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Congenital isolated hyperinsulinism

ORPHA657
Synonym(s) CHI
PHHI
Persistent hyperinsulinemic hypoglycemia of infancy
Prevalence 1-9 / 100 000
Inheritance Autosomal dominant
or Autosomal recessive
Age of onset Childhood
Infancy
Neonatal
ICD-10
  • E16.1
OMIM -
UMLS
  • C1257959
MeSH
  • D044903
MedDRA -

Summary

Congenital isolated hyperinsulinism (CHI), a rare endocrine disease is the most frequent cause of severe and persistent hypoglycemia in the neonatal period and early infancy and is characterized by an excessive or uncontrolled insulin secretion (inappropriate for the level of glycemia) and recurrent episodes of profound hypoglycemia requiring rapid and intensive treatment to prevent neurological sequelae. CHI comprises 2 different forms: diazoxide-sensitive diffuse hyperinsulinism and diazoxide-resistant hyperinsulinism (see these terms).

Prevalence is estimated at 1/50,000 live births, but it may be as high as 1/2,500 in communities with substantial consanguinity.

CHI onset varies from birth through early adulthood. Neonatal onset is the most frequent; newborns, often macrosomic present with poor feeding, intolerance to fasting and persistent hypoglycemia. Hypoglycemic episodes range from mild (lethargy, hypotonia and irritability) to severe and potentially fatal episodes (apnea, seizures or coma) that lead to neurologic sequelae. In late onset CHI, patients generally present with features of hypoglycemia (pallor, profuse sweating and tachycardia). In some forms hypoglycemia may be triggered by anaerobic exercise (exercise-induced hyperinsulinism) or protein rich meals (hyperinsulinism-hyperammonemia syndrome and hyperinsulinism due to 3-hydroxylacyl-CoA dehydrogenase deficiency, see these terms).

Nine genes are associated to CHI among which mutations in the genes encoding the ATP-sensitive potassium channel in pancreatic beta cells (ABCC8, KCNJ11) represent the most common defect.

Persistent hypoglycemic episodes (that require intravenous glucose infusion rates of >8 mg/kg/min to maintain normoglycemia) and responsiveness to glucagon are highly indicative of CHI. Detectable serum insulin/C-peptide, low ketone bodies, suppressed fatty acids and suppressed branch chain-amino acids during hypoglycemic episodes (glycemia of <3 mmol/l) all indicate CHI. Later onset CHI may require provocative testing (e.g. oral glucose or leucine loading; formal exercise testing). Cases unresponsive to diazoxide should be classified in to focal and diffuse HI by genetic testing for (ABCC8/ KCNJ11mutations and imaging, particularly DOPA-Positron emission tomography (PET).

Differential diagnosis includes transient hyperinsulinemic hypoglycemia in newborns of mothers with diabetes mellitus or after perinatal stress. Many syndromes present with hypoglycemia: PMM2-CDG and MPI-CDG (congenital disorder of glycosylation Ia and Ib) and the Beckwith-Wiedemann, Perlman, insulin resistance, Sotos, Timothy, Ondine and Usher 1 syndromes. Insulinoma (see these terms) and drug induced hypoglycemia (beta blockers, cibenzoline, and leukocyte growth factors) must be considered in late-onset CHI.

Antenatal genetic testing is possible when a proband has been identified.

Genetic testing may be offered in affected families when a proband has been identified.

Normoglycemia must be rapidly recovered and maintained to prevent irreversible brain damage. Acute management includes continuous glucose infusion by a central intravenous along, oral feeding with a glucose polymer and intravenous fluids. In severe cases glucagon may be administered. Diazoxide is the first line of medical therapy and Octreotide is added as an adjunct. Pancreatic resection is offered to focal HI (located by PET); Near-total pancreatectomy may be reserved to patients resistant to diet and medical treatment. Diazoxide responders are assessed for fasting tolerance and then followed carefully to monitor growth and development.

Long term complications include neurological sequelae and in cases of subtotal pancreatectomy, glucose intolerance and diabetes mellitus.

Expert reviewer(s)

  • Pr Pascale DE LONLAY

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Detailed information

Summary information
Review article
  • EN (2011)
Clinical practice guidelines
  • DE (2010)
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