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The disease has an estimated birth prevalence of 1/20,000 - 50,000. Wolf-Hirschhorn syndrome (WHS) occurs more frequently in females than in males (2:1).

Marked intra-uterine growth retardation and slow, postnatal weight gain are observed. The distinctive facies is characterized by a broad nasal bridge continuing to the forehead (which is visible more clearly before puberty), microcephaly, high forehead with prominent glabella, high-arched eyebrows, hypertelorism, epicanthus, poorly formed ears with pits/tags, short philtrum, downturned mouth, micrognathia, and, in some cases, cleft lip/palate. Skeletal anomalies include kyphosis or scoliosis with malformed vertebral bodies, accessory or fused ribs, clubfeet and split hand. Patients suffer from hypotonia with muscle underdevelopment, possibly causing frequent feeding difficulties and failure to thrive. Developmental delay is severe: most children do not achieve sphincter control, self-feeding or dressing, and less than 50% walk, with or without support. Intellectual disability is moderate to severe, rarely mild. Speech is limited to guttural or disyllabic sounds, although a few patients achieve simple sentences. Seizure onset is frequently observed between the neonatal period and 36 months (in up to 95% of patients); seizure type varies and is often triggered by fever. Status epilepticus occurs in half of patients, and children may develop atypical absences (over 30%). Seizures stop in childhood in approximately half of patients. Most patients have structural central nervous system defects, mainly including thinning of the corpus callosum. Other frequent anomalies include congenital heart defects (50%), ophthalmologic, auditory and dental anomalies. Patients may have recurrent respiratory tract infections and otitis media, due to antibodies deficiency (IgA or IgG2 subclass). Urinary tract malformations have been described, and half of male patients have hypospadias and cryptorchidism.

WHS is due to a deletion in the short arm of chromosome 4 with contribution of genes within a 1.5-1.6 Mb region in the ~0.4-1.9 Mb terminal of 4p16.3. Deletions greater than 3-5 Mb seem to be associated with higher risk of heart defects and cleft palate.

Diagnosis is based on physical examination and confirmed by molecular genetics or cytogenetic analysis. Fluorescence in situ hybridization (FISH), and genome-wide chromosomal microarray analysis (CMA) being the methods of choice. Electroencephalographic (EEG) investigations show typical findings in 90% of patients.

Differential diagnosis includes many syndromes displaying growth failure, intellectual disability and/or facial dysmorphism such as Seckel, CHARGE, Smith-Lemli-Opitz, Opitz G/BBB, Williams, Rett, Angelman and Smith-Magenis syndromes.

Antenatal testing is feasible when a 4p16.3 chromosome rearrangement is already identified in a family member.

Most cases are sporadic, but an unbalanced translocation may be inherited from a parent with a balanced rearrangement.

Treatment is symptomatic and requires multidisciplinary management including diverse rehabilitation programs, appropriate seizure treatment (phenobarbital; valproic acid with or without ethosuccimide; levetiracetam) and feeding therapies.

WHS patients survive into adult life. Most individuals require close to total care; about 30% are partly independent requiring supervision on daily routines. More than 65% enjoy overall good health.