Wolf-Hirschhorn Syndrome (WHS), A Case Report and Review of Literature Submit Manuscript

Abstract

Background: Wolf-Hirschhorn Syndrome (WHS) is a congenital malformation syndrome characterized by growth deficiency and varying developmental delays based on genomic deletions and characteristic facies. The majority of WHS cases are caused by a deletion of 4p16.3 regions on chromosome 4, which includes the Wolf-Hirschhorn Syndrome Candidate genes (WHSC1 and WHSC2). WHSC1 protein is required to inhibit DNA damage by regulating the methylation of histones. The diagnosis of WHS is established by detection of a heterozygous deletion of the Wolf-Hirschhorn Syndrome Critical Region (WHSCR) with 4p16.3 at approximately 1.4-1.9 kb from the terminus. The WHSCR region is restricted to a 165-kb interval in the 4p16.3. Some of the associated structural defects, such as cleft lip and palate, occur more frequently in individuals with greater than 3 megabase (Mb) deletions. The quantity of base deletions is an important factor in explaining phenotypic variability WHS. The deletion size has a partial correlation to severity, but not a direct correlation, as the phenotypic affect may be more or less severely affected than would be expected by the size of the deleted megabase. Most individuals affected by this disorder have distinctive facial features, such as a broad, flat nasal bridge and a high forehead described as the “Greek warrior helmet” appearance in which the eyes are protruding and widely spaced. Other facial features include a shortened distance between the nose and the upper lip (a short philtrum), a down-turned mouth, a small chin (micrognathia), poorly formed ears with small holes (pits) of flaps of skin (tags), a small head (microcephaly). Intellectual disability ranges from mild to severe in people with WHS. Compared to people with other forms of intellectual disability, their socialization skills are strong, while verbal, communication, and language skills tend to be weaker. Case: We present the identification during routine obstetric sonographic imaging of growth restricted fetus affected by WHS with co-morbid oligohydramnios and abnormal prenatal obstetrics ultrasound studies, which showed micrognathia, echogenic kidneys and echogenic bowel, in addition to a three-week discrepancy between the estimated ultrasound age and the gestational age by last menstrual period (LMP), compatible with intrauterine growth restriction (IUGR). Prenatal genetic testing demonstrated female karyotype with a satellite chromosome on chromosome 4 short arm and mosaicism for an additional marker chromosome (47, XX, 4ps, +mar (8)/46, XX, 4ps). The prenatal diagnostic approach included fetal sonographic assessment and molecular cytogenetic investigation. After engaging in a multidisciplinary informed consent process at our institution, the patient chose to continue prenatal care and not electively terminate the pregnancy. Conclusion: A 4p deletion on chromosome 4 can be associated with subtle chromosome imbalances in other chromosomes. For example, the t(4;8)(p16;p23) translocation may be undetected in routine cytogenetics, suggesting that this translocation may be more the most frequent translocation after the most common reciprocal translocation in humans, t(11q;22q). The extent of the Mb deleted within the 4p region located on chromosome 4 correlates with the severity of the WHS phenotype. Genetic counseling provides families with information on the nature and implications of inherited genetic disorders, as a means of facilitating shared health care decisions.