Wolf-Hirschhorn syndrome is a condition that affects many parts of the body. The major features of this disorder include a characteristic facial features, delayed growth and development, intellectual disability, and seizures.

Almost everyone with this disorder has distinctive facial features, including a broad nasal bridge, large and protruding eyes, and a high forehead. This combination is described as a "Greek warrior helmet" appearance. Other characteristic facial features include a shortened distance between the nose and upper lip (a short philtrum), a downturned mouth, a small chin (micrognathia), and poorly formed ears with small holes (pits) or flaps of skin (tags). Additionally, affected individuals may have asymmetrical facial features and an unusually small head (microcephaly).

People with Wolf-Hirschhorn syndrome experience delayed growth and development. Slow growth begins before birth, and affected infants tend to have problems feeding and gaining weight (failure to thrive). They also have weak muscle tone (hypotonia) and underdeveloped muscles. Motor skills such as sitting, standing, and walking are significantly delayed. Most children and adults with this disorder also have short stature.

Intellectual disability ranges from mild to severe in people with Wolf-Hirschhorn syndrome. Compared to people with other forms of intellectual disability, their socialization skills are strong, but verbal communication and language skills tend to be weaker. Most affected children also have seizures, which may be resistant to treatment. Seizures tend to disappear with age.

Additional features of Wolf-Hirschhorn syndrome include skin changes, such as mottled or dry skin; skeletal abnormalities, such as abnormal curvature of the spine (scoliosis and kyphosis); dental problems including, missing teeth; and an opening in the roof of the mouth (cleft palate) and/or a split in the upper lip (cleft lip). Wolf-Hirschhorn syndrome can also cause abnormalities of the eyes, heart, and genitourinary tract.

A condition called Pitt-Rogers-Danks syndrome has features that overlap with those of Wolf-Hirschhorn syndrome. Researchers now recognize that these two conditions are actually part of a single syndrome with variable signs and symptoms.

Wolf-Hirschhorn syndrome is caused by a deletion of genetic material near the end of the short (p) arm of chromosome 4. This chromosomal change is sometimes written as 4p-. The size of the deletion varies among affected individuals; studies suggest that larger deletions tend to result in more severe intellectual disability and physical abnormalities than smaller deletions.

The signs and symptoms of Wolf-Hirschhorn are related to the loss of multiple genes on the short arm of chromosome 4. NSD2, LETM1, and MSX1 are the genes that are deleted in people with the typical signs and symptoms of this disorder. These genes play significant roles in early development, although many of their specific functions are unknown.

Researchers believe that the loss of the NSD2 gene can cause many of the characteristic features of Wolf-Hirschhorn syndrome, including the distinctive facial appearance and developmental delay. The deletion of the LETM1 gene and other nearby genes (including CPLX1) may cause seizures or other abnormal electrical activity in the brain. The loss of the MSX1 gene may be responsible for the dental abnormalities and cleft lip and/or palate that are often seen in people with this condition.

Scientists are working to identify additional genes at the end of the short arm of chromosome 4 that contribute to the characteristic features of Wolf-Hirschhorn syndrome.

Normal Function

The LETM1 gene provides instructions for making a protein whose function is not well understood. This protein is active in mitochondria, which are structures within cells that convert the energy from food into a form that cells can use. The LETM1 protein may be involved in the transport of charged calcium atoms (calcium ions) across membranes within mitochondria. Researchers suspect that the protein also plays a role in determining the shape and volume of mitochondria.

Health Conditions Related to Genetic Changes

Wolf-Hirschhorn syndrome

The LETM1 gene is located in a region of chromosome 4 that is deleted in people with the typical features of Wolf-Hirschhorn syndrome. The features of this condition include a characteristic facial appearance, delayed growth and development, intellectual disability, and seizures.

As a result of this deletion in chromosome 4, affected individuals are missing one copy of the LETM1 gene in each cell. Studies suggest that a loss of this gene alters the structure of mitochondria; however, it is unclear how this abnormality is related to the signs and symptoms of Wolf-Hirschhorn syndrome. The deletion of the LETM1 gene and other nearby genes can cause seizures or other abnormal electrical activity in the brain.

Other Names for This Gene

• LETM1_HUMAN
• leucine zipper-EF-hand containing transmembrane protein 1

Genomic Location

Normal Function

The MSX1 gene provides instructions for making a protein that regulates the activity of other genes. The MSX1 gene is part of a larger family of homeobox genes, which control the formation of many body structures during early development. Specifically, this gene is critical for the normal development of the teeth and other structures in the mouth. It may also be important for the development of fingernails and toenails.

Health Conditions Related to Genetic Changes

Wolf-Hirschhorn syndrome

The MSX1 gene is often deleted in people with Wolf-Hirschhorn syndrome. The features of this condition include a characteristic facial appearance, delayed growth and development, intellectual disability, and seizures.

A loss of the MSX1 gene probably disrupts the regulation of several other genes, particularly genes involved in the development of the mouth and teeth. Researchers believe that a deletion of the MSX1 gene disrupts the formation of oral structures in early development, leading to missing teeth and other dental abnormalities. A loss of the MSX1 gene probably also causes an opening in the roof of the mouth (cleft palate) and/or a split in the upper lip (cleft lip) seen in some people with Wolf-Hirschhorn syndrome.

Other disorders

MSX1 gene variants (also called mutations) are associated with abnormalities of mouth and tooth development. For example, changes in this gene contribute to some cases of cleft lip and/or cleft palate in people who do not have Wolf-Hirschhorn syndrome. These genetic variations have been associated with isolated cleft lip and cleft palate in several different populations worldwide. MSX1 gene variants appear to be one of many genetic and environmental factors that play a role in oral clefting.

At least six MSX1 gene variants are responsible for oligodontia, a condition in which multiple teeth fail to develop. Some individuals with MSX1 gene variants have a combination of oligodontia and cleft lip and/or cleft palate. Variants in the MSX1 gene likely reduce the amount of functional MSX1 protein within cells, which disrupts the early development of structures in the mouth.

Another variant in the MSX1 gene has been found to cause Witkop syndrome (also known as tooth-and-nail syndrome). This rare condition is characterized by missing teeth and abnormalities of the fingernails and toenails. The MSX1 gene variant mutation responsible for Witkop syndrome leads to the production of an abnormally short, nonfunctional version of the MSX1 protein. A loss of this protein disrupts the formation of the teeth and nails during early development.

Other Names for This Gene

• homeobox 7
• homeobox protein MSX-1
• HOX7
• HYD1
• msh homeo box 1
• MSH Homeo Box Homolog 1 (Drosophila) Gene
• msh homeobox homolog 1
• MSX1_HUMAN
• OFC5

Genomic Location

Normal Function

The NSD2 gene provides instructions for making at least three very similar proteins known as MMSET I, MMSET II, and RE-IIBP. These proteins are active both before and after birth in many of the body's cells and tissues. They appear to play an important role in normal development.

At least two of the proteins produced from the NSD2 gene, MMSET II and RE-IIBP, likely help regulate the activity of other genes. Studies suggest that these proteins function as histone methyltransferases, which are enzymes that modify proteins called histones. By adding a molecule called a methyl group to histones, histone methyltransferases can turn off (suppress) the activity of certain genes. Scientists are working to identify the genes targeted by the MMSET II and RE-IIBP proteins.

Health Conditions Related to Genetic Changes

Wolf-Hirschhorn syndrome

The NSD2 gene is located in a region of chromosome 4 that is deleted in people with Wolf-Hirschhorn syndrome. The features of this condition include a characteristic facial appearance, delayed growth and development, intellectual disability, and seizures.

As a result of this deletion in chromosome 4, affected individuals are missing one copy of the NSD2 gene in each cell. A loss of the NSD2 gene probably disrupts the regulation of several other genes, although these genes have not been identified. Research shows that abnormal gene regulation during development contributes to some of the features of Wolf-Hirschhorn syndrome.

Cancers

A chromosomal rearrangement (translocation) involving the NSD2 gene has been associated with multiple myeloma, a cancer that starts in bone marrow cells. This rearrangement is found in 15 to 20 percent of all multiple myelomas. The translocation abnormally fuses the NSD2 gene on chromosome 4 with part of another gene on chromosome 14. The fusion of these genes overactivates the NSD2 gene, which appears to promote the uncontrolled growth and division of cancer cells.

Other Names for This Gene

• FLJ23286
• IL5 promoter REII region-binding protein
• KIAA1090
• MGC176638
• MMSET
• multiple myeloma SET domain protein
• NSD2_HUMAN
• Nuclear SET domain-containing protein 2
• Probable histone-lysine N-methyltransferase NSD2
• Protein trithorax-5
• REIIBP
• trithorax/ash1-related protein 5
• TRX5
• WHSC1
• Wolf-Hirschhorn syndrome candidate 1

Genomic Location

Chromosome 4 spans about 191 million DNA building blocks (base pairs) and represents more than 6 percent of the total DNA in cells. Chromosome 4 likely contains 1,000 to 1,100 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 4.

Cancers

Changes in chromosome 4 have been identified in several types of human cancer. These genetic changes are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. For example, rearrangements (translocations) of genetic material between chromosome 4 and several other chromosomes have been associated with leukemias, which are cancers of blood-forming cells.

A specific translocation involving chromosome 4 and chromosome 14 is commonly found in multiple myeloma, which is a cancer that starts in cells of the bone marrow. The translocation, which is written as t(4;14)(p16;q32), abnormally fuses the WHSC1 gene on chromosome 4 with part of another gene on chromosome 14. The fusion of these genes overactivates WHSC1, which appears to promote the uncontrolled growth and division of cancer cells.

Facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy is caused by genetic changes involving the long (q) arm of chromosome 4. This condition is characterized by muscle weakness and wasting (atrophy) that worsens slowly over time. It results from changes in a region of DNA known as D4Z4, located near the end of the chromosome at a position described as 4q35. The D4Z4 region consists of 11 to more than 100 repeated segments, each of which is about 3,300 DNA base pairs (3.3 kb) long. The entire D4Z4 region is normally hypermethylated, which means that it has a large number of methyl groups (consisting of one carbon atom and three hydrogen atoms) attached to the DNA. Facioscapulohumeral muscular dystrophy results when the region is hypomethylated, with too few methyl groups attached. In facioscapulohumeral muscular dystrophy type 1 (FSHD1), hypomethylation occurs because the D4Z4 region is abnormally shortened (contracted), containing between 1 and 10 repeats instead of the usual 11 to 100 repeats. In facioscapulohumeral muscular dystrophy type 2 (FSHD2), hypomethylation most often results from mutations in a gene called SMCHD1, which normally hypermethylates the D4Z4 region.

The segment of the D4Z4 region closest to the end of chromosome 4 contains a gene called DUX4. Hypermethylation of the D4Z4 region normally keeps the DUX4 gene turned off (silenced) in most adult cells and tissues. In people with facioscapulohumeral muscular dystrophy, hypomethylation of the D4Z4 region prevents the DUX4 gene from being silenced in cells and tissues where it is usually turned off. Although little is known about the function of the DUX4 gene when it is turned on (active), researchers believe that it influences the activity of other genes, particularly in muscle cells. It is unknown how abnormal activity of the DUX4 gene damages or destroys these cells, leading to progressive muscle weakness and atrophy.

The DUX4 gene is located next to a regulatory region of DNA known as a pLAM sequence, which is necessary for the production of the DUX4 protein. Some copies of chromosome 4 have a functional pLAM sequence, while others do not. Copies of chromosome 4 with a functional pLAM sequence are described as 4qA or "permissive." Those without a functional pLAM sequence are described as 4qB or "non-permissive." Without a functional pLAM sequence, no DUX4 protein is made. Because there are two copies of chromosome 4 in each cell, individuals may have two "permissive" copies of chromosome 4, two "non-permissive" copies, or one of each. Facioscapulohumeral muscular dystrophy can only occur in people who have at least one "permissive" copy of chromosome 4. Whether an affected individual has a contracted D4Z4 region or a SMCHD1 gene mutation, the disease results only if a functional pLAM sequence is also present to allow DUX4 protein to be produced.

PDGFRA-associated chronic eosinophilic leukemia

PDGFRA-associated chronic eosinophilic leukemia is caused by genetic abnormalities that involve the PDGFRA gene, a gene found on chromosome 4. This condition is a type of blood cell cancer characterized by an increased number of eosinophils, a type of white blood cell involved in allergic reactions.

The PDGFRA gene abnormalities are somatic mutations, which are mutations acquired during a person's lifetime that are present only in certain cells. The most common of these abnormalities is a deletion of genetic material from chromosome 4 that removes approximately 800 DNA building blocks (nucleotides) and brings together parts of two genes, FIP1L1 and PDGFRA, creating the FIP1L1-PDGFRA fusion gene. Occasionally, through mechanisms other than deletion, genes other than FIP1L1 are fused with the PDGFRA gene. Rarely, mutations that change single DNA building blocks in the PDGFRA gene (point mutations) cause this condition.

The protein produced from the FIP1L1-PDGFRA fusion gene (as well as other PDGFRA fusion genes) has the function of the PDGFRA protein, which stimulates signaling pathways inside the cell that control many important cellular processes, such as cell growth and division (proliferation) and cell survival. Unlike the normal PDGFRA protein, however, the fusion protein is constantly turned on (constitutively activated), which means the cells are always receiving signals to proliferate. Similarly, point mutations in the PDGFRA gene can result in a constitutively activated PDGFRA protein. When the FIP1L1-PDGFRA fusion gene or point mutations in the PDGFRA gene occur in blood cell precursors, the growth of eosinophils (and occasionally other blood cells) is poorly controlled, leading to PDGFRA-associated chronic eosinophilic leukemia. It is unclear why eosinophils are preferentially affected by this genetic change.

Wolf-Hirschhorn syndrome

Wolf-Hirschhorn syndrome is caused by a deletion of genetic material near the end of the short (p) arm of chromosome 4 at a position described as 4p16.3. The signs and symptoms of this condition are related to the loss of multiple genes from this part of the chromosome. The size of the deletion varies among affected individuals; studies suggest that larger deletions tend to result in more severe intellectual disability and physical abnormalities than smaller deletions.

The region of chromosome 4 that is deleted most often in people with Wolf-Hirschhorn syndrome is known as Wolf-Hirschhorn syndrome critical region 2 (WHSCR-2). This region contains several genes, some of which are known to play important roles in early development. A loss of these genes leads to developmental delay, a distinctive facial appearance, and other characteristic features of the condition. Scientists are working to identify additional genes at the end of the short arm of chromosome 4 that contribute to the characteristic features of Wolf-Hirschhorn syndrome.

Other chromosomal conditions

Some deletions of genetic material from the short (p) arm of chromosome 4 do not involve the critical region WHSCR-2. These deletions cause signs and symptoms that are distinct from those of Wolf-Hirschhorn syndrome, including mild intellectual disability and, in some cases, rapid (accelerated) growth. People with this type of deletion usually do not have seizures.

Trisomy 4 occurs when cells have three copies of chromosome 4 instead of the usual two copies. Full trisomy 4, which occurs when all of the body's cells contain an extra copy of chromosome 4, is not compatible with life. A similar but somewhat less severe condition called mosaic trisomy 4 occurs when only some of the body's cells have an extra copy of chromosome 4. The signs and symptoms of mosaic trisomy 4 vary widely and can include heart defects, abnormalities of the fingers and toes, and other birth defects. Mosaic trisomy 4 is very rare; only a few cases have been reported.

Other changes in the number or structure of chromosome 4 can have a variety of effects including delayed growth and development, intellectual disability, distinctive facial features, heart defects, and other medical problems. Changes involving chromosome 4 include an extra piece of the chromosome in each cell (partial trisomy 4), a missing segment of the chromosome in each cell (partial monosomy 4), and a circular structure called a ring chromosome 4. Ring chromosomes occur when a chromosome breaks in two places and the ends of the chromosome arms fuse together to form a circular structure.

Cancers

Changes in chromosome 4 have been identified in several types of human cancer. These genetic changes are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. For example, rearrangements (translocations) of genetic material between chromosome 4 and several other chromosomes have been associated with leukemias, which are cancers of blood-forming cells.

A specific translocation involving chromosome 4 and chromosome 14 is commonly found in multiple myeloma, which is a cancer that starts in cells of the bone marrow. The translocation, which is written as t(4;14)(p16;q32), abnormally fuses the WHSC1 gene on chromosome 4 with part of another gene on chromosome 14. The fusion of these genes overactivates WHSC1, which appears to promote the uncontrolled growth and division of cancer cells.

In general, Wolf-Hirschhorn syndrome (WHS) affects many parts of the body and is often characterized by a unique facial appearance, delayed growth and development, intellectual disability, and seizures. Although the cognitive-behavioral features of individuals with WHS have not been studied systematically, a few studies have been performed that are beginning to look at these behavioral characteristics.

In one study, children with WHS were found to be more severely impacted cognitively and had lower overall adaptive behavior than children with other deletion syndromes. However, this study also found that children with WHS often have strengths in socialization skills and are less likely to have autistic-like features than children with other deletion syndromes.

Another study, which examined a larger population of children, adolescents, and adults with WHS, found a very large range of cognitive-behavioral symptoms exhibit by individuals with WHS. Some individuals showed decreased communication and expressive language skills, while others showed advanced expressive language skills.

A study of 12 children, ages 4-17 years, showed that cognitive deficits in affected individuals ranged from mild to severe; strengths were in verbal and quantitative reasoning and socialization. ADHD was seen in 7 out of 12 children and 1 child appeared to have mild autism.

It is difficult to say whether the behavioral symptoms your daughter is expressing are related to WHS. The range of cognitive-behavioral symptoms has been shown to be very wide among individuals with WHS and some studies have shown more severe cognitive-behavioral issues than others. Given this, we recommend discussing your concerns with a genetics professional or your daughter’s personal health care provider if you have not done so already. Below, we have listed resources for finding a genetics professional in your community.

Between 85 and 90 percent of all cases of Wolf-Hirschhorn syndrome are not inherited. They are caused by a chromosomal deletion that occurs as a random (de novo) event during the formation of reproductive cells (eggs or sperm) or during early embryonic development. More complex chromosomal rearrangements can also occur as de novo events, which may help explain the variability in the condition's signs and symptoms. De novo chromosomal changes occur in people with no history of the disorder in their family.

An unusual chromosomal abnormality called a ring chromosome can also cause Wolf-Hirschhorn syndrome. Ring chromosomes occur when a chromosome breaks in two places and the ends of the chromosome arms fuse together to form a circular structure. In the process, genes near the ends of the chromosome are lost. In a small percentage of people with Wolf-Hirschhorn syndrome, the disorder is caused by chromosome 4 becoming a ring chromosome.

In the remaining cases of Wolf-Hirschhorn syndrome, an affected individual inherits a copy of chromosome 4 with a deleted segment. In these cases, one of the individual's parents carries a balanced translocation, which occurs when chromosome 4 trades genetic information with another chromosome. No genetic material is gained or lost in a balanced translocation, so these chromosomal changes usually do not cause any health problems. However, translocations can become unbalanced as they are passed to the next generation. Some people with Wolf-Hirschhorn syndrome inherit an unbalanced translocation that deletes genes near the end of the short arm of chromosome 4. A loss of these genes results in the intellectual disability, slow growth, and other health problems that are characteristic of this disorder.

Risks to family members and their children depend on the mechanism of how the deletion occurred in the person with Wolf-Hirschhorn syndrome (WHS).

The parents of a person with WHS are unaffected. However, in some cases, a parent has a balanced rearrangement (when chromosome material is rearranged but there is no extra or missing material) that resulted in the child having WHS. For this reason, it is recommended that the parents of a person with WHS have genetic testing to see if one carries a balanced rearrangement.

The risk to siblings of a person with WHS depends on the genetic status of the parents. If it is found that the deletion in the affected person is de novo (not inherited and occurring for the first time), the risk to siblings is negligible. If a parent carries a chromosome rearrangement, the siblings are at increased risk for a chromosome abnormality or rearrangement, and other family members are also at risk of carrying the rearrangement.

If a parent is known to be a carrier of a chromosome 4p rearrangement, prenatal testing via chorionic villus sampling or amniocentesis is possible, and preimplantation genetic diagnosis (PGD) may be an option.

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

The prevalence of Wolf-Hirschhorn syndrome is estimated to be 1 in 50,000 births. However, it is likely that some affected individuals are never diagnosed.

For unknown reasons, Wolf-Hirschhorn syndrome occurs in about twice as many females as males.