Sindrome di Wolf-Hirschhorn

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

Epidemiologia

• The incidence is estimated at 1 in 50,000 births.²

• Female-to-male ratio is 2:1.

Genetica

WHS occurs due to partial deletion of the short arm of chromosome 4 (4p-).³About 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.⁴These 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.

Presentazione⁵⁶

• Severe growth restriction, microcephaly, hydrocephalus, corpus callosum agenesis.

• Severe general learning disability, 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, cardiac septal defects).

• Hypoplasia of the kidneys and genital tract. Diaphragmatic hernia with secondary lung hypoplasia.

• Immunodeficiency.

Diagnosi differenziale

• Similar multiple congenital anomalies and intellectual developmental disorders, including proximal 4p syndrome and Seckel's syndrome.

Indagini

• Diagnosi prenatale:
  

  • Anomaly ultrasound scan will suggest distinct physical characteristics and should be followed by karyotyping.⁷

  • 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 - eg, agenesis of the corpus callosum and enlarged ventricles.

Gestione

• 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.

Prognosi

• 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.

Prevenzione

Consulenza genetica valuterà il rischio per i membri della famiglia, basandosi sul meccanismo di origine della delezione. Il test prenatale è possibile quando uno dei genitori è noto per essere portatore della condizione.⁶