American Journal of Medical Genetics 137A:302–304 (2005)
Recurrence of Mowat–Wilson Syndrome in Siblings With
the Same Proven Mutation
Julie McGaughran,1* Stephen Sinnott,2Florence Dastot-Le Moal,5Meredith Wilson,3David Mowat,4
Bridget Sutton,2and Michel Goossens5
1Queensland Clinical Genetics Service, Royal Children’s Hospital, Brisbane, Queensland, Australia
2Centre for Fetal Diagnosis and Treatment, Royal Women’s Hospital, Brisbane, Australia
3Department of Clinical Genetics, The Children’s Hospital at Westmead, Sydney, Australia
4Department of Medical Genetics, Sydney Children’s Hospital and School of Paediatrics,
University of New South Wales, Sydney, Australia
5Service de Biochimie et Ge ´ne ´tique, Unite ´ INSERM 468, Ho ˆpital Henri Mondor, Cre ´teil, France
Mowat–Wilson syndrome (MWS) is a mental
retardation syndrome associated with distinctive
facial features, microcephaly, epilepsy, and a
including Hirschsprung disease (HSCR), agenesis
of the corpus callosum, genitourinary abnormal-
ities, and congenital heart disease. Heterozygous
ZFHX1B (previously SIP1) [OMIM 605802] have
recently been found to cause MWS. There have
previously been noreportsofasiblingrecurrence
of this syndrome. A brother and sister are
described with clinical features of MWS, where
both have the same truncating mutation in exon 8
of ZFHX1B. As their parents are phenotypically
normal and do not have the mutation in lympho-
cyte-derived DNA, the most likely explanation is
? 2005 Wiley-Liss, Inc.
involving the gene
KEY WORDS: Mowat–Wilson syndrome; sibling
recurrence; germ-line mosaicism
Mowat et al.  reported six sporadic patients with
microcephaly, mental retardation, and similar dysmorphism,
five of whom had Hirschsprung disease (HSCR). This condi-
tion, now designated Mowat–Wilson (MWS) syndrome, was
the ZFHX1B gene [Cacheux et al., 2001; Wakamatsu et al.,
2001]. A series of subsequent publications have further
delineated the phenotype [Zweier et al., 2002; Mowat et al.,
2003; Wilson et al., 2003; Ishihara et al., 2004]. Other common
features described in these patients include agenesis of the
corpus callosum, congenital heart malformations, and genital
and urinary tract anomalies. No convincing sibling pairs with
MWS, with or without a proven mutation, have been reported.
Here we describe a sister and brother with phenotypic MWS
syndrome and the same mutation in ZFHX1B.
PATIENTS AND METHODS
The female sibling was born to a 20-year-old primigravida
mother at 41 weeks gestation. The parents were healthy,
Caucasian and non-consanguineous. Antenatal scanning had
demonstrated the presence of mild renal pelvic dilatation. She
weighed 3.3 kg (10th centile) at birth. She was diagnosed with
short segment HSCR and had a pull-through procedure. A
postnatal renal tract ultrasound was normal. She was
reviewed by a pediatrician at 11 months because of parental
concerns about developmental delay. She was assessed as
functioning at a 3–4 month level. She was noted to have a
divergent strabismusandsomedysmorphic features.Cerebral
MRI showed agenesis of the corpus callosum. A karyotype was
normal, and no syndrome diagnosis was made at this time.
During the parents’ next pregnancy, a nuchal translucency
scan was reported as normal. Detailed fetal ultrasound
examination at 18 weeks-of-gestation showed agenesis of the
corpus callosum, which was confirmed on fetal MRI (Fig. 1).
The finding of agenesis of the corpus callosum suggested a
possible recurrence of the sister’s condition. The mother had a
cerebral MRI at the same time as the fetal MRI, which
confirmed that she had a normal corpus callosum. There was
also concern about the left side of the fetal heart, which
appeared to be small. Amniocentesis showed an apparently
normal male karyotype. The male baby was delivered at 38
34 cm (50th centile). Echocardiogram on day 1 showed
coarctation of the aorta down to 2 mm at the ductal origin.
This was repaired in the 1st week of life by a patch graft. He
developed signs of bowel obstruction and on day 3 at
laparotomy, theabsenceofganglioncells wasnotedinsections
from bowel distal to the left transverse colon. A transverse
colostomy was performed. Ophthalmological assessment
demonstrated the presence of colobomas bilaterally. Subse-
quent retinal examination showed an aplastic left optic nerve
with central chorio-retinal coloboma. On the right only the
choroid was affected with a lacuna around the disc. A renal
tract ultrasound was normal.
The older sibling was first evaluated by a clinical geneticist
after the birth of her affected brother. She had not begun
had no history of epilepsy. She had the typical dysmorphic
features seen in Mowat–Wilson syndrome with an open-
mouthed, smiling expression. Her eyebrows had disorganized
nasal tip and prominent chin seen in the condition. She had
sparse, fine hair. Her ears had upturned lobes with the central
depression typically seen in MWS (Fig. 2). Her brother had
*Correspondence to: Julie McGaughran, M.D., Queensland
Clinical Genetics Service, Royal Children’s Hospital and Health
Service District, Herston, Brisbane 4029, Queensland, Australia.
Received 1 November 2004; Accepted 2 June 2005
? 2005 Wiley-Liss, Inc.
similar dysmorphic features with the typical upturned ears
with the central depression in the lobe. He had deep set eyes
with a prominent nasal bridge and chin (Fig. 3).
Mutation analysis of ZFHX1B was performed after ampli-
fication of the nine coding exons from genomic DNA using
specific primers covering each exon and flanking sequences.
Specific primers and PCR procedures were described pre-
viously [Cacheux et al., 2001].
All PCR products were gel-purified usinga gel extraction kit
(Macherey-Nalgen, Du ¨ren, Germany) and sequenced with the
ABI PRISM BigDye Terminator cycle sequencing kit (Perkin
Elmer, Foster City, CA) using an Applied Biosystems model
Direct sequencing of ZFHX1B revealed a heterozygous
frameshift mutation nt1862delT in exon 8, resulting in a stop
codon at position 645. The mutation predicts a truncated
protein missing the homeodomain and the C-terminal zinc
finger domain. Both siblings were shown to have the same
mutation, which was absent in the parental lymphocyte-
Mowat–Wilson syndrome (MWS) was originally reported as
a syndromic form of HSCR, but is it now recognized that it
frequently occurs without HSCR and can be diagnosed based
on the combination of mental retardation and the striking
facialphenotype. Anumberofindividuals havebeenidentified
without HSCR but with mutations in ZFHX1B [Horn et al.,
phenotypic abnormalities seen in the condition. However, this
is only the second report of ocular coloboma in patients with
proven ZFHX1B mutation [Gregory-Evans et al., 2004]. The
patient reported by Gregory-Evans et al., who had trisomy 21,
HSCR and a phenotype considered not consistent with MWS,
had a missense mutation in ZFHX1B, whereas to date all
published mutations in typical MWS have been truncating or
null, including the mutation in these siblings. The findings in
our patient suggest that haploinsufficiency of ZFHX1B could
diagnosed with MWS should have a formal ophthalmological
have been suspected based on the prenatal ultrasound finding
of an absent corpus callosum (ACC), if the first sibling had
previously been diagnosed. In general, however, ACC alone is
not a sufficiently specific feature upon which to make the
clinical variability of the phenotype, even with the same
mutation, is emphasized by the differing associated anomalies
in these siblings, who were discordant for congenital heart
facies, HSCR, and ACC. It is important that the diagnosis be
associated congenital anomalies.
Germ-line mosaicism is a well-described phenomenon and
to intragenic mutations, including osteogenesis imperfecta,
tuberous sclerosis, and achondroplasia [Zlotogora, 1998; Rose
callosum in the fetus (Coronal T2 HASTE weighted image).
Antenatal MRI scan demonstrating absence of the corpus
typical features of Mowat–Wilson syndrome.
Phenotypic appearance of the older sibling at diagnosis with
Fig. 3. Appearance of affected male sibling.
Sibling Recurrence in Mowat–Wilson Syndrome303
et al., 1999]. While theoretical methods to estimate the risk of Download full-text
recurrence due germ-line mosaicism have been outlined [van
der Meulen et al., 1995], empiric recurrence risks where
parents are clinically unaffected vary significantly in different
disorders, from <1% in achondroplasia to 6% in osteogenesis
imperfecta [Zlotogora, 1998; Mettler and Fraser, 2000]. Little
is known about the mechanisms underlying germinal þ/?
somatic mosaicism in new dominant disorders, but molecular
analyses in several conditions have shown that somatic
mosaicism in an apparently unaffected parent is not uncom-
mon where more than one child is affected [Zlotogora, 1998].
This is the first time presumed germ-line mosaicism has
been described in MWS, with over 50 mutation positive cases
reported in the literature so far, but stresses the importance of
including this possibility when counseling parents of a single
affected child. However, given the paucity of information at
present it is difficult to give accurate recurrence risk figures,
especially where more than one child is affected. Prenatal
diagnosis of recurrence of MWS may be strongly suggested by
abnormal ultrasound findings such as ACC, but mutation
analysis is necessary for confirmation in the prenatal setting.
This stresses the importance of molecular confirmation of a
clinical diagnosis of MWS in probands where parents are
considering further children and wish to have accurate
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