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 possible in a newborn or young infant. The patients have a wide distance between the eyes, a broad nasal root, arched eyebrows, outwards and downward sloping eyes, and strabismus (exotropia); colobomas, cleft lip and cleft palate, ear dysplasia, heart and kidney malformations, and hypospadias (in boys) are common. 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 classic presentation of WHS, and very large deletions (22-25 Mb) are associated with a very severe presentation that bears no similarity to WHS. In classical WHS, the deletions are often detectable by conventional chromosomal analysis. Interstitial deletions with preserved subtelomeric regions also occur. Between 85 and 90% of the deletions are new, and the remainder are due to structural chromosomal rearrangements which may be present in the parents in a balanced form. The frequency is estimated at 1:20,000 to 1:50,000.
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