Mowat-Wilson syndrome presenting with Shone’s complex cardiac anomaly

Abstract

A female infant, who was diagnosed antenatally with complex heart disease, confirmed to be Shone’s complex postnatally, underwent bilateral pulmonary artery banding, patent ductus arteriosus stent insertion and balloon aortic valvuloplasty soon after birth. She was found to have bilateral megaureters, left hydronephrosis and asplenia. She was on lifelong prophylactic antibiotics and extra vaccines. She had two episodes of pseudo-obstruction of the small bowel, but barium follow-through was normal. She also had a large bowel obstruction and work-up for Hirschsprung disease confirmed the diagnosis. It was noticed that she had developmental delay and hypotonia, together with subtle dysmorphism. She also had failure to thrive and difficulty feeding. Exome sequencing revealed a diagnosis of Mowat-Wilson syndrome (MWS). This case shows a previously undescribed association of Shone’s complex, a complex left-sided obstructive heart defect, and MWS. It also highlights the usefulness of trio-exome sequencing in detecting such rare mutations.

Background

• Mowat-Wilson syndrome (MWS) has been described clinically in the literature since 1998, yet most of the heart defects known to be associated with it are not as complex as Shone’s anomaly.

• Knowing the association of Mowat-Wilson disease with Shone’s anomaly will help in choosing the genetic modality of testing early on. In our case, although the baby’s microarray was negative, MWS was detected by trio-exome sequencing.

Case presentation

A normal appearing female infant was born by elective caesarean section due to failure of induction and suspicious cardiotocography (CTG) in a tertiary maternity hospital as she was diagnosed antenatally with complex heart disease. She was found antenatally to have an increased nuchal translucency at 12 weeks, with a negative karyotype and a low probability harmony test. There were concerns about the heart in the period between 24 and 26 weeks gestation. Amniotic fluid sampling for FISH 22q11.2 was negative but prenatal microarray was not performed. At 36–38 weeks gestation left hydronephrosis was noted.

She was born at term and her birth weight was on the 75th centile. Her APGAR score was 9 and 9 at 1 and 5 min, respectively. She is the first child of a non-consanguineous caucasian couple. Both parents were healthy and the family history was unremarkable.

Shone’s complex was confirmed by postnatal echocardiography with the following findings: critical aortic stenosis with monocusp hypoplastic aortic valve, hypoplastic aortic arch, mild mitral valve hypoplasia, large perimembranous ventricular septal defect (VSD) and two moderate sized muscular VSDs together with mild left ventricular hypoplasia. She underwent bilateral pulmonary artery banding, patent ductus arteriosus stent insertion (hybrid stage 1) and balloon aortic valvoplasty on day 3 of life with no complications. Blood for microarray and a kidney ultrasound were requested in the NICU just after birth, the latter showed mild right renal pelviectasis and moderate left renal pelviectasis. Repeated kidney ultrasound on day 24 demonstrated bilateral megaureters with moderate to marked pelviectasis on the left and mild on the right side, more pronounced compared with the previous study. Micturating cystourethrogram detected no reflux, moderate right calexial dilation and pelvic prominence, and moderate to marked dilatation of left ureter. Investigations including full blood count and urea and electrolytes were normal. She was then commenced on trimethoprim prophylaxis along with her other medications which included erythromycin, diuretics and aspirin. In addition, continuous high-calorie nasogastric feeding, weekly weight checks and oxygen saturations were advised. She also underwent a hearing test which was normal.

At the 6-week developmental check, she was fixing and following, cooing and lifting up her head in the prone position, but she had poor head control with significant head lag. At 13 weeks of age, she was noticed to be developmentally delayed. As a result, she was referred to early intervention services. Her weight was noted to be between the second and ninth centile with ongoing reflux issues for which she was on omeprazole and under dietitian care.

At 15 weeks of age, she was admitted with features suggestive of small bowel pseudo-obstruction (vomiting after each feed, abdominal distention and irritability for 1 day). Abdominal X-ray showed small bowel dilatation. Enteral feed was recommenced, vomiting had settled and she opened her bowel the following day. She was then transferred to a tertiary hospital for further management of aortic valve stenosis and possible heart failure. She was noted to be hypertensive on arrival for which she was commenced on propranolol. Balloon aortic valvoplasty was done. She had a barium meal and follow-through there which was normal (no gut malrotation) and commenced on continuous feeds. She was reviewed by the immunology team as her previous abdominal ultrasounds showed no splenic tissue. Amoxicillin prophylaxis and a modified vaccination schedule (adding MEN ACWY and influenza vaccine) were recommended. The microarray which was done shortly after birth came back normal. MAG3 scan illustrated bilateral hold-up at the UV junction with the left being worse than the right, but split kidney function was normal.

When she was 4 months old, there were ongoing concerns with subtle dysmorphia including a symmetrical wedge-like area in the pinna of the ears, high arched palate, slightly deep-set eyes, a tendency to gaze upward and single palmer crease bilaterally as well as emerging global developmental delay. She was admitted again at the age of 5 months with a similar picture of pseudo-obstruction which was treated conservatively. At that point exome sequencing (trio-exome) was sent and results were indicative of a genetic diagnosis of MWS. She is heterozygous for the pathogenic ZEB2 frameshift variant which was not detected in her parents; therefore, it is likely to have arisen de novo. MRI brain postdiagnosis showed thin corpus callosum.

At the age of 9 months, she was presented to the emergency department with retching and irritability for 4 days, multiple non-bilious vomits and reduced feeds. Abdominal X-ray showed distended descending colon with no air in the rectum suggestive of Hirschsprung disease. She did not improve with conservative treatment; therefore, she was urgently transferred to a paediatric tertiary centre. Later during the admission, due to lack of improvement in the tertiary centre, she underwent laparotomy. Rectal segment biopsy confirmed the diagnosis of Hirschsprung disease and regular bowel washouts were recommended. During the admission, she underwent another balloon dilatation of the aortic arch. Her condition improved and she gained weight in the subsequent follow-up visits. At 11 months old, she was admitted for planned cardiac surgery; unfortunately, she died from complications of surgery a few days later.

Investigations

Haematology

Full blood count was normal and blood film showed Howell Jolly bodies.

Biochemistry

Urea and electrolytes were normal.

Radiology

Echocardiography

Critical aortic stenosis with monocusp hypoplastic aortic valve, hypoplastic aortic arch/coarctation, mild mitral valve hypoplasia, large perimembranous VSD, two moderate sized muscular VSDs, together with mild left ventricular hypoplasia.

Kidney ultrasound

Day 1: mild right kidney pelviectasis and moderate left kidney pelviectasis.

Day 24: bilateral megaureters with moderate to marked pelviectasis on the left and mild on the right side, more pronounced compared with the previous study.

Abdominal ultrasound

Asplenia

Barium meal and follow-through

Normal excluding malrotation.

Abdominal X-ray

15 weeks: small bowel dilatation.

9 months: distended descending colon with no air in the rectum suggestive of Hirschsprung disease.

Micturating cystourethrogram

Normal

MAG3 scan

Bilateral holdup at the UV junction with the left being worse than the right, normal split kidney function.

MRI brain

Abnormal thinned corpus callosum.

Genetics

Microarray was normal, while trio-exome sequencing detected a pathogenic variant of ZEB2, that is heterozygous and de novo inheritance located in Chr2(GRCh37):g.145161574del.

Treatment

Pharmacological

For her cardiac condition, diuretics in the form of furosemide and spironolactone, and aspirin were prescribed. Propranolol was also commenced to control the blood pressure. Omeprazole and erythromycin helped to manage the feeding intolerance. Trimethoprim was commenced as prophylaxis against urinary tract infections. Additional vaccines including influenza and Men ACWY vaccines were given, together with palivizumab and lifelong amoxicillin to manage immunodeficiency resulting from congenital asplenia.

Non-pharmacological

Supportive

She was required continuous nasogastric feeding with a high-calorie formula to manage the poor weight gain and Carobel to thicken feeds and manage the gastro-oesophageal reflux.

Surgical

She underwent bilateral pulmonary artery banding, patent ductus arteriosus stent insertionand balloon aortic valvuloplasty initially. She then needed aortic balloon valvuloplasty twice and balloon dilatation of the aortic arch once.

Multidisciplinary team (MDT)

This involved the neonatologist, paediatric cardiologist, dietician, immunologist, paediatric surgeon, dentist, audiologist, geneticist, nephrologist, urologist, paediatric gastroenterologist, early intervention service, physiotherapist, community paediatrician, ophthalmologist, and speech and language therapist.

Discussion

MWS is a rare learning difficulty syndrome with numerous congenital anomaly syndrome named after Mowat’s initial description in 1998 of six children with postnatal microcephaly, Hirschsprung disease, developmental delay and unique facies.¹ It is embodied by recognisable facial phenotype, moderate to severe intellectual disability and severe speech impairment which is classically restricted to a few words or is absent, with reasonable preservation of receptive language skills.²

Facial ‘gestalt’ tends to change with age. This is typically associated with a high forehead, frontal bossing, large deep-set eyes and hypertelorism in infancy. Additionally, earlobes are large and uplifted, the nose is saddle with a prominent nasal tip, the columella is prominent, the mouth is open appearing with an M-shaped upper lip and a prominent narrow chin.^{3 4} In older children, eyebrows become horizontal, broad and heavy, with medial sparseness and a wide middle separation. The columella is more pronounced, the nasal point lengthens and becomes more depressed, leading to the appearance of a short philtrum, the nasal profile becomes convex, the face tends to elongateand the jaw becomes very noticeable.^{3 5 6}

Variable multiple congenital anomalies are associated with the syndrome, including Hirschsprung disease, chronic constipation, structural eye anomalies, hypogenesis or agenesis of the corpus callosum, urogenital anomalies, microcephaly and seizure disorder. Congenital heart disease has been reported in about 50% of patients with MWS. The heart anomalies reported include patent ductus arteriosus, atrial septal defect, VSD, tetralogy of Fallot, pulmonary atresia, pulmonary stenosis, aortic coarctation, bicuspid aortic valve and aortic valve stenosis.^7–11 Structural heart defects are variable but seem to frequently involve the pulmonary arteries and/or valves.⁴ There are no similar published cases that describe the finding of Shone’s complex in patients with MWS.

Weight and length in newborns with MWS are usually distributed as in the general population, while head circumference would be slightly smaller, with an average below the 30th centile, weight, and height distribution shifts to slightly lower values than in the general population up to the age of 7 years; after that, the difference increased further, as 50% of the affected children were below the fifth centile of the general population. Microcephaly is occasionally present at birth, but in most cases, it could develop gradually during infancy; many children have a small head circumference, between the third and the 10th centile, instead of being typically microcephalic (at least 2 SD below the mean).¹² Most affected people have a wide-based gait and a happy demeanour that can at times be confused with Angelman syndrome.²

Haploinsufficiency of ZEB2 (also known as ZFHX1B or SIP-1) genes constitutes all typical cases, with over 100 distinct mutations now described.¹³ Around 80% of patients have a nonsense or frameshift mutation detectable by sequencing, with the remainder having significant deletions requiring a dosage-sensitive assay.¹³ It is an autosomal dominant disorder, yet almost all individuals described to date have been simplex cases (ie, a single occurrence in a family) resulting from a de novo genetic alteration; infrequently, when a parent has a low level of somatic or presumed germline mosaicism for an MWS-causing pathogenic variant, recurrence in a family has been reported.²

Individuals with MWS are not known to reproduce. Prenatal testing may be offered to parents of a child with MWS, once the causative genetic alteration has been identified in the proband, because of the recurrence risk associated with the possibility of parental mosaicism or a balanced chromosome rearrangement.²

There are little data about the survival of the patients affected by MWS.⁴ Treatment of those with MWS is directed towards the individual’s needs and targeted towards associated conditions including Hirschsprung disease, heart defects and seizures. These require MDT approach of specialists including neurologists, cardiologists, cardiothoracic surgeons and general surgeons. Allied health specialists such as physiotherapists, occupational and speech and language therapists are also helpful to meet the children’s developmental needs.

Learning points.

• Early involvement of geneticists in babies with subtle dysmorphic features and multiorgan abnormalities is very useful. Most cases of Mowat-Wilson syndrome (MWS) can be diagnosed clinically by a geneticist without the need for whole exome sequencing (WES) which could reduce costs of genetic testing.

• Recognise the limitation of microarray in detecting specific deletions.

• The degree of heart defect complexity in MWS could determine the level of morbidity for the patient.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s).