Endocrine Abstracts (2006) 11 P283

A TCF1 mutation may cause transient congenital hyperinsulinism followed by MODY3

K Brusgaard1, HBT Christesen2, T Hansen3, P Njölstad4, J Malec1 & B Brock Jacobsen2


1Odense University Hospital, Dept. of Clinical Gentics, Odense, Denmark; 2Odense University Hospital, Dept. of Paediatrics, Odense, Denmark; 3Steno Diabtes Center, Copenhagen, Denmark; 4University of Bergen, Bergen, Norway.


In congenital hyperinsulinism (CHI), mutations have been found in 5 different genes, ABCC8, KCNJ11, GCK, GLUD1 and SCHAD. In approximately 50% of all cases, however, no genetic explanation can be found.

A mature newborn girl presented macrosomic, birth weight 4378 g, and a blood glucose down to 1.3 mmol/l at day 1. Hyperinsulinism was documented. The child responded to diazoxide treatment, initially in combination with prednisolone, chlorothiazide and octreotide.

The parents were non-consanguineous, the mother had no diabetes. The father and several members of his family had MODY 3 segregating with the previously described R159Q mutation in the TCF1 gene encoding HNF-1α. The mutation was found in the girl, too. The girl had no mutations in the ABCC8, KCNJ11 and GCK genes (DHPLC and sequencing). Her p-ammonia and urine ß-hydroxy glutaric acid were normal, excluding the possibility of a GLUD1 mutation and a SCHAD mutation. Sequencing of the MODY1 gene (HNF-4α) showed no mutations. Diazoxide was discontinued at the age of 3 y, no diet restrictions. Subsequent fasting blood glucose values, OGTT, p-proinsulin and p-C-peptide values were normal (p-insulin failed).

In the other members of the MODY3 family, no signs of hypoglycaemia in the neonatal or infancy period were recorded by questioning. Our patient had neonatal onset CHI, but no mutations in the candidate genes for CHI; GLUD1 and SCHAD mutations were ruled out by biochemical data. The hyperinsulinism was transient with normalisation after 3 years.

MODY3 has until now never been associated with transient CHI. MODY3 is characterised by a progressive insulin secretion defect. It is hypothesised, that the TCF1 mutation R159Q, perhaps influenced by unknown other genetic factors, may cause a transient hypersecretion of insulin in the neonatal period and infancy followed by euglycaemia and later MODY3. Hyperinsulinaemic hypoglycaemia may occur in other young children of MODY3 families.

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