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Mild Fasting Hyperglycemia in a Child: Importance of New Genetic Tools
By Bassem Dekelbab, MD
The last 2 decades have witnessed a much better understanding of monogenic diabetes (commonly referred to as mature onset diabetes of the youth or MODY). Such diabetes results from dominantly or recessively inherited, or a de novo genetic mutation with subsequent dysregulation of insulin secretion by the pancreatic beta-cells.1
It is estimated that monogenic diabetes accounts for 1% to 2% of diabetes cases, and it is often misdiagnosed as type 1 or type 2 diabetes. A timely diagnosis of monogenic diabetes will predict clinical course, explain associated features, and guide therapy of the index case as well as other diabetic family members.2
At least seven single-gene mutations have been described to be associated with monogenic diabetes with more candidate genes being investigated for other types of monogenic diabetes. MODY2 accounts for about 20% of cases of monogenic diabetes. It is caused by heterozygous loss of function in glucokinase, the enzyme that catalyzes the first step of glucose metabolism in the pancreatic beta-cells. This leads to regulation of glucose at a higher set point with nondeteriorating mild fasting hyperglycemia.3 Treatment is not usually required, as microvascular or macrovascular complications have been rarely described. Administration of insulin results in reduction of endogenous insulin secretion with no change of gylcemic status (see case discussion).
As genetic testing for monogenic diabetes is currently commercially available (Table 1), clinicians now are able to accurately confirm such diagnosis. The following case illustrates the importance of considering this diagnosis in children with asymptomatic mild fasting hyperglycemia with family history of diabetes and lack of evidence of autoimmunity against the pancreatic beta-cells.
CASE DISCUSSION:
A 10-year-old Caucasian girl was seen at her pediatrician office for a routine physical exam. A urinalysis revealed isolated glycosuria, and a random serum glucose was 153 mg/dL. She had no symptoms suggestive of diabetes. Her pediatrician obtained an oral glucose tolerance test with the following blood glucose: 102, 174, 216, 233, and 195 mg/dL at 0, 30, 60, 90, and 120 minutes, respectively. A1C at the local hospital laboratory was 6.3%. Her past medical history was unremarkable except for allergic rhinitis, which was treated with montelukast sodium (Singulair, Merck & Co., Inc.), mometasone furoate monohydrate (Nasonex, Schering Corporation), and loratidine (Claritin, Schering-Plough Corporation). Her paternal uncle and grandmother have a history of mild type 2 diabetes, and her father has hypothyroidism.
The patient was referred to a pediatric endocrinologist for further evaluation. She had a normal exam with a weight of 42.6 kg, height of 151.9 cm, and body mass index of 18.4 kg/m2. Human insulin, islet cell antigen 512 and antiglutamic acid decarboxylase 65 antibodies were negative. She was started on 5 units of glargine insulin (Lantus, Sanofi Aventis) daily. She did not require insulin coverage for her meals giving her mild hyperglycemia (Table 2). After 6 months, her glycemic control remained unchanged with an office A1C of 5.8%.
Her presentation, clinical course, and family history raised the possibility of monogenic diabetes. Genetic evaluation through Athena Diagnostics (Worcester, MA) revealed heterozygous p.His317Gln mutation of the glucokinase gene consistent with the diagnosis of monogenic diabetes MODY2.
The patient's insulin was stopped without change of her blood glucose (Table 2). Healthy diet and scheduled physical activity were recommended. Her father was asked to check his blood glucose and was found to have mild fasting hyperglycemia consistent with an autosomal dominant pattern of MODY2 (Table 2). She continued to be asymptomatic 1 year after stopping insulin with unchanged A1C of 5.8 %.
CONCLUSION
The recent advances and availability of genetic testing for monogenic diabetes represent an important tool for clinicians who take care of diabetic patients as monogenic diabetes accounts for 1% to 2% of the diabetic population. Making the right diagnosis will have valuable prognostic and therapeutic implications. The discussed case illustrates how such diagnosis saved this child and her family years of psychological, physical, and economic burden of otherwise unnecessary treatment.
Bassem Dekelbab, MD, is in the Division of Pediatric Endocrinology at St. John Hospital and Beaumont Children's Hospital, Detroit. Dr. Dekelbab disclosed that he is a paid consultant to Athena Diagnostics. He may be reached at Dekelbab@pol.net.
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