Razi Journal of Medical Sciences

fa گزارش موردی: دو مورد از دیابت مونوژنیک GCK-MODY در خواهر و برادر خردسال ایرانی با ازدواج فامیلی در بیمارستان کودکان حضرت علی اصغر(ع) تهران Case Report: Two Cases of Monogenic GCK-MODY Diabetes in Young Iranian Siblings with Consanguineous Marriage at Hazrat Ali Asghar Children's Hospital in Tehran غدد اطفال pediatric Endocrinology موردنگاري case report <div style="text-align: justify;">زمینه و هدف: دیابت مونوژنیک ناشی از جهش ژن گلوکوکیناز Maturity Onset Diabetes of the Young  (GCK-MODY) نوعی دیابت  ارثی تک ژنی است که توسط جهش‌های هتروزیگوت در ژن آنزیم گلوکوکیناز (GCK) ایجاد می‌شود. این بیماری معمولاً با هیپرگلیسمی خفیف ناشتا و قندهای نرمال دو ساعت بعد از غذا و همچنین عدم وجود علائم کلاسیک دیابت مانند پرنوشی، پرادراری و کاهش وزن مشخص می شود و وراثت اتوزومال غالب دارد. هدف مطالعه حاضر شناسایی ویژگی‌های بالینی و ژنتیکی دو کودک مبتلا به دیابت مونوژنیک نوع GCK-MODY در یک خانواده ایرانی دارای ازدواج فامیلی بود، با تأکید بر اهمیت تشخیص افتراقی این نوع دیابت از دیابت نوع ۱ و ۲، و بررسی نقش غربالگری ژنتیکی در جلوگیری از درمان‌های غیرضروری است. معرفی مورد: دختری ۳ ساله که برای ارزیابی رشد به درمانگاه غدد مراجعه کرده بود، در بررسی‌های اولیه آزمایشگاهی  قند خون ناشتای  103 mg/dL و هموگلوبین %2/6  A1c: داشت. بیمار هیچگونه علایم بالینی کلاسیک دیابت از جمله پرادراری، پرنوشی یا کاهش وزن نداشت. برادرش نیز  تنها یافته‌های آزمایشگاهی مشابهی را نشان داد. سابقه خانوادگی به دلیل نسبت فامیلی و ابتلای چندین عضو به دیابت قابل توجه بود. یافته‌ها: غربالگری ژنتیکی کودکان و والدین، جهش هتروزیگوت GCK (missense – p.Gly223Ser) را نشان داد که تشخیص خانوادگی GCK-MODY را تأیید می‌کند. نتیجه‌گیری: تشخیص ژنتیکی زودهنگام GCK-MODY امکان مدیریت با نظارت بر رژیم غذایی و اجتناب از دارودرمانی غیرضروری را فراهم می‌کند. در بیماران خردسال با هیپرگلیسمی خفیف پایدار و سابقه خانوادگی دیابت، انجام آزمایش ژنتیکی برای شناسایی موارد احتمالی MODY-GCK ضروری است، زیرا این بیماران معموالً نیازی به درمان دارویی ندارند. </div> <div style="text-align: justify;">Background & Aims: Maturity-Onset Diabetes of the Young (MODY) is a group of monogenic forms of diabetes characterized by autosomal dominant inheritance, which present mostly with early onset of hyperglycemia, and primary defects in pancreatic beta-cell function. Among the different subtypes of this disorder, the inactive heterozygous mutation in the glucokinase Genene (GCK-MODY), also known as MODY type 2, is one of the most prevalent forms. This gene encodes a key enzyme involved in glucose sensing and regulation of insulin secretion in pancreatic beta cells. Unlike type 1 and type 2 diabetes mellitus, GCK-MODY is typically associated with mild, stable fasting hyperglycemia and rarely progresses to severe metabolic complications. Due to its asymptomatic presentation and subtle biochemical abnormalities, it is often misdiagnosed as either type 1 or type 2 diabetes, potentially leading to unnecessary pharmacological interventions. Methods: The present study describes the clinical, biochemical, and genetic characteristics of two pediatric cases of GCK-MODY identified within a consanguineous Iranian family. The primary objective was to emphasize the importance of early genetic screening in children presenting with persistent mild hyperglycemia, particularly in the presence of a positive family history of diabetes, to prevent misdiagnosis and avoid inappropriate treatment. Case: The first case involved a 3-year-and-2-month-old girl referred to a pediatric endocrinology clinic for growth evaluation. Initial laboratory investigations revealed a fasting blood glucose level of 103 mg/dL and a glycated hemoglobin (HbA1c) level of 6.3%. Notably, the patient exhibited no classic clinical manifestations of diabetes such as polyuria, polydipsia, or weight loss. Her medical history was largely unremarkable except for occasional constipation and reduced appetite. She had been born at term via normal vaginal delivery with a birth weight of 3 kilograms. She had a previously diagnosed mild ventricular septal defect (VSD) that resolved spontaneously during follow-up. The patient’s family history was significant for diabetes mellitus affecting multiple members, including her father, aunt, and paternal grandfather. Additionally, the parents were first-degree relatives (cousins), increasing the likelihood of inherited genetic disorders. Despite treatment with metformin at a dose of 1000 mg per day, the father continued to exhibit hyperglycemia and had an elevated body mass index (BMI). Repeated measurements of the patient’s fasting blood glucose over subsequent months showed persistent mild elevation of fasting plasma glucose (115 mg/dL and 122 mg/dL), while HbA1c remained within the borderline diagnostic range for diabetes. As part of a comprehensive family assessment, fasting and postprandial blood glucose levels were measured for all members using a glucometer. During this process, the patient’s 18-month-old brother was found to have unexpectedly elevated fasting glucose levels, despite lacking any overt symptoms of diabetes. Given his young age and abnormal biochemical findings, he was hospitalized for further evaluation to rule out type 1 diabetes mellitus. Arterial blood gas analysis excluded diabetic ketoacidosis, and autoantibody testing associated with type 1 diabetes returned negative results. Considering the possibility of monogenic diabetes, the patient was started on repaglinide, a meglitinide class oral hypoglycemic agent. Follow-up assessments demonstrated normalization of blood glucose levels and a reduction in HbA1c to below 5%. In addition, both siblings exhibited improvement in growth parameters over time. These findings prompted further investigation through genetic testing to establish a definitive diagnosis. ReWhole Exome Sequencing (WES) was subsequently performed for four family members, including both affected children and their parents. The analysis identified a heterozygous missense mutation in the glucokinase gene (NM_000162.5:c.667G>A; p.Gly223Ser) in the father and both children, whereas the mother did not carry this variant. This specific mutation has previously been classified as pathogenic in established genetic databases and is known to be associated with GCK-MODY. The presence of the same mutation in multiple family members confirmed an autosomal dominant inheritance pattern. From a physiological standpoint, glucokinase functions as a glucose sensor within pancreatic beta cells, playing a critical role in regulating insulin secretion in response to circulating glucose levels. Loss-of-function mutations in the GCK gene reduce the enzyme’s catalytic activity and impair glucose sensing. As a result, insulin secretion is triggered only at higher-than-normal glucose concentrations, typically around 7–8 mmol/L. This shift in the glucose threshold leads to persistent mild fasting hyperglycemia, which is the hallmark of GCK-MODY. Clinically, individuals with GCK-MODY generally exhibit fasting glucose levels ranging from approximately 5.5 to 8.0 mmol/L (99–144 mg/dL) and HbA1c values between 5.6% and 7.3% before the age of 40. Importantly, this form of diabetes is usually non-progressive and is not associated with significant risks of microvascular or macrovascular complications. Therefore, pharmacological treatment is often unnecessary, and management typically focuses on dietary monitoring and lifestyle modifications. Exceptions may arise in specific situations such as pregnancy, obesity, or the coexistence of other metabolic conditions. The cases described in this report highlight the diagnostic challenges associated with GCK-MODY, particularly in young children who present with mild hyperglycemia in the absence of classical diabetic symptoms. Without genetic testing, such patients may be mistakenly diagnosed with type 1 or type 2 diabetes and subjected to lifelong medication or insulin therapy. In the present family, temporary treatment with repaglinide was initiated due to occasional glucose readings exceeding 200 mg/dL. This intervention resulted in rapid glycemic improvement within 24 hours and a sustained reduction in HbA1c over a six-month follow-up period. Nevertheless, consistent with existing literature, long-term pharmacotherapy is generally not required for most patients with GCK-MODY. It is also noteworthy that individuals with GCK-MODY may still develop type 2 diabetes in the presence of obesity or metabolic syndrome, or type 1 diabetes in the context of autoimmune processes. Consequently, ongoing monitoring of body weight, dietary habits, and autoimmune markers is recommended in patients with clinical suspicion of disease progression. Conclusion: In conclusion, GCK-MODY should be considered in pediatric patients presenting with persistent mild fasting hyperglycemia and a positive family history of diabetes, especially in consanguineous families. Early genetic diagnosis not only facilitates accurate classification of the disease but also prevents unnecessary pharmacological treatment and guides appropriate clinical management. Routine measurement of fasting and postprandial glucose levels in at-risk family members may serve as a simple and effective preliminary screening strategy. While pharmacological therapy is seldom required, short-term use of oral hypoglycemic agents may be beneficial in selected cases with higher glucose levels or additional metabolic risk factors.</div> دیابت مونوژنیک, جهش ژن, گلوکوکیناز, MODY type 2 Monogenic Diabetes melitus, MODY- GCK, Mody Type 2, Genetic mutation 1 7 http://rjms.iums.ac.ir/browse.php?a_code=A-10-8642-1&slc_lang=fa&sid=1 Mona Nourbakhsh مونا نوربخش nourbakhsh.mo@iums.ac.ir 3900319475328460091097 3900319475328460091097 Yes Department of Paediatrics, School of Medicine, Iran University of Medical Sciences, Aliasghar Clinical Research Development Center, Tehran, Iran گروه کودکان، دانشکده پزشکی، دانشگاه علوم پزشکی ایران، بیمارستان کودکان حضرت علی اصغر(ع)، مرکز توسعه تحقیقات بالینی، تهران، ایران Farhad Abolhasan Choobdar فرهاد ابوالحسن چوبدار 3900319475328460091098 0009-0009-2287-8205 No Iran University of Medical Sciences, Ali Asghar Children's Hospital, Tehran, Iran دانشگاه علوم پزشکی ایران، بیمارستان کودکان حضرت علی اصغر(ع) ، تهران، ایران Roya Isa Tafreshi رویا عیسی تفرشی 3900319475328460091099 3900319475328460091099 No Iran University of Medical Sciences, Ali Asghar Children's Hospital, Tehran, Iran دانشگاه علوم پزشکی ایران، بیمارستان کودکان حضرت علی اصغر(ع) ، تهران، ایران