Mowat–Wilson syndrome: Facial phenotype changing with age: Study of 19 Italian patients and review of the literature

Garavelli, Livia; Zollino, Marcella; Mainardi, Paola Cerruti; Gurrieri, Fiorella; Rivieri, Francesca; Soli, Fiorenza; Verri, R.; Albertini, Enrico; Favaron, Elena; Zignani, Michela; Orteschi, Daniela; Bianchi, Paolo Pietro; Faravelli, Francesca; Forzano, Francesca; Seri, Marco; Wischmeijer, Anita; Turchetti, Daniela; Pompilii, Eva; Gnoli, Maria; Cocchi, Guido; Mazzanti, Laura; Bergamaschi, R.; Brasi, Daniele De; Sperandeo, Maria Pia; Mari, Francesca; Uliana, Vera; Mostardini, Rosa; Cecconi, Massimiliano; Grasso, Marina; Sassi, Silvia; Sebastio, Gianfranco; Renieri, Alessandra; Silengo, Margherita; Bernasconi, Sergio; Wakamatsu, Nobuaki; Neri, G.

doi:10.1002/ajmg.a.32693

Cited by 104 publications

(111 citation statements)

References 37 publications

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“…Despite the fact that the facial gestalt is consistent with this diagnosis from an early age, a change in certain facial features with age has been reported. 15 In childhood, earlobes seem to be uplifted, with a central depression, and eyebrows are large, medially flaring, and sparse in the middle. Facial features at this age also consist of a rounded skull, sparse and fine hair, puffy anterior neck, and excess skin on the rear of the neck.…”

Section: Discussionmentioning

confidence: 99%

“…3,4 In 2002 Zweier et al 5 further delineated the phenotype of MWS with or without HSCR, invariably characterized by ZEB2 gene defects, and proposed that the condition be named Mowat-Wilson syndrome. More than 300 patients have been reported so far [6][7][8][9][10][11][12][13][14][15][16][17] (additional reviewed articles are listed in Supplementary File S1 online).…”

Section: Mowat-wilson Syndrome (Mws) (Omim # 235730) Ismentioning

confidence: 99%

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

Ivanovski

Djurić

Caraffi

et al. 2018

Genetics in Medicine

131

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ORIGINAL RESEARCH ARTICLEPurpose: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS. Methods:In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations. Conclusion:Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.

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Section: Discussionmentioning

confidence: 99%

Section: Mowat-wilson Syndrome (Mws) (Omim # 235730) Ismentioning

confidence: 99%

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

Ivanovski

Djurić

Caraffi

et al. 2018

Genetics in Medicine

131

View full text Add to dashboard Cite

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“…Mutations in Zinc finger E‐box‐binding homeobox 2 in 2q22.3 and microdeletions in 2q21–q23 have been linked to epilepsy producing Mowat–Wilson syndrome (Garavelli et al. 2009). Deletions in 2q21.1 have also been linked to five families with attention‐deficit hyperactivity disorder with various developmental difficulties and epilepsy (Dharmadhikari et al.…”

Section: Discussionmentioning

confidence: 99%

Chromosome loci vary by juvenile myoclonic epilepsy subsyndromes: linkage and haplotype analysis applied to epilepsy and EEG 3.5–6.0 Hz polyspike waves

Wight

Nguyen

Medina³

et al. 2016

Molec Gen & Gen Med

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Juvenile myoclonic epilepsy (JME), the most common genetic epilepsy, remains enigmatic because it is considered one disease instead of several diseases. We ascertained three large multigenerational/multiplex JME pedigrees from Honduras with differing JME subsyndromes, including Childhood Absence Epilepsy evolving to JME (CAE/JME; pedigree 1), JME with adolescent onset pyknoleptic absence (JME/pA; pedigree 2), and classic JME (cJME; pedigree 3). All phenotypes were validated, including symptomatic persons with various epilepsies, asymptomatic persons with EEG 3.5–6.0 Hz polyspike waves, and asymptomatic persons with normal EEGs. Two‐point parametric linkage analyses were performed with 5185 single‐nucleotide polymorphisms on individual pedigrees and pooled pedigrees using four diagnostic models based on epilepsy/EEG diagnoses. Haplotype analyses of the entire genome were also performed for each individual. In pedigree 1, haplotyping identified a 34 cM region in 2q21.2–q31.1 cosegregating with all affected members, an area close to 2q14.3 identified by linkage (Z max = 1.77; pedigree 1). In pedigree 2, linkage and haplotyping identified a 44 cM cosegregating region in 13q13.3–q31.2 (Z max = 3.50 at 13q31.1; pooled pedigrees). In pedigree 3, haplotyping identified a 6 cM cosegregating region in 17q12. Possible cosegregation was also identified in 13q14.2 and 1q32 in pedigree 3, although this could not be definitively confirmed due to the presence of uninformative markers in key individuals. Differing chromosome regions identified in specific JME subsyndromes may contain separate JME disease‐causing genes, favoring the concept of JME as several distinct diseases. Whole‐exome sequencing will likely identify a CAE/JME gene in 2q21.2–2q31.1, a JME/pA gene in 13q13.3–q31.2, and a cJME gene in 17q12.

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“…Point mutations of the ZEB2 gene or microdeletions of the region encompassing it lead to MWS, a genetic autosomal dominant syndrome that is characterised by microcephaly, mental retardation and distinct facial features. 25 It seems that haploinsufficiency of ZEB2 and other genes mapping to the same region may explain the phenotype of a patient who has been diagnosed as having RSTS but also has signs overlapping those of MWS ( Table 2).…”

Section: Discussionmentioning

confidence: 99%

High frequency of copy number imbalances in Rubinstein–Taybi patients negative to CREBBP mutational analysis

et al. 2010

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Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant disorder characterised by facial dysmorphisms, growth and psychomotor development delay, and skeletal defects. The known genetic causes are point mutations or deletions of the CREBBP (50-60%) and EP300 (5%) genes. To detect chromosomal rearrangements indicating novel positional candidate RSTS genes, we used a-CGH to study 26 patients fulfilling the diagnostic criteria for RSTS who were negative at fluorescence in situ hybridisation analyses of the CREBBP and EP300 regions, and direct sequencing analyses of the CREBBP gene. We found seven imbalances (27%): four de novo and three inherited rearrangements not reported among the copy number variants. A de novo 7p21.1 deletion of 500 kb included the TWIST1 gene, a suggested candidate for RSTS that is responsible for the Saethre-Chotzen syndrome, an entity that enters in differential diagnosis with RSTS. A similar issue of differential diagnosis was raised by a large 4.3 Mb 2q22.3q23.1 deletion encompassing ZEB2, the gene responsible for the Mowat-Wilson syndrome, whose signs may overlap with RSTS. Positional candidate genes could not be sought in the remaining pathogenetic imbalances, because of the size of the involved region (a 9 Mb 2q24.3q31.1 deletion) and/or the relative paucity of suitable genes (a 5 Mb 3p13p12.3 duplication). One of the inherited rearrangements, the 17q11.2 379Kb duplication, represents the reciprocal event of the deletion underlying an overgrowth syndrome, both being mediated by the NF1-REP-P1 and REP-P2 sub-duplicons. The contribution of this and the other detected CNVs to the clinical RSTS phenotype is difficult to assess.

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Mowat–Wilson syndrome: Facial phenotype changing with age: Study of 19 Italian patients and review of the literature

Cited by 104 publications

References 37 publications

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

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

Chromosome loci vary by juvenile myoclonic epilepsy subsyndromes: linkage and haplotype analysis applied to epilepsy and EEG 3.5–6.0 Hz polyspike waves

High frequency of copy number imbalances in Rubinstein–Taybi patients negative to CREBBP mutational analysis

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