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Beckwith-Wiedemann syndrome (BWS)
Was ist Beckwith-Wiedemann? syndrom?
Beckwith-Wiedemann syndrom ist eine genetische und angeborene (bei der Geburt vorhandene) Überwucherungsstörung, die zu einer Prädisposition für Tumore und in einigen Fällen Krebs führt.
Charakteristisch für diese seltene Erkrankung ist eine große Körpergröße (Makrosomie).
Ihr Schweregrad variiert von Person zu Person, und obwohl angenommen wird, dass sie bei 1 bei 11,000 Geburten auftritt, kann diese Zahl aufgrund einer Unterdiagnose der . tatsächlich höher sein syndrom in weniger schweren Fällen.
Diese syndrom ist auch bekannt als:
BWS Emg Syndrom Exomphalos-Makroglossie-Gigantismus Syndrom Wiedemann-beckwith Syndrom; Wbs
Welche Genveränderung verursacht Beckwith-Wiedemann syndrom?
Änderungen der Gene im Chromosom 11, insbesondere in der als 11 p15 bekannten Region des Chromosoms. In 85% der Fälle erfolgt die Veränderung oder Mutation spontan, ohne dass eine Familienanamnese bekannt ist. In 15% der Fälle wird die Bedingung vererbt und vom Elternteil an das Kind übergeben.
In einigen Fällen kann ein genetisches Syndrom das Ergebnis einer De-novo-Mutation und der erste Fall in einer Familie sein. In diesem Fall handelt es sich um eine neue Genmutation, die während des Fortpflanzungsprozesses auftritt.
was sind die wichtigsten symptome von Beckwith-Wiedemann syndrom?
Das Wichtigste symptome von Beckwith-Wiedemann syndrom gehören ein großes Geburtsgewicht und -länge. Sowie ein rotes Muttermal auf der Stirn oder den Augenlidern und Falten in den Ohrläppchen.
Eine große Zunge, auch Makroglossie genannt, ist ebenfalls charakteristisch für die Erkrankung. Ebenso wie Überwucherung auf einer Seite oder einem Teil des Körpers.
Andere Gesundheitszustände im Zusammenhang mit der syndrom umfassen Defekte in der Bauchdecke, die Hernien, vergrößerte Bauchorgane und eine hohe Prädisposition für Krebs im Kindesalter verursachen.
Mögliche klinische Merkmale/Merkmale:
Autosomal-dominante Vererbung, vordere Falten des Ohrläppchens, melanozytärer Nävus, breiter Mund, Überwucherung, Überwucherung der äußeren Genitalien, Pankreashyperplasie, Omphalozele, polyzystische Nierendysplasie, vergrößerte Niere, exokrine Pankreasinsuffizienz, Malares Zwerchfell, Zwerchfellhernie, Koenitalis Merkmale, Diastase recti, Kryptorchismus, Cutis laxa, Dandy-Walker-Fehlbildung, Anomalie der Helix, Anomalie der Nebennieren, Anomalie des Ohrs, Anomalie der periaurikulären Region, Kardiomyopathie, Kardiomegalie, Beschleunigte Skelettreifung, Nebennierenrindenzytokortikales Karzinom, Adreno Anomalie der Zunge, Asymmetrisches Wachstum, Apnoe, Hemihypertrophie, Hepatomegalie, Hepatoblastom, Gonadoblastom, Prominent Okziput, Hypothyreose, Hypoglykämie, Hypertrophe Kardiomyopathie, Nabelbruch, Sarkom, Urogenitalfistel, Proptose, Splenomegalie, Hochgewachsene, neurologische Statur, Nephroblast , Neona tale Hypoglykämie
Wie wird jemand auf Beckwith-Wiedemann getestet syndrom?
Die ersten Tests für das Beckwith-Wiedemann-
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 Beckwith-Wiedemann syndrome (BWS)
Wiedemann et al., (1997) estimates the frequency of this condition as high as 1 in 12000. Females may be preferentially affected over boys. The major anomalies include macroglossia, abdominal wall defects, hypoglycemia, visceromegaly (liver, spleen, kidneys, adrenals) and gigantism, often but not always present at birth. Stratakis and Garnica (1995) make the point that the condition may be difficult or impossible to diagnose in a premature infant. The features are however variable, hence the many reports of variable penetrance. Other important clinical features are the ear creases or pits either on the front or the back of the lobes, often looking like bite marks, nevus flammeus and midfacial hypoplasia. Hemihypertrophy should be looked for. Hemihypertrophy of the face might be the sole manifestation (Sathienkijkanchai et al., 2008). Polydactyly and cleft palate are low frequency associations. Hypertrophy of the placenta and maternal hypertension and proteinuria may be found during pregnancy (McCowan and Becroft, 1994). Silengo et al., (2002) suggest that the presentation can occasionally be with prune belly syndrome. A giant omphalocele and prune belly sequence were reported by Sinico et al., (2004). Goldman et al., (2003) studied 18 patients and found that 4 had normocalcaemic hypercalciuria. Elliott and Maher (1994) provide a good review of the clinical features. Genital anomalies (hypospadias) have also been reported (Welsh et al., 2012). Sensorineural deafness and extra flexion creases on the fingers were reported by Kantaputra et al., (2013). Very rarely a meningocele has been reported (Mbuyi-Musanzayi et al., 2014)
There is a known association with certain malignancies, especially Wilms tumour, and hemihypertrophy is found in 40% of cases that develop this tumour. Screening for Wilms tumour in these cases is controversial, but many authors recommend ultrasound examination every 3 months until the age of 5 years and then yearly until growth is complete (25% of children with Wilms tumour are older than 5 years) (Clericuzio, 1993). Other authors have suggested screening every 4 months (Choyk et al., (1999). McNeil et al., (2001) examined the cost-effectiveness of these screening programmes. Craft et al., (1995) suggest that screening with abdominal ultrasound is not of proven value and recommend a regimen of abdominal palpation by parents. Beckwith (1998) also discusses the issues of monitoring for Wilms tumour. Pritchard-Jones (2002) reviewed the management of Wilms tumour. The overall risk of malignancy is 7.5%, and if hemihypertrophy is absent, closer to 1%. Wiedemann et al., (1997) suggests that tumours rarely develop after the age of 10-years. DeBaun et al., (1998) provide information from a 183 children followed up to 4 years and found that 13 (7%) developed tumours by this age. DeBaun et al., (1998) present data suggesting that nephromegaly is a significant risk factor for development of Wilms tumour.
Other tumours that have been reported include hepatoblastoma, adrenal carcinoma, fibromas of the heart, brain stem glioma, umbilical myxoma, ganglioneuroma, carcinoid tumour of the appendix, rhabdomyosarcoma, adrenal adenoma, lymphoma, pancreatoblastoma and hepatic haemangioepitheliomas (Drut et al., 1992). Occasional cases may have pancreatic cysts (Fremond et al., 1997). Van den Akker et al., (2002) reported a 19-year-old female with congenital hemihypertrophy, who presented with bilateral benign pheochromocytoma. They review the literature and suggest that pheochromocytoma could be part of the clinical spectrum of the Beckwith-Wiedemann syndrome. Another case with bilateral pheochromocytomas was reported by Baldisserotto et al., (2005). Jonas and Kimonis (2001) reported a case with a chest wall hamartoma. They review the spectrum of tumours in Beckwith-Wiedemann syndrome. Muszynska-Roslan et al., (2007) reported a 3-year-old boy with a primitive neuroectodermal tumour and Kuroiwa et al., (2009) a 15 day-old child with nodules on the head, trunk and buttock (""blueberry muffin baby"" - not a nice term MB) that turned out to be an alveolar rhabdomyosarcoma.
Chromosome analysis is usually normal but 11p duplications have been found and should be looked for. There are several reports of discordant monozygotic twins, and in these reports there is a 10:1 female:male sex ratio (Leonard et al., 1996). Slavotinek et al., (1997) reported a family where two individuals inherited an 11p15.5 duplication from their fathers, and review other cases of duplication in the literature. They note that these cases are more likely to have developmental delay, less likely to have hypoglycaemia, and are less likely to have a facial nevus. There also appears to be a characteristic face in these cases consisting of a prominent occiput, a prominent or flat forehead with frontal bossing, a round face with full or puffy cheeks, epicanthic folds, hypertelorism, a broad flat nasal bridge, micrognathia or retromicrognathia, deep set eyes, strabismus, short or narrow palpebral fissures that may be downslanting, and a frontal upsweep of hair. In cases with a duplication of 11p15.5 the parental origin is usually paternal (Moutou et al., 1992). The patient reported by Niemitz et al., (2004) had a deletion which took out the entire LIT1 gene, causing the silencing of p57Kip2.
There is good evidence that the syndrome can be caused by paternal disomy for the segment of 11p15.5 containing the IGF2 gene and that the maternal allele for this gene is normally inactivated (Henry et al., 1991; Beldjord et al., 1992; Giannoukakis et al., 1993; Ohlsson et al., 1993; Weksberg and Squire, 1996). Drut and Drut (1996) reported a family where a balanced (10;11)(q26;p15) translocation gave rise to Beckwith syndrome presenting with nonimmune hydrops and placentomegaly when an unbalanced karyotype causing trisomy 11p15 was passed on by male carriers. On the other hand cases with a balanced 11p15.5 translocation or insertion are maternal in origin (reviewed by Tommerup et al., 1993). Maternally transmitted translocations are clustered in two locations centromeric to IGF2 but several megabases apart. The nearest cluster is 200-400 kb from IGF2. In familial cases maternal transmission results in a more severe phenotype, suggesting that an over-expression of a paternal gene, relative to its maternal homologue, is a causative factor. In Wilms tumours in these patients there is usually evidence of disomy for paternal 11p15 markers. Reik et al., (1995) reported evidence for an imprinting mutation in some cases causing the maternal IGF2 and H19 alleles to have a paternal allelic methylation pattern. This meant that IGF2 was expressed from both alleles and H19 not expressed in fibroblasts. However Joyce et al., (1997) reported cases where IGF2 showed biallelic expression even though H19 expression and methylation status was normal, indicating a possible separate imprinting centre for H19. Catchpoole et al., (1997) found that 14 out of 83 informative cases (17%) could be demonstrated to have uniparental disomy for 11p15.5. In addition, 5 out of 63 cases (8%) had normal biparental inheritance but studies showed hypermethylation of the H19 gene consistent with an imprinting centre mutation or an imprinting error lesion. Exomphalos was significantly more common in cases with possible imprinting mutations. Brown et al., (1996) studied a family where an inv(11)(p11.2;p15.5) had been passed on by a mother to two affected sibs. There was biallelic expression of IGF2 but H19 imprinting was normal. Sun et al., (1997) showed that mice overexpressing Igf2 have features of Beckwith-Wiedemann syndrome including prenatal overgrowth, polyhydramnios and an enlarged tongue. Other features of Beckwith-Wiedemann syndrome such as exomphalos might be caused by abnormalities of p57 expression (Hastie et al.,1997). Li et al., (1997) provide a good review of the genetic situation up to the end of 1997.
Hoban et al., (1995) reported a patient where both Wilms tumour tissue and nephrogenic rest tissue (thought to be a precursor of Wilms) showed loss of maternal alleles from all informative autosomal markers used. This finding was also observed in normal renal tissue. The Wilms tumour in the patient apparently arose from cells containing no maternal chromosomes. Normal renal tissue also showed this genetic complement.
Moutou et al., (1992) conclude that these findings cannot be explained by a single locus hypothesis but could be explained by invoking two or more closely linked genes, one for enhanced growth that is maternally inactive and one for tumour suppression that is paternally inactive. The H19 gene, transcripts of which are abundant in the early fetal period and in embryonal carcinoma cells, and which maps to 11p15, shows paternal inactivation in contrast to the IGF2 gene (Zhang and Tycko, 1992). Reid et al., (1996) report progress in isolating a Wilms tumor gene at 11p15.5. Microdeletions in H19 DMR have now been shown to result in loss of IGF2 imprinting, with resultant Beckwith-Wiedemann syndrome (Sparago et al., 2004).
Henry et al., (1993) demonstrated somatic mosaicism for partial paternal isodisomy in four patients with Beckwith-Wiedemann syndrome. They suggested that the risk of Wilms tumour in this group of patients is around 50% as opposed to 7.5% for Beckwith-Wiedemann patients as a whole. However Slatter et al., (1994) did not find a significant difference between the incidence of Wilms tumour in Beckwith-Wiedemann patients with mosaic uniparental disomy (UPD) and those without. They suggested that the incidence of Wilms in UPD patients is 26%. In their study 28% of informative patients out of a population of 49, were shown to have mosaic UPD. Schneid et al., (1993) reported abnormalities in methylation of the IGF2 gene. Weksberg et al., (1993) demonstrated biallelic expression of IGF2 in fibroblasts of four out of six patients with Beckwith-Wiedemann syndrome. Interestingly, three patients had hemihypertrophy but UPD was excluded. Mannens et al., (1994) demonstrated hypomethylation of the insulin and IGF2 genes in cases with balanced translocations, which were maternally inherited. This suggests that relaxation of maternal imprinting might be a causative factor in a proportion of cases. It should be noted that Steenman et al., (1994) showed loss of maternal imprinting of the IGF2 gene in Wilms tumours and this was associated with an 80-fold down regulation of H19 expression. Moulton et al., (1994) showed similar findings. Bliek et al., (2001) showed that increased tumour risk correlates with aberrant H19 and not KCNQ1OT1 methylation.
Morison et al., (1996) described four children with overgrowth associated with nephromegaly and Wilms tumour in two cases, but no other signs of Beckwith syndrome. Relaxation of IGF2 imprinting with overexpression of IGF2 and disruption of H19 methylation was demonstrated.
Hatada et al., (1996), (1997) demonstrated point mutations in the p57 gene (CDKN1C) which codes for a tight-binding inhibitor of several G1 cyclin/Cdk complexes and which is a negative regulator of cell proliferations. Knockout mice for CDKN1C have features of Beckwith-Wiedemann syndrome (reviewed by Swanger and Roberts 1997). This gene is maternally expressed in mice and humans. In one case a missense mutation was transmitted from the patients carrier mother. However Lee et al., (1997) only found 2 cases out of 40 with a p57 mutation. O`Keefe et al., (1997) found mutations in the CDKN1C gene in 1 out of 5 cases of Beckwith-Wiedemann syndrome. However, Okamoto et al., (1998) found no mutations in the CDKN1C gene in 40 patients and Gaston et al., (2000) found no mutations in 21 patients with no 11p15 UPD. Lam et al., (1999) found CDKN1C mutations in three out of seven (43%) of familial cases and four out of fifty-four (4%) of sporadic cases. These cases had a significantly higher frequency of exomphalos than cases with imprinting or disomy and there was no association with embryonal tumours such as Wilms. Li et al., (2001) studied 10 dominant families and 65 sporadic BWS cases and found mutations in the CDKN1C gene in 4. Two were associated with biallelic IGF2 expression and normal H19 and KCNQ1OT1 imprinting. A review of other studies suggested that CDKN1C mutations accounted for about 5% of Beckwith patients. A large family with the CDKN1C mutation was reported by Lew et al., (2004). The mutation was maternally transmitted and was located in the poy-G tract which has a role in promoting splicing.
Lee et al., (1997) demonstrated that the KVLQT1 gene, which is situated between CDKN1C and IGF2, was imprinted. Mutations in this gene are responsible for Romano-Ward and Jervell-Lange-Nielsen syndrome in some families. Translocations associated with Beckwith syndrome disrupted this gene, as well as a balanced chromosomal translocation in an embryonal rhabdoid tumour. The authors suggested that the lack of parental origin effect in long QT syndrome families might be due to relative lack of imprinting in cardiac muscle. Horike et al., (2000) produced a human chromosome 11 with a targeted deletion of the LIT1 CpG island within the KvLQT1 gene. LIT1 is a paternally expressed antisense RNA within the KvLQT1 locus. In chicken DT40 cells the mutation abolished LIT1 expression on the paternal chromosome, and this was accompanied by activation of the normally silent paternal alleles of KvLQT1 and p57. There was no effect on imprinting of H19. Reik and Maher (1997) and Li et al., (1998) provide good reviews of the complex imprinting situation in Beckwith-Wiedemann syndrome. Further reviews are provided by Maher and Reik (2000) and Weksberg et al., (2003) and evidence for a second imprinting centre is provided by Engemann et al., (2000). Baujat et al., (2004) found 2 patients thought to have BWS to have Sotos mutations.
There are other breakpoints, 5Mb and 7Mb, proximal to the common breakpoint also associated with a Beckwith phenotype (Redeker et al., 1994). Alders et al., (2000) studied a breakpoint in the 5Mb proximal region and showed disruption of 2 out of 5 spliced transcripts of the ZNF215, zinc-finger gene.
Howard et al., (1993) demonstrated monoallelic expression of the IGF1R gene in lymphocytes and kidneys from one out of four patients with Beckwith-Wiedemann syndrome. The paternal allele was not expressed. This gene is located at 15q25-qter. The same authors also demonstrated a lack of imprinting in normal individuals. Brewer et al., (1998) reported a female infant with Beckwith syndrome who showed loss of IGF2 imprinting but no evidence of uniparental disomy. There was a deletion of 18q22.1. The authors suggested that there might be a transactivating element for maintenance of IGF2 imprinting at 18q22. Cole (1998) provides a good review of overgrowth syndromes and the overlap between Beckwith-Wiedemann syndrome and Simpson-Golabi-Behmel syndrome. Dutly et al., (1998) reported seven cases including one with complete paternal isodisomy for chromosome 11 in a mosaic form. Sperandeo et al., (2000) reported a family where a female gave birth to a son with Beckwith-Wiedemann syndrome, whereas her sister had a child with Klippel-Trenaunay-Weber syndrome. In both children relaxation of maternal IGF2 imprinting was demonstrated although they inherited different 11p15.5 alleles from their mothers. The child with Beckwith-Wiedemann syndrome also displayed hypomethylation at the KvDMR1 locus within the KvLQT1 gene, although the child with Klippel-Trenaunay-Weber syndrome did not. Other studies suggested the possibility that a defective modifier or regulatory gene unlinked to 11p15 caused a spectrum of epigenetic alterations in the germline or early development of both cousins. This also suggested that IGF2 has a role in the overgrowth not only in Beckwith syndrome, but also Klippel-Trenaunay-Weber syndrome.
Engel et al., (2000) found that 35 out of 69 (51%) of sporadic cases of Beckwith syndrome, without UPD had loss of methylation at KvMR1. This was often but not invariably associated with loss of imprinting of IGF2. The incidence of exomphalos was not significantly different from that in patients with germline KDKN1C mutations but was significantly greater than that in patients with UPD. DeBaun et al., (2002) showed that the frequency of altered DNA methylation of H19 was higher in patients with cancer (56%) compared to patients without (17%). The frequency of altered DNA methylation of LIT1 was higher in patients with body wall defects and macrosomia (65% and 60%) than those without (34% and 18%). Paternal uniparental disomy was associated with hemihypertrophy, cancer and hypoglycaemia. Rump et al., (2005) provided a careful meta-analysis of the tumor risks in the various subgroups within BWS and found an absolute risk of 3% in the group with isolated LIT1 hypomethylation (no Wilms tumor reported), 43% in the group of isolated H19 imprinting disturbance, and 28% in the group with both LIT1 and H19 methylation abnormalities.
Maher et al., (2003) reviewed the incidence of assisted reproduction technology (ART) births in a cohort of 149 sporadic patients with Beckwith-Wiedemann syndrome. Six patients (4%) were born after ART compared to 1.2% in the general population. DeBaun et al., (2003) carried out a prospective study of the prevalence of assisted reproduction technology in Beckwith syndrome and found it to be 4.6% as compared to a background rate of 0.8% in the United States population. A further four cases seem to have been ascertained retrospectively. Of the seven cases, five were conceived after intracytoplasmic sperm injection. Gicquel et al., (2003) presented similar data suggesting that no specific form of ART predisposed to the increased risk. See Gosden et al., (2003) for discussion. Yoon et al., (2005) reported a case of dizygotic, monochorionic twins, one of whom had Klinefelter and Beckwith-wiedemann syndromes.
Brioude et al. (2015) identified 37 CDKN1C mutations in 38 families (50 patients and seven fetuses). In all cases except one the mutation was inherited from the mother. Macrosomia at birth was observed in only 45.8%. All cases (except for two cases with the recurrent c.209C>T mutation) presented with an abdominal wall defect (exomphalos/umbilical hernia). 78% of the cohort demonstrated all features of the BWS phenotype. All fetuses had adrenal cytomegaly. Malformations of the central nervous system were identified in six patients, most frequently a defect of the posterior cranial fossa. Genitourinary anomalies were identified in 13 patients, cardiac anomalies in four patients and anomalies of the palate in four patients. Mean final height was +2.1 SDS. No patient showed hyperplasia of an entire body half; two patients showed hemihyperplasia limited to a leg. Tumors occurred in four patients, including one abdominal ganglioneuroblastoma, one acute lymphocytic leukemia, one neuroblastoma and one superficial spreading melanoma. Frameshift mutations were associated with the most severe phenotype, with all but one patient presenting with exomphalos at birth. All the four tumors occurred in patients with frameshift mutations. The authors concluded that CDKN1C sequencing should be performed for BWS patients presenting with abdominal wall defects or cleft palate without 11p15 methylation defects or body asymmetry, or in familial cases of BWS.
* This information is courtesy of the L M D.
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