Thompson & Thompson Genetics in Medicine, 8th Edition

Case 6. Beckwith-Wiedemann Syndrome (Uniparental Disomy and Imprinting Defect, MIM 130650)

Chromosomal with Imprinting Defect

Principles

• Multiple pathogenic mechanisms

• Imprinting

• Uniparental disomy

• Assisted reproductive technology

Major Phenotypic Features

• Age at onset: Prenatal

• Prenatal and postnatal overgrowth

• Macroglossia

• Omphalocele

• Visceromegaly

• Embryonal tumor in childhood

• Hemihyperplasia

• Renal abnormalities

• Adrenocortical cytomegaly

• Neonatal hypoglycemia

History and Physical Findings

A.B., a 27-year-old gravida 1/para 0 woman, presented to a prenatal diagnostic center for level II ultrasonography and genetic counseling after a routine ultrasound examination revealed a male fetus, large for gestational age with possible omphalocele. The pregnancy, the first for each of his parents, was undertaken without assisted reproductive technology. After confirmation by level II ultrasonography, the family was counseled that the fetus had a number of abnormalities most consistent with Beckwith-Wiedemann syndrome, although other birth defects were also possible. The couple decided not to undergo amniocentesis. The baby, B.B., was delivered by cesarean section at 37 weeks with a birth weight of 9 pounds, 2 ounces and a notably large placenta. Omphalocele was noted, as were macroglossia and vertical ear lobe creases.

A genetics consultant made a clinical diagnosis of Beckwith-Wiedemann syndrome. When hypoglycemia developed, B.B. was placed in the newborn intensive care unit and was treated with intravenous administration of glucose for 1 week; the hypoglycemia resolved spontaneously. The findings on cardiac evaluation were normal, and the omphalocele was surgically repaired without difficulty. Methylation studies of the KCNQOT1 gene confirmed an imprinting defect at 11p15 consistent with the diagnosis of Beckwith-Wiedemann syndrome. Abdominal ultrasound examination to screen for Wilms tumor was recommended every 3 months until B.B. was 8 years old, and measurement of serum alpha-fetoprotein level was recommended every 6 weeks as a screen for hepatoblastoma for the first 3 years of life. At a follow-up visit, the family was counseled that in view of their negative family history and normal parental karyotypes, the imprinting defect was consistent with sporadic Beckwith-Wiedemann syndrome, and the recurrence risk was low.

Background

Disease Etiology and Incidence

Beckwith-Wiedemann syndrome (BWS, MIM 130650) is a panethnic syndrome that is usually sporadic but may rarely be inherited as an autosomal dominant. BWS affects approximately 1 in 13,700 live births.

BWS results from an imbalance in the expression of imprinted genes in the p15 region of chromosome 11. These genes include KCNQOT1 and H19, noncoding RNAs (see Chapter 3), and CDKN1C and IGF2, which do encode proteins. Normally, IGF2 and KCNQOT1 are imprinted and expressed from the paternal allele only while CDKN1C and H19 are expressed from the maternal allele only. IGF2 encodes an insulin-like growth factor that promotes growth; in contrast, CDKN1C encodes a cell cycle suppressor that constrains cell division and growth. Transcription of H19 and KCNQOT1 RNA suppresses expression of the maternal copy of IGF2 and the paternal copy of CDKN1C, respectively.

Unbalanced expression of 11p15 imprinted genes can occur through a number of mechanisms. Mutations in the maternal CDKN1C allele are found in 5% to 10% of sporadic cases and in 40% of families with autosomal dominant BWS. The majority of patients with BWS, however, have loss of expression of the maternal CDKN1C allele because of abnormal imprinting, not mutation. In 10% to 20% of individuals with BWS, loss of maternal CDKN1C expression and increased IGF2 expression are caused by paternal isodisomy of 11p15. Because the somatic recombination leading to segmental uniparental disomy occurs after conception, individuals with segmental uniparental disomy are mosaic and may require testing of tissues other than blood to reveal the isodisomy. A few are BWS patients have a detectable chromosomal abnormality, such as maternal translocation, inversion of chromosome 11, or duplication of paternal chromosome 11p15. Rare microdeletions in KCNQOT1 or H19 that disrupt imprinting have also been found in BWS.

Pathogenesis

During gamete formation and early embryonic development, a different pattern of DNA methylation is established within the KCNQOT1 and H19 genes between males and females. Abnormal imprinting in BWS is most easily detected by analysis of DNA methylation at specific CpG islands in the KCNQOT1 and H19 genes. In 60% of patients with BWS, there is hypomethylation of the maternal KCNQOT1. In another 2% to 7% of patients, hypermethylation of the maternal H19 gene decreases its expression, resulting in excess IGF2 expression. Inappropriate IGF2 expression from both parental alleles may explain some of the overgrowth seen in BWS. Similarly, loss of expression of the maternal copy of CDKN1C removes a constraint on fetal growth.

Phenotype and Natural History

BWS is associated with prenatal and postnatal overgrowth. Up to 50% of affected individuals are premature and large for gestational age at birth. The placentas are particularly large, and pregnancies are frequently complicated by polyhydramnios. Additional complications in infants with BWS include omphalocele, macroglossia (Fig. C-6), neonatal hypoglycemia, and cardiomyopathy, all of which contribute to a 20% mortality rate. Neonatal hypoglycemia is typically mild and transient, but some cases of more severe hypoglycemia have been documented. Renal malformations and elevated urinary calcium level with nephrocalcinosis and nephrolithiasis are present in almost half of BWS patients. Hyperplasia of various body segments or of selected organs may be present at birth and may become more or less evident over time. Development is typically normal in individuals with BWS unless they have an unbalanced chromosome abnormality.

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FIGURE C-6 Characteristic macroglossia in a 4-month-old male infant with Beckwith-Wiedemann syndrome. The diagnosis was made soon after birth on the basis of the clinical findings of macrosomia, macroglossia, omphalocele, a subtle ear crease on the right, and neonatal hypoglycemia. Organomegaly was absent. Karyotype was normal, and molecular studies showed hypomethylation of the KCNQOT1 gene. See Sources & Acknowledgments.

Children with BWS have an increased risk for development of embryonal tumors, particularly Wilms tumor and hepatoblastoma. The overall risk for neoplasia in children with BWS is approximately 7.5%; the risk is much lower after 8 years of age.

Management

Management of BWS involves treatment of presenting symptoms, such as omphalocele repair and management of hypoglycemia. Special feeding techniques or speech therapy may be required due to the macroglossia. Surgical intervention may be necessary for abdominal wall defects, leg length discrepancies, and renal malformations. If hypercalciuria is present, medical therapy may be instituted to reduce calcium excretion. Periodic screening for embryonal tumors is essential because these are fast-growing and dangerous neoplasias. The current recommendations for monitoring for tumors are an abdominal ultrasound examination every 3 months for the first 8 years of life and measurement of serum alpha-fetoprotein level for hepatoblastoma every 6 weeks for the first few years of life. In addition, an annual renal ultrasound examination for affected individuals between age 8 years and midadolescence is recommended to identify those with nephrocalcinosis or medullary sponge kidney disease.

Recurrence Risk

The recurrence risk for siblings and offspring of children with BWS varies greatly with the molecular basis of their condition.

Prenatal screening for pregnancies not previously known to be at increased risk for BWS by ultrasound examination and maternal serum alpha-fetoprotein assay may lead to the consideration of chromosome analysis and/or molecular genetic testing. Specific prenatal testing is possible by chromosome analysis for families with an inherited chromosome abnormality or by molecular genetic testing for families in whom the molecular mechanism of BWS has been defined.

Increased Risk for Beckwith-Wiedemann Syndrome with Assisted Reproductive Technologies

Assisted reproductive technologies (ARTs), such as in vitro fertilization (IVF) and intracytoplasmic sperm injection, have become commonplace, accounting now for 1% to 2% of all births in many countries. Retrospective studies demonstrated that ART had been used 10 to 20 times more frequently in pregnancies that resulted in infants with BWS compared with controls. The risk for BWS after IVF is estimated to be 1 in 4000, which is threefold higher than in the general population.

The reason for the increased incidence of imprinting defects with ART is unknown. The incidence of Prader-Willi syndrome (Case 38), a defect in paternal imprinting, has not been shown to be increased with IVF, whereas the frequency of Angelman syndrome, a maternal imprinting defect, is increased with IVF, suggesting a specific relationship between ART and maternal imprinting. Because the paternal imprint takes place well before IVF, whereas maternal imprinting takes place much closer to the time of fertilization, a role for IVF itself in predisposing to imprinting defects merits serious study.

Questions for Small Group Discussion

1. Discuss possible reasons for embryonal tumors in BWS. Why would these decline in frequency with age?

2. Discuss reasons why imprinted genes frequently affect fetal size. Name another condition associated with uniparental disomy for another chromosome.

3. Besides imprinting defects, discuss other genetic disorders that may cause infertility and yet can be passed on by means of ART.

4. In addition to mutations in the genes implicated in BWS, discuss how a mutation in the imprinting locus control region could cause BWS.

References

Jacob KJ, Robinson WP, Lefebvre L. Beckwith-Wiedemann and Silver-Russell syndromes: opposite developmental imbalances in imprinted regulators of placental function and embryonic growth. Clin Genet. 2013;84:326–334.

Shuman C, Beckwith JB, Smith AC, et al. Beckwith-Wiedemann syndrome. [Available from] http://www.ncbi.nlm.nih.gov/books/NBK1394/.

Uyar A, Seli E. The impact of assisted reproductive technologies on genomic imprinting and imprinting disorders. Curr Opin Obstet Gynecol. 2014;26:210–221.