Unusual Glycemic Presentations in a Child with a Novel Heterozygous Intragenic INSR Deletion

Abstract

<b><i>Background:</i></b> Mutations of the insulin receptor (INSR) gene lead to a wide spectrum of inherited insulin resistance (IR) syndromes. Among these, type A-IR, usually caused by dominant negative <i>INSR</i> mutations, generally presents peri-pubertally in girls. <b><i>Case:</i></b> A 2.8-year-old girl was referred due to recurrent postprandial and fasting hypoglycemia. She had been born at full-term with birth weight 1.89 kg, and had developed transient neonatal diabetes. Examination showed satisfactory growth, reduced adipose tissue, acanthosis nigricans, and isolated thelarche. After 12 h of fasting, she developed hypoglycemia (glucose 2.8 mmol/L), with inappropriately raised plasma insulin concentration of 5.4 mU/L and suppressed fatty acids and ketone bodies. Oral glucose tolerance testing showed severely increased plasma insulin concentration (>300 mU/L) with hypoglycemia (glucose 1.6 mmol/L) at 2.5 h. She was initially managed on dietary modifications, cornstarch, and then trialed on acarbose for postprandial hyperinsulinemic hypoglycemia (PPHH) with some response. However, she was noted to have increased frequency of hyperglycemia after a couple of years of treatment. She was then switched to metformin and continued to have dietary carbohydrate modification including cornstarch that improved fasting tolerance, hyperglycemia, and postprandial hypoglycemia. Genetic testing identified heterozygous deletion of the last exon of the <i>INSR</i> gene, exon 22. <b><i>Conclusion:</i></b> We present a case of type A-IR, caused by a novel <i>INSR</i> deletion, presenting unusually early with transient neonatal diabetes, followed by episodes of hypoglycemia and hyperglycemia during later childhood. Early life presentations, including neonatal diabetes and PPHH, should lead to consideration of type A-IR.

The crucial role and mechanism of insulin resistance in metabolic disease

“…Impaired INSR binding mainly refers to a decrease in the affinity and number of target receptors on the cell membrane or structural abnormalities of the target receptors that affect insulin binding to the receptor (125). There are several, albeit rare, severe diseases of insulin resistance, including leprechaun's disease, Rabson-Mendenhall syndrome, or type A insulin resistance syndrome, where insulin binding is severely reduced due to mutations in the insulin receptor gene (88). The insulin receptor substrate protein is generally considered a node in the insulin signaling system, which is closely related to the development of insulin insensitivity.…”

“…Mutations in certain insulin-related genes produce mutant human insulins, including Chicago insulin (F25BL*), Los Angeles insulin (F25BS) and Wakayama insulin (V3AL), which have been shown to have significantly reduced insulin bioactivity and decreased binding affinity to the insulin receptor, with consequent effects on insulin sensitivity ( 86 , 87 ). There are also rare mutations in insulin receptor genes leading to reduced number of cell surface receptors and defective insulin receptor pathways causing hereditary IR, which are found in patients with genetic syndromes of severe IR, such as type A syndrome of extreme IR, leprechaunism, Rabson-Mendenhall syndrome and Donohue syndrome ( 88 , 89 ). More importantly, since many molecular pathways are involved in energy homeostasis and metabolism, IR is the result of a certain number of mutations in multiple genes, such as those related to type 4 glucose transporter (GLUT4), glucokinase, and Peroxisome proliferator-activated receptor (PPAR) nuclear receptor family, among others ( 90 , 91 ).…”

Insulin-resistance in paediatric age: Its magnitude and implications

“…The occurrence of several heterozygous mutations in the same person (a compound heterozygote) even when recessive; could have additive effects and produce significant consequences[ 18 , 19 ]. Insulin receptor pathway defects may occur due to mutations of the insulin receptor gene, causing a broad spectrum of inherited IRS, including type A syndrome of extreme IR, leprechaunism, Rabson-Mendenhall syndrome, and polymorphism in plasma cell membrane glycoprotein-1[ 20 ]. Insulin-like growth factor 1 (somatomedin C or IGF-1) is a hormone produced mainly by the liver, like insulin in the molecular structure, and plays a crucial role in childhood growth.…”

Comparison of the Clinical Utility of Two Insulin Resistance Indices: IRI-HOMA and IRI-Belfiore in Diagnosing Insulin Resistance and Metabolic Complications in Children Based on the Results Obtained for the Polish Population

“…However, obesity is not the sole determinant of IR. Among other well-known factors, one should mention the excess of growth hormone (GH) (acromegaly/gigantism) or glucocorticosteroids (Cushing disease/syndrome) or the chronic use of glucocorticosteroids, as well as genetically conditioned IR [1,7,8]. The prevalence of IR varies among different populations, depending largely on ethnicity, genetic factors, and environmental factors, as well as the diversity in methods used to assess IR, cut-off points for numerical values of selected indicators for diagnosing IR, and the methodology employed for data acquisition [1].…”