Beckwith-Wiedemann Syndrome

Most often a sporadically occurring syndrome with exomphalos, macroglossia, gigantism, and hypoglycemia caused by hyperinsulinism.

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Wiedemann-Beckwith Syndrome; Beckwith Syndrome; Wiedemann Syndrome; Wiedemann-Beckwith-Combs Syndrome; Infantile Gigantism; EMG Syndrome; Exomphalos-Macroglossia-Gigantism Syndrome; Familial Macroglossia-Omphalocele Syndrome; Macroglossia-Omphalocele-Visceromegaly Syndrome.

1:13,700 live births in West India. The incidence in other countries is approximately 1.5:100,000 live births.

Most cases are sporadic; however, approximately 15% are inherited in an autosomal dominant mode with incomplete penetrance and variable expressivity. Failure of normal biparental inheritance of chromosome 11p15 (11p ter p15).

The 11p15 chromosome region contains a growth-promoting and a tumor-suppression gene. The genetic anomaly results in increased expression of the “insulin-like growth factor-2” gene IGF-2, which is responsible for the somatic overgrowth and predisposition to tumors. Altered placental endocrine physiology may play a role in producing many of the features already found during the neonatal period. Omphalocele, anomalies of intestinal rotation and fixation, and diaphragmatic eventration may be secondary to early visceromegaly.

During pregnancy, polyhydramnios, and a very large placenta (up to twice the normal size) with increased length of the umbilical cord are characteristic. The birth weight for boys and girls is around the 95th and 75th percentile, respectively. Growth velocity is increased in the first 4 to 6 years of life (postnatal growth >90th percentile) and associated with advanced bone age, but normalization thereafter. Severe hypoglycemia is present in approximately 30 to 60% of newborns, with the highest incidence in the first 3 days of life. Macroglossia and omphalocele or umbilical defects, ear lobe grooves, and circular depression on the posterior rim of helix are other features.

Macroglossia is present in 98% of cases. Visceromegaly is characteristic: nephromegaly (with dysplasia of the renal medulla in 97%), splenomegaly (82%), and hepatomegaly (73%). Adrenocortical cytomegaly and pituitary amphophil hyperplasia have been reported. Intestinal malrotation with pyloric and/or ileal stenosis, imperforate anus, and atresia of the colon occasionally occur. Omphalocele and umbilical hernia may partially result from visceromegaly. Midface hypoplasia (hypoplastic maxilla) is associated with prominent occiput, ear anomalies, somatic gigantism, cryptorchidism, overgrowth of external genitalia, hypospadias, and bicornuate uterus. Conductive deafness may develop. Hemihypertrophy has been reported and is more often associated with malignant tumors (adrenal carcinoma, nephroblastoma [Wilms tumor], hepatoblastoma, thoracic neuroblastoma, rhabdomyosarcoma, congenital gastric teratoma) and require regular followups. The incidence of benign tumors (adrenal adenoma, myxoma, ganglioneuroma, carcinoid tumors) is increased. Hypoglycemia, if present in the neonatal period, may persist during the first years of life. Hypoglycemia is a result of relative hyperinsulinism associated with pancreatic islet hyperplasia. Mental retardation may result from neonatal hypoglycemia, but is otherwise rare (approximately 12% of patients). Hyperlipidemia, hypercholesterolemia, and hypocalcemia or hypercalcemia are commonly found. Sporadic cases with cardiomyopathy, congenital cardiac lesions (atrial septal defect, ventricular septal defect, hypoplastic left heart syndrome, tetralogy of Fallot, pulmonary artery stenosis), or cardiac hamartomas have been described. Infant mortality is high (up to 20%) and usually results from heart and respiratory failure.

All patients must be checked for hypoglycemia and corrected if necessary (10% dextrose to provide 6-8 mg/kg/min of dextrose). Evaluate for difficult direct laryngoscopy and tracheal intubation as a result of macroglossia and maxillary hypoplasia. Echocardiography may be indicated. Surgery in children consists mainly of omphalocele repair, tumoral surgery and partial glossectomy.

The patient may be a giant premature baby, combining the risks of prematurity with those of macroglossia and its potential subsequent respiratory complications. Possible difficult tracheal intubation must be anticipated and a fiberoptic bronchoscope must be available immediately. Tracheomalacia resulted in failed extubation and subsequent tracheostomy in a case report of a 3-month-old boy. Use of laryngeal mask is relatively contraindicated because of the risks of regurgitation and aspiration. Close monitoring of glycemia and avoidance of hypoglycemia-inducing drugs are recommended throughout the perioperative period.

Avoid nitrous oxide in cases of bowel obstruction. Depending on the presence and the pathophysiology of an associated cardiac lesion, drugs with negative inotropic or peripheral vasodilating action can be contraindicated. Subacute bacterial endocarditis prophylaxis may be required.

Aniridia: It is estimated that approximately one third of patients with sporadic aniridia will develop a Wilms tumor, whereas approximately half of patients with aniridia, genitourinary anomalies (e.g., hypospadias), and mental retardation will develop a Wilms tumor. Most patients have prominent lips and macrognathia. Other features may include congenital cataracts, nystagmus, ptosis, and blindness. The presence of ptosis and generalized hypotonia in a subgroup of patients may suggest a susceptibility to malignant hyperthermia.

WAGR Syndrome: Unusual association of Wilms tumor, ocular signs, and mental retardation.

Denys-Drash Syndrome: Consists of the triad of congenital nephropathy, Wilms tumor, and ambiguous genitalia; manifests in small children.