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Congenital hyperinsulinism is a medical term referring to a variety of congenital disorders in which hypoglycemia is caused by excessive insulin secretion. Congenital forms of hyperinsulinemic hypoglycemia can be transient or persistent, mild or severe. These conditions are present at birth and most become apparent in early infancy. The severe forms can cause obvious problems in the first hour of life, but milder forms may not be detected until adult years. Mild cases can be treated by frequent feedings, more severe cases can be controlled by medications that reduce insulin secretion or effects, and a minority of the most severe cases require surgical removal of part or most of the pancreas to protect the brain from damage due to recurrent hypoglycemia.

Types of congenital hyperinsulinism:

1. Transient neonatal hyperinsulinism

2. Focal hyperinsulinism

• Paternal SUR1 mutation with clonal loss of heterozygosity of 11p15
• Paternal Kir6.2 mutation with clonal loss of heterozygosity of 11p15

3. Diffuse hyperinsulinism

a. Autosomal recessive forms

• i. SUR1 mutations
• ii. Kir6.2 mutations
• iii. Congenital disorders of glycosylation

b. Autosomal dominant forms

• i. Glucokinase gain-of-function mutations
• ii. Hyperammonemic hyperinsulinism (glutamate dehydrogenase gain-of-function mutations)
• iii. Short chain acyl coenzyme A dehydrogenase deficiency

4. Beckwith-Wiedemann syndrome (thought to be due to hyperinsulinism but pathophysiology still uncertain: 11p15 mutation or IGF2 excess)

Congenital hyperinsulinism (CHI or HI) is a condition leading to recurrent hypoglycemia due to an inappropriate insulin secretion by the pancreatic islet beta cells. HI has two main characteristics:

• a high glucose requirement to correct hypoglycemia and
• a responsiveness of hypoglycemia to exogenous glucagon.

HI is usually isolated but may be rarely part of a genetic syndrome (e.g. Beckwith-Wiedemann syndrome, Sotos syndrome etc.). The severity of HI is evaluated by the glucose administration rate required to maintain normal glycemia and the responsiveness to medical treatment. Neonatal onset HI is usually severe while late onset and syndromic HI are generally responsive to a medical treatment. Glycemia must be maintained within normal ranges to avoid brain damages, initially, with glucose administration and glucagon infusion then, once the diagnosis is set, with specific HI treatment. Oral diazoxide is a first line treatment.

In case of unresponsiveness to this treatment, somatostatin analogues and calcium antagonists may be added, and further investigations are required for the putative histological diagnosis:

• pancreatic (18)F-fluoro-L-DOPA PET-CT and
• molecular analysis.

Indeed, focal forms consist of a focal adenomatous hyperplasia of islet cells, and will be cured after a partial pancreatectomy.

Diffuse HI involves all the pancreatic beta cells of the whole pancreas. Diffuse HI resistant to medical treatment (octreotide, diazoxide, calcium antagonists and continuous feeding) may require subtotal pancreatectomy which post-operative outcome is unpredictable.

The genetics of focal islet-cells hyperplasia associates

• a paternally inherited mutation of the ABCC8 or
• the KCNJ11 genes, with
• a loss of the maternal allele specifically in the hyperplasic islet cells.

The genetics of diffuse isolated HI is heterogeneous and may be

• recessively inherited (ABCC8 and KCNJ11) or
• dominantly inherited (ABCC8, KCNJ11, GCK, GLUD1, SLC16A1, HNF4A and HADH).

Syndromic HI are always diffuse form and the genetics depend on the syndrome. Except for HI due to

• potassium channel defect (ABCC8 and KCNJ11),

most of these HI are sensitive to diazoxide.

The main points sum up the management of HI:

• i) prevention of brain damages by normalizing glycemia and
• ii) screening for focal HI as they may be definitively cured after a limited pancreatectomy.

Source & References:

http://en.wikipedia.org/wiki/Congenital_hyperinsulinism

http://www.ncbi.nlm.nih.gov/pubmed/20550977