Wolf-Hirschhorn syndrome

Definition

Wolf-Hirschhorn syndrome (WHS) refers to a condition that is caused by a missing part (deletion) of the short arm of chromosome 4. This missing genetic material results in severe developmental retardation, a characteristic facial appearance, and may include a variety of other birth defects.

Description

This syndrome was reported in 1965 in published reports by Wolf and Hirschhorn, who described that the characteristics of the syndrome were associated with a deletion of part of the short arm of chromosome 4. The short arm of a chromosome is called the "p" arm. Thus, this syndrome is also known as 4p-syndrome or deletion 4p syndrome, and occasionally as Wolf syndrome.

A normal human karyotype consists of 23 pairs of chromosomes. Each pair is numbered 1 through 22 and the twenty-third pair are the sex chromosomes. On each chromosome are hundreds of genes that determine how our bodies look and function. WHS is a contiguous gene syndrome. A contiguous gene syndrome occurs when a chromosome is either missing material (deletion) or has extra material (duplication) of several genes in the same region of the chromosome. Each time that the deletion or duplication of those genes occur, they cause specific characteristics that come to be known as a particular syndrome. This is in contrast to having just one particular gene cause a syndrome. Some patients who have WHS may have a small deletion on 4p, while others may be missing up to half of 4p. For this reason, some individuals have a less severe case of WHS than others do. The band 4p16.3 needs to be deleted in order for an individual to have full expression of WHS.

WHS frequently presents prenatally with slow growth (intrauterine growth retardation). Some infants with WHS can be stillborn or die shortly after birth. As many as one-third of reported patients have died in the first year of life. Individuals with WHS have been described as having a characteristic facial appearance likened to a "Greek Helmet facies." This can be described as having a small head size (microcephaly), eyes spaced widely apart (ocular hypertelorism), downturned mouth, short upper lip and short groove between the upper lip and nose (philtrum) or bilateral cleft lip and small chin (micrognathia).

These children have severe developmental retardation. Other significant problems can include heart defects, cleft lip and/or palate, hearing impairment, and eye problems. Most children who have WHS have seizures (approximately 90%). Seizures are one of the major health concerns in children with WHS. These seizures begin between five and 23 months of age, however approximately 50% of the individuals stop having seizures between age three and 11. Sleeping problems are also common in children who have WHS. Although it seems that most of the literature focuses on children who have WHS, there are adults who have WHS.

Genetic profile

Frequently, with routine chromosome analysis, it is possible to identify that the short arm of chromosome 4 is missing some genetic material. The size of the missing material may vary from patient to patient. At times, the deletion is so small that it cannot be detected by routine chromosome analysis. If a patient is suspected to have WHS and an obvious deletion is not detected by routine chromosome analysis, more detailed studies, including fluorescent in situ hybridization , are warranted and may identify the missing genetic material. WHS may also present as mosaicism. Mosaicism for 4p-syndrome means that the individual has some cells that have normal number 4 chromosomes and other cells that are missing some of the genetic material from 4p.

Approximately 85–90% of cases of WHS occur as the result of a new deletion in the affected individual. This is also known as a de novo deletion and simply means that the affected individual's parents did not have any chromosome arrangement that led to the deletion. In this case, the chance for recurrence in future pregnancies of a couple whom has an affected child is not increased. In the remaining 10–15% of cases, one of the parents of the affected individual carries a balanced translocation. A balanced translocation is a rearrangement in the individual's chromosomes that causes that individual no problems since they have all the necessary genetic material that they need. However, when they produce eggs or sperm, the eggs or sperm may end up with an unbalanced arrangement and could lead to the conception of a child who has missing or extra genetic material. This could lead to miscarriage or to the birth of a child with conditions, such as WHS.

When a parent is identified as being a carrier of a balanced translocation, with each pregnancy they have an increased chance for having a child with an unbalanced chromosome arrangement. The chance of this is determined by the individual's specific translocation, how it was identified, and which parent is the carrier of the translocation. Genetic counseling should be offered for any family in which a child is diagnosed to have WHS. Other family members should also be offered counseling and chromosome analysis to determine if they are carriers of a balanced translocation.

Demographics

The incidence of this condition is rare and estimated to be approximately one in 50,000 births. However, as with many genetic conditions, the condition may be misdiagnosed or may not be diagnosed in all individuals who are affected, especially if the condition results in pregnancy loss or loss in the early newborn period. It has been estimated that approximately 35% of individuals who have WHS die within the first two years of life. Also, with the advent of prenatal diagnosis, some fetuses with ultrasound abnormalities may be detected prenatally and the parents may elect to terminate the pregnancy. Approximately two-thirds of reported cases have been females.

Signs and symptoms

It is important to remember that each individual who may have a particular genetic syndrome is a unique individual. Therefore, all individuals with WHS do not have all of the same signs and symptoms. The most important reason for diagnosing an individual with a syndrome is not to put a label on that person. The reason for a diagnosis is so that predictions can be made to determine the needs of that person, based on the history available from other individuals affected with the same condition.

Signs and symptoms that can be associated with WHS include:

• slow growth before birth
• slow growth after birth (postnatal growth deficiency)
• small head size (microcephaly)
• week cry in infancy
• poor muscle tone (hypotonia)
• seizures
• severe developmental retardation
• severe retardation of motor skills
• crossed eyes (Strabismus)
• widely spaced eyes (hypertelorism)
• droopy eyelids (ptosis)
• skin folds in the corner of the eyes (epicanthal folds)
• cleft lip and/or palate
• short upper lip and philtrum
• small chin (micrognathia)
• asymmetry of the skull (cranial asymmetry)
• skin tag or pit in front of the ear (preauricular tag or pit)
• downturned mouth
• prominent triangular area of the forehead (glabella)
• scalp defects on the center of the back of the head
• underdeveloped fingerprints (dermal ridges)
• a single crease across the palm of the hands (Simian crease)
• misaligned bones in the front part of the foot/clubfoot (talipes equinovarus)
• turned up fingernails
• urinary opening on the underside of the penis (hypospadias)
• undescended testicles (cryptorchidism)
• dimple at the base of the spine
• heart defects
• curvature of the spine (scoliosis)
• underdeveloped bones of the hands and pelvis

Diagnosis

When WHS is suspected, chromosome analysis should be performed and the laboratory should be informed as to what syndrome is suspected. This ensures that the laboratory carefully looks at chromosome 4 and if the deletion is not visible, then fluorescent in situ hybridization (FISH) can be done specifically for the critical 4p16.3 region of chromosome 4. FISH analysis is a procedure that is used in the laboratory to identify pieces of genetic material that are too small to see by looking at the chromosome under the microscope. Instead, DNA that is specific to a particular area of a chromosome is fluorescently labeled, so that it is visible under the microscope. This labeled DNA is then added to the sample and allowed to attach itself to the particular piece of DNA in question. This enables the laboratory technician to then look under the microscope for the fluorescent spot on the chromosome and identify extra or missing pieces of DNA that are too small to see by just looking at the chromosome alone. With this procedure, those individuals who have deletions so small that they cannot be detected by routine chromosome analysis may be able to have the deletion detected by FISH.

Interestingly, there is a syndrome called Pitt-Rogers-Danks syndrome (PRDS) that has been reported to have similar characteristics to WHS. Several individuals who have initially been diagnosed with PRDS subsequently had FISH analysis that detected a deletion of 4p, and thus the individuals were reclassified as having WHS. Some feel that PRDS is actually WHS without obvious deletions of 4p.

When a couple has had a child diagnosed to have WHS, and a member of that couple carries a balanced translocation, genetic counseling should be offered to discuss reproductive options. One option is choosing sperm or egg donation so that the parent who has the translocation does not pass unbalanced genetic material on to his or her child. Another option is preimplantation genetic diagnosis. Preimplantation genetic diagnosis is a very complex process that involves in vitro fertilization and diagnosing the embryos before they are placed into the mother's uterus. Thus, only unaffected embryos are transferred to the uterus. Lastly, the options of CVS and amniocentesis for prenatal diagnosis should be discussed. All of these options have allowed couples with balanced translocations to realize the dream of having more children when the fear of having another affected child may have otherwise stopped them from choosing to add to their families.

If ultrasound examination reveals findings consistent with the possibility of WHS in a family with no history of WHS, genetic counseling and prenatal diagnosis should be offered. These ultrasound findings may include heart defects, microcephaly, agenesis of the corpus collosum (missing a specific part of the brain), micrognathia, cleft lip and palate , a hole in the diaphragm (diaphragmatic hernia), hypospadius, and clubbed feet. Keep in mind that these findings can also be consistent with other genetic syndromes.

Treatment and management

There is no treatment for the underlying condition of WHS. Treatment and management for patients who have WHS are specific to each individual. For example, some individuals who have WHS may have heart defects or a cleft lip and/or palate that may require surgery, while others may not. Therefore, there is no specific treatment for individuals who have WHS, rather, the treatment and management is geared toward that particular individual's needs and is likely to include several medical specialists. Information about patients who have WHS has been compiled and provides a comprehensive look into the natural history of this condition. It also allows the following management guidelines to be recommended. The collection of this information has shown that many of these individuals may achieve more development than was previously believed possible.

The following management recommendations have been made by Drs. Battaglia and Carey:

• Feeding problems should be addressed and may require intervention such as placement of a gastrostomy tube.
• Characterization of seizures is important and treatment with antiepileptic medications such as valproic acid should be investigated and may help control the seizure activity in many individuals.
• Skeletal abnormalities such as clubfoot should be addressed and treatment should be considered. It should not be assumed that clubfoot does not need addressed because the child will never walk. Children with WHS have learned to walk unassisted.
• As approximately 30% of individuals may have congenital heart defects, the heart should be examined. Usually, the heart lesions are not severe and may be repaired easily or may not even require surgery.
• Hearing loss may occur and because some children are able to learn to talk in short sentences, they should be screened for hearing problems.
• Eye abnormalities may be present and thus an ophthalmology exam should be performed to rule out any eye problems, even if no obvious signs are present.
• In regards to the development of patients with WHS, it is suggested that individuals participate in personal development programs to assist with social skills and occupational therapy for motor skills.

Prognosis

Infants who have WHS may be stillborn or die in the newborn period and prognosis during the newborn period depends upon what birth defects are present. It has been estimated that approximately 35% of individuals who have WHS die within the first two years of life. Many individuals who have WHS survive to adulthood. Universally, children with WHS have severe or profound developmental retardation, however, there are many affected individuals who are able to walk and some that are able to talk in short sentences. It is evident that many patients seem to proceed farther than was previously thought possible. The actual lifespan for individuals who have WHS is unknown, although there are several individuals who have WHS who are in their 20–40s.

Resources

BOOKS

Schaefer, G. Bradley, et al. Wolf-Hirschhorn Syndrome (4p-): A Handbook for Families. Munroe-Meyer Media Center, 1996. (1-800-656-3937).

PERIODICALS

Battaglia, Agatino, and John C. Carey. "Health Supervision and Anticipatory Guidance of Individuals With Wolf-Hirschhorn Syndrome." American Journal of Medical Genetics (Semin. Med. Genet.) 89 (1999): 111-115.

ORGANIZATIONS

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.

WEBSITES

4p-Support Group. <http://www.4p-supportgroup.org>.

Renee A. Laux, MS