Beckwith-Wiedemann syndrome

Beckwith-Wiedemann syndrome: Description, Causes and Risk Factors: Abbreviation: BWS. An overgrowth syndrome characterized by exomphalos (an umbilical hernia at birth in which some abdominal organs push into the umbilical cord), macroglossia, and gigantism, often with neonatal hypoglycemia; there is an association with hemihypertrophy and Wilms tumor. Autosomal dominant inheritance, with most cases sporadic; influenced by genomic imprinting and uniparental disomy; caused by mutation in the P57 (KIP2) gene on chromosome 11p. Beckwith-Wiedemann syndrome represents a complex disorder both phenotypically and genetically and provides unique opportunities to explore a number of intriguing biological phenomena. Such phenomena include genomic imprinting, monozygotic twins with discordant phenotypes, and genetic contributions to embryonal tumor development. The timing of monozygotic twinning and imprint reestablishment during preimplantation development appears to be a critical period for the incorporation of epigenetic errors in the plastic embryonic genome. Such epigenetic errors determine a range of phenotypes associated with Beckwith-Wiedemann syndrome including the predisposition to embryonal tumor development. BWS has been documented in a variety of ethnic populations with an incidence of 1/13,700 and is equally represented in males and females. However, as molecular testing continues to expand the phenotypic spectrum, positive molecular test results in ``atypical'' cases of Beckwith-Wiedemann syndrome, will likely increase the reported incidence. In fact, the phenotypic spectrum of this disorder now appears to include at least a proportion of cases of isolated hemihyperplasia. The syndromic designation of BWS was coined following the ?rst descriptions of this syndrome by Beck with in 1963 and Wiedemann in 1964. However, artistic depictions suggestive of BWS have been found dating back to the beginning of the Common Era. Beckwith-Wiedemann syndrome is caused by imprinting errors in the 11p15 chromosomal region. This region includes genes encoding growth factors and tumor suppressor genes. The paternally expressed genes (maternally imprinted) have growth enhancing activity and the maternally expressed genes (paternally imprinted) have growth suppressing activity. The 11p15 region is organized into two domains: a telomeric domain including the IGF2 and H19 genes and a centromeric domain including the CDKN1C (Cyclin Dependant Kinase Inhibitor 1C), KCNQ1 (Potassium voltage-gated channel, subfamily Q, member 1) and KCNQ1OT1 (KCNQ1-Overlapping transcript 1) genes. Each domain is controlled by its own imprinting center (IC1 and IC2 for the telomeric and the centromeric domains, respectively).Beckwith-Wiedemann syndrome The incidence of Beckwith-Wiedemann syndrome (1 per 13,700 livebirths) has been reported in only one study and is probably underestimated. Symptoms:

Individuals with BWS may grow at an increased rate during the latter half of pregnancy and in the first few years of life. Growth parameters typically show height and weight around the 97th percentile with head size closer to the 50th percentile. Adult heights are generally in the normal range.Abnormal growth may also manifest as hemihyperplasia and/or macroglossia; the latter can lead to difficulties in feeding, speech and less frequently, sleep apnea. A recognizable facial gestalt is common and may include prominent eyes with infraorbital creases, facial nevus flammeus, midfacial hypoplasia, macroglossia, full lower face with a prominent mandible, anterior earlobe creases and posterior helical pits3. The Beckwith-Wiedemann syndrome facies often normalizes across childhood so that evaluation of adolescents or adults suspected to have BWS benefits from assessment of early childhood photographs. Development is usually normal unless there is chromosome 11p15.5 duplication or serious perinatal complications, including prematurity or uncontrolled hypoglycemia. Hypoglycemia is reported in 30-50% of babies with BWS,likely caused by islet cell hyperplasia and hyperinsulinemia.

Diagnosis: Careful cytogenetic analysis of the 11p15 region and fluorescent in situ hybridization (FISH) can be used to recognize the rare translocations, inversions and trisomies. Molecular diagnosis is difficult, mostly because of the large spectrum of genetic and epigenetic abnormalities. Molecular tests must differentiate the various abnormalities in the 11p15 region: patients with 11p15 paternal UPD, patients with hypermethylation of the H19 gene, patients with demethylation of the KCNQ1OT1 gene and patients with a mutation in the CDKN1C gene. As demethylation of the KCNQ1OT1 gene is never associated with abnormal methylation of the H19 gene except in patients with 11p15 paternal UPD, analysis of the methylation status of both the KCNQ1OT1 and H19 genes leads to the diagnosis of more than 90% of 11p15 defects. Isolated demethylation of the KCNQ1OT1 gene.
  • Isolated hypermethylation of the H19 gene.
  • It is not yet possible to determine precisely the percentage of cases with epigenetic defects displaying a microdeletion of IC1 or IC2.
  • Hypermethylation of the H19 gene associated with demethylation of the KCNQ1OT1 gene is indicative of 11p15 paternal UPD, which should be confirmed by analysis of markers of the 11p15 region and of parental DNA. 11p15 paternal UPD always occurs as mosaicism and, because tissue distribution of mosaicism is variable, tissue from a second source (such as fibroblasts) may be helpful.
  • If the methylation status of the KCNQ1OT1 and H19 genes is normal, then sequencing of the CDKN1C gene is indicated, particularly in patients with exomphalos and/or a family history of BWS.
Prenatal diagnosis by ultrasound scan can be used to assess fetal growth and to detect abdominal wall defects, thereby helping to prevent neonatal complications. Cytogenetic testing is appropriate for the diagnosis of translocation, inversion or duplication. Molecular diagnosis is also possible for 11p15 paternal UPD or CDKN1C gene mutation. The reliability of testing for epigenetic modifications is unknown. Treatment: Neonates with exomphalos should undergo abdominal wall repair soon after birth. Hypoglycemia during the first few days of life can be anticipated by monitoring glycemia in newborns with BWS every six hours for the first few days. Serious neurological sequelae can therefore be prevented. Over the next few years, we expect that much progress will be made in research on BWS. In order to translate these data rapidly to the clinical arena, it will be important to periodically review the status of both clinical and molecular aspects of Beckwith-Wiedemann syndrome. Clinical diagnosis, molecular testing, genetic counseling, and management will likely all be impacted. The available clinical data may improve as we develop better protocols for complete ascertainment of BWS cases and as the total number of cases studied continues to rise. Further, MS-MLPA and other testing modalities will more accurately reflect the total number of BWS cases with identified molecular lesions, although there will likely be new molecular etiologies identified for both familial and sporadic cases. NOTE: The above information is for processing purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.


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