Wolf-Hirschhorn syndrome (WHS) is characterized by a combination of distinctive external features, congenital malformations, severe developmental delay and short stature. In many cases, a visual diagnosis is already possible in the newborn or young infant. The patients have a wide distance between the eyes, a broad nasal root, high arched eyebrows, outwardly downward running eyelid axes, strabismus divergens, often iris colobomas and LKG clefts, auricular dysplasia, heart and kidney malformations, hypospadias (in boys). Approximately 80% of patients have seizures. WHS is caused by deletions of different sizes of the terminal short arm of chromosome 4 (4p16.3). Smaller deletions (up to 3.5 Mb) are associated with a milder presentation without malformations, medium deletions (5 to 18 Mb) are associated with the “classic” WHS, and very large deletions (22-25 Mb) are associated with a very severe presentation with no similarity to the WHS. In classical WHS, the deletions are often detectable by conventional chromosomal analysis. Interstitial deletions with preserved subtelomeric regions also occur. 85 to 90% of the deletions are new, the remainder are due to structural chromosomal rearrangements which may already be present in the parents in balanced form. The frequency is estimated at 1:20,000 to 1:50,000.
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