Newborn With Macroglossia, Mass in Umbilical Area, and Hypoglycemia

What's Your Diagnosis?
Sharpen Your Physical Diagnostic Skills

HISTORY
Male neonate born to a 20-year-old primiparous mother at 36 weeks’ gestation after an uncomplicated pregnancy. Cesarean section performed because of failure to induce labor. Apgar scores were 3 and 9, at 1 minute and 5 minutes, respectively. Neonate jittery in the immediate neonatal period. Unremarkable family history.

PHYSICAL EXAMINATION
Weight, 3.95 kg (8.7 lb); length, 53 cm; head circumference, 33.5 cm. Anterior and posterior fontanelles, 4 × 2 cm and 1 × 1 cm, respectively. Horizontal creases noted on both ear lobes. Large and protruding tongue. Heart rate, 84 beats per minute and regular. Ejection systolic murmur over the precordium with fixed splitting of the second heart sound. Liver 2 cm below the costal margin.

Mass found in the umbilical area. Testes not palpable.

LABORATORY INVESTIGATIONS
Normal complete blood cell count and serum calcium level. Serum glucose, 17 mg/dL.

WHAT'S YOUR DIAGNOSIS?

(answer on next page.)

WHAT'S YOUR DIAGNOSIS?
ANSWER: BECKWITH-WIEDEMANN SYNDROME

Beckwith-Wiedemann syndrome, originally described by Beckwith^1,2 and Wiedemann,³ is a congenital overgrowth syndrome characterized by  acrosomia, macroglossia, abdominal wall defects, and neonatal hypoglycemia.

The incidence is approximately 1 in 10,000 to 15,000 live births.⁴ The sex ratio is equal.⁴

ETIOLOGY
Most cases occur sporadically.⁵ Approximately 10% to 15% of cases have an autosomal dominant mode of inheritance with incomplete penetrance and variable expression.^5,6 The affected genes have been mapped to chromosome 11p15.⁴ Genetic imprinting with loss of maternally expressed tumor or growth suppressor genes as well as duplications or uniparental disomy of paternally expressed growth promoter genes can lead to Beckwith-Wiedemann syndrome.⁷

CLINICAL MANIFESTATIONS
The diagnosis is clinical and based on the presence of macrosomia, macroglossia, and abdominal wall defects (omphalocele, umbilical hernia, diastasis recti).^8,9 Other features may include distinctive ear lobe creases, preauricular pits, prominent facial nevus flammeus or other hemangiomata, characteristic facies with midfacial hypoplasia, prominent eyes, large fontanelles, prominent occiput, mild microcephaly, visceromegaly, hemihypertrophy, cryptorchidism, cardiomegaly or structural cardiac anomalies, joint laxity, scoliosis, thoracic cage abnormalities, neonatal hypoglycemia, neonatal polycythemia, and advanced bone age.^5,8-12 In affected infants, there may be a history of in vitro fertilization, gestational hypertension, polyhydramnios, prematurity, or placentomegaly.^5,9,13


COMPLICATIONS
Embryonal tumors develop in children with Beckwith-Wiedemann syndrome approximately 600 times more often than in the general population.¹⁴ Wilms tumor accounts for approximately 65% of the tumors in children with Beckwith-Wiedemann syndrome.¹⁵ Other tumors include adrenocortical carcinoma, hepatoblastoma, and neuroblastoma.¹⁶ The risk of malignancy is significantly increased in patients who also have hemihypertrophy.^8,11

Approximately 4% of persons with Beckwith-Wiedemann syndrome are mentally retarded.⁷ This retardation is usually mild to moderate and can be attributed to the chromosomal anomaly, prematurity, or hypoglycemia.⁷

Macroglossia can partially occlude the airway and lead to feeding difficulties and obstructive sleep apnea.¹⁷ Macroglossia can also impair speech articulation and might result in malocclusion since growth of the mandible depends to a certain extent on the size of the tongue.⁹

DIFFERENTIAL DIAGNOSIS
The differential diagnosis includes an infant of a diabetic mother, congenital hypothyroidism, Simpson-Golabi-Behmel syndrome, Sotos syndrome, Perlman syndrome, and Costello syndrome.^9,18 The clinical features of the various conditions usually permit a straightforward differentiation.

INVESTIGATIONS
Neonates with Beckwith-Wiedemann syndrome should undergo abdominal CT or MRI scanning. Serial abdominal ultrasonography is indicated at 3-month intervals until the child is 8 years old. Regular measurements of the serum α-fetoprotein concentration are needed until age 5 years.^9,12,14 Tumors associated with elevated α-fetoprotein include hepatoblastoma and other hepatic neoplasms, yolk sac tumors, and germ cell tumors.¹⁴ The serum α-fetoprotein concentration is greater in children with Beckwith-Wiedemann syndrome and declines at a slower rate than in children without Beckwith-Wiedemann syndrome.

TREATMENT
Treatment is symptomatic and individualized. Genetic counseling should be offered. The risk of recurrence is as high as 50% if the family history is positive and if p57^kip2 or CDKNIC mutations or paternal chromosomal abnormalities are detected.^9,12 Mosaicism for 11p15 uniparental disomy is the result of a post-zygotic event and has a low risk of recurrence.⁹

REFERENCES:
1. Beckwith JB. Extreme cytomegaly of the foetal adrenal cortex, omphalocele, hyperplasia of kidneys and pancreas, and Leydig-cell hyperplasia—another syndrome? Presented at: the Annual Meeting of the Western Society for Pediatric Research; November 11, 1963; Los Angeles.
2. Beckwith J. Macroglossia, omphalocele, adrenal cytomegaly, gigantism, and hyperplastic visceromegaly. Birth Defects: Original Articles Series. 1969;5:188-196.
3. Wiedemann HR. Complexe malformatif familial avec hernie ombilicale et macroglosse: un syndrome nouveau? J Genet Hum. 1964;13:223-232.
4. Rump P, Zeegers MP, van Essen AJ. Tumor risk in Beckwith-Wiedemann syndrome: a review and meta-analysis. Am J Med Genet A. 2005;136:95-104.
5. Cytrynbaum CS, Smith AC, Rubin T, Weksberg R. Advances in overgrowth syndromes: clinical classification to molecular delineation in Sotos syndrome and Beckwith-Wiedemann syndrome. Curr Opin Pediatr. 2005;17:740-746.
6. Chen L, Li Y, Lin JH. Intraneural perineurioma in a child with Beckwith-Wiedemann syndrome. J Pediatr Surg. 2005;40:e12-e14.
7. Munns CF, Batch JA. Hyperinsulinism and Beckwith-Wiedemann syndrome. Arch Dis Child Fetal Neonatal Ed. 2001;84:F67-F69.
8. DeBaun MR, Tucker MA. Risk of cancer during the first four years of life in children from the Beckwith-Wiedemann syndrome registry. J Pediatr. 1998;132:398-400.
9. Weksberg R, Shuman C, Smith AC. Beckwith-Wiedemann syndrome. Am J Med Genet C Semin Med Genet. 2005;137:12-23.
10. Gerber LH, Chaudhry U, DeBaun M. Joint laxity, scoliosis, and thoracic cage abnormalities in children with Beckwith-Wiedemann syndrome. Eur J Pediatr. 2001;160:143-144.
11. Leung AK, Fong JH, Leong AG. Hemihypertrophy. J R Soc Health. 2002;122:24-27.
12. Williams DH, Gauthier DW, Maizels M. Prenatal diagnosis of Beckwith-Wiedemann syndrome. Prenat Diagn. 2005;25:879-884.
13. Wangler MF, Chang AS, Moley KH, et al. Factors associated with preterm delivery in mothers of children with Beckwith-Wiedemann syndrome: a case cohort study from the BWS registry. Am J Med Genet A. 2005;134:187-191.
14. Everman DB, Shuman C, Dzolganovski B, et al. Serum alpha-fetoprotein levels in Beckwith-Wiedemann syndrome. J Pediatr. 2000;137:123-127.
15. Porteus MH, Narkool P, Neuberg D, et al. Characteristics and outcome of children with Beckwith-Wiedemann syndrome and Wilms’ tumor: a report from a National Wilms Tumor Study Group. J Clin Oncol. 2000;18:2026-2031.
16. Hamada Y, Takada K, Fukunaga S, Hoiki K. Hepatoblastoma associated with Beckwith-Wiedemann syndrome and hemihypertrophy. Pediatr Surg Int. 2003;199:112-114.
17. Kamata S, Kamiyama M, Sawai T, et al. Assessment of obstructive apnea by using polysomnography and surgical treatment in patients with Beckwith-Wiedemann syndrome. J Pediatr Surg. 2005;40:e17-e19.
18. Leung AK, McArthur RG, Ross SA, et al. Thyroxine-binding globulin deficiency in Beckwith syndrome. J Pediatr. 1979;95:752-754.