Over the past two decades, improved knowledge and awareness of monogenic diabetes, along with the development of increasingly more accurate and worldwide available molecular diagnostic techniques, have led to an increased estimate of the prevalence of MODY. The identification of genetic diagnosis is extremely important when choosing the most proper treatment plan. It is well established that patients affected by GCK-MODY do not require any pharmacological treatment [15], while patients with HNF1A or HNF4A-MODY have a good response to sulfonylureas in term of glycaemic control and prevention of micro- and macrovascular complications [24].
Our 12-year-long experience identified a prevalence of MODY of 6.5% among a population of children and adolescents newly diagnosed with diabetes. This finding is consistent with a previous Italian multicentre study, which found a prevalence of 5.5% [25]. Conversely, other studies on paediatric diabetic populations revealed lower rates of prevalence ranging from 0.65% to 2.5% [13, 26-30]. The gap between these prevalence rates may be explained by different selection criteria adopted for patients undergoing genetic tests for MODY. Several studies on paediatric diabetic populations have systematically used diabetes-specific autoantibody negativity in combination with other biochemical parameters (i.e. basal C-peptide value and urinary C-peptide creatinine ratio) as screening methods to identify eligible patients for genetic tests for MODY [13, 30]. In an observational U.S. multicentre study, only patients with absence of diabetes-specific autoimmunity and C-peptide levels within the normal range were genetically investigated, resulting in a prevalence of MODY of 1.2% among children and adolescents with diabetes [13]. Similarly, Shepherd et al. [30] screened 808 UK children with diabetes. Only patients who had negative T1D autoantibodies and normal urinary C-peptide creatinine ratio underwent genetic tests, resulting in 20 patients diagnosed with MODY out of 82 selected children. Conversely, Johnson et al. found a prevalence of 2.1% in 821 Australian paediatric patients with diabetes screened for MODY regardless of their clinical features [28].
In our centre, genetic investigations for MODY were performed in presence of a clinical suspicion of non-T1D, without any strict criteria. We can speculate that serum C-peptide value alone is too stringent as it is well-known to be correlated with patients’ age and BMI [31]. Basal serum C-peptide was low in many of our patients affected by MODY, especially in the GCK-MODY subgroup. Furthermore, we found that diabetes-specific autoantibodies were positive in 2 patients diagnosed with MODY. GADA were present in both patients. GADA, especially alone, have a low predictive value for T1D when compared to other autoantibodies [32]. Existing evidence has shown a comparable incidence of positivity to autoantibodies between patients with MODY and the general population, of approximately 1% [33]. Finally, we can affirm that if we had excluded patients from gene sequencing on the basis of these strict criteria, we would have missed 13 diagnoses.
Interestingly, we found a relatively high number of patients belonging to the MODY group who presented HLA haplotype predisposing to T1D. Data from other studies show that the presence of HLA alleles DR3 and DR4 is not rare among MODY patients, ranging from 20% to 35.1% [29, 34]. The presence of HLA alleles DR3 or DR4 has been previously investigated as a discriminating factor between T1D and MODY [35]. However, our findings suggest that HLA alone cannot be considered as a relevant parameter to suspect MODY.
Regarding the frequency among MODY forms, most of our MODY patients have GCK gene mutations, confirming previous evidence among Caucasian populations [25, 26, 28, 29]. Discordance with other studies showing a higher prevalence of HNF1A-MODY [12, 13, 27] could be related to differences between national healthcare systems. The Italian health service provides universal coverage to residents and public healthcare is largely free of charge. GCK-MODY is characterized by mild clinical signs that could be overlooked resulting in failure to diagnose unless the patient accesses tertiary diabetes outpatient services. This could explain its higher prevalence in countries providing easier access to tertiary care, in comparison to countries with other forms of public health, such as insurance-based ones.
In our study, mean HbA1c at diagnosis in GCK-MODY patients was lower than in HNF1A-MODY, confirming the results of another study [36], in which the assessment of HbA1c in combination with fasting glucose was proposed in the differential diagnosis between these two subtypes in subjects with suspect monogenic diabetes. In particular, those authors suggested considering HNF1A-MODY as the first hypothesis in patients presenting with HbA1c > 7.3% (56 mmol/mol) and fasting glucose < 8.33 mmol/l. However, in our study GCK and HNF1A patients showed comparable levels of fasting glucose, and none of them had a level of fasting glucose > 8.33 mmol/l, except for the HNF1A patient who presented DKA at diabetes onset.
It may be thought that dysglycaemia in obese children indicates a case of type 2 diabetes (T2D). However, auxological parameters from the MODY group show a significant number of patients presenting with a condition of overweight or obesity. A study on a cohort of obese and overweight patients with a clinical diagnosis of T2D reported that 4.5% of them were actually affected by monogenic diabetes [37]. Our data confirm that BMI may not only be indicative of T2D but also MODY should be suspected if other anamnestic and clinical conditions coexist.
To date, there are few data [38, 39] on OGTT response in children and adolescents affected by MODY. As expected, we found that patients affected by HNF1A-MODY had a markedly higher response to OGTT in terms of two hours postload blood glucose compared to GCK-MODY patients. Indeed, defects of the GCK gene cause a higher glycaemic set point of insulin secretion resulting in mild fasting hyperglycaemia, in contrast to other subtypes which are characterized by impaired insulin secretion and high glycaemic response after meals and during OGTT [4].
The coexistence of GCK MODY and cystic fibrosis is very rare. To the best of our knowledge, only two other cases of children suffering from both cystic fibrosis and GCK-MODY have been reported in literature [40, 41]. It is well known that patients with cystic fibrosis have a gradual deterioration in their glucose tolerance status that begins in the first years of the disease leading to the onset of cystic fibrosis related diabetes (CFRD) [42]. This type of diabetes is characterized by clinical signs at the onset that are very similar to those of MODY. Our experience highlights the need to consider monogenic diabetes also in children and adolescents with cystic fibrosis. Recognition of non-CFRD forms of diabetes in these patients is crucial in planning the most suitable treatment and follow-up.