Identifying monogenic diabetes in a pediatric cohort with presumed type 1 diabetes.

Monogenic diabetes (MD) may be misdiagnosed as T1D in children. MD is rare and is reported to range between 1 and 5% of all cases of diabetes (1-5). The overall prevalence of MD is between 0.17 and 0.2 cases per 100 000 (6, 7). Identifying MD in a cohort of pediatric patients with T1D can be challenging and most often is pursued when patients have atypical characteristics of type 1 or type 2 diabetes. Identification of patients with MD can alter therapy and provide the ability to accurately predict the risk of diabetes in other family members. The 2009 ISPAD Clinical Practice Consensus Guidelines on diagnosing and treating MD in pediatrics reported that the following clinical criteria may suggest a diagnosis of MD: (i) neonatal onset, (ii) diabetes in a parent, (iii) evidence of a low exogenous insulin requirement, and (iv) negative pancreatic autoantibodies (8). Absence of high-risk HLA alleles for T1D has also been used as a potential indicator of MD (9-11), but this expensive test is infrequently performed outside of a research setting. Several studies screening for MD among children and adolescents with T1D have been published (9-15). Moller et al. examined 39 Danish type 1 diabetes (T1D) patients with an affected first-degree relative who had no high-risk HLA haplotypes and found that 10% of them had a mutation in the hepatocyte nuclear factor type 1 alpha (HNF1α) gene (MODY3) (9). Interestingly, one of the probands had a positive GAD antibody titer, suggesting that islet autoantibody positivity does not exclude a patient from having MD (9). Kawasaki et al. identified that 7% of patients in an antibody-negative T1D cohort were found to have HNF1α mutations. In contrast to the previous study, in this series all probands with mutations had a high-risk HLA haplotype (10). Lambert et al. sought to determine the prevalence of HNF1α mutations in a cohort of families with multiple (at least three) generations of family members with diabetes (11). They found that a strong family history alone was not predictive of HNF1α gene mutations, but instead suggest that a ‘step-wise approach’ using both family history and negative pancreatic autoantibodies could effectively screen for HNF1α gene mutations. Rubio-Cabezas et al. examined a cohort of 25 patients with antibody-negative T1D, looking for mutations in either KCNJ11 or insulin genes if the diabetes began as a neonate, or HNF1α or HNF4α genes in patients with an older age of onset. Rubio-Cabezas showed that two of the 25 patients had insulin gene mutations causing MD (12). Autoantibody negativity alone was not a good predictor of HNF1α or HNF4α mutations (GCK was not tested in this study.). Urinary C-peptide creatinine ratio has been proposed as a useful and non-invasive biomarker in distinguishing adult patients with HNF1α and HNF4α from patients with long-standing (>5 yr duration) T1D (16). To date, this has not been validated in children and will not be helpful in a patient with newly diagnosed diabetes who may still have pancreatic beta cell reserve. No study has published criteria that have been able to reliably identify candidates at high risk for MD in a population of patients thought to have T1D. Given the expense of genetic testing, there is a need to clinically identify patients with a high likelihood of having the two most common forms of MD before performing genetic sequencing. GCK accounts for 10–60% of MD cases and is most prevalent in French and Italian families, whereas HNF1α accounts for 20–65% of MD cases most often in families from Great Britain (5). The clinical impact of a diagnosis of MD is significant. Depending on the type of MD, molecular classification may allow for discontinuation of insulin and transition to an oral agent, as in the case of patients with mutations in HNF1α who can usually achieve euglycemia with sulfonylurea therapy. Patients found to have mutations in GCK who may be on small doses of insulin, can discontinue insulin and be maintained on diet alone. It may also help to identify family members at risk for diabetes and inform management of diabetes in family members, allow for informed reproductive options during pregnancy, and provide important prognostic information regarding risk of future diabetic complications. We hypothesized that pediatric patients with MD resulting from mutations in GCK or HNF1α can be identified among a cohort of patients thought to have T1D using clinical data that are easily accessible to physicians. The aim of this study was to develop a reliable, cost-effective predictive tool using readily available clinical data to identify these two common forms of MD in a population of children originally diagnosed with T1D.