What Is Wolf-Hirschhorn Syndrome

  • Dora Freitas Bachelor's degree, BSc Human Sciences, University College London

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Wolf-Hirschhorn syndrome (WHS) is a rare genetic disorder caused by a deletion (missing piece) in chromosome 4. This deletion will cause symptoms such as delayed growth, facial dysmorphism, intellectual disabilities, decreased muscle tone and seizures. The disease can also cause reduced hearing, heart defects, and urinary tract or brain malformations. WHS’s first symptoms usually appear in embryos during pregnancy or as a newborn and continue throughout life. The condition was first described in 1965 by researchers Wolf and Hirschhorn.1 The techniques available at that time only allowed the researchers to understand that the disease was caused by a severe deletion of a portion of chromosome 4. Nowadays, advances in genetic testing and diagnosis allow for a better understanding of the genetic basis of WHS, and research has been able to identify the specific genes within chromosome 4 that are responsible for the features of WHS.

WHS is estimated to affect around 1 in 20,000 births and predominantly affects females (2:1 ratio). Even if it is a rare disorder this article will help parents or carers of children who are affected by WHS to know more about the disorder. We will discuss the cause of WHS, the common symptoms, the diagnosis and finally, the ongoing research on WHS.2

Causes of the wolf-hirschhorn syndrome

Deletion in chromosome 4

Wolf-Hirschhorn syndrome is mainly caused by a deletion of the distal short arm of chromosome 4 (4p 16.3); however, sometimes it can be due to other chromosomal transformations such as translocation. Translocation is the phenomenon where a chromosome breaks and the fragmented parts re-attach themselves to new chromosomes. A translocation can either be balanced or unbalanced. If it is balanced, there is an equivalent exchange of genetic material between the two chromosomes, whereas when it is unbalanced, a chromosome can end up with extra or missing genetic material. These phenomena can either occur randomly or be inherited by a healthy parent and can lead to WHS.2

Variability in deletion size

The size of the deletion on chromosome 4 differs between people affected by WHS and can affect the intensity of the symptoms. Some people will have a small deletion with under 3.5 megabases (Mb), leading to milder symptoms. The large deletions are the most frequent and correspond to 5 to 18 Mb and usually result in more noticeable developmental delay, hypotonia, neurodevelopmental impairment, and malformations. Finally, the large deletions are bigger than 22 Mb and affected people have the most severe symptoms.2,3

Wolf-hirschhorn syndrome critical region

The Wolf-Hirschhorn Syndrome Critical Region is the genetic region situated next to the telomeres, which are at the far end of a chromosome which usually contains the genes present in people with WHS. For example, genes WHSC1 and WHSC2 are linked with WHS, and genes LETM1, PIGG and CPLX1 (complexin-1) contribute to seizures in WHS. The main objective of determining a critical region is to pinpoint the key genes that cause the characteristics of WHS, including seizures and facial abnormalities.2,3

Signs and symptoms

  • Seizures
  • Low weight
  • Hypotonia (80% with WHS have decreased muscle tone)
  • Intellectual disabilities
  • Languages disorders
  • Craniofacial dysmorphism (“Greek warrior helmet appearance”)
  • Widely spaced eyes
  • Highly arched eyebrows
  • Cleft lip and palate (present in one-third of those with WHS)
  • Skeletal anomalies
  • Heart defects
  • Eye defects
  • Hearing loss
  • Genitourinary tract defects4

Seizures are a common symptom that affects approximately 90% of people with WHS and usually start before the age of 3. Although all WHS patients can be affected by seizures, it is particularly prevalent in patients that have a deletion greater than 21 Mb.

Even if high deletion can cause strong intellectual disabilities, studies show that nowadays, one-third of WHS patients have high socialization communication skills and, therefore, could be defined as only having mild or moderate cognitive delays.5


One way to identify WHS during pregnancy is to note if fetal movement is lower, as it is lower in most cases of WHS. Once the baby is born, it often has a lower birth weight.6 However, to officially diagnose the patient, a clinical examination and a genetic analysis are needed. The different methods used to detect genetic abnormalities are as follows:

  • The Karyotype will detect deletions of over 5 Mb

However, to detect microdeletions, more precise genetics analysis methods are needed:

  • Standard chromosomal analysis can detect about 50–60% of chromosomal deletion
  • The Fluorescent in Situ Hybridization (FISH) will detect more than 95% of deletions
  • Chromosomal Microarray (CMA): Detects all known deletions of the WHSCR and will be able to determine if the deletion is pure or part of a complex rearrangement
  • Multiplex Ligation-dependent Probe Amplification (MLPA): A high-throughput technique used for gene dosage analysis. It can be used to detect microdeletions, especially when combined with specific kits for microdeletion screening and confirmation2

To proceed to a Chromosomal Microarray, patient DNA is collected, labelled with fluorescent tags, and it is fragmented into smaller parts. Then, the fluorescence patterns of the patient's DNA are compared to a healthy sample, and CMA can detect if there is a deletion.

Management and treatment

There are no cures for WHS as it is a genetic condition resulting from a chromosomal abnormality. To manage WHS, there is a need for an interdisciplinary approach as the patient will need to consult with paediatricians, geneticists, speech therapists, physical therapists and an orthopaedic.3

Most children with WHS have prenatal growth deficiency. Once they are born and throughout their lives, they will have difficulty gaining weight and height even if they consume sufficient calories and protein. This is due to factors such as difficulty in swallowing and sucking, oral facial clefts, or acid reflux. In these cases, one of the treatments used is a Haberman feeder. A Haberman feeder is a feeding bottle that does not require active suction by the child, and it is, therefore, very useful for WHS patients. Other treatments, such as reflux medications and gastrostomy tubes, can help in gaining weight, but most WHS patients will remain underweight.7

To manage seizures, they are specific drugs given to patients with WHS. Drugs such as clobazam, levetiracetam, and lamotrigine are the most used for WHS patients as they are the most effective antiepileptic drugs in the case of WHS. Clobazam acts on the GABA neurotransmitters, which will help reduce abnormal electrical activity. Levetiracetam acts on calcium channels and stabilizes the excitement of neurons. Finally, Lamotrigine acts on neurotransmitters to reduce neuronal firing.8

Craniofacial features are an important characteristic of WHS and to monitor any changes in those features a tool called cephalometric analysis is used. Cephalometric analysis is a significant tool for assessing growth patterns in craniofacial features. It enables the tracking of changes over time and can be beneficial for orthodontic treatment planning. Cephalometric analysis proves particularly valuable because changes in craniofacial features play a crucial role in finding appropriate treatment strategies and monitoring the disorder throughout time. Cephalometric measurements, including parameters such as mandible growth direction, mandible shape and dental condition, provide quantifiable data that can help  manage the craniofacial aspects of WHS.9

New emerging therapies

Emerging treatments like gene therapy and gene editing methods such as CRISPR-Cas9 show potential for addressing genetic disorders like WHS. Although these approaches are in their early developmental phases, they could potentially become viable treatments for WHS in the future.10 


Wolf-Hirschhorn syndrome is a rare genetic disorder characterized by a deletion in chromosome 4. It leads to symptoms such as delayed growth, facial dysmorphism, intellectual disabilities, low muscle tone, and seizures. Other possible effects include hearing loss, heart defects, and urinary tract or brain malformations.

The primary cause of WHS is a deletion in the distal short arm of chromosome 4 (4p 16.3), which can result from chromosomal transformations like translocations. The size of the deletion varies among patients, influencing the severity of their symptoms.

The Wolf-Hirschhorn Syndrome Critical Region, located near the chromosome's telomere, typically contains genes associated with WHS. Understanding this critical region helps identify the key genes responsible for various WHS features, including seizures and facial abnormalities.

Common WHS symptoms include seizures (affecting around 90% of patients), low weight, hypotonia (reduced muscle tone in 80% of individuals), intellectual disabilities, language disorders, craniofacial dysmorphism, eye and heart defects and hearing loss.

Diagnosing WHS involves clinical examination and genetic analysis. Various methods, such as karyotyping, chromosomal analysis, Fluorescent in Situ Hybridization (FISH), Chromosomal Microarray (CMA), and Multiplex Ligation-dependent Probe Amplification (MLPA), help detect genetic abnormalities.

While there is no cure for WHS, a multidisciplinary approach involving paediatricians, geneticists, therapists, and orthopaedic specialists helps manage the condition. Treatments may include specialized feeders, reflux medications, and gastrostomy tubes to help with low weight.

Emerging therapies, such as gene therapy and gene editing (e.g., CRISPR-Cas9), hold potential for addressing WHS and other genetic disorders. While these approaches are in the early development stages, they offer hope for future treatments.


  1. Nevado J, Ho KS, Zollino M, Blanco R, Cobaleda C, Golzio C, et al. International meeting on Wolf‐Hirschhorn syndrome: Update on the nosology and new insights on the pathogenic mechanisms for seizures and growth delay. American J of Med Genetics Pt A. 2020 [cited 2023 Sep 20]; 182(1):257–67. Available from: https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.61406.
  2. Gavril E-C, Luca AC, Curpan A-S, Popescu R, Resmerita I, Panzaru MC, et al. Wolf-Hirschhorn Syndrome: Clinical and Genetic Study of 7 New Cases, and Mini Review. Children]. 2021 [cited 2023 Sep 20]; 8(9):751. Available from: https://www.mdpi.com/2227-9067/8/9/751.
  3. National Center for Advancing Translational Sciences . Wolf-Hirschhorn syndrome [Internet]. [cited 2023 sep 20]]. Available from: https://rarediseases.info.nih.gov/diseases/7896/wolf-hirschhorn-syndrome.
  4. Tezcan B, Bredaki FE. Prenatal Diagnosis of Rare Familial Unbalanced Translocation of Chromosomes 7 and 12. Case Reports in Obstetrics and Gynecology [Internet]. 2015 [cited 2023 Sep 20]; 2015:1–4. Available from: http://www.hindawi.com/journals/criog/2015/905946/.
  5. Berrocoso S, Amayra I, Lázaro E, Martínez O, López-Paz JF, García M, et al. Coping with Wolf-Hirschhorn syndrome: quality of life and psychosocial features of family carers. Orphanet J Rare Dis. 2020 [cited 2023 Sep 20]; 15(1):293. Available from: https://ojrd.biomedcentral.com/articles/10.1186/s13023-020-01476-8.
  6. Battaglia A, Carey JC, South ST. Wolf–Hirschhorn syndrome: A review and update. American J of Med Genetics Pt C [Internet]. 2015 [cited 2023 Sep 19]; 169(3):216–23. Available from: https://onlinelibrary.wiley.com/doi/10.1002/ajmg.c.31449.
  7. Devi Es, Sai Sankar A, Manoj Kumar M, Sujatha B. Maiden morsel - feeding in cleft lip and palate infants. J Int Soc Prevent Communit Dent [Internet]. 2012 [cited 2023 Sep 19]; 2(2):31. Available from: https://journals.lww.com/10.4103/2231-0762.109350.
  8. Ho KS, Markham LM, Twede H, Lortz A, Olson LM, Sheng X, et al. A survey of antiepileptic drug responses identifies drugs with potential efficacy for seizure control in Wolf–Hirschhorn syndrome. Epilepsy & Behavior. 2018 [cited 2023 Sep 20]; 81:55–61. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1525505017308685.
  9. Popescu DE, Marian D, Zeleniuc M, Samoila Ch, Belengeanu V. Features of the Wolf-Hirschhorn Syndrome (WHS) from Infant to Young Teenager. Balkan Journal of Medical Genetics. 2023 [cited 2023 Sep 20]; 26(1):75–82. Available from: https://www.sciendo.com/article/10.2478/bjmg-2023-0006.
  10. Yu C, Yao X, Zhao L, Wang P, Zhang Q, Zhao C, et al. Wolf–Hirschhorn Syndrome Candidate 1 ( whsc1 ) Functions as a Tumor Suppressor by Governing Cell Differentiation. Neoplasia [Internet]. 2017 [cited 2023 Sep 25]; 19(8):606–16. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1476558617300155.

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Dora Freitas

Bachelor's degree, BSc Human Sciences, University College London

Dora is a dedicated human scientist specializing in molecular cell biology and global health and development. Her academic journey at University College London and National University Singapore has ignited her passion for public health and the democratization of scientific knowledge. With experience in medical writing, data analysis, and laboratory work, she's committed to bridging the gap between science and the public.

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