Pediatric Annals

Special Issue Article 

Pediatric Monogenic Diabetes: A Unique Challenge and Opportunity

Anastasia Harris, MPH; Rochelle N. Naylor, MD


Monogenic diabetes affects approximately 120,000 people in the United States but continues to be misdiagnosed. Within the pediatric population, 1% to 3% of diabetes is monogenic, and early diagnosis and genetically targeted management of congenital diabetes and maturity onset diabetes of the young (MODY) can have a tremendous impact on future health outcomes and quality of life. In some of the more common monogenic diabetes types, patients can switch from insulin therapy to sulfonylureas or even discontinue glucose-lowering therapy with stable glycemic control. Advancements in the field have identified tools and resources to aid in distinguishing patients likely to have monogenic diabetes from the more common forms of type 1 and type 2 diabetes. However, genetic testing with accurate interpretation of results is necessary to confirm a diagnosis and direct treatment selection and disease management. This article discusses challenges and opportunities in monogenic diabetes in the pediatric population. [Pediatr Ann. 2019;48(8):e319–e325.]


Monogenic diabetes affects approximately 120,000 people in the United States but continues to be misdiagnosed. Within the pediatric population, 1% to 3% of diabetes is monogenic, and early diagnosis and genetically targeted management of congenital diabetes and maturity onset diabetes of the young (MODY) can have a tremendous impact on future health outcomes and quality of life. In some of the more common monogenic diabetes types, patients can switch from insulin therapy to sulfonylureas or even discontinue glucose-lowering therapy with stable glycemic control. Advancements in the field have identified tools and resources to aid in distinguishing patients likely to have monogenic diabetes from the more common forms of type 1 and type 2 diabetes. However, genetic testing with accurate interpretation of results is necessary to confirm a diagnosis and direct treatment selection and disease management. This article discusses challenges and opportunities in monogenic diabetes in the pediatric population. [Pediatr Ann. 2019;48(8):e319–e325.]

Monogenic diabetes is characterized by single gene mutations or chromosomal abnormalities that cause elevated blood sugars. Monogenic diabetes encompasses two subgroups: congenital infancy-onset diabetes (commonly referred to as neonatal diabetes) and maturity-onset diabetes of the young (MODY). Although up to 3.5% of patients with diabetes diagnosed before age 30 years have a monogenic form, many are misdiagnosed for years because the clinical presentation overlaps with type 1 (T1D) and type 2 diabetes (T2D).1 Accurate diagnosis affects treatment decisions and can improve health outcomes, including neurodevelopment of children.

The field of monogenic diabetes is constantly expanding, with medical teams around the world working to screen, test, and diagnose affected patients and advance broader clinical implementation of genetic testing for diabetes classification. A number of “clinically actionable” genetic causes of diabetes have been identified with defined first-line therapy and clinical surveillance that differs from T1D or T2D. This review will focus on the following genetic causes of monogenic diabetes, with specific attention to pediatric cases: GCK, HNF1A, HNF4A, HNF1B, INS, KCNJ11, ABCC8, and 6q24.

Overview of Congenital Diabetes

Permanent Congenital Diabetes

Permanent congenital diabetes is defined as hyperglycemia that develops within the first year of life, with most cases presenting before age 6 months.2 The incidence of permanent congenital diabetes in youth younger than age 20 years is estimated at 1 in 252,000 live births with variation across populations due to age parameters used in prevalence assessment and frequency of consanguinity.2 The most common gene mutations are KCNJ11, ABCC8, and INS, which account for 60% of all permanent congenital diabetes diagnosed cases.2

KCNJ11 and ABCC8 encode for adenosine triphosphate-sensitive potassium subunit channels Kir6.2 and sulfonylurea receptor 1, which are not only found in the pancreas, affecting insulin secretion, but also in the brain and muscle tissue. KCNJ11 and ABCC8 mutations are primarily de novo, so a family history of diabetes may not be present.3

Mutations in the INS gene are the second most common cause of permanent congenital diabetes and can be a rare cause of MODY. In permanent congenital diabetes, mutations in the INS gene can cause abnormal protein folding, resulting in endoplasmic reticulum stress and beta-cell death.4 Patients are insulin-dependent but early diagnosis may lead to improved treatment outcomes.5

Transient Congenital Diabetes

Transient congenital diabetes is defined as hyperglycemia that presents typically within the first week of postnatal life, then spontaneously goes into remission between 3 and 18 months. The estimated prevalence of transient congenital diabetes is 1 in 200,000 to 1 in 400,000 live births.6

The most common form of transient congenital diabetes, accounting for 70% of cases, is due to abnormalities in the 6q24 region of chromosome 6 affecting the methylation of genes PLAGL1 and HYMAI.7 Although less frequent, mutations in ABCC8, INS, KCNJ11, and HNF1B can also cause transient diabetes.8 Nearly one-half of all transient congenital diabetes cases relapse around puberty or early adulthood, and female patients with 6q24-related diabetes may relapse during pregnancy.6 The mechanisms involved in the remission and relapse of hyperglycemia are still unknown, but increased insulin resistance during puberty or pregnancy likely plays a role.

Overview of Maturity-Onset Diabetes of the Young

MODY is defined as young-onset, autosomal dominantly inherited hyperglycemia. Prevalence ranges from 1% to 2.5% among the pediatric diabetes populations.9,10 Of the (at least) 13 genetic causes of MODY, the most common forms are GCK-MODY, HNF1A-MODY, HNF4A-MODY, and HNF1B- MODY, accounting for about 32%, 52%, 10%, and 6%, respectively, of MODY cases in a cohort in the United Kingdom.11 The GCK gene encodes glucokinase, which acts as the glucose sensor in the beta cell to regulate glucose metabolism and insulin secretion.12 Mutations in HNF1A and HNF4A perturb beta cell development and function, causing a progressive insulin secretory defect and resulting hyperglycemia.13 Mutations in the HNF1B gene affect development of various organs including the pancreas and kidneys, as well as the reproductive system. The most common clinical outcome is developmental renal disease. However, HNF1B mutations can also cause diabetes in isolation, diabetes with renal cysts or diabetes with multiple organ systems affected.14,15

Misdiagnosis of Monogenic Diabetes

Although there are published best practices on which patients should have diabetes genetic testing, misdiagnosis of monogenic diabetes in pediatrics is common.16 The SEARCH for Diabetes in Youth study2 found 66.7% of participants with a congenital form of diabetes were previously misdiagnosed with T1D.2 The SEARCH study also found only 6% of youth with MODY were correctly diagnosed.9 A diagnosis of MODY is more commonly considered in people who are of normal weight. However, the Treatment Options for Type 2 Diabetes in Adolescents and Youth clinical trial17 found a monogenic diabetes prevalence of 4.5% in an overweight/obese pediatric cohort with continued endogenous insulin production and absence of pancreatic autoantibodies. The authors concluded “that monogenic diabetes diagnosis should be considered in children and adolescents… regardless of BMI.”17

The cost of genetic testing for diabetes classification remains high and is not always covered by medical insurance. However, routine screening for monogenic diabetes in pediatric patients has been found to reduce health care costs and improve quality of life in cost-effectiveness analyses examining the scenarios of neonatal diabetes and clinically diagnosed pediatric T1D.18,19

Identifying Whom to Test

A patient's clinical presentation can provide insight into a suspected form of monogenic diabetes. Diabetes onset in infancy is unusual and should immediately prompt consideration of a genetic cause of diabetes. Diabetes onset before age 6 months is almost invariably due to genetic causes. Although the prevalence of T1D increases after age 6 months, many advocate for genetic testing for diabetes classification in all those with onset prior to age 1 year.20

Congenital Diabetes

In the case of infants, the main challenge is distinguishing those with congenital diabetes from those with transient neonatal hyperglycemia due to prematurity, intrauterine growth restriction, lipid infusions, and sepsis.21,22 In particular, increasing prematurity and very low birth-weight infants have high rates of hyperglycemia.21 In these instances, elevated blood glucose levels can present in the first 3 to 10 days of postnatal life, but typically resolve within 2 to 3 days of onset.22 Conversely, in congenital diabetes, hyperglycemia persists beyond 1 week. Thus, all infants presenting with persistent insulin-dependent hyperglycemia should have genetic testing to rule out a monogenic cause.

Type 1 Diabetes

For a patient clinically diagnosed with T1D, genetic testing for monogenic diabetes should be considered in the following situations:

  • Absence of islet cell antibodies. T1D is characterized by the presence of islet cell antibodies, but such antibodies are present in fewer than 1% of those with MODY.23 A study of 469 Norwegian children diagnosed with diabetes before age 15 years and negative for glutamic acid decarboxylase and islet antigen 2 antibodies found that 6.5% (n = 58) had a genetic variant (class 3–5) in a known MODY gene.24

  • Continued significant endogenous insulin production beyond the honeymoon period. This can be detected via measurement of serum C-peptide or urinary C-peptide to creatinine ratio (UCPCR). C-peptide is a biologically inactive peptide that is released in equal amounts to insulin and provides a measure of endogenous insulin production. This is an especially useful biomarker because it can be used in patients currently on insulin therapy.25,26

The effectiveness of using UCPCR and negative islet cell antibodies to identify pediatric patients with monogenic diabetes was demonstrated in a population-based assessment of 808 patients diagnosed with diabetes before age 20 years. The prevalence of monogenic diabetes in this cohort was 2.5%.10

Presence of an affected parent. The presence of an affected parent in T1D is uncommon (2%–6%) and thus should lead to consideration of a diagnosis of monogenic diabetes.

Type 2 Diabetes

Distinguishing pediatric T2D from monogenic diabetes is more difficult. Certainly, in those without obesity or metabolic features, genetic causes of diabetes should be assessed. But as discussed above, presence of overweight status or obesity does not preclude monogenic diabetes.17 Affected parents are similarly common in T2D and MODY, but a strong family history (three or more generations) of young-onset, non–insulin-dependent diabetes can suggest monogenic diabetes. There are clinical features specific to subtypes of MODY that can help to identify children with a high likelihood of monogenic diabetes (Table 1).

Clinical Features of MODY Subtypes that May Aid in Identifying Affected Patients

Table 1:

Clinical Features of MODY Subtypes that May Aid in Identifying Affected Patients

Additional Biomarkers

Additional biomarkers and tools that can be helpful in identifying who to test for monogenic diabetes include the following:

  • Type 1 diabetes genetic risk score. A T1D genetic risk score captures the polygenic susceptibility to T1D through genotyping HLA and non-HLA loci.27 The T1D genetic risk score is able to predict a person's likelihood of having T1D through <5th to >75th percentiles with 94% specificity and 50% sensitivity. A cohort of 242 Europeans with neonatal diabetes were tested and 90% were within the <5th percentile, suggesting that a low T1D risk score can differentiate monogenic diabetes from T1D.

  • High-sensitivity C-reactive protein. Biomarkers for specific monogenic variants have also been identified with the validation of high-sensitivity C-reactive (hsCRP) protein being lower in HNF1A-MODY than other diabetes types. A cohort of 457 participants with an HNF1A-MODY variant had significantly lower rates of hsCRP as compared to GCK-MODY (n = 404), HNF4A-MODY (n = 54), and T2D (n = 582) groups.28 Therefore, among European populations, hsCRP is a clinically valid biomarker to measure when determining an HNF1A-MODY variant. However, among an Asian cohort of 252 participants diagnosed with diabetes before age 45 years, the use of hsCRP did not improve the diagnostic yield.29 Therefore, it is important to consider race/ethnicity and other clinical features when interpreting the result of any screening tool.

  • MODY probability calculator. The University of Exeter created an online MODY probability calculator to analyze various clinical features of patients diagnosed with diabetes before age 35 years.30 The results provide an odds ratio of having MODY and indicate if further testing should be completed to rule out T1D. The calculator was developed using a European population and, therefore, may perform differently in other racial/ethnic groups with potentially varying clinical features.

Clinical Presentation and Treatment

Congenital Diabetes

Mutations in the KCNJ11 and ABCC8 genes cause hyperglycemia in 30% to 58% of patients within the first 6 months of life, but diagnosis up to 12 months has been reported.31 The clinical presentation of ABCC8 congenital diabetes is typically hyperglycemia and low birth weight. KCNJ11 congenital diabetes includes the former characteristics in addition to neonatal diabetes DEND syndrome (developmental delay, epilepsy, and muscle weakness).3 Sulfonylureas have been shown to be the most effective treatment in achieving glycemic control as compared to insulin treatment, with minimal hypoglycemic episodes.32 If patients are currently on an insulin regimen, it is recommended to begin 0.1 mg/kg per day of oral sulfonylurea tablets and increase the dosage by 0.1 to 0.2 mg/kg per day until the patient achieves glycemic stabilization.33 Age at SU initiation may affect dosage, as a study found that initiation later in life required a higher dose, up to 2 mg/kg per day to achieve glycemic control due to age-related loss of beta cell function.34

Clinical presentation of INS mutations can vary from severe congenital onset to mild adult onset of diabetes depending on the location of the mutation in the coding sequence and untranslated region of the insulin gene. Most patients are diagnosed in the first 6 months of life, but cases up to the toddler years have been reported.31 Most mutations are heterozygous dominant, and those with a recessive inheritance present with a lower birth weight and are diagnosed earlier.35 Patients with an INS mutation are likely to require insulin treatment throughout their lives, and early and aggressive insulin interventions can preserve beta cell function, which may improve glycemic control.5

Transient Diabetes

Abnormalities in the 6q24 gene region result in congenital diabetes, small-for-gestational age (SGA) births, dehydration, and the absence of diabetic ketoacidosis. Most infants are diagnosed with insulin-requiring diabetes shortly after birth and can present with the following clinical features: macroglossia, umbilical hernia, intrauterine growth retardation, deafness, renal malformations, and epilepsy.7 At diagnosis most patients require insulin, but dosage may decrease until remission. High-dose sulfonylurea treatments have been effective in maintaining glycemic control at diagnosis but require further studies.36

Maturity Onset Diabetes of the Young

In addition to the aforementioned characteristics, GCK-MODY is unique because people have stable, mild, fasting hyperglycemia (range 99–140 mg/dL; hemoglobin A1c 5.6%–7.6%), so treatment is not necessary outside of pregnancy. Often, patients with GCK-MODY live years without knowing of their elevated blood sugars and are only made aware during a routine or prenatal doctor visit. Studies show that hemoglobin A1c is not altered by pharmacologic treatment.37 Microvascular complications have been shown to be exceedingly rare in a cohort of patients with GCK-MODY compared to their relatives without the gene mutation and patients with T2D.38

Patients with HNF1A- and HNF4A-MODY have a similar clinical presentation, with most patients being diagnosed before age 35 years with negative autoimmune antibodies and a high sensitivity to sulfonylurea medications.13HNF4A mutations present with higher rates of macrosomia and hyperinsulinemic hypoglycemia, but hyperinsulinemic hypoglycemia has also been described in HNF1A-MODY. Although increased high-density lipoprotein is a feature of HNF1A-MODY, rates of cardiovascular disease are higher in affected people compared to unaffected family members.39 Treatment among these patients varies from small doses of sulfonylurea to meglitinides to glucagon-like peptide 1 receptor agonists, with all achieving good glycemic control.40–42

An HNF1B-MODY mutation can affect multiple systems, with renal cysts being the most common feature. Patients also present with renal abnormalities such as a renal malformation, a missing kidney, early-onset diabetes, pancreatic hypoplasia, impaired liver function, genital tract abnormalities, neurodevelopment delays, and early-onset gout.15 Nearly 30% of pediatric patients with renal abnormalities had a mutation in the HNF1B gene, highlighting the importance of genetic testing after identifying the preceding clinical features. Treatment for HNF1B-MODY includes insulin and sulfonylurea therapies, with most patients requiring insulin for adequate glycemic control.14

Genetic Testing

When a monogenic cause of diabetes is suspected, genetic testing must be obtained to confirm a mutation and guide treatment options. Currently, the most effective and efficient testing method is multigene next-generation sequencing panels.19 DNA isolated from saliva, blood, or other cultured cells samples can detect previously described and novel mutations, with more comprehensive whole-exome testing available. Many commercial laboratories have monogenic diabetes testing capabilities but may require prior authorization for insurance coverage. Unfortunately, some insurance companies do not cover 100% of genetic testing costs but many commercial laboratories offer payment plans and other assistance to qualifying patients (often these must be requested before the test is completed). When commercial testing is not an option, research-based genetic testing can be carried out through a university or center, such as the University of Chicago Monogenic Diabetes Registry.43 Confirmation of genetic test results through a clinical laboratory improvement amendments-certified laboratory is advised and is substantially cheaper than initial genetic testing. It is important to consult with someone with expertise in monogenic diabetes for interpretation of any unclear genetic testing results prior to making changes in management.


Identifying those who may have monogenic diabetes can be challenging, but it also presents a unique opportunity to improve management and outcomes of pediatric patients with a suspected genetic form of diabetes. Unlike diagnosing T1D and T2D, monogenic diabetes can be confirmed through comprehensive genetic testing. Results from such testing can provide insight into best treatment options and family planning decisions, as well as improve overall quality of life for patients of all ages. Monogenic diabetes is uncommon, but with the current advancements and opportunity for improved health it is worthwhile to explore all suspected cases.


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Clinical Features of MODY Subtypes that May Aid in Identifying Affected Patients

MODY Subtype Clinical Features
GCK12 Stable, mild hyperglycemia present from birth but typically discovered later on routine blood work or incidentally during evaluation of a medical problem Fasting glucose ranging from 99–144 mg/dL Small incremental increase between fasting and 2-hour glucose on OGTT (<90 mg/dL) Hemoglobin A1c in the range of 5.6%–7.3% in those younger than age 40 years
HNF1A13 Glycosuria at lower serum blood glucose levels Large incremental increase between fasting and 2-hour glucose values on OGTT Low hsCRP levelsa28 High HDL Personal or family history of sensitivity to low doses of sulfonylureas
HNF4A13 Personal or family history of neonatal macrosomia, or transient neonatal hyperinsulinemic hypoglycemia
HNF1B14,15 Pedigree notable for renal cystic disease and diabetes Personal or family history of renal cysts, hypoplasia of the pancreas with or without exocrine pancreatic dysfunction, elevated liver enzymes, genitourinary tract abnormalities

Anastasia Harris, MPH, is a Clinical Research Coordinator. Rochelle N. Naylor, MD, is an Assistant Professor of Medicine. Both authors are affiliated with the Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago.

Disclosure: The authors have no relevant financial relationships to disclose.

Address correspondence to Rochelle N. Naylor, MD, Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, MC 5053, Chicago, IL 60637; email:


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