Wolf-Hirschhorn syndrome
Wolf-Hirschhorn syndrome (WHS) is a genetic disorder caused by a partial deletion of the short arm of chromosome 4. This condition is characterized by a range of congenital malformations, significant intellectual disability, and a distinct facial appearance often described as a "Greek warrior helmet." WHS is estimated to occur in at least 1 in 50,000 births, with a higher prevalence in females. The majority of cases are linked to paternal genetic factors during meiosis. Common symptoms include growth delays, seizures, and various midline defects such as cleft lip/palate and skeletal malformations. Diagnosis typically involves advanced genetic screening techniques, as standard karyotyping can miss many cases. While there is currently no cure, treatment can address specific health challenges like feeding difficulties and seizures. Despite the challenges posed by WHS, many individuals show improvements in communication and daily living skills as they grow.
Wolf-Hirschhorn syndrome
ALSO KNOWN AS: 4p-syndrome; monosomy 4p; del(4p); includes Pitt-Rogers-Danks syndrome
DEFINITION Wolf-Hirschhorn syndrome (WHS) is caused by a partial deletion of the short arm of human chromosome 4. The syndrome is characterized by multiple congenital malformations accompanied by intellectual disability and is estimated to occur in at least 1 out of 50,000 births.
Risk Factors
Two-thirds of existing cases of Wolf-Hirschhorn syndrome occur in females. About 75 percent of WHS cases can be linked to a paternal origin, which is likely the result of the preponderance of subtelomeric genetic that is known to occur during meiosis in the male germ line.
Etiology and Genetics
A case report of a child exhibiting symptoms now associated with WHS was first published in 1961 by the laboratory of Kurt Hirschhorn, an Austrian-born American geneticist and pediatrician who also linked this disorder with a deletion on either human chromosome 4 or 5. Three years later, a partial deletion of the short arm of chromosome 5 was demonstrated to be the causal factor of cri du chat syndrome, and the following year WHS was described in detail in simultaneous reports by Hirschhorn’s group as well as by German geneticist Ulrich Wolf and colleagues.
As techniques were later developed that allowed for the physical mapping of human chromosomes, scientists sought to delineate the minimal deletion which would define WHS, as well as to characterize the genes that contribute to the disorder. Noting that about 20 percent of WHS cases have deletions restricted to 4p16.3, the terminal 2 percent of the chromosome, a WHS “critical region” was defined that encompassed this area. The subsequent description of rare patients who had submicroscopic deletions was able to reduce this critical region by more than half, an area in which the human genome sequencing project revealed there were at least a dozen genes, including WHSC1 (Wolf-Hirschhorn syndrome candidate 1), LETM1 (Leucine zipper-EF-hand containing transmembrane protein 1), and FGFR3 (Fibroblast growth factor receptor 3).
The most promising research to determine how the WHS critical region contributes to the disorder comes from mouse models in which the corresponding genes have been mutated experimentally. Mice with mutations in WHSC1 are seen to have growth impairment accompanied by craniofacial deformations and congenital heart defects, while those with mutations in FGFR3 demonstrate specific skeletal defects. Although no mice-bearing mutations in the LETM1 homolog have been reported, this gene has been linked with the appearance of seizures by examining patients with atypical patterns of deletion. It is clear that experiments involving mice will play a central role in elucidating the of this syndrome in the future.
Symptoms
WHS can display a wide range of symptoms, but just four are considered to define the core set of minimal diagnostic criteria. The first of these is a facial appearance which has been described as a “Greek warrior helmet.” This includes a broad bridge of the nose which continues to the forehead, a prominent space between the eyebrows, an increased distance between the eyes, and high-arched eyebrows. Other facial features include a small head with an undersized jaw, a “carp-shaped” mouth with a short infranasal depression, and low-set ears. The other core symptoms are growth delay, intellectual disability, and seizures (or at least detectable EEG anomalies). In addition to these core characteristics, some patients display a set of symptoms which have been characterized as “midline defects” and which include a cleft lip/palate; specific defects in such organs as the heart, esophagus, and diaphragm; and skeletal malformations such as scoliosis and clubfoot.
Screening and Diagnosis
Initial screening techniques used to detect WHS included basic cytogenetic procedures such as human karyotyping accompanied by staining to detect chromosome banding patterns, but these tended to miss about 40 percent of WHS cases. High-resolution banding techniques or FISH (fluorescence in situ hybridization), using probes which bind to the WHS critical region, are required to detect the smaller deletions which can lead to WHS.
Treatment and Therapy
The two most consistent treatable medical problems in children with WHS are major feeding difficulties and seizures. The former is usually treated by gastrostomy, creating a surgical opening into the stomach for feeding via a tube, while the latter has often been controlled by the use of antiepileptic drugs. Surgical intervention is also available to treat clubfoot and scoliosis, as well as to repair congenital heart defects.
Prevention and Outcomes
There is presently no cure for WHS. Over time, all cases of WHS will be expected to make improvements in communication skills, with about half of the cases learning how to walk, a fifth being able to help with simple household tasks, and a tenth becoming self-feeders. A tenth of WHS cases will also go on to achieve fecal continence during the day.
Bibliography
Bailey, Regina. "Wolf-Hirschhorn Syndrome." Advances in Neonatal Care 14.5 (2014): 318–21. Print.
Battaglia, Agatino, John C. Carey, and Tracy J. Wright, “Wolf-Hirschhorn (4p-) Syndrome.” Advances in Pediatrics 48 (2001): 75–113. Print.
Kerzendorfer, C., et al. "Meier-Gorlin Syndrome and Wolf-Hirschhorn Syndrome: Two Developmental Disorders Highlighting the Importance of Efficient DNA Replication for Normal Development and Neurogenesis." DNA Repair 12.8 (2013): 637–44. Print.
Nimura, Keisuke, et al. “A Histone H3 Lysine 36 Trimethyltransferase Links Nkx2-5 to Wolf-Hirschhorn Syndrome.” Nature 9 July 2009: 287–91. Print.
Searle, Claire J., Emma Shearling, and Oliver W. Quarrell. "Wolf-Hirschhorn Syndrome." Clinical Dysmorphology 22.4 (2013): 149–51. Print.
Simon, Ruth, and Andrew D. Bergemann. “Mouse Models of Wolf-Hirschhorn Syndrome.” American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 148C (2008): 275–80. Print.
"Wolf-Hirschhorn Syndrome." National Organization for Rare Disorders, 25 July 2024, rarediseases.org/rare-diseases/wolf-hirschhorn-syndrome/. Accessed 5 Sept. 2024.