Wolf-Hirschhorn Syndrome

Synonyms and related keywords: chromosome 4p deletion syndrome, 4p- syndrome, monosomy 4p syndrome, Wolf syndrome, Pitt-Rogers-Danks syndrome, Wolf-Hirschhorn syndrome, mental retardation, seizures, distinct facial appearance, midline closure defects, congenital heart defect, marked growth failure, contracture of hands, contracture of wrists, contracture of feet, hypotrophic placenta, microcephaly, congenital hypotonia, hypoplasia of the cerebellum, agenesis of corpus callosum, microgyria, migration defects, hydrocephalus, frontal bossing, high frontal hairline, hemangioma, prominent glabella, hypertelorism, broad beaked nose, epicanthal folds, strabismus, coloboma, proptosis, ectopic pupils, exotropia, ptosis, microphthalmia, megalocornea, sclerocornea, hypoplastic anterior chamber, congenital nystagmus, Reiger anomaly, Reiger’s anomaly, hypodontia, chronic otitis media, atrial septal defect, ventricular septal defect, lung hypoplasia, diastasis recti, umbilical hernia, inguinal hernia, accessory spleen, hypoplastic kidney, cysticdysplastic kidneys, unilateral renal agenesis, cryptorchidism, hypospadias, hypoplastic müllerian derivatives, talipes equinovarus, cleft palate

Background

Cooper and Hirschhorn first documented Wolf-Hirschhorn syndrome in 1961.¹ They described a child with midline fusion defects, and subsequent cytogenetic studies revealed a chromosomal deletion of the short arm of chromosome 4. In 1965, back-to-back publications in Humangenetik by Hirschhorn et al and Wolf et al brought the disease to the attention of geneticists and other medical professionals.^{2, 3} Numerous cases were subsequently published. Clinical features include mental retardation, seizures, distinct facial appearance, and midline closure defects.

Pathophysiology

Wolf-Hirschhorn syndrome results from the deletion of the distal short arm of chromosome 4. Deletion of the terminal band (4p16.3) is essential for full expression of the phenotype.

A large deletion several megabases (Mb) in length, easily detected using conventional chromosome analysis, is usually associated with severe phenotypic expression, including multiple malformations. However, a microdeletion of band 4p16.3, detected only by molecular probes, is usually associated with a milder phenotype without malformations.

Most phenotypic manifestations in this syndrome reflect a contiguous gene syndrome, leading to a phenotypic map of chromosome arm 4p. However, similar genetic rearrangements in this syndrome may determine variable phenotypic effects, most likely as a consequence of allelic variation in the homologous 4p region. The former Pitt-Rogers-Danks syndromes, caused by overlapping 4p deletions, are now considered to be a part of Wolf-Hirschhorn syndrome.

Frequency

United States

The incidence rate is estimated at 1 in 50,000 births.

Mortality/Morbidity

Mortality rate is estimated at 34% in the first 2 years of life. However, because many affected children die before the anomaly is diagnosed or suspected, the mortality rate is underestimated. The usual cause of death is a heart defect, aspiration pneumonia, infection, or seizure.

• Prenatal mortality rate of Wolf-Hirschhorn syndrome is not significantly augmented because 4p deletions are not reported as an increase in spontaneous abortions.
• Associated adulthood morbidity includes congenital heart defect; marked growth failure; contracture of hands, wrists, and feet; poor development of secondary sexual characteristics; and severe growth and intellectual impairment.

Race

Wolf-Hirschhorn syndrome has no ethnic predilection.

Sex

Wolf-Hirschhorn syndrome is more common in females than in males, with a male-to-female ratio of 1:2.

Age

Usually, the condition is detected in the newborn period because of dysmorphic features.

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