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Mowat-Wilson syndrome Rome 2009 3rd European Course in Dysmorphology Meredith Wilson Children’s Hospital at Westmead University of Sydney The start…. 1996 Clinical Genetics Department Weekly Review Meeting Children’s Hospital at Westmead, Sydney • • • • • • David Mowat presented a child with severe intellectual handicap, Hirschsprung disease (HSCR) facial dysmorphism, microcephaly, & seizures, with “Angelman-like” smiling, upturned face Meredith Wilson recalled another patient with MR, HSCR and markedly similar facies MW recalled a third patient, known to have a 2q22 deletion 4th patient found by discussion with HSCR Surgical Research team at CHW Paediatrician of 4th (Jeff Chaitow) recognised 5th patient by facial phenotype – did not have HSCR Bronwyn Kerr identified 6th patient after discussion with MW Literature searching Published “HSCR-microcephaly-MR” disorders – A heterogeneous group, none well delineated – Goldberg-Shprintzen syndrome (reported 1981 in sibs), not well defined, but possibly autosomal recessive Published 2q22 deletions – Lurie et al review 2q deletions included one patient with del 2q22, HSCR and severe MR (no photo) Syndrome features • • • • • • del 2q22-23 no HSCR • • • ALL Typical facies Mental retardation – usually severe MAJORITY Microcephaly Epilepsy Hirschsprung Short stature SOME Congenital heart disease Hypospadias Agenesis corpus callosum Conclusions JMG 1998 • Either a contiguous gene syndrome or a new dominant single gene disorder involving a locus in 2q22-q23 • Not Goldberg-Shprintzen syndrome, based on both dysmorphism and likely AD inheritance • Distinctive facies the key to diagnosis • HSCR not obligatory • Other major malformations (heart, urogenital, CNS) variable 2001: SIP1 gene identified 2 groups independently reported heterozygous mutations in SIP1 (encodes Smad-interacting protein-1) • Wakamatsu et al Nature Genetics (April) • Cacheux et al, Hum Mol Genetics (July) Wakamatsu, N. et al. Nat Genet. 27 (April 2001) Further studies 2001-2002 • Amiel et al Am J Hum Genet (Oct 2001) • Yamada et al Am J Hum Genet (Dec 2001) • Zweier et al (March 2002) Confirmed phenotype and added genotype data American Journal of Medical Genetics 108:177-181 (2002) “We demonstrate that there is a recognisable clinical entity with a specific facial gestalt, mental retardation and variable MCAs which we propose be called the ‘Mowat-Wilson' syndrome” >200 patients published since MWS phenotype • Distinctive facial features • Intellectual handicap moderate-profound • Majority have ≥1 major anomaly involving HSCR, heart, CNS or genitourinary system • Most have epilepsy MWS- Prenatal/Birth • Prenatal Occasional reports NT Cardiac malformation Agenesis corpus callosum • Neonatal Weight, length, head circumference often normal Hypotonia, poor feeding +/- Hirschsprung disease +/- congenital malformation Facial features • *** Fleshy uplifted ear lobes, central depression • ** Puffy anterior neck • ** Triangular chin • Round head, tall forehead, square face, full cheeks • Excess nuchal skin • Deep set but “large” eyes • Splayed “M” contour upper vermilion • Rounded prominent nasal tip • Deep central philtrum • Earlobes uplifted, rounded, fleshy, central depression • Shaped like red blood corpuscle (or orecchiette pasta) MWS - Infants • upper lip more prominent • everted lower lip • “M” shaped upper lip: full medially, narrow laterally; • prominent philtral pillars • high paramedian peaks of crista philtrae • deep philtrum Square face, triangular chin MWS- children • Uplifted face with open mouth/smiling expression • Broad separated eyebrows with sparse medial flare • Some have disorganized hair growth patterns within the brows but brows well confined (no synophrys) • Ear lobes less uplifted, less central depression • Aquiline nasal profile developing • Overhanging nasal tip with prominent columella • Disproportionate lengthening of lower face • Prominent chin or prognathism Facial phenotype evolves with age • In older children, the eyebrows are broad and horizontal with a wide medial separation • The nasal tip lengthens and depresses and the columella becomes more prominent • The mid-portion of the nose starts to fill, eventually becoming convex • In adolescents and adults the face is long, the nasal tip overhangs the philtrum, and there is often prognathism with a long, pointed or “chisel-shaped” chin Hand and foot anomalies • • • Slender fingers Mild camptodactyly Thickening of the interphalangeal joints in older individuals • • Talipes EV or positional talipes, everted foot position Broad halluces, unilateral duplication hallux, hypertrophy of the first ray of the foot reported • • Hypoplastic phalanges but long halluces (Garavelli 2003) Brachytelephalangy with broad thumbs and halluces in patient with missense mutation (Heinritz 2006). Hypoplasia of the halluces in patient with 11 Mb deletion (Zweier 2003) • 8 years 15 years Large/long halluces Talipes equinovarus MWS - feet Pes planus, everted feet MWS: congenital anomalies • • • • • Hirschsprung disease (HSCR) Congenital heart defect Hypospadias Agenesis corpus callosum Structural eye anomalies Clinical features in 57 patients with MWS Our series (n=57) Published (n=102) Male: Female 30: 27 (1:1) 62:40 (1.5:1) Mental retardation All All Microcephaly 47/57 (82%) 78/94 (83%) Seizures 24/31 (77%) 71/97 (73%) HSCR 26/57 (46%) 65/102 (64%) Congenital heart disease 32/57 (56%) 50/99 (50%) Urogenital/renal anomalies 28/57 (49%) 45/88 (51%) Hypo/agenesis of corpus callosum 24/57 (42%) 36/87 (41%) Structural eye anomalies 6 1 Dastot–Le Moal, Wilson and Mowat et al., Hum Genet 2007 Summary of literature 2009 Clinical feature Percentage Male: Female Typical facies Mod-severe MR Epilepsy Microcephaly Short stature Hirschsprung Agenesis/hypoplasia corpus callosum Congenital heart disease Pulmonary artery sling +/- tracheal stenosis Hypospadias Renal anomalies Structural eye anomalies 1.4 98 99 75 80 50 45-55 45-50 50 3 50-55 (males) 12 4 Hirschsprung disease (HSCR) • Failure of vagal neural crest (NC) cells to migrate, proliferate, differentiate or survive in the bowel wall to form both plexuses of the enteric nervous system B A C Ba enema Classification of HSCR based on length of intestine with aganglionosis. A=Short segment HSCR B=Long segment HSCR C=Total colonic aganglionosis Genetics of isolated HSCR Familial clustering • Low penetrance : risk to sibs ~ 4% overall • Variable expression: USS-SS-LS-TCA • Sex dependent; M:F ratio 4:1 for S-HSCR Coding sequence mutations in RET • 50% of familial cases • 15% sporadic cases Polymorphisms in RET • Intron 1 polymorphism leading to a hypomorphic RET allele in ~90% of sporadic HSCR Complex inheritance • RET mutations/polymorphisms occur in conjunction with other autosomal susceptibility loci HSCR in MWS • Typical newborn presentation in most • Long segment (LS) or short segment (SS) - most have SS disease • Total colonic aganglionosis reported • Chronic constipation – late diagnosis • Sex affected penetrance; M>F but not as marked as in isolated HSCR • No definite genotype:phenotype correlation HSCR in MWS • Early series affected by ascertainment bias: HSCR in >80% • Later series lower incidence 2003 Wilson et al 2005 Zweier et al 2007 Dastot-Le Moal et al 2009 Garavelli et al Published overall 61% 41% 46% 31% 54% Role of RET in syndromic HSCR Penetrance of HSCR in isolated and syndromic cases c.f. frequency of the hypomorphic RET “T” allele HSCR RET-dependent in syndromes for which epidemiologic data are closer to those observed in isolated HSCR • • HSCR RET-independent in syndromes for which the HSCR penetrance is high, e.g. MWS and WS4 Clinical outcome HSCR in MWS Bonnard et al J Ped Surg (2009): only published series HSCR Recurrent enterocolitis Enteral feeding Continent ZEB2 Ex 8 mut 1 TCA 2 RS 3 TCA + 4 TCA + + deletion 5 RS + + deletion + Ex 8 mut deletion Suggested outcome may be worse in MWS: ? due to more extensive myenteric dysplasia causing persistent problems ….not proven Upper GIT in MWS • Pyloric stenosis reported in 5% – also reported in non-syndromic HSCR • • • • Swallowing incoordination Dysphagia Gastroesophageal reflux Enteral feeding Congenital heart disease 50-55% of reported individuals • patent ductus arteriosus • atrial septal defect • ventricular septal defect • tetralogy of Fallot • pulmonary atresia • pulmonary valve stenosis • pulmonary artery sling or stenosis* • aortic coarctation • aortic valve stenosis Pulmonary artery sling (PAS) • Rare • LPA arises from RPA and forms a vascular ring around the trachea • Frequently associated with tracheal stenosis or complete tracheal rings: “ring-sling” syndrome • PAS +/- tracheal stenosis reported in 3% MWS Consider MWS in dysmorphic neonate with PAS PAS/tracheal stenosis Reference Mutation Pulmonary Tracheal artery sling stenosis Other/ cardiac Ishihara et al., 2004 Patient 28 c.857_858delAG, p.Glu286ValfsX7 (exon 7) + + PDA Zweier et al., 2005 Patient 5 c.696C>G, p.Tyr232X (exon 6) + + Asplenia Zweier et al., 2005 (sibs) c.852_853delCA, p.Tyr285ArgfsX9 (exon 7) + + + Atypical LPA Patient 22 Patient 23 PFO Adam et al, 2006 Patient 9 c.1910 C>T , S637X (exon 8) + Dastot-Le Moal et al, 2007 c.2231_2232dupTA, p.Ala745X (exon 8) ? + Aortic valve stenosis Strenge et al, 2007 c.821_823insC, p.Q275fsX279 (exon 7) + + PDA, VSD, coarctation Pending + - VSD, coarct, splenic cysts Wilson, 2009 (not published) CNS structural • Absent/ hypoplastic corpus callosum • • • • Frontotemporal hypoplasia Hippocampal hypoplasia Pachygyria Nodular subependymal heterotopia • Not reported with polymicrogyria (typical in Goldberg-Shprintzen syndrome) MRI abnormalities in MWS Corpus callosum Agenesis Temporal lobe Hypoplasia Temporal hypoplasia Hippocampal dysplasia Genitourinary abnormalities Reported in ~ 50% • Hypospadias in 45-50% of males • Bifid scrotum • Webbed penis • Undescended testes • Vesico-ureteral reflux • Megacystis • Neurogenic bladder Ocular abnormalities • Strabismus common (>50%) • Nystagmus (resolving) • Hypermetropia/myopia • Astigmatism • Chorioretinal/ iris coloboma • Microphthalmia • Cataract • 4% in literature Dental anomalies • wide diastema upper +/- lower central incisors • chisel-shaped central incisors • small and palatally placed lateral incisors Hearing & Pigmentation • Occasional reports of sensorineural or conductive deafness – probably coincidental • Several reports of patchy depigmentation hair/skin (personal communications) • Note patient with cutis tricolore syndrome (Ruggiero et al 2003) and overlapping phenotype Epilepsy • • • • • • Present in ~ 75% reported individuals Age of onset months-10 years Mixed seizure types No consistent EEG findings Some have resistant seizure disorder Several individuals have dramatically seizure control improved after puberty Autonomic dysfunction? • Neurogenic bladder in several patients • One patient with episodic bradycardia, urinary retention, hypersomnolence, hypercarbia, hypoxia, coma, pinpoint pupils • Possible diffuse ANS dysregulation Neurodevelopmental • • • • Disability moderate- severe- profound Most described as placid and happy Frequent smiling and uptilted head posture, Do not exhibit unusual laughter • Very limited speech, usually few recognizable words • Many have better receptive abilities • Signing may aid communication • Frequent chewing/mouthing/drooling • Bruxism • Retching to gain attention Milestones Milestone N Mean SD Min Max Age of sitting 53 21.46 mo 13.87 mo 6 mo 60 mo Age of cruising 41 39 mo 16.68 mo 12 mo 102 mo Age of walking 40 49.05 mo 19.7 mo 18 mo 96 mo Data collected by Liz Evans, Sydney, Australia PhD candidate University of NSW 2009 Intellectual disability Data collected by Liz Evans, Sydney, Australia PhD candidate University of NSW 2009 Estimated ID of 29 participants who received developmental assessments Estimated Level of ID Moderate Severe Profound Total N 4 23 2 29 Percent of sample 14% 79% 7% 100% Intellectual disability Data collected by Liz Evans, Sydney, Australia PhD candidate University of NSW 2009 Estimated level of ID assigned to all 71 MWS participants (from assessment or by interview) Level of ID Mild Moderate Severe Profound TOTAL N 1 9 45 16 71 Percent 1.41 12.68 63.38 22.54 100.00 MWS patients mainly from Australia/USA/Italy/Japan/UK) Other concerns • Many adults (>35%) underweight • Sleep disturbance frequently reported • Frequent chewing, mouthing, bruxism Summary • Intellectual disability at least moderate range but more often in the severe range • Better receptive than expressive skills • Many display a happy, sociable demeanour. • Interventions recommended for – – – – improving expressive communication skills increasing independence in activities of daily living managing sleep disturbance managing feeding difficulties MWS survival • No long term data • Early death (infancy or childhood) reported, but not usual • 50 year old patient known Differential diagnoses • Goldberg-Shprintzen • Pitt-Hopkins • Ruggieri-Happle (cutis tricolore) Goldberg-Shprintzen syndrome • First described 1981 in sibs with HSCR, microcephaly, hypertelorism, short stature, submucous cleft palate • Since, individuals with HSCR-MR-microcephaly often published as “Goldberg-Shprintzen” despite clinical and genetic differences • Brooks et al (2005) reported AR mutations in KIAA1279 confirming “GOSHS” as a separate syndrome Goldberg-Shprintzen syndrome • • • • • • • • MR severe Microcephaly Synophrys Arched brows Hypertelorism HSCR (most) Polymicrogyria Coloboma Facies differ from MWS Pitt-Hopkins syndrome • • • • • • • • AD, de novo mutations involving TCF4 Severe MR, microcephaly, +/- seizures Deep-set eyes, thin eyebrows Prominent lips, exaggerated Cupid’s bow Prognathism Clubbed fingertips Hyperventilation HSCR described but uncommon Clinical features differentiating MWS, GOSH and PHS Feature MWS GOSH PHS Hypospadias ++ - - Congenital heart disease ++ - - Agenesis corpus callosum ++ - (hypo) Polymicrogyria - ++ - Hyperventilation - - + Severe myopia - - + Clubbed fingertips - - + ZEB2 gene SIP1 Smad-interacting protein 1 ZFHX1B Zinc finger homeobox 1B ZEB2 Zinc finger E-box binding homeobox 2 Location 2q22.3 Genomic organisation of ZEB2 • Coding sequence exons 2-10 • Functional domains N-ZF: N-terminal zinc finger cluster SBD: Smad-binding domain HD: Homeodomain CtBP: C-terminal binding protein interacting C-ZF: C-terminal zinc finger cluster Figure: Wilson et al, Mowat-Wilson syndrome, in Epstein (Ed), Inborn Errors of Development, 2008 ZEB2 mutations reported to Nov 2009 221 reported, over 115 different mutations Approximately 50% of mutations in exon 8 (largest exon) Type of mutation Number % Total All Cytogenetic deletion Translocation disrupting gene Large gene deletions Small insertions/deletions Nonsense Complex Splicing* Missense* Inframe del* 221 2 2 43 91 72 2 5 3 1 <1 <1 19 41 32 <1 2 1.3 <0.5 * some reported with mild/atypical phenotypes MWS-recurrence risk • • • • McGaughran et al 2005 Zweier et al 2005 Ohtsuka et al 2008 Cecconi et al 2008 2 sibs 2 sibs* 3 sibs 2 sibs * Paternal somatic mosaicism shown Clinical features vary between siblings Empiric recurrence risk ~ 2% (0.6-5.75%) Interesting…. • Ballarati et al (2009) report patient with MR and some MWS features & complex chromosome rearrangement involving 2q22 • 46,XY,t(1;15) (q42;q11.2)ins(1;2)(q42;q?21q?31) • 2q22 segment including ZEB2 translocated & inserted into chromosome 1 • ZEB2 not deleted (mutation analysis not done) • Breakpoint 794 kb from ZEB2 ? position effect ZEB2 genotype:phenotype • No genotype: phenotype correlation established* • Most mutations lead to drastic C-terminal truncation of protein (unstable product) • Haploinsufficiency likely mechanism of pathology • Large deletions (involving contiguous genes) may give additional features *few reports atypical phenotype with rare mutations Atypical patients with ZEB2 mutations Reference Mutation Phenotype Yoneda et al (2002) 3bp inframe del exon 3 mild-mod MR constipation Heinritz et al (2006) missense Q1119R exon 10 cleft lip/palate brachydactyly severe MR Zweier et al (2006) splice acceptor IVS1-1G>A 5’ UTR mild MR subtle facies Gregory-Evans (2004) missense R953G exon 8 Trisomy 21 + MWS facies HSCR coloboma Missense mutations ZEB2 • Missense mutations are very uncommon (only 3 reported) • 2 with atypical phenotypes (Heinritz 2006, Zweier 2006) • 1 with typical but severe phenotype (DastotLe Moal 2007) • Missense mutation → other phenotypes? Approach to mutation testing 1. ZEB2 FISH for deletions larger than 200–300 kb (15%) 2. Direct sequencing of ZEB2 (80%) 3. MLPA or qPCR for single or multiple exon deletions (5%) ZEB2 zinc finger E-box binding homeobox 2 • Encodes Smad-interacting protein-1(SIP1) • SIP1: one of two members of the vertebrate ZFHX1 family zinc finger (ZF) and homeodomain/ homeodomain-like (HX)- containing proteins • SIP1: transcriptional co-repressor (mainly): involved in the transforming growth factor-β (TGF-β) signalling pathway • ZEB2 highly evolutionarily conserved, widely expressed in embryological development transforming growth factor-β (TGF-β) signalling pathway Smad proteins cytoplasmic mediators with pivotal role in relaying TGF-β signals from cell surface receptors to the nucleus. SIP1 interacts with Smads 1-5 SIP1 functions as co-repressor of many genes SIP1 binding to target genes SIP1 “two-handed” ZF binding to motifs in promoter region of target genes Figure courtesy M Goossens SIP1 expression • strongly transcribed early developing peripheral and central nervous systems of mice and humans – neural crest–derived cells, including enteric nervous system and facial neurectoderm – neural retina, predominantly retina ganglion cell layer, and whole lens • transcribed in early developing human and mouse heart, yolk sac, thymus, liver, skeletal muscles, genital tubercle, kidneys and bladder • likely to have pleiotropic effects in early embryogenesis Neural crest (NC) derivatives Cranial connective tissue and musculoskeletal structures head & face Vagal populate gastrointestinal tract and cardiovascular region Truncal peripheral sensory neurons, glial cells, some neuroendocrine cells, melanocytes Mouse Models Heterozygote SIP1 null mice Van de Putte et al 2003 • most have agenesis corpus callosum, do not have HSCR Homozygous SIP1 knockout mouse • • lethal E9.5 (4-5 wks human): severe growth retardation, neural tube failure to close, cardiovascular function defects Migration arrest neural crest cells: no vagal or truncal NC cells Conditional SIP1 KO in neural crest-derived cells Van de Putte et al 2007 • survives to juvenile • hippocampus and corpus callosum consistently missing • defective craniofacial, heart, melanocytes, enteric nervous system and sympatho-adrenal function MWS – prenatal diagnosis Fetal ultrasound unreliable/inconclusive • Nuchal translucency – several reports • Agenesis/hypoplasia corpus callosum • Congenital heart disease DNA testing for known family mutation Acknowledgements David Mowat Department of Medical Genetics Sydney Children’s Hospital Florence Dastot-Le Moal Michel Goossens Service de Biochimie et Génétique Hôpital Henri Mondor, Paris Liz Evans University of NSW Patient photographs Mowat-Wilson Raoul Hennekam Lesley Adès Julie McGaughran Kate Gibson Sharron Worthington ..and many others Parents of individuals with MWS Goldberg-Shprintzen Alice Brooks Kristi Jones