Diagnosis: Wolf-Hirschhorn syndrome

Wolf-Hirschhorn syndrome (WHS) is an extremely rare chromosomal disorder caused by a missing segment (partial deletion or monosomy) of the short arm of chromosome 4. Key features can include widely spaced eyes (ocular hypertelorism) with a broad or beaked nose, small head (microcephaly), low-set ears, slow growth, heart defects, and intellectual disabilities. The severity and presentation vary among individuals depending on the size and location of the deleted portion of chromosome 4.

Diagnosis:
Chromosomes are located in the nucleus of all body cells and carry the genetic traits of each individual. Human chromosomes are numbered 1 to 22, with the 23rd pair being the sex chromosomes (XX for females, XY for males). Each chromosome has a short arm labeled “p” and a long arm labeled “q.” Chromosomes are further divided into numbered bands. For example, “chromosome 4p16.3” refers to band 16.3 on the short arm of chromosome 4. Numbered bands are used to precisely locate genes on each chromosome.

This disorder is caused by a deletion of part of the short arm of chromosome 4 (4p). The region 4p16.3 is considered the “critical region” for the syndrome, meaning that deletion of this area leads to the full expression of Wolf-Hirschhorn syndrome (WHS). In most cases, the deletion causing WHS occurs very early in development (likely in the egg or sperm before fertilization) and is not inherited from the parents. Much less commonly, the disorder is inherited from a parent with a balanced translocation. WHS is extremely rare. Studies conducted about 25 years ago estimated its occurrence at approximately 1 in 50,000 live births, with a female-to-male ratio of 2:1. More recent studies suggest the prevalence may be underestimated due to misdiagnosis.

Diagnosis of WHS can be suggested by characteristic facial features, growth failure, or developmental delays. Confirmation is made by detecting a deletion in the Wolf-Hirschhorn syndrome critical region (WHSCR) through cytogenetic (chromosome) analysis. Conventional cytogenetic analysis detects less than half of WHS-causing deletions. Fluorescence in situ hybridization (FISH) using a WHSCR probe has a much higher detection rate than standard karyotyping and can identify most patients. The preferred diagnostic test is chromosomal microarray analysis, which can detect nearly all WHSCR deletions and define their size. Microarray analysis can also identify additional chromosomal rearrangements, such as extra segments from other chromosomes, which are present in many WHS patients.

Treatment:
Because WHS is a highly variable syndrome, treatment and interventions must be tailored to the individual’s needs. Patients with a known or suspected diagnosis of WHS should undergo a comprehensive evaluation by an experienced geneticist. Most patients will need to see multiple specialists. Following diagnosis, early assessments should include neurological evaluation, detailed cardiological (heart) examination, eye and hearing tests, kidney function assessment, nutritional evaluation, and developmental assessment. Kidney function must be continuously monitored. All individuals require comprehensive developmental and rehabilitative support, including assistance with feeding, augmentative communication, speech therapy, physical therapy, occupational therapy, and educational support. Genetic counseling is recommended for families of children with Wolf-Hirschhorn syndrome.

Wolf-Hirschhorn syndrome

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