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NeoQuest July 2024: Large for gestational age fetus with multiple anomalies

June 26, 2024

A 27-year-old primigravid woman is referred at 30 weeks’ gestation to a maternal-fetal medicine specialist. Her previous ultrasonography revealed polyhydramnios, fetal nephromegaly.  Her prenatal ultrasonography findings are shown in Figure 1A and 1B. The fetus has an estimated fetal weight in the 95th percentile. Her cell-free fetal DNA screening returned a low risk for aneuploidies.


Figure 1: A. Prenatal ultrasonography showing findings in the fetal abdominal wall (white star). B. Prenatal ultrasonography showing the facial profile of the fetus. Image from: Bridges A, Hwang J, Edwards E, Feist C, Dukhonvy S. Neoreviews. (2024);25(7):e457–e465.1

Based on the constellation of fetal findings, which of the following tests should be performed on the infant to confirm the diagnosis after birth?

  1. Chromosomal microarray
  2. Karyotyping
  3. Methylation studies
  4. Thyroid function test
  5. Whole exome sequencing

Answer: C. Methylation studies

Explanation:

The fetus in the given vignette is large for gestational age (LGA), with nephromegaly and an abdominal wall defect consistent with an omphalocele (Figure 1). In addition, based on the facial profile on the ultrasonography (USG), the fetus has macroglossia. This constellation of clinical findings is consistent with Beckwith-Weidemann syndrome (BWS).1

BWS is an overgrowth syndrome that impacts multiple organs and has an overall prevalence of 1:10,000-13,700 live births.1, 2 The risk of BWS increases 10-fold when assisted reproductive techniques are used.1–3 Figure 2 displays the clinical and molecular features used in the diagnosis of BWS.2


Figure 2: Schematic showing the clinical and molecular features used in the diagnosis of Beckwith-Wiedemann syndrome (BWS).  Based on material from Shuman C, Kalish JM, Weksberg R, et al. Beckwith-Wiedemann syndrome. GeneReviews. 2023 Sep 21. Seattle (WA): University of Washington, Seattle; 1993–2023.2

In patients with BWS, genomic imprinting occurs due to epigenetic modification, typically via DNA methylation of either the maternal or paternal chromosome, which leads to differential gene expression in the offspring.2 BWS occurs due to disorders in genomic imprinting involving chromosome 11p15.5, where the imprinting center 1 (IC1) and IC2 genes are located.1, 2  IC1 regulates the expression of IGF2 and H19 genes, whereas IC2 regulates the expression of CDKN1CKCNQ10T1, and KCNQ1 genes. These genes regulate cell cycle progression and postnatal somatic growth.1, 2 Fifty percent of BWS cases are due to the loss of methylation of the IC2 gene on the maternal chromosome.1,2,4 Other mechanisms include parental uniparental disomy (UPD) (~20%), idiopathic etiology (~20%), gain of methylation of the maternal chromosome (~5%), maternal CDKN1C mutations (5%), and cytogenic mechanisms such as inversions, duplications and translocations (~1%). 1,2,4 The genetic diagnosis of BWS can be made by performing methylation studies (Option C) to identify an abnormal methylation pattern in chromosome 11p15.5.

Determining the specific molecular mechanism will help identify the risk of future complications in the neonate and delineate the risk of recurrence in future offspring. BWS poses an increased risk of malignancy in the first year of age by 5-10%, when compared to the healthy population.1 Specific tumors associated with BWS include Wilms tumor (52%), hepatoblastoma (14%), neuroblastoma (10%), rhabdomyosarcoma (5%), and adrenal carcinoma (3%).1,2 The American Association of Cancer Research Childhood Cancer Predisposition Workshop recommends abdominal USG and alpha-fetoprotein (AFP) levels at diagnosis and every three months until the child reaches four years of age.1,2 Additionally, renal USG is recommended every 3 months from 4–7 years of age.1

The fetus in this vignette has an omphalocele, as noted on the USG (Figure 1). Postnatally, if unruptured, an omphalocele can be differentiated from gastroschisis by the location and presence of an amniotic sac.5 In contrast to an omphalocele, which is located midline at the umbilical ring, gastroschisis is located to the right of the umbilical cord, has no covering sac or membrane, and is typically not associated with a genetic anomaly (Figures 3A and 3B).5 Omphaloceles can be associated with other anomalies in 50–70% of cases, with the most common being cardiac (14–47%- tetralogy of fallot, atrial septal defect) and central nervous system anomalies (3–33%-neural tube defects).1,5,6 Omphaloceles can also occur in specific syndromes such as pentalogy of Cantrell, Meckel-Gruber syndrome, OEIS complex (bladder exstrophy or the omphalocele, exstrophy of the cloaca, imperforate anus, and spinal defects), and cleft palato-omphalocele syndrome.1,5,6 BWS is diagnosed in 10–20% of fetuses who have an omphalocele.1,5,6 Aneuploidy is associated with omphaloceles in 30–49% of cases and chromosomal aberrations in 30–70% of cases,1,5,6 which can be detected using chromosomal microarray (CMA) (Option A). However, a CMA ​should not be used in isolation when clinical suspicion for BWS is high, because it will not detect disorders in genomic imprinting.


Figure 3: A. A neonate with gastroschisis, characterized by an abdominal defect located to the right of the umbilicus and abdominal contents without a membranous sac. B. A neonate with an omphalocele is characterized by an abdominal defect at the umbilicus and herniated abdominal contents contained within an intact membranous sac. Image from: Slater BJ, Pimpalwar A. Abdominal wall defects. Neoreviews. 2020;21(6):e383-e391.5

With the advent of next-generation sequencing, whole exome sequencing has been introduced into clinical practice. This process helps detect abnormalities in the coding regions of the genome (1-2% of the genome).7 Whole exome sequencing (Option E) has been utilized in the diagnosis of a genetic syndrome when there is clinical suspicion, typically after karyotype analysis and CMA have not revealed a genetic diagnosis.7 Whole exome sequencing can detect single nucleotide variants in neonates with a broad differential diagnosis such as inborn errors of metabolism, infantile epileptic encephalopathies, and cardiac malformations, with a diagnostic yield of 25–32%.7 Although a broad diagnostic tool, whole exome sequencing cannot detect variants associated with imprinting such as BWS, which is suspected in the vignette of the fetus.7  

The fetus in the vignette also has macroglossia, which is defined as a tongue that extends beyond the alveolar ridge at baseline (Figure 4).8 The differential diagnosis of macroglossia includes BWS, trisomy 21 syndrome, congenital hypothyroidism, and isolated macroglossia.8 The prenatal cell-free DNA screen can help evaluate for aneuploidies. Cell-free DNA screening has a high detection rate of trisomies 13, 18, and 21, and a low combined false-positive rate of 0.13%.9 If prenatal findings of trisomy 21 are suspected, a postnatal karyotype (Option B) identifying three copies of chromosome 21 can confirm the diagnosis. Although karyotyping can identify cytogenic abnormalities in BWS such as chromosomal inversion, translocations, or duplications, these mechanisms are relatively rare (~1%), and methylation studies must be performed as the initial diagnostic test when BWS is considered.1 


Figure 4: Neonate with macroglossia in BWS. Image from: Bresnahan M, Wojcik MH. Follow-up for a preterm infant with Beckwith-Wiedemann syndrome. Neoreviews. 2022;23(1):e60-e66.4

Congenital hypothyroidism should be considered in neonates with macroglossia. These patients are typically asymptomatic at birth but can present with temperature dysregulation, an umbilical hernia, poor feeding, constipation, and prolonged jaundice.10 The passage of thyroid hormone from the pregnant person in-utero provides a protective effect on the fetus.10 The state newborn screen for congenital hypothyroidism can help identify neonates with thyroid stimulating hormone and free thyroxine abnormalities, thus thyroid function tests (Option D) can confirm the diagnosis, as shown in Figure 5.10 Neonates with congenital hypothyroidism are less likely to have the features noted in the vignette of the fetus. While there can be occurrences of BWS with congenital hypothyroidism, this association is relatively rare, with only 4 existing case reports describing the association in the literature.11


Figure 5: Schematic showing the laboratory evaluation for congenital hypothyroidism. Image from: Weiner A, Oberfield S, Vuguin P. The laboratory features of congenital hypothyroidism and approach to therapy. Neoreviews. 2020;21(1):e37-e44.10

Did you know?
Neonatal hypoglycemia occurs in ~ 50% of infants with BWS, and up to 50% of infants with BWS have congenital hyperinsulinism.12 Hypoglycemia in BWS can be severe, typically requiring GIRs >10-12 mg/kg/min to maintain euglycemia. 13

What are some of the technologies commonly used for genetics diagnosis in neonates?
For a detailed description of each technique, comparison, strengths, and limitations, refer to the table in Senaratne TN, Saitta SC. Evaluating genetic disorders in the neonate: the role of exome sequencing in the NICU. Neoreviews. 2022;23(12):e829-e840.7

NeoQuest July 2024 Authors:
Srirupa Hari Gopal, MBBS, FAAP, Baylor College of Medicine, Houston, TX
Faith Kim, MD, Columbia University Medical Center, New York, NY

References

  1. Bridges A, Hwang J, Edwards E, Feist C, Dukhonvy S. Prenatal diagnosis of Beckwith-Wiedemann syndrome with omphalocele. Neoreviews. (2024);25(7):e457–e465
  2. Shuman C, Kalish JM, Weksberg R, et al. Beckwith-Wiedemann syndrome. GeneReviews. 2023 Sep 21. Seattle (WA): University of Washington, Seattle; 1993–2023
  3. Johnson J, Hartman T, Colby CE. Developmental and genetic outcomes in children conceived through assisted reproductive technologies. Neoreviews. 2006 ;7(12):e615-e626
  4. Bresnahan M, Wojcik MH. Follow-up for a preterm infant with Beckwith-Wiedemann syndrome. Neoreviews. 2022;23(1):e60-e66
  5. Slater BJ, Pimpalwar A. Abdominal wall defects. Neoreviews. 2020;21(6):e383-e391
  6. Gamba P, Midrio P. Abdominal wall defects: prenatal diagnosis, newborn management, and long-term outcomes. Semin Pediatr Surg. 2014;23(5):283-290
  7. Senaratne TN, Saitta SC. Evaluating genetic disorders in the neonate: the role of exome sequencing in the NICU. Neoreviews. 2022;23(12):e829-e840
  8. Vachharajani A, Bindom S. A newborn with a large tongue. Neoreviews. 2017;18(3):e190-e192
  9. Fiorentino DG, Hughes F. Fetal screening for chromosomal abnormalities. Neoreviews. 2021;22(12):e805-e818
  10. Weiner A, Oberfield S, Vuguin P. The laboratory features of congenital hypothyroidism and approach to therapy. Neoreviews. 2020;21(1):e37-e44
  11. Ramadan GI, Kennea NL. Beckwith-Wiedemann syndrome associated with congenital hypothyroidism in a preterm neonate: a case report and literature review. J Perinatol. 2009;29(6):455-457
  12. Sims K. Congenital hyperinsulinism. Neoreviews. 2021;22(4):e230-e240
  13. DeBaun, M.R., King, A.A. and White, N. Hypoglycemia in Beckwith-Wiedemann syndrome. Semin Perinatol. April 2000;24(2), 164-171.
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