Hernia

Toddler With Elfin Face, Cardiovascular Abnormalities, Hypercalcemia, and Developmental Delays

C. Pion Kao, MD
James S. Leung, BSc
Volume 8 - Issue 11 - November 2009

HISTORY

Four-year-old boy born at 35 weeks’ gestation to a gravida 2, para 1, 23-year-old mother via emergency cesarean delivery because of fetal distress. Birth weight, 1670 g (3 lb 11 oz). Apgar scores, 8 and 9 at 1 minute and 5 minutes, respectively. At birth, child found to have supravalvular aortic stenosis, peripheral pulmonary stenosis, and ventricular septal defect. Gastroesophageal reflux, laryngomalacia, bilateral inguinal hernias, hypothyroidism, hypercalcemia, growth retardation, and developmental delays noted at various times during the first 4 years of life. Family history, unremarkable.

PHYSICAL EXAMINATION

Weight, 11.79 kg (25.99 lb) (1.71 kg [3.77 lb] below the 3rd percentile) and height 94.5 cm (37.2 in) (1 cm [0.39 in] below the 3rd percentile). Child had hypotonia, long philtrum, full lips, an upturned nose, micrognathia, and periorbital fullness. A harsh systolic crescendodecrescendo murmur radiating to the neck noted in the second intercostal space at the right sternal border. Both irides had a stellate pattern.

ANSWER: WILLIAMS SYNDROME

Classically, Williams syndrome presents with transient infantile hypercalcemia that usually resolves by childhood, congenital cardiovascular defects, dysmorphic craniofacial features, a characteristic cognitive and personality profile, growth retardation, and developmental delays.1,2 This multisystem neurodevelopmental disorder was first described by Williams in 1961 and shortly afterward by Beuren (in 1962).3,4 Hence, it is also known as Williams-Beuren syndrome.

INCIDENCE AND ETIOLOGY

The incidence is about 1 in 7500 live births.5 Boys and girls are equally affected.5

Williams syndrome is caused by a hemizygous microdeletion of the ELN gene and contiguous genes on chromosome 7 at band 7q11.23.6,7 This microdeletion results from an unequal meiotic crossover event in one of the parents.8 Deletions of the ELN gene, which encodes for the protein elastin, are found in virtually all patients with Williams syndrome and are directly implicated in the pathogenesis of cardiovascular disease in these patients.6,9,10 However, because ELN is not expressed in significant levels in the brain, ELN deletions are not thought to be responsible for the visuospatial cognition problems, mental retardation, and facial dysmorphology associated with Williams syndrome.11 Instead, these features have been attributed to the combined effects of LIM-K, CYLN2, GTF2IRD1, and GTF2I gene deletions.9,12

Although most cases appear sporadically from de novo mutations, occasional cases of autosomal dominant transmission—occurring when adults with Williams syndrome have children—have been reported.13

CLINICAL MANIFESTATIONS

About 75% of patients have congenital cardiovascular defects, notably supravalvular aortic stenosis (at least 65% of all patients), followed by peripheral pulmonary stenosis (24%) and ventricular septal defects (12%).1 Renal, coronary, mesenteric, cerebral, and carotid artery stenosis may also occur but usually develop in older children and adults.2,10 Renal disease, in particular, needs to be evaluated early because it can lead to renal failure.

The craniofacial phenotype is characterized by mild microcephaly, upturned nostrils, a flat nasal bridge, full lips, wide mouth, long philtrum, bitemporal depressions, periorbital fullness, stellate irides, micrognathia, epicanthal folds, microdontia, malocclusion, enamel hypoplasia, dental aplasia, and fan-shaped orientation of the front teeth (elfin face).1,2

Children with Williams syndrome consistently exhibit a personality profile characterized by highly sociable and overly friendly behaviors accompanied by seemingly paradoxical anxieties, phobias, and poor daily living skills (“cocktail party” personality).14-17 These children have a happy affect—they cheer you up if you are having a bad day in clinic—and remarkable musical ability, which is one of their paradoxical strengths and gives parents hope. Affected children often have mild to moderate mental retardation, extremely severe visuospatial construction problems, and delayed vocabulary acquisition but have normal grammatical, facial recognition, and auditory rote memory skills.14,17 These children tend to be hyperactive (63% to 87% of children) and are 4 times more likely to have attention-deficit/hyperactivity disorder.1,18

Children with Williams syndrome typically exhibit global growth delays during the first few years of life, followed by a period of childhood catch-up growth; however, they ultimately have short stature in adulthood. Many have precocious puberty.1,19

COMPLICATIONS

Cardiovascular disease continues to be a chief concern as persons with Williams syndrome progress into adulthood.20 Many adults report worsening of preexisting supravalvular aortic stenosis.21 Hypertension may develop secondary to renal artery stenosis.20 Myocardial infarction, congestive heart failure, and stroke have also been reported with increased frequency.2 Affected persons are at increased risk for sudden death attributed mainly to coronary artery stenosis or severe biventricular outflow tract obstruction.22,23

Other associated anomalies and complications include gastroesophageal reflux, peptic ulcer disease, diverticulitis, cholelithiasis, bladder calculi, chronic urinary tract infections, premature gray hair, hypothyroidism, esotropia, bilateral inguinal hernias, joint laxity, joint contractures, scoliosis, kyphosis, lordosis, hypotonia, anxiety, and depression.2,18,20,21

DIAGNOSIS

The differential diagnosis of Williams syndrome includes supravalvular aortic stenosis, infantile hypercalcemia, autism, and Down syndrome.13,17,24,25 The unique clinical features of these conditions often allow a straightforward differentiation to be made. However, the diagnosis of Williams syndrome can be delayed because of a lack of significant clinical features during infancy.1

Suspected cases of Williams syndrome can be confirmed cytogenetically. The preferred diagnostic test is fluorescence in situ hybridization.26 In the patient described, results of this test showed a deletion of the ELN gene at 7q11.23.

TREATMENT

Treatment is largely symptomatic and supportive. A multidisciplinary approach is important; the treatment team should include a pediatrician, cardiologist, geneticist, ophthalmologist, neurologist, physiotherapist, psychologist, dentist, schoolteacher, and social worker. Support groups are also available for families (in Canada: the Canadian Association for Williams Syndrome [http://www.caws-can.org]; in the United States: The Williams Syndrome Association [http://www.williamssyndrome. org]).

References

1. Morris CA, Demsey SA, Leonard CO, et al. Natural history of Williams syndrome: physical characteristics. J Pediatr. 1988;113:318-326.
2. Lashkari A, Smith AK, Graham JM Jr. Williams-Beuren syndrome: an update and review for the primary physician. Clin Pediatr (Phila). 1999;38:189-208.
3. Williams JC, Barratt-Boyes BG, Lowe JB. Supravalvular aortic stenosis. Circulation. 1961;24:1311-1318.
4. Beuren AJ, Apitz J, Harmjanz D. Supravalvular aortic stenosis in association with mental retardation and certain facial appearance. Circulation. 1962;26: 1235-1240.
5. Strømme P, Bjørnstad PG, Ramstad K. Prevalence estimation of Williams syndrome. J Child Neurol. 2002;17:269-271.
6. Ewart AK, Morris CA, Atkinson D, et al. Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet. 1993;5:11-16.
7. Paterson SJ, Schultz RT. Neurodevelopmental and behavioral issues in Williams syndrome. Curr Psychiatry Rep. 2007;9:165-171.
8. Urbán Z, Helms C, Fekete G, et al. 7q11.23 deletions in Williams syndrome arise as a consequence of unequal meiotic crossover. Am J Hum Genet. 1996;59: 958-962.
9. Osborne L, Pober B. Genetics of childhood disorders, pt 27: genes and cognition in Williams syndrome. J Am Acad Child Adolesc Psychiatry. 2001;40:732-735.
10. Donnai D, Karmiloff-Smith A. Williams syndrome: from genotype through to the cognitive phenotype. Am J Med Genet. 2000;97:164-171.
11. Ashkenas J. Williams syndrome starts making sense. Am J Hum Genet. 1996;59:756-761.
12. Francke U. Williams-Beuren syndrome: genes and mechanisms. Hum Mol Genet. 1999;8:1947-1954.
13. Metcalfe K, Simeonov E, Beckett W, et al. Autosomal dominant inheritance of Williams-Beuren syndrome in a father and son with haploinsufficiency for FKBP6. Clin Dysmorphol. 2005;14:61-65.
14. Mervis CB, Klein-Tasman BP. Williams syndrome: cognition, personality, and adaptive behavior. Ment Retard Dev Disabil Res Rev. 2000;6:148-158.
15. Dykens E. Anxiety, fears and phobias in persons with Williams syndrome. Dev Neuropsychol. 2003;23:291-316.
16. Klein-Tasman BP, Mervis CB. Distinctive personal characteristics of 8-, 9- and 10-year-olds with Williams syndrome. Dev Neuropsychol. 2003;23:269-290.
17. Mervis CB, Becerra AM. Language and communicative development in Williams syndrome. Ment Retard Dev Disabil Res Rev. 2007;13:3-15.
18. Leyfer OT, Woodruff-Borden J, Klein-Tasman BP, et al. Prevalence of psychiatric
disorders in 4 to 16-year-olds with Williams syndrome. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:615-622.
19. Partsch CJ, Dreyer G, Gosch A, et al. Longitudinal evaluation of growth, puberty, and bone maturation in children with Williams syndrome. J Pediatr. 1999;134:82-89.
20. Howlin P, Udwin O. Outcome in adult life for people with Williams syndrome—results from a survey of 239 families. J Intellect Disabil Res. 2006; 50(pt 2):151-160.
21. Lopez-Rangel E, Maurice M, McGillivray B, Friedman JM. Williams syndrome in adults. Am J Med Genet. 1992;44:720-729.
22. Bird LM, Billman GF, Lacro RV, et al. Sudden death in Williams syndrome: report of ten cases. J Pediatr. 1996;129:926-931.
23. Wessel A, Gravenhorst V, Buchhorn R, et al. Risk of sudden death in the Williams-Beuren syndrome. Am J Med Genet. 2004;127A:234-237.
24. Morris CA, Mervis CB. Williams syndrome and related disorders. Annu Rev Genomics Hum Genet. 2000;1:461-484.
25. Mervis CB, Robinson BF. Expressive vocabulary ability of toddlers with Williams syndrome or Down syndrome: a comparison. Dev Neuropsychol. 2000; 17:111-126.
26. Cagle AP, Waguespack SG, Buckingham BA, et al. Severe infantile hypercalcemia associated with Williams syndrome successfully treated with intravenously administered pamidronate. Pediatrics. 2004;114:1091-1095.