Wolf-Hirschhorn Syndrome

A developmental disorder characterized by typical craniofacial features, prenatal and postnatal growth impairment, intellectual disability, severe delayed psychomotor development, seizures, and hypotonia.

Epidemiology

The disease has an estimated prevalence of 1:50,000 births.

Clinical description

Wolf-Hirschhorn syndrome (WHS) occurs more frequently in females than in males (2:1). Marked intra-uterine growth retardation and ongoing postnatal slow weight gain are observed. Patients have a distinctive facies characterized by the ''Greek warrior helmet'' appearance (broad nasal bridge continuing to the forehead), visible more clearly before puberty, microcephaly, high forehead with prominent glabella, hypertelorism, epicanthus, highly arched eyebrows, short filtrum, downturned mouth, micrognathia, poorly formed ears with pits/tags 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 may lead to failure to thrive. Developmental delay is severe: most patients do not achieve sphincter control, self-feeding or dressing, and less than 50% walk, with or without support, between 2 and 12 years of age. Intellectual deficit is moderate to severe, rarely mild. Speech is limited to guttural or disyllabic sounds, except in a few patients achieving formulation of simple sentences. Various types of seizures are observed in up to 95%, onset is between the neonatal period and 36 months and the triggering factor is often fever. Status epilepticus occurs in half of patients. Over 30% of children develop atypical absences by age 1 to 6. In approximately 50%, seizures stop in childhood. Most patients have structural central nervous system defects, mainly including thinning of the corpus callosum. Congenital heart defects, and mostly atrial septal defect, are seen in 50%. Ophtalmologic, auditory and dental anomalies are also frequently observed. Patients may have recurrent respiratory tract infections and otitis media, due to antibodies deficiency (Ig1 or IgG2 subclass). Urinary tract malformations have been described, and half of male patients have hypospadias and cryptorchidism.

Etiology

WHS is due to a deletion in the short arm of the 4th chromosome (4p16.3 region), including at least part of the LETM1 and WHSC1 genes. Deletions greater than 3 Mb seem to be associated with higher risk of heart defects and cleft palate.

Diagnostic methods

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

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 (see these terms).

Antenatal diagnosis

Antenatal testing is feasible when a 4p16.3 chromosome rearrangement is already identified in one parent.

Genetic counseling

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

Management and treatment

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

Prognosis

WHS patients survive into adult life.