Forms of Monogenic Diabetes With Their Associated Mutations, Clinical Findings, and Management (12,13)
| Monogenic Forms of Diabetes | Genetic Locus of Mutation | Important Diagnostic Findings | Treatment Modality |
| MODY (maturity-onset diabetes of the young) | |||
| MODY 1 | HNF4A | Increased birth weight/macrosomia | Sensitive to sulfonylurea Treatment; may progress to require insulin |
| MODY 2 | GCK | Mild fasting hyperglycemia | Usually not required except in pregnancy (may require insulin) |
| MODY 3 | HNF1A | Low renal glucose threshold (glycosuria), raised HDL cholesterol, increased cardiovascular risk | Sensitive to sulfonylurea Treatment; may progress to require insulin |
| MODY 4 | IPF1 | Early- to late-onset diabetes (heterozygous form), pancreatic agenesis (homozygous) | |
| MODY 5 | HNF1B | Renal cystic disease, genitourinary anomaly, pancreatic atrophy | |
| MODY 6 | NEUROD1 | None | |
| NDM (neonatal diabetes mellitus) | |||
| Transient NDM (TNDM) | UDP6 (most common) | Macroglossia and umbilical hernia | Insulin |
| KATP channel (ABCC8 and KCNJ11) | Developmental delay and epilepsy | Sulfonylureas (high dose) | |
| Permanent NDM (PNDM) | KATP channel (ABCC8 and KCNJ11) | Developmental delay and epilepsy | Sulfonylureas (high dose) |
| INS | None | Insulin | |
| Wolcott-Rallison syndrome | EIF-2Ak3 | Spondylo-epiphyseal dysplasia, renal and acute hepatic failure, developmental delay | Insulin |
| Lipoatrophic diabetes | |||
| Koberling-Dunnigan syndrome | LMNA | Face-sparing partial lipoatrophy | Insulin/leptin |
| Berardinelli-Seip syndrome | AGPAT2 or seipin gene product | Congenital generalized lipoatrophy | Insulin/leptin |
| Diabetes with extra pancreatic features | |||
| RCAD syndrome | HNF1B | Renal cysts, exocrine pancreatic deficiency, genitourinary abnormalities | Insulin |
| Wolfram syndrome | WFS1 | Optic atrophy, diabetes insipidus, deafness, renal tract and neurological abnormalities | Insulin |
| MIDD | Mitochondrial m.3243A>G mutation | Neurosensory deafness, maternal diabetes or deafness, short stature, pigmentary retinopathy | Oral sulfonylurea initially, but rapid insulin requirement |
| TRMA syndrome | SLC19A2 | Megaloblastic anemia, deafness, cardiac and neurological abnormalities | Thiamine and/or sulfonylurea and/or early insulin |
| Insulin resistance syndrome | |||
| Type A insulin resistance | Insulin receptor | Hyperandrogenism, acanthosis nigricans, insulin resistance (HAIR-AN) | Metformin, thiazolidinediones, insulin |
| Leprechaunism (Donohue syndrome) | Insulin receptor | IUGR, fasting hypoglycemia, lipoatrophy, and death in infancy | Insulin (high doses) |
| Rabson-Mendenhall syndrome | Insulin receptor | Short stature, protuberant abdomen, and abnormalities of teeth and nails; coarse senile facies; paradoxical fasting hypoglycemia | Insulin (high doses) |
| Monogenic Forms of Diabetes | Genetic Locus of Mutation | Important Diagnostic Findings | Treatment Modality |
| MODY (maturity-onset diabetes of the young) | |||
| MODY 1 | HNF4A | Increased birth weight/macrosomia | Sensitive to sulfonylurea Treatment; may progress to require insulin |
| MODY 2 | GCK | Mild fasting hyperglycemia | Usually not required except in pregnancy (may require insulin) |
| MODY 3 | HNF1A | Low renal glucose threshold (glycosuria), raised HDL cholesterol, increased cardiovascular risk | Sensitive to sulfonylurea Treatment; may progress to require insulin |
| MODY 4 | IPF1 | Early- to late-onset diabetes (heterozygous form), pancreatic agenesis (homozygous) | |
| MODY 5 | HNF1B | Renal cystic disease, genitourinary anomaly, pancreatic atrophy | |
| MODY 6 | NEUROD1 | None | |
| NDM (neonatal diabetes mellitus) | |||
| Transient NDM (TNDM) | UDP6 (most common) | Macroglossia and umbilical hernia | Insulin |
| KATP channel (ABCC8 and KCNJ11) | Developmental delay and epilepsy | Sulfonylureas (high dose) | |
| Permanent NDM (PNDM) | KATP channel (ABCC8 and KCNJ11) | Developmental delay and epilepsy | Sulfonylureas (high dose) |
| INS | None | Insulin | |
| Wolcott-Rallison syndrome | EIF-2Ak3 | Spondylo-epiphyseal dysplasia, renal and acute hepatic failure, developmental delay | Insulin |
| Lipoatrophic diabetes | |||
| Koberling-Dunnigan syndrome | LMNA | Face-sparing partial lipoatrophy | Insulin/leptin |
| Berardinelli-Seip syndrome | AGPAT2 or seipin gene product | Congenital generalized lipoatrophy | Insulin/leptin |
| Diabetes with extra pancreatic features | |||
| RCAD syndrome | HNF1B | Renal cysts, exocrine pancreatic deficiency, genitourinary abnormalities | Insulin |
| Wolfram syndrome | WFS1 | Optic atrophy, diabetes insipidus, deafness, renal tract and neurological abnormalities | Insulin |
| MIDD | Mitochondrial m.3243A>G mutation | Neurosensory deafness, maternal diabetes or deafness, short stature, pigmentary retinopathy | Oral sulfonylurea initially, but rapid insulin requirement |
| TRMA syndrome | SLC19A2 | Megaloblastic anemia, deafness, cardiac and neurological abnormalities | Thiamine and/or sulfonylurea and/or early insulin |
| Insulin resistance syndrome | |||
| Type A insulin resistance | Insulin receptor | Hyperandrogenism, acanthosis nigricans, insulin resistance (HAIR-AN) | Metformin, thiazolidinediones, insulin |
| Leprechaunism (Donohue syndrome) | Insulin receptor | IUGR, fasting hypoglycemia, lipoatrophy, and death in infancy | Insulin (high doses) |
| Rabson-Mendenhall syndrome | Insulin receptor | Short stature, protuberant abdomen, and abnormalities of teeth and nails; coarse senile facies; paradoxical fasting hypoglycemia | Insulin (high doses) |
ABCC8, ATB-binding cassette subfamily C; AGPAT2, 1-acyl-sn-glycerol-3-phosphate acyltransferase-2; GCK, glucokinase; EIF-2Ak3, eukaryotic translation initiation factor 2-alpha kinase 3; HAIR-AN, hyperandrogenism, insulin resistance, and acanthosis nigricans; HNF, hepatocyte nuclear factor; INS, insulin gene; IPF, insulin promoter factor; IUGR, intrauterine growth retardation; KATP channel, adenosine triphosphate-sensitive potassium channel (ABCC8 and KCNJ11); KCNJ11, potassium inwardly rectifying channel, subfamily J, member 11 gene; LMNA, lamin A/C; MIDD, maternally inherited diabetes and deafness; mitochondrial m.3243A>G mutation, heteroplasmic G to A substitution of the mitochondrial DNA at nucleotide pair 3243 in one of the two tRNA(Leu) genes; NeuroD1, neurogenic differentiation 1; RCAD, renal cysts and diabetes; SLC19A2, solute carrier family 19, member 2 gene; UDP6, uniparental disomy 6 chromosome (6q24) abnormality; TRMA, thiamine responsive megaloblastic anemia; WFS1, Wolfram syndrome 1 (wolframin).