Wolf-Hirschhorn Syndrome Health Article

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.