Macroglossia and omphalocele in neonate

August 1, 2018

A 33-year-old female, G3P1011, was transferred from an outside facility at 33 weeks and 6 days gestation for anticipated preterm delivery secondary to preeclampsia. On prenatal ultrasound, her fetus was diagnosed with an omphalocele and delivery was preferred at an institution with a neonatal intensive care unit to manage the infant.

The case

A 33-year-old female, G3P1011, was transferred from an outside facility at 33 weeks and 6 days gestation for anticipated preterm delivery secondary to preeclampsia. On prenatal ultrasound, her fetus was diagnosed with an omphalocele and delivery was preferred at an institution with a neonatal intensive care unit (NICU) to manage the infant.

History

The infant was subsequently delivered at 34 weeks and 1 day via cesarean delivery, with a weight of 2.825 kg (92nd percentile). At birth, length and head circumference were 47.5 cm (3rd percentile) and 31.0 cm (less than 1st percentile), respectively. One- and 5-minute Apgar scores were 8 and 9. Initial physical exam revealed macroglossia, bilateral earlobe creases, and a 4-cm by 4-cm omphalocele with an intact membrane (Figure 1). Neurologically, the baby was alert, active, and had normal tone and appropriate reflexes for age.

Examination and testing

Given the mother’s premature onset of labor, a blood culture was obtained in order to ensure the infant was not septic. Per protocol, the patient was started on ampicillin and tobramycin prophylactically. The culture was negative and the antibiotics were discontinued after 2 days.

Upon admission to the NICU, the infant was stable on room air but was intubated preoperatively for primary closure of the omphalocele with appendectomy. Per surgical consultation, the decision was made to remove the appendix in order to prevent an atypical presentation of appendicitis later on. Surgery occurred on first day of life (Figure 2).

The infant’s initial electrolytes were all within normal limits. The first Dextrostick revealed a serum glucose of 50 mg/dL, which improved once she was placed on intravenous fluids. Total parental nutrition was started on postoperative day one. Her first oral feed was on the fourth day of life.

A 2-D echocardiogram was completed both in preparation for the operating room and given the high suspicion of a syndrome diagnosis. It showed no cardiomegaly or ventricular hypertrophy; normal biventricular systolic function; patent foramen ovale with left-to-right shunting at the atrial level; and no evidence of pulmonary hypertension. A head ultrasound also was performed and showed no pathology.

On day 2 of life, the patient had a bilateral sonogram of the kidneys showing mild left pelvocaliectasis, confirmed on repeat imaging 5 days later. Given the renal findings, Perlman syndrome was added to the differential; however, Beckwith-Wiedemann syndrome (BWS) remained high on the list given the characteristic facial features.

Differential diagnosis

History, physical exam, lab work, and imaging revealed underlying pathologies pointing to different diagnoses (Table 1).

Perlman syndrome

Perlman syndrome presents with neonatal macrosomia and polyhydramnios. It is caused by mutations in the DIS3L2 gene, which plays a role in mitosis and cell proliferation. Loss of the regulatory mechanism of this gene results in increased cell proliferation. Characteristic facial features include a broad and flat nasal bridge; a V-shaped upper lip; deep-set eyes and low-set ears; and a prominent forehead. Associated congenital anomalies are renal dysplasia; abdominal dystocia caused by visceromegaly involving the heart, liver, spleen, pancreas, and kidneys; severe hypotonia; and cryptorchidism in males.1

Sotos syndrome

Sotos syndrome involves increased birth weight and length as well as an advanced bone age. It is caused by an intragenic loss of function mutation, particularly the gene encoding NSD1. It can be distinguished from other overgrowth syndromes in that it has distinctive facial features including macrodolichocephaly; frontal bossing; down-slanting palpebral fissures; a long and narrow inferior mandible; hypertelorism; and a frontoparietal receding hairline. Brain formation abnormalities include an absent corpus callosum, prominent cortical sulci, trigone, occipital horns, and a dilatation of cerebral ventricles. Because of these abnormalities, approximately 50% of afflicted patients have seizures.1

Weaver syndrome

Weaver syndrome, caused by mutations in EZH2, a gene associated with transcriptional repression, presents with prenatal overgrowth including accelerated osseous maturation, resulting in very tall stature. Characteristic craniofacial appearance includes macrocephaly, a broad forehead, true hypertelorism, a long prominent philtrum, micrognathia, and loose skin with redundant nuchal skin folds. Weaver syndrome also can have neurologic manifestations including cysts of the septum pellucidum, cerebral atrophy, and pachygyria. Consequently, it is common to have some mild tone abnormalities as well as motor development delays and mild intellectual disability.1

Simpson-Golabi-Behmel syndrome 

Simpson-Golabi-Behmel syndrome, an X linked disorder with mutations in the GPC3 gene associated with an exonic deletion, presents with both prenatal and postnatal overgrowth with characteristic facies and orthopedic abnormalities. Common facial features include hypertelorism; down-slanting palpebral fissures; epicanthic folds; macrostomia; macroglossia; a short nose with a broad nasal bridge; and, in some cases, a cleft lip and palate. Orthopedic characteristics include short and broad hands and feet with metatarsus varus, talipes equinovarus, cutaneous syndactyly, and postaxial polydactyly. Other features include organomegaly and skeletal findings.1

Discussion

Beckwith-Wiedemann syndrome (BWS) was first described in 1969 and is the most common genetic overgrowth syndrome. It is characterized by macrosomia, macroglossia, hemihypertrophy, omphalocele, organomegaly, and facial nevus flammeus.2 Prevalence is 1 per 13,700 to 15,000 births, and BWS shows equal prevalence among males and females.3

Babies that initially present with BWS are larger in size, and as they grow they continue to exhibit either symmetric or asymmetric overgrowth. Additional features of BWS include proptosis with periorbital fullness; earlobe creases and pits; and organomegaly. Children with BWS are at an increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma. The risk for these tumors is up to 7.5% until age 8 years. Children affected also can have hypoglycemia and hypocalcemia. The hypoglycemia can persist throughout childhood and is often refractory to treatment.

Beckwith-Wiedemann syndrome is caused by genetic abnormalities involving chromosome 11p15. Loss of methylation on the maternal chromosome, in particular in the imprinting control region (ICR) 2, is the most common cause of BWS and this leads to reduced expression of CDKN1C, a gene that normally negatively regulates cell proliferation. With reduced expression of CDKN1C, there is consequently cell proliferation, thus leading to the overgrowth characteristically seen in BWS.2

Diagnosis of BWS is made clinically if the patient has 3 major criteria or 2 major and 1 minor criteria (Table 2).4 In a patient with suspected BWS, if loss of methylation or abnormal methylation of ICR2 is found on genetic testing, the diagnosis can be confirmed.2

In a newborn with BWS, one would note macroglossia, macrosomia, and abdominal wall defects. However, it is recognized that not all patients with BWS have these particular features.5 Hemihyperplasia, particularly unilateral renal hyperplasia, is also present in some infants. Furthermore, alpha fetoprotein (AFP) may be initially elevated, but more so than the first value, it is the trend in AFP that is important. For example, in the case of a hepatoblastoma, there is a progressively increasing AFP.

Management and treatment

Acute management of a patient with BWS is multifactorial and often targeted at the specific clinical manifestations. An omphalocele requires surgical repair, which can be either a primary or a staged procedure. Prior to having an operation, a cardiac evaluation is necessary as cardiomegaly is a possible sequelae of the overgrowth syndrome. Additionally, if the infant presents with macroglossia, it is then imperative to assess the airway thoroughly prior to undergoing anesthesia. A significantly large tongue can compromise the airway so much so that a tracheostomy may have to be considered. Macroglossia also may impede feeding. Severe cases call for tongue reduction surgery.

Endocrine abnormalities are also common, including hypothyroidism, hyperlipidemia, and/or hypercholesterolemia. Hypoglycemia, thought to be caused by hyperinsulinism, is often one of the first problems to manifest in the neonate. Prompt treatment must ensue in order to prevent severe central nervous system (CNS) problems including seizures and poor neurologic development. Most cases of hypoglycemia will resolve within the first few days of life.

Patients with BWS need certain screening both during infancy and into adulthood. A child with BWS requires tumor surveillance until aged 8 years, and an annual renal ultrasound through adolescence. Hypercalciuria also should be monitored with a urine calcium/creatinine ratio. In terms of facial hemihyperplasia, surgical correction is possible. As an adult with BWS, concerns include renal medullary dysplasia as well as decreased fertility in males. An echocardiography should be done every 3 to 5 years to evaluate for possible cardiomyopathy and, similarly to children, adults also need a renal ultrasound annually, renal function tests every 3 to 5 years, and a hearing evaluation every 2 to 3 years.2

Without the development of malignant tumors, the prognosis for children affected with BWS is generally good. Growth rate slows around age 7 or 8 years.4 In fact, if there were to be adverse developmental outcomes, these can be attributed to complications of prematurity or extreme hypoglycemia, not the actual syndrome.1

Final diagnosis and patient outcome

Given this patient’s specific physical exam findings, genetic testing for Beckwith-Wiedemann syndrome was ordered. Results revealed hypomethylation on IC2, consistent with a diagnosis of Beckwith-Wiedemann syndrome.

She was discharged home on breast milk feeds ad lib, with follow-up appointments with the high risk clinic, cardiology, and general surgery.

References:

1. Edmondson AC, Kalish JM. Overgrowth syndromes. J Pediatr Genet. 2015;4(3):136-143.

2. Pappas JG. The clinical course of an overgrowth syndrome, from diagnosis in infancy through adulthood: the case of Beckwith-Wiedemann syndrome. Curr Probl Pediatr Adolesc Health Care. 2015;45(4):112-117.

3. Tsukamoto M, Hitosugi T, Yokoyama T. Perioperative airway management of a patient with Beckwith-Wiedemann syndrome. J Dent Anesth Pain Med. 2016;16(4):313-316.

4. Tower P, Tolia VN. Another preemie with hypoglycemia? Beckwith-Wiedemann syndrome-a case study. Neonatal Netw. 2015;34(3):178-182.

5. Brioude F, Kalish JM, Mussa A, et al. Expert consensus document: clinical and molecular diagnosis, screening, and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol. 2018;14(4):229-249. 

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