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Abstract
This patient is an infant with Williams–Beuren syndrome (WBS) who was diagnosed at 2 months of age. He was born by caesarean section with a low birth weight (LBW) of 2.1 kg and was small for gestational age. His para 1+1 (1 alive) mother in her mid-30s had intrauterine growth restriction during pregnancy. On examination at birth, he appeared phenotypically normal, but at 2 weeks old, he had subtle phenotypic features of WBS of fused filtrum, ulnar deviation of fingers and wide anterior fontanelle, a systolic murmur and mild gaseous distension of the abdomen.
All neonatal reflexes were normal. The author saw this patient at 6 months of age at the well-baby clinic for his 6-month vaccinations during which examination revealed periorbital fullness. Investigations including chromosomal microarray analysis confirmed the diagnosis of WBS. Laboratory tests were essentially normal except for raised creatinine, chloride and liver aspartate transaminase and viral serology that showed reactive cytomegalovirus antibody IgG, rubella antibody IgG, toxoplasma IgG and positive herpes simplex virus type 1 IgG. Echocardiography revealed mild pulmonary artery stenosis. ECG revealed right ventricular hypertrophy. Abdominal ultrasonography was normal and so was cranial sonography. This is a unique case of early diagnosis of WBS in an infant with atypical chromosome 7 deletion in Qatar, Middle East. The patient is undergoing further multidisciplinary follow-up.
- Primary Care
- Genetics
- Paediatrics
- Congenital disorders
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Background
Williams–Beuren syndrome (WBS) was first described in 1961.1 It is a rare genetic syndrome with a prevalence of approximately one in 10 000–20 000 births in the USA or a prevalence of 1/7500 to 1/20 000. It equally affects males and females of all races and is due to a 1.5–1.8 million base (Mb) pair microscopic DNA deletion on chromosome 7q11.23 band, a segment containing about 26–28 genes, some of which include the elastin gene that seems to be responsible for some of the abnormalities in WBS.2 3 WBS is a congenital malformation characterised by possible neurodevelopmental problems, cardiovascular defects and structural abnormalities of the urinary tract.4–6 Most cases arise de novo or sporadically, while others are inherited, so there will be a need for parents to have genetic testing and subsequent counselling. They usually present with dysmorphic facial features and cardiovascular problems (like supravalvular aortic stenosis, elastin arteriopathy and peripheral pulmonary stenosis) as well as intellectual disability and endocrine abnormalities such as hypercalcaemia, hypercalciuria, hypothyroidism and precocious puberty. They also have an unusual cognitive presentation with overfriendliness and can often present with a broad forehead, bitemporal narrowing, periorbital fullness, strabismus, short nose, broad nasal tip, malar flattening, thick vermilion of the upper and lower lips, wide mouth, small jaw and large ear lobes. Hypotonicity is also frequently seen in infants with WBS who typically have hyperextensible joints and delayed motor development. Connective tissue abnormalities like inguinal or umbilical hernia, bowel or bladder diverticula and rectal prolapse can also be seen. Though WBS penetrance is 100%, the expression of its phenotypic features is variable in patients.7 People with WBS do not always have a predictable genotypic and phenotypic correlation, and the clinical diagnosis of WBS tends to be made in early childhood based on the unique dysmorphic facial characteristics.1 3 4 Most patients with WBS have a typical deletion of 1.55 Mb (90%) or 1.85 Mb deletion, but only 2% of patients have less than 1.55 Mb and tend to present with atypical problems.8 This author describes a peculiar case of diagnosis of WBS in an infant with atypical chromosome 7 microdeletion in Qatar, who is currently undergoing further multidisciplinary follow-up.
Case presentation
This patient is an infant born by elective caesarean section at 37 weeks who was small for gestational age (SGA) with low birth weight (LBW, 2.1 kg). His mother was a para 1+1 (1 alive) woman in her mid-30s who had placenta praevia, was hepatitis B positive and had intrauterine growth retardation (IUGR). His appearance, pulse, grimace, activity and respiration (APGAR) score at birth was 9 at 1 min and 10 at 5 min. On examination, the baby was pink and active. Head and neck, central nervous system, back, limbs, chest, cardiovascular and abdominal examinations were all normal. The external genitalia revealed normal male phenotype. Vital signs were all normal except for mild tachypnea of 52 beats per minute. Oxygen saturation was 98% in room air, which was also normal. Blood sugar was 3.4 mmol/L. Bacille Calmette–Guerin (BCG) vaccine was not given, but other routine vaccinations according to the Qatar national immunisation schedule were up to date, having been given the second, fourth and sixth months’ vaccinations previously.9 10
Postnatal care
He was breastfed after birth and had first-day vital signs check which revealed a blood pressure of 83/36 on the right upper limb (RUL), his mean heart rate (HR) was 128 beats per minute, and his oxygen saturation was also normal at 98%. A grade 3/6 ejection systolic murmur was noted at the left upper sternal border on cardiovascular examination. A chromosomal microarray test was ordered. At 2 weeks old, he was reviewed by a consultant neonatologist which revealed subtle dysmorphic features of fused filtrum, ulnar deviation of fingers and wide anterior fontanelle as well as mild gaseous distension of the abdomen. All neonatal reflexes were normal, including routing and Moro reflexes. At 3 weeks old, he presented with excessive crying and was diagnosed with infantile colic and treated with simethicone drops. At 6 weeks old, he was referred for cardiology review for grade 2/6 systolic murmur. At 8 weeks, he was diagnosed with WBS and referred to the genetic team at a tertiary children’s hospital. Well-baby immunisation clinic reviews at 6, 8 and 32 weeks’ vaccination appointments revealed persistent poor weight gain, infantile colic and periorbital fullness. His WHO growth charts revealed head circumference and length for age measurements below the third centile while the weight for length and body mass index measurements were variable.9 10 The author saw this patient at 6 months of age at the well-baby clinic at the primary healthcare centre for his 6-month vaccinations during which examination revealed periorbital fullness and a missed BCG vaccine was arranged for the child. In addition to obtaining an informed consent, the author also had extensive consultations with the parent of the child regarding vitamin D supplementation restrictions and discussed the literature review evidence on WBS, as well as its management and prognosis and the support institutions available for them to access as the child grows if needed.
Investigations
Genetic testing
Chromosomal microarray analysis was performed for this patient at 2 months of age using a genome-wide oligonucleotide array-based comparative genomic hybridisation (aCGH) platform. An atypical deletion of 1.4 Mb was identified for the long arm of chromosome 7 within cytogenetic band 7q11.23, containing ELN and other genes. This patient’s parents had a chromosomal study to assess if the condition was inherited from them, but it was negative. The patient’s whole-genome array CGH test revealed pathogenic arr [GRCh37]7q11.23 (72721410_74139527) X1.
Imaging
Cranial neurosonography was normal, while abdominal ultrasound scan was also normal with no structural urinary tract deformities.
Electrocardiography
Electrocardiography revealed sinus rhythm with right ventricular hypertrophy and a heart rate of 131 beats per minute (see figure 1).
ECG showing Right Ventricular Hypertrophy.
Echocardiography
Echocardiography revealed a mild gradient across the right pulmonary artery (PG (Peak Gradient) 24 mm HG) with mild right pulmonary artery stenosis (see figure 2A,B).
(A,B) Echocardiography showing right pulmonary artery stenosis.
Laboratory tests
The patient is group A and rhesus positive. Glucose-6-phosphate dehydrogenase deficiency screen was normal. Urea and electrolytes revealed slightly raised creatinine and chloride, and liver function tests showed raised aspartate transaminase which may be normal considering he is an SGA infant. Glucose was also normal at 4.8 and so was bilirubin screening. Viral serology was all normal except a reactive cytomegalovirus IgG, rubella IgG, toxoplasma IgG and a positive herpes simplex virus type 1 IgG. Neonatal screening tests for haemoglobinopathy screen were normal, including total galactose, thyroid-stimulating hormone, homocysteine, galactose-1-phospho-uridyl transferase, biotinidase, 17-hydroxyprogesterone amino acid and acylcarnitine screening, which were all normal.9
Differential diagnosis
There are a few congenital malformations or syndromes that can mimic WBS, one of which is Noonan syndrome which also causes pulmonary artery stenosis, but there is also hypertelorism, ptosis, short stature and coronary heart disease.11 Another one is idiopathic infantile hypercalcaemia, a condition in which newborn babies have raised blood calcium levels without any obvious cause. They may present with anorexia, muscle pains and weakness, irritability or confusion. However, they do not present the usual phenotypical features of WBS. Leprechaunism is another possible differential diagnosis of WBS, a rare endocrine condition that presents with pancreatic hyperplasia, resistance to insulin and oestrogen excess and is inherited. It causes IUGR and can present with elfin-like face and a flat broad nose like patients with WBS but without congenital heart malformations2
Treatment
This patient has been seen by cardiologists, family physicians and paediatricians and has been treated for excessive crying, infantile colic symptoms and poor weight gain but with no serious medical complications. He has taken all his childhood immunisations up to date and is having ongoing follow-up at these clinics. His developmental milestones are being monitored.9 10
Outcome
The infant is generally well, has taken all his childhood immunisations up to date and is having ongoing follow-up at these clinics. His developmental milestones are being monitored.9 10
Discussion
WBS is a rare genetic condition which can be inherited in an autosomal dominant manner with a causative allele inherited from either parent. It can also develop de novo as in the author’s index case report. As an autosomal dominant condition, only one copy of the abnormal gene inherited from either the father or mother is enough to lead to the disease expression in a child. The risk of a child inheriting from an affected parent is 50% for each pregnancy irrespective of the child’s sex.2 The patient discussed in this case report did not have a genetic inheritance as the patient’s parents’ genetic testing was negative. WBS patients tend to have typical deletion of 1.55 Mb (90%) or 1.85 Mb deletion, but only 2% of patients have less than 1.55 Mb and tend to present with atypical problems, a category our patient belongs to.8 The author conducted a literature search in the last 20 years of the term ‘William–Beuren syndrome’ and included English, peer-reviewed, open access human articles, which revealed several important papers after sorting for relevance. Several cases of WBS with unique characteristics like the author’s patient have been reported in different parts of the world. Takeuchi et al.’s study in Japan revealed a high cardiovascular risk factor in children and adolescent WBS patients.12 A case report on an 18-month-old female patient who was admitted for failure to thrive due to feeding revealed that 15% of patients with WBS present with hypercalcaemia during infancy, which tends to be mild and resolves spontaneously before 4 years of age, but this patient does not have any calcium abnormalities.13 A retrospective Turkish study also revealed all 27 WBS patients manifested phenotypic dysmorphic features, an observation also seen in all 47 patients in a Mexican paper.7 14 Zamani et al. emphasised the importance of early further evaluation of childhood heart murmurs in patients with WBS, especially in the presence of suspicious facial features.11 The index patient had pulmonary stenosis as a heart deformity rather than the commoner supravalvular aortic stenosis in patients with WBS.1 15 The Turkish study of 27 children revealed that 37% of them had pulmonary stenosis, while a Mexican study of 40 WBS cases reported that 56% had supravalvular aortic stenosis.7 15 The index patient was diagnosed very early in infant, which is quite uncommon for WBS patients, as the Turkish study of 27 patients found 4 years as the median age of diagnosis, a Brazilian study of 55 patients revealed a median diagnostic age of 14 years,16 while two Mexican studies described mean ages of diagnosis of 4.4 and 6 years, respectively.14 15 Also, WBS patients often present with or suffer from endocrine conditions, some of which are diagnosed as they grow older. Kim et al.’s study reports short stature with an incidence of 28.3%, as well as other endocrine conditions like precocious puberty, hypothyroidism and hypercalcaemia.17
Diagnosis of WBS is by specific molecular tests like polymorphic microsatellite markers, chromosomal microarray analysis, multiplex ligation-dependent probe amplification (MLPA) and fluorescence in situ hybridisation, which is 99.8% sensitive and is an important diagnostic technique. However, the microsatellite DNA markers and MLPA techniques can also be used to confirm its diagnosis, especially in resource-poor countries because they are cheaper and quicker, and Lumaka et al. highlighted the diagnosis of WBS in a patient who presented with meningitis.17 18 The majority of WBS cases are diagnosed postnatally in early childhood; however, prenatal diagnosis with ultrasonography combined with amniocentesis and chorionic villus sampling and genetic analysis can reveal in utero diagnosis. Huang et al.’s retrospective study described eight cases where they found ultrasonographic Ventricular Septal Defect incidence of 37.5%, IUGR of 25% and aortic coarctation of 25%.19 Also, patients with WBS often present with childhood and adolescent behavioural and mental health problems. The incidence of autistic spectrum disorders in WBS is six times the general population even though the neurobehavioural features of WBS are actually opposite to ASD mild-to-moderate intellect disability, hypersociability, overfriendliness and relatively preserved language skills.4 An interesting issue about patients with WBS was highlighted by Ferrero et al. who discovered a genotype–phenotype correlation in which their patient with WBS probably had a milder phenotypic feature and normal intelligence because of a shorter 1 Mb atypical deletion.4 When phenotype–genotype correlation and disease progression projections based on deleted genes are considered, the MLPA is used. In patients with WBS, genetic mutation and rearrangements like deletions, inversions and duplications do occur, with some patients with duplications expressing a diagnostic severe expressive language delay and behavioural abnormalities.8 20 21 WBS patients’ phenotypic expressions have been largely studied in European populations, but a study explored 137 patients from other populations in 19 countries clinically and by facial analysis technology. They found a mean age of 11 years, 45% female gender and a majority (>90%) with periorbital fullness and intellectual disability and greater than 75% with malar flattening, long filtrum, wide mouth and small jaws. Their comparison of 286 African, Asian, Caucasian and Latin American patients using facial analysis technology with matched controls revealed that the technology accuracy increased when they were analysed by ethnicity (p value < 0.001).22–24 In summary, typical phenotypic features of WBS include supravalvular aortic stenosis, mild-to-moderate mental retardation, mild short stature and different abnormalities in the genitourinary, skeletal, endocrinological and ophthalmological systems as well as facial dysmorphisms like high forehead, medial broadening of the eyebrows, periorbital fullness, depressed nasal bridge, malar hypoplasia, thick lips and long nasolabial philtrum.16 Atypical features include increased rates of autistic spectrum disorders, infantile spasms, epilepsy and more severe mental retardation as well as varying degrees of social and behavioural problems and systemic involvement.24
Treatment of WBS depends on the abnormalities that the patient presents with and will require a multidisciplinary approach at several stages of development in the life of the child or patient. They will need paediatricians who will likely monitor them for several years, including coordinating their care and referral to different specialists. For example, children with congenital heart malformations will need cardiology reviews and might need cardiothoracic surgeons if operations are needed; paediatricians and dietitians will need to monitor their diet as well as calcium and vitamin D levels, as the importance of dietary calcium and vitamin D restriction was emphasised in a case report of an infant with WBS with severe hypercalcaemia. Some cases with hypercalcaemia may require bisphosphonate therapy and hyperhydration.2 12 13 Some patients with WBS have normal intelligence, but the majority have a mild intellectual impairment (62.9 %) and will need special educational programmes designed to enable them to achieve their potentials, while others may need social services, speech and language therapy, occupational therapy and vocational training. Others may require mental health support services. In Qatar, there are several centres that help to support special needs children like those with WBS. Genetic counselling may be of benefit for people with Williams-Beuren syndrome and their families.2 4 7 The limitation of this case report is that this was an isolated case report, and a meta-analysis of several case reviews on the subject will strengthen the evidence.
Learning points
Early infantile diagnosis of Williams–Beuren syndrome (WBS) is not common.
This is a rare diagnosis of WBS in an infant living in the Middle East.
Most WBS patients have a typical deletion of 1.55 Mb (90%) or 1.85 Mb deletion, but only 2% of patients have less than 1.55 Mb and tend to present with atypical problems, a category our patient belongs to.
This patient presented with relatively mild phenotypic features and a heart murmur later diagnosed as pulmonary stenosis.
WBS patients tend to need multidisciplinary care and socioeducational and behavioural support as they grow older.
Ethics statements
Patient consent for publication
Footnotes
Contributors The following authors were responsible for drafting the text, sourcing and editing of the clinical images, investigation of results, drawing original diagrams and algorithms and critical revision for important intellectual content: AAO. The following authors gave final approval of the manuscript: AAO.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors but sponsorship from the author's employer Primary health Care Corporation Qatar has been applied for but is yet to be approved as at the time of publication.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.