Wolf-Hirschhorn syndrome

Posted by Dr. Han Thi Thu Huong - Medical Genetics Block, Vinmec High Technology Center

Wolf-Hirschhorn syndrome (WHS) is an extremely rare chromosomal disorder caused by a partial lack of the short arm of chromosome 4 (partial loss or monosomy). Wolf-Hirschhorn syndrome is also known by several names: 4p- syndrome; Pitt-Rogers-Danks syndrome; WHS; Monosomy 4p.

Major symptoms of Wolf-Hirschhorn Syndrome may include ocular hypertelorism or hook nose, microcephaly, lower-than-normal ear deformities, growth deficiency, disability heart disease, intellectual disability and epilepsy. These symptoms vary based on the size and location of the missing segment of chromosome 4.
Wolf-Hirschhorn syndrome occurs in approximately 1:50,000 live births with a female-to-male ratio of 2:1. Many recent studies have shown that the frequency of the disorder is underestimated due to misdiagnoses. .

The characteristic feature of people with Wolf-Hirschhorn syndrome is having a typical face. The area of ​​​​the base of the nose between the eyebrows is wide and prominent (glabella), the eyes are convex, far apart, the eyebrows are arched, the palate is open. This makes the bridge of the nose the focal point of the face.
Common symptoms of people with WHS include: growth problems (low weight and height) right before birth; intellectual disability (may vary from person to person, but is usually quite pronounced); low muscle tone (hypotonia) and epilepsy.
Other common signs include microcephaly; eyes that are different from normal (droopy eyelids, eye defects); cleft lip and palate; abnormality of the penis, testicles, or vagina; kidney abnormalities; problems with bones and teeth.
Congenital heart defects are common in people with WHS, but are often simple, such as an atrial septal defect or ASD, and can be treated with surgery or cardiac catheterization.

Many people with WHS have an increased risk of infection. Some are actually immunocompromised, most commonly a reduced ability to make antibodies.
Feeding problems can be quite serious for some sick people. The majority of affected individuals require tube nutrition at some point in life, and many are dependent on this modality for life. Some individuals experience serious problems with the gut including malrotation (abnormal rotation and fixation of the bowel), bowel dysfunction or malabsorption of nutrients.
Intellectual and developmental problems vary from person to person but are significant in most people with WHS. People with WHS struggle in many areas including: communication, gross motor skills, fine motor skills, and quantitative reasoning. People with WHS need speech aids or sign language to facilitate communication.

Wolf-Hirschhorn syndrome is an extremely rare chromosomal disorder caused by a deletion of WHSCR (Wolf Hirschhorn syndrome critical region) on the short arm of chromosome 4 (4p).
Most cases of Wolf-Hirschhorn syndrome occur due to unexplained de novo generation very early in embryonic development (possibly in the egg or sperm before fertilization) ). A less common cause is that the disorder is inherited from a parent with a balanced translocation mutation.

Wolf-Hirschhorn syndrome can be diagnosed by ultrasound while the baby is still in the womb or by appearance after birth by characteristic facial expressions, developmental delays, and seizures.
Some tests to identify deletions on the short arm of chromosome 4:
Karyotyping (Chromosome formula): a technique to test the number and structure of the human chromosome, however, due to the limitation of the method, the ratio low detection rate. FISH (Fluorescent In situ Hybridization) using the WHSCR probe has a much better detection rate than Karyotype and detects most deletions in most patients. Array-CGH (Comparative Genome Hybrid) detects all WHSCR deletions and the size of the missing fragment.

Because Wolf-Hirschhorn syndrome affects so differently, treatment and interventions must be tailored to the individual needs of the patient. Patients with a known or suspected diagnosis of WHS should be comprehensively evaluated by an experienced genetic specialist. Most patients will need to be monitored by multiple specialists. Patients should have a neurological evaluation of seizures, detailed cardiovascular, ophthalmic examination, hearing testing, renal assessment, feeding, and developmental assessment as soon as possible after diagnosis. Renal function must be continuously monitored. Patients must receive comprehensive developmental and rehabilitation support including: feeding therapy, communication support, speech, physical therapy, occupational therapy and school support. Genetic counseling is recommended for families of children with Wolf-Hirschhorn syndrome.
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References: rarediseases.org