PEDIATRICS Vol. 107 No. 5 May 2001, pp. 1192-1204

AMERICAN ACADEMY OF PEDIATRICS:
Health Care Supervision for Children With Williams Syndrome

Committee on Genetics

	ABSTRACT

Top Abstract Introduction References

This set of guidelines is designed to assist the pediatrician to care for children with Williams syndrome diagnosed by clinical features and with regional chromosomal microdeletion confirmed by fluorescence in situ hybridization.

	INTRODUCTION

Top Abstract Introduction References

Williams syndrome (WS, also Williams-Beuren syndrome), now recognized to be caused by a microdeletion of chromosome 7, is a multisystem disorder first identified as a distinct clinical entity in 1961.¹ It is present at birth and affects boys and girls equally. As routine genetic amniocentesis does not typically detect chromosome microdeletions, children with WS usually come to the attention of pediatricians during infancy or childhood. Initially thought to be a rare genetic disorder, increased awareness of the clinical features and establishment of a reliable diagnostic test have revealed WS to be one of the more commonly recognized genetic disorders in childhood. Williams syndrome is characterized by dysmorphic facies (100%), cardiovascular disease (most commonly supravalvar aortic stenosis [80%]), mental retardation (75%), a characteristic cognitive profile (90%), and idiopathic hypercalcemia (15%)^2-5 (Table 1).

The diagnosis historically has been made on the basis of clinical criteria (Fig 1), but recently it has been shown that 99% of patients with WS have a hemizygous submicroscopic deletion of 7q11.23 detectable by fluorescence in situ hybridization (FISH).^6-8 Chromosome analysis and the Williams Syndrome Chromosomal Region FISH test are recommended for confirmation of the diagnosis. (A child with the clinical features of WS and a negative FISH result should be referred to a clinical geneticist for further evaluation.) The deleted portion of the chromosome includes the ELN gene that codes for the structural protein elastin, an important component of the elastic fibers found in the connective tissue of many organs. The elastin deletion explains some of the characteristics of WS, such as some of the facial features, hoarse voice, bladder and bowel diverticula, cardiovascular disease, and orthopedic problems. The pathogenesis of other characteristics, such as hypercalcemia, mental retardation, and unique personality traits, remains unexplained. One possibility is that the loss of 1 or more genes contiguous to the ELN gene contributes to the phenotype.

View larger version (63K): [in this window] [in a new window]   Fig. 1.   Williams syndrome diagnostic scoring table: clinical diagnosis.

The pediatrician can use knowledge of the clinical manifestations (Table 1) and natural history of WS to anticipate medical problems and to educate the family. Most children with WS are described as having similar facial features.^4,9 Although these features are often subtle, they tend to become more distinctive with advancing age. Facial features often include periorbital fullness, short nose with bulbous nasal tip, long philtrum, wide mouth, full lips, and mild micrognathia. Infants have full cheeks and a flat facial profile, whereas older children and adults often have a long narrow face and a long neck.^10,11 Blue- and green-eyed children with WS have a prominent "starburst" pattern to their irides (stellate iris).¹² Mild prenatal growth deficiency and a postnatal growth rate about 75% of normal are consistently observed features of the condition.^8,13

The majority of children with WS have cardiovascular anomalies.^1,2,4 The most common cardiovascular defect is supravalvar aortic stenosis, an often progressive condition that may require surgical repair.^10,11 Peripheral pulmonary artery stenosis is often present in infancy and usually improves over time. Coarctation of the aorta, renal artery stenosis, and systemic hypertension are complications that when present may worsen over time.^4,11,14,15 Because the elastin protein is an important component of elastic fibers in the arterial wall, any artery may become narrowed.

Idiopathic infantile hypercalcemia is an intriguing feature of WS that can contribute to the presence of extreme irritability, vomiting, constipation, and muscle cramps associated with this condition.^4,9 Symptomatic hypercalcemia usually resolves during childhood, but lifelong abnormalities of calcium and vitamin D metabolism may persist. Hypercalciuria is common and predisposes to nephrocalcinosis. The cause of the abnormality in calcium metabolism is unknown.

An infant with WS often has difficulty feeding and may be brought for medical care because of gastroesophageal reflux, colic, or failure to thrive.^4,9,16 Other medical problems include Chiari I malformation, strabismus,¹² hyperopia,¹² chronic otitis media, hypodontia, malocclusion, bowel or bladder diverticula, hernias, joint laxity, joint contractures,¹⁷ kyphosis, lordosis, renal or urinary tract malformations,^14,15 hypothyroidism, and rectal prolapse.

Children with WS have a unique cognitive and behavioral profile.^3,5,18 Cognitive, motor, and language delay are universal, and in 75% of the children, mental retardation is ultimately diagnosed.^19,20 Older children demonstrate a relative strength in language and auditory memory, with a significant weakness in visuospatial cognition.^5,18 Behavioral problems may include hypersensitivity to sound, sleep problems, attention-deficit/hyperactivity disorder,²⁰ and anxiety. Overfriendliness and an empathetic nature are commonly observed.¹⁷

The medical care of children with WS requires an understanding of the natural history of the disorder, awareness of potential clinical complications, and ongoing assessment and periodic review at appropriate ages (Fig 2). Because the clinical manifestations during the neonatal period are variable, the diagnosis may not be suspected during early infancy. Accordingly, this statement includes a series of evaluations that should be considered at the time the diagnosis is suspected clinically; the diagnosis should be confirmed by FISH analysis. The evaluations include the following:

• Complete physical and neurologic examination
• Growth parameters plotted on WS growth charts (Fig 3A-F)
• Cardiology evaluation
  -Full clinical evaluation by a cardiologist with expertise and experience in pediatric patients that includes 4-limb blood pressure measurements and echocardiography
  

• Genitourinary system evaluation
  -Ultrasonography of bladder and kidneys
  - Renal function studies (serum urea nitrogen and creatinine levels) -Urinalysis
  

• Calcium determinations (serum calcium, spot urine calcium, and creatinine levels) (Table 2)
• Thyroid function tests
• Ophthalmologic evaluation
• Multidisciplinary developmental evaluation (older than 2 years)
• FISH to determine ELN deletion

View larger version (55K): [in this window] [in a new window]   Fig. 2.   Health supervision for children with Williams syndrome*.

Referral to a clinical geneticist should be considered for individualized assessment and recommendations; a more extensive discussion of the clinical manifestations, natural history, recurrence risks, and future reproductive options; and evaluation of genetic risks for other family members.

View larger version (45K): [in this window] [in a new window]   Fig. 3A.   Williams syndromestature, females. Height for patients with Williams syndrome (61 females, 47 males). Normal curvesdashed lines; affected patientssolid lines. Reprinted with permission from Saul RA, Geer JS, Seaver LH, Phelan MC, Sweet KM, Mills MS. Growth References: Third Trimester to Adulthood. Greenwood, SC: Greenwood Genetic Center; 1998.

	SPECIAL CONSIDERATIONS FOR THE CHILD DIAGNOSED WITH WS

1. Do not give multivitamin preparations to children with WS because of the potential deleterious effects of vitamin D. Recommend diligent use of sunscreen to minimize autologous production of vitamin D.
2. Perform periodic cardiovascular evaluations, even after a baseline examination with normal findings.
3. Baseline cardiology evaluation should be performed by a cardiologist with pediatric expertise and experience.
4. Screen for the development of hypertension periodically according to guidelines of the American Academy of Pediatrics.
5. Establish a medical home with clear emphasis on continuity of care and the role of the family members as partners in the ongoing management and care of the child.

	HEALTH SUPERVISION FROM BIRTH TO 1 YEAR (INFANCY)

Examination

1. Review and note clinical features and confirm diagnosis with FISH analysis
2. Routine health maintenance examinations and baseline evaluation
3. Growth and developmental evaluations using WS growth charts (Fig 3A-F)
4. Baseline cardiology evaluation by a cardiologist with pediatric expertise and experience
5. Review feeding issues (reflux, refusal, disordered suck or swallow, vomiting or symptoms of colic).
6. Consider pediatric ophthalmologic evaluation for strabismus, amblyopia, and refractive errors
7. Check for inguinal hernia
8. Objective hearing assessment at 6 to 12 months (recurrent otitis media is common)
9. Blood pressure measurement (both arms) annually and careful evaluation of femoral pulses
10. Early recognition and management of constipation
11. Pediatric anesthesia consultation for any child requiring surgery (several reports of unexpected deaths have been associated with the administration of anesthesia)²²

Laboratory

1. Williams Syndrome Chromosomal Region FISH to confirm clinical diagnosis

2. Serum creatinine level

3. Urinalysis

4. Calcium levels
a. Serum*

b b. Spot urine test to determine calcium-creatinine ratio

5. Thyroid screen for newborns (according to state mandate)

6. Baseline ultrasonographic examination of the bladder and kidneys

Anticipatory Guidance

1. Individual support for the family (by family, friends, clergy), support groups, or both (see list)
2. Review increased risk for otitis media
3. Feeding (difficulty in transition to textured foods)
4. Do not prescribe multivitamin preparations containing vitamin D
5. Refer to early childhood intervention program

	HEALTH SUPERVISION FROM 1 TO 5 YEARS (EARLY CHILDHOOD)

Examination

1. Annual health maintenance examinations and baseline evaluation (including careful auscultation of chest and abdomen for murmurs or bruits)
2. Developmental evaluation and growth evaluation using WS growth charts (Fig 3A-F)
3. Annual cardiology evaluation from 1 to 5 years
4. Feeding issues: watch for rectal prolapse and avoid constipation with stool softeners if necessary
5. Annual hearing and vision screening; objective audiologic evaluation and an ophthalmologic evaluation before age 3 years
6. Orthopedic issues: musculoskeletal and neurologic assessments to evaluate joints, muscle tone, spasticity, and hyperactive reflexes¹⁷
7. Pediatric anesthesia consultation for any child requiring surgery (several reports of unexpected deaths have been associated with the administration of anesthesia)²²
8. Annual blood pressure measurement (both arms) and careful examination of femoral pulses
9. Multidisciplinary developmental assessment and treatment in early intervention programs (0-3 years) or school based programs (3 years and older)^1,5,19
10. Dental referral

Laboratory

1. Yearly urinalysis
2. Annual total calcium measurement if the level was elevated at baseline or as needed if the child becomes symptomatic; if level was normal, measure every 2 to 3 years
3. Urinary calcium-creatinine ratio every 2 years
4. Thyroid function test every 4 years
5. Serum creatinine level every 4 years

Anticipatory Guidance

1. Individual support for the family (by family, friends, clergy), support groups, or both
2. Review increased risk for otitis media
3. Ongoing feeding and dietary assessments
4. Therapy as needed (physical, speech and language, and occupational, including sensory integration)
5. Review constipation as a possible problem
6. Children with unexplained fever should be evaluated for urinary tract infection
7. Discuss developmental status, early intervention programs, and preschool programs

	HEALTH SUPERVISION FROM 5 YEARS TO 12 YEARS (LATE CHILDHOOD)

Examination

1. Annual health maintenance examinations and baseline evaluation
2. Developmental evaluation and growth evaluation using WS growth charts (Fig 3A-F)
3. Annual blood pressure measurements (both arms) and careful evaluation of femoral pulses
4. Cardiology evaluation as indicated by previous clinical findings. If results of previous evaluations are negative, repeated cardiology evaluation (for arterial stenoses, hypertension) should be performed at puberty
5. Ophthalmologic evaluation for strabismus and hyperopia
6. Orthopedic problems (eg, joint limitation, kyphosis, lordosis, scoliosis, and spasticity)
7. Hearing and vision screening annually
8. Pediatric anesthesia consultation for any child requiring surgery (several reports of unexpected deaths have been associated with the administration of anesthesia²²)
9. School readiness and placement and Individual Educational Plan at 5 years
10. Developmental and psychoeducational assessment; formal evaluation for attention-deficit hyperactivity disorder, anxiety, or both and discussion of treatment options²³

Laboratory

1. Yearly urinalysis
2. Thyroid function tests every 4 years
3. Annual total calcium level if baseline result was elevated or child becomes symptomatic; otherwise measure level every 4 years
4. Urinary calcium-creatinine ratio every 2 years
5. Serum creatinine level every 2 to 4 years

Anticipatory Guidance

1. School readiness and placement
2. Therapy as needed (physical, speech and language, and occupational, including sensory integration)
3. Long-term vocational planning
4. Discuss sexuality and adolescence; puberty is often early in WS, but true precocious puberty is rare
5. Discuss diet and exercise as obesity may become apparent in late childhood
6. Discuss treatment options for anxiety (counseling, relaxation techniques, and medications)
7. Estate planning for parents of a child with special needs

	HEALTH SUPERVISION FROM 13 YEARS TO 18 YEARS (ADOLESCENCE)

Progressive medical problems including hypertension, progressive joint limitations, recurrent urinary tract infections, and gastrointestinal problems are common beginning in this age group and continuing throughout adult life.

View larger version (46K): [in this window] [in a new window]   Fig. 3B.   Williams syndromestature, males. Height for males with Williams syndrome. Normal curvesdashed lines; affected patientssolid lines. Reprinted with permission from Saul RA, Geer JS, Seaver LH, Phelan MC, Sweet KM, Mills MS. Growth References: Third Trimester to Adulthood. Greenwood, SC: Greenwood Genetic Center; 1998.

View larger version (43K): [in this window] [in a new window]   Fig. 3C.   Williams syndromeweight, females. Weight for females with Williams syndrome. Normal curvesdashed lines; affected patientssolid lines. Reprinted with permission from Saul RA, Geer JS, Seaver LH, Phelan MC, Sweet KM, Mills MS. Growth References: Third Trimester to Adulthood. Greenwood, SC: Greenwood Genetic Center; 1998.

View larger version (44K): [in this window] [in a new window]   Fig. 3D.   Williams syndromeweight, males. Weight for males with Williams syndrome. Normal curvesdashed lines; affected patientssolid lines. Reprinted with permission from Saul RA, Geer JS, Seaver LH, Phelan MC, Sweet KM, Mills MS. Growth References: Third Trimester to Adulthood. Greenwood, SC: Greenwood Genetic Center; 1998.

View larger version (52K): [in this window] [in a new window]   Fig. 3E.   Williams syndromehead circumference, females. Head circumference for females with Williams syndrome. Normal curvesdashed lines; affected patientssolid lines. Reprinted with permission from Saul RA, Geer JS, Seaver LH, Phelan MC, Sweet KM, Mills MS. Growth References: Third Trimester to Adulthood. Greenwood, SC: Greenwood Genetic Center; 1998.

View larger version (52K): [in this window] [in a new window]   Fig. 3F.   Williams syndromehead circumference, males. Head circumference for males with Williams syndrome. Normal curvesdashed lines; affected patientssolid lines. Reprinted with permission from Saul RA, Geer JS, Seaver LH, Phelan MC, Sweet KM, Mills MS. Growth References: Third Trimester to Adulthood. Greenwood, SC: Greenwood Genetic Center; 1998.

Examination

1. Annual health maintenance examinations and baseline evaluation; blood pressure measurement (both arms)
2. Developmental evaluation and growth evaluation using WS growth charts (Fig 3A-F)
3. Cardiology evaluation if indicated by previous clinical findings
4. Pediatric anesthesia consultation for any child requiring surgery (several reports of unexpected deaths have been associated with the administration of anesthesia²²)
5. Consider ophthalmologic evaluation for hyperopia
6. Orthopedic problems (eg, joint limitation, kyphosis, lordosis, scoliosis, and spasticity)
7. Hearing and vision screening annually
8. Developmental and psychoeducational assessment; school placement and resource enhancement; vocational training; social skills training for peer interaction^10,11
9. Gastrointestinal issues: consider diverticulitis and diverticulosis, cholelithiasis, and chronic constipation in adolescents with abdominal pain
10. Screen for generalized anxiety disorder¹⁹

Laboratory

1. Yearly urinalysis
2. Thyroid function test every 4 years
3. Total calcium level only if adolescent becomes symptomatic, otherwise, every 4 years
4. Urinary calcium-creatinine ratio every 2 years
5. Bladder and renal ultrasonography at puberty and every 5 years thereafter
6. Serum creatinine level every 2 to 4 years

Anticipatory Guidance

1. School placement
2. Therapy as needed (physical, occupational, speech, and language)
3. Discuss diagnosis with the adolescent; support groups for the adolescent (see American Academy of Pediatrics statement on "Transition of Care Provided for Adolescents With Special Needs")²⁴
4. Discuss sexuality and reproductive issues
5. Encourage career counseling
6. Foster independence
7. Assist in transition to adult care (especially for cardiology care). Many pediatricians feel comfortable continuing to provide primary care well into young adulthood
8. Encourage daily exercise to include range of motion
9. Encourage prompt medical attention for urinary tract or gastrointestinal symptoms
10. Mental health issues

Committee on Genetics, 2000-2001

Christopher Cunniff, MD, Chairperson

Jaime L. Frias, MD

Celia I. Kaye, MD, PhD

John Moeschler, MD

Susan R. Panny, MD

Tracy L. Trotter, MD

Liaisons

Felix de la Cruz, MD, MPH

National Institute of Child Health and Human Development

John Williams III, MD

American College of Obstetricians and Gynecologists

James W. Hanson, MD

}American College of Medical Genetics

Cynthia A. Moore, MD, PhD

Centers for Disease Control and Prevention

Michele Lloyd-Puryear, MD, PhD

Health Resources and Services Administration

Section Liaison

H. Eugene Hoyme, MD

Section on Genetics

Consultants

Paige Kaplan, MD

Ron Lacro, MD

Karen Levine, PhD

Martin Levinson, MD

Carolyn Mervis, PhD

Colleen A. Morris, MD

Beth A. Pletcher, MD

Barbara Pober, MD

Laurie Sadler, MD

Paul Wang, MD

Staff

Lauri A. Hall

	FOOTNOTES

The recommendations in this statement do not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate.

^* If hypercalcemia is found, dietary calcium restriction should be implemented and diet should be monitored in conjunction with a pediatric dietician/nutritionist. Referral to a pediatric renal specialist should be considered.

If hypercalciuria is found, 2 repeated urine studies of the calcium-creatinine ratio (morning and afternoon) should be performed. If the level is still elevated, repeat measurement of the serum calcium level and perform renal ultrasonography for nephrocalcinosis. Assess dietary calcium intake.²¹

	ABBREVIATIONS

WS, Williams syndrome; FISH, fluorescence in situ hybridization.

	REFERENCES

Top Abstract Introduction References

1. Williams JC, Barratt-Boyes BG, Lowe JB Supravalvular aortic stenosis. Circulation 1961; 24:1311-1318 [Abstract/Free Full Text]
2. Beuren AJ Supravalvular aortic stenosis: a complex syndrome with and without mental retardation. Natl Found March Dimes Birth Defects Orig Art Ser 1972; 8:45-56
3. Burn J Williams syndrome. J Med Genet 1986; 23:389-395 [Free Full Text]
4. Morris CA, Demsey SA, Leonard CO, Dilts C, Blackburn BL Natural history of Williams syndrome: physical characteristics. J Pediatr 1988; 113:318-326 [CrossRef][Medline]
5. Udwin O, Yule W A cognitive and behavioural phenotype in Williams syndrome. J Clin Exp Neuropsychol 1991; 13:232-244 [Medline]
6. Ewart AK, Morris CA, Atkinson D, Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet 1993; 5:11-16 [CrossRef][Medline]
7. Lowery MC, Morris CA, Ewart A, Strong correlation of elastin deletions, detected by FISH, with Williams syndrome: evaluation of 235 patients. Am J Hum Genet 1995; 57:49-53 [Medline]
8. Wu Y-Q, Sutton VR, Nickerson E, Delineation of the common critical region in Williams syndrome and clinical correlation of growth, heart defects, ethnicity, and parental origin. Am J Med Genet 1998; 78:82-89 [CrossRef][Medline]
9. Martin ND, Snodgrass GJ, Cohen RD Idiopathic infantile hypercalcemia: a continuing enigma. Arch Dis Child 1984; 59:605-613 [Abstract/Free Full Text]
10. Lopez-Rangel E, Maurice M, McGillivray B, Friedman JM Williams syndrome in adults. Am J Med Genet 1992; 44:720-729 [CrossRef][Medline]
11. Morris CA, Leonard CO, Dilts C, Demsey SA Adults with Williams syndrome. Am J Med Gen Suppl 1990; 6:102-107
12. Greenberg F, Lewis RA The Williams syndrome: spectrum and significance of ocular features. Ophthalmology 1988; 95:1608-1612 [Medline]
13. Saul RA, Stevenson RE, Rogers RC, Skinner SA, Prouty LA, Flannery DB. Williams syndrome. In: Proceedings of the Greenwood Genetic Center. Greenwood, SC: Greenwood Genetic Center; 1988:204-209
14. Pankau R, Partsch C-J, Winter M, Gosch A, Wessel A Incidence and spectrum of renal abnormalities in Williams-Beuren syndrome. Am J Med Genet 1996; 63:301-304 [CrossRef][Medline]
15. Pober BR, Lacro RV, Rice C, Mandell V, Teele RL Renal findings in 40 individuals with Williams syndrome. Am J Med Genet 1993; 46:271-274 [CrossRef][Medline]
16. Morris CA, Mervis CB. Williams syndrome. In: Goldstein S, Reynolds CR, eds. Handbook of Neurodevelopmental and Genetic Disorders in Children. New York, NY: The Guilford Press; 1999;555-590
17. Kaplan P, Kirschner M, Watters G, Costa MT Contractures in patients with Williams syndrome. Pediatrics 1989; 84:895-899 [Abstract/Free Full Text]
18. Wang PP, Hesselink JR, Jernigan TL, Doherty S, Bellugi U Specific neurobehavioral profile of Williams' syndrome is associated with neocerebellar hemispheric preservation. Neurology 1992; 42:1999-2002 [Abstract/Free Full Text]
19. Chapman CA, du Plessis A, Pober BR Neurologic findings in children and adults with Williams syndrome. J Child Neurol 1996; 11:63-65 [Abstract/Free Full Text]
20. Pober BR, Filiano JJ Association of Chiari I malformations and Williams syndrome. Pediatr Neurol 1995; 12:84-88 [CrossRef][Medline]
21. Sargent JD, Stukel TA, Kresel J, Klein RZ Normal values for random urinary calcium to creatinine ratios in infancy. J Pediatr 1993; 123:393-397 [CrossRef][Medline]
22. Bird LM, Billman GF, Lacro RV, Sudden death in Williams syndrome: report of ten cases. J Pediatr 1996; 129:926-931 [CrossRef][Medline]
23. Power TJ, Blum NJ, Jones SM, Kaplan PE Brief report: response to methylphenidate in two children with Williams syndrome. J Autism Dev Dis 1997; 27:79-87
24. American Academy of Pediatrics, Committee on Children With Disabilities Transition of care provided for adolescents with special health care needs. Pediatrics 1996; 98:1203-1206 [Abstract/Free Full Text]

	RESOURCES FOR PARENTS

1. March of Dimes, 1275 Mamaroneck Ave, White Plains, NY 10605; Telephone: 914/428-7100; http://www.modimes.org
2. The Williams Syndrome Association, PO Box 297, Clawson, MI 48017; Telephone: 248/541-3630; http://www.williams-syndrome.org
3. Williams Syndrome Foundation, University of California, Irvine, CA 92679; Telephone: 949/824-7259; http://www.wsf.org