Case of the Week #613

Oueslati Boujemaa (1), Javier Cortejoso (2)
(1) Centre d Echographie et de Medecine Foetale; Belveder Centre, Tunis, TUNISIE; (2) Hospital Recoletas Campo Grande, Valladolid, Spain

Posting Dates: Sep 15, 2024 - Sep 29, 2024

A 34-year-old woman with no notable history except primary hypofertility presents at 18 weeks of pregnancy for a second opinion before considering termination of pregnancy. Her first pregnancy was conceived by in vitro fertilization. The karyotye and whole exome sequencing was normal.

**Image 12** 30 weeks gestation. BIP: biparietal diameter; PC: head circumference; Cervelet: cerebellum; PA: Abdominal circumference; Humerus: humerus; LF: femur length; Grande cisterne: Cisterna magna; Carrefours: ventricular junction

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Answer

We present a case of Beckwith-Wiedemann syndrome. The child was born at term by cesarean section with a birth weight of 4800g and underwent operation for his omphalocele. Genetic testing of chromosome 11p15 demonstrated hypomethylation at the TSS-DMR region of the KCNQ1OT1 gene. At follow up 4 years later, the child is doing well without significant problems.

Our images demonstrate:

Image 1: Omphalocele contains only the intestines; normal bladder, absence of macroglossia, male gender
Image 2 and 3: anomaly of the posterior fossa with communication of V4 with the greater cistern. There is an appearance of elevation of the cerebellar tentorium and unclear morphology of the vermis that may be explained by the elevation of the vermis and early gestational age (18 weeks)
Video 1: abdominal and thoracic scan demonstrated absence of other anomalies. In particular, absence of cardiac anomalies and cardiomegaly
Image 4: at 23 weeks gestation, the kidneys are normal and the renal pelvises are not particularly dilated
Image 5: a small cyst in the spleen
Image 6: at 23 weeks, there is still absence of macroglossia
Image 7: absence of anomalies of the posterior fossa with normal cerebellar tent, vermis and absence of signs suggestive of Dandy Walker syndrome
Image 8: normal face without macroglossia
Image 9: normal ear and hand without polydactyly
Image 10: at 30 weeks, there is mild pyelectasis
image 11: at 30 weeks, there is slight nephromegaly
Image 12: at 30 weeks, slight macrosomia probably underestimated by the "usual" method of measuring abdominal girth that excludes the omphalocele

**Image 1** Postnatal image of neonate with omphalocele.

Discussion

Beckwith–Wiedemann syndrome (OMIM 130650), a phenotypically and genetically heterogeneous disorder, is the most common congenital disorder characterized by neonatal overgrowth and gigantism [1]. Also known as Wiedemann-Beckwith syndrome and Beckwith-Wiedemann spectrum, the condition is characterized by a variable set of anomalies that most commonly include macrosomia, macroglossia, visceromegaly, and omphalocele [2]. It was first described in 1963 by John Bruce Beckwith, an American pediatric pathologist [3], and in 1964 by Hans-Rudolf Wiedemann, a German paediatrician geneticist [4]. It was originally called EMG syndrome based on the presence of Exomphalos, Macroglossia, and Gigantism in many cases [5]. Prenatal diagnosis of Beckwith–Wiedemann syndrome was first reported in 1980 by Weinstein and Anderson [6] and, since then, about 60 cases have been reported in the literature.

Its prevalence is approximately 1 in 10,000 live births [7], though it is 10 times greater (1 in 1000) in children conceived through assisted reproductive techniques [8] and in monozygotic twins, in particular female twins with asymmetric expression of the syndrome [9]. The genetic mechanisms leading to Beckwith–Wiedemann syndrome are complex, and involve alterations in the balance of growth regulatory genes located at chromosome 11p15.5 [10-13]. This region includes two differentially methylated regions, known as IC1 and IC2, that control imprinting within the domain. Epigenetics and genomic defects are observed in 70% to 80% of patients, though 20% are idiopathic. Mutations identified are loss of methylation of IC2 on the maternal chromosome (50%), paternal uniparental disomy of 11p15.5 (20%), gain of methylation of IC1 on the maternal chromosome (5%), mutation of the maternal CDKN1C allele (5% of sporadic cases, but up to 40% in familial cases), and cytogenetic duplications, inversions or translocations of 11p15.5 (1%). Some correlation between genotype and phenotype has been identified, with abdominal wall defects dominant in fetuses with IC2 hypomethylation while macrosomia, organomegaly and tumoral predisposition are more frequent in patients with IC1 hypermethylation [12]. Genetic testing for Beckwith–Wiedemann syndrome can include DNA methylation studies, single-gene testing, copy number analysis for 11p15.5, chromosomal microarray, karyotype, and use of multigene panels that include genes in the Beckwith–Wiedemann syndrome critical region [13].

Beckwith-Wiedemann syndrome is considered a clinical spectrum, in which affected individuals may have many or only some of the characteristic clinical features [14]. Postnatally, these include overgrowth, macroglossia, abdominal wall defects, renal and urologic malformations, neonatal hyperinsulinemic hypoglycemia, lateralized overgrowth, lobe creases or helical pits, facial nevus flammeus, organomegaly, and increased risk of embryonal tumors in childhood [13,14]. The risk is increased (4%-21%) for embryonal tumors, particularly Wilms tumor (nephroblastoma) but also hepatoblastoma, neuroblastoma, adrenocortical carcinoma, and rhabdomyosarcoma [15].

Prenatal diagnosis of Beckwith–Wiedemann syndrome is challenging because although the omphalocele, the most common prenatal finding, is usually detected early in pregnancy, associated findings of macrosomia, macroglossia, and visceromegaly, when present, are detected later in gestation [16]. Some prenatal signs should alert the clinician, such as the rapid increase in growth of the abdominal circumference in the 3rd trimester with associated polyhydramnios, especially in the absence of maternal diabetes. Ultrasound examination should then look for signs more suggestive of Beckwith-Wiedemann syndrome, such as macroglossia, visceromegaly and placental hypertrophy [17]. Abdominal wall defects (umbilical hernia or omphalocele) are the most prevalent prenatal sign detected in 43% of cases, which is followed by polyhydramnios (33%), macrosomia (33%), macroglossia (18%), organomegaly including nephromegaly, hepatomegaly, and cardiomegaly (18%), placentomegaly (8%), tumors (4%), and anomalies of the corpus callosum (1%) [12]. In addition to abnormalities of the corpus callosum, Gardiner et al [18] reported seven cases of Beckwith-Wiedemann syndrome associated with posterior fossa abnormalities including Blake’s pouch cyst, hypoplasia of the inferior part of the vermis, and Dandy–Walker malformation. These cases nearly all had molecular defects in the imprinted domain 2. Several systems classifying prenatal findings into major and minor criteria have been described, however the results are limited due to the large number and variability of the findings in Beckwith–Wiedemann syndrome and the difficulty in identifying these prenatally [19, 20].

Placental enlargement and/or thickening is sometimes accompanied by characteristic ultrasound findings (edematous and spongy placenta with multiple small lacunae, without high vascularisation) that correspond to the pathologic diagnosis of placental mesenchymal dysplasia [21]. Placentomegaly may cause an increase in beta-hCG and inhibin-A levels, while high levels of maternal serum alpha fetoprotein and uE3 may be associated with visceral organ enlargement including liver and adrenal gland. Given that elevation of all biomarkers of the triple screen/quad test is rarely reported to be specific to any other disorder, this finding may be clinically useful for early detection of Beckwith-Wiedemann syndrome [21, 22].

Some maternal pregnancy complications have a higher frequency in Beckwith-Wiedemann syndrome, especially gestational hypertension, pre-eclampsia, HELLP syndrome and eclampsia. Placentomegaly may contribute to excessive beta-hCG levels seen in the second trimester. The relationship between increased beta-hCG and AFP levels, and preeclampsia is well established. Additionally, elevated beta-hCG can contribute to overstimulation of the ovaries [22]. Premature labor and delivery can occur in pregnancies affected with Beckwith-Wiedemann syndrome due to preeclampsia, macrosomia and polyhydramnios. Delivery should occur in a tertiary center to prevent complications from macroglossia and hypoglycemia, and if present, perform surgical repair of the omphalocele. After childhood, complications are infrequent, and development is usually normal unless there are hypoxic episodes or untreated hypoglycemia [2, 23].

Several overgrowth syndromes that show features of macrosomia but are usually not associated with visceromegaly, macroglossia, or omphalocele should be differentiated from Beckwith-Wiedemann syndrome, such as Simpson–Golabi–Behmel syndrome, Perlman syndrome, and Sotos syndrome [12].

References

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