DEFINITION
A genetic syndrome resulting from a partial deletion on the short arm of chromosome 4 (4p deletion syndrome). It is characterized by mental retardation, microcephaly, seizures, muscle hypotonia, a distinctive facial appearance with prominent forehead and wide set eyes, growth failure with malformations of the spine, hands, and feet, congenital heart defects, and genitourinary malformations ( NCI Thesaurus, 2011_02D)
Karyotype of the father of a WHS patient, 46,XY t(4;8)(p15.2;p22)
EPIDEMIOLOGY
Shannon et al. published an epidemiological study. They studied the minimum birth incidence calculated from the number of WHS cases born in the 10 years between 1989 and 1998 and the number of live births in the United Kingdom over this period. This gave a minimum birth incidence of 1 in 95.896. This compared with a previous estimate of 1 in 50.000. Given that WHS is a relatively rare condition, this varies from year to year and has increased over time. For unknown reasons it occurs in about twice as many females as males. The number could be underestimated because some affected individuals are never diagnosed, especially people who have little alterations.
Between 1989 and 1998, 79 children with WHS were born, of whom 23 subsequently died (29.1%). It has been estimated that approximately 35% of individuals who have WHS die within the first two years of life. A greater proportion of the inherited translocations compared to de novo deletions died within the first five years of life. The survival curves of de novo deletions never reach 50% which means that the median survival time for de novo deletions was greater than 34 years, while for translocation cases it was greater than 18 years.
SYMPTOMS
All individuals with WHS do not have all of the same signs and symptoms. A reason for a diagnosis is so that predictions can be made to determine the needs of that person, based on the history available from other individuals affected with the same condition. Individuals with WHS have been described as having a characteristic facial appearance called “Greek Helmet facies”: small head size (microcephaly), eyes spaced widely apart (ocular hypertelorism), downturned mouth, short upper lip and short groove between the upper lip and nose (philtrum) or bilateral cleft lip and/or palate, small chin (micrognathia).
Patients with WHS that show the tipical Greek Helmet facies
Other signs and symptoms are: slow growth before birth, slow growth after birth (postnatal growth deficiency), weak cry in infancy, poor muscle tone (hypotonia), seizures, severe developmental delays, severe delay of motor skills, crossed eyes (Strabismus), droopy eyelids (ptosis), skin folds in the corner of the eyes (epicanthal folds), asymmetry of the skull (cranial asymmetry), skin tag or pit in front of the ear (preauricular tag or pit), prominent triangular area of the forehead (glabella), scalp defects on the center of the back of the head, underdeveloped fingerprints (dermal ridges), a single crease across the palm of the hands (Simian crease), misaligned bones in the front part of the foot/clubfoot (talipes equinovarus), turned up fingernails, urinary opening on the underside of the penis (hypospadias), undescended testicles (cryptorchidism), dimple at the base of the spine, heart defects, curvature of the spine (scoliosis), underdeveloped bones of the hands and pelvis.
DIAGNOSIS
When WHS is suspected, chromosome analysis should be performed and the laboratory should be informed as to what syndrome is suspected. This ensures that the laboratory carefully looks at chromosome 4 because sometimes deletions are too short and it is not possible to observe them in karyotype, so when there is the suspect of WHS it is possible to use fluorescence in situ hybridization (FISH). With this method you can use a probe that hybridizes on 4p16.3 and it’s also used a probe as control that hybridizes on the centromere of chromosome 4.
FISH of a WHS patient (red probe is 4p16.3 and aqua is CEP4)
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. These ultrasound findings may include heart defects, microcephaly, agenesis of the corpus callosum (missing a specific part of the brain), micrognathia, cleft lip and palate, a hole in the diaphragm (diaphragmatic hernia), hypospadius, and clubbed feet. If the alterations are undetectable with FISH, but there is the dubious that it can be WHS, it can also be used the Array-CGH.
Array-CGH of the chromosome 4. The deleted part is pointed by brace
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; an option is preimplantation genetic diagnosis. Preimplantation genetic diagnosis is a very complex process that involves in vitro fertilization and diagnosing the embryos before they are placed into the mother’s uterus. Thus, only unaffected embryos are transferred to the uterus. Lastly, the options of CVS and amniocentesis for prenatal diagnosis should be discussed.
PATHOGENESIS
This syndrome was firstly reported in 1965 in published reports by Wolf and Hirschhorn. Wolf-Hirschhorn syndrome refers to a phenotype resulting from a partial deletion of chromosomal material of the short arm of chromosome 4, this genetic heterogeneity leads to more or less severe phenotypes. The typical genetic lesion is the hemizygous deletion of chromosome 4p16.3 which causes the full expression of WHS. WHS is characterize by severe developmental delays, a characteristic facial appearance, and may include a variety of other birth defects. Some infants with WHS can be stillborn or die shortly after birth, about 35% of patients die in the first two years of life. The 85-90% of WHS patients carry de novo mutations and in the remaining 10-15% of cases the deletion derives from a balanced translocation inherited by one parent.
After the initial hypothesis that a single gene could be responsible for the whole WHS phenotype, the pathogenesis of WHS is considered to be multigenic, with different genes involved in the production of distinctive clinical signs. Genomic rearrangements productive of the core WHS phenotype are expected to be chromosome deletions event in all cases, and no typical WHS patients are expected to harbor a single gene mutation. The characteristic signs and symptoms of this syndrome are associated with the loss of WHSC1, LETM1; these genes are contiguous in the 4p so the rearrangments often involve them all.
Image of the 4p; it is possible to notice the contiguity of LETM1 and WHSC1
At a molecular level, comparative analysis of either terminal and interstitial deletions allowed the description of the first critical region, WHSCR, limited to a 165 kb interval at about 2 Mb from the telomere, defined by the loci D4S166 and D4S3327; this genes are involved in different pathways. It seems that loss of WHSC1 is associated with distinctive facial appearance and developmental delay; this gene is a H3K36me3-specific histone methyltransferase. LETM1 (leucine zipper/EF-hand-containing transmembrane (OMIM 604407)), is a protein active in the mitochondria; it seems to be involved in Ca2 signalling and in determining the shape and volume of mitochondria. It is probably associated with seizures or other abnormal electrical activity in the brain.
MSX1 is another gene associated to dental abnormalities and cleft lip and/or palate; this gene is placed on the 4p16.2 and is often associated to WHS in largest chromosomal rearrangements.
Characterizing the pathogenic genes for these signs could allow the design of a gene therapy for WHS. Given that haploinsufficiency is the basic pathogenetic mechanism in WHS, the unaltered copies of each deleted gene on the homologous chromosome are the ideal target for attempts at enhancing their expression by reactivating drugs.
TREATMENT AND MENAGEMENT
Treatment and management for patients who have WHS are specific to each individual. 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. For some pathological manifestations are recommended appropriate therapies, such as:
• feeding problems should be addressed and may require intervention such as placement of a gastrostomy tube;
• characterization of seizures is important and treatment with antiepileptic medications 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. Children with WHS have learned to walk unassisted;
• as approximately 30% of individuals may have congenital heart defects, the heart should be examined. Usually, the heart lesions are not severe and may be repaired easily or may not even require surgery;
• 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 should be performed to an ophthalmology exam to rule out any eye problems, even if no obvious signs are present;
• physical and occupational therapy can help maintain muscle strength and joint mobility, so it is recommended to contact a physiotherapist.
