Download Mowat-Wilson syndrome

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
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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
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•
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•
•
•
del 2q22-23
no HSCR
•
•
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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
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•
•
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
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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
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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
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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
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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
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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
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MR severe
Microcephaly
Synophrys
Arched brows
Hypertelorism
HSCR (most)
Polymicrogyria
Coloboma
Facies differ from MWS
Pitt-Hopkins syndrome
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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