What is William Campbell syndrome?

Williams Syndrome (Williams-Beuren Syndrome)

Williams syndrome is a multisystem genetic disorder caused by a deletion of 1.5 to 1.8 Mb on chromosome 7q11.23 containing 26-28 genes, including the elastin (ELN) gene, resulting in characteristic dysmorphic facial features, cardiovascular disease (particularly supravalvular aortic stenosis), intellectual disability, and a unique cognitive-behavioral profile. 1

Genetic Basis and Inheritance

• The syndrome results from a de novo deletion in approximately 95% of cases, with affected individuals having a 50% chance of transmitting the deletion to offspring 1
• The deletion includes the ELN gene coding for elastin, a structural protein critical for elastic fibers in connective tissue, explaining cardiovascular, facial, and connective tissue manifestations 1
• Deletion of contiguous genes in the region accounts for intellectual disability and other neurological features 1
• A chromosomal inversion polymorphism in this region occurs in 6% of the general population and 25% of parents of affected individuals, increasing recurrence risk 1

Epidemiology

• Prevalence: 1 in 7,500 live births 1
• Affects males and females equally 1
• Usually identified during infancy or early childhood 1

Cardinal Clinical Features

Facial Dysmorphology (100% of cases) 1

• Infants and young children: Broad forehead, bitemporal narrowness, periorbital fullness, epicanthal folds, full cheeks, flat facial profile, short nose with bulbous tip, wide mouth, full lips, mild micrognathia 1
• Older children and adults: Narrow face, long neck, stellate/lacy iris pattern 1
• Dental: Small widely-spaced teeth (microdontia 95%), malocclusion (85%) 1

Cardiovascular Disease (80% of cases) 1

• Supravalvular aortic stenosis (SVAS): 75% of patients 1
• Supravalvular pulmonic stenosis: 25% 1
• Peripheral pulmonary artery stenosis: 50% 1
• Other arterial stenosis: 20% 1
• Hypertension: 50% in older children and adults 1
• Prolonged QTc interval: 13% 1
• Critical consideration: Patients are at increased risk for myocardial ischemia, acute hemodynamic deterioration, and sudden death, particularly during sedation 1

Neurodevelopmental Profile

Cognitive features 1:

• Developmental delay: 95% 1
• Intellectual disability: 75% 1
• Normal intelligence: Only 5% 1
• Impaired visuospatial constructive cognition: 95% 1
• Characteristic cognitive profile: 90% demonstrate unique pattern 1

Behavioral manifestations 1:

• ADHD: 65% 1
• Anxiety disorders (specific phobia, generalized): 70% 1
• Sleep disorders: 65% 1

Neurological findings 1:

• Axial hypotonia (central): 80% in infancy 1
• Peripheral hypertonia: 50% in older children 1
• Hyperactive deep tendon reflexes: 75% 1
• Chiari I malformation: 10% 1

Growth and Endocrine

• Mild prenatal growth deficiency with postnatal growth rate approximately 75% of normal 1
• Microcephaly: 33% of affected individuals 1
• Hypercalcemia: 15-40% (higher prevalence in children <2 years) 1
• Hypercalciuria: 30% 1
• Hypothyroidism: 5-10% 1
• Diabetes mellitus: 15% in adults 1
• Obesity: 30% in older children and adults 1

Musculoskeletal and Connective Tissue

• Joint hypermobility: 90% in young children 1
• Joint contractures: 50% (develops with age, leading to awkward gait 60%) 1
• Radioulnar synostosis: 20% (does not respond to therapy or surgery) 1
• Scoliosis: 18% 1
• Lordosis: 40% 1
• Kyphosis: 20% 1
• Soft, lax skin: 90% 1
• Inguinal hernia: 40% 1
• Umbilical hernia: 50% 1

Sensory Systems

Auditory 1:

• Hypersensitivity to sound: 90% (across all ages) 1
• Recurrent otitis media: 50% in infancy and childhood 1
• Progressive sensorineural hearing loss: 65% in older children and adults 1

Ocular 1:

• Esotropia: 50% in infancy 1
• Hyperopia: 50% in older children and adults 1

Genitourinary

• Bladder diverticula: 50% 1
• Enuresis: 50% (daytime continence typically achieved by age 4; nocturnal continence in 50% by age 10) 1
• Structural anomalies: 5% 1
• Nephrocalcinosis: 5% 1

Gastrointestinal

• Feeding difficulties: 70% in infancy and early childhood 1
• Constipation: 50% (all ages) 1
• Colon diverticula: 30% 1
• Rectal prolapse: 15% 1

Diagnosis

• Chromosomal microarray is the primary diagnostic method, detecting the typical 7q11.23 deletion 1
• Fluorescence in situ hybridization (FISH) or multiplex ligation-dependent probe amplification (MLPA) are alternative confirmatory tests 1
• Medical genetics evaluation is recommended to discuss clinical manifestations, natural history, and recurrence risks 1
• Growth parameters should be plotted on Williams syndrome-specific growth charts 1

Critical Distinction

Williams-Campbell syndrome is an entirely different condition mentioned in the evidence 1 - it is a rare congenital disorder characterized by deficiency of airway cartilage leading to bronchiectasis, not related to Williams syndrome (chromosome 7 deletion) 2, 3, 4. This represents a nomenclature coincidence only.

Management Framework

According to the American Academy of Pediatrics 2020 guidelines 1:

• Multidisciplinary care coordination is essential given multisystem involvement
• Early intervention programs for physical, occupational, and speech therapy 1
• Cardiovascular surveillance and management by pediatric cardiology
• Monitoring for hypercalcemia, particularly in children under 2 years 1
• Renal function assessment at diagnosis (serum urea nitrogen, creatinine, urinalysis) 1
• Nightly stretching range-of-motion exercises for joint contractures 1
• Screening for symptoms of Chiari malformation (headache, dizziness, dysphagia) with pediatric neurology referral as needed 1