Wolf-Hirschhorn syndrome

**Genetics / Pathophysiology** - Caused by a terminal or interstitial deletion of 4p16.3 (46,XX or XY, del(4p)). It is a contiguous gene deletion syndrome. - About 85% of cases are de novo. Roughly 10-15% result from an unbalanced translocation inherited from a parent carrying a balanced translocation, so parental karyotype or FISH is worth checking for recurrence risk. - The deleted critical region includes WHSC1 (NSD2), which is linked to growth delay and craniofacial features, and LETM1, which is linked to seizures. Deletion size correlates with severity. - Females are affected more often than males (about 2:1).

**Clinical features** - **Craniofacial ("Greek warrior helmet" appearance):** broad or beaked nasal bridge continuing to the forehead, microcephaly, high forehead, prominent glabella, hypertelorism, a short philtrum, downturned mouth, and micrognathia. Cleft lip and/or palate can occur. - **Growth:** prenatal and postnatal growth restriction (IUGR, failure to thrive, short stature). - **Neurologic:** severe intellectual disability, global developmental delay, hypotonia, and seizures. Seizures occur in over 90% of patients, often febrile and starting in infancy, and may progress to status epilepticus. - **Other:** congenital heart defects (ASD is most common), hypospadias or cryptorchidism, renal anomalies, coloboma and other eye defects, hearing loss, and immune deficiency with recurrent infections (e.g., IgA or IgG subclass deficiency).

**Diagnosis** - Chromosomal microarray is the first-line test, and FISH for 4p16.3 can also be used. Standard karyotype may miss small deletions.

**Management** - Supportive and multidisciplinary: seizure control, feeding support, cardiac and renal evaluation, hearing and vision screening, and early intervention and therapies.

**High-yield board associations** - Wolf-Hirschhorn = 4p deletion ("Wolf" has a W, and W looks like a "4" shape is a common memory aid; "warrior helmet" is the key phrase). - Compare with similar deletion syndromes that the USMLE tests: - Cri-du-chat: 5p deletion (high-pitched cat-like cry, microcephaly, VSD). - Williams: 7q11.23 deletion (elfin facies, supravalvular aortic stenosis, hypercalcemia). - DiGeorge (22q11.2): CATCH-22. - Prader-Willi and Angelman: 15q11-q13 deletion. - The vignette is typically an infant with microcephaly, hypotonia, seizures, growth failure, and a characteristic facial appearance.