Maturity Onset Diabetes of the Young due to Glucokinase, HNF1-A, HNF1-B, and HNF4-A Mutations in a Cohort of Turkish Children Diagnosed as Type 1 Diabetes Mellitus

Abstract

Background/Aims: Maturity onset diabetes of the young (MODY) is a rare condition often misdiagnosed as type 1 diabetes (T1D). The purposes of this study were: to identify any patients followed in a large Turkish cohort as T1D, with an atypical natural history, who may in fact have MODY, and to define the criteria which would indicate patients with likely MODY as early as possible after presentation to allow prompt genetic testing. Methods: Urinary C-peptide/creatinine ratio (UCPCR) was studied in 152 patients having a diagnosis of T1D for at least 3 years. Those with a UCPCR ≥0.2 nmol/mmol were selected for genetic analysis of the Glucokinase (GCK), Hepatocyte nuclear factor 1a (HNF1A), Hepatocyte nuclear factor 4a (HNF4A), and Hepatocyte nuclear factor 1b (HNF1B) genes. This UCPCR cut-off was used because of the reported high sensitivity and specificity. Cases were also evaluated using a MODY probability calculator. Results: Twenty-three patients from 152 participants (15.1%) had a UCPCR indicating persistent insulin reserve. The mean age ± SD of the patients was 13.6 ± 3.6 years (range 8.30–21.6). Of these 23, two (8.7%) were found to have a mutation, one with HNF4A and one with HNF1B mutation. No mutations were detected in the GCK or HNF1A genes. Conclusion: In Turkish children with a diagnosis of T1D but who have persistent insulin reserve 3 years after diagnosis, up to 9% may have a genetic mutation indicating a diagnosis of MODY.

Clinical and laboratory clues of maturity‐onset diabetes of the young and determination of association with molecular diagnosis

“…1 It is reported that urinary C-peptide measurements will also be used as a marker for MODY screening. 23 T A B L E 5 HNF4A, HNF1A The most common cause of MODY globally and in Turkey is mutations in the GCK gene. 11,24 Otherwise, mutations in the HNF1A gene is the most common cause in some countries.…”

“…4 MODY is often misdiagnosed as type 1 (T1DM) or type 2 diabetes mellitus (T2DM). 5 Unlike the obvious clinical signs in T1DM and T2DM, MODY mostly presents with hidden or mild findings. Molecular analyses that make a definitive diagnosis are expensive and may not always be available and clinical manifestations gradually appear over a long period of time.…”

“…Moreover, clinic presentations are mostly characterized by specific phenotypes that vary depending on mutations in MODY-causing genes. 5 GCK-MODY (MODY2) is characterized by fasting hyperglycemia in the neonatal period and it usually remains asymptomatic in childhood. Diagnosis is mostly made incidentally.…”

“…While MODY3 may present with renal glycosuria, macrosomia at birth may be associated with MODY1. 5 On the other hand, differential diagnosis may not always be easily made, even if a specific expert is available to interpret the analyses. Therefore, to overcome these challenges, the screening criteria are defined in the cases with clinical suspicion of MODY.…”

“…Despite recent advances in diagnostic molecular analysis, most cases are considered to be undiagnosed due to the atypical clinical presentations of diabetes, one reason of which is mild hyperglycemia 4 . MODY is often misdiagnosed as type 1 (T1DM) or type 2 diabetes mellitus (T2DM) 5 . Unlike the obvious clinical signs in T1DM and T2DM, MODY mostly presents with hidden or mild findings.…”