphalangeal joints from late childhood, and calcaneovalgus feet. Up to 50% have pectus excavatum or carinatum, scoliosis, adducted thumbs, ulnar deviation of the hands, mild contractures or camptodactyly, genu valgum, flat feet, long toes, long broad great toes, hallux valgus, delayed bone age or syndactyly [1, 3]. In the cohort of 87 on which GeneReviews relies, the frequency of each of these abnormalities was below half: scoliosis 26/79 (33%), genu valgum 20/69 (29%), delayed bone age 9/39 (23%), hallux valgus 15/68 (22%), pectus excavatum 15/74 (20%), adducted thumbs 11/75 (15%), mild contractures 10/76 (13%), ulnar deviation of the hands 8/72 (11%), pectus carinatum or excavatum 8/72 (11%), camptodactyly 8/73 (11%) and syndactyly 6/76 (8%); only long tapering fingers (55/77, 71%), long toes (38/72, 53%) and flat feet (39/77, 51%) exceeded half, and mild calcaneovalgus feet came close to it (33/71, 46%) [6]. The French PNDS, which lists the same abnormalities, assigns them collectively a frequency of more than 50% of patients, which the cohort denominators do not support; the reference value is the “up to 50%” of GeneReviews [1, 6, 10]. Some patients have broad thumbs and great toes, and at least one had radial deviation resembling Rubinstein–Taybi syndrome [1]. Osteoporosis and frequent fractures have been described, probably secondary to reduced weight-bearing; in a report of a personal observation, fractures responded to bisphosphonates [1, 39].

3.13. Immunity and Spleen

Several patients have asplenia, and one had a severe course with purpura fulminans [1, 65]. Among six Australian patients studied in detail, two had recurrent sinopulmonary infections (one with recurrent oral candidiasis), one had lymphopenia, two had thrombocytopenia and three had positive antinuclear antibodies, with normal immunoglobulins and vaccine responses; the percentage of CD8 lymphocytes was lower than in controls (median 16.4% versus 25%; p=0.0048) and the CD4:CD8 ratio higher (2.6 versus 1.8; p=0.038). The authors concluded that evidence of immunodeficiency in MWS is insufficient [66]. Some patients with antibody deficiency and recurrent infections received intravenous immunoglobulin (IVIG), according to a personal observation cited in GeneReviews, and a case of B-cell deficiency due to IKAROS deficiency has been published in a patient with MWS, without an established causal relationship [1, 67].

3.14. Tumours and Other Rare Findings

Isolated reports have been published of rhabdomyosarcoma [68], CNS tumours [9] and, at autopsy in a 4-year-old girl who died from sepsis with otitis media, a suprasellar spindle cell lipoma with loss of RB1 on immunohistochemistry [69]. Tumour risk has not been quantified, and the sources do not justify cancer screening. Other rare findings include laryngomalacia, rocker-bottom feet, deep palmar and plantar creases, and idiopathic intracranial hypertension [3, 28, 39].

3.15. Natural History and Treated Disease

The frequencies in this article describe patients receiving usual care (cardiac and intestinal surgery, antiseizure treatment, rehabilitation), rather than untreated natural history. The severe acute complications listed in the care recommendations are repeated seizures, aspiration pneumonia, heart failure from congenital heart disease, obstruction and enterocolitis from Hirschsprung disease, and severe infections in children with asplenia [6]; in the Robert-Debré series, one of the 10 patients with Hirschsprung disease died in the first months of life [57]. The sources do not describe life expectancy (section 11).

4. Clinical Recognition and Warning Signs

4.1. When to Suspect the Condition, by Age

Prenatally, suspicion may arise with congenital heart disease, particularly involving the pulmonary arteries and valves, or an absent or short corpus callosum on ultrasound, but these findings are non-specific and diagnosis depends on genetic testing (section 5.7) [1, 9]. In a newborn, the combination of Hirschsprung disease, congenital heart disease and hypospadias, with broad medially flaring eyebrows and uplifted earlobes with a central depression, should suggest MWS; the face of a young infant is less characteristic than later, and diagnosis may require reassessment [3, 4, 6]. An isolated pulmonary artery sling, rare in the general population, warrants consideration of MWS [1, 6]. The French National Diagnosis and Care Protocol (PNDS) summarises the postnatal presentations as two: an early multiple-malformation picture (Hirschsprung disease, heart disease, agenesis of the corpus callosum, facial dysmorphism) followed by a neurodevelopmental disorder, or a neurodevelopmental disorder (hypotonia, delayed milestones, intellectual disability, sometimes epilepsy) with dysmorphism and without malformations; in both, the face may point immediately to the diagnosis [10].

In infants and young children, presenting signs include global developmental delay with hypotonia, acquired microcephaly, a first focal seizure, often triggered by fever, and chronic constipation [1, 6]. In older children, the triad of moderate to severe intellectual disability, absent or minimal speech with relatively preserved comprehension, and a happy disposition, with a broad-based ataxic gait and raised arms, overlaps with Angelman syndrome. Smith recommends considering MWS when suspected Angelman syndrome is not confirmed, and the Clinical Utility Gene Card includes Pitt–Hopkins syndrome in the early differential diagnosis [2, 3, 70]. In adolescents and adults, the face is more recognisable (long pointed chin, hanging nasal tip), and many adults with intellectual disability have not undergone contemporary genetic testing, so MWS is probably underdiagnosed in this age group [1, 23]. The Oxford Desk Reference includes MWS in the differential diagnosis of Hirschsprung disease, hypospadias, structural intracranial abnormalities, seizures with developmental delay, and Angelman syndrome [70–74].

4.2. Warning Signs and Emergencies

The care recommendations by Ivanovski and colleagues list acute complications requiring urgent action, by age group [6].

Reduced pain responsiveness changes the clinical presentation: fever without an apparent focus, irritability, food refusal or a change in behaviour may be the only manifestation of otitis media, a fracture, severe constipation or an acute abdomen [1, 6]. Cognitive or motor regression, or new-onset ataxia or dyspraxia, should prompt sleep EEG to exclude ESES [1, 47]. Severe abdominal distension after pull-through suggests enterocolitis or dysmotility [75].

4.3. Newborn Screening

There is no newborn screening for MWS. Diagnosis depends on clinical recognition and genetic testing; the methylation episignature has been proposed as a diagnostic aid in the neonatal period, when the face is less characteristic [8].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical Criteria

No formal clinical criteria have been published. The recognisable face, associated with Hirschsprung disease or chronic constipation and developmental delay or intellectual disability, permits clinical diagnosis [1]. GeneReviews lists suggestive findings: typical face (widely spaced eyes, broad eyebrows with medial flaring, low-hanging columella, open mouth, prominent pointed chin, uplifted earlobes with a central depression); growth restriction with microcephaly; moderate to severe intellectual disability with severely affected speech and relatively preserved comprehension; congenital heart disease with a predilection for the pulmonary arteries and valves; Hirschsprung disease or chronic constipation; urogenital abnormalities, particularly hypospadias; epilepsy, including ESES; broad-based gait; a happy personality; corpus callosum abnormalities on MRI; and, in the family history, a single case in the family, with rare affected siblings [1]. Diagnosis is established in a proband with the typical face and developmental delay or intellectual disability and a heterozygous pathogenic or likely pathogenic ZEB2 variant (approximately 84%) or a heterozygous 2q22.3 deletion including ZEB2 (approximately 15%); rearrangements disrupting the gene account for approximately 1% [1]. The French National Diagnosis and Care Protocol (PNDS) confirms the absence of formal clinical criteria or a published clinical score and the same proportions (84%, 15% and 1%); it accepts a point variant detected by targeted sequencing, panel, exome or genome sequencing, a 2q22.3 deletion detected by microarray, FISH or MLPA, and more complex chromosomal rearrangements that disrupt ZEB2 expression [10].

Facial gestalt has diagnostic value in its own right. Wenger and colleagues diagnosed 28 new cases through facial recognition, including presentations resembling CHARGE syndrome, craniosynostosis and mild MWS [76]. Computational phenotyping has begun to be applied: in a 4-year-old boy with an undiagnosed neurodevelopmental disorder and a de novo ZEB2 variant, GestaltMatcher ranked MWS first in the differential diagnosis, and PEDIA (phenotype coded in the Human Phenotype Ontology, HPO, combined with the exome) prioritised ZEB2. The authors proposed Bayesian facial score thresholds for applying criterion PP4 of the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) classification (phenotypic specificity): three of four photographs reached the moderate level and one the supporting level. This was a single exploratory case [77].

5.2. Non-Molecular Investigations

There is no confirmatory biochemical test. Investigations characterise the manifestations and support suspicion: dysmorphology assessment, brain MRI (corpus callosum, hippocampus, ventricles), awake and sleep EEG (ESES), echocardiography with attention to the pulmonary arteries and valves, suction rectal biopsy when Hirschsprung disease is suspected, abdominal ultrasound (kidneys and spleen), ophthalmological assessment and growth charts [1, 4, 6]. When Hirschsprung disease is suspected, the French PNDS describes a water-soluble contrast enema, which shows the calibre disproportion with dilatation proximal to the aganglionic segment, and histological confirmation by the absence of ganglion cells in a rectal biopsy taken with Noblett forceps [10].

5.3. Genetic Testing: Order of Tests

GeneReviews proposes two approaches. When the phenotype is suggestive, targeted testing is performed: ZEB2 sequencing and, if negative, targeted deletion/duplication analysis (quantitative polymerase chain reaction, qPCR, long-range PCR, MLPA, multiplex ligation-dependent probe amplification, or targeted microarray). Chromosomal microarray (CMA) detects genomic deletions including ZEB2 and defines their size and adjacent genes, which targeted testing does not; a multigene panel including ZEB2 and differential diagnosis genes is an alternative, with gene content and sensitivity varying between laboratories [1]. When the phenotype is atypical, exome sequencing (more commonly used) or genome sequencing is indicated. The American College of Medical Genetics and Genomics (ACMG) and American Academy of Pediatrics (AAP) recommend exome or genome sequencing as a first- or second-line test in children with global developmental delay, intellectual disability or multiple congenital anomalies [1, 78, 79]. If previous studies are negative and the phenotype is compatible, karyotyping seeks rearrangements disrupting the gene [1, 23, 80]. The methylation episignature is the next step when clinical suspicion persists without a detected variant, or when a VUS has been found in ZEB2 [1, 8].

The values in this table are proportions of known variants detectable by each method, calculated from recorded variants, rather than the clinical sensitivity of the test in a patient with suspected MWS [1]. The 2011 Clinical Utility Gene Card estimated analytical sensitivity above 90% and analytical specificity close to 100% “in the experience” of the authors, with approximately 10% of patients having a highly compatible phenotype and negative testing; clinical sensitivity depends on the experience of the clinician selecting patients, and almost all patients with an incompatible phenotype test negative. The card predates routine exome and genome sequencing and the episignature [2].

5.4. Test Limitations

A negative result does not exclude MWS. Single-gene or exome sequencing does not reliably detect single- or few-exon deletions, which require MLPA or validated CNV analysis; exome and genome sequencing detect CNVs with lower sensitivity than targeted methods [1]. Deep intronic variants and regulatory-region alterations escape exome sequencing; some patients with a compatible phenotype and no coding variant may have variants in proximal or distal regulatory elements [8]. Mobile element insertions may be missed by standard next-generation sequencing analysis pipelines, as shown by the exon 8 Alu insertion confirmed by long reads (Nanopore) [38]. Balanced translocations are not detected by exon sequencing or microarray [23, 80]. Low-level somatic mosaicism in parents may not be detected in leucocyte DNA, and exclusively gonadal mosaicism is not detectable in blood [1].

Analytical validation follows practical rules described in the card: a deletion identified by multiple MLPA probes or by an array with sufficient probes requires no additional validation; if there are few probes, confirmation is performed by fluorescence in situ hybridisation (FISH), qPCR, additional MLPA probes or a higher-density array. A single-exon deletion detected by a single MLPA probe requires sequencing of the exon to exclude a variant at the probe-binding site and confirmation by real-time PCR or the phenotype. Deletions visible by FISH warrant parental FISH testing to exclude a balanced chromosomal insertion including ZEB2 or a mosaic deletion. Point variants are validated by bidirectional sequencing, expected functional impact and absence in healthy parents [2].

5.5. Methylation Episignature

MWS has a DNA methylation signature in peripheral blood leucocytes. Caraffi and colleagues studied 29 individuals (17 female) with pathogenic or likely pathogenic variants, 24 in the discovery phase and 5 in validation, using the Illumina EPIC array and a support vector machine classifier (MVP score). They identified 296 differentially methylated probes, 98.6% hypomethylated, consistent with the repressor function of ZEB2, and differential methylation at the ZEB2 locus itself. The 5 validation individuals had MVP scores above 0.75, and maximum overlap with the 56 episignatures in the EpiSign v3 platform was 10–11% (CHARGE and BAFopathies). The score did not correlate with clinical severity. The only patient with a missense variant, c.3160C>G p.(Pro1054Ala), a mild phenotype and no epilepsy, had a low score, as did some patients with truncating variants and a locus deletion [8]. The statement that the test is “highly sensitive” rests on 29 reference cases and does not equate to population-level clinical sensitivity. Hypomorphic missense variants may not produce the signature, and one author declared shareholding in the company marketing the test [8]. In the April 2026 revision, GeneReviews added that the episignature may help classify VUS [1].

5.6. Report Content, VUS and Segregation

The report should state the gene, transcript with version (NM_014795.4), HGVS nomenclature at the coding DNA and protein levels, zygosity (heterozygous), classification according to ACMG/AMP criteria and, for deletions, genomic coordinates, size and included genes [1, 5]. A VUS neither establishes nor excludes the diagnosis; the episignature, demonstration that the variant is de novo (with confirmed parentage), and phenotypic specificity (PP4, supported by computational phenotyping when available) help reclassify it [1, 8, 77]. Missense variants should be interpreted cautiously because their phenotype may be mild and their inclusion in the diagnosis of MWS is discussed case by case [6]. When a molecular diagnosis is not reached, banking the proband's DNA is recommended [1].

5.7. Prenatal Diagnosis

The sources consulted describe no ultrasound signs specific to MWS; published prenatal diagnoses (by array in the second trimester, by fetal exome sequencing, in fetuses with recurrent structural malformations or a short corpus callosum) are isolated reports. Congenital heart disease and corpus callosum dysgenesis are the findings that may prompt broad fetal genetic testing [1, 9]. The French PNDS adds that prenatal ultrasound may be normal; that chromosomal microarray performed for an ultrasound anomaly (of the corpus callosum, heart or kidneys, or intrauterine growth restriction) may reveal a 2q22.3 deletion including ZEB2; and that, since a point variant is the most frequent mechanism, the diagnosis is made prenatally only when testing proceeds to a panel targeted to the ultrasound finding (for example, in agenesis of the corpus callosum) or to exome sequencing for a multiple-malformation picture, a practice still uncommon in 2021 [10]. In the case in section 10, complex heart disease was diagnosed prenatally, but amniocentesis with karyotyping and microarray was normal, and the diagnosis was made only at approximately 1 year by a gene panel [28]. Prenatal diagnosis and preimplantation genetic testing targeting a familial variant are discussed in section 8.

6. Differential Diagnosis

6.1. Comparative Table

Note on Angelman syndrome: the risk to siblings is below 1% for deletion and uniparental disomy and may reach 50% for an imprinting defect or a UBE3A variant [1]. Note on Ruggieri–Happle syndrome: the sources consulted describe the phenotypic overlap but not the gene for this syndrome.

6.2. Main Differential Diagnoses

Angelman syndrome is the most frequent differential diagnosis because it shares absent speech, a happy disposition, an ataxic gait with raised arms, microcephaly and seizures; in infants, both may present solely with hypotonia [1, 4]. They are distinguished by the MWS face and congenital anomalies (Hirschsprung disease, heart disease, hypospadias, corpus callosum abnormalities), which are absent in Angelman syndrome [3, 70]. Pitt–Hopkins syndrome shares the severity of intellectual disability, absent speech, stereotypies, seizures and constipation; the 2011 card recommended array and TCF4 testing after negative MWS testing, a step now covered in a single test by exome sequencing with CNV analysis [1, 2]. The French National Diagnosis and Care Protocol (PNDS) lists the same core differentials (CHARGE, Smith–Lemli–Opitz, Goldberg–Shprintzen, Rubinstein–Taybi, Pitt–Hopkins and Angelman) and stresses that Angelman syndrome involves few malformations and has no dysmorphism of its own [10].

CHARGE syndrome is the main differential diagnosis when coloboma, heart disease and genital hypoplasia are present, and CHARGE-like presentations of MWS have been published; the ears, choanal atresia and absence of Hirschsprung disease point towards CHARGE, and the two episignatures are distinct, with 10–11% probe overlap [1, 8, 76]. In a child with congenital heart disease and dysmorphism, MWS should be included in the differential diagnosis, especially with involvement of the pulmonary arteries and valves or a pulmonary artery sling [21, 81]. In intellectual disability with a suggestive face but no malformations, hypomorphic ZEB2 missense variants make mild MWS a diagnosis to consider [27, 82].

Many MWS abnormalities (hypospadias, congenital heart disease, Hirschsprung disease, agenesis of the corpus callosum) occur in isolation in people without a syndrome, so the presence of one alone is insufficient to raise suspicion [1]. In Hirschsprung disease, the Oxford Desk Reference recommends ZEB2 testing when microcephaly, intellectual disability and the typical face with uplifted earlobes are present [71].

7. Treatments and Risk Management Strategies

7.1. Principles and Organisation of Care

There is no disease-modifying therapy. Management is symptomatic, anticipatory and multidisciplinary, with quality of life as its aim [1, 6]. The care recommendations by Ivanovski and colleagues (2018) and GeneReviews (2026 revision) are the two international management references; they are cohort-based expert opinion, without formal evidence grading, and there is no international consensus or European Reference Network guideline specific to MWS [1, 6]. In France, the 2021 National Diagnosis and Care Protocol (Protocole National de Diagnostic et de Soins, PNDS), drafted by the Île-de-France reference centre for developmental anomalies and malformation syndromes (Hôpital Robert-Debré, AnDDI-Rares filière) according to the 2012 HAS method, with support from the ERN ITHACA project team, is the third reference; it also does not grade the evidence, and the bibliographic rationale supporting it is published separately by the filière [10]. The PNDS recommends that the initial assessment be coordinated by a clinical geneticist or paediatrician from a reference centre of the AnDDI-Rares or DéfiScience filières, together with the paediatrician or general practitioner, and that long-term coordination rest with the paediatrician, the geneticist or the general practitioner, depending on age and the type of involvement. It assigns to the attending physician referral to a reference or competence centre, routine follow-up (growth and HC, psychomotor development, vaccination), detection of complications (seizures, sleep, behaviour, recurrent infections, digestive disorders), initiation of rehabilitation or referral to a local service, and coordination with the centre. The coordination visit at the reference or competence centre is six-monthly in the first 2–3 years of life, annual in childhood and every 3 to 5 years in adulthood [10]. Because the syndrome is unfamiliar to most clinicians, Ivanovski and colleagues propose coordination by paediatricians, neurologists or clinical geneticists and genetic counsellors, with an increasing role for neurologists and geneticists as the number of adults grows; the team includes paediatrics, neurology, cardiology, nephrology and gastroenterology, particularly in early childhood. The authors strongly recommend AAC as a central element of care [6].

7.2. Initial Evaluation Following Diagnosis

Unless otherwise indicated, the rows in this table follow GeneReviews [1].

The initial assessment in the French PNDS covers the same systems, with some differences. It calls for investigation of inadequate vitamin intake as part of the growth work-up and for assessment of oral feeding skills by a speech and language therapist or a specialised psychologist. It indicates brain MRI in the presence of microcephaly, abnormal movements, epilepsy or walking acquired after 2 years (to look for a cortical abnormality), rather than routinely, and EEG only when epilepsy is suspected. It adds neuropsychological assessment to guide rehabilitation and schooling, polysomnography in a sleep centre if needed, testicular ultrasound if needed, spinal radiography and an orthopaedic consultation if needed, an audiogram with an ear, nose and throat consultation, a dental and orthodontic consultation, and immunological assessment with an immunology consultation in the presence of recurrent infections; abdominal and renal ultrasound looks simultaneously for renal anomalies and asplenia. It does not include the annual general laboratory tests proposed by Ivanovski [6, 10].

7.3. Epilepsy and Sleep

Seizures respond to standard antiseizure medications (antiepileptic drugs) in most patients [1]. In the longitudinal study of 40 Italian patients, valproate was the most commonly used and most effective drug, followed by levetiracetam [26]; in the Chinese series of 31 children, 30 were treated, levetiracetam and valproate were effective as monotherapy or polytherapy, 16 had been controlled for more than 6 months and 7 for more than 1 year [48]. These are observational data, without randomised comparison. No MWS-specific source (Ivanovski, GeneReviews, PNDS) gives doses, and the PNDS specifies that epilepsy treatment has no syndrome-specific features and follows the indications and conditions of the marketing authorisation; the reference doses are therefore those in the labels, extrapolated from epilepsy in general [10]. For levetiracetam, the European SmPC for Keppra® indicates, from 6 months to 17 years and below 50 kg, 10 mg/kg twice daily orally (100 mg/ml oral solution, preferred below 6 years and 25 kg), increasing by 10 mg/kg twice daily every 2 weeks to a maximum of 30 mg/kg twice daily; from 1 to under 6 months, 7 mg/kg twice daily up to 21 mg/kg twice daily; and, from 50 kg, 500 mg twice daily up to 1500 mg twice daily, with adjustment for renal function and gradual withdrawal. As monotherapy, the SmPC provides for use only from 16 years (focal seizures); below that age the indication is adjunctive therapy [83]. For valproate, the US label for valproic acid oral solution indicates, for focal seizures (from 10 years) and absence seizures, 10–15 mg/kg/day, increasing by 5–10 mg/kg per week; a response is usually obtained below 60 mg/kg/day, which acts as a limit because safety above it has not been established, with usual therapeutic plasma levels of 50–100 µg/ml and division of doses above 250 mg/day. The same label carries a boxed warning on fatal hepatotoxicity, with a markedly increased risk below 2 years, especially with polytherapy and in children with intellectual disability and severe epilepsy, on potentially fatal pancreatitis and on fetal risk (malformations and reduced intelligence quotient after intrauterine exposure); the label advises against valproate for epilepsy in women who are pregnant or planning a pregnancy, unless alternatives have failed or are unacceptable [84]. For valproate in particular, the dose is always individualised by paediatric neurology. Drug resistance affects approximately one-quarter of patients (25.9% in the cohort of 87), with a higher proportion among whole-gene deletions [6, 9]. Vagus nerve stimulation reduced seizure frequency in at least two patients, and in one adult antiseizure medications were discontinued without recurrence [1, 85]. Usual improvement in adolescence does not justify discontinuing surveillance: drug-resistant status epilepticus after 26 seizure-free years shows that late relapse is possible; control was achieved with new antiseizure medication combinations [26, 49]. The French PNDS, which considers withdrawal of antiseizure medications in adulthood a possible option because there are cases without relapse, adds two practical rules: when a previously stable epilepsy worsens, look for a trigger (pain from constipation, an orthopaedic or dental problem, urinary tract infection or otitis, sleep disturbance, poor adherence), especially in a patient who communicates little; and, when motor or cognitive regression or a change in behaviour occurs in a patient without known epilepsy, look for epileptic phenomena. The PNDS also notes that epilepsy does not appear to depend on the brain malformations and that vagus nerve stimulation was useful in rare cases [10].

ESES should be sought with sleep EEG at school age and with any regression, because its treatment may improve behaviour, motor function and cognition [1, 47]. The sources consulted describe no MWS-specific ESES treatment regimen. Sleep disorders should be screened for routinely (for example, using the SDSC), and patients with complaints should be referred to a sleep clinic for polysomnography [1, 50, 51]. The French PNDS adds bedtime routines and the usual symptomatic treatments, without naming drugs [10].

7.4. Hirschsprung Disease, Constipation and Feeding

Hirschsprung disease is treated by resection of the aganglionic segment and pull-through, using standard techniques [1]. In MWS, aganglionosis tends to be more extensive and outcomes are worse, as the published series show.

These series are small, retrospective and from referral centres, and do not allow direct comparison. They suggest that the pull-through decision should be individualised and made by a multidisciplinary team, that patients without recurrent enterocolitis or chronic dysmotility may be candidates for conservative treatment, and that prevention and postoperative bowel management should be intensified [57, 75, 87]. Croaker, a co-author of the original description, observed that the degree of developmental delay influences Hirschsprung disease outcomes and asked whether MWS differs from other syndromes with intellectual disability and aganglionosis, such as trisomy 21 [88]. Constipation may persist after surgery [2]. The French PNDS, coordinated by a co-author of the 2020 series and with the first author of the 2009 series in its working group, offers a less pessimistic reading: long-segment forms, extending beyond the left colic flexure, are more frequent than in non-syndromic Hirschsprung disease; the surgical technique is the same (not least because the syndrome is often not yet diagnosed in the neonatal period); early postoperative complications are more frequent, without it being known whether this is due to the extent of disease or to the syndrome; and some patients need a diverting stoma, almost always temporary and permanent in some because of persistent bowel dysfunction; in the longer term, in patients without diversion, functional outcomes approach those of the non-syndromic form. In all cases it recommends prolonged follow-up at a specialist centre [10, 57].

Chronic constipation is treated with standard measures, including osmotic laxatives and suppositories, with referral to a motility clinic if refractory; its control may improve urinary incontinence [1]. The French PNDS adds dietary and lifestyle measures and enemas and notes that, in these children, Hirschsprung disease will generally have been excluded by contrast enema and/or rectal biopsy [10]. None of the MWS sources gives doses; by extrapolation from chronic constipation in children in general, the UK SmPC for macrogol 3350 with electrolytes in paediatric sachets (Movicol® Paediatric Plain, 6.9 g) indicates, from 1 to 11 years, 1 sachet daily from 1 to 6 years and 2 sachets daily from 7 to 11 years, each dissolved in 62.5 ml of water, adjusting every 2 days until regular soft stools are obtained, with a maximum of 2 sachets daily below 2 years and, usually, 4 daily from 2 to 11 years; it is not indicated below 1 year, and from 12 years the adult formulation is used. The SmPC contraindicates macrogol in intestinal obstruction due to a structural or functional disorder of the gut wall, ileus and toxic megacolon, which requires untreated Hirschsprung disease or enterocolitis to be excluded before use [89]. In a 2-year-old boy with intestinal pseudo-obstruction, paradoxical abdominal pain and progressively restricted oral intake, low-dose off-label pyridostigmine (Mestinon®), an acetylcholinesterase inhibitor, improved pain and enabled a return to baseline activity; this is the only report of this use in MWS, and the dose is not given in the abstract consulted [60].

Oromotor dysfunction should be assessed at each visit. Choking, poor weight gain, frequent respiratory infections or food refusal warrant feeding assessment and a radiological swallowing study. Treatment options include feeding therapy, thickened or cold foods, positioning after meals and, in severe cases or with poorly coordinated sucking and swallowing, a nasogastric tube or gastrostomy. Gastro-oesophageal reflux disease (GORD) may require pharmacological treatment [1]. Dietary assessment is guided by the clinical course [6]. The French PNDS regards a nasogastric tube as an often temporary solution and gastrostomy as a team decision (gastroenterology, cardiology, paediatric neurology), depending on the severity of the feeding difficulties, calorie dependence on the tube and the risk of aspiration; it calls for specialised speech and language therapy in the presence of sucking–swallowing incoordination or an oral feeding disorder. For GORD, it proposes thickened feeds, correct positioning during and after meals and the usual H2-receptor antagonists or proton pump inhibitors, and allows a Nissen fundoplication to be discussed during the same operation as the gastrostomy when reflux and an oral feeding disorder coexist [10]. In the absence of a specific dose, the US label for omeprazole (Prilosec®, oral suspension, which can also be given via a nasogastric or gastric tube) indicates, for symptomatic GORD from 1 to 16 years, 5 mg (5 to <10 kg), 10 mg (10 to <20 kg) or 20 mg (≥20 kg) once daily before a meal, for up to 4 weeks, and, for erosive oesophagitis, the same doses for 4–8 weeks; from 1 to 12 months, for erosive oesophagitis only, 2.5 mg (3 to <5 kg), 5 mg (5 to <10 kg) or 10 mg (≥10 kg) once daily for up to 6 weeks [90].

7.5. Heart, Kidneys, Genital Tract and Skeleton

Congenital heart disease follows standard paediatric cardiology and cardiac surgery treatment, often in the first days or months; cardiological follow-up is determined by the abnormalities present [1, 2, 6]. The French PNDS states explicitly that, if no heart disease is found on the consultation and echocardiogram performed at diagnosis, systematic cardiological follow-up is not needed in the absence of symptoms [10]. Hydronephrosis and vesicoureteric reflux are followed by urology and nephrology, and hypospadias, cryptorchidism and bifid scrotum may require surgery [1, 2]; the PNDS adds endocrinological follow-up for hypospadias and cryptorchidism, with the same treatment as in the general population [10]. Urinary incontinence requires a urological approach adapted to cognitive abilities and comorbidities [1].

Foot and ankle malposition, flat feet, calcaneovalgus deformity and scoliosis are followed by orthopaedics [1, 2]. Physiotherapy aims to maximise mobility and reduce late orthopaedic complications (contractures, scoliosis, hip dislocation, fractures), using adaptive equipment (wheelchairs, walkers, bath chairs, orthoses and adaptive pushchairs) [1]. Spasticity is managed by orthopaedics, physical and rehabilitation medicine, physiotherapy and occupational therapy, with stretching to prevent contractures and falls; specialists may consider baclofen (Lioresal®), tizanidine, botulinum toxin (Botox®) or orthopaedic surgery, according to standard indications and doses, which GeneReviews does not specify [1]. The French PNDS emphasises prevention (physiotherapy, splints), because spasticity and joint stiffness frequently develop in hypotonic and poorly mobile patients and cause pain, positioning difficulties and loss of motor skills, and allows muscle relaxants or botulinum toxin with a physical and rehabilitation medicine or orthopaedic consultation; correction of clubfoot, contractures and genu valgum should be undertaken by an orthopaedic surgeon experienced with children who walk late, and spinal posture should be examined at each visit [10]. As no MWS source gives doses, the label doses for spasticity in general are used. The UK SmPC for oral baclofen (Lioresal®) indicates, from 0 to 17 years, starting at approximately 0.3 mg/kg/day in 2–4 divided doses (preferably 4), increasing cautiously at intervals of about 1 week to a usual maintenance dose of 0.75–2 mg/kg/day, with a maximum of 40 mg/day below 8 years and 60 mg/day above 8 years; in adults, 5 mg three times daily with increases every 3 days, usual control up to 60 mg/day and more than 100 mg/day only in hospital. The tablets are not suitable below 33 kg (the oral solution is used), withdrawal is gradual over 1–2 weeks because of the risk of a withdrawal syndrome with seizures, and the SmPC warns that baclofen may lower the seizure threshold in patients with epilepsy, requiring monitoring and adequate antiseizure therapy [91]. The US label for an oral solution (Ozobax® DS) provides the same titration scheme in adults, but with a maximum of 80 mg/day [92]. For botulinum toxin type A, the US label for Botox® authorises treatment of spasticity from 2 years, with 3–6 U/kg (maximum 200 U) in the upper limb and 4–8 U/kg (maximum 300 U) in the lower limb, divided among the affected muscles, not exceeding in children the lesser of 10 U/kg or 340 U in a 3-month interval; the boxed warning refers to distant spread of toxin effect, with potentially fatal dysphagia and breathing difficulties and a risk probably greater in children treated for spasticity, and the label considers patients with pre-existing swallowing or breathing difficulties more susceptible [93]. Frequent fractures warrant maintaining weight-bearing (standing and walking) and considering a bisphosphonate with endocrinology, based on a personal observation of response [1]. To prevent fractures, the PNDS proposes a regular and sufficient dietary calcium intake, regular physical activity and vitamin D supplementation if deficient [10]. Without a defined dose for MWS, the 2016 global consensus on nutritional rickets, applied here by extrapolation to vitamin D deficiency, defines deficiency as 25-hydroxyvitamin D below 30 nmol/l and recommends oral treatment for at least 12 weeks with 2000 IU/day below 12 months, 3000–6000 IU/day from 1 to 12 years and 6000 IU/day above 12 years, followed by maintenance with 400 IU/day in the first year of life and 600 IU/day thereafter, always with at least 500 mg/day of calcium; these are fixed doses by age, reassessed at 3 months, and not maximum doses [94].

Oral health has its own rules in the PNDS: toothbrushing from the eruption of the first teeth, systematic dental follow-up to detect crowding, malpositioned teeth and caries, and conventional treatment whenever possible; depending on the patient's cooperation and anxiety, some procedures require conscious sedation with an equimolar mixture of oxygen and nitrous oxide (MEOPA), in an authorised dental practice or in hospital [10].

7.6. Development, Rehabilitation and Communication

Rehabilitation (physiotherapy, psychomotor therapy and speech and language therapy) should begin as early as possible [2, 6, 22]. Occupational therapy addresses the fine motor skills needed for feeding, hygiene, dressing and writing [1]. Speech is almost always severely limited (typically between 0 and 100 words), and AAC, introduced early by an experienced speech and language therapist, ranges from low-technology approaches (gestures, picture exchange such as PECS, Makaton) to speech-generating devices. AAC does not impede speech development but supports it, drawing on relatively preserved comprehension [1, 2, 4]. GeneReviews describes the American organisation of services (early intervention from 0 to 3 years, a preschool programme with an individualised education plan from 3 to 5 years, annual plan review and transition in adolescence) [1].

The French PNDS describes the equivalent organisation in France. Early detection and follow-up of neurodevelopmental disorders follow the HAS recommendation on identifying and referring at-risk children, with nothing specific to MWS. Hypotonia and postural and motor delay require assessment and early intervention with physiotherapy or psychomotor therapy, with referral to an early medico-social action centre (CAMSP), which coordinates rehabilitation up to 6 years; thereafter, follow-up passes to a special education and home care service (SESSAD), a medico-psychological or medico-psycho-pedagogical centre, or is provided in a medico-educational institute (IME). Speech and language therapy starts early, after an ear, nose and throat assessment to exclude an aggravating factor, with AAC (PECS, Makaton). Schooling is adapted to abilities: inclusion in mainstream education with a support worker for pupils with disabilities (AESH), a localised unit for school inclusion (ULIS) or an IME, the latter being the most suitable for most children with MWS; a neuropsychological assessment at about 5 years helps to guide rehabilitation and schooling, and needs are reassessed regularly. The departmental centre for persons with disabilities (MDPH) awards the education allowance for a child with a disability (AEEH), which covers psychomotor therapy sessions not reimbursed by health insurance when rehabilitation takes place outside the CAMSP, and the AESH, which must be requested in advance [10]. The sources consulted do not describe the organisation in Portugal or Brazil, which depends on national early intervention and education systems.

7.7. Behaviour and Continence

Developmental paediatrics guides behavioural strategies and, if necessary, medication [1]. Incontinence and psychological problems should be screened for routinely [53]. Sleep disorders, ADHD and anxiety warrant neuropsychiatric assessment [1]. The French PNDS asks for behavioural disorders to be assessed at each visit, to look for their cause and try to reduce them, and notes that constipation may contribute to the lack of urinary continence [10].

7.8. Immunity and Asplenia

In asplenia, pneumococcal vaccination and other indicated vaccines are recommended, and prophylactic antibiotics should be considered in children [1]; paediatric immunological assessment is recommended in children with asplenia, and severe infections and sepsis are the acute complication specific to this group [6]. Patients with immunoglobulin deficiency and recurrent infections may receive IVIG [1]; by extrapolation from primary immunodeficiency, the European SmPC for an IVIG (Privigen®) indicates a starting dose of 0.4–0.8 g/kg followed by at least 0.2 g/kg every 3–4 weeks, adjusted to maintain trough IgG above 6 g/l and to the incidence of infections, with no fixed maximum dose (the reference maintenance range is 0.2–0.8 g/kg per month), and the same weight-based dosage from 0 to 18 years [95]. All vaccines in the national programme are recommended [2]. The French PNDS maintains the usual vaccination schedule, with pneumococcal protection in asplenia, but accepts antibiotic prophylaxis only for recurrent infections with an immune deficiency detected at the initial assessment, and not for isolated asplenia; this diverges from GeneReviews (section 7.15) [1, 10]. No MWS source gives regimens; those for asplenia in general apply. The Canadian Paediatric Society recommends prophylaxis in all asplenic children under 5 years, with amoxicillin–clavulanic acid 10 mg/kg/dose twice daily from birth to 3 months (alternatives: phenoxymethylpenicillin 125 mg or amoxicillin 10 mg/kg/dose twice daily), phenoxymethylpenicillin 125 mg or amoxicillin 10 mg/kg/dose twice daily from 3 months to 5 years, and phenoxymethylpenicillin 250–300 mg or amoxicillin 250 mg twice daily after 5 years, all orally and at fixed doses, with no maximum dose defined for the weight-based regimens; it considers lifelong prophylaxis ideally recommended, weighing adherence, access to care and resistance. It also recommends pneumococcal conjugate vaccine according to age and, after 24 months, the 23-valent polysaccharide vaccine at least 8 weeks after the last conjugate dose, with a booster 5 years later and at most two doses in a lifetime [96].

7.9. Anaesthesia and the Perioperative Period

In a study of 11 Italian families, with 37 procedures under general anaesthesia, only 2 patients had anaesthesia-related complications. The authors found no additional syndrome-specific anaesthetic risk beyond difficult intubation, longer ventilator weaning and concomitant lower respiratory tract infection. Risk perception was based on parental observations collected through a retrospective questionnaire and interview [97]. Cases of a difficult airway and of uneventful anaesthetic management have been described [98, 99]. GeneReviews concludes that a difficult airway is rare and that the syndrome does not appear to confer an intrinsically increased anaesthetic risk, citing longer ventilator weaning, anaemia and concomitant lower respiratory tract infection as the reported events [1]. The French PNDS takes the same position (no syndrome-specific anaesthetic risk, but difficulties with intubation and with weaning from ventilatory support have been described) and adds two principles: surgical techniques do not differ from those used in other children, but each procedure should be preceded by an ethical discussion weighing the expected benefits against the risks to the patient, and the postoperative period should be prepared with particular care in patients with multivisceral involvement or profound multiple disabilities [10].

7.10. Drugs Used in MWS

No drug has a specific indication for MWS; all those mentioned are used for their general indications (epilepsy, spasticity, constipation, reflux, osteoporosis, antibody deficiency, infection prevention) or off-label, and the French PNDS stresses that they should be used within the conditions of the marketing authorisation [10]. MWS-specific sources do not give doses; the doses in the table come from labels or from a guideline for the general condition, applied by extrapolation, and the details (titration, renal adjustment, warnings) are given in sections 7.3–7.8.

7.11. Agents to Avoid, Pregnancy and Transition

In one patient with tantrums and difficulty concentrating, a therapeutic trial of a stimulant worsened aggression, and GeneReviews recommends using these drugs with caution [1, 101]. No other drugs are specifically contraindicated in MWS. Reproduction in individuals with classic MWS is not known, and the sources consulted describe no pregnancies; contraception, menstrual management and protection from sexual abuse are not specifically addressed in the sources consulted [1]. Transition to adult care remains an open issue: most adults depend on others for activities of daily living, epilepsy may relapse late, spasticity and osteoporosis develop with age, and incontinence persists [1, 6, 49, 53]. Ivanovski and colleagues anticipate an increasing coordination role for adult neurologists and geneticists [6]. In adulthood, the French PNDS maintains an annual visit with the general practitioner (bowel function, feeding, sleep), neurology consultation according to symptoms, to detect spasticity, stiffness and seizures, and the geneticist as support for coordination, with a reference centre visit every 3 to 5 years [10].

Therapeutic education, according to the PNDS, begins when the diagnosis is disclosed and is directed at the parents and, once some autonomy has been acquired or adulthood reached, at the patient. Its objectives are to understand the disease and its treatments (adverse effects and precautions), to know how to act in the event of epileptic seizures, discomfort and chronic constipation, to avoid complications and to master technical skills (feeding and nutritional education, seizure management, dental hygiene). It may be individual or in groups, with several professionals [10].

7.12. Regulatory Status

7.13. Clinical Trials and Research

The ClinicalTrials.gov search (API v2, terms “Mowat-Wilson OR ZEB2”, 10 October 2026) found no interventional trial in MWS. The only specific study is observational [11].

The absence of trials means that all available therapeutic recommendations rest on observational studies, case series and expert opinion; antiseizure medication response proportions and surgical outcomes come from retrospective referral-centre series without a control group, except for the Chinese Hirschsprung disease series with matched controls [26, 75]. There are no negative, suspended or withdrawn trials to record. A negative trial search does not imply an absence of research: in 2022, the Mowat-Wilson Syndrome Foundation provided more than USD 143,000 for projects on brain organoids, genetic and cellular interactions with and without Hirschsprung disease, the relationship of ZEB2 to vocal imitation, and epilepsy, with a further USD 50,000 in 2023; the foundation's patient registry has existed since 2016 [13].

7.14. Developments in the Last 12 Months

Between October 2025 and October 2026, there were no authorisations, regulatory opinions or interventional trials. Developments are classified by level of evidence:

7.15. Reference Source Recommendations and Differences

The recommendations by Ivanovski and colleagues (2018) and GeneReviews (2025, revised in 2026) agree on growth monitoring frequency (every 6 months for the first 3 years, then annually), cardiological assessment at diagnosis, awake and sleep EEG and MRI when seizures are suspected, and early rehabilitation with AAC [1, 6]. They differ on several points, summarised in the surveillance table in section 11: ophthalmology is every six months until 6 years in Ivanovski and annually until 6 years in GeneReviews; audiology is performed at diagnosis and as clinically indicated in Ivanovski, and annually until 3 years in GeneReviews; abdominal ultrasound is annual in Ivanovski and only initial in GeneReviews; Ivanovski proposes annual laboratory tests (including thyroid function, anti-transglutaminase antibodies, IGF1 and IGFBP3) that GeneReviews does not include; and GeneReviews adds a baseline overnight EEG at 3–4 years to screen for ESES. Neither source justifies these differences with comparative data. The 2011 Clinical Utility Gene Card recommends audiology, all vaccines and periodic follow-up, without intervals [2].

The 2021 French PNDS agrees with both sources on growth, cardiology at diagnosis, early rehabilitation with AAC and the absence of specific therapy, and diverges on the following points [1, 6, 10]:

8. Reproductive Options and Family Counselling

8.1. Inheritance and Recurrence Risks

MWS is autosomal dominant, but almost all patients are the only case in the family, due to a de novo variant or deletion [1, 6]. In the cohort of 87, all alterations were de novo except in two sisters with the same variant and parents testing negative in blood, in whom germline mosaicism was presumed; there was no consanguinity, and mean paternal and maternal ages at delivery were 34 years and 6 months and 31 years and 7 months [6]. Sibling recurrence has been described in at least four families, including three affected siblings and a recurrent intragenic multiexon deletion in a Turkish family, explained by gonadal or somatic and gonadal mosaicism in a parent [3, 39, 103–106]. A parent with somatic and gonadal mosaicism may be mildly affected [1].

8.2. Testing Parents and Relatives

In an apparently isolated case, parents are tested for the proband's alteration [1]. Leucocyte DNA does not detect all somatic mosaicism or exclusively gonadal mosaicism, so a negative parental result does not eliminate the residual risk; the expected detection rate for somatic mosaicism in parents is low [1, 2]. When the deletion is visible by FISH, parents should undergo FISH to exclude a balanced insertion including ZEB2 or a mosaic deletion; for rearrangements, parental karyotyping and FISH seek a balanced rearrangement involving 2q22.3, and relatives of the carrier parent may be tested [1, 2]. Since non-mosaic variants have complete penetrance, healthy relatives other than parents are not at risk of being carriers and are not eligible for testing; for the same reason, testing healthy minor siblings is not indicated [2]. The French PNDS recommends segregation analysis in the parents even when a de novo alteration is presumed, because it confirms absence from parental blood and may reveal somatic mosaicism; for deletions and rearrangements, it recommends parental karyotyping and FISH to look for a balanced 2q22.3 rearrangement and, if one is found, family testing extended to adults at risk of being carriers [10].

8.3. Prenatal Diagnosis and Preimplantation Genetic Testing

Prenatal diagnosis and preimplantation genetic testing require prior identification of the alteration in the proband or of a balanced rearrangement in a parent. They are offered in subsequent pregnancies to the parents of a patient, targeting the index case's variant, despite the low risk [1, 2]. Perspectives on prenatal diagnosis vary among professionals and families, and the decision is personal [1]. The French PNDS recommends raising the possibility of prenatal diagnosis at the consultation at which the molecular result is given, for the couple's subsequent pregnancies or those of each parent if they are separated, and proposes a genetics clinic appointment when the result is given by a non-geneticist; it describes prenatal diagnosis by chorionic villus sampling from 11 weeks of gestation or by amniocentesis from 16 weeks. It diverges from GeneReviews on preimplantation diagnosis, which it reserves for high-risk situations, that is, a parent with somatic mosaicism or carrying a balanced chromosomal rearrangement [1, 10].

8.4. Counselling Content

Counselling explains the nature of the disorder, its almost always de novo origin, the residual risk from mosaicism and reproductive options, ideally before a further pregnancy. When there is no molecular diagnosis, banking the proband's DNA for future studies is recommended [1]. The French PNDS describes the disclosure of the diagnosis: a dedicated consultation, in a suitable setting and preferably with both parents or guardians, with the clinician who requested the test, an MWS expert if the requesting clinician is not one and, depending on the context, a psychologist, genetic counsellor or nurse. The information covers the disease and its complications, multidisciplinary follow-up, the test results, the mode of transmission and genetic counselling, the latter possibly explored further at a second consultation. It recommends the involvement of a psychologist during or soon after disclosure and during follow-up, provision of the contacts of patient associations and, in France, an application for 100% health insurance coverage and for recognition of disability by the MDPH [10]. Counselling also includes family support: in the Chinese series of 42 families, most had dysfunction scores in behaviour control and affective involvement, and family income was associated with better overall functioning, unlike the child's age and the severity of impairment [102].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and What Each Figure Measures

The authors of the earliest series considered the syndrome underdiagnosed, particularly without Hirschsprung disease, and the 2006 American series identified 12 patients over two years [21–23]. The M:F ratio of 183:161 in the combined cases dispels the impression of male predominance from early reports [1, 6]. Since mild missense phenotypes and adults without genetic testing are probably under-represented, the above figures underestimate the true frequency of the ZEB2 spectrum [1, 4].

9.2. Geography and Populations

MWS has been described across several continents and ancestries, and the sources consulted describe no founder variants or geographical clustering [6, 25]. Published series are predominantly European, Australian and North American: the predominantly European international cohort of 87 patients, Italian series (19 patients in 2009, 40 in the longitudinal epilepsy study and 54 in the neuroimaging study), the American series of 12 patients, the Polish series of 28, the French Robert-Debré series of 23, and the Turkish series of 10 [6, 9, 21, 24, 26, 39, 45, 57]. Chinese series have multiplied in recent years (22 patients in 2022, 31 with epilepsy, 42 families and 35 patients in 2026) [41, 48, 59, 102]. Each is a clinical case series and none measures prevalence. The growth charts combined 99 patients of 20 nationalities, predominantly from Italy (38) and the USA (16) [25].

Data from Portugal and Brazil in the sources consulted are scarce. From Portugal, there are three patients in the growth charts and the series of two patients by Engenheiro and colleagues (2008), with Portuguese and Danish authorship, whose abstract does not state the patients' origin [23, 25]. From Brazil, there is one patient in the growth charts and a neurological and molecular study of seven patients (Paz and colleagues, 2015), whose content was not consulted beyond the title [25, 108]. The absence of further data in the sources consulted does not establish their non-existence.

9.3. Special Populations

Adults with MWS are probably underdiagnosed because many adults with intellectual disability have never undergone contemporary genetic testing; known adults depend on others, have persistent incontinence, may develop spasticity and osteoporosis, and remain at risk of seizures [1, 49, 53]. People with missense variants or a mild phenotype may be diagnosed only through exome sequencing during investigation of intellectual disability without malformations [1, 27]. Patients with asplenia constitute a subgroup at risk of infection [6].

9.4. Reference Networks and Patient Associations

In the European Union, the relevant European Reference Network is ERN ITHACA (rare congenital malformations and rare intellectual disability) [12]. Patient associations providing information and registries include the Mowat-Wilson Syndrome Foundation in the USA, founded in 2013 by parents and grandparents, with a patient registry since 2016 (migrated to the Matrix platform in 2022) and international conferences (most recently in Minneapolis in June 2024), and Associazione Italiana Mowat Wilson, which collaborated on the growth charts and the ORALMOWAT26 study [11, 13, 14, 25]. GeneReviews also lists the MedlinePlus information sheet and the Pull-thru Network, a patient association for anorectal malformations and Hirschsprung disease [1].

In France, patients are followed at the reference and competence centres for developmental anomalies and malformation syndromes of the AnDDI-Rares filière, organised into six regional reference centres (Île-de-France, coordinated by Hôpital Robert-Debré, Sud-Ouest Occitanie Réunion, Inter-région Nord-Ouest, Ouest, Est and Sud-Est), with competence centres that include the overseas departments (Guadeloupe, Martinique, Réunion), and at the reference centres for intellectual disability of rare cause of the DéfiScience filière; the reference centres for language and learning disorders (CRTLA) are another resource. The PNDS serves as a reference for the attending physician for the care protocol that grants exemption from patient co-payments as an off-list long-term condition (ALD) and for the medical certificate in the MDPH application. At the time of the PNDS there was no French MWS association; a family group on a social network, created in 2014, is linked to the American association, and a family's web page (“Le rêve extraordinaire de Louise”) is listed as a useful contact. The PNDS recommends always offering contact with associations, leaving the decision to the family [10].

10. Illustrative Clinical Case

St Peter and colleagues (2024) described a girl with MWS and complex heart disease, followed from the prenatal period until her death at approximately 5 years [28]. Complex single-ventricle heart disease was diagnosed prenatally, but genetic amniocentesis was normal. She was born at 37 weeks with double-outlet right ventricle, subaortic and anterior muscular VSDs, hypoplastic mitral and tricuspid valves, and hypoplastic left heart. Her two siblings were healthy, and there was no consanguinity. She initially received palliative care at home, but subsequently underwent several cardiac procedures between 1 and 6 months, including Glenn and Fontan operations, with partial recovery. Karyotyping and microarray performed in early childhood were normal, and she became gastrostomy-fed.

At approximately 1 year, a connective tissue gene panel including ZEB2 identified the heterozygous exon 8 variant c.2471_2475del, normalised as NM_014795.4:c.2471_2475del p.(Met824ArgfsTer15), a frameshift. It was considered de novo on the basis of family history, but the parents were not tested [5, 28]. The full cardiac findings included hypoplastic left heart, VSD, a left pulmonary artery sling with tracheomalacia, a dysplastic tricuspid valve with severe regurgitation, and partial anomalous pulmonary venous drainage. She also had a duplex kidney with vesicoureteric reflux, visual impairment, dental abnormalities, hypotonia and global delay, secondary renal and hepatic problems, and idiopathic intracranial hypertension. Gastrointestinal problems dominated the course: she could not tolerate feeding (severe abdominal pain, intractable vomiting, gastrointestinal bleeding and colitis), with hospitalisations lasting weeks for intravenous fluids or parenteral nutrition; she depended on gastrostomy feeding with elemental formula and had gastroparesis and chronic constipation, with Hirschsprung disease excluded by rectal biopsy. Repeated EEGs were normal, and she never had seizures [28].

At approximately 3 years she measured 87.3 cm (6th percentile), weighed 11.7 kg (7th percentile) and had oxygen saturation of 80%; at 5 years and 4 months she measured 102.1 cm and weighed 14.3 kg (both at the 3rd percentile). She wrote, recognised some written words and spoke at the level of a 2-and-a-half-year-old child, with verbal and gestural communication. Progressive decline followed, with palliative care, and death occurred at approximately 5 years. Figure 1 of the article shows the child in infancy, early childhood and before death, published with consent (https://pmc.ncbi.nlm.nih.gov/articles/PMC10932183/figure/ijms-25-02838-f001/) [28].

The case illustrates four points. First, complex heart disease may dominate the presentation and delay syndromic suspicion, particularly when karyotyping and microarray are normal. Second, diagnosis came from a panel chosen for another indication, reinforcing the role of broad panels and exome sequencing. Third, the absence of epilepsy and relatively developed speech show phenotypic variability, even with a truncating exon 8 variant. Fourth, severe gastrointestinal dysmotility may exist without Hirschsprung disease. The case is exceptional in its cardiac severity and does not represent the usual course; confirmation that the variant is de novo would require parental testing, as recommended by the reference sources [1, 28].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Whether life expectancy is reduced in classic MWS is unknown: the sources consulted provide no survival or cause-of-death data from series. One patient was alive at 60 years, showing that survival into later adulthood is possible, and adults are probably under-recognised and under-reported [1]. The cohort of 87 included patients up to 36 years [6]. Causes of death described in case reports include complex heart disease and gastrointestinal complications (section 10), and sepsis with otitis media in a 4-year-old child; in a series of 10 patients with Hirschsprung disease, one death occurred in the first months, without a cause stated in the abstract consulted [28, 57, 69].

Functional prognosis is dominated by moderate to severe intellectual disability: in the cohort of 87, 38.3% did not walk independently and 67.4% had no speech at the last assessment, and most adults need help with activities of daily living [6]. Epilepsy tends to improve in adolescence and adulthood, with disappearance of absences after 16 years, but late relapse is possible [26, 49]. Whole-gene deletions are associated with later milestone acquisition and greater drug resistance; variants producing a defective protein and missense variants are associated with milder presentations [6, 9, 27]. Incontinence persists in most patients, although the ability to use the toilet improves with age [53]. Hirschsprung disease outcomes are worse than in the isolated form, with second surgery in 80% in one French series and persistent stomas in some patients [44, 57].

11.2. Surveillance

The table combines the recommendations of GeneReviews, Ivanovski and colleagues and the French National Diagnosis and Care Protocol (PNDS); where they differ, all are stated (section 7.15).

Follow-up by cardiology, gastroenterology, neurology, urology and developmental paediatrics is tailored to each patient's needs [1]. In adulthood, surveillance should continue to address seizure control, bone mineral density and fractures, spasticity and contractures, bowel function and continence [1, 49]. The French PNDS summarises its schedule in an appendix by professional and by age (0–2 years, childhood, adulthood), reflected in the rows of the table above; for nephrology, orthopaedics, endocrinology and immunology it provides for visits only as needed at all ages [10].

12. Summary and Final Considerations

Mowat–Wilson syndrome results from haploinsufficiency of ZEB2, a transcriptional repressor that interacts with SMAD proteins and is required for the neural crest and central nervous system development. Almost all cases are de novo, due to truncating variants (approximately 84% of alterations) or 2q22.3 deletions (approximately 15%), and the recurrence risk for siblings is approximately 2%, owing to parental mosaicism. The face is the most specific diagnostic feature and changes with age: broad, medially flaring eyebrows, uplifted earlobes with a central depression, prominent columella and, from adolescence, a long, pointed chin. These are accompanied by moderate to severe intellectual disability with absent or minimal speech and relatively preserved comprehension, epilepsy (78.5%), microcephaly (77.7%), congenital heart disease with a predilection for the pulmonary arteries and valves (58.1%), Hirschsprung disease (44.2%) or chronic constipation, hypospadias (59.7% of boys) and corpus callosum abnormalities (79.6% on systematic MRI).

Diagnosis is confirmed by ZEB2 sequencing and copy number analysis, or by exome or genome sequencing in atypical phenotypes; the methylation episignature supports the classification of variants of uncertain significance, and a negative result does not exclude the disease, particularly in the presence of mosaicism, mobile element insertions, balanced rearrangements or regulatory variants. Missense and some distal truncating variants produce a milder spectrum that may extend to intellectual disability without malformations. The main differential diagnoses are Angelman, Pitt–Hopkins and CHARGE syndromes.

There is no specific treatment or interventional trial. Management is based on the 2018 recommendations for care, GeneReviews and, in France, the 2021 National Diagnosis and Care Protocol (PNDS), which adds an age-based visit schedule and the organisation of care in reference centres: surgery for heart disease and Hirschsprung disease (with poorer bowel outcomes than in the isolated form), conventional antiseizure medications (valproate and levetiracetam were the most commonly used), active investigation for electrical status epilepticus during sleep, early rehabilitation with augmentative communication, attention to reduced pain responsiveness, which conceals otitis, fractures and abdominal complications, and assessment of the spleen. The three reference sources differ on several surveillance intervals (ophthalmology, hearing, ultrasonography, laboratory tests, EEG screening for ESES) and on antibiotic prophylaxis in asplenia, without comparative data. Gaps remain regarding life expectancy, adulthood, reproduction and epidemiology, including in Portugal and Brazil.

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