Wolf-Hirschhorn Syndrome: Introduction

Wolf-Hirschhorn syndrome (WHS) is a rare chromosomal disorder caused by a partial deletion of the short arm of chromosome 4. It is characterized by intellectual disability, developmental delay, seizures, and distinctive facial features.

Key points:

• Genetic cause: Partial deletion of the short arm of chromosome 4 (4p-)
• Inheritance: Most cases are de novo deletions; some result from unbalanced translocations
• Prevalence: Estimated at 1 in 50,000 births, with a female predominance (2:1)
• Critical region: 4p16.3, including the WHSC1 and LETM1 genes

Clinical Features of Wolf-Hirschhorn Syndrome

Craniofacial Features:

• "Greek warrior helmet" appearance of the nose
• High forehead
• Widely spaced eyes (hypertelorism)
• Microcephaly
• Micrognathia
• Cleft lip and/or palate
• Preauricular tags or pits

Neurological Issues:

• Intellectual disability (usually severe)
• Developmental delay
• Seizures (90% of cases)
• Hypotonia
• Corpus callosum abnormalities

Growth and Development:

• Intrauterine growth restriction
• Postnatal growth deficiency
• Feeding difficulties
• Delayed or absent speech

Skeletal Abnormalities:

• Scoliosis
• Club feet
• Fused vertebrae
• Joint contractures

Cardiac Defects:

• Atrial septal defects
• Ventricular septal defects
• Patent ductus arteriosus

Additional Features:

• Hearing loss
• Ocular abnormalities (e.g., coloboma, strabismus)
• Renal anomalies
• Genital abnormalities (e.g., hypospadias in males)
• Recurrent respiratory infections

Diagnosis of Wolf-Hirschhorn Syndrome

Diagnosis is based on clinical features, cytogenetic analysis, and molecular genetic testing.

Clinical Diagnosis:

Suspicion is based on characteristic facial features, growth delay, developmental delay, and seizures.

Cytogenetic Testing:

• Chromosomal microarray analysis (CMA) - preferred initial test
• Fluorescence in situ hybridization (FISH) - can detect smaller deletions
• G-banded karyotype - may miss smaller deletions

Molecular Genetic Testing:

• Multiplex ligation-dependent probe amplification (MLPA)
• Quantitative PCR

Additional Assessments:

• EEG to evaluate seizure activity
• Brain MRI to assess structural abnormalities
• Echocardiogram to detect cardiac defects
• Renal ultrasound to evaluate kidney structure
• Hearing and vision tests

Differential Diagnosis:

• Angelman syndrome
• Phelan-McDermid syndrome
• 1p36 deletion syndrome
• Other chromosome deletion syndromes

Management of Wolf-Hirschhorn Syndrome

Management is multidisciplinary and focuses on addressing specific symptoms and improving quality of life.

Neurological Management:

• Anticonvulsant therapy for seizure control
• Regular neurodevelopmental assessments
• Early intervention programs

Developmental Support:

• Special education services
• Speech and language therapy
• Occupational therapy
• Physical therapy

Feeding and Nutrition:

• Feeding therapy
• Gastrostomy tube placement if necessary
• Nutritional supplementation

Cardiac Care:

• Regular cardiac evaluations
• Surgical intervention for congenital heart defects if required

Orthopedic Management:

• Monitoring and treatment of scoliosis
• Management of joint contractures
• Orthotics or surgical intervention for club feet

Respiratory Care:

• Management of recurrent respiratory infections
• Pneumonia prevention strategies

Additional Care:

• Regular hearing and vision assessments
• Dental care (may have dental anomalies)
• Management of urinary tract infections and renal anomalies

Genetic Counseling:

• Discuss recurrence risk (low in de novo cases, higher if parent has balanced translocation)
• Offer parental chromosome analysis
• Discuss prenatal diagnosis options for future pregnancies

Family Support:

• Psychosocial support for families
• Connection with patient support groups
• Respite care options