Abstract
Objective
The phenotype mediated by HNF4A/HNF1A mutations is variable and includes diazoxide-responsive hyperinsulinaemic hypoglycaemia (HH) and maturity-onset diabetes of the young (MODY).
Design
We characterised an international multicentre paediatric cohort of patients with HNF4Aor HNF1Amutations presenting with HH over a 25-year period (1995–2020).
Methods
Clinical and genetic analysis data from five centres were obtained. Diazoxide responsiveness was defined as the ability to maintain normoglycaemia without intravenous glucose. Macrosomia was defined as a birth weight ≥90th centile. SPSS v.27.1 was used for data analysis.
Results
A total of 34 patients (70.6% female, n = 24) with a mean age of 7.1 years (s.d. 6.4) were included. A total of 21 different heterozygous HNF4Amutations were identified in 29 patients (four novels). Four different previously described heterozygous HNF1A mutations were detected in five patients. Most (97.1%, n = 33) developed hypoglycaemia by day 2 of life. The mean birth weight was 3.8 kg (s.d. 0.8), with most infants macrosomic (n = 21, 61.8%). Diazoxide was commenced in 28 patients (82.3%); all responded. HH resolved in 20 patients (58.8%) following a median of 0.9 years (interquartile range (IQR): 0.2–6.8). Nine patients (n = 9, 26.5%) had developmental delay. Two patients developed Fanconi syndrome (p.Arg63Trp, HNF4A) and four had other renal or hepatic findings. Five (14.7%) developed MODY at a median of 11.0 years (IQR: 9.0–13.9). Of patients with inherited mutations (n = 25, 73.5%), a family history of diabetes was present in 22 (88.0%).
Conclusions
We build on the knowledge of the natural history and pancreatic and extra-pancreatic phenotypes of HNF4A/HNF1Amutations and illustrate the heterogeneity of this condition.
Introduction
Hyperinsulinaemic hypoglycaemia (HH) presents most often in neonatal life and is characterised by inappropriate insulin secretion despite hypoglycaemia. In the pancreatic β-cell, glucose-mediated insulin release is regulated by the ATP-sensitive potassium channel (KATP channel). Several genetic causes of HH have been identified (1, 2). Loss-of-function mutations in KCNJ11and ABCC8 –which code for the Kir6.2 and SUR1 subunits of the KATP channel, respectively – are the most common. HH can also arise from loss-of-function mutations in the coding and regulatory regions of HNF4A(20q12), a nuclear transcription factor expressed in liver, gut, kidney, and pancreatic islet cells (3, 4, 5). Mutations in a second nuclear transcription factor, HNF1A(12q24), have more recently been identified as a cause (6, 7). HNF4Aand HNF1Aform a regulatory loop: HNF1A activates transcription of HNF4Avia the P2 promoter region, which activates HNF1Atranscription in turn (8, 9, 10).
The clinical presentations of HH mediated by mutations in HNF4Aand HNF1Aappear to be phenotypically similar. Affected neonates tend to be macrosomic, likely due to in uteroinappropriate insulin secretion, and are usually diagnosed within the first day or two of life (10, 11). The clinical severity of HH is markedly variable and ranges from mild, transient hypoglycaemia to severe, persistent hypoglycaemia requiring definitive treatment for up to several years (5, 12, 13, 14). Infants requiring treatment respond well to diazoxide, a first-line treatment for HH that maintains normoglycaemia by binding to the SUR1 regulatory subunit of the KATP channel to keep it open, preventing insulin secretion.
The clinical sequelae of mutations in HNF4Aand HNF1Aextend beyond neonatal life. Mutations in both genes cause maturity-onset diabetes of the young (MODY), a clinically heterogeneous group of monogenic defects in pancreatic β-cell function characterised by early-onset non-ketotic diabetes mellitus (15). Mutations in at least ten genes can cause MODY, with HNF1Athe most common (HNF1A-MODY, responsible for 52% of MODY in the UK) and HNF4A a rarer cause (HNF4A-MODY, responsible for 10%) (4, 16, 17, 18, 19, 20). It is by now well established that heterozygous HNF4Agene mutations therefore give rise to a biphasic phenotype: diazoxide-responsive HH in infancy and early childhood and MODY from the second decade onwards (11). The more recent association of HNF1Amutations with neonatal HH gives rise to an apparently very similar phenotype (7, 21). The mechanism for this biphasic phenotype is unknown but may arise from insulin hypersecretion resulting in β-cell exhaustion or from differences in HNF4Adependent gene expression over time (11).
Elucidating the specific genetic mechanism underlying neonatal HH has clear benefits. Identification of HNF4Aand HNF1Amutations in infancy allows for careful screening for HNF4A/HNF1A MODY with annual HbA1c and/or oral glucose tolerance tests from an early age (usually from 10 years) (11). It can also guide treatment, as HNF4A/HNF1A MODY responds particularly well to low-dose sulfonylureas (11, 22). Furthermore, detecting the same mutation in a parent or sibling(s) of affected babies identifies individuals who have unrecognised MODY or who are at risk of developing it. A genetic diagnosis may also have implications for future pregnancies and births. More recently, mutation-specific effects have been recognised, which can further guide the optimal management of these infants. For example, the p.Arg114Trp HNF4A mutation has been reported to result in a distinct phenotype of infants of normal birth weight and a tendency to develop MODY later in life than with other mutations (23). The p.Arg63Trp HNF4Amutation can cause atypical autosomal dominant Fanconi syndrome with nephrocalcinosis in addition to its effect on glycaemic control (7, 24, 25, 26, 27, 28, 29, 30). This was recently expanded to include hepatic abnormalities, including hepatomegaly, deranged transaminases, and prolonged conjugated hyperbilirubinaemia (25, 26, 31).
This large, multicentre case series describes 34 infants with HH caused by HNF4A/HNF1Amutations and follows them into childhood, refining our understanding of an important and increasingly complex clinical entity.
Patients and methods
Clinical data
We studied 34 patients presenting with HH due to confirmed pathogenic mutations in the HNF4A and HNF1A genes over a 25-year period (1995–2020). Five centres were included: Great Ormond Street Hospital for Children, London, United Kingdom (fifteen patients); Children’s Health Ireland Temple Street, Dublin, Republic of Ireland (six patients); Endocrinology Research Centre, Moscow, Russia (six patients); Hans Christian Andersen Children’s Hospital, Odense, Denmark (six patients); Hacettepe University, Faculty of Medicine, Ankara, Turkey (one patient). Clinical and molecular genetic analysis data were obtained by contributing centres following case note review. As this was a retrospective study, the length of follow-up depended on patient age. Clinical presentation, family history, treatment, and outcomes were reviewed from birth to the present. Fourteen children were followed up for over five years and 10 of these were followed up for over 10 years. HH was defined as a blood glucose level <3 mmol/L in the presence of detectable serum insulin and/or c-peptide. Diazoxide responsiveness was defined as the ability to maintain normoglycaemia without intravenous glucose. Macrosomia was defined as a birth weight ≥90th centile (≥1.3 s.d.S). s.d.S for birthweights were calculated using the publicly accessible PediTools based on the LMS parametrisation method and according to gestational week (32). SPSS v.27.1 was used for statistical analysis. Data on neurodevelopment were collected from routine clinical reviews by paediatricians and primary care providers. Demographic and clinical data were presented as median (interquartile range (IQR)) or mean (s.d.) as appropriate. Fisher’s exact tests (two-sided) and independent sample t-tests were used for statistical analysis.
Genetic data
Local R&D ethical approval for retrospective data collection was obtained as per institutional requirements of contributing centres (e.g. the ethics committee of Great Ormond Street Hospital). Informed consent was obtained from the parents of all patients prior to genetic testing which was conducted as part of routine clinical care. The study was conducted in accordance with the Declaration of Helsinki (2000). HNF4A and HNF1A were screened by Sanger sequencing or targeted next-generation sequencing according to local laboratory guidelines. For patients with a known history of HNF4A/HNF1Amutations, targeted Sanger sequencing was performed.
Genomic DNA was extracted from peripheral leukocytes using standard protocols. The ten coding exons and intron/exon boundaries of the HNF4Aand HNF1Agenes and the P2 pancreatic promoter of HNF4A were amplified by PCR. PCR products were sequenced using standard procedures. The order of genetic testing depended on the clinical presentation and known family history. A positive HNF4A/HNF1A mutation prompted testing of both parents, if possible, to establish the mode of inheritance.
Results
A total of 21 different heterozygous HNF4Amutations (four (19%) novel) were identified in 29 patients. Four different previously described heterozygous HNF1A mutations were detected in five patients (Fig. 1 and Table 1). All mutations were classified as pathogenic/likely pathogenic according to ACGS/ACMG best practice guidelines (33).
Schematic representation of HNF4A and HNF1A proteins with pathogenic variants annotated. (A) The ten coding exons, promoter regions, and key domains of the HNF4a protein with pathogenic variants identified in this study are highlighted. Novel variants are highlighted in bold. (B) The ten coding exons and key domains of the HNF1A protein with variants are highlighted.
Citation: European Journal of Endocrinology 186, 4; 10.1530/EJE-21-0897
Schematic representation of HNF4A and HNF1A proteins with pathogenic variants annotated. (A) The ten coding exons, promoter regions, and key domains of the HNF4a protein with pathogenic variants identified in this study are highlighted. Novel variants are highlighted in bold. (B) The ten coding exons and key domains of the HNF1A protein with variants are highlighted.
Citation: European Journal of Endocrinology 186, 4; 10.1530/EJE-21-0897
Schematic representation of HNF4A and HNF1A proteins with pathogenic variants annotated. (A) The ten coding exons, promoter regions, and key domains of the HNF4a protein with pathogenic variants identified in this study are highlighted. Novel variants are highlighted in bold. (B) The ten coding exons and key domains of the HNF1A protein with variants are highlighted.
Citation: European Journal of Endocrinology 186, 4; 10.1530/EJE-21-0897
Characteristics of heterozygous HNF4A/HNF1A mutations in the patient cohort. All described mutations are pathogenic or likely pathogenic in accordance with ACGS/ACMG best practice guidelines for variant interpretation and explain the patient’s clinical phenotype. Variants are described according to Human Genome Variation Society (HGVS) nomenclature guidelines v20.05 and using the reference sequences NM_000545.5 for HNF1A and NM_175914.4 for HNF4Aunless otherwise indicated. Novel mutations (in bold) have been classified as pathogenic/likely pathogenic according to ACGS/ACMG best practice guidelines.
| Patient | Mode of inheritance | Genomic change | Protein change | Exon | Predicted effect | Previously reported?** |
|---|---|---|---|---|---|---|
| HNF4A | ||||||
| 1 | Paternally inherited | c.48C>A | p.(Tyr16*) | Exon 1 | Nonsense | Carlsson et al. (45) |
| 2 | Paternally inherited | c.438del | p.(Val147fs) | Exon 5 | Frameshift | Novel (Pathogenic: PVS1, PM2, PP1) |
| 3 | Maternally inherited | c.931C>T | p.(Arg311Cys) | Exon 8 | Missense | Yorifuji et al. (46); Globa et al. (47) |
| 4 | De novo | c.187C>T | p.(Arg63Trp) | Exon 2 | Missense | Flanagan et al. (5); Hamilton et al. (24); Stanescu et al. (7) |
| 5 | Maternally inherited | c.340C>T | p.(Arg114Trp) | Exon 4 | Missense | Frayling et al. (48); Furuta et al. (49) |
| 6 | Maternally inherited | c.868C>T | p.(Arg290Cys) | Exon 8 | Missense | Kyithar et al. (50) |
| 7 | Paternally inherited | c.438del | p.(Val147fs) | Exon 5 | Frameshift | Novel (Pathogenic: PVS1, PM2, PP1) |
| 8 | Maternally inherited | c.340C>T | p.(Arg114Trp) | Exon 4 | Missense | Frayling et al. (48); Furuta et al. (49) |
| 9 | Paternally inherited | c.914dup | p.(Gln306fs) | Exon 8 | Frameshift | Flanagan et al. (5)* |
| 10 | De novo | c.956_958dup | p.(Leu319dup) | Exon 8 | In-frame duplication | Pearson et al. (51) |
| 11 | Not tested | c.1045C>T | p.(Gln349*) | Exon 8 | Nonsense | Flanagan et al. (5)* |
| 12 | Maternally inherited | c.-181G>A | N/A | P2 promoter | Regulatory | Hansen et al. (52) |
| 13 | Maternally inherited | c.187C>T | p.(Arg63Trp) | Exon 2 | Missense | Flanagan et al. (5); Hamilton et al. (24); Stanescu et al. (7) |
| 14 | De novo | c.309G>A | p.(Met103Ile) | Exon 3 | Missense | Flanagan et al. (5); Arya et al. (53) |
| 15 | Paternally inherited | c.948_1002del | p.(Leu317fs) | Exon 8 | Frameshift | Kapoor et al.* (13) |
| 16 | Maternally inherited | c.179G>T | p.(Gly60Val) | Exon 2 | Missense | Novel (Likely Pathogenic: PM2, PM1, PP2, PP3) |
| 17 | Maternally inherited | c.179G>T | p.(Gly60Val) | Exon 2 | Missense | Novel (Likely Pathogenic: PM2, PM1, PP2, PP3) |
| 18 | Maternally inherited | c.240C>G | p.(Cys80Trp) | Exon 3 | Missense | Ellard & Colclough* (22) |
| 19 | Paternally inherited | c.270del | p.(Arg119fs) | Exon 4 | Frameshift | McGlacken-Byrne et al.* (12) |
| 20 | Paternally inherited | c.270del | p.(Arg119fs) | Exon 4 | Frameshift | McGlacken-Byrne et al.* (12) |
| 21 | Maternally inherited | c.868C>T | p.(Arg290Cys) | Exon 8 | Missense | Kyithar et al. (50) |
| 22 | De novo | c.278G>C | p.(Cys93Ser) | Exon 3 | Missense | McGlacken-Byrne et al.* (12); Flanagan et al.* (5) |
| 23 | De novo | c.191G>C | p.(Arg64Thr) | Exon 2 | Missense | McGlacken-Byrne et al.* (12) |
| 24 | Paternally inherited | c.270del | p.(Arg119fs) | Exon 4 | Frameshift | McGlacken-Byrne et al.* (12) |
| 25 | Maternally inherited | c.931C>T | p.(Arg311Cys) | Exon 8 | Missense | Yorifuji et al. (46) |
| 26 | De novo | c.900C>A | p.(Tyr300*) | Exon 8 | Nonsense | Novel (Pathogenic: PM2, PVS1, PP3) |
| 27 | De novo | c.177G>C | p.(Lys59Asn) | Exon 2 | Missense | Novel (Likely pathogenic: PM1 PM2 PP2 PP3) |
| 28 | Maternally inherited | c.322G>A | p.(Val108Ile) | Exon 3 | Missense | Monney et al. (54) |
| 29 | Paternally inherited | c.200G>A | p.(Arg67Gln) | Exon 2 | Missense | Johansson et al. (55) |
| HNF1A | ||||||
| 30 | Maternally inherited | c.526C>T | p.(Gln176*) | Exon 2 | Nonsense | Xu et al. (56) |
| 31 | Maternally inherited | c.526C>T | p.(Gln176*) | Exon 2 | Nonsense | Xu et al. (56) |
| 32 | Paternally inherited | c.476G>A | p.(Arg159Gln) | Exon 2 | Missense | Frayling et al. (57); Iwasaki et al. (58) |
| 33 | Paternally inherited | c.872dup | p.(Gly292fs) | Exon 4 | Frameshift | Yamagata et al. (19); Ellard & Colclough (22) |
| 34 | Not tested | c.1137del | p.(Val380fs) | Exon 6 | Frameshift | Bellanné-Chantelot et al. (36) |
*This patient has been previously reported in this publication; **Not an exhaustive list. Mutations described as novel have not yet been reported elsewhere to the best of our knowledge.
Clinical characteristics at diagnosis
At diagnosis, 70.6% (n = 24) of the probands were female (see Table 2 for full clinical characteristics of the cohort). The mean age at recruitment to the study was 7.1 years (s.d. 6.4). There were four sets of siblings; the remainder of the cohort were unrelated. Most patients (n = 33, 97.1%) developed hypoglycaemia within the first 2 days of life (median age 1 day, IQR 1–1.25). One patient presented at 24 days of life when being weaned onto enteral feeds following a complicated initial neonatal course. The cause for hypoglycaemia was diagnosed retrospectively in three patients; two who had younger siblings diagnosed with HH at birth and one who developed MODY in later childhood. The mean birth weight and s.d.S from the mean were 3.8 kg (s.d. 0.8) and 1.6 s.d.S (s.d. 1.3), respectively, with the majority of infants macrosomic (n = 21, 61.8%). Babies were born preterm (<37 weeks gestation) in 35.3% (n = 12) of cases. Those with a positive family history of hyperinsulinism (n = 6, 17.6%) were screened at birth, had capillary blood glucose monitoring checked regularly during the first few days of life, and had a formal fast provocation test prior to discharge. HH was confirmed biochemically with endocrine/metabolic profiles at the time of hypoglycaemia. The mean glucose at presentation was 1.5 mmol/L (s.d. 0.7) with a mean glucose requirement of 13.1 mg/kg/min (s.d. 4.7). Other presenting symptoms and signs included hypotonia (n = 1, 2.9%), seizures (n = 4, 11.8%), jaundice (n = 1, 2.9%), respiratory distress (n = 5, 14.7%), and lethargy (n = 3, 8.8%).
Clinical characteristics of patients with HH due to HNF4A/HNF1A mutations.
| Patient | Sex | Gestational age (weeks) | Birth weight (kg) | Birth weight s.d.S | Age at presentation (day of life) | Current age (years) | Age HH resolved | Clinical MODY | Age developed MODY | Developmental delay |
|---|---|---|---|---|---|---|---|---|---|---|
| HNF4A | ||||||||||
| 1 | Female | 38 | 3.25 | 0.41 | 1 | 2.5 | 0.7 | No | No | |
| 2§ | Male | 40 | 3.23 | −0.47 | 730 | 6.8 | 5.0 | No | No | |
| 3 | Female | 35+3 | 3.35 | 1.90 | 1 | 1.7 | Ongoing | No | No | |
| 4 | Male | 38+2 | 3.99 | 1.64 | 2 | 4.9 | Ongoing | No | Yes | |
| 5 | Male | 35+3 | 2.95 | 0.82 | 1 | 3.9 | Ongoing | No | Yes | |
| 6 | Female | 38+1 | 3.97 | 1.71 | 1 | 6.6 | Ongoing | No | Yes | |
| 7§ | Female | 39+2 | 3.60 | 0.61 | 2 | 3.9 | Ongoing | No | No | |
| 8 | Female | 36+4 | 3.87 | 2.25 | 1 | 10.4 | 0.1 | No** | Yes | |
| 9 | Female | 40 | 4.50 | 1.93 | 1 | 11.6 | 0.9 | No** | No | |
| 10 | Female | 37 | 3.97 | 2.21 | 1 | 1.6 | Ongoing | No | No | |
| 11 | Female | 35 | 3.53 | 2.51 | 1 | 13.8 | 6.8 | No | No | |
| 12 | Female | 36 | 3.36 | 1.60 | 2 | 24.8 | 0.1 | Yes | 11.01 | Yes |
| 13* | Male | 30+2 | 1.53 | 0.30 | 24 | 0.5 | 0.5* | No | Yes | |
| 14 | Male | 38 | 3.00 | −0.35 | 1 | 17.5 | 1.5 | Yes | 16.23 | No |
| 15 | Male | 39 | 5.90 | 4.89 | 1 | 13.3 | 3.0 | Yes | 11.58 | Yes |
| 16§ | Male | 36+1 | 3.25 | 1.11 | 1 | 13.0 | 11.0 | No | No | |
| 17§ | Male | 38+0 | 2.69 | −1.06 | 1 | 10.0 | 7.0 | No | No | |
| 18 | Female | 33+5 | 3.00 | 2.21 | 1 | 0.4 | 0.1 | No | No | |
| 19§ | Female | 39 | 4.90 | 2.88 | 1 | 2.6 | Ongoing | No | No | |
| 20§ | Female | 38+4 | 4.10 | 1.76 | 1 | 10.3 | 8.4 | No | No | |
| 21 | Female | 37+6 | 3.90 | 1.70 | 1 | 0.4 | 0.6 | No | No | |
| 22 | Male | 40+6 | 4.10 | 0.70 | 1 | 18.0 | 13.1 | No | No | |
| 23 | Female | 40 | 4.56 | 2.02 | 1 | 7.4 | 4.5 | No | No | |
| 24§ | Female | 37+6 | 4.90 | 3.33 | 1 | 0.1 | Ongoing | No | No | |
| 25 | Female | 36 | 3.41 | 1.70 | 1 | 2.6 | Ongoing | No | Yes | |
| 26 | Female | 38 | 4.20 | 2.16 | 2 | 5.1 | 0.2 | No | No | |
| 27 | Male | 36 | 4.60 | 3.7 | 1 | 1.8 | Ongoing | No | No | |
| 28 | Female | 37 | 3.06 | 0.43 | 1 | 0.8 | 0.1 | No | No | |
| 29 | Female | 39 | 4.75 | 3.07 | 1 | 0.8 | Ongoing | No | No | |
| HNF1A | ||||||||||
| 30§ | Female | 38+5 | 4.72 | 2.71 | 1 | 12.0 | 0.2 | Yes | 10 | No |
| 31§ | Female | 36+6 | 3.93 | 2.22 | 1 | 11.0 | 0.2 | Yes | 8 | Yes |
| 32 | Female | 39+2 | 3.78 | 0.94 | 1 | 17.0 | 0.2 | No | No | |
| 33 | Female | 39 | 3.70 | 0.90 | 2 | 1.8 | Ongoing | No | No | |
| 34 | Female | 36 | 2.58 | −0.16 | 1 | 0.92 | Ongoing | No | No |
§Indicates that patients are sets of siblings: patients 2 and 7 are siblings; 16 and 17 are brothers; 19, 20, and 24 are sisters; 30 and 31 are sisters; *This patient died at the age of 6 months; **These patients have not been diagnosed with MODY but do have impaired glucose tolerance on oral glucose tolerance test.
LFTs, liver function tests; SVT, supraventricular tachycardia; TOF, tetralogy of Fallot; VSD, ventricular septal defect.
Treatment course
Diazoxide was commenced in 28 patients (82.4%) at a median of 10.0 days of life (IQR: 4.0–16.0). The mean maximum diazoxide dose required to obtain normoglycaemia was 7.9 mg/kg/day (s.d. 4.0, range: 2.1–20.0) and all patients treated were diazoxide responsive. Four patients (11.8%, including the three patients diagnosed with HH retrospectively) were treated with intravenous dextrose alone. Five patients (14.7%) received octreotide therapy (two patients received octreotide alone as first-line therapy, three received octreotide as adjunctive therapy alongside diazoxide) for a median of 6.0 days (IQR: 3.0–6.0). No patients received treatment with lanreotide, nifedipine, or sirolimus. The median time to discharge was 4.0 weeks (IQR: 2.8–5.2). HH resolved in 20 patients (58.8%) following a median of 0.9 years (IQR: 0.2–6.8). Only 10 (29.4%) patients in total had HH that resolved by the age of 1 year. Of the 28 patients commenced on diazoxide, 14 patients (50.0%) remain in this medication for HH (mean age: 1.2 years, s.d. 1.3). All children had a regular follow-up to assess fasting tolerance and to review the need for diazoxide. One patient (patient 13) died unexpectedly at home at the age of 6 months due to other co-morbidities; he was still receiving treatment for HH at the time. The duration of diazoxide therapy for all 28 treated patients ranged from 3 days to 13.1 years (latter patient now successfully weaned off diazoxide). Five patients (14.7%) developed MODY at a median age of 11.0 years (IQR: 9.0–13.9) and are maintained on oral hypoglycaemic medication (Fig. 2). Two patients (5.9%) have impaired glucose tolerance on OGTT (developed at the ages of 8.2 and 8.5 years) but have not yet developed overt diabetes mellitus.
Proportion of patients with hyperinsulinaemic hypoglycaemia (HH) and maturity-onset diabetes of the young (MODY) caused by HNF4A/HNF1Amutations over time. Left panel: Proportion of patients with HH over time. Note: several patients are still in early childhood. Right panel: Proportion of patients diagnosed with MODY over time.
Citation: European Journal of Endocrinology 186, 4; 10.1530/EJE-21-0897
Proportion of patients with hyperinsulinaemic hypoglycaemia (HH) and maturity-onset diabetes of the young (MODY) caused by HNF4A/HNF1Amutations over time. Left panel: Proportion of patients with HH over time. Note: several patients are still in early childhood. Right panel: Proportion of patients diagnosed with MODY over time.
Citation: European Journal of Endocrinology 186, 4; 10.1530/EJE-21-0897
Proportion of patients with hyperinsulinaemic hypoglycaemia (HH) and maturity-onset diabetes of the young (MODY) caused by HNF4A/HNF1Amutations over time. Left panel: Proportion of patients with HH over time. Note: several patients are still in early childhood. Right panel: Proportion of patients diagnosed with MODY over time.
Citation: European Journal of Endocrinology 186, 4; 10.1530/EJE-21-0897
Associated clinical characteristics
A total of 25 (73.5%) patients have had reportedly normal neurodevelopment to date. Nine (26.5%) had a developmental delay in one or more developmental domains, with three patients (8.8%) attending a special school. Two of the three children with seizures had later developmental delays. Developmental delay was associated with preterm birth (P = 0.033) and lower mean blood sugar level (BSL) at presentation (t (7.8) = 2.7, P = 0.028).
Two of these children with developmental delay and p.Arg63Trp HNF4Amutations have been diagnosed with renal Fanconi syndrome (patients 4 and 13). One of these patients (Table 2; patient 4) also had conjugated hyperbilirubinaemia and multiple liver cysts and liver haemangiomas at birth; these resolved and subsequent nodular regeneration of the liver remains under review. Four other patients had hepatic or renal findings outside of the context of the p.Arg63Trp HNF4Amutation: transiently deranged liver function tests (patient 33; p.Gly292fs, HNF1A), mild hepatic enlargement and heterogeneity (patient 3; p.Arg290Cys, HNF4A), pyelectasis (patient 34; p.Val380fs, HNF4A), and renal hypoplasia (patient 32; p.Arg159Gln, HNF1A). Five patients had cardiac pathology: ventricular septal defects (patients 3, 13, 19), supraventricular tachycardia (patient 31), and tetralogy of Fallot (patient 14).
Family history
One patient had consanguineous parents. De novomutations in HNF4A were found in seven unrelated patients (20.6%) (Table 2). None of the seven patients with de novomutations nor the probands with untested parent(s) (n = 2) had a family history of diabetes nor neonatal hypoglycaemia.
Of patients with inherited mutations (n = 25, 73.5%), a family history of diabetes (type 1, type 2, or MODY) in at least one first-degree relative was present in 22 (88.0%). Half of these patients (n = 11) had relatives with a known history of confirmed HNF4A/HNF1A MODY. Three parents (including the mother of two siblings) had an existing diagnosis of antibody-negative T1DM or T2DM re-classified as HNF4A/HNF1A MODY after their child’s diagnosis. Five parents (including the father of three siblings) were diagnosed with HNF4A/HNF1A MODY diabetes for the first time after their child’s diagnosis based on confirmatory genetic analysis and a supporting oral glucose tolerance test.
Seven patients (20.6%) had a family history of neonatal hypoglycaemia. The mother of one patient with HH and renal Fanconi syndrome due to a maternally inherited HNF4Amutation did not have clinical diabetes mellitus but did have a history of previously unexplained childhood hypoglycaemia and rickets. Five patients in this study were the younger siblings of patients with previously diagnosed HH due to HNF4Amutations. One other patient had a family history of neonatal hypoglycaemia in a paternal cousin.
Discussion
This series clearly illustrates the heterogeneity and unpredictability associated with the clinical phenotype of HNF4A/HNF1Amutations. The age of hypoglycaemia onset was similar and usually occurred within the first 2 days of life. The presence of macrosomia was variable in our study, as was the severity and duration of hypoglycaemia. While hypoglycaemia was transient and did not require diazoxide treatment in some, others required diazoxide therapy well into childhood – the eldest being 13 years on diazoxide discontinuation. The age of MODY onset in this cohort was similarly variable, with five patients developing overt diabetes mellitus by their teenage years. Furthermore, three pre-pubertal patients developed either MODY or impaired glucose tolerance before the age of 10 years, suggesting deferring screening for diabetes until the age of 10 may result in a delayed diagnosis in the subset of children who develop impaired glucose tolerance before this time. Although the biphasic phenotype of HNF4A/HNF1Amutations is by now well-recognised, its variability remains unexplained and does not appear to be reproducibly mutation-specific. Earlier age of HNF1A MODY onset has been associated with maternally inherited mutations (possibly due to intrauterine hyperglycaemia exposure) and with truncating rather than missense mutations (34, 35, 36). Both siblings with a maternally inherited mutation did develop HNF1A MODY diabetes by the age of 10 years. Furthermore, their mutation was also in exon 2 of the HNF1Agene, echoing previous findings that patients with mutations within the first six exons of the gene developed diabetes on average 12 years earlier than others (37). However, the other three patients who developed early-onset MODY had HNF4Amutations that did not reflect these associations: a paternally inherited frameshift mutation,a de novomissense mutation,and a maternally inherited missense mutation. It is worth noting that there will be bias within this cohort towards earlier detection of MODY. Broadly, the clinical heterogeneity of HH and MODY caused by HNF4A/HNF1Amutations suggests that although these mutations are inherited in a Mendelian fashion their phenotypic manifestation is likely influenced by unrecognised environmental factors or genetic and epigenetic modifiers.
Spontaneous mutations in HNF4Aand HNF1Awere at one time thought to be rare, with patients undergoing molecular testing in the context of a positive family history (10). Screening for hypoglycaemia in these instances is essential to reduce the risk of brain injury associated with hypoglycaemia. However, there is now an awareness that a significant proportion of HNF4A/HNF1A mutations occur de novo (5, 12, 38). Seven de novo mutations were found in this cohort of 30 patients. Importantly, although the majority of patients in this series with inherited mutations ultimately were found to have a positive family history, only half of the affected relatives had a known HNF4A/HNF1Amutation at the time of the child’s diagnosis. Some of these newly diagnosed parents had diagnoses of diabetes mellitus that were re-classified as MODY at the time of their child’s diagnosis; others were diagnosed with diabetes for the first time. Most patients did not have a family history of neonatal hypoglycaemia, reflecting previous studies (5). This may reflect under-recognised cases of HH, as hypoglycaemia is a common and non-specific presentation in early life. It may also be due to the incomplete penetrance of HH with these mutations. Taken together, once the more common KATP channel mutations have been excluded, the need to screen for HNF4A/HNF1Amutations in infants with HH regardless of family history is clear. This has implications beyond the presenting patient, as correctly identifying MODY pedigrees facilitates improved diabetes care, screening, and management of subsequent pregnancies (20). Furthermore, HNF4A/HNF1Amutations can be transmitted from father to child in an autosomal dominant manner, highlighting how early-onset paternal diabetes should prompt genetic testing in babies presenting with diazoxide-responsive HH even in the absence of macrosomia or maternal diabetes (39).
Recently, the phenotype of HNF4A/HNF1Amutations has been expanded to include extra-pancreatic features, and this was reflected in our series. The above-described renotubular Fanconi syndrome associated with the HNF4Ap.Arg63Trp mutation was seen in two unrelated patients in this series. One of these patients also had conjugated hyperbilirubinaemia, multiple liver cysts, and liver haemangiomas at birth, expanding the hepatic phenotype associated with this mutation. HNF4A is expressed in hepatocytes and in renal proximal tubules, but only the Arg63Trp mutation has been found to cause Fanconi syndrome (28). The Arg63 residue is in the DNA-binding domain and has been associated with defective interaction of HNF4A with key regulatory genes, resulting in the mutation-specific phenotype (24, 40). Interestingly, four patients with other mutations also had renal and hepatic findings, described earlier. While these findings may have been unrelated to their underlying genetic mutation, the fact that they occurred outside of the context of the p.Arg63Trp mutation is worth noting. Of note too is the novel association of renal hypoplasia and the p.Gly292fs (c.872dup) HNF1Amutation in one patient. While a mouse model deficient for HNF1Adeveloped Fanconi syndrome, no patients to date with HNF1Amutations have been described to have a renal phenotype (41). The five patients with HNF4Amutations and cardiac anomalies also warrant emphasis. This may be coincidental; cardiac defects are relatively common in the general population, and HNF4A is expressed only at low levels in (adult) myocytes (42). However, given the propensity of diazoxide to precipitate volume overload, an awareness of underlying cardiac defects amongst infants with HH is essential and this potential association should be explored in future studies (43).
Lastly, the developmental delay occurred in 26.5% of our patients, a similar rate to previous studies (44). This was associated with prematurity and with lower blood glucose level at presentation. Previous studies did not find an association with prematurity but did find an association between maximum diazoxide dose and developmental delay (44). It is certainly reasonable to assume that severe or prolonged hypoglycaemia – especially if non-ketotic – carries with it a risk of neurodevelopmental sequelae and further highlights the benefit of screening in cases with a positive family history.
This large, multicentre case series of patients with heterozygous HNF4A/HNF1Amutations expand our knowledge of the natural history of the clinical phenotype and clarifies some emerging genotype–phenotype correlations. Limitations of this study included its retrospective approach and the fact that several patients have not reached adulthood. Additionally, genetic analysis for underlying causes of HH has only recently formed part of standard clinical care, meaning that a proportion of as yet untested older patients from participating centres may have unidentified genetic variants explaining their condition. Furthermore, genetic testing was limited to the above-described HH panel, raising the outside possibility that some patients have a second genetic abnormality explaining their phenotype. Lastly, this study was not powered to detect differences in genotype/phenotype correlations between patients with HNF1Aand HNF4Amutations. Larger, prospective studies may refine our understanding of potential mutation-specific effects and extra-pancreatic features associated with HNF4A/HNF1Amutations which would allow a more tailored management approach to this complex condition. Scientific interrogation of the unique natural history of HNF4A/1A MODY would not just advance our understanding of the physiology and genetic regulation underpinning this disorder but more broadly would contribute to our understanding of the genesis of disorders of β-cell function.
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
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
References
- 1↑
Senniappan S, Shanti B, James C, Hussain K. Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management. Journal of Inherited Metabolic Disease 2012 35 589–601. (https://doi.org/10.1007/s10545-011-9441-2)
- 2↑
Galcheva S, Al-Khawaga S, Hussain K. Diagnosis and management of hyperinsulinaemic hypoglycaemia. Best Practice and Research: Clinical Endocrinology and Metabolism 2018 32 551–573. (https://doi.org/10.1016/j.beem.2018.05.014)
- 3↑
Sladek FM, Zhong WM, Lai E, Darnell JE. Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes and Development 1990 4 2353–2365. (https://doi.org/10.1101/gad.4.12b.2353)
- 4↑
Yamagata K, Oda N, Kaisaki PJ, Menzel S, Furuta H, Vaxillaire M, Southam L, Cox RD, Lathrop GM & Boriraj VV et al.Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature 1996 384 455–458. (https://doi.org/10.1038/384455a0)
- 5↑
Flanagan SE, Kapoor RR, Mali G, Cody D, Murphy N, Schwahn B, Siahanidou T, Banerjee I, Akcay T & Rubio-Cabezas O et al.Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations. European Journal of Endocrinology 2010 162 987–992. (https://doi.org/10.1530/EJE-09-0861)
- 6↑
Dusatkova P, Pruhova S, Sumnik Z, Kolouskova S, Obermannova B, Cinek O, Lebl J. HNF1A mutation presenting with fetal macrosomia and hypoglycemia in childhood prior to onset of overt diabetes. Journal of Pediatric Endocrinology and Metabolism 2011 24 187–189. (https://doi.org/10.1515/jpem.2011.083)
- 7↑
Stanescu DE, Hughes N, Kaplan B, Stanley CA, De León DD. Novel presentations of congenital hyperinsulinism due to mutations in the MODY genes: HNF1A and HNF4A. Journal of Clinical Endocrinology and Metabolism 2012 97 E2026–E2030. (https://doi.org/10.1210/jc.2012-1356)
- 8↑
Odom DT, Zizlsperger N, Gordon DB, Bell GW, Rinaldi NJ, Murray HL, Volkert TL, Schreiber J, Rolfe PA & Gifford DK et al.Control of pancreas and liver gene expression by HNF transcription factors. Science 2004 303 1378–1381. (https://doi.org/10.1126/science.1089769)
- 9↑
Wang H, Maechler P, Antinozzi PA, Hagenfeldt KA, Wollheim CB. Hepatocyte nuclear factor 4alpha regulates the expression of pancreatic beta-cell genes implicated in glucose metabolism and nutrient-induced insulin secretion. Journal of Biological Chemistry 2000 275 35953–35959. (https://doi.org/10.1074/jbc.M006612200)
- 10↑
Colclough K, Bellanne-Chantelot C, Saint-Martin C, Flanagan SE, Ellard S. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia. Human Mutation 2013 34 669–685. (https://doi.org/10.1002/humu.22279)
- 11↑
Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, Ellard S, Ferrer J, Hattersley AT. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Medicine 2007 4 e118. (https://doi.org/10.1371/journal.pmed.0040118)
- 12↑
McGlacken-Byrne SM, Hawkes CP, Flanagan SE, Ellard S, McDonnell CM, Murphy NP. The evolving course of HNF4A hyperinsulinaemic hypoglycaemia – a case series. Diabetic Medicine 2014 31 e1–e5. (https://doi.org/10.1111/dme.12259)
- 13↑
Kapoor RR, Locke J, Colclough K, Wales J, Conn JJ, Hattersley AT, Ellard S, Hussain K. Persistent hyperinsulinemic hypoglycemia and maturity-onset diabetes of the young due to heterozygous HNF4A mutations. Diabetes 2008 57 1659–1663. (https://doi.org/10.2337/db07-1657)
- 14↑
Bacon S, Kyithar MP, Condron EM, Vizzard N, Burke M, Byrne MM. Prolonged episodes of hypoglycaemia in HNF4A-MODY mutation carriers with IGT. Evidence of persistent hyperinsulinism into early adulthood. Acta Diabetologica 2016 53 965–972. (https://doi.org/10.1007/s00592-016-0890-9)
- 15↑
Schober E, Rami B, Grabert M, Thon A, Kapellen T, Reinehr T, Holl RW & DPV-Wiss Initiative of the German Working Group for Paediatric Diabetology. Phenotypical aspects of maturity-onset diabetes of the young (MODY diabetes) in comparison with type 2 diabetes mellitus (T2DM) in children and adolescents: experience from a large multicentre database. Diabetic Medicine 2009 26 466–473. (https://doi.org/10.1111/j.1464-5491.2009.02720.x)
- 16↑
Murphy R, Ellard S, Hattersley AT. Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes. Nature Clinical Practice: Endocrinology and Metabolism 2008 4 200–213. (https://doi.org/10.1038/ncpendmet0778)
- 17↑
Byrne MM, Sturis J, Fajans SS, Ortiz FJ, Stoltz A, Stoffel M, Smith MJ, Bell GI, Halter JB, Polonsky KS. Altered insulin secretory responses to glucose in subjects with a mutation in the MODY1 gene on chromosome 20. Diabetes 1995 44 699–704. (https://doi.org/10.2337/diab.44.6.699)
- 18↑
Byrne MM, Sturis J, Menzel S, Yamagata K, Fajans SS, Dronsfield MJ, Bain SC, Hattersley AT, Velho G & Froguel P et al.Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes susceptibility gene MODY3 on chromosome 12. Diabetes 1996 45 1503–1510. (https://doi.org/10.2337/diab.45.11.1503)
- 19↑
Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ, Fajans SS, Signorini S, Stoffel M, Bell GI. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature 1996 384 458–460. (https://doi.org/10.1038/384458a0)
- 20↑
Shields BM, Hicks S, Shepherd MH, Colclough K, Hattersley AT, Ellard S. Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia 2010 53 2504–2508. (https://doi.org/10.1007/s00125-010-1799-4)
- 21↑
Yau D, Colclough K, Natarajan A, Parikh R, Canham N, Didi M, Senniappan S, Banerjee I. Congenital hyperinsulinism due to mutations in HNF1A. European Journal of Medical Genetics 2020 63 103928. (https://doi.org/10.1016/j.ejmg.2020.103928)
- 22↑
Ellard S, Colclough K. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha (HNF1A) and 4 alpha (HNF4A) in maturity-onset diabetes of the young. Human Mutation 2006 27 854–869. (https://doi.org/10.1002/humu.20357)
- 23↑
Laver TW, Colclough K, Shepherd M, Patel K, Houghton JAL, Dusatkova P, Pruhova S, Morris AD, Palmer CN & McCarthy MI et al.The common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes. Diabetes 2016 65 3212–3217. (https://doi.org/10.2337/db16-0628)
- 24↑
Hamilton AJ, Bingham C, McDonald TJ, Cook PR, Caswell RC, Weedon MN, Oram RA, Shields BM, Shepherd M & Inward CD et al.The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype. Journal of Medical Genetics 2014 51 165–169. (https://doi.org/10.1136/jmedgenet-2013-102066)
- 25↑
Improda N, Shah P, Güemes M, Gilbert C, Morgan K, Sebire N, Bockenhauer D, Hussain K. Hepatocyte nuclear factor-4 Alfa mutation associated with hyperinsulinaemic hypoglycaemia and atypical renal Fanconi syndrome: expanding the clinical phenotype. Hormone Research in Paediatrics 2016 86 337–341. (https://doi.org/10.1159/000446396)
- 26↑
Numakura C, Hashimoto Y, Daitsu T, Hayasaka K, Mitsui T, Yorifuji T. Two patients with HNF4A-related congenital hyperinsulinism and renal tubular dysfunction: a clinical variation which includes transient hepatic dysfunction. Diabetes Research and Clinical Practice 2015 108 e53–e55. (https://doi.org/10.1016/j.diabres.2015.03.005)
- 27↑
Marchesin V, Pérez-Martí A, Le Meur G, Pichler R, Grand K, Klootwijk ED, Kesselheim A, Kleta R, Lienkamp S, Simons M. Molecular basis for autosomal-dominant renal Fanconi syndrome caused by HNF4A. Cell Reports 2019 29 4407 .e5–4421.e5. (https://doi.org/10.1016/j.celrep.2019.11.066)
- 28↑
Marable SS, Chung E, Adam M, Potter SS, Park JS. Hnf4a deletion in the mouse kidney phenocopies Fanconi renotubular syndrome. JCI Insight 2018 3. (https://doi.org/10.1172/jci.insight.97497)
- 29↑
Walsh SB, Unwin R, Kleta R, Van’t Hoff W, Bass P, Hussain K, Ellard S, Bockenhauer D. Fainting Fanconi syndrome clarified by proxy: a case report. BMC Nephrology 2017 18 230. (https://doi.org/10.1186/s12882-017-0649-8)
- 30↑
Anyiam O, Wallin E, Kaplan F, Lawrence C. A complicated pregnancy in an adult with HNF4A p.R63W-associated Fanconi syndrome. Case Reports in Medicine 2019 2019 2349470. (https://doi.org/10.1155/2019/2349470)
- 31↑
Clemente M, Vargas A, Ariceta G, Martínez R, Campos A, Yeste D. Hyperinsulinaemic hypoglycaemia, renal Fanconi syndrome and liver disease due to a mutation in the HNF4A gene. Endocrinology, Diabetes and Metabolism Case Reports 2017 2017 160133. (https://doi.org/10.1530/EDM-16-0133)
- 32↑
Chou JH, Roumiantsev S, Singh R. Peditools electronic growth chart calculators: applications in clinical care, research, and quality improvement. Journal of Medical Internet Research 2020 22 e16204. (https://doi.org/10.2196/16204)
- 33↑
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E & Spector E et al.Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine 2015 17 405–424. (https://doi.org/10.1038/gim.2015.30)
- 34↑
Klupa T, Warram JH, Antonellis A, Pezzolesi M, Nam M, Malecki MT, Doria A, Rich SS, Krolewski AS. Determinants of the development of diabetes (maturity-onset diabetes of the young-3) in carriers of HNF-1alpha mutations: evidence for parent-of-origin effect. Diabetes Care 2002 25 2292–2301. (https://doi.org/10.2337/diacare.25.12.2292)
- 35↑
Stride A, Shepherd M, Frayling TM, Bulman MP, Ellard S, Hattersley AT. Intrauterine hyperglycemia is associated with an earlier diagnosis of diabetes in HNF-1alpha gene mutation carriers. Diabetes Care 2002 25 2287–2291. (https://doi.org/10.2337/diacare.25.12.2287)
- 36↑
Bellanné-Chantelot C, Carette C, Riveline JP, Valéro R, Gautier JF, Larger E, Reznik Y, Ducluzeau PH, Sola A & Hartemann-Heurtier A et al.The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3. Diabetes 2008 57 503–508. (https://doi.org/10.2337/db07-0859)
- 37↑
Harries LW, Ellard S, Stride A, Morgan NG, Hattersley AT. Isomers of the TCF1 gene encoding hepatocyte nuclear factor-1 alpha show differential expression in the pancreas and define the relationship between mutation position and clinical phenotype in monogenic diabetes. Human Molecular Genetics 2006 15 2216–2224. (https://doi.org/10.1093/hmg/ddl147)
- 38↑
Stanik J, Dusatkova P, Cinek O, Valentinova L, Huckova M, Skopkova M, Dusatkova L, Stanikova D, Pura M & Klimes I et al.De novo mutations of GCK, HNF1A and HNF4A may be more frequent in MODY than previously assumed. Diabetologia 2014 57 480–484. (https://doi.org/10.1007/s00125-013-3119-2)
- 39↑
Chandran S, Rajadurai VS, Hoi WH, Flanagan SE, Hussain K, Yap F. A novel HNF4A mutation causing three phenotypic forms of glucose dysregulation in a family. Frontiers in Pediatrics 2020 8 320. (https://doi.org/10.3389/fped.2020.00320)
- 40↑
Chandra V, Huang P, Potluri N, Wu D, Kim Y, Rastinejad F. Multidomain integration in the structure of the HNF-4α nuclear receptor complex. Nature 2013 495 394–398. (https://doi.org/10.1038/nature11966)
- 41↑
Pontoglio M, Barra J, Hadchouel M, Doyen A, Kress C, Bach JP, Babinet C, Yaniv M. Hepatocyte nuclear factor 1 inactivation results in hepatic dysfunction, phenylketonuria, and renal Fanconi syndrome. Cell 1996 84 575–585. (https://doi.org/10.1016/s0092-8674(0081033-8)
- 42↑
Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson Å, Kampf C, Sjöstedt E & Asplund A et al.Proteomics. Tissue-based map of the human proteome. Science 2015 347 1260419. (https://doi.org/10.1126/science.1260419)
- 43↑
Timlin MR, Black AB, Delaney HM, Matos RI, Percival CS. Development of pulmonary hypertension during treatment with diazoxide: a case series and literature review. Pediatric Cardiology 2017 38 1247–1250. (https://doi.org/10.1007/s00246-017-1652-3)
- 44↑
Avatapalle HB, Banerjee I, Shah S, Pryce M, Nicholson J, Rigby L, Caine L, Didi M, Skae M & Ehtisham S et al.Abnormal neurodevelopmental outcomes are common in children with transient congenital hyperinsulinism. Frontiers in Endocrinology 2013 4 60. (https://doi.org/10.3389/fendo.2013.00060)
- 45
>45 Carlsson A, Shepherd M, Ellard S, Weedon M, Lernmark Å, Forsander G, Colclough K, Brahimi Q, Valtonen-Andre C, Ivarsson SA et al. Absence of Islet Autoantibodies and Modestly Raised Glucose Values at Diabetes Diagnosis Should Lead to Testing for MODY: Lessons From a 5-Year Pediatric Swedish National Cohort Study. Diabetes Care 2020 43 82–89. (https://doi.org/10.2337/dc19-0747)
- 46
Yorifuji T, Fujimaru R, Hosokawa Y, Tamagawa N, Shiozaki M, Aizu K, Jinno K, Maruo Y, Nagasaka H & Tajima T et al. Comprehensive molecular analysis of Japanese patients with pediatric-onset MODY-type diabetes mellitus. Pediatric Diabetes 2012 13 26–32. (https://doi.org/10.1111/j.1399-5448.2011.00827.x)
- 47
Globa E, Zelinska N, Elblova L, Dusatkova P, Cinek O, Lebl J, Colclough K, Ellard S & Pruhova S. MODY in Ukraine: genes, clinical phenotypes and treatment. Journal of Pediatric Endocrinology and Metabolism 2017 30 1095–103. (https://doi.org/10.1515/jpem-2017-0075)
- 48
Frayling TM, Evans JC, Bulman MP, Pearson E, Allen L, Owen K, Bingham C, Hannemann M, Shepherd M & Ellard S et al. beta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors. Diabetes 2001 50 (Supplement 1) S94-S100. (https://doi.org/10.2337/diabetes.50.2007.s94)
- 49
Furuta H, Iwasaki N, Oda N, Hinokio Y, Horikawa Y, Yamagata K, Yano N, Sugahiro J, Ogata M & Ohgawara H et al. Organization and partial sequence of the hepatocyte nuclear factor-4 alpha/MODY1 gene and identification of a missense mutation, R127W, in a Japanese family with MODY. Diabetes 1997 46 1652–1657. (https://doi.org/10.2337/diacare.46.10.1652)
- 50
Kyithar MP, Bacon S, Pannu KK, Rizvi SR, Colclough K, Ellard S & Byrne MM. Identification of HNF1A-MODY and HNF4A-MODY in Irish families: phenotypic characteristics and therapeutic implications. Diabetes & Metabolism 2011 37 512–519. (https://doi.org/10.1016/j.diabet.2011.04.002)
- 51
Pearson ER, Pruhova S, Tack CJ, Johansen A, Castleden HAJ, Lumb PJ, Wierzbicki AS, Clark PM, Lebl J & Pedersen O et al. Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha mutations in a large European collection. Diabetologia 2005 48 878–885. (https://doi.org/10.1007/s00125-005-1738-y)
- 52
Hansen SK, Párrizas M, Jensen ML, Pruhova S, Ek J, Boj SF, Johansen A, Maestro MA, Rivera F & Eiberg H et al. Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF-4alpha is essential for human pancreatic beta cell function. Journal of Clinical Investigation 2002 110 827–833. (https://doi.org/10.1172/jci15085)
- 53
Arya VB, Guemes M, Nessa A, Alam S, Shah P, Gilbert C, Senniappan S, Flanagan SE, Ellard S & Hussain K. Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations. European Journal of Endocrinology 2014 171 685–695. (https://doi.org/10.1530/eje-14-0353)
- 54
Monney CT, Kaltenrieder V, Cousin P, Bonny C & Schorderet DF. Large Family With Maturity-Onset Diabetes of the Young and a Novel V121I Mutation in HNF4A. Human Mutation 2002 20 230–231. (https://doi.org/10.1002/humu.9050)
- 55
Johansson S, Irgens H, Chudasama KK, Molnes J, Aerts J, Roque FS, Jonassen I, Levy S, Lima K & Knappskog PM et al. Exome sequencing and genetic testing for MODY. PLoS One 2012 7 e38050. (https://doi.org/10.1371/journal.pone.0038050)
- 56
Xu JY, Chan V, Zhang WY, Wat NMS & Lam KSL. Mutations in the hepatocyte nuclear factor-1alpha gene in Chinese MODY families: prevalence and functional analysis. Diabetologia 2002 45 744–746. (https://doi.org/10.1007/s00125-002-0814-9)
- 57
Frayling TM, Bulamn MP, Ellard S, Appleton M, Dronsfield MJ, Mackie AD, Baird JD, Kaisaki PJ, Yamagata K, Bell GI et al. Mutations in the hepatocyte nuclear factor-1alpha gene are a common cause of maturity-onset diabetes of the young in the UK. Diabetes 1997 46 720–725. (https://doi.org/10.2337/diab.46.4.720)
- 58
Iwasaki N, Oda N, Ogata M, Hara M, Hinokio Y, Oda Y, Yamagata K, Kanematsu S, Ohgawara H & Omori Y et al. Mutations in the hepatocyte nuclear factor-1alpha/MODY3 gene in Japanese subjects with early- and late-onset NIDDM. Diabetes 1997 46 1504–1508. (https://doi.org/10.2337/diab.46.9.1504)
