Infantile Hypercalcaemia (Williams' Syndrome)

Synonyms: William's Syndrome, Williams-Beuren syndrome (WBS)

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 the past 20 years, at approximately 18 cases per year in the United Kingdom - approximately 2 per 100,000 total live births.¹
• There is no racial predilection, however the prevalence of particular features may vary among populations e.g. people living in Greece have a lower rate of cardiovascular anomalies.²
• The deletion is equally prevalent in males and females. A greater severity and earlier presentation of cardiovascular disease may exist in males.³

It is caused by a microdeletion at 7q11. 23.^4,5 This affects the elastin gene and causes a tight constriction in the aorta, directly above the sinuses of Valsalva. It is accompanied by a similar abnormality in the pulmonary arteries.

Clinical manifestations of Williams syndrome are evident from birth through adulthood. However, features that may be detected at antenatal ultrasound include the characteristic cardiovascular lesions.

• There is an uneven cognitive profile, with mild mental retardation.
• Relatively good verbal skills
• Very deficient visuo-spatial abilities⁷
• Prefer the company of adults to peers
• Lack shyness with strangers

Associated physical abnormalities include:

• Dysmorphic face:
  • Abnormal teeth (tooth enamel hypoplasia, malocclusion and cavities)
  • Large lips
  • Round blue eyes
  • Stellate pattern on iris
• Short stature
• Cardiovascular abnormalities e.g. supraventricular aortic stenosis
• Hypotonia and easy fatigability
• Chest pain and syncope
• Bilateral corneal opacities

Psychological features include:

• Approximately 70% also suffer from attention deficit disorder
• Many experience anxiety and simple phobias

However, there are also strengths in certain complex faculties e.g. language,⁸ music, face processing and sociability.⁹ This excessive sociability is present across differing cultures, but appears to vary in intensity by culture.¹⁰ They may have charismatic speech with a wide vocabulary and may be very expressive musically.

Fetal ultrasound of neonates with Williams syndrome have revealed multicystic dysplastic kidney in addition to the congenital heart lesions.¹¹ Associated findings on prenatal screening include:

• Increased fetal nuchal translucency
• Low maternal serum alpha fetoprotein (MSAFP)

• Fluorescent in situ hybridization (FISH) for the 7q11.23 elastin gene deletion should be performed in patients in whom Williams syndrome is suspected.¹²
• In addition a routine chromosomal analysis should be performed.
• Testing is routinely performed on peripheral blood leukocytes.
• FISH testing and karyotype are performed in cytogenetics laboratories.

• Aortic stenosis can lead to severe obstruction to left ventricular outflow, with left ventricular failure and occasionally sudden death.
• Surgery may be required.
• Long term morbidity in these children is mainly due to mental handicap and arteriopathy, but hypertension (29%), kyphoscoliosis (19%), hyperacusis (75%) and obesity (50%) may be added complications.¹

Many have behavioural and social difficulties into adulthood with most required some supervision and support in everyday activities:

• Recent research has highlighted the continuing high rates of physical problems in this group into adulthood and apparent increases in rates of mental health problems with age. Parents of sufferers also expressed their concerns about the lack of adequate support and care.
• Educational and employment attainments were found to be generally low and self-help skills relatively poor.¹³