Infantile Hypercalcaemia Williams' Syndrome

Synonyms: WS; Williams-Beuren syndrome (WBS), chromosome 7q11.23 deletion syndrome

In 1961, Williams and colleagues described this disorder in four unrelated children with mental deficiency, an unusual facies and supravalvular aortic stenosis. Many more cases have been described since and the syndrome is characterised by cardiovascular disease, distinctive facies, connective tissue abnormalities, intellectual disability, a specific cognitive profile, unique personality characteristics, growth abnormalities and endocrine abnormalities.^[1]

Epidemiology

It is a rare autosomal dominant disease, but the majority of cases occur de novo.

• The estimated incidence of idiopathic infantile hypercalcaemia alone has remained constant for a period of 20 years, at approximately 18 cases per year in the UK - approximately 2 per 100,000 total live births.^[2]
• A study from Norway reported a prevalence of 1:7,500.^[3]
• There is no racial predilection; however, the prevalence of particular features may vary among populations - eg, people living in Greece have a lower rate of cardiovascular anomalies.^[4]
• The deletion is equally prevalent in males and females. A greater severity and earlier presentation of cardiovascular disease may exist in males.^[5]

Genetics

Infantile hypercalcaemia is a contiguous gene deletion syndrome caused by hemizygous deletion of 1.5 to 1.8 Mb on chromosome 7q11.23.^[6]

The affected area of chromosome is known as the Williams-Beuren syndrome critical region (WBSCR) and encompasses the elastin gene (ELN). Over 99% of individuals with clinical diagnosis of infantile hypercalcaemia have this continuous gene deletion, which can be detected using fluorescent in situ hybridisation (FISH) and or deletion/duplication testing.

Presenting features

Clinical manifestations of infantile hypercalcaemia are evident from birth through to adulthood.^[7]

The WS phenotype is variable and no single clinical feature is required to establish the diagnosis. It should be suspected in individuals with following findings:^[1]

• Cardiovascular disease (elastin arteriopathy):
• Supravalvular aortic stenosis (SVAS) is the most common and clinically significant condition occurring in 75% of individuals.
• Peripheral pulmonic stenosis (PPS) is common in infancy, although any artery can be affected.
• Distinctive facies:
• Broad forehead, bitemporal narrowing, periorbital fullness.
• Stellate iris pattern, strabismus.
• Short nose with broad nasal tip.
• Long philtrum, wide mouth with thick vermilion of upper and lower lips.
• Connective tissue abnormalities:
• Hoarse voice, inguinal/umbilical hernia.
• Bowel/bladder diverticulae, rectal prolapse.
• Joint limitation or laxity and soft lax skin.
• Intellectual disability:
• Most patients have intellectual disability ranging from mild to severe.
• Some individuals have normal intelligence.
• Specific cognitive profile:
• Strength - verbal short-term memory and language.
• Very poor visuospatial construction.
• Unique personality:
• Overly friendly and empathetic with excessive sociability.^[8]
• Generalised anxiety, specific phobias and attention deficit.
• Growth abnormalities:
• Prenatal growth deficiency with failure to thrive in infancy.
• Rate of linear growth is less than normal with resulting short stature.
• Endocrine abnormalities:
• Idiopathic hypercalcaemia and hypercalciuria.
• Hypothyroidism and early puberty.

Prenatal diagnosis

• For pregnancies at risk for infantile hypercalcaemia, FISH testing may be used to detect the deletion of WBSCR in fetal cells obtained by chorionic villous sampling or amniocentesis.
• For pregnancies not known to be at increased risk for infantile hypercalcaemia, prenatal testing is possible but rarely used.

Diagnosis

• Molecular genetic testing that detects deletion of WBSCR should be performed in patients in whom infantile hypercalcaemia is suspected. The options include FISH or deletion/duplication analysis.
• Multiplex ligation-dependent probe amplification (MLPA) has recently been reported as an effective method to detect the deletion of WBSCR.^[9]
• In addition, a routine chromosomal analysis and microarray should be performed.

Management

Once a diagnosis of infantile hypercalcaemia has been made, a comprehensive evaluation should be carried out to define the systems affected and target medical management.^[1]This includes:

• Physical and neurological examination with developmental evaluation.
• Cardiac evaluation including ECG and echocardiogram.
• Urinary evaluation including ultrasound of bladder and kidneys and renal function tests.
• Serum calcium and urinary calcium:creatinine ratio.
• TFTs.
• Ophthalmological and audiological evaluation.

Ideally, a multidisciplinary team should be involved.

General measures

• These include early intervention programmes, education programmes and vocational training. Access to speech/language, physical, occupational and sensory integration therapies is also beneficial.
• Infants often benefit from feeding therapy.
• Psychological and psychiatric evaluation should guide therapy for the individual.
• Referral to a nephrologist is necessary for management of nephrocalcinosis and persistent hypercalcaemia and/or hypercalciuria.

Pharmacological

• Behavioural counselling and psychotropic medication are often used to manage behavioural problems, especially attention deficit hyperactivity disorder and anxiety.
• Treatment of hypercalcaemia may include diet modification, oral corticosteroids and/or intravenous pamidronate.^[10]
• Children should not be given multivitamins because all paediatric multivitamin preparations contain vitamin D.

Surgical

• Surgery may be required for supravalvular aortic stenosis in 20-30% of patients.^[11]
• Surgical treatment of mitral valve insufficiency or renal artery stenosis may be required.

Ongoing management

• Surveillance includes yearly: medical evaluation, vision screening, measurement of blood pressure, calculation of calcium:creatine ratio in a random spot urine test and urinalysis.^[1]
• Additional periodic evaluations during childhood include: serum concentration of calcium, thyroid function, hearing and renal and bladder ultrasound examination.
• Periodic evaluations during adulthood include: glucose tolerance, cardiac evaluation for mitral valve prolapse, aortic insufficiency and arterial stenosis and ophthalmological evaluation for cataracts.

Prognosis^[12]

• Patients with infantile hypercalcaemia need lifelong medical attention.
• During infancy, colic, sleep problems, recurrent ear infections and strabismus occur much more frequently than in the general population, prompting 10 extra visits to the doctor in the first year of life.
• Premature greying of hair, diverticulosis, diabetes mellitus and sensorineural hearing loss commonly develop during adolescence or young adulthood.
• Most adults with infantile hypercalcaemia require ongoing supervision both at home and at work.
• Educational and employment attainments have been found generally to be low and self-help skills relatively poor.^[13]
• Cardiovascular complications are the major cause of death in infantile hypercalcaemia.
• Aortic stenosis can lead to severe obstruction to left ventricular outflow, with left ventricular failure and, occasionally, sudden death.

Genetic counselling

• Infantile hypercalcaemia is transmitted in an autosomal dominant manner. Most cases are de novo occurrences; however, occasionally, parent-to-child transmission is observed.
• In the absence of clinical findings of infantile hypercalcaemia in the parents, FISH testing of parents is not warranted.
• When the parents are clinically unaffected, the risk of having another sibling with infantile hypercalcaemia is low while if the parent is affected, the risk is 50%.