Hypoglycemia in Beckwith-Wiedemann syndrome

doi:10.1053/sp.2000.6366

Seminars in Perinatology

Volume 24, Issue 2, April 2000, Pages 164-171

https://doi.org/10.1053/sp.2000.6366 Get rights and content

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with macrosomia, macroglossia, abdominal wall defects, hypoglycemia in the neonatal period and embryonal cancers of infancy and early childhood. The frequency of hypoglycemia in this population is between 30% and 50%. The majority of infants with hypoglycemia will be asymptomatic and have resolution of the hypoglycemia within the first 3 days of life. Less than 5% will have hypoglycemia beyond the neonatal period requiring either continuous feeding or a partial pancreatectomy. The cause of hypoglycemia is unclear, but direct and indirect evidence supports a hyperinsulinemia as the major factor. Recent identification of the majority of genes associated with BWS in the 11p15 region and the genotype of persistent hyperinsulinemia hypoglycemia of childhood also in the 11p15 region may provide a molecular basis for hypoglycemia in BWS, particularly for the occasional patients with hypoglycemia requiring a partial pancreatectomy. Detailed genotype phenotype evaluations are needed and should provide an insight as to why patients with BWS have hypoglycemia.

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Cited by (87)

Divergent metabolic phenotypes in two genetic syndromes of low insulin secretion
2023, Diabetes Research and Clinical Practice
Citation Excerpt :
While GRS in Ecuadorian subjects can be caused by different genetic mutations, at this time we have only fully defined one of them, an autosomal dominant gain-of-function (gof) mutation in the CDKN1c, which encodes a cyclin-dependent kinase N1c (CDKN1c also known as p57/KIP2) [20]. CDKN1c inhibits various cyclin/CDK complexes; hence, is a potent regulator of cell proliferation and differentiation [16,20,21]. We herein exclusively report findings in subjects with homozygous (ss180/ss180) LS, compared to GRS subjects confirmed to have the gofCDKN1c mutation [19–21] alongside unaffected GRS family members.
We examined the effect of growth hormone (GH) counter-regulation on carbohydrate metabolism in individuals with life-long diminished insulin secretion (DIS).
Adults homozygous for the E180 splice site mutation of GHR [Laron syndrome (LS)], adults with a gain-of-function mutation in CDKN1c [Guevara-Rosenbloom syndrome (GRS)], and controls were evaluated for body composition, leptin, total and high molecular weight (HMW) adiponectin, insulin-like growth factor (IGF) axis molecules, and a 5-hour oral glucose tolerance test (OGTT), with measurements of glucose, insulin, glucagon, ghrelin, pancreatic polypeptide, gastric inhibitory peptide, glucagon-like peptide-1, peptide YY, and islet amyloid polypeptide (IAPP).
Both syndromic cohorts displayed DIS during OGTT. LS subjects had higher serum concentrations of total and HMW adiponectin, and lower levels of IGF-I, IGF-II, and IGF-Binding Protein-3 than individuals in other study groups. Furthermore, they displayed normal glycemic responses during OGTT with the lowest IAPP secretion. In contrast, individuals with GRS had higher levels of protein glycation, deficient glucose control during OGTT, and increased secretion of IAPP.
A distinct metabolic phenotype depending on GH counter-regulatory status, associates with diabetes development and excess glucose-induced IAPP secretion.
Neonatal Hypoglycemia and Hyperglycemia
2023, Avery's Diseases of the Newborn
Glucose homeostasis in the newborn period is complex and essential for normal neonatal development. Glucose is the primary metabolic fuel for the neonatal brain. Maintaining normal glucose levels in the peripheral circulation and across the blood-brain barrier is essential for normal neurologic function and development. The perinatal period represents a transition from fetal metabolism of delivered maternal glucose to active regulation of glucose and energy levels through glycolysis, gluconeogenesis, and lipolysis. During this period, healthy neonates may have glucose levels considered low for older children. Still, it is also a period where infants with underlying abnormalities of glucose regulation are at high risk for severe symptomatic hypoglycemia. Neonatal hypoglycemia can be due to abnormalities in insulin, growth hormone, or cortisol secretion, with therapy dictated by the underlying abnormality. Additionally, inborn errors of metabolism or other genetic conditions can also present with neonatal hypoglycemia. Infants with hyperinsulinemic hypoglycemia are at particular risk for brain injury due to the simultaneous suppression of alternate metabolic fuels for the brain. Hyperglycemia is usually transient in neonates and can be managed with supportive care and insulin infusion. However, some infants will have diabetes beyond 3 months of age, which is likely to have a genetic cause. Patients with neonatal diabetes due to pathogenic variants affecting the K_ATP channel can be treated with oral sulfonylurea in place of insulin therapy.
Hypoglycemia in the Newborn and Infant
2020, Sperling Pediatric Endocrinology: Expert Consult - Online and Print
A newborn or infant with hypoglycemia presents an urgent diagnostic and therapeutic challenge. The clinical features must be rapidly assessed and a plan of action developed based on the infant’s age, maternal and parturition history, severity and persistence of hypoglycemia, and all other relevant clinical clues for definitive diagnosis and treatment. In this chapter, we review the normal physiology of glucose metabolism and the pathophysiology of the most common disorders resulting in hypoglycemia in the neonate and infant, with an emphasis on the approach to the diagnosis and management of these pathologies.
Tissue variations of mosaic genome-wide paternal uniparental disomy and phenotype of multi-syndromal congenital hyperinsulinism
2020, European Journal of Medical Genetics
Citation Excerpt :
Beckwith-Wiedemann syndrome (BWS) most commonly occurs as a sporadic, genetic disorder with typical features such as macroglossia, abdominal wall defects, lateralized overgrowth, visceromegaly, and increased risk of embryonal tumours (Weksberg et al., 2010; DeBaun et al., 2000; Brioude et al., 2018).
Mosaic genome-wide paternal uniparental disomy (GW-pUPD) is a rarely recognised disorder. The phenotypic manifestations of multilocus imprinting defects (MLIDs) remain unclear. We report of an apparently non-syndromic infant with severe congenital hyperinsulinism (CHI) and diffuse pancreatic labelling by 18F*-DOPA-PET/CT leading to near-total pancreatectomy. The histology was atypical with pronounced proliferation of endocrine cells comprising >70% of the pancreatic tissue and a small pancreatoblastoma. Routine genetic analysis for CHI was normal in the blood and resected pancreatic tissue. At two years’ age, Beckwith-Wiedemann Syndrome (BWS) stigmata emerged, and at five years a liver tumour with focal nodular hyperplasia and an adrenal tumour were resected. pUPD was detected in 11p15 and next in the entire chromosome 11 with microsatellite markers. Quantitative fluorescent PCR with amplification of chromosome-specific DNA sequences for chromosomes 13, 18, 21 and X indicated GW-pUPD. A next generation sequencing panel with 303 SNPs on 21 chromosomes showed pUPD in both blood and pancreatic tissue. The mosaic distribution of GW-pUPD ranged from 31 to 35% in blood and buccal swap to 74% in the resected pancreas, 80% in a non-tumour liver biopsy, and 100% in the liver focal nodular hyperplasia and adrenal tumour. MLID features included transient conjugated hyperbilirubinaemia and lack of macrosomia from BWS (pUPD6); and behavioural and psychomotor manifestations of Angelman Syndrome (pUPD15) on follow-up. In conclusion, atypical pancreatic histology in apparently non-syndromic severe CHI patients may be the first clue to BWS and multi-syndromal CHI from GW-pUPD. Variations in the degree of mosaicism between tissues explained the phenotype.
Disorders of Carbohydrate Metabolism
2018, Avery's Diseases of the Newborn: Tenth Edition
- •
  Neonatal hypoglycemia requires diagnostic consideration and urgent management to prevent recurrent hypoglycemia and neurologic injury.
- •
  Neonatal metabolism in the first few days of life reflects a transition from the passive glucose consumption of the fetus to the active regulation of glucose in a fasting neonate.
- •
  Diagnosing the cause of hypoglycemia requires an evaluation of the hormonal and metabolic response to hypoglycemia. Patients with hyperinsulinemic hypoglycemia should be assessed for diazoxide responsiveness, and nonresponsive patients should have an evaluation to determine if the process is focal or diffuse.
- •
  Diabetes diagnosed before 6 months of age is very likely to have a genetic cause.
- •
  Patients with neonatal diabetes because of mutations in the ATP-sensitive potassium channel genes can be treated with oral sulfonylurea therapy in place of insulin therapy.
Epigenetics in formation, function, and failure of the endocrine pancreas
2017, Molecular Metabolism
Citation Excerpt :
As a result, expression of the tumor suppressor p57 (encoded by CDKN1C) is lost, as it is only transcribed from the maternal chromosome, resulting in impaired cell cycle control. In about half of the Beckwith–Wiedemann patient population, the resulting excess of β-cell mass results in hyperinsulinemia and hypoglycemia [4]. Another imprinted locus affecting insulin secretin is Transient Neonatal Diabetes Mellitus (TNDM).
Epigenetics, in the broadest sense, governs all aspects of the life of any multicellular organism, as it controls how differentiated cells arrive at their unique phenotype during development and differentiation, despite having a uniform (with some exceptions such as T-cells and germ cells) genetic make-up. The endocrine pancreas is no exception. Transcriptional regulators and epigenetic modifiers shape the differentiation of the five major endocrine cell types from their common precursor in the fetal pancreatic bud. Beyond their role in cell differentiation, interactions of the organism with the environment are also often encoded into permanent or semi-permanent epigenetic marks and affect cellular behavior and organismal health. Epigenetics is defined as any heritable – at least through one mitotic cell division – change in phenotype or trait that is not the result of a change in genomic DNA sequence, and it forms the basis that mediates the environmental impact on diabetes susceptibility and islet function.
We will summarize the impact of epigenetic regulation on islet cell development, maturation, function, and pathophysiology. We will briefly recapitulate the major epigenetic marks and their relationship to gene activity, and outline novel strategies to employ targeted epigenetic modifications as a tool to improve islet cell function.
The improved understanding of the epigenetic underpinnings of islet cell differentiation, function and breakdown, as well as the development of innovative tools for their manipulation, is key to islet cell biology and the discovery of novel approaches to therapies for islet cell failure.

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Hypoglycemia in Beckwith-Wiedemann syndrome

J Pediatr

J Pediatr

Am J Hum Genet

Int J Biochem Cell Biol

J Pediatr

Pediatr Clin North Am

Clinical features and natural history of Beckwith-Wiedemann syndrome: Presentation of 74 new cases

Clin Genet

Wiedemann-Beckwith Syndrome: Clinical, cytogenetical and radiological observations in 39 new cases

Genet Couns

Hypoglycemia in the Neonate. Disorders of Carbohydrate Metabolism in Infancy. Major Problems in Clinical Pediatrics

The EMG syndrome (exomphalos, macroglossia, gigantism)

Prog Pediatr Surg

Wiedemann-Beckwith syndrome: Presentation of clinical and cytogenetic data on 22 new cases and review of the literature

Hum Genet

Macroglossia, omphalocele, adrenal cytomegaly, gigantism, and hyperplastic visceromegaly

Birth Defects: Original Articles

Management of prolonged hypoglycemia in Beckwith's syndrome

Postgrad Med J

Apparent postnatal onset of some manifestations of the Wiedemann-Beckwith syndrome

Am J Med Gen

Hyperinsulinism in infancy: Diagnosis by demonstration of abnormal response to fasting hypoglycemia

Pediatrics