Synonyms: chromosome 4p deletion syndrome, 4p- syndrome, monosomy 4p syndrome

Wolf-Hirschhorn syndrome (WHS) is characterised by learning difficulties, epilepsy, growth delay and craniofacial dysgenesis.¹

Epidemiology

• The incidence is estimated at 1 in 50,000 births.²
• Female to male ratio is 2:1.

Genetics

Wolf-Hirschhorn syndrome (WHS) occurs due to partial deletion of the short arm of chromosome 4 (4p-).³ About half of patients have a de novo pure deletion of 4p16 and about 40%-45% have an unbalanced translocation with both a deletion of 4p and a partial trisomy of a different chromosome arm.⁴ These unbalanced translocations may be de novo or inherited from a parent with a balanced rearrangement. The remainder have other complex rearrangements leading to a 4p16.3 deletion.

Presentation⁵

• Severe growth restriction, microcephaly, hydrocephalus, corpus callosum agenesis.
• Severe mental retardation, severe limitation of comprehension and speech, seizures, ataxic gait, hypotonia, muscle hypertrophy.
• Microcephaly, a distinct "Greek warrior helmet" face with characteristic broad beaked nose, high frontal hairline and frontal bossing.
• Contracture of hands, wrists, and feet.
• Poor development of secondary sexual characteristics.
• Closure defects (cleft lip or palate, coloboma of the eye, and cardiac septal defects).
• Hypoplasia of kidneys and genital tract. Diaphragmatic hernia with secondary lung hypoplasia.
• Immunodeficiency.

Differential diagnosis

• Similar multiple congenital anomalies and mental retardation syndromes, including proximal 4p syndrome and Seckel's syndrome.

Investigations

• Prenatal diagnosis:
  • Anomaly ultrasound scan will suggest distinct physical characteristics and should be followed by karyotyping.
  • Chromosomal analysis from amniocentesis or chorionic villus sampling.
  • Umbilical blood sampling for rapid fetal karyotyping.
• Immunoglobulin and T-cell numbers and function for likely immunodeficiency.
• Electroencephalography (EEG): characterised by distinctive seizure and EEG patterns.³
• Echocardiography: possible atrial septal defect or ventricular septal defect.
• Imaging of the urinary tract.
• MRI and CT scans for underlying brain pathology, e.g. agenesis of the corpus callosum and enlarged ventricles.

Management

• No treatment exists for the underlying disorder, and management is supportive.
• Seizures may be difficult to control.
• The management plan will require a multidisciplinary team approach and depend on the range of associated developmental, physical and behavioural problems.

Prognosis

• Frequently results in stillbirth, or death within the first year.
• If patients survive beyond infancy, they have slow but constant progress in terms of development.
• About one third die within the first two years of life, usually due to a heart defect, aspiration pneumonia, other severe infection or resulting from a seizure.
• Recurrence risk is negligible unless a parent is a translocation carrier.

Prevention

Genetic counselling will assess the risk to family members, based on the mechanism of origin of the deletion. Prenatal testing is possible where one parent is known to be a carrier of the condition.⁵

Document references

1. Bergemann AD, Cole F, Hirschhorn K; The etiology of Wolf-Hirschhorn syndrome. Trends Genet. 2005 Mar;21(3):188-95. [abstract]
2. Battaglia A, Carey JC, Wright TJ; Wolf-Hirschhorn (4p-) syndrome. Adv Pediatr. 2001;48:75-113. [abstract]
3. Battaglia A, Carey JC; Seizure and EEG patterns in Wolf-Hirschhorn (4p-) syndrome. Brain Dev. 2005 Aug;27(5):362-4. Epub 2005 Apr 22. [abstract]
4. Wolf-Hirschorn Syndrome, Online Mendelian Inheritance in Man (OMIM)
5. Battaglia A, Carey JC, South ST, et al; Wolf-Hirschhorn Syndrome [abstract]

Internet and further reading

• Chen H; Wolf-Hirschhorn Syndrome, Medscape, Jun 2009

Acknowledgements