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Martes, Marso 12, 2013

Wolf-Hirschhorn Syndrome


 


Characteristics/Phenotype
Wolf-Hirschhorn syndrome in 1961. They described a child with midline fusion defects, and subsequent cytogenetic studies revealed a chromosomal deletion of the short arm of chromosome 4.  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 delays, a characteristic facial appearance, and may include a variety of other birth defects. 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.

Almost everyone with this disorder has distinctive facial features, including a broad, flat nasal bridge and a high forehead. 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.

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 delays, however, there are many affected individuals who are able to walk and some that are able to talk in short sentences.

Frequency
The prevalence of Wolf-Hirschhorn syndrome is estimated to be 1 in 50,000 births. However, this may be an underestimate because 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.

Diagnosis
When WHS is suspected, chromosome analysis should be performed and the laboratory should be informed as to what syndrome is suspected. 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.
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.
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.


Causes
Wolf-Hirschorn is caused by 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. 
Between 85 and 90 percent of all cases of Wolf-Hirschhorn syndrome are not inherited.

Treatment
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. Physiotherapy and occupational therapy are recommended. Some patients require physical aids, e.g. wheel chair, splints, hearing aids etc. Patients with congenital heart defects, clubfeet, and cryptorchidism have to be surgically treated. Those with seizures need  recurrent EEGs and antiepileptic drugs. Information about patients who have WHS has been compiled and provides a comprehensive look into the natural history of this condition and the needed management. 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 @ http://wolfhirschhorn.org/about-wolf-hirschhorn-syndrome/:
  • Feeding problems should be addressed and may require interventionsuch 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.
  • 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.

Advices
 In regards to the development of patients with WHS, it is suggested that individuals participate in personal development programs to assist with social and occupational therapy for motor skills.

References
http://ghr.nlm.nih.gov/condition/wolf-hirschhorn-syndrome

Photos from:
http://3.bp.blogspot.com/-D9zJ2UlSlFQ/TY-EsaJSAlI/AAAAAAAAARY/8iKdcpDs6BQ/s1600/DSC_0033soft.jpg
http://upload.wikimedia.org/wikipedia/commons/f/ff/Wolf-hirschhorn.jpg

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