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Activating Mutations in the Gene Encoding Kir6.2 Alter Fetal and Postnatal Growth and Also Cause Neonatal Diabetes

Institute of Biomedical and Clinical Science (A.S.S., A.T.H.), Peninsula Medical School, Exeter EX2 5DW, United Kingdom; and Department of Cardiology (A.S.S.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

Address all correspondence and requests for reprints to: Professor Andrew T. Hattersley, Peninsula Medical School, Barrack Road, Exeter EX2 5DW, United Kingdom. E-mail: a.t.hattersley{at}ex.ac.uk.

Context: Birth weight is a bioassay for fetal insulin secretion because altered insulin secretion in utero alters insulin-mediated growth. Activating mutations in Kir6.2 are the major cause of neonatal diabetes and reduce insulin secretion by altering the closure of the ß-cell ATP-sensitive potassium channel in the presence of ATP.

Objective: Our objective was to examine fetal and postnatal growth in patients with activating Kir6.2 mutations and identify whether this was modified by severity of mutation or maternal diabetes.

Patients and Methods: We used SD scores (SDS) for birth and postnatal growth in an international series of patients (n = 49) with Kir6.2 mutations and related this to their clinical phenotype.

Results: Birth weight was greatly reduced [–1.73 (–3.68 to 1.41), median (range) SDS], but there was postnatal catch-up because present weight was normal [–0.37 (–4.37 to 2.34) SDS]. Catch-up growth for height and weight was not seen until insulin treatment was started. Birth weight was not influenced by severity of postnatal phenotype but was increased by maternal diabetes –0.12 vs. –1.81 SDS (P = 0.037). Patients with the severe neurological developmental delay, epilepsy, and neonatal diabetes syndrome did not catch up (present weight –2.2 vs. –0.24 SDS (P = 0.003).

Conclusions: Kir6.2 mutations greatly reduce fetal insulin secretion and hence fetal growth, but this is independent of mutation severity. Increased fetal growth in response to maternal diabetes suggests that either the Kir6.2 mutated fetal ß-cell is still glucose responsive or there is a non-insulin-mediated increase in fetal growth. Postnatal catch-up requires insulin treatment but is complete, except in those with epilepsy.

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