Abstract
Objective
Transient neonatal diabetes mellitus (TNDM) is caused by activating mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We wanted to assess whether these different genetic aetiologies result in distinct clinical features.
Design
Retrospective analysis of the Italian data set of patients with TNDM.
Methods
Clinical features and treatment of 22 KATP/TNDM patients and 12 6q24/TNDM patients were compared.
Results
Fourteen KATP/TNDM probands had a carrier parent with abnormal glucose values, four patients with 6q24 showed macroglossia and/or umbilical hernia. Median age at diabetes onset and birth weight were lower in patients with 6q24 (1 week; −2.27 SD) than those with KATP mutations (4.0 weeks; −1.04 SD) (P = 0.009 and P = 0.007, respectively). Median time to remission was longer in KATP/TNDM than 6q24/TNDM (21.5 weeks vs 12 weeks) (P = 0.002). Two KATP/TNDM patients entered diabetes remission without pharmacological therapy. A proband with the ABCC8/L225P variant previously associated with permanent neonatal diabetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with KATP mutations were successfully treated with sulfonylurea monotherapy; four cases with relapsing 6q24/TNDM were treated with insulin, metformin or combination therapy.
Conclusions
If TNDM is suspected, KATP genes should be analyzed first with the exception of patients with macroglossia and/or umbilical hernia. Remission of diabetes without pharmacological therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remission of diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy.
Introduction
Transient neonatal diabetes mellitus (TNDM) is a subtype of neonatal diabetes (defined as a diagnosis of diabetes at ≤180 days of life) characterized by remission within a few months from onset (1). About 50% of patients with TNDM have a relapse of diabetes at the time of puberty (1). TNDM is rare (2) and almost invariably associated either with mutations in genes ABCC8 (3) and KCNJ11 (4), encoding for the two subunits of the ATP-dependent potassium channel (KATP), or with defects in chromosome 6 (5, 6). TNDM can be also caused by mutations in SLC2A2 in subjects who later develop full-blown Fanconi-Bickel syndrome, and by mutations in the promoter of the INS gene (7). The distinct genetic abnormalities associated with the two main TNDM subtypes, that is, 6q24/TNDM and KATP/TNDM cause neonatal hyperglycaemia through different mechanisms. Activating mutations of ABCC8 or KCNJ11 linked to TNDM are characterised by moderate changes in the sensitivity to ATP (4) and/or in ATPase activity (8, 9) that alter the ATP-dependent closure of the KATP channel of the pancreatic β cell. This, in turn, impacts cell membrane depolarization and voltage-gated Ca2+ channels opening, leading to an impaired glucose-stimulated insulin secretion. On the other hand, aberrations in 6q24, a genetic region that is subjected to imprinting (5, 6, 10), lead to the overexpression of PLAGL1 (also known as ZAC) and HYMAI genes, that likely causes TNDM by altering pancreatic islet organogenesis (11).
In light of this, our aim was to assess if and how these distinct mechanisms of disease have an impact on clinical features of patients, by directly comparing groups of individuals with KATP/TNDM and 6q24/TNDM.
Methods
We reviewed the 34 TNDM patients of the Italian data set: 22 carrying a variant in ABCC8 (12 patients) or KCNJ11 (10 patients) genes, and 12 patients with a defect in chromosome 6. All but 3 patients were of Italian descent; 2 were from central and south America and 1 from central Africa.
In all patients, the clinical diagnosis of TNDM was reached utilizing the following criteria: plasma glucose (PG) ≥ 7.0 mmol/L (126 mg/dL) (12) lasting for at least 5 days to exclude short-lived, stress hyperglycaemia.
Patients included in the study were diagnosed with TNDM between 1982 and 2017 in 15 Italian centres for paediatric diabetes. Genetic data of eight patients with KATP mutations included in this paper had been previously reported by our group (2, 13, 14, 15).
Patients had been investigated for TNDM mutations as part of specific research projects or as part of normal diagnostic procedures, depending on the time of diagnosis (patients diagnosed with TNDM before 2004 and negative to 6q24 aberrations were investigated again for ABCC8 and KCNJ11 genes after the discovery of KATP genes as a major cause of TNDM). Informed consent was obtained from parents or legal guardians at the hospitals where clinical diagnosis had been made. Approval for this study has been granted by the Ethics Committee of Bambino Gesù Paediatric Hospital with the # RRC-2018-2365812.
Mutations in ABCC8 and KCNJ11 were identified by direct DNA sequencing of coding regions by Sanger method as previously described (16) or by next-generation sequencing (15). Current rules of the American College of Medical Genetics were applied to assess the pathogenicity of newly described KATP variants (17). KATP mutations that had already been reported by multiple groups were considered pathogenic.
Most patients with suspected 6q24 defects were investigated by a methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) assay that detects aberrant methylation of the PLAGL1 gene on chromosomal region 6q24 (ME033-A1, MrC Holland, Amsterdam, the Netherlands). This probemix can also be used to detect deletions/duplications in PLAGL1. Microsatellite analysis for paternal uniparental disomy (UPD), with five microsatellite markers in the chromosomal regions 6q22 and 6q24 was utilized to establish the parental origin of chromosome 6. For two patients the occurrence of paternal uniparental disomy was assessed using chromosome 6 Variable Number of Tandem Repeat (VNTR) analysis in the proband and in the parents. Results were analysed with the Gene-Mapper 5 tool (Applied Biosystems).
As a consequence of the lack of centralized screening and of the three decades long period of patient collection, there was no pre-established diagnostic sequence for genetic analysis; however, the 27 probands who had been referred to the laboratory in Rome were first screened for KATP genes, and those who resulted negative were referred to the laboratory in Reggio Calabria.
For each patient/family we collected the following clinical data from their clinicians: the presence of congenital abnormalities, birth weight, gestational age, age at diabetes onset, mode of diabetes presentation, therapy at diabetes onset, age at diabetes remission, HbA1c at diabetes remission (if available) and, if relapse of diabetes had occurred, therapy at diabetes relapse. Standard ADA criteria for diagnosis of diabetes were utilized to establish if relapse had occurred (18).
We also gathered the probands’ family history, including information on age, mode of presentation and therapy of diabetes in family members carrying relevant mutations.
Statistical analysis was performed using SPSS, version 20 for MacOs (IBM Corp, Armonk, NY). Birth weight of each patient was reported as Standard Deviation Score (SDS) according to Italian neonatal anthropometric charts (19); the results were reported as median and interquartile range (IQR). The median values were compared by the Mann–Whitney U test and the correlation analysis was done by Spearman test. The level of significance was set at a = 0.05, two-sided level.
Results
Genetic analysis
Investigation of 6q24 abnormalities showed UPD6 in six patients, a methylation defect in four patients and 6q24 duplication in two patients (Table 1).
Clinical features of patients with TNDM.
| Kindred#, generation# individual# | Genetic defect | Gestational age, sex (F/M) | Birth weight (g), SDS1 | Age at diabetes onset (weeks) | Plasma glucose mmol/L (mg/dL) at diagnosis | DKA2 at presentation | Therapy | Age at remission (weeks) | Time to remission (weeks) | HbA1c % (mmol/mol) at remission | Current age (y, m) | Age at relapse (y, m) | Therapy at relapse |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ABCC8 | |||||||||||||
| ndT-NO/1 II, 1 | H105Y | NA, F | NA | 34 | 39.8 (717) | Yes | Insulin | 72 | 38 | 5.8% (40) | 19, 4 | 11 | Glibenclamide 0.05 mg/kg/day |
| ndT-RM/UI II, 1 | L225P | 39, M | 2470 (−2.16) | 12 | 22.9 (413) | No | Insulin (17 d) > Ins+SU3 0.4 mg/kg/day > SU1 (13 m) | 72 | 60 | 5.1% (32) | 7, 8 | No relap. | / |
| ndT-NA/1 II, 1 | S459R | 38, F | 1970 (−2.56) | 2½ | 13.9 (251) | No | Insulin | 11½ | 9 | 4.9% (30) | 14, 9 | No relap. | / |
| ndT-PV/1 II, 1 | R826W | 38, M | 2550 (−1.58) | 3 | 11.3 (205) | No | Insulin | 24 | 21 | 5% (31) | 17, 7 | No relap. | / |
| ndT-FI/1 II, 1 | R826W | 30, M | 1065 (−1.08) | 1 | 19.4 (350) | No | Insulin | NA | 19 | NA | 4, 10 | No relap. | / |
| ndT-MI/1 II, 1 | R1380H | 38, F | 3150 (0.22) | 2 | 14 (252) | No | Insulin | 16 | 14 | 4.3% (23) | 19, 2 | 18, 4 | Glibenclamide 0.03 mg/kg/day |
| ndT-RM/4 II, 1 | R1380H | 40, F | 3000 (−0.82) | 1 | 13 (235) | No | No therapy | 18 | 17 | 5.5% (37) | 4, 0 | No relap. | / |
| ndT-MI/2 II, 1 | R1380C | 38, M | 2650 (−1.34) | 11 | 27.7 (500) | Yes | Insulin | 29 | 18 | NA | 12, 8 | No relap. | / |
| ndT-NA/2 II, 5 | R1380C | 38, M | 2500 (−1.69) | 5½ | 73.5 (1324) | No | Insulin | 104 | 99 | 5.1% (32) | 14, 5 | 11, 2 | Glyclazide 0.42 mg/kg/day+insulin 0.4 U/kg/day |
| ndT-NA/2 III, 2 | R1380C | 38, F | 2640 (−1.04) | 1½ | 8.9 (160) | No | Insulin | 4 | 2 ½ | NA | 3, 4 | No relap. | / |
| ndT-NA/2 III, 3 | R1380C | 34, F | 2180 (0.11) | 1 | 11.6 (210) | No | Insulin | 4 | 3 | NA | 2, 4 | No relap. | / |
| ndT-MO/1 II, 1 | V1523M | 38, M | 2875 (−0.81) | 9 | 78.6 (1415) | Yes | Insulin | 37 | 28 | 5.7% (39) | 11, 7 | No relap. | / |
| KCNJ11 | |||||||||||||
| ndT-BZ/2 II, 1 | R50Q | 39+3, F | 2410 (−2.08) | 2 | 17.1 (308) | No | Insulin > SU3 0.1 > 0.01 mg/kg/day | 158 | 156 | 5.8% (40) | 9, 11 | No relap. | / |
| ndT-BZ/2 II, 2 | R50Q | 40, M | 2550 (−2.29) | 1 | 14.4 (260) | No | SU3 0.1 > 0.005 mg/kg/day | NA | NA | NA | 4, 0 | NA | / |
| ndT-BZ/2 I, 2 | R50Q | 38, F | 2900 (−0.41) | 4 | NA | NA | Insulin | 28 | 24 | NA | 37 | 20 | Insulin |
| ndT-PA/1 II, 1 | R50Q | 38, M | 3050 (0.37) | 2 | 11.1 (200) | No | No therapy | 24 | 22 | NA | 5, 2 | No relap. | / |
| ndT-RM/1 II, 1 | R50Q | 38, M | 2870 (0.82) | 6 | 77.2 (1390) | Yes | Insulin > SU3 0.05 mg/kg/dL | 49 | 43 | 6.3% (45) | 8, 11 | No relap. | / |
| ndT-TO/1 II, 1 | E179K | 38, M | 2600 (−1.46) | 12 | 72.2 (1300) | Yes | Insulin | 24 | 12 | NA | 16, 7 | Lost at follow up | / |
| ndT-GE/1 III, 1 | E227L | 38, M | 3180 (−0.05) | 16 | 20.7 (370) | No | Insulin | 40 | 24 | 5.3% (34) | 15, 6 | 12, 9 | NA |
| ndT-BZ/1 III, 1 | E229K | 40, M | 3340 (−0.33) | 11 | 48.9 (880) | Yes | Insulin | 26 | 15 | 6% (42) | 14, 8 | Lost at follow up | / |
| ndT-NA/3 II, 1 | E229K | 38, M | 2600 (−1.46) | 26; onset after cortisone therapy | 29.2 (527) | No | Cortisone stopped No therapy | 64 | 38 | 5.7% (39) | 8, 5 | No relap. | / |
| ndT-TO/2 III, 1 | T293S | 39, M | 3550 (0.51) | 21 | 33.3 (600) | Yes | Insulin > SU3 0.17 > 0.025 mg/kg/day | 73 | 52 | 5.8% (40) | 4, 1 | No relap. | / |
| CHR 6 | |||||||||||||
| ndT-NA/4 II, 1 | UPD6 | 39, F | 2100 (−2.66) | 3 | 50 (900) | No | Insulin | 8 | 5 | NA | 6 | No relap. | / |
| ndT-PN/1 II, 1 | UPD6 | 39+3, F | 2950 (−0.78) | 5 | 38.2 (688) | No | Insulin | 8 | 3 | NA | 2, 6 | No relap. | / |
| ndT-RM/2 II, 1 | METH. DEFECT | 39, F | 2620 (−1.47) | 1 | NA | NA | Insulin | 18 | 17 | NA | 27, 8 | 12 | Insulin |
| ndT-RMUI°/2 II, 1 | METH. DEFECT | 30, F | 1252 (−0.21) | 2 | 11.1 (200) | No | Insulin | NA | 18 | NA | 4, 9 | No relap. | / |
| ndT-RM/3 II, 1 | UPD6 | 38, M | 2240 (−2.27) | 4 | 36.6 (660) | No | Insulin | 5½ | 1½ | NA | 9, 6 | No relap. | / |
| ndT-TO/3 II, 1 | METH. DEFECT | NA, M | NA | 2 | NA | NA | Insulin | NA | NA | NA | 24, 8 | 16 | Glicazide+pioglitazone+insulin |
| ndT-TA/1 II, 1 | METH. DEFECT | 41+3, F | 2750 (−1.64) | 1 | 10 (180) | No | Insulin > SU3 | 8 | 7 | NA | 0, 9 | No relap. | / |
| ndT-CT/1 II, 1 | DUPL. 6q24 | 37, F | 1600 (−2.9) | 1 | 39.8 (718) | Yes | Insulin | 16 | 16 | 5.5% (37) | 10, 1 | 10 | Insulin → Metformin |
| ndT-FI/2 II, 1 | UPD6 | 33, F | 1300 (−1.67) | 1 | 19.4 (350) | No | Insulin | 28 | 28 | NA | 17, 7 | 12 | Insulin+metformin |
| ndT-FI/3 II, 1 | DUPL. 6q24 | 39, F | 2230 (−2.37) | 1 | NA | No | Insulin | 12 | 12 | NA | 15, 8 | No relap. | / |
| ndT-MI/3 II, 1 | UPD6 | 37+1, M | 1480 (−3.46) | 1 | NA | NA | Insulin | 12 | 12 | NA | 5, 4 | No relap. | / |
| ndT-/MI/4 II, 1 | UPD6 | 36, M | 1570 (−2.75) | 1 | NA | NA | Insulin | 4 | 4 | NA | 4, 11 | No relap. | / |
1SDS, standard deviation score; 2DKA, diabetic ketoacidosis; 3SU, glibenclamide.
NA, not available.
Most of ABCC8 and KCNJ11 variants detected in our patients had been previously reported and considered pathogenic: ABCC8/L225P (associated with PNDM) (20, 21), ABCC8/R826W (9, 20), ABCC8/R1380C (3, 8, 20), ABCC8/R1380H (20, 22, 23), ABCC8/V1523M (2, 20), KCNJ11/R50Q (20, 24), KCNJ11/E227L (13, 20) and KCNJ11/E229K (20, 25, 26, 27). Three variants were considered pathogenic or likely pathogenic according to ACMG rules (Supplementary Table 1, see section on supplementary materials given at the end of this article): the novel KCNJ11/E179K, (associated with TNDM as an unpublished observation from Andrew T. Hattersley group, Exeter) ((20), Supplementary Table 1), the novel KCNJ11/T293S (REVEL score of 0.745) (28) and ABCC8/S459R (2) (also identified in another patient with TNDM; Kevin Colclough, Exeter, personal communication). ABCC8/H105Y has been considered a variant of uncertain significance (VUS) (17).
Clinical features of 6q24/TNDM vs KATP/TNDM
Clinical features of probands with KATP/TNDM mutations (analysed as a single group) and of 6q24/TNDM are shown in Table 1. Some data from the carrier of the ABCC8/H105Y (VUS) variant (age at diabetes onset, age at remission, time to remission and mode of presentation) were excluded from this comparison.
Minor malformations (macroglossia, umbilical hernia) were present in 4 patients (33%) with 6q24 defects. Median age at diagnosis of diabetes was lower in patients with 6q24/TNDM (1 week) than those with KATP mutations (4.0 weeks) (P = 0.009) (Table 1). Of note, six KATP patients (28.6%; proband with ABCC8/H105Y not counted) and only 1 with 6q24 (8.3%) presented with diabetic ketoacidosis (DKA) at onset.
Patients with 6q24 defects were more prone to be born prematurely (3/12, 25%) than KATP (2/21, 9.5%) (29) and had a lower birth weight (−2.27 SDS) than KATP probands (−1.04) (P = 0.007) (Fig. 1). Overall, birth weight and age at diabetes onset were significantly correlated (r2 = 0.496, P = 0.004). In addition, the birth weight of 6q24 patients was also lower when compared only to KATP patients with diabetes onset within 5 weeks of age (11 individuals) (P = 0.033). Median time to remission was longer for KATP/TNDM (21.5 weeks) than 6q24/TNDM (12 weeks) (P = 0.010) (Fig. 1); two patients in the KATP/TNDM group made the transition to normal glucose values without any pharmacological therapy (Table 1). Additionally, the diabetes of a patient with the ABCC8/L225P mutation (previously associated with PNDM) (20, 21) remitted after 1 year of treatment with sulfonylureas and is still in remission at the time of writing (6 years and 8 months) (Table 1).
Graph of age at diabetes onset (weeks), time to remission (weeks) and birth weight (SDS), of patients with KATP/TNDM (open circles) vs 6q24/TNDM (full triangles). The median values were compared by the Mann−Whitney U test, the level of significance was set at a = 0.05, two-sided level.
Citation: European Journal of Endocrinology 184, 4; 10.1530/EJE-20-1030
Graph of age at diabetes onset (weeks), time to remission (weeks) and birth weight (SDS), of patients with KATP/TNDM (open circles) vs 6q24/TNDM (full triangles). The median values were compared by the Mann−Whitney U test, the level of significance was set at a = 0.05, two-sided level.
Citation: European Journal of Endocrinology 184, 4; 10.1530/EJE-20-1030
Graph of age at diabetes onset (weeks), time to remission (weeks) and birth weight (SDS), of patients with KATP/TNDM (open circles) vs 6q24/TNDM (full triangles). The median values were compared by the Mann−Whitney U test, the level of significance was set at a = 0.05, two-sided level.
Citation: European Journal of Endocrinology 184, 4; 10.1530/EJE-20-1030
HbA1c ranged from 4.3% (23 mmol/mol) to 6.3% (45 mmol/mol) in the 14 patients with KATP/TNDM who were tested at the time of remission (Table 1). In the 6q24/TNDM group, only one 6q24 patient (out of 12) had been HbA1c tested at remission (Table 1).
At the time of writing, relapse of diabetes had occurred in nine patients (five KATP, including ABCC8/H105Y and four 6q24) at ages ranging from 10 to 20 years (Table 1), while four out of six pubertal patients remained normoglycemic and two were lost at follow up. Currently, among KATP patients with recurrent diabetes, two are treated with sulfonylureas (SU), one with metformin, one with insulin and one with insulin+SU. Of the four 6q24 cases with relapsing diabetes, one is treated with insulin, one with metformin, one with insulin+metformin and one with insulin+SU+pioglitazone.
Inspection of family trees and DNA sequencing results revealed that variants of KATP genes had arisen spontaneously in 7 patients and were inherited in 14 (10 families); parents’ DNA was not available for 1 patient (Fig. 2). Notably, all KATP/TNDM patients’ family members who carried a KATP variant had some form of glucose metabolism abnormality (Fig. 2 and Table 2). In contrast, none of the patients with 6q24/TNDM had a parent or siblings with hyperglycaemia, including the two carrying a duplication of 6q24 (Table 1).
Family trees of TNDM patients with inherited KATP mutations: panel A: ABCC8, panel B: KCNJ11. Inside symbols: upper left red: TNDM; upper right blue: MODY; centre pink dot: type 2 diabetes; low left yellow: IGT; low right green: IFG; upper left black: gestational diabetes; low left black: TNDM ?; centre blue square: low birth weight, epilepsy. Below symbols: number of individual, genotype, current age, age at diabetes presentation (d, days; m, months), current therapy (adult onset) or therapy at relapse (yes/no) of diabetes. SU, sulfonylureas; Ins, insulin; Met, metformin; n.t., not tested; n.a., not available.
Citation: European Journal of Endocrinology 184, 4; 10.1530/EJE-20-1030
Family trees of TNDM patients with inherited KATP mutations: panel A: ABCC8, panel B: KCNJ11. Inside symbols: upper left red: TNDM; upper right blue: MODY; centre pink dot: type 2 diabetes; low left yellow: IGT; low right green: IFG; upper left black: gestational diabetes; low left black: TNDM ?; centre blue square: low birth weight, epilepsy. Below symbols: number of individual, genotype, current age, age at diabetes presentation (d, days; m, months), current therapy (adult onset) or therapy at relapse (yes/no) of diabetes. SU, sulfonylureas; Ins, insulin; Met, metformin; n.t., not tested; n.a., not available.
Citation: European Journal of Endocrinology 184, 4; 10.1530/EJE-20-1030
Family trees of TNDM patients with inherited KATP mutations: panel A: ABCC8, panel B: KCNJ11. Inside symbols: upper left red: TNDM; upper right blue: MODY; centre pink dot: type 2 diabetes; low left yellow: IGT; low right green: IFG; upper left black: gestational diabetes; low left black: TNDM ?; centre blue square: low birth weight, epilepsy. Below symbols: number of individual, genotype, current age, age at diabetes presentation (d, days; m, months), current therapy (adult onset) or therapy at relapse (yes/no) of diabetes. SU, sulfonylureas; Ins, insulin; Met, metformin; n.t., not tested; n.a., not available.
Citation: European Journal of Endocrinology 184, 4; 10.1530/EJE-20-1030
Clinical features of KATP/TNDM probands’ relatives.
| Kindred#, generation#, individual# | Gene/ mutation | Age at diagnosis (years) | Therapy | Other features |
|---|---|---|---|---|
| ndT-NO/1, I, 1 | ABCC8/H105Y | 49 | None | IFG1, IGT2. Lean. |
| ndT-PV/1, I, 1 | ABCC8/R826W | 44 | None | IFG, IGT |
| ndT-FI/1, I, 2 | ABCC8/R826W | NA | Insulin during pregnancy | GDM3 |
| ndT-MI/1, I, 2 | ABCC8/R1380H | 12 | Insulin from age 12 y to 34 y, then glibenclamide | / |
| ndT-NA/2, II, 2 | ABCC8/R1380C | 11 | Insulin | Onset after betamethasone at 11 y, remission after ins therapy and relapse at 17 y. Overweight |
| ndT-NA/2, II, 4 | ABCC8/R1380C | 18 | glibenclamide, then metformin, then insulin+metfornim | Overweight, acanthosis nigricans |
| ndT-PA/1, I, 2 | KCNJ11/R50Q | 7 | NA | ?? |
| ndT-TO/1, I, 1 | KCNJ11/E179K | 50 | SU4 at diagnosis, then diet | / |
| ndT-GE/1, I, 2 | KCNJ11/E227L | 14 | Insulin from age 14 to 30, then SU | |
| ndT-GE/1, II, 2 | KCNJ11/E227L | 33 | Diet | IGT |
| ndT-GE/1, II, 4 | KCNJ11/E227L | 26 | SU, diet | / |
| ndT-TO/2, I, 2 | KCNJ11/T293S | NA | SU | / |
| ndT-TO/2, II, 1 | KCNJ11/T293S | NA | Diet | / |
| ndT-TO/2, II, 3 | KCNJ11/T293S | NA | Diet | / |
1IFG, Impaired Fasting Glucose; 2IGT, Impaired Glucose Tolerance; 3GDM, Gestational Diabetes Mellitus; 4SU, Sulfonylureas.
NA, not available.
Twelve relatives had been referred to a diabetologist for hyperglycaemia prior to the identification of a KATP mutation, while two (case ndT-NO/1, I, 1 and ndT-PV/1, I, 1) were investigated by OGTT after having a positive result at genetic screening (Table 2). A single patient (ndT-MI/1, I, 2) has been switched from insulin to sulfonylureas after genetic diagnosis as an adult. Nine out of 14 relatives bearing a KATP variant were diagnosed with diabetes, either MODY or Type 2 diabetes-like (Fig. 2 and Table 2); among these 9, 4 are currently treated with SU, 3 with diet therapy, and 2 with insulin or insulin+metformin. The latter two (twin sisters of kindred ndT-NA/2, Fig. 2, panel A) are overweight (Table 2).
Discussion
Transient neonatal diabetes mellitus recognizes two main causes, 6q24 abnormalities and mildly activating mutations of KATP genes ABCC8 and KCNJ11. Interestingly, due to the nature of genetic aberrations seen in individuals with 6q24/TNDM, risk for family members is modest (30) and recurrence has only been described in the case of 6q24 duplication or ZFP57 mutations (31). In contrast, an autosomal dominant inheritance pattern of glucose metabolism abnormalities is often detected in KATP/TNDM (3, 4, 22, present study). Thus, the difference in familial presentation we observed between the two groups is easily explained and can be exploited to guide genetic analysis. Of interest, the autosomal dominant pattern observed in KATP/TNDM seems to be associated with the mild effect of its ABCC8 and KCNJ11 mutations, a factor that favours carriers’ survival. The observation that mutations in most patients with KATP/PNDM arose spontaneously, as described by Gloyn (32) and by our group (16, 33), supports this hypothesis. Nevertheless, there is no clear-cut separation between KATP genotype and its phenotypic consequences and only 4 mutations out of 12 of our data set (ABCC8/S459R, ABCC8/R1380C, KCNJ11/E179K, KCNJ11/E229K) could be consistently associated with TNDM, though most of these variants can also cause a less severe form of diabetes rather than PNDM.
KATP/TNDM and 6q24/TNDM showed other relevant clinical differences. Half of the patients with KATP/TNDM had diabetes onset beyond 5 weeks of age, that is, above the upper limit of diabetes presentation in neonates with 6q24/TNDM within our data set, and well above the mean age at presentation (8 days) of patients with 6q24/TNDM described by Docherty et al. (6). These results are similar to those obtained by others (22) and cannot be ascribed to clinicians overlooking the diagnosis in the specific KATP/TNDM subtype but must be linked to differences in the pathophysiology of hyperglycaemia development between the two subtypes.
Pancreatic islet immaturity (in utero) has been hypothesized as a cause for 6q24/TNDM (11) along with an impaired glucose-stimulated insulin secretion caused by one or more mechanisms downstream of the unaltered intracellular Ca2+ influx (34, 35), and these seem to be pathogenic factors consistent with the precocious onset of diabetes and the greatly diminished birth weight observed in 6q24/TNDM patients. There are, however, rare exceptions, such as those observed in 3 Japanese patients with 6q24 defects, who were born small for gestational age but developed diabetes in childhood/adolescence with no neonatal hyperglycaemia (36).
Differently, murine KATP-NDM models evidence the reduced cytosolic Ca2+ response to glucose stimulation linked to these mutations (37, 38). The reduction in ATP sensitivity of KATP/TNDM mutations may be moderate enough to cause either TNDM with a ‘delayed’ onset or even milder conditions, such as impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or gestational diabetes mellitus (GDM) (Fig. 1 and Table 2). Moreover, in keeping with the observation that 2 patients with KATP/TNDM experienced remission of diabetes without pharmacological therapy (Table 1), it is also conceivable that ‘mild’ TNDM could have been overlooked in parents bearing the mutation, who then developed diabetes in adolescence or adulthood. This specific finding should also prompt a revision of the definition of (T)NDM that takes into account that insulin therapy at onset of hyperglycaemia is not an absolute requirement. On the other hand, a more frequent occurrence of DKA at presentation was observed in KATP/TNDM patients and was independent of the age at onset of diabetes. We hypothesize that an impaired suppression of glucagon secretion by hyperglycaemia, as the one observed in individuals carrying the common KCNJ11/E23K polymorphism, may favour severe diabetic hyperglycaemia and ketoacidosis in these patients (39, 40) seeing as glucagon secreting cells seem to be preserved in KATP/NDM (41).
In this report, we included a patient carrying the PNDM mutation ABCC8/L225P (14) a variant already described in three patients with the permanent form of the disease (PNDM) (21, 42, 43) two of which were transferred from insulin to sulfonylureas at 1 year (21) and 3.7 years of age (41), respectively (Diva De Leon-Crutchlow and Pamela Bowman, personal communications). In contrast, our patient started treatment with SU 1 month after diabetes onset (4 months of age) and 13 months later entered diabetes remission that is still ongoing. This phenomenon has been already described in mice (44) and humans (45). In β cell-specific Rip-DTG mice, early treatment with intraperitoneal glibenclamide for 6 days around the time of diabetes induction by tamoxifen, allowed 30% of animals to remain euglycemic without any other treatment for a period of 70 days, at which point they were sacrificed (44). The experiment was replicated with identical results using oral glibenclamide (44). Marshall et al. described a patient with neonatal diabetes bearing the ABCC8/T488I mutation who was switched from insulin to glibenclamide at 20 days of age with optimal results. Sulfonylurea was stopped 10 days later, and the patient remained off insulin for a year (latest follow up) (45). Our case (14), and the one described a year earlier (45), support the findings of Remedi in mice and warrant early treatment with SU beyond its hypothesized usefulness for preventing/decreasing neurological symptoms of KATP mutations observed in patients with the permanent form. In addition, a patient carrying the ABCC8/H105Y variant has also been described here despite being a variant of uncertain significance according to the current ACMG criteria. Recently, gene-specific rules for variant interpretation are being developed by several Clin Gen Expert panels (46, 47). Thus, we suggest that a long-lasting, positive response to sulfonylureas at diabetes relapse in a carrier of a KATP variant might be incorporated among criteria indicating pathogenicity.
The size of our data set does not allow to draw firm conclusions about the fraction of TNDM patients with relapsing diabetes, which at the time of writing is 69% in individuals who reached puberty (9 out of 13 patients with available follow up data), but provides some insights about therapy in those cases where diabetes does reoccur. Of the 5 patients with KATP mutations, 2 were successfully treated with glibenclamide, 1 obese case with glibenclamide +insulin; 1 refused any SU trial and has always been on insulin and 1 we lack data on. In contrast, none of the 4 relapsing 6q24 patients had SU as monotherapy. In another paper reporting on 4 patients with 6q24/TNDM and recurring diabetes, only one was successfully treated with SU alone (48). In another study two 6q24/TNDM patients with relapsing diabetes failed to be switched from insulin to SU or to obtain good control with SU monotherapy (49). A defective mechanism downstream of the ATP-dependent closing of KATP channels of the beta-cell appears to be at work in the impaired insulin release seen in 6q24/TNDM (35, 37). Taking into account that insulin resistance is not a feature of 6q24/TNDM (50), this distinctive mechanism of β cell malfunction could explain the comparatively lower efficacy of SU therapy in patients with 6q24/TNDM.
The relatively small number of patients involved in our study is a limitation. However, the rarity of TNDM (3) hampers the collection of large cohorts in a single country, though such an approach has the advantage of increasing the homogeneity and quality of data sets. Though confirmatory of another study in some respects (22) our paper provides a systematic view of diagnostic and therapeutic approach to TNDM and adds new data on the benefits of early SU therapy on β cell function. However, more research is needed to establish the determinants of successful therapy for 6q24/TNDM, and of predictive factors, if any, of diabetes relapse in both TNDM subtypes.
In conclusion, clinical features of 6q24/TNDM and KATP/TNDM are distinct and reflect the different disease mechanisms underlying these subtypes of transient neonatal diabetes. These results indicate that patients with TNDM should be tested for KATP genes first, because swift genetic diagnosis favours the implementation of early SU therapy in patients positive to the screening and may determine remission of diabetes even in those with more severe mutations. Patients with macroglossia and/or umbilical hernia constitute an exception and should be screened for 6q24 defects first.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/EJE-20-1030.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study.
Funding
F B received support from ESPE Career Development Award. None of the Authors have conflicts of interest to declare.
Author contribution statement
All authors researched data. F B conceived the study, collected data and wrote the manuscript. R B, D I, I R, L I critically revised the manuscript, L R, V G, M M, A N, A M, P C, C M performed genetic analysis, G D, M D performed statistical analysis, G D performed proof-reading. F B is the guarantor of the manuscript.
Acknowledgements
Part of this work has been presented at the ADA annual meeting, Chicago, USA, 2020.
Members of the Diabetes Study Group of Italian Society of Pediatric Endocrinology and Diabetes (ISPED/SIEDP): Monica Aloe (Catanzaro), Simona Amadeo, Claudia Arnaldi (Viterbo), Marta Bassi (Genova), Luciano Beccaria (Milano), Marzia Benelli (Lecce), Giulia Maria Berioloi (Perugia), Enrica Bertelli (Alessandria), Martina Biagioni (Ancona), Adriana Bobbio (Aosta), Stefano Boccato (Belluno-Feltre), Oriana Bologna (Trapani), Franco Bontempi (Mantova), Clara Bonura, Giulia Bracciolini (Alessandria), Claudia Brufani (Tarquinia), Patrizia Bruzzi (Modena), Pietro Buono (Napoli), Valeria Calcaterra (Milano), Roberta Cardani (Varese), Giuliana Cardinale (Casarano), Alberto Casertano (Napoli), Maria Cristina Castiglione (Palermo), Vittoria Cauvin (Trento), Valentino Cherubini (Ancona), Franco Chiarelli (Chieti), Giovanni Chiari (Parma), Stefano Cianfarani (Roma), Dante Cirillo (Legnano), Felice Citriniti (Catanzaro), Susanna Coccioli (Brescia), Anna Cogliardi (Lecco), Santino Confetto (Napoli), Giovanna Contreas (Verona), Anna Corò (Treviso), Elisa Corsini (Firenze), Nicoletta Cresta (Campobasso), Dante Cirillo (Milano), Fiorella De Berardinis (Cetraro), Valeria De Donno (Cuneo), Giampaolo De Filippo, Rosaria De Marco (Cosenza), Annalisa Deodati (Roma), Elena Faleschini (Trieste), Valentina Fattorusso (Napoli), Valeria Favalli (Milano), Barbara Felappi (Brescia), Lucia Ferrito (Ancona), Graziella Fichera (Savona), Franco Fontana (Alessandria), Elena Fornari (Verona), Roberto Franceschi (Trento), Francesca Franco (Udine), Adriana Franzese (Napoli), Anna Paola Frongia (Cagliari), Alberto Gaiero (Savona), Francesco Gallo (Brindisi), Luigi Gargantini (Bergamo), Elisa Giani (MIlano), Chiara Giorgetti (Ancona), Giulia Bianchi, Vanna Graziani (Ravenna), Antonella Gualtieri (Avezzano), Monica Guasti (Firenze), Gennaro Iannicelli (Salerno), Antonio Iannilli (Ancona), Ignaccolo Giovanna (Torino), Dario Ingletto (Tricase), Stefania Innaurato (Vicenza), Elena Inzaghi (Roma), Brunella Iovane (Parma), Peter Kaufmann (Bolzano), Alfonso La Loggia (Caltanissetta), Rosa Lapolla (Potenza), Anna Lasagni (Reggio Emilia), Nicola Lazzaro (Crotone), Lorenzo Lenzi (Firenze), Riccardo Lera (Alessandria), Gabriella Levantini (Chieti), Fortunato Lombardo (Messina), Antonella Lonero (Bari), Silvia Longhi (Bolzano), Sonia Lucchesi (Livorno), Lucia Paola Guerraggio (Tradate), Sergio Lucieri (Castrovillari), Patrizia Macellaro (Legnano), Claudio Maffeis (Verona), Bendetta Mainetti (Forlì), Giulio Maltoni (Bologna), Chiara Mameli (Milano), Francesco Mammì (Locri), Maria Luisa Manca-Bitti (Roma), Melania Manco (Roma), Monica Marino (Ancona), Matteo Mariano (Foggia), Marco Marigliano (Verona), Alberto Marsciani (Rimini), Costanzo Mastrangelo (Foggia), Maria Cristina Matteoli (Roma), Elena Mazzali (Mantova), Franco Meschi (Milano), Antonella MIgliaccio (Catanzaro), Anita Morandi (Verona), Gianfranco Morganti (Busto Arsizio), Enza Mozzillo (Napoli), Gianluca Musolino (Varese), Rosa Nugnes (Napoli), Federica Ortolani (Bari), Daniela Pardi (Massa Carrara), Filomena Pascarella (Caserta), Stefano Passanisi (Messina), Annalisa Pedini (Rimini), Cristina Pennati (Bergamo), Angelo Perrotta (Caserta), Sonia Peruzzi, Paola Peverelli (Belluno-Feltre), Giulia Pezzino Catania), Anita Claudia Piona (Verona), Gavina Piredda (Olbia), Carmelo Pistone (Pavia), Elena Prandi (Brescia), Barbara Pedieri (Modena), Procolo Di Bonito (Napoli), Anna Pulcina (Firenze), Maria Quinci (Mazara del Vallo), Emioli Randazzo (Pisa), Rossella Ricciardi (Cagliari), Carlo Ripoli (Cagliari), Rosanna Roppolo (Palermo), Irene Rutigliano (San Giovanni Rotondo), Alberto Sabbio (Verona), Silvana salardi (Bologna), Alessandro Salvatoni (Varese), Anna Saporiti (Varese), Rita Sardi (Massa Carrara), Mariapiera Scanu (Carbonia), Andrea Scaramuzza, (Cremona), Eleonardo Schiven (Arzignano), Andrea Secco (Alessandria), Linda Sessa (Napoli), Paola Sogno Valin (Imola), Silvia Sordelli (Mantova), Luisa Spallino (Cernobbio), Stefano Stagi (Firenze), Filomena Stamati (Cosenza), Tosca Suprani (Cesena), Valentina Talarico (Catanzaro), Tiziana Timapanaro (Catania), Antonella Tirendi (Mantova), Letizia Tomaselli (Catania), Gianluca Tornese (Trieste), Adolfo Andrea Trettene (Varese), Stefano Tumini (Chieti), Giuliana Valerio (Napoli), Claudia Ventrici (Locri), Matteo Viscardi (Milano), Silvana Zaffani (Verona), Maria Zampolli (Como), Giorgio Zanette (Pordenone), Clara Zecchino (Bari), Maria Antonietta Zedda (Cagliari), Silvia Zonca, Stefano Zucchini (Bologna).
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