Wolf-Hirschhorn Syndrome

Disease Overview

Summary

Wolf-Hirschhorn syndrome (WHS) is an extremely rare chromosomal disorder caused by a missing piece (partial deletion or monosomy) of the short arm of chromosome 4. Major symptoms may include extremely wide-set eyes (ocular hypertelorism) with a broad or beaked nose, a small head (microcephaly), low-set malformed ears, growth deficiency, heart (cardiac) defects, intellectual disability, and seizures. The symptoms of this syndrome vary from person to person based the size and location of the missing piece of chromosome 4.

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Synonyms

• 4p- syndrome
• Pitt-Rogers-Danks syndrome
• WHS
• monosomy 4p

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Signs & Symptoms

The features of WHS can vary widely between different affected individuals. The most distinctive feature of WHS is the typical facial appearance. Individuals with WHS usually have widening and prominence of the area located at the top of the nose between the eyebrows (the glabella). This is associated with prominent, wide-spaced eyes, arched eyebrows, and a smallness of the lower part of the face, including a short upper lip and smallness of the mouth and jaw. This leads to the bridge of the nose being the focal point of the face.

Findings present in nearly all individuals with WHS include: marked growth problems (both low weight and low height) starting prior to birth and resistant to intervention, intellectual deficits (which are variable, but are often quite marked), low muscle tone (hypotonia), and seizures.

Other common findings include small head (microcephaly); eye differences (turning in or out of the eyes, droopy eyelids, eye malformations); ear differences (small, simple, tags and/or pits); cleft lip and/or palate; abnormalities of the penis, testicles, or vagina; abnormalities of the kidneys; problems with bones; problems with teeth.

Birth defects of the heart are common in individuals with WHS, but are usually simple, such as a hole between the two top chambers of the heart (atrial septal defect or ASD), and able to be corrected with surgery.
Many individuals have an increased number of infections. Some have a true immune deficiency, most commonly a decreased ability to make antibodies.

Feeding problems are extremely common and may be quite severe. The majority of affected individuals require tube feeding at some point in their lives, and many need this lifelong. Some individuals have serious problems with their gut, including malrotation (a birth defect of the gut which increases the risk that it may twist and cut off blood supply), very poor movement of the gut (dysmotility), or poor ability of the gut to absorb nutrients.

The intellectual and developmental problems are variable but are quite significant in most people with WHS. Individuals struggle with all areas including: communication, gross motor skills, fine motor skills, and quantitative reasoning. Bowel and bladder control is typically delayed into late childhood and is sometimes not achieved. Most individuals require facilitation of communication with speaking devices or sign language.

Originally, Pitt-Rogers-Danks syndrome (PRDS) was described as a separate disorder from WHS. However, individuals with PRDS were eventually found to also have deletions of the short arm of the fourth chromosome in the same region associated with WHS, so this condition is now felt to be a description of the milder end of WHS.

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Causes

Wolf-Hirschhorn syndrome is an extremely rare chromosomal disorder in which the WHSCR (Wolf Hirschhorn syndrome critical region) on the short arm of chromosome 4 is missing (deleted). In most instances, additional material around the WHSCR is deleted as well.

Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with the 23rd pair made up of the X and Y chromosomes, with XX associated with female sex, and XY associated with male sex. Each chromosome has a short arm designated “p” and a long arm designated “q.” Chromosomes are further sub-divided into numbered bands. For example, “chromosome 4p16.3” (pronounced “four p one-six point three”) refers to band 16.3 on the short arm of chromosome 4. The numbered bands are used to specify the location of the genes found on each chromosome.

Deletion of part of the short arm of chromosome 4 (4p) causes this disorder. It is believed that a portion of band 16.3 on chromosome 4p (4p16.3) is the “critical region” for the disorder, meaning that deletion of this area leads to full expression of Wolf-Hirschhorn syndrome.

In most people, the deletion causing WHS happened extremely early in that individual’s development (possibly in the egg or sperm prior to fertilization) and is not inherited from that person’s parents (this is referred to as spontaneous or de novo). Much less commonly, the disorder is inherited from a parent who has a balanced translocation.

A translocation is an abnormal chromosome made when pieces of two or more chromosomes break off and trade places. If all of the parts of both chromosomes that participated in the swap are present, this is said to be “balanced.” Because a person with a balanced translocation has all the necessary genetic material for normal development, individuals with balanced translocations do not usually have health problems related to their abnormal chromosome. Unfortunately, a balanced translocation can be transmitted to a child in an unbalanced fashion, leading to missing or extra genetic material in a child and causing a chromosome disorder like WHS. Chromosome (cytogenetic) testing can determine if a parent has a balanced translocation.

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Affected populations

WHS is an extremely rare disorder. Studies undertaken about 25 years ago suggested that the disorder occurred in approximately 1 in about 50,000 live births with a female to male ratio of 2:1. More recent studies suggest that the frequency of the disorder is underestimated because of misdiagnosis.

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Disorders with Similar Symptoms

Syndromes involving deletions of other chromosomes may be similar to Wolf- Hirschhorn syndrome. Comparisons may be useful for a differential diagnosis.
Chromosomal disorders that involve extra chromosomes (trisomy) have some similarities (particularly growth failure and marked developmental impacts) to Wolf-Hirschhorn syndrome. (For more information on these disorders, choose “Trisomy,” “Trisomy 13,” and “Trisomy 18” as your search terms in the Rare Disease Database.)

Cri-du-chat syndrome is a congenital chromosomal disorder that involves a partial deletion of chromosome 5. It can also have overlapping features with WHS, particularly including poor growth, small head, feeding problems and intellectual impacts. Persons with this disorder have breathing and airway problems and a high, shrill cry. They have distinctive facial features that are not the same as those seen in WHS.

Down syndrome is a congenital chromosomal disorder involving three copies of chromosome 21. Distinctive facial features (different from those seen in WHS), low muscle tone, small stature, and intellectual disability are major symptoms. Serious birth defects such as heart defects and abnormalities of the GI tract are also common.

Angelman syndrome (AS), is characterized by severe developmental delay, intellectual disability, severe speech impairment, posture and movement problems, microcephaly and seizures. Abnormalities in the q11.2-q13 region of chromosome 15 are associated with AS.

Williams syndrome (WS) is characterized by mild intellectual disability, unique personality characteristics, distinctive facial features, and cardiovascular disease. Kidney problems and digestive issues may occur due to calcium build up in different parts of the body. WS is caused by the deletion of the WSCR (Williams syndrome critical region) in the 11.23 region of the long arm of chromosome 7.

Smith-Lemli-Opitz syndrome (SLOS) is characterized by growth delay, small head, intellectual disability, distinctive facial features, heart defects and under-developed penis and testicles in males.
For more information about these conditions, search for them in the Rare Disease Database.

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Diagnosis

A diagnosis of WHS may be suggested by the characteristic facial appearance, growth failure, developmental delays, and seizures. The diagnosis is confirmed by detection of a deletion of the Wolf-Hirschhorn syndrome critical region (WHSCR) by cytogenetic (chromosome) analysis. Conventional cytogenetic analysis (karyotype) detects less than half of the deletions that cause WHS. Fluorescence in situ hybridization (FISH) using a WHSCR probe has much better detection rate than standard karyotype and will detect most patients. However, the diagnostic test of choice is chromosomal microarray, which detects essentially all deletions of the WHSCR and defines the size of the deletion. Chromosomal microarray can also find other chromosome rearrangements, such as extra pieces of other chromosomes that are seen in many patients with WHS.

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Standard Therapies

Treatment
Because WHS is so variable, treatment and intervention must be tailored to the affected individual’s needs. Patients with a known or suspected diagnosis of WHS should have a comprehensive evaluation by an experienced genetics professional. Most patients will need to be followed by multiple subspecialists. Patients should have a neurology evaluation with evaluation for seizures, detailed cardiology (heart) evaluation, eye exam, hearing exam, kidney evaluation, feeding evaluation, and developmental evaluation as soon as possible after diagnosis. Kidney function must be monitored on an ongoing basis. All patients benefit from comprehensive developmental and rehabilitation support including: feeding therapy, assistive communication, speech, physical therapy, occupational therapy, and school support. Genetic counseling is recommended for families of children with Wolf-Hirschhorn syndrome.

Early intervention is important to make sure that children affected with this syndrome reach their highest potential. Services that may be beneficial include special remedial education, physical therapy, speech therapy, special services and other medical, social and/or vocational services.

Antiseizure medication can be useful for controlling seizures. Surgery may be performed to treat a variety of associated symptoms including congenital heart defects, ocular problems, cleft palate and cleft lip.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS
Battaglia A. Deletion 4p: Wolf-Hirshhorn Syndrome. In: Cassidy SB and Allanson, JE, eds. Management of Genetic Syndromes, 3rd ed. Wiley-Blackwell. Hoboken, NJ; 2010: 249-261.

Hirschhorn K. Wolf-Hirschhorn Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:272.

Jones KL. ed. Smith’s Recognizable Patterns of Human Malformation. 5th ed. W. B. Saunders Co., Philadelphia, PA; 1997:46-47.

Gorlin RJ, Cohen MM Jr, Levin LS. eds. Syndromes of the Head and Neck. 3rd ed. Oxford University Press, London, UK; 1990:38-39.

JOURNAL ARTICLES
Horiguchi A, Koichihara R, Kikuchi K, Nonoyama H, Daida A, Oba D, Hirata Y, Matsuura R, Ohashi H, Hamano SI. Efficacy of antiseizure medications in Wolf-Hirschhorn syndrome. Neuropediatrics. 2023 Oct;54(5):339-343. https://pubmed.ncbi.nlm.nih.gov/37075791/

Carey JC, Lortz A, Mendel A, Battaglia A. Natural history study of adults with Wolf-Hirschhorn syndrome 2: Patient-reported outcomes study. Am J Med Genet A. 2021 Jul;185(7):2065-2069. https://pubmed.ncbi.nlm.nih.gov/33949758/

INTERNET
Battaglia A, Carey JC, South ST. Wolf-Hirschhorn Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. 2002 Apr 29 [Updated 2015 Aug 20]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1183/ Accessed September 30, 2020.

McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Wolf-Hirschhorn Syndrome; Entry Number: 194190. Last Edit Date: 07/17/2017. Available at: https://omim.org/entry/194190 Accessed September 30, 2020.

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Programs & Resources

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