Wolf-Hirschhorn Syndrome

Updated: Feb 15, 2015
  • Author: Harold Chen, MD, MS, FAAP, FACMG; Chief Editor: Luis O Rohena, MD  more...
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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 intellectual disability, seizures, distinct facial appearance, and midline closure defects. (See the images below.)

A child with Wolf-Hirschhorn syndrome. Note the ch A child with Wolf-Hirschhorn syndrome. Note the characteristic dysmorphic facial features, including prominent glabella, hypertelorism, beaked nose, and frontal bossing, collectively described as "Greek warrior helmet" facies.
A girl with Wolf-Hirschhorn syndrome showing chara A girl with Wolf-Hirschhorn syndrome showing characteristic features of the condition.


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. Other changes in chromosome 4 can involve a ring structure or translocation. (See the image below.)

G-banded karyotype showing deletion of 4p, derived G-banded karyotype showing deletion of 4p, derived from the mother, with balanced translocation (4p;8p).

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.

The genotype-phenotype correlation is as follows [4] :

  • Clinically, the minimal diagnostic criteria for Wolf-Hirschhorn syndrome (ie, ‘‘core’’ phenotype) consists of typical facial appearance, intellectual disability, growth delay, and seizures (or EEG anomalies). (EEG abnormalities are present in 90% of patients. [5] )
  • Three different categories of the Wolf-Hirschhorn syndrome phenotype are defined and generally correlate with the extent of the 4p deletion. The first is composed of a small deletion (≤3.5 Mb) that is usually associated with a mild phenotype, lacking major malformations. This category is likely under-diagnosed. The second and far more frequent category is identified by large deletions that average 5-18 Mb and cause the widely recognizable Wolf-Hirschhorn syndrome phenotype. The third clinical category results from a very large deletion that exceeds 22–25 Mb, causing a severe phenotype that can hardly be defined as typical Wolf-Hirschhorn syndrome.
  • Factors involved in prediction of prognosis include the extent of the deletion, the occurrence of complex chromosome anomalies, and the severity of seizures.
  • The core phenotype maps within the terminal 1.9 Mb region of chromosome 4p. Therefore, WHSCR-2 should be considered the critical region for this condition.
  • Pathogenesis of Wolf-Hirschhorn syndrome is multigenic.



United States

  • The frequency is estimated to be 1 case per 50,000 births to 1 case per 20,000 births. [6, 7]


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  • 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.


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  • Wolf-Hirschhorn syndrome has no ethnic predilection.


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


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