Case study

A 30-year-old G3P2 mother was followed prenatally for 19-week ultrasound findings of single amniotic band and shortened cervix. Follow-up at 20 weeks also showed echogenic kidneys and bowel without evidence of amniotic bands. There was a remote history of THC use, but the pregnancy history was otherwise unremarkable.

A female was born 1869g (90th percentile) at 30 6/7 weeks gestation via emergent cesarean section for non-reassuring fetal rhythm strip and poor biophysical profile. APGARs were 7/9, and only routine care was required in the delivery room.

Of note, the baby had signs of hydrops, initial glucose was 22 and persistent profound hypoglycemia continued, requiring multiple D10 boluses + IV fluids with GIRs (glucose infusion rates) as high as 14 mg/kg/min. The birth hospital course included CPAP for 2 days; suspected medical NEC on day of life (DOL) 4; phototherapy for 24 hours with a notable hemoglobin of 8.4. An ECHO showed PDA, and an abdominal u/s was done for enlarged liver, which showed slight rotation of the right kidney with a bladder mass. The Parvo B19 PCR was positive, explaining the anemia and hydrops noted at birth.

The baby was transferred to The Children’s Hospital of Philadelphia (CHOP) on DOL 17 for further evaluation and management of suspected hyperinsulinism (HI), with chief complaint of persistent low blood sugars, bladder mass and leg size discrepancy.

Prior diagnosis of parvovirus infection with hydrops was resolving when transferred to CHOP. Initial diagnosis was hemihypertrophy, persistent hypoglycemia, anemia, bladder mass, mild branch pulmonary artery stenosis and PFO. Endocrine, Genetics, General Surgery and Urology were consulted as part of a multidisciplinary team approach.

An extensive workup was done including abdominal u/s revealing two nodular soft tissue foci in the posterior wall of the urinary bladder; a CT-PET scan with findings of a 3 cm soft tissue mass in R suprarenal region (concerning for neuroblastoma); the liver was noted to be markedly heterogeneous with at least two areas of rounded hypodensity.

An MR of the abdomen found a pancreatic tail cyst; size discrepancy of the kidneys, with the right kidney measuring larger than the left; numerous tiny medullary cysts, suspicious for Beckwith-Wiedemann syndrome (BWS); and a right adrenal mass, with numerous enhancing hepatic lesions. At this time, it was highly suspected the infant had BWS, with some of these findings compatible with metastatic neuroblastoma.

On DOL 31, the bladder tumor was resected by Urology and the baby was placed on diazoxide as feeds were initiated. Surprising results from genetics studies found that, in addition to the confirmed diagnosis of BWS with hyperinsulinism, the baby had a very unusual genetic situation, with two completely different genetic variations revealing whole genome uniparental disomy (UPD) notable for 95 percent paternal copies (double dose of father’s genetic material).

Also notable were the two different skin whorls showing the different cell lines. On DOL 60, GIR remained extreme at 30 mg/kg/min and a new suprarenal mass was diagnosed. These masses were later noted to be hamartomas and on DOL 63, a near total pancreatectomy and G-tube was done. The baby remained in the newborn/infant intensive care unit (NIICU) for ongoing care with counseling and education for the family on Beckwith-Wiedemann syndrome.

On DOL 78, the baby was discharged, but was readmitted to the pediatric intensive care unit (PICU) on DOL 130 due to bowel obstruction. After an exploratory laparotomy and lysis of adhesions, the baby underwent primary bowel reanastomosis with an uncomplicated second post-operative course.

Care of this patient involved a multidisciplinary CHOP team, including Oncology, Orthopaedics, General Surgery, Endocrinology, Genetics, Neonatology and Dermatology. Oncology recommended close monitoring of AFPs with follow-up for risk of hepatic tumors to age 3, renal tumors to age 7, and adrenal tumors to adulthood. Subsequent short-term follow-up revealed her AFPs were stable and she is cognitively near normal with enrollment in early intervention.

Questions and answers

1. What is the differential of severe hypoglycemia in neonate?

• Prolonged stress
• Sepsis
• Inborn error of metabolism: MSUD, Propionic Acidemia, tyrosinemia, MMA
• Liver disease
• Stress induced hyperinsulinism
• Congenital hyperinsulinism
• Genetic syndromes such as Beckwith-Wiedemann Syndrome 

2. What is the significance of hemihypertrophy on physical exam?

Body/limb asymmetry representing an overgrowth syndrome

The differential diagnosis should always include:

• Amniotic band syndrome
• Venous thrombosis
• Venolymphatic malformation
• Genetic syndrome:
  • Beckwith-Wiedemann syndrome, BWS (our patient had)
  • Proteus Syndrome
  • Russell-Silver Syndrome
  • Klippel-Trenaunay-Weber syndrome
  • Chromosomal Mosaicism, (our patient had) 

3. What are the major findings with BWS?

• Macrosomia (height and weight >97 percent)
• Growth velocity decreases at 7-8 years, adult height normal
• Anterior linear ear lobe creases/posterior helical pits
• Macroglossia
• Omphalocele (exomphalos)/umbilical hernia
• Visceromegaly including liver, spleen, kidneys, adrenals and pancreas
• Embryonal tumor (e.g. Wilms, hepatoblastoma, neuroblastoma, rhabdomyosarcoma)
• Hemihyperplasia
• Adrenocortical cytomegaly
• Renal abnormalities (e.g. structural, nephromegaly or nephrocalcinosis)
• Cleft palate (rare)

4. What are the causes and genetics associated with this syndrome and testing needed?

• Beckwith-Wiedemann syndrome is caused by epigenetic and/or genetic alterations that dysregulate imprinted genes within the chromosomal region 11p15.5
• Genomic imprinting – phenomenon by which certain genes are expressed in a parent-of-origin specific manner
• Epigenetic alteration – changes in gene expression caused by mechanisms other than changes in the underlying DNA sequence
• Examples: methylation, histone deacetylation, etc.
• Testing:
  • UPD testing: SNP array is the best test
  • Karyotype/FISH: translocation/inversion
  • Methylation testing of 11p15.5
  • CDKNiC sequencing: familial

5. What are other notable Imprinting Disorders?

• Prader-Willi syndrome
• Angelman syndrome
• Russell-Silver syndrome
• Neonatal diabetes mellitus

6. What are the mechanism of genome-wide UPD?

• Two copies of father’s chromosomes

7. What are the oncologic concerns and follow-up needed for BWS?

• Risk for neoplasms (7.5 percent) 
• Wilms tumor, hepatoblastoma, neuroblastoma, adrenocortical carcinoma, rhabdomyosarcoma
• Monitoring includes blood AFP level until 4 years of age (every 6 weeks) and abdominal ultrasound until 7-8 years old 

8. How is the persistent and severe hyperinsulinism related to this disorder?

• Congenital HI & BWS: What’s the relationship? Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome that is clinically and genetically heterogeneous.
• Hyperinsulinemic hypoglycemia occurs in about 50 percent of children with BWS and, in the majority of infants, it resolves spontaneously.
• Total 9 cases reported.
• All cases are mosaic genome-wide UPD.
• Main phenotypic features are usually BWS phenotype.
• Variable phenotypic features associated with patUPDs (+/-) autosomal recessive conditions

However, in a small group of patients the hypoglycemia can be persistent and may require pancreatectomy. The mechanism of persistent hyperinsulinemic hypoglycemia in this group of patients is unclear.

9. What are the differences between focal and diffuse hyperinsulinism?

Focal usually has specific genetic mutations-often paternal mutation. Surgery is easier and outcomes are better. Diffuse is difficult surgery. One-third are diabetic later in life, one-third still have hyperinsulinism and require glucose supplement. Children also have poor oral feeds and usually require a long-term tube feedings.

10. What are the complications of a subtotal pancreatectomy?

Surgical complications: Major bleeding, abscess, fistula formation, duodenal, splenic, bile duct injury with stricture and late small bowel obstruction. About one-third may experience persistent hypoglycemia and up to 50 percent may ultimately develop diabetes mellitus.

— Contributed by Janet Lioy, MD, attending neonatologist, and Dan Swarr, MD