What is Wolf-Hirschhorn syndrome?

What is Wolf-Hirschhorn syndrome?

Overview of the disease

Wolf-Hirschhorn syndrome is a rare chromosomal disorder caused by a deletion in the distal part of the short arm of chromosome 4 (including 4p16). It is also known as 4p deletion syndrome or 4p-syndrome WHS. The size of the deletion varies among individuals, but larger deletions tend to cause more severe developmental delays and physical disabilities. Commonly deleted genes include NSD2, LETM1, and MSX1. The specific roles of these genes are not yet fully understood, but they are known to play crucial roles in development. Deletion of the NSD2 gene is associated with characteristic facial features and developmental delays. Deletion of the LETM1 gene is thought to be related to seizures and other abnormal electrical activity. Deletion of the MSX1 gene is implicated in abnormalities in tooth development as well as in cleft lip and palate. Currently, scientists are investigating additional genes located at the terminal end of the short arm of chromosome 4.

Frequency of the condition

Wolf-Hirschhorn syndrome is considered a rare disease, with an estimated frequency of 1 in 50,000 individuals. It is more prevalent in females than in males, with a ratio of approximately 1:2.

Genetic inheritance

In 85-90% of cases, Wolf-Hirschhorn syndrome is not inherited genetically. This is because the deletion of the chromosome occurs randomly during the formation of reproductive cells or early embryo development. While more complex chromosome rearrangements can also occur, in cases without a family history of Wolf-Hirschhorn syndrome, these changes are typically random. Some individuals with Wolf-Hirschhorn syndrome have a ring chromosome. A ring chromosome forms when a chromosome breaks in two places and the ends of each chromosome fuse together during cell division. This process results in loss of genetic material from the ends of the chromosomes, leading to various impairments.

In some cases of Wolf-Hirschhorn syndrome, individuals inherit a copy of chromosome 4 with a deleted portion. In these instances, one parent has undergone a chromosome rearrangement between chromosome 4 and another chromosome, termed a balanced translocation. Balanced translocations involve an exchange of genetic material between chromosomes without any net gain or loss, hence they typically do not cause health issues in the carrier. However, when passed on to the next generation, there is a risk that the balance of the translocation could be disrupted, leading to an unbalanced state. In such cases, a child may be born with Wolf-Hirschhorn syndrome even though neither parent shows symptoms.

What are the symptoms of Wolf-Hirschhorn syndrome?

The face shows a broad prominence from the forehead to the nasal area (Greek-Warrior Appearance), with decreased muscle tone, developmental delay, growth impairment starting from fetal development, epilepsy, eating disorders, microcephaly, prominent glabella, shortened philtrum, congenital heart defects, and hearing impairment among various symptoms. Particularly, epilepsy occurs in almost 100% of infants with Wolf-Hirschhorn syndrome by the age of one, and preventing seizures is crucial for improving quality of life. Seizure patterns include atonic, tonic, tonic-clonic, and others, often triggered by fever. This condition causes both growth impairment and intellectual disability. Specifically, despite proper intake of protein and energy, there is poor weight gain and intrauterine growth restriction. Severe intellectual disability commonly occurs in Wolf-Hirschhorn syndrome, typically resulting in impaired communication skills, although there have been recent cases where individuals can speak bisyllabically in specific circumstances.

Are there diagnostic methods for Wolf-Hirschhorn syndrome?

In diagnosing Wolf-Hirschhorn syndrome, initial chromosome analysis is typically conducted to check for major deletions or translocations. Genetic testing is particularly useful for confirming the syndrome, with screening for subtelomeric deletions using FISH (Fluorescence In Situ Hybridization) being highly sensitive and specific. The majority of translocations involve subtelomeric regions, and screening these regions can identify the other chromosome involved in a translocation case. Array CGH (Comparative Genomic Hybridization) may also be used in addition to FISH. For traditional cytogenetic testing, identifying an additional segment attached to 4p is crucial, and methods such as SKY (Spectral Karyotyping) or M-FISH (Multiplex Fluorescence In Situ Hybridization) are employed for this purpose.

What are the treatments for Wolf-Hirschhorn syndrome?

Wolf-Hirschhorn syndrome is a disease caused by a congenital genetic abnormality, so there is no curative treatment. Therefore, it is important to provide individualized treatment for the symptoms.

Next, let's discuss typical conditions associated with Wolf-Hirschhorn syndrome and their respective treatments.

Developmental delay

Training to improve motor development, cognition, language, and social skills is beneficial. It's also essential to assess individuals thoroughly and customize rehabilitation programs accordingly. There used to be concerns that excessive use of gestures might hinder speech development, but now it's understood that gestures can actually enhance a child's motivation to communicate. Therefore, it's recommended to actively encourage the use of gestures and similar methods. Early training and subsequent environmental choices are therefore crucial.

Except for infants under one year old, individuals with Wolf-Hirschhorn syndrome can potentially receive disability certificates or rehabilitation certificates, granting access to appropriate services. It's also noted that children with Wolf-Hirschhorn syndrome may qualify for welfare support such as special child-rearing allowances or home visit services due to associated complications, which should be utilized as needed.

Feeding difficulties

We will conduct feeding training.

For children without cleft palate or those before surgical intervention, feeding equipment such as the Haberman Feeder can be used. In cases of children with weak swallowing ability, tube feeding may also be performed.

If complicated by gastroesophageal reflux disease, procedures such as pyloroplasty or gastrostomy may be performed.

Seizures

Managing epilepsy in children with Wolf-Hirschhorn syndrome is a crucial challenge. Generally, medications such as valproic acid or diazepam are commonly used, but recently, oral administration of potassium bromide has been found to be effective. Even if the EEG is abnormal, it may be acceptable to discontinue antiepileptic drugs if there have been no evident seizures for more than five years.

For other congenital anomalies, congenital heart diseases, or hearing impairments, surgical interventions are performed based on individual assessments of the situation.

References

• Journal of the Japanese Society of Red Cross Nursing - Kahoru Kitagawa, Michiko Okazaki, A Study on Self-Help Functions of Family Social Meetings for Children with Disabilities
• NIH  U.S. National Library of Medicine - Wolf-Hirschhorn syndrome