Permanent Neonatal Diabetes Mellitus (PNDM) in a patient with R201H/KCNJ11 gene mutation: Unusual clinical course

KCNJ11 gene encodes Kir6.2, subunit of the β-cell ATP-dependent K-channel (made up of 4 Kir6.2 and 4 sulfonylurea receptor 1 subunits); its heterozygous activating mutation is a frequent cause of PNDM. Our 20y old pt was the only child born from healthy unrelated parents (BW 2.3Kg, L 48cm). High plasma glucose (PG) (10-16.7mmol/l) and glycosuria (no ketonuria) appeared at 2d of life reaching 33.3mmol/l at 12d. Despite the progressive PG increase and low fasting C-peptide (Cp) (149pmol/l at 12d, nv 178-680), she showed good health conditions and regular weight gain until 35d old. Insulin (Ins) (1 IU/Kg/d) was started at 37d of life, because of ketonuria and failure to thrive (PG 32mmol/l). Ins/Kg/d, progressively reduced, was stopped at 2.5y because of good metabolic control and frequent hypoglycaemic events. Cp decreased from 149pmol/l (at 12d) to undetectable value (8.5m old) with a subsequent increase (119pmol/l, at 20m). At diagnosis anti-Ins and anti-β-cell antibodies (AA) were negative. OGTT at 2.9y: normal fasting PG (4.5mmol/l) and Ins (47.3pmol/l), impaired GT (8.4mmol/l at 120‘), blunted Ins peak (87.5pmol/ l). HbA1c constantly <7%. At 4.1y and 7.5y: PG at 120‘ 7.2 and 11.7mmol/l, respectively. At 8y, Ins therapy was restored (0.8 U/kg/d) having high HbA1c values (10.2-11.5%) and anti-gliadin AA were detected; asymptomatic celiac disease was confirmed by biopsy. At 19.7y, IVGTT showed low basal (231pmol/l, nv 281-1317pmol/l) and peak (265pmol/l) Cp. A transition G->A at position 602, with a His->Arg at codon 201 (R201H), was identified in the KCNJ11 gene (mutation absent in parents). Ins was progressively reduced and stopped within 11d and glibenclamide (Gl) administered (increasing dose: after 3m 0.39mg/Kg/d, no HbA1c increase). After 4w on Gl, Cp raised to 1158pmol/l. This mutation is the most frequent genetic defect associated with PNDM: no one of 9 described pts currently older than 3y experienced honey moon, 8/9 being constantly Ins-treated (1 adult pt on tolbutamide since childhood). Our data indicate that this mutation can confer a broad range of clinical presentation and prompts the KCNJ11 gene analysis in all cases of NDM