IMIP – Instituto Materno Infantil Professor Fernando Figueira.
Author Address: Marcelo Marques de Souza Lima. Major Armando Souza Melo street, number 207 / Boa Viagem. City: Recife / State: Pernambuco / Brazil. CEP: 51130-040. Cell phone: 081-99964950.

Case report

A 33-year-old G4P2 referred to our unit at 31st week of gestation because of a fetal abdominal wall defect. The ultrasound examination showed a male singleton fetus with an omphalocele. The fetal biometry was concordant with the gestational age and the estimated fetal weight was 1830 g (70th percentile). Polyhydramnios was also present.

Images 1 and 2: Image 1 - prenatal ultrasonography showing omphalocele. Image 2 - postnatal appearance of the omphalocele.

At 37 weeks the polyhydramnios had increased and the estimated fetal weight was 3856 g (92nd percentile). Macroglossia was evident. These findings led us to the diagnosis of Beckwith-Wiedemann syndrome. Cesarean section was performed five days later because of obstetrical indications. The male baby weighted 4080 g (95th percentile); Apgar score was 8 and 9. The baby exhibited seizures and hypoglycemia. Postnatal echocardiography showed no cardiovascular disorders and ultrasonography of the kidneys was normal. At the 11th day after delivery an operation of the omphalocele was done.

The Beckwith-Wiedemann syndrome was confirmed based on the combination of macroglossia, omphalocele, glucose disorders, macrosomia and the finding of the ear-lobe groove. The further development of the baby was satisfying without any neurological abnormalities.

Images 3 and 4: Postnatal appearance of the baby. Image 3 - macroglossia of the baby. Image 2 - ear lobe groove.

Definition

Initially described by Beckwith in 1963 and after by Wiedemann in 1964, the classic triad of this syndrome consists in macrosomia, omphalocele, and macroglossia [1, 2].

Incidence

Estimated in 0.72:10,000 births and more than 500 cases are reported in the literature [3, 4].

Etiology

Beckwith-Wiedemann syndrome is a genetically heterogeneous disorder; most cases are sporadic but approximately 15% are familial and a small number of Beckwith-Wiedemann syndrome patients have cytogenetic abnormalities involving chromosome 11p15. Genomic imprinting effects have been implicated in familial and non-familial Beckwith-Wiedemann syndrome, and uniparental disomy for chromosome 11 has been reported in sporadic cases [5].

Pathogenesis

Beckwith-Wiedemann syndrome is a part of the generalized visceromegaly probably secondary to fetal hyperinsulinism [6]. This is mediated by elevated hPL (human placental lactogen) levels in chronic hypoglycemia due to hyperplasia of Langerhans islet cells [7] or by raised growth factors, especially in familial cases where cytogenetic abnormalities involving bands p13-15 of chromosome 11 can be found (p15-pter) [8,9,10]. Recently uniparental paternal disomy has been shown to be the underlying disorder in some cases of Beckwith-Wiedemann syndrome using 11p15.5 markers, a region, that also carries the code for insulin and insulin-like growth hormones [11, 12].

Diagnosis

The fetal finding of macrosomia, omphalocele and macroglossia associated with normal karyotype makes, in most of cases, the diagnosis of Beckwith-Wiedemann syndrome. A diagnostic schema was proposed including two major criteria (abdominal wall defect, macroglossia, macrosomia) or one major plus two minor criteria (nephromegaly/dysgenesis, adrenal cytomegaly, aneuploidy/abnormal loci, polyhydramnios) to establish a guideline [13]. Other features occurring in variable incidence include hepatomegaly, polyhydramnios, diaphragmatic hernia and cardiac defects [14, 15].

Differential diagnosis

Chromosomal analysis must be performed to exclude Down’s syndrome due to the occurrence of macroglossia in both conditions. Diabetic fetopathy is another cause of macrosomia, and thus a differential diagnosis. Normal levels of maternal glucose exclude this possibility. Zellweger syndrome can also combine liver and kidney enlargement, and may be diagnosed prenatally by measuring fatty acid concentration and activity of marker enzymes [16].

Prognosis

Neonatal mortality rate is approximately 21%, caused mainly by congestive heart failure. Among the survivors, the prognosis is favorable in most cases, depending on the severity of the associated anomalies and long term complications [3]. Neonatal hypoglycemia is an important complication and may result in further cerebral dysfunction, such as seizures, mild to moderate mental retardation, or neonatal death in more severe cases [17, 18]. Macroglossia can cause variable complications ranging from feeding difficulties to airway obstruction and death. Long term complications include high risk for abdominal tumors, in particular Wilms tumor, hepatoblastoma, neuroblastoma, and adrenal cortical carcinoma [3, 18].

Management

In countries where termination of pregnancy is not allowed, the antenatal diagnosis allows to optimize perinatal care. When diagnosed before viability, termination of the pregnancy can be offered in countries, where it is legal. Fetal macrosomia may lead to cesarean section due to the risk of shoulder dystocia. Delivery in a tertiary center is recommended with consequent abdominal wall defect repairment and treatment of the hypoglycemia. Hypoglycemia in the neonatal period is common in these babies and requires early detection and appropriate management to prevent long-term intellectual complications. Sonograghic screening for abdominal tumors each trimester is recommended during the first 6 years of life [3, 16].

References

1. Beckwith JB: Extreme citomegaly of the adrenal fetal cortex, omphalocele, hyperplasia of kidneys and pancreas, and Leydig-cell hyperplasia. Another syndrome? Present at annual meeting of western society for pediatric research, Los Angeles, California, November 11, 1963.
2. Wiedemann HR: Complex malformatif. Familial avec hernie omblicale e macroglossie-un “syndrome noveau”? J. Hum Genet 13: 223-232, 1964.
3. Whisson CC, Whyte A, Ziesing P. (1994): Beckwith-Wiedemann syndrome: antenatal diagnosis. Australian Radiology 38: 130-131.
4. Viljoen DL. Jaquire Z. Wood DL. (1991): Prenatal diagnosis in autossomal dominant Beckwith-Wiedemann syndrome. Prenat Diagn. 11, 167-175.
5. Slatter RE, Elliott M, Welham K, Carrera M, Schofield PN, Barton DE, Maher ER. Mosaic uniparental disomy in Beckwith-Wiedemann syndrome. J Med Genet 1994 Oct; 31(10): 749-53.
6. Pettenati MJ, Haines JL, Higgins RR, et al. Wiedemann-Beckwith syndrome: presentation of clinical and cytogenetic data on 22 new cases and review of the literature. Hum Genet 1986; 74: 143.
7. Wieacker P, Wilhelm Ch, Greiner P, et al. Prenatal diagnosis of Wiedemann-Beckwith syndrome. J Perinat Med 1989; 17: 351-55.
8. Ping AJ, Reeve AE, Law DJ, et al. Genetic linkage of Beckwith-Wiedemann syndrome to 11p15. Am J Hum Genet 1989; 44: 720-3.
9. Koufos A, Grundy P, Morgan K, Aleck KA, Hadro T, Lampkin BC, Kalbakji A, Cavenee WK. (1989): Familial Beckwith-Wiedemann syndrome and a second Wilms tumor locus both map to 11p15.5. Am J Hum Genet 44: 711.
10. Waziri M, Patil SR, Hanson JW, et al. Abnormality of chromosome 11 in patients with features of Beckwith-Wiedemann syndrome. J Pediatr 1983; 102: 873.
11. Henry I, Bonaiti-Pellié C, Chehensse V, et al. Uniparental paternal disomy in a genetic cancer-predisposing syndrome. Nature, 21st June 1991; 351: 665-7.
12. Spencer GSG, Shabel F, Frisch H. Raised somatomedin associated with normal growth hormone. Arch Dis Child 1987; 55: 151.
13. Williams DH, Gauthier DW, Maizels M. Prenatal diagnosis of Beckwith-Wiedemann syndrome. Prenat Diagn. 2005 Oct;25(10):879-84.
14. Fremond B, Poulain P, Odent S, Milon J, Treguier C, Babut JM. (1997): Prenatal detection of a congenital pancreatic cyst and Beckwith-Wiedemann syndrome. Prenat Diagn 17(3): 276-280.
15. Ranzini AC, Day-Salvatory, Turner T, Smulian JC, Vintzileos AM. (1997): Intrauterine growth and ultrasound findings with Beckwith-Wiedemann syndrome. Obstet Gynecol. 89(4) 538-542.
16. Nowotny T, Bollmann R, Pfeifer L, Windt E. (1994): Beckwith-Widiemann syndrome: difficulties with prenatal diagnosis. Fetal Diagn. Ther. 9: 256-260.
17. Winter SC, Curry CJR, Smith C, Kassel S, Miller L, Andrea J. (1986): Prenatal diagnosis of the Beckwith-Wiedemann syndrome. Am J Med Gent. 24: 137-141.
18. Hewitt B, Bankier A. (1994) Prenatal ultrasound diagnosis of Beckwith-Wiedemann syndrome. Aust NZ J Obstet Gynaecol 34(4): 488-490.