What is 4p Deletion Syndrome (Wolf-Hirschhorn Syndrome)? Explained by Doctors
Table of Contents
Introduction
4p Deletion Syndrome (Wolf-Hirschhorn Syndrome, hereinafter WHS) is a rare genetic disorder caused by the deletion of genes at the terminal end of the short arm of chromosome 4.
In this article, we explain the basic knowledge of WHS, diagnostic methods in prenatal testing, symptoms, treatments, and care based on scientific evidence. Please use this as important information when considering prenatal testing.
Basic Knowledge
■ Origin of Name
WHS was first reported in 1961 by the American physicians Hirschhorn and Cooper, and was described in detail in 1965 by Wolf et al.※1
Therefore, it is called "Wolf-Hirschhorn Syndrome (WHS)" after the names of these two physicians.
■ Causes of Onset
The cause of this disorder is the deletion of a region called "4p16.3". This area contains multiple genes involved in various aspects of development and neurological functions.※1
Among them, the loss of the NSD2 gene is believed to be the cause of WHS's characteristic facial features and developmental delay.
In addition, the deletion of the LETM1 gene or surrounding genes (e.g., CPLX1) can trigger epileptic seizures or abnormal electrical activity in the brain. Furthermore, the deletion of the MSX1 gene is considered the cause of dental abnormalities, cleft lip, and cleft palate often observed in patients with WHS.※2
■ Frequency and Inheritance Mode
The prevalence is estimated to be 1 in 20,000 to 50,000 live births, and WHS is known to be more common in females than in males (male-to-female ratio of 1:2).
※3The vast majority of cases (85-90%) are sporadic chromosomal abnormalities (de novo mutations) and are not inherited from parents.※1
■ Prognosis
Although WHS is a rare disorder, it is reported that the mortality rate within the first two years of life reaches approximately 30%.※4 Major causes of death include lower respiratory tract infections, congenital heart disease, multiple congenital anomalies, and sudden unexplained death.
However, cases with a relatively small deletion tend to have milder symptoms.※3
Symptoms and Characteristics: Diverse Clinical Picture Caused by Chromosomal Anomalies
Characteristic Facial Features and Developmental Delays
The most famous external feature of WHS is the facial appearance called the "Greek warrior helmet". This is formed by a combination of a broad, flat nasal bridge, a high nasal root extending to the forehead, and a prominent glabella.※1,4
Other characteristic facial features include:
- ・Microcephaly and micrognathia
- ・Short philtrum and downturned mouth corners
- ・High forehead and widely spaced eyes (hypertelorism)
- ・Low-set, malformed ears
- ・Cleft palate and cleft lip
These facial abnormalities serve as diagnostic clues immediately after birth. In addition, intrauterine growth restriction is observed in 80-90% of cases, and growth failure and hypotonia tend to persist after birth.※1,3
Impact on Neurological and Intellectual Functions
In many WHS cases, intellectual developmental delays, language barriers, and a high frequency of epileptic seizures are observed. Epileptic seizures often onset at 6 to 12 months of age, and are seen in over 90% of patients.※1
The types of seizures mainly include generalized tonic-clonic seizures (approx. 70%), atonic seizures, or focal seizures restricted to certain parts of the body, which can be triggered by fever or infection.※1
Some cases present with status epilepticus, where seizures persist for a long time, and the prognosis tends to be worse when the genetic deletion is large.※1
Other Complications
WHS is known to cause complications across multiple organs, with the following conditions reported.※4
- ・Congenital heart disease (ventricular septal defect, patent ductus arteriosus, etc.)
- ・Renal malformations (renal hypoplasia, bladder exstrophy, etc.)
- ・Immunodeficiency (susceptibility to infections due to IgA or IgG2 deficiency)
- ・Gastrointestinal symptoms (dysphagia, gastroesophageal reflux, etc.)
- ・Skeletal abnormalities (scoliosis, sacral dimple, etc.)
Treatment and Care
■ No Specific Cure, but Multidisciplinary Support is Crucial
There is currently no established treatment that repairs the cause of WHS itself, but supportive therapy aimed at symptom relief is effective for many symptoms. Collaborative team medical care involving pediatric neurology, cardiology, ophthalmology, urology, orthopedics, dentistry, otolaryngology, and genetic counseling is essential.※3
For instance, surgery or drug therapy may be considered for congenital heart disease or renal malformations. Physical therapy is also effective for motor function delays associated with hypotonia. Feeding/swallowing rehabilitation or introduction of a gastrostomy tube is considered to prevent swallowing difficulties and malnutrition.※5
■ Epilepsy Management is a Key Challenge
As mentioned above, epilepsy occurs in over 90% of WHS patients starting from early infancy. Although the frequency and severity of seizures vary widely, status epilepticus can be life-threatening. Therefore, early diagnosis and prompt treatment intervention with antiepileptic drugs are crucial.※1
Summary
WHS is a rare chromosomal disorder, but advances in NIPT technology have increased opportunities for prenatal diagnosis. This syndrome is a condition where early diagnosis and appropriate support can significantly improve the quality of life of patients and their families.
Currently, treatment is mainly symptomatic, but a multidisciplinary support system and family understanding encourage independence in daily life and social participation. It is expected that the spread of accurate information and progress in research will continue to improve the quality of medical and social support surrounding WHS.
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Author
Doctor of Medicine / Physician
Tasuku Hiroshige
Doctor of Medicine, Specialist/Instructor of the Japanese Urological Association, Certified Physician of the Japan Society of Clinical Oncology, Specialist of the Japanese Society of Anti-Aging Medicine, Certified Industrial Physician of the Japan Medical Association, Certified Physician of the Japanese Society for Chemotherapy, Certified Physician of the Japanese Society for Sexually Transmitted Infections, Certificate of da Vinci system Training As a Console Surgeon, etc.
After graduating from Kagoshima University Faculty of Medicine in 2010, he has extensive clinical experience as a urologist. In addition to clinical practice, he actively participates in academic activities such as conference presentations, paper writing, and research grant acquisition. He holds professional qualifications in various fields including urology, cancer treatment, anti-aging medicine, and infectious disease treatment. Utilizing his rich medical knowledge and skills, he provides medical care tailored to each patient.