What is Wolff-Hirschhorn syndrome? Characteristics, Causes, and Symptoms (*Written with Supervision of a Doctor)  

4p deletion syndrome (Wolff-Hirschhorn syndrome), a nationally designated intractable disease.

The 4p deletion syndrome is characterized by a number of symptoms, including a broad, prominent nasal bridge extending from the frontal area, which has been described as ‘Greek soldier’s helmet-like’, growth retardation from the prenatal period, and delayed mental development.

However, it is believed that the disease may now be occurring more frequently because the accuracy of conventional diagnostic techniques did not allow for a higher rate of accurate diagnosis.

In this article, we will explain the characteristics, causes, and specific symptoms of 4p deletion syndrome (Wolff-Hirschhorn syndrome), as well as the current treatments and their relationship to NIPT (Non-invasive Prenatal Testing), in order to deepen your understanding of the disease.

Characteristics of 4p Deletion Syndrome

The 4p deletion syndrome (Wolff-Hirschhorn syndrome) is one of the most common full-length partial deletion disorders of all autosomal chromosomes, and it has been difficult to detect its symptoms by conventional chromosome testing.

As a result, the disease is often overlooked, and even today the probability of its occurrence is not certain.

Although the disease is partly genetic, it has been considered a rare chromosome abberation syndrome because most of these cases are mutational in nature.

In the following, we will first explain what 4p deletion syndrome (Wolff-Hirschhorn Syndrome) is characterized by, including its distinctive features, causes, main symptoms, treatment, and all other aspects.

What is 4p Deletion Syndrome?

The 4p deletion syndrome refers to a disease caused by microdeletion of a gene in a part of chromosome 4 (short arm 4p16.3 region). This disease was first reported by Dr. Cooper and Dr. Hirschhorn in 1961, and is also called “Wolff-Hirschhorn Syndrome” (WHS), and is currently recognized by the Ministry of Health, Labor and Welfare as a disease that should be classified as a designated incurable disease.

The estimated incidence of 4p deletion syndrome is about 1 in 50,000, but the disease may actually be a bit more frequent, as the deletion and other symptoms may be overlooked in milder cases. The ratio of women to men is 2:1.

Also, as mentioned earlier, 4p deletion syndrome is a disease caused by deletion of a gene on the short arm of chromosome 4 and is called “chromosome aberration” (a disease caused by a change in the number or shape of chromosomes). Chromosome aberrations are difficult to detect by conventional testing, and advanced testing which can detect whole autosomal partial deletions and duplications is necessary instead of the conventional testing procedures.

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Causes of 4p Deletion Syndrome

Traditionally, human genetic information is contained within what are called chromosomes. The nucleus of a human cell contains 23 pairs or 46 chromosomes, 44 autosomes, one pair each for chromosomes 1 through 22, and one pair or two sex chromosomes, which determine the gender.

The 4p deletion syndrome is thought to be caused by the loss of genetic information when chromosome testing demonstrates a deletion in the short arm of the 4th chromosome (4p16.3 region).

Most cases of this disease are not genetic; the majority are simple deletions due to mutations. However, in some cases, both parents may be genetically predisposed to the disease, and only in this case can a certain percentage of children be expected to develop the disease. Part of the cause is also that WHSC1 (Wolf Hischhorn Syndrome Candidate 1) is a histone methyltransferase, and some of the manifestations of the 4p deletion syndrome (Wolf-Hirschhorn syndrome) are associated with abnormal histone methylation.

It is also estimated that approximately 75% of patients with 4p deletion syndrome (Wolff-Hirschhorn syndrome) developed a new 4p16 deletion, another 12% developed a less frequent structural abnormality such as chromosome 4, and approximately 13% developed a deletion of the 4p16 region due to an unequal reciprocal translocation resulting from a parental equal-impulse reciprocal translocation.

Main Symptoms of 4p Deletion Syndrome

Symptoms of 4p deletion syndrome vary depending on the extent of the chromosome that is deleted, even when patients suffer from the same condition.

Below are some specific symptoms of 4p deletion syndrome:

Distinctive Facial Features

The most distinctive symptom of the 4p deletion syndrome is its distinctive facial appearance.

Specifically, the main features include prominent intereyebrows (hirsutus), high arched eyebrows, a wide nasal bridge, distant eyes (interocular divergence), a downturned mouth, and drooping upper eyelids (ptosis), sometimes referred to as a ‘Greek soldier’s helmet’ appearance. These symptoms are present at birth and during childhood in all patients, but gradually become milder and less prominent during puberty.

Growth Retardation

One of the symptoms of 4p deletion syndrome includes growth retardation.

This condition begins in the uterus and continues after birth with growth retardation, and applies to all those who suffer from the condition.

Other Symptoms & Complications

Other symptoms of 4p deletion syndrome may also be present, such as muscle weakness, intractable epilepsy, and eating disorders, as well as abnormalities in the digestive and urinary systems, hearing loss, congenital heart disease, and sleep disorders.

Specific Treatments of 4p Deletion Syndrome

The 4p deletion syndrome can have any number of symptoms, including distinctive facial features, delayed mental development, and growth retardation, each of which should be treated with a corresponding symptomatic approach. Therefore, it is important to diagnose the syndrome as early as possible and provide appropriate treatment to lessen the severity of the symptoms.

In the case of 4p deletion syndrome, specific treatments can be classified into two categories: treatments such as medication and various diagnostics, and educational support, including physical therapy.

For example, for mental developmental delays, individualized rehabilitation programs include training to develop each component of motor development, social skills, language and cognition.

The main treatment for seizures caused by patients with 4p deletion syndrome is to start anticonvulsants (valproic acid) appropriately, skill-focused feeding training for feeding disorders, and early treatment (physical therapy and surgery) for skeletal deformities. Complications also require appropriate treatment and care as recommended by the medical institution.

The treatments for the symptoms described in this article refer only to typical treatments that are performed after the development of 4p deletion syndrome and are not attributed to any individual.

For more stable and effective treatment, please consult with a physician familiar with 4p deletion syndrome to ensure that the appropriate treatment is tailored to the patient’s needs.

Things to Keep in Mind about 4p Deletion Syndrome

Patients with 4p deletion syndrome require different attention depending on the nature of their symptoms and complications and the status of their treatment. For example, patients with congenital heart disease or refractory epilepsy may require single or multiple medications, regular visits to the doctor, and restrictions on exercise and diet, depending on their doctor.

Therefore, if you have 4p deletion syndrome, it is important that not only you but also your family members have a better understanding of the disease and follow your doctor’s instructions.

The 4p deletion syndrome also includes symptoms such as developmental disorders.

There are many areas of developmental disabilities that have yet to be determined, and there are no clear diagnostic criteria or precautions. Therefore, in addition to regular rehabilitation and educational support at hospitals and medical institutions, it is important that children attend preschool at various facilities and receive medication according to their individual conditions as an option.

In some cases, each approach may be counterproductive and worsen symptoms, so be sure to support the patient based on an understanding of the type and condition of the disorder as well as the nature of the 4p deletion syndrome.

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Relationship between 4p deletion syndrome and NIPT (Non-invasive Prenatal Testing)

In conventional prenatal testing, risks to the mother and fetus and, low test accuracy have been raised as issues. However, the newly developed NIPT (Non-invasive Prenatal Testing) makes it possible to test not only the three autosomal chromosomes but also all autosomal chromosomes, including sex chromosomes.

The following section describes the characteristics of NIPT (Non-invasive Prenatal Testing) and its relationship to the 4p deletion syndrome.

What is NIPT (Non-invasive Prenatal Testing)?

NIPT (Non-invasive Prenatal Testing), also called “maternal blood fetal chromosome test,” refers to a test to examine chromosomal abnormalities by taking blood samples from the mother and analyzing the DNA fragments of the fetus (baby) through testing the blood samples.

If NIPT (Non-invasive Prenatal Testing) is positive, amniotic fluid testing (FISH method, microarray method) will be used to confirm the results (Definitive Test).

NIPT (Non-invasive Prenatal Testing) is characterized by its extremely high test accuracy in terms of sensitivity (indicating the probability that the test is positive and remains positive after birth) and specificity (indicating the probability that the test is negative and remains negative after birth) compared to conventional prenatal diagnostic methods such as maternal serum markers based on blood sampling.

In addition, because 4p deletion syndrome is a disorder with numerous physical complications, it is important to consider not only NIPT (Non-invasive Prenatal Testing) but also additional tests for complications.

The features of NIPT (Non-invasive Prenatal Testing) are as follows:

Risks to the mother and baby can be avoided

Conventional definitive tests (amniotic fluid test and chorionic villus test) involve risks to the mother and fetus, such as miscarriage and stillbirth. On the other hand, the currently recommended NIPT (Non-invasive Prenatal Testing) not only requires only blood sampling but also has higher sensitivity and accuracy than conventional tests, making it possible to test for more accurate abnormal chromosome numbers safely and without risk.

However, since NIPT (Non-invasive Prenatal Testing) is a non-definitive genetic test, it is still important to be aware of the need for a definitive diagnosis (amniotic fluid test).

Testing can be performed at an early stage

Conventional non-definitive tests (maternal serum markers, combined tests) are only performed after 11 weeks of pregnancy, at the earliest. With NIPT (Non-invasive Prenatal Testing), however, it is possible to take the test as early as 10 or later weeks of pregnancy, which is beneficial for pregnant women who want to know about the condition of the baby at an early stage.

What is the relationship between 4p deletion syndrome and NIPT (Non-invasive Prenatal Testing)?

Conventional prenatal testing is effective in testing for the three chromosome abnormalities trisomy 13 (Patau syndrome), trisomy 18 (Edwards) syndrome, and trisomy 21 (Down syndrome), which is 2/3 compared to all chromosome abnormalities.

Therefore, previous tests were not meant to confirm chromosomal disorders, but rather to diagnose only part of the possibilities, or so-called “non-definitive” tests. However, with NIPT (Non-invasive Prenatal Testing), it is possible to perform not only the conventional basic tests for trisomies 13, 18, and 21, but also tests for partial deletion disorders of all autosomal regions, including 4p deletion syndrome, with a very high degree of accuracy. This enables us to provide reliable diagnosis and results to pregnant women who are concerned before the birth of their child.

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Summary

The 4p deletion syndrome (Wolff-Hirschhorn syndrome), caused by a chromosomal abnormality, is classified as an all-autosomal whole region partial deletion/duplication disease because it occurs within a relatively small segment and has been difficult to diagnose by conventional chromosome examination.

Therefore, in many cases, the disease itself is overlooked even when it does occur, and precise numbers have yet to be proven.

In recent years, however, NIPT has been attracting attention as a new type of prenatal testing that can perform fetal chromosome aberrations with a high system of both sensitivity and specificity in a way that does not impose a burden on the mother.

Therefore, the future will contribute not only to the early and accurate detection of 4p deletion syndromes, but also to the preliminary study of appropriate procedures, measures, and treatments for each syndrome.

Unlike conventional non-definitive tests, NIPT (Non-invasive Prenatal Testing), which has a higher test accuracy (sensitivity, specificity, and positive predictive value), will become a test that attracts more and more attention internally in the future.

It is anticipated that this will be an opportunity not only to deepen the understanding of 4p deletion syndrome (Wolff-Hirschhorn syndrome) and other whole autosomal partial deletions and duplications, but also to acquire knowledge about the new NIPT (Non-invasive Prenatal Testing), which is expected to lead to more active discussions.