Wolf-Hirschhorn Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY

Excerpt

NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE.

Clinical characteristics: Wolf-Hirschhorn syndrome (WHS) is characterized by typical craniofacial features in infancy consisting of "Greek warrior helmet" appearance of the nose (wide bridge of the nose continuing to the forehead), microcephaly, high anterior hairline with prominent glabella, widely spaced eyes, epicanthus, highly arched eyebrows, short philtrum, downturned corners of the mouth, micrognathia, and poorly formed ears with pits/tags. All affected individuals have prenatal-onset growth deficiency followed by postnatal growth retardation and hypotonia with muscle underdevelopment. Developmental delay/intellectual disability of variable degree is present in all. Seizures occur in 90% to 100% of children with WHS. Other findings include skeletal anomalies (60%-70%), congenital heart defects (~50%), hearing loss (mostly conductive) (>40%), urinary tract malformations (25%), and structural brain abnormalities (33%).

Diagnosis/testing: The diagnosis of WHS is established by the finding of a heterozygous deletion of the Wolf-Hirschhorn syndrome critical region (WHSCR) on chromosome 4p16.3 by chromosomal microarray (CMA), conventional G-banded cytogenetic analysis, or fluorescence in situ hybridization (FISH).

Management: Treatment of manifestations: Treatment includes: rehabilitation, speech/communication therapy and sign language; valproic acid for atypical absence seizures; benzodiazepines for status epilepticus; special feeding techniques, gavage feeding, and/or gastrostomy for feeding difficulties. Standard care is recommended for skeletal anomalies, ophthalmologic abnormalities, congenital heart defects, hearing loss, sleep disturbance, and hepatic adenomas.

Prevention of secondary complications: Antibiotic prophylaxis for vesicoureteral reflux; IVIG infusions or continuous antibiotics for those with antibody deficiencies.

Surveillance: Systematic follow up to monitor rehabilitation and treatment as needed; annual complete blood count and renal function testing; consideration of routine liver ultrasounds.

Agents/circumstances to avoid: Carbamazepine may worsen atypical absence seizures.

Genetic counseling: WHS is caused by deletion of the WHSCR of chromosome 4p16.3 by one of several genetic mechanisms. About 50%-60% of individuals with WHS 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. These unbalanced translocations may be de novo or inherited from a parent with a balanced rearrangement. The remaining have other complex rearrangements leading to a 4p16.3 deletion (e.g., ring 4). Risks to family members depend on the mechanism of origin of the deletion. Prenatal testing is possible for families in which one parent is known to be a carrier of a chromosome rearrangement involving 4p16.3.