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Wolf–Hirschhorn syndrome

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Wolf–Hirschhorn syndrome
Other namesChromosome deletion Dillan 4p syndrome, Pitt–Rogers–Danks syndrome (PRDS), Pitt syndrome[1][2]
Young girl displaying characteristic facial features of Wolf–Hirschhorn syndrome
SpecialtyMedical genetics Edit this on Wikidata

Wolf–Hirschhorn syndrome (WHS) is a chromosomal deletion syndrome resulting from a partial deletion on the short arm of chromosome 4 [del(4)(p16.3)].[3] Features include a distinct craniofacial phenotype and intellectual disability.

Signs and symptoms[edit]

The most common characteristics include a distinct craniofacial phenotype (microcephaly, micrognathia, short philtrum, prominent glabella, ocular hypertelorism, dysplastic ears and periauricular tags), growth restriction, intellectual disability, muscle hypotonia, seizures, and congenital heart defects. [4]

Less common characteristics include hypospadias, colobomata of the iris, renal anomalies, and deafness.[5] Antibody deficiencies are also common, including common variable immunodeficiency and IgA deficiency. T-cell immunity is normal.[6]


Wolf–Hirschhorn syndrome is a microdeletion syndrome caused by a deletion within HSA band 4p16.3 of the short arm of chromosome 4, particularly in the region of WHSCR1 and WHSCR2.[7] The phenotypic characteristics of WHS are thought to be caused by the haploinsufficiency of the genes Wolf-Hirschhorn syndrome candidate 1 (WHSC1), which is associated with craniofacial features and growth delay, and Homo Sapiens leucine zipper-EF-hand containing transmembrane protein 1 (LETM1), which is associated with seizures.[8]

About 87% of cases represent a de novo deletion, while about 13% are inherited from a parent with a chromosome translocation.[4] In the cases of familial transmission, there is a 2 to 1 excess of maternal transmission. Of the de novo cases, 80% are paternally derived.[citation needed]

A more uncommon cause for WHS is the formation of a ring chromosome. A ring chromosome can form when a chromosome breaks apart and forms a circular structure to fuse together. That process may initiate gene loss towards the ends of the chromosome.[9]

Severity of symptoms and expressed phenotype differ based on the amount of genetic material deleted. The critical region for determining the phenotype is at 4p16.3 and can often be detected through genetic testing and fluorescence in situ hybridization (FISH). Genetic testing and genetic counseling is offered to affected families.[citation needed]


Initial diagnosis is based on a distinct craniofacial phenotype after birth.[4] Diagnosis of WHS is confirmed by the detection of a deletion in the WHSCR. Chromosomal microarray and Cytogenetic analysis.D4S96 or D4Z1 chromosome band 4p16.3–specific probe (Wolf-Hirschhorn region, Vysis, Inc) is available for FISH study.[4]


The symptoms can vary from person to person, so the patient should receive different types of evaluations including a neurological, cardiac, and renal evaluation. Eye and hearing exams are essential, as well as a feeding and developmental evaluation.[10] Clinicians treat WHS by addressing the symptoms experienced by the individual. Some treatment methods are surgery for growth abnormalities, educational programs that can help with cognition, physical therapy for muscle building, and medication for seizures.[11]


The minimum birth incidence has been estimated as 1 in 50,000.[4] For unknown reasons, WHS occurs twice as often in females than in males.[12]


Wolf–Hirschhorn syndrome was first described in 1961 by the Austrian-born American pediatrician Kurt Hirschhorn and his colleagues.[13]

Thereafter, the syndrome gained worldwide attention after publications by the German geneticist Ulrich Wolf and his co-workers, specifically their articles in the German scientific magazine Humangenetik.[13][14]


  1. ^ Online Mendelian Inheritance in Man (OMIM): Wolf-Hirschhorn syndrome - 194190
  2. ^ Rapini RP, Bolognia JL, Jorizzo JL (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. pp. 892, 894. ISBN 978-1-4160-2999-1.
  3. ^ Dufke A, Seidel J, Schöning M, Döbler-Neumann M, Kelbova C, Liehr T, Beensen V, Backsch C, Klein-Vogler U, Enders H (2000). "Microdeletion 4p16.3 in three unrelated patients with Wolf-Hirschhorn syndrome". Cytogenetics and Cell Genetics. 91 (1–4): 81–4. doi:10.1159/000056823 (inactive 2024-07-15). PMID 11173835. S2CID 19641395.{{cite journal}}: CS1 maint: DOI inactive as of July 2024 (link)
  4. ^ a b c d e Paradowska-Stolarz AM (2014). "Wolf-Hirschhorn syndrome (WHS) - literature review on the features of the syndrome". Adv Clin Exp Med. 23 (3): 485–9. doi:10.17219/acem/24111. PMID 24979523.
  5. ^ Wieczorek D (September 2003). "Wolf-Hirschhorn syndrome" (PDF). Orphanet encyclopedia. Archived from the original (PDF) on 2021-03-09. Retrieved 2004-11-13.
  6. ^ Hanley-Lopez J, Estabrooks LL, Stiehm R (July 1998). "Antibody deficiency in Wolf-Hirschhorn syndrome". The Journal of Pediatrics. 133 (1): 141–3. doi:10.1016/S0022-3476(98)70194-5. PMID 9672528.
  7. ^ Rauch A, Schellmoser S, Kraus C, Dörr HG, Trautmann U, Altherr MR, Pfeiffer RA, Reis A (April 2001). "First known microdeletion within the Wolf-Hirschhorn syndrome critical region refines genotype-phenotype correlation". American Journal of Medical Genetics. 99 (4): 338–42. doi:10.1002/ajmg.1203. PMID 11252005.
  8. ^ Mbuyi-Musanzayi, Sébastien; Lumaka, Aimé; Kasole, Toni; Ilunga, Erick; Asani, Bienvenu; Tshilobo, Prosper; Muenze, Prosper; Reychler, Hervé; Katombe, François; Devriendt, Koenraad (September 2017). "Wolf-Hirschhorn Syndrome: Clinical and Genetic Data from a First Case Diagnosed in Central Africa". Journal of Pediatric Genetics. 06 (3): 186–190. doi:10.1055/s-0037-1599194. PMC 5548528. PMID 28794913.
  9. ^ "Wolf-Hirschhorn syndrome: MedlinePlus Genetics". medlineplus.gov. Retrieved 2023-10-10.
  10. ^ "Wolf-Hirschhorn Syndrome - Symptoms, Causes, Treatment | NORD". rarediseases.org. Retrieved 2023-10-10.
  11. ^ "Wolf-Hirschhorn Syndrome: Symptoms & Causes". Cleveland Clinic. Retrieved 2023-10-10.
  12. ^ "Wolf-Hirschhorn syndrome: MedlinePlus Genetics". medlineplus.gov. Retrieved 2023-10-10.
  13. ^ a b Hirschhorn K, Cooper HL, Firschein IL (1961). "Deletion of short arms of chromosome 4-5 in a child with defects of midline fusion". Humangenetik. 1 (5): 479–82. doi:10.1007/bf00279124. PMID 5895684. S2CID 32805973.
  14. ^ Wolf U, Reinwein H, Porsch R, Schröter R, Baitsch H (1965). "[Deficiency on the short arms of a chromosome No. 4]". Humangenetik (in German). 1 (5): 397–413. PMID 5868696.

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