Williams-Beuren syndrome (WBS)

Was ist Williams-Beuren syndrome (WBS)?

Das Williams-Beuren-Syndrom ist eine genetische Erkrankung mit einem charakteristischen Gesicht. Zu den mit dieser Entwicklungsstörung verbundenen Gesundheitszuständen gehören Herzfehler und insbesondere eine supravalvuläre Aortenstenose. Leichte bis mittelschwere geistige Behinderungen oder Lernprobleme und oft einzigartige Persönlichkeitsmerkmale kennzeichnen diesen Zustand. Patienten haben oft ein typisches Gesicht für dieses Syndrom, das einen breiten Mund, hervorstehende Lippen und eine kleine Nase umfasst. Die Störung ist selten und tritt bei ungefähr 1 bei 10,000 Personen auf.

Syndrom Synonyme:
williams-beuren

Was Genveränderungen verursachen Williams-Beuren syndrome (WBS)?

Es wird verstanden, dass die Deletion von genetischem Material aus einer bestimmten Region von Chromosom 7 das Williams-Beuren-Syndrom verursacht. Die typischerweise deletierten Gene umfassen CLIP2, ELN, GTF2I, GTF2IRD1 und LIMK1. Es wird davon ausgegangen, dass die Deletion dieser und möglicherweise auch anderer Gene zu den einzigartigen Verhaltensmerkmalen und anderen kognitiven Schwierigkeiten von Menschen mit Williams-Beuren-Syndrom beiträgt. Das Syndrom wird normalerweise nicht vererbt, sondern tritt während der Bildung von Fortpflanzungszellen beim Elternteil des betroffenen Individuums auf. Personen mit dieser Erkrankung haben jedoch eine 50% ige Chance, dass die Erkrankung von ihren zukünftigen Kindern geerbt wird.

Mikrodeletionsvererbung tritt auf, wenn mehrere Gene auf einem Chromosom deletiert werden. Das spezifische Chromosom, auf dem die Deletionen auftreten, bestimmt das Syndrom, das sie verursachen.

Gene, Orte und Vererbungsmodi
ELN, 7 q11. 23 - Autosomal Dominant, Mikrodeletion
MLXIPL, 7 q11. 23 - Autosomal Dominant, Mikrodeletion
GTF2IRD1, 7 q11. 23 - Autosomal Dominant, Mikrodeletion
GTF2I, 7 q11. 23 - Autosomal Dominant, Mikrodeletion
TBL2, 7 q11. 23 - Autosomal Dominant, Mikrodeletion
RFC2, 7 q11. 23 - Autosomal Dominant, Mikrodeletion
BAZ1B, 7 q11. 23 - Autosomal Dominant, Mikrodeletion
DLG4, 17 S. 13. 1 - Autosomal Dominant, Microdeletion
CLIP2, 7 q11. 23 - Autosomal Dominant, Mikrodeletion
LIMK1, 7 q11. 23 - Autosomal Dominant, Mikrodeletion

OMIM-Nummer - - 194050 (Bitte überprüfen Sie die OMIM-Seite für aktualisierte Informationen)

Was sind die wichtigsten symptome von Williams-Beuren syndrome (WBS)?

Die Hauptsymptome des Williams-Beuren-Syndroms sind charakteristische Gesichtsmerkmale wie ein breiter Mund, eine kleine nach oben gerichtete Nase, weit auseinander liegende Zähne und volle Lippen. ADS, Angstzustände und Phobien sind bei Personen mit dem Syndrom ebenso häufig wie Lernstörungen und Sprachverzögerungen.
Säuglinge können Koliken und Ernährungsprobleme sowie ein niedriges Geburtsgewicht und einen niedrigen Muskeltonus aufweisen.

Andere körperliche Erkrankungen können Kleinwuchs, Weitsichtigkeit und eine versunkene Brust sein. Nierenanomalien sind auch ein Symptom des Syndroms.

Mögliche klinische Merkmale / Merkmale:
Kognitive Beeinträchtigung, Anfall, Patent ductus arteriosus, porencephale Zyste, Mikrozephalie, Arnold-Chiari-Missbildung, Vorhofseptumdefekt, Autismus, Aufmerksamkeitsdefizit-Hyperaktivitätsstörung

Wie wird jemand getestet? Williams-Beuren syndrome (WBS)?

Die ersten Tests für das Williams-Beuren-Syndrom können mit einem Screening der Gesichtsanalyse über die FDNA Telehealth Telegenetics-Plattform beginnen, mit der die Schlüsselmarker des Syndroms identifiziert und die Notwendigkeit weiterer Tests aufgezeigt werden können. Eine Konsultation mit einem genetischen Berater und dann einem Genetiker wird folgen. 

Basierend auf dieser klinischen Konsultation mit einem Genetiker werden die verschiedenen Optionen für Gentests geteilt und die Zustimmung für weitere Tests eingeholt.

Medizinische Informationen zu Williams-Beuren syndrom

Williams et al., first described this syndrome in 1961 and Beuren et al., (1962) expanded the phenotype. The main features are a characteristic face, heart defects, mental retardation with an outgoing personality and sometimes hypercalcaemia in infancy. The facial features consist of periorbital fullness, medial eyebrow flare, a stellate iris pattern, a flat nasal bridge, a flat malar region with full cheeks and lips, and a wide mouth with a long smooth philtrum.
Balacco-Gabrieli et al., (1985) reported a case with Rieger anomaly and megaloureter.
The facies may become coarser with age (Lopez-Rangel et al., 1992).
Hypercalcaemia may be difficult to document by the time the child has developed the full clinical features, but occasionally it is severe and persists. Enamel hypoplasia, strabismus and inguinal hernias are common. Pober et al., (1993) studied 40 children with Williams syndrome and found that seven (18%) had renal anomalies, however, only two had nephrocalcinosis - the remainder had abnormalities of size or shape of the kidneys. Mild renal artery stenosis was found in four out of nine patients studied, but only two had hypertension, which did not correlate with the renal artery stenosis.
Pankau et al., (1993) point out that radio-ulnar synostosis can be a feature in about 10% of cases (see also Bzduch, 1994). Curran et al., (1993) reported a disruption of the elastin gene at 7q11 in a family segregating for supravalvular aortic stenosis and a balanced translocation. Morris et al., (1993) suggested that the elastin gene on 7q11 may be involved in this syndrome, as cases with supravalvular aortic stenosis where disruption of the elastin gene has been demonstrated, have features of Williams syndrome. Ewart et al., (1993) identified hemizygosity of the elastin gene in four familial and five sporadic cases of Williams syndrome.
Ardinger et al., (1994) reported a 2-year-old boy with evidence of carotid and cerebral arterial stenosis with cerebral ischaemia.
There was a very high ESR and some response to steroids and the possibility of a vasculitis was considered. Two other cases of cerebrovascular narrowing in patients with Williams syndrome were reviewed from the literature. Further cases with cerebrovascular abnormalities have also been reported (Greally et al., 1994; Kaplan et al., 1995; Soper et al., 1995; Wollack et al., 1996). Pankau et al., (1996) examined 130 patients with Williams syndrome and found renal anomalies in 17.7%. 4-5% had renal agenesis or renal hypoplasia, 7% had a duplicated kidney, and around 6% had renal artery stenosis although hypertension was uncommon.
Pober and Filiano (1995) reported two cases with a Chiari type I malformation with fusion of the cervical spine. Nickerson et al., (1995) studied 44 clinically diagnosed cases and found elastin gene deletions in 40 (91%). Lowery et al., (1995) studied 235 cases with classic Williams syndrome and found deletions in 96%. Mari et al., (1995) reported similar findings in a series of 60 patients.
Mammi et al., (1996) reported a case who developed malignant hyperthermia after a general anaesthestic. They review the literature on anesthetic complications. Winter et al., (1996) review the eye findings in 152 patients. 77% of patients had blue irides, 74% showed a typical stellate iris pattern and 54% had strabismus. Occasional anomalies included cataracts, Rieger anomaly, ptosis and Marcus-Gunn phenomenon. Bird et al., (1996) reported 10 cases who suffered sudden death. Coronary artery stenosis and severe biventricular outflow tract obstruction seemed to be the main causes. Cases without deletions were felt to be clinically atypical. Joyce et al., (1996) found deletions in 22 out of 23 cases with classical Williams syndrome. The remaining patient had an 11q13.5-14.2 interstitial deletion. Perez Jurado et al., (1996) presented data suggesting that a gene or genes within the Williams deletion might be imprinted. Individuals who carry the deletion on the maternal 7 are smaller than those with deletions on the paternal chromosome 7. Dutly and Schinzel (1996) demonstrated that most deletions were due to unequal crossing over at meiosis with a small proportion being due to intrachromosomal (i.e. between chromatids) rearrangements. Tassabehji et al., (1996) showed that the LIM kinase gene (LIMK1) is also deleted in Williams cases. This gene codes for a novel protein kinase that is likely to be a component of an intracellular signalling pathway involved in brain development. Frangiskakis et al., (1996) showed that the LIM-kinase and elastin genes were deleted in two families with a partial Williams syndrome phenotype with developmental features of Williams syndrome and vascular abnormalities. They concluded that hemizygosity for the LIMK1 gene leads to impaired visuospatial constructive cognition.
Chodirker et al., (1997) reported five cases where a low maternal serum alpha fetoprotein level was noted in pregnancy. Scothorn and Butler (1997) reported a female case with precocious puberty. They suggest, anecdotally, that precocious puberty might be more common in Williams syndrome. Bawden et al., (1997) report their experience with using methylphenidate to treat hyperactivity in the disorder. Tsao and Westman (1997) reported two cases with infantile spasms. Fryssira et al., (1997) reported a male with normal intelligence and no features of Williams syndrome who had a deletion of the elastin gene by FISH analysis. Wang et al., (1997) reported another gene, homologous to the Drosophila frizzled wnt receptor, that seem to be included in Williams deletions. Osborne et al., (1997) reported deletions of the Syntaxin 1A gene in cases of Williams syndrome.
Mizugishi et al., (1998) reported a case with a visible 7q11.32-q21.11 deletion with Williams syndrome features also with infantile spasms. Sadler et al., (1998) showed that the mean carotid wall thickness in Williams syndrome was significantly greater than controls. Urban et al., (1996) and Baumer et al., (1998) presented data suggesting that deletions might be caused by unequal crossing over. Perez-Jurado et al., (1998) characterised the common deletion breakpoints and demonstrated a duplicated gene encoding BAP-135 a protein phosphorylated by Bruton's tryosine kinase in B-cell as well as the multiple functional transcription factor TFII-I. Arber et al., (1998) and Yang et al., (1998) showed that LIMK1 acts through phosphorylation of cofilin. Cofilin appears to be the enzyme required for actin depolymerization - a process involved in cell movement (Rosenblatt and Mitchison 1998). LIMK was deleted in 20 out of 20 Williams syndrome patients also deleted for the elastin gene. Sadler et al., (1993), Morris et al., (1993) and Ounap et al., (1998) reported convincing parent to child transmission, although most cases are sporadic.
Cherniske et al., (1999) reported evidence for early puberty. Botta et al., (1999) reported a patient not deleted for the Syntaxin 1A or frizzled genes with classical features of the condition. However, Tassabehji et al., (1999) presented data suggesting that the LIMK1 and STX1A genes were not involved in any of the Williams phenotype. They confirm that deletion of the ELN gene was responsible for the cardiological features of Williams syndrome. Tassabehji et al., (1999) showed that a transcription factor involved in skeletal muscle expression, GTF3, is located in the Williams critical region. Kara-Mostefa et al., (1999) reported sibs with an elastin gene deletion but normal parents. There was evidence suggesting maternal germ-line mosaicism.
Osborne et al., (2001) demonstrated a 1.5-base pair inversion polymorphism in families with Williams syndrome. Donnai and Karmiloff-Smith (2000) provide a good review of the molecular genetics and cognitive phenotype. Pamkau et al., (2001) reported two families with mother to child transmission, where the mothers were relatively mildly affected. Cunniff et al., (2001) set out suggestions for healthcare providers in children and young adults with Williams syndrome. There may also be stenosis of the abdominal aorta (Rose et al., 2001). Sadler et al., (2001) presented data suggesting that cardiovascular abnormalities were more severe in males.
The characteristic heart defect is a supravalvular aortic stenosis or a peripheral pulmonary artery stenosis. The cardiac abnormalities are well reviewed by Eronen et al., (2002). In 75 patients supravalvular aortic stenosis occurred in 73% of cases, pulmonary artery stenosis in 41% and an aortic or mitral valve defect in 11%. One case had tetralogy of Fallot. Renal artery stenosis can occur. Duba et al., (2002) reported a family segregating for a balanced t(7;16) (q11.23;q13). Phenotypes of translocation carriers in the family range from a hoarse voice, to a full Williams syndrome phenotype. The breakpoints disrupted intron 5 of the elastin gene, although without apparent deletion. The authors conclude that this suggests a position effect.
MRI scans of the brain are usually normal (Brinkmann et al., 1997), however, Faravelli et al., (2003) reported a child with the condition with microcephaly and a simplified gyral pattern of the parietal and frontal lobes. A deletion of 7q11.23 (see below) was demonstrated but it is not certain how large this was. Partsch et al., (2003) reported an estimated prevalence of precocious puberty of one in five to six girls with Williams syndrome (18.3%). Mean menarcheal age of 86 girls with Williams syndrome was 11.5 +/- 1.7 (+/-SD) years. Kalbhenn et al., (2003) reported a case with multiple infarctions and a spontaneous intracerebral haemorrhage. Stagi et al., (2003) reported two children with aplasia of the left lobe of the thyroid, and Bini and Pela (2004) reported a child with clinical signs of hypothyroidism. Karmiloff-Smith et al., (2003) studied a patient with supravalvular aortic stenosis and no physical or cognitive features of Williams syndrome who had an LIMK1 deletion. Gagliardi et al., (2003) studied a patients with an atypical smaller deletion who had a supravalvular aortic stenosis and vesicoureteric reflux with megaureter. There was normal development with mild language delay. The facial features were suggestive of Williams syndrome. The deletion included ELN, LIMK1 and at least part of the CYLN2 gene.
Giannotti et al., (2001) studied 63 cases with Williams syndrome, and found six with biopsy-proven coeliac disease (9.5%), compared to 0.54% in Italian students. Diverticulitis is relatively common in adults (Partsch et al., 2005). Metcalfe et al., (2005) reported a father and son with good clinical evidence of the condition, and both were found to have the common heterozygous deletion (which included FKBP6, known in the mouse to be involved in infertility). Scherer et al., (2005) reported two families with affected sibs and normal parents. One was the Kara-Mostefa et al., (1999) family. In both families, the WBSinv-1 variant, which is an inversion polymorphism, was present in the transmitting parent.
An adult patient, who had a stroke and evidence of a myocardial infarction was reported by Blanc et al., (2006). Ferland et al., (2006) reported a Williams patient with periventricular nodular heterotopia who had a deletion that was 1.5 Mb beyond the telomeric end of the typical Williams deletion, suggesting a more extended contiguous gene syndrome. See also Cammareri et al., (1999), Cambiaso et al., (2007) and Selicorni et al., (2006). These latter authors found 74% of their 96 patients had evidence of thyroid gland hypoplasia.
Craniosynostosis might occur (Ueda et al., 2015).
Walsh et al., (2017) described a male patient with Williams syndrome and congenital lobar emphysema. Wojcik et al., (2017) described a 49 years old male patient with Williams-Beuren syndrome and severe bullous lung emphysema.
Kruszka et. al. (2018) reviewed clinical findings in 137 patients from diverse populations. Most prevalent symptoms were intellectual disability (100%), malar flattening (99%), periorbital fullness (95%), long philtrum (93%), wide mouth (91%), growth abnormalities (91%), stellate iris (85%), small jaw (82%), short nose (74%), epicanthic folds (73%), broad eyebrows (63%) and strabismus (57%). The authors used facial analysis technology which was more accurate when considering the specific population.

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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