Severe constipation in a patient with Myhre syndrome: a case report

Abstract

Myhre syndrome is a rare autosomal dominant genetic condition characterized by short stature, distinctive facial dysmorphisms, generalized muscle hypertrophy, skeletal abnormalities, decreased joint motility, developmental delay, deafness and cardiac defects. Myhre syndrome and the allelic laryngeal stenosis, arthropathy, prognathism and short stature syndrome are caused by a missense mutation of SMAD4, resulting in altered expression of transforming growth factor β and bone morphogenic protein, affecting cell growth and differentiation. Here, we report on the case of a 7-year-old girl showing symptoms of Myhre syndrome and with a known SMAD4 mutation presenting with the novel symptom of severe constipation.

Full text

Severe constipation in a patient with Myhre syndrome:
a case report
John K. Bassett
a
, Sofia Douzgou
b
and Bronwyn Kerr
b
Myhre syndrome is a rare autosomal dominant genetic
condition characterized by short stature, distinctive facial
dysmorphisms, generalized muscle hypertrophy, skeletal
abnormalities, decreased joint motility, developmental
delay, deafness and cardiac defects. Myhre syndrome and
the allelic laryngeal stenosis, arthropathy, prognathism and
short stature syndrome are caused by a missense mutation
of SMAD4, resulting in altered expression of transforming
growth factor βand bone morphogenic protein, affecting
cell growth and differentiation. Here, we report on the case
of a 7-year-old girl showing symptoms of Myhre syndrome
and with a known SMAD4 mutation presenting with the
novel symptom of severe constipation. Clin Dysmorphol
25:54–57 Copyright © 2016 Wolters Kluwer Health, Inc. All
rights reserved.
Clinical Dysmorphology 2016, 25:54–57
Keywords: constipation, growth disorders, laryngeal stenosis,
arthropathy, prognathism and short stature syndrome, learning disabilities,
Myhre syndrome, SMAD4 mutation
a
Faculty of Health and Medicine, Lancaster University, Lancaster and
b
Manchester
Centre for Genomic Medicine, University of Manchester, St Mary's Hospital,
Manchester, UK
Correspondence to Sofia Douzgou, Manchester Centre for Genomic Medicine,
Central Manchester University Hospitals NHS Foundation Trust, Saint Mary's
Hospital, Oxford Road, Manchester M13 9WL, UK
Tel: + 44 1612 766268; e-mail: sofia.douzgou@cmft.nhs.uk
Received 30 September 2015 Accepted 10 November 2015
Introduction
Myhre syndrome is a very rare genetic condition caused
by a missense mutation in the SMAD4 gene on chromo-
some 18q21.2 (Caputo et al., 2014). It was first described
in two unrelated male adults in 1981 as a growth defi-
ciency syndrome that was apparent both prenatally and
postnatally, with adult heights reaching 140 and 146 cm,
respectively. It was observed that both patients had facial
dysmorphisms, manifesting as maxillary hypoplasia,
prognathism, short palpebral fissures, a short philtrum
and a small mouth. Generalized muscle hypertrophy,
decreased joint motility, cryptoorchidism, intellectual
impairment, mixed sensorineural and conductive hearing
loss, and skeletal changes (brachydactyly, thickened
calvaria, broad ribs, hypoplastic iliac wings, shortened
long and tubular bones and large flattened vertebrae
giving a square body shape) were also found (Myhre et al.,
1981).
In 2012, a heterozygous de-novo mutation of SMAD4 at
ile500 was identified as the pathogenic change (Caputo
et al., 2012; Le Goff et al., 2012). So far, three variants of
this mutation have been described (I500T, I500V and
I500M; Caputo et al., 2012; Le Goff et al., 2012) in the
majority of patients tested (Michot et al., 2014). However,
Myhre syndrome is, probably, a disorder of hetero-
geneous genetic causes (Michot et al., 2014). All cases
described so far have arisen de novo, and advanced par-
ental age has been seen in the majority of cases (Michot
et al., 2014).
Since then, several new manifestations have been evi-
denced as part of the condition including retinal disease,
thickened skin (Michot et al., 2014), obesity, arterial
hypertension, excessive keloid scar formation (Van
Steensel et al., 2005), bronchopulmonary insufficiency,
laryngealtracheal stenosis, pericarditis and, unfortunately,
early death in four patients due to restrictive respiratory
insufficiency, restrictive pericarditis, sudden death due to
cardiogenic shock and massive mesenteric ischaemia of
an unexplained cause (Michot et al., 2014).
Because of the extremely rare nature of this condition
and its relatively recent discovery, there is still much to
be understood about both the symptoms and the patho-
physiology of this disease, and Lindor et al. (2012) con-
ceded that there may well be several symptoms of the
syndrome that are currently unknown and will only
become apparent as the patients age. Here, we report on
a case of severe constipation seen in a child with Myhre
syndrome in an effort to explore whether this symptom
may contribute to the clinical comorbidities of this rare
condition.
Case report
The proband is the second child of healthy non-
consanguineous parents with no relevant family history,
referred for concerns with regard to her developmental
delay, first noticed at 4 months. She has an older brother
who was fit and well at the age of 9 years.
During the pregnancy, there were concerns with regard
to polyhydramnios, intrauterine growth restriction and
decreased foetal movement, and the mother was hospi-
talized several times for oedema and hypertension. The
child was born at 37 weeks of gestation by rapid vaginal
54 Original article
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delivery, with a weight of 1645 g and head circumference
of 29.5 cm (0.4th centile for both measures). She
remained small as an infant, with her head circumference
remaining on the 0.4th centile (43.5 cm) and her length
and weight on the second centile (70 cm and 8.42 kg,
respectively) at 13 months. By the age of 7 years, her
height was still on the second centile (111 cm) and her
head circumference was 48.5 cm. Immediately after birth,
she was diagnosed with a pyloric web on day 4 because of
persistent vomiting, which was corrected on day 5. She
was also found to have a patent ductus arteriosus and
foramen ovale, both of which resolved spontaneously.
She was observed to have a deep sacral cleft and devel-
opmental delay; she smiled by 6 months, sat unaided by
10 months, rolled over by 12 months and walked by
20 months. At 4 years and 5 months of age, her language
was comparable to that of a 2-year-old. At this time, she
was both urinary and faecally incontinent. She had also
been diagnosed with moderate, bilateral conductive
hearing loss.
The patient had dysmorphic facial features that, how-
ever, became apparent towards the end of 1 year of age
(Fig. 1). She had upslanting, narrow, palpebral fissures; a
small mouth; a thin upper lip and protuberant tongue;
and ears with narrow ear canals. She had bilateral fifth
finger clinodactyly and deep palmar creases. She also had
overlapping fourth and fifth toes with small toenails, as
well as inverted nipples. Her dysmorphic features
evolved and became more prominent over time, and by
the age of 7 years, she was additionally observed to have
deep-set small eyes, prognathism and a small mouth. She
was also observed to have marked truncal hypertonia as
an infant, and at the age of 7 years, she had joint
hypermobility and eczema over her arms. Her behaviour
at her nursery was deemed challenging, including the
lack of a sense of danger and occasional self-harm, after
which she attended special school the age of 5 years.
At 7 years of age, she attended the accident and emer-
gency department on two occasions for severe and
painful constipation. The later episode lasted ∼7 days,
with a small amount of hard stool passed on day 5, with
one episode of vomiting. Minimal faecal loading was
observed in the abdomen, with some overflow incon-
tinence. She also had reduced fluid and food intake.
Before this, bowel motions were loose, occurring five to
six times a day. She was treated with analgesia (ibuprofen
and paracetamol) and given movicol, after which her
constipation resolved.
Investigations
Normal investigations included brain and spine MRI,
renal ultrasound, karyotyping, thyroid function test,
peripheral blood array comparative genomic hybridiza-
tion, transferrin isoelectric focusing and 7-dehy-
drocholesterol testing. Creatine kinase was mildly raised
(220 U/l). The parents consented to participation in the
Deciphering Developmental Disorders study (Firth and
Wright, 2011) for whole DNA exome sequencing when
the patient was 3 years of age. The study revealed the
SMAD4 c.1498A >G (p.Ile500V) mutation. After the
results were obtained, a skeletal survey at the age of
4 years and 6 months revealed mild clinodactyly and
slightly higher lumbar pedicles compared with the pos-
terior vertebral bodies. Cardiologic evaluation including
heart auscultation and echocardiography showed no
structural nor functional abnormality of the heart.
Discussion
Constipation has so far been described in two patients
with Myhre syndrome (Michot et al., 2014), although the
exact details of these presentations have not been
reported. Congenital Hirschsprung’s disease has also
been described in a single individual (Caputo et al., 2012)
with the clinical presentation of Myhre syndrome and, as
mentioned previously, a case of massive mesenteric
ischaemia of unexplained cause has been reported in
another individual with Myhre syndrome, which unfor-
tunately was fatal (Michot et al., 2014).
In addition, a single patient with the Myhre syndrome
allelic disorder laryngeal stenosis, arthropathy, prognath-
ism and short stature syndrome had constipation from
childhood (Lindor et al., 2002). She subsequently
developed endometrial cancer, for which she had a hys-
terectomy, after which she suffered life-threatening
bowel adhesions (Lindor et al., 2012).
Fig. 1
Photograph of the patient. Note the deep-set, small eyes, the wide nasal
bridge, prognathism and the small mouth with a thin upper lip.
Constipation in Myhre syndrome Bassett et al.55
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In both laryngeal stenosis, arthropathy, prognathism and
short stature syndrome and Myhre syndrome, the ile500
missense mutation of SMAD4 in the Mad homology 2
domain leads to defective ubiquitination of SMAD4,
which in turn leads to altered and uninhibited expression
of transforming growth factor β(TGFβ) and bone mor-
phogenic protein target genes, resulting in defective
transcriptional regulation during development (Le Goff
et al., 2012), culminating in aberrant connective tissue
matrix deposition, as well as impaired function of matrix
metalloproteases (Piccolo et al., 2014). Although the exact
downstream mechanism of TGFβand bone morphogenic
protein are not yet fully understood, it is thought that
defective ubiquitination of SMAD4 leads to increased
expression of TGFβ. Interestingly, Hirschsprung’s dis-
ease is one of the features of the Mowat–Wilson syn-
drome caused by ZFHX1B mutations, the protein
product of which is involved in the TGFβsignalling
pathway (Dastot-Le Moal et al., 2007).
Chronic constipation has been described as a significant
clinical comorbidity in patients with other genetic syn-
dromes. For example, constipation is highly prevalent in
the Rett and Opitz–Kaveggia syndrome, despite ade-
quate fibre and fluid intake (Schwartzman et al., 2008),
and causes bloating in many patients, leading to sig-
nificant discomfort and reduced quality of life for both
the patient and the carer (Anderson et al., 2014). Chronic
constipation can also cause complications such as
encopresis, enuresis, anal fissures, rectal prolapse and
faecal impaction, the latter of which can lead to bowel
obstruction; hence, prompt and effective treatment of
constipation is crucial. As a result, it is recommended that
bowel function should be closely monitored in Rett
syndrome (Anderson et al., 2014), and in cases of con-
stipation, disimpaction and maintenance with polythene
glycol should be implemented (Giesbers et al., 2012).
The prevalence of constipation in children with severe
learning difficulties in general is also increased and has
been estimated at 26–50% (Sullivan, 2008) compared
with the median prevalence in the general paediatric
population of ∼12% (Mugie et al., 2011). This may be
because of communication problems, vagueness of
symptoms or, simply, other problems being prioritized at
the expense of constipation (Marsh and Sweeney, 2008).
People with learning disabilities also tend to have
reduced mobility and are more likely to refuse to eat,
both of which can contribute towards constipation. Other
causes of severe constipation include hypercalcaemia and
hypothyroidism, and spinal cord lesions are unlikely to be
directly related to Myhre syndrome; however, they are
more likely to remain unnoticed in children with severe
learning difficulties as they may not be able to commu-
nicate their symptoms effectively.
The patient described in this case report represents an
atypical presentation of Myhre syndrome, as she did not
present for short stature, but rather for concerns with
regard to developmental delay and dysmorphic facial
features. By the age of 7 years, she was still not mani-
festing any of the skeletal signs that are typically asso-
ciated with Myhre syndrome. The implication is that
there may be a degree of phenotypic heterogeneity in the
presentation of Myhre syndrome, such as this novel
presentation of facial dysmorphisms, developmental
delay and constipation, in the absence of skeletal
abnormalities, which illustrates the challenge of diag-
nosing this rare syndrome.
Conclusion
It is difficult to determine whether the constipation
observed in our patient is directly related to Myhre
syndrome. It is possible that because constipation is not
one of the cardinal nor most striking features of Myhre
syndrome, it goes unreported. Further, similar observa-
tions would be necessary to draw a safe conclusion on
patient management. However, as with any syndrome
that affects cognitive function, constipation is a symptom
that should be enquired about, and clinicians should have
a low threshold for treatment to prevent complications
and maximize the quality of life for the patients and their
carers.
Acknowledgements
The authors thank the family for kindly consenting to
this publication.
Conflicts of interest
There are no conflicts of interest.
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