Wolf Hirschhorn syndrome

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Wolf-Hirschhorn syndrome

What is Wolf-Hirschhorn syndrome

Wolf-Hirschhorn syndrome is an extremely rare chromosomal disorder caused by a missing piece (partial deletion or monosomy) of genetic material near the end of the short (p) arm of chromosome 4 (written as 4p-), that affects many parts of the body. The size of the deletion varies among people with Wolf-Hirschhorn syndrome, and studies suggest larger deletions tend to result in more severe features. Most cases of Wolf-Hirschhorn syndrome are not inherited, but some cases are inherited from a parent who does not have Wolf-Hirschhorn syndrome 1.

The major features of Wolf-Hirschhorn syndrome include a characteristic facial appearance, delayed growth and development, intellectual disability, low muscle tone (hypotonia), and seizures occur in 90% to 100% of children. Other features may include skeletal abnormalities, congenital heart defects, hearing loss, urinary tract malformations, and/or structural brain abnormalities.

Almost everyone with Wolf-Hirschhorn syndrome has distinctive facial features, including a broad, flat nasal bridge and a high forehead. This combination is described as a “Greek warrior helmet” appearance. The eyes are widely spaced and may be protruding. 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, while 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 in the lip (cleft lip). Wolf-Hirschhorn syndrome can also cause abnormalities of the eyes, heart, genitourinary tract, and brain.

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 an extremely rare disorder. Studies undertaken about 25 years ago suggested that Wolf-Hirschhorn syndrome occurred in approximately 1 in about 50,000 live births with a female to male ratio of 2:1. More recent studies suggest that the frequency of the disorder is underestimated because of misdiagnosis. It is unknown why Wolf-Hirschhorn syndrome occurs in about twice as many females as males.

Wolf-Hirschhorn syndrome treatment depends on the symptoms. Treatment includes rehabilitation, speech/communication therapy and sign language; valproic acid for atypical absence seizures; benzodiazepines for status epilepticus; special feeding techniques, gavage feeding, and/or gastrostomy for feeding difficulties. Standard care is recommended for skeletal anomalies, ophthalmologic abnormalities, congenital heart defects, hearing loss, sleep disturbance, and hepatic (liver) adenomas.

How common is it for a person to have more than one child with Wolf-Hirschhorn syndrome?

In most cases of Wolf-Hirschhorn syndrome, there is only one affected individual in a family. Between 85 percent and 90 percent of all cases of Wolf-Hirschhorn syndrome are not inherited and occur in people with no history of the disorder in their family. In the remaining cases of this syndrome, an affected individual inherits an abnormal chromosome 4 from a parent. A genetic test called a chromosome analysis can determine if one of the parents carries a chromosomal rearrangement between chromosome 4 and another chromosome. This rearrangement is called a balanced translocation. 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 one end of chromosome 4. A loss of these genes results in the intellectual disability, slow growth, and other health problems characteristic of Wolf-Hirschhorn syndrome 2.

If a parent is found to have a balanced translocation involving chromosome 4, they may be at risk of having additional children with Wolf-Hirschhorn syndrome. Once a translocation is found, other family members can also be tested to see if they are carriers of the same balanced translocation.

What are the risks to family members of a person with Wolf-Hirschhorn syndrome?

Risks to family members and their children depend on the mechanism of how the deletion occurred in the person with Wolf-Hirschhorn syndrome 1.

The parents of a person with Wolf-Hirschhorn syndrome 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 Wolf-Hirschhorn syndrome. For this reason, it is recommended that the parents of a person with Wolf-Hirschhorn syndrome have genetic testing to see if one carries a balanced rearrangement 1.

The risk to siblings of a person with Wolf-Hirschhorn syndrome 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 1.

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 may be an option 1.

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

Resources for locating a genetics professional in your community are available online:

Have cognitive-behavioral issues been reported in those with Wolf-Hirschhorn syndrome?

In general, Wolf-Hirschhorn syndrome affects many parts of the body and is often characterized by a unique facial appearance, delayed growth and development, intellectual disability, and seizures 1. Although the cognitive-behavioral features of individuals with Wolf-Hirschhorn syndrome 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 Wolf-Hirschhorn syndrome 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 Wolf-Hirschhorn syndrome often have strengths in socialization skills and are less likely to have autistic-like features than children with other deletion syndromes 3.

Another study 4, which examined a larger population of children, adolescents, and adults with Wolf-Hirschhorn syndrome, found a very large range of cognitive-behavioral symptoms exhibit by individuals with Wolf-Hirschhorn syndrome. Some individuals showed decreased communication and expressive language skills, while others showed advanced expressive language skills.

A study of 12 children 5, 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 Wolf-Hirschhorn syndrome. The range of cognitive-behavioral symptoms has been shown to be very wide among individuals with Wolf-Hirschhorn syndrome 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, is a list of resources for finding a genetics professional in your community.

Resources for locating a genetics professional in your community are available online:

What causes 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. 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 loss of the NSD2 gene is associated with many of the characteristic features of Wolf-Hirschhorn syndrome, including the distinctive facial appearance and developmental delay. Deletion of the LETM1 gene appears to be associated with seizures or other abnormal electrical activity in the brain. A loss of the MSX1 gene may be responsible for the dental abnormalities and cleft lip and/or palate that are often seen 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.

Wolf-Hirschhorn syndrome inheritance pattern

Between 85 and 90 percent of all cases of Wolf-Hirschhorn syndrome are not inherited. They result from a chromosomal deletion that occurs as a random (de novo) event during the formation of reproductive cells (eggs or sperm) or in 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.

A small percentage of all people with Wolf-Hirschhorn syndrome have the disorder as a result of an unusual chromosomal abnormality such as 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. In the process, genes near the ends of the chromosome are lost.

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 chromosomal rearrangement between chromosome 4 and another chromosome. This rearrangement is called a balanced translocation. 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 characteristic of this disorder.

Wolf-Hirschhorn syndrome symptoms

The features of Wolf-Hirschhorn syndrome can vary widely between different affected individuals. The most distinctive feature of Wolf-Hirschhorn syndrome is the typical facial appearance. Individuals with Wolf-Hirschhorn syndrome usually have widening and prominence of the area located at the top of the nose between the eyebrows (the glabella). This is associated with prominent, wide-spaced eyes, arched eyebrows, and a smallness of the lower part of the face, including a short upper lip and smallness of the mouth and jaw. This leads to the bridge of the nose being the focal point of the face.

Findings present in nearly all individuals with Wolf-Hirschhorn syndrome include: marked growth problems (both low weight and low height) starting prior to birth and resistant to intervention, intellectual deficits (which are variable, but are often quite marked), low muscle tone (hypotonia), and seizures.

Other common findings include small head (microcephaly); eye differences (turning in or out of the eyes, droopy eyelids, eye malformations); ear differences (small, simple, tags and/or pits); cleft lip and/or palate; abnormalities of the penis, testicles, or vagina; abnormalities of the kidneys; problems with bones; problems with teeth.

Birth defects of the heart are common in individuals with Wolf-Hirschhorn syndrome, but are usually simple, such as a hole between the two top chambers of the heart (atrial septal defect or ASD), and able to be corrected with surgery.

Many individuals have an increased number of infections. Some have a true immune deficiency, most commonly a decreased ability to make antibodies.

Feeding problems are extremely common and may be quite severe. The majority of affected individuals require tube feeding at some point in their lives, and many need this lifelong. Some individuals have serious problems with their gut, including malrotation (a birth defect of the gut which increases the risk that it may twist and cut off blood supply), very poor movement of the gut (dysmotility), or poor ability of the gut to absorb nutrients.

The intellectual and developmental problems are variable but are quite significant in most people with Wolf-Hirschhorn syndrome. Individuals struggle with all areas including: communication, gross motor skills, fine motor skills, and quantitative reasoning. Bowel and bladder control is typically delayed into late childhood and is sometimes not achieved. Most individuals require facilitation of communication with speaking devices or sign language.

Originally, Pitt-Rogers-Danks syndrome was described as a separate disorder from Wolf-Hirschhorn syndrome. However, individuals with Pitt-Rogers-Danks syndrome were eventually found to also have deletions of the short arm of the fourth chromosome in the same region associated with Wolf-Hirschhorn syndrome, so this condition is now felt to be a description of the milder end of Wolf-Hirschhorn syndrome.

Wolf-Hirschhorn syndrome diagnosis

A diagnosis of Wolf-Hirschhorn syndrome may be suggested by the characteristic facial appearance, growth failure, developmental delays, and seizures. The diagnosis is confirmed by detection of a deletion of the Wolf-Hirschhorn syndrome critical region (Wolf-Hirschhorn syndromeCR) by cytogenetic (chromosome) analysis. Conventional cytogenetic analysis detects less than half of the deletions that cause Wolf-Hirschhorn syndrome. Fluorescence in situ hybridization (FISH) using a Wolf-Hirschhorn syndrome critical region probe has much better detection rate than standard karyotype and will detect most patients. However, the diagnostic test of choice is chromosomal microarray, which detects essentially all deletions of the Wolf-Hirschhorn syndrome critical region and defines the size of the deletion. Chromosomal microarray can also find other chromosome rearrangements, such as extra pieces of other chromosomes that are seen in many patients with Wolf-Hirschhorn syndrome.

Wolf-Hirschhorn syndrome prognosis

The prognosis (long-term outlook) for people with Wolf-Hirschhorn syndrome depends on the specific features present and the severity of those features. Muscle weakness may increase the risk of having chest infections and ultimately may reduce the life expectancy. Many people, in the absence of severe heart defects, chest infections, and uncontrollable seizures, survive into adulthood 6.

Wolf-Hirschhorn syndrome life expectancy

Wolf-Hirschhorn syndrome average life expectancy is unknown.

Wolf-Hirschhorn syndrome treatment

Because Wolf-Hirschhorn syndrome is so variable, treatment and intervention must be tailored to the affected individual’s needs. Patients with a known or suspected diagnosis of Wolf-Hirschhorn syndrome should have a comprehensive evaluation by an experienced genetics professional. Most patients will need to be followed by multiple subspecialists. Patients should have a neurology evaluation with evaluation for seizures, detailed cardiology (heart) evaluation, eye exam, hearing exam, kidney evaluation, feeding evaluation, and developmental evaluation as soon as possible after diagnosis. Kidney function must be monitored on an ongoing basis. All patients benefit from comprehensive developmental and rehabilitation support including: feeding therapy, assistive communication, speech, physical therapy, occupational therapy, and school support. Genetic counseling is recommended for families of children with Wolf-Hirschhorn syndrome.

Evaluations following initial diagnosis

To establish the extent of disease and needs in an individual diagnosed with Wolf-Hirschhorn syndrome, the following evaluations are recommended:

  • Measurement of growth parameters and plotting on growth charts
  • Evaluation of cognitive, language, and motor development and social skills
  • Waking/sleeping video-EEG-polygraphic studies in childhood (mainly ages 1-6 years) to detect atypical absence seizures that may be subtle 7
  • Evaluation for feeding problems and gastroesophageal reflux with referral to a dysphagia team
  • Physical examination for skeletal anomalies (e.g., clubfoot, scoliosis, kyphosis); if anomalies are present, referral for orthopedic and physical therapy evaluation (including full biomechanical assessment)
  • Ophthalmology consultation in infancy even in the absence of overt anomalies
  • Examination of the heart (auscultation, electrocardiogram, echocardiography) in infancy
  • Testing for immunodeficiency (particularly plasma Ig levels, lymphocyte subsets, and polysaccharide responsiveness); although limited data on immunodeficiency in individuals with Wolf-Hirschhorn syndrome are available, such testing should be considered when clinically appropriate.
  • Complete blood count to evaluate for hematopoietic dysfunction
  • Comprehensive evaluation by an otolaryngologist and comprehensive audiologic screening (brain stem auditory evoked responses) as early as possible to allow appropriate interventions
  • Renal function testing and renal ultrasonography in infancy to detect structural renal anomalies and/or vesicoureteral reflux 8
  • Baseline liver ultrasound to evaluate for hepatic adenoma
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of manifestations

Intellectual disability

Enrollment in a personalized rehabilitation program with attention to motor development, cognition, communication, and social skills is appropriate 9. Use of sign language enhances communication skills and does not inhibit the appearance of speech. Early intervention and, later, appropriate school placement are essential.

Seizures

Because almost 95% of individuals with Wolf-Hirschhorn syndrome have multiple seizures, most often triggered by fever, and almost one third later develop valproic acid-responsive atypical absence seizures, it is appropriate to start treatment with valproic acid soon after the first seizure. Atypical absence seizures are well controlled on valproic acid alone or in association with ethosuccimide 7.

Sodium bromide has recently been proposed as the initial treatment for the prevention of the development of status epilepticus 10.

Clonic, tonic-clonic, absence, or myoclonic status epilepticus can be well controlled by intravenous benzodiazepines (Diazepam) 11.

Because individuals with Wolf-Hirschhorn syndrome have distinctive EEG abnormalities not necessarily associated with seizures 7, it seems appropriate to withdraw antiepileptic drugs in individuals who have not experienced seizures for five years.

Feeding difficulties

Feeding therapy with attention to oral motor skills is also appropriate. Special feeding techniques or devices such as the “Haberman feeder” can be used for feeding a hypotonic infant/child without a cleft palate or those with a cleft palate prior to surgical repair.

Gavage feeding may be indicated in individuals with poorly coordinated swallow.

Gastroesophageal reflux should be addressed in a standard manner.

In one study, almost 44% of individuals with Wolf-Hirschhorn syndrome were managed with gastrostomy and, occasionally, gastroesophageal fundoplication 12.

Skeletal abnormalities

  • Skeletal abnormalities (e.g., clubfoot, scoliosis, kyphosis) need to be addressed on an individual basis. Early treatment (both physical therapy and surgery) is suggested.

Eye abnormalities

  • Ophthalmologic abnormalities are treated in the standard manner.

Congenital heart defects

  • Congenital heart defects are usually not complex and are amenable to repair.

Hearing loss

  • Hearing loss is treated with a trial of hearing aids.

Sleeping problems

  • If no medical factors (e.g., otitis media, gastroesophageal reflux, eczema, obstructive sleep apnea) are involved and if sleeping problems are reinforced by parental attention, the “extinction of parental attention” is an effective behavioral treatment 13.

Hepatic adenomas

  • Medical treatment (either surgery or chemotherapy) varies in relation to the number and size of the adenomas.

Other

  • Other structural anomalies (e.g., diaphragmatic, gastrointestinal, dental) should be addressed in a standard manner.

Prevention of secondary complications

  • Antibiotic prophylaxis is indicated for vesicoureteral reflux (VUR).
  • Intravenous immunoglobulin (Ig) infusions or continuous antibiotics may be indicated for those with antibody deficiencies.

Surveillance

Systematic follow up allows for adjustment of rehabilitation and treatment as skills improve or deteriorate and medical needs change 14.

  • Complete blood count annually to evaluate for hematopoietic dysfunction
  • Annual renal function testing, including serum BUN (blood urea nitrogen), creatinine, and cystatin C; urinalysis; and creatinine clearance test
  • Consideration of routine liver ultrasonography to evaluate for liver adenomas

Agents/Circumstances to Avoid

Carbamazepine may worsen atypical absence seizures 11.

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