Maturity-onset diabetes of the young (MODY) is a group of monogenic disorders characterized by autosomal dominantly inherited non-insulin dependent form of diabetes classically presenting in adolescence or young adults before the age of 25 years. MODY is a rare cause of diabetes (1% of all cases) and is frequently misdiagnosed as Type 1 diabetes (T1DM) or Type 2 diabetes (T2DM). A precise molecular diagnosis is essential because it leads to optimal treatment of the patients and allows early diagnosis for their asymptomatic family members. Mutations in the glucokinase (GCK) (MODY 2) and hepatocyte nuclear factor (HNF)1A/4A (MODY 3 and MODY 1) genes are the most common causes of MODY. GCK mutations cause a mild, asymptomatic, and stable fasting hyperglycemia usually requiring no specific treatment. However, mutations in the HNF1A and HNF4A cause a progressive pancreatic β-cell dysfunction and hyperglycemia that can result in microvascular complications. Sulfonylureas are effective in these patients by acting on adenosine triphosphate (ATP)-sensitive potassium channels, although insulin therapy may be required later in life. Mutations in the HNF1B (MODY 5) is associated with pancreatic agenesis, renal abnormalities, genital tract malformations, and liver dysfunction. Compared to MODY 1, 2, 3, and 5, the remaining subtypes of MODY have a much lower prevalence. In this review, we summarize the main clinical and laboratory characteristics of the common and rarer causes of MODY.
Context:Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken.Objective:Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS.Patients, Design, and Setting:We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico.Results:Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases.Conclusions:The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.
A better understanding of the remission phase, while residual beta-cell function is still present in recently diagnosed type 1 (insulin dependent) diabetes mellitus (IDDM), is very important because of the potential for pharmacological intervention to preserve this function. To evaluate the natural course and characteristics of the remission phase in children and adolescents with IDDM, a retrospective study was performed on patients diagnosed with IDDM under the age of 18 years during the years 1991-1998. Sixty-two patients whose medical records were available were included in the study. Data were collected by reviewing the hospital records of patients from the time of diagnosis through the first 24 months after diagnosis. The duration of symptoms and history of infection prior to presentation, diabetic ketoacidosis (DKA) at diagnosis, length of hospitalization, initial glucose level, basal C-peptide levels at diagnosis, daily insulin requirements per kg body weight and HbA1c at diagnosis and at each visit were recorded. Thirty-five patients (56.5%) entered partial remission. We observed similar remission rates in those aged <10 and > or =10 years at diagnosis and in boys and girls. History of infection and presentation with DKA were associated with a lower rate of remission (p<0.001, p<0.0001, respectively) and were more commonly observed under the age of 10 years (p<0.0001, p<0.0001, respectively). The average insulin requirements per kg body weight calculated at diagnosis decreased with increasing age (r = -0.31, p = 0.012). The length of time until remission was 1.36+/-1.03 (mean +/- SD) months and positively correlated with insulin requirements at discharge from the hospital (r = 0.63, p<0.0001). Mean duration of remission was 11.67+/-5.82 months and was much longer in boys than girls (p<0.05). Six patients, all boys, entered total remission for 3.80+/-3.73 months. HbA1c concentrations in the first year of the disease were significantly lower in patients who underwent a remission phase (7.31+/-1.24% vs. 8.24+/-1.47%, p <0.05). However, this difference was not observed during the second year of the disease. In conclusion, history of infection prior to presentation and DKA at diagnosis were associated with young age and were the most important factors negatively influencing the remission rate in newly diagnosed IDDM patients.
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