Supervisors info:
Ελένη Φρυσίρα, Καθηγήτρια, Ιατρική, ΕΚΠΑ
Μαρία Τζέτη, Αναπληρώτρια Καθηγήτρια, Ιατρική, ΕΚΠΑ
Ιωάννα Traeger-Συνοδινού, Καθηγήτρια, Ιατρική, ΕΚΠΑ
Summary:
Williams syndrome (WS, also Williams-Beuren syndrome) is a multisystem disorder caused by the deletion of 26-28 contiguous genes on chromosome 7q11.23. It is present at birth and affects boys and girls equally, with an incidence of 1/7,500 to 10,000. As routine genetic amniocentesis does not typically detect chromosome microdeletions, children with WS usually come to the attention of pediatricians during infancy or childhood. The WS phenotype is characterized by dysmorphic facial features (100%), elastin arteriopathy (75-80%) most commonly supravalvar aortic stenosis-SVAS, mental retardation (75%), a unique personality and cognitive profile (90%), idiopathic infantile hypercalcemia (15%) and other endocrine abnormalities (early puberty, hypothyroidism, diabetes), short stature and connective tissue abnormalities. Feeding difficulties often lead to poor weight gain in infancy. Hypotonia and hyperextensible joints can result in delayed attainment of motor milestones. Penetrance is 100% but the WS phenotype is variable. No single clinical feature is required to establish the diagnosis.
WS is a genomic disorder that occurs due to nonallelic homologous recombination (NAHR) in a region of chromosome 7 containing blocks of low copy repeats (LCRs) with high sequence homology that predispose to rearrangements during meiosis and thus can lead to deletion, duplication, or inversion of the WS region. The Williams syndrome chromosome critical region (WSCR) comprise either 1.55Mb (90%-95%) or 1.84Mb (5%-10%), the size depending on which blocks of low copy repeats are involved in NAHR. The diagnosis historically has been made on the basis of clinical criteria, but it has been shown that 99% of patients with WS have a hemizygous submicroscopic deletion of 7q11.23 detectable by targeted deletion analysis by fluorescence in situ hybridization (FISH) or chromosomal microarray analysis (CMA). The deleted portion of the chromosome includes the ELN gene that codes for the structural protein elastin, an important component of the elastic fibers found in the connective tissue of many organs. The elastin deletion explains some of the characteristics of WS, such as some of the facial features (periorbital fullness and full cheeks in infancy), cardiovascular disease, hoarse voice, soft skin, lax ligaments bladder and bowel diverticula, hernias, and joint abnormalities. The pathogenesis of other characteristics, such as hypercalcemia, mental retardation, and unique personality traits, remains unexplained. Although several genes of interest (e.g., ELN) are within the 1.5-1.8-Mb recurrent microdeletion, no single gene in which pathogenic variants are causative of WS has been identified. One possibility is that the loss of 1 or more genes contiguous to the ELN gene contributes to the phenotype. Studies suggest that deletion of CLIP2, GTF2I, GTF2IRD1, LIMK1, and perhaps other genes may help explain the characteristic difficulties with visual-spatial tasks, unique behavioral characteristics, and other cognitive difficulties seen in people with Williams syndrome. Loss of the GTF2IRD1 gene may also contribute to the distinctive facial features often associated with this condition. Researchers believe that when the NCF1 gene is included in the part of the chromosome that is deleted, affected individuals are less likely to develop hypertension. The relationship between other genes in the deleted region of chromosome 7 and the signs and symptoms of WS is under investigation or unknown.
The most significant cause of morbidity and mortality in WS is the cardiovascular disease. WS is transmitted in an autosomal dominant manner. Most cases are de novo occurrences, but occasionally, parent-to-child transmission is observed. Prenatal testing is possible but is rarely used because most cases occur in a single family member only, and no prenatal indicators exist for low-risk pregnancies.
Treatment and follow up for people with WS requires a multidisciplinary professional team and may be individualized depending on the symptoms and severity in each person. Management mainly include: feeding therapy for infants with feeding problems, early intervention programs and special education programs for children with varying degrees of developmental disabilities, behavioral counseling and/or medications for attention deficit disorder and/or anxiety, surgery for certain heart abnormalities, medications or diet modifications for hypercalcemia, orthodontic appliances or other treatments for malocclusion of teeth and gonadotroping-releasing hormone agonist for precocious puberty.
Keywords:
Williams-Beuren syndrome, Chromosome 7, Microdeletion, Supravalvar aortic stenosis, Elastin
