Monogenic diabetes due to an <i>INSR</i> mutation in a child with severe insulin resistance

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Abstract

Summary

We report a case of an 11-year-old girl presenting with a new diagnosis of diabetes associated with a heterozygous missense mutation in the insulin receptor (INSR) gene. This case highlights that INSR gene variants can be a cause for monogenic diabetes in children and adolescents and the need for genetic evaluation in atypical presentations of diabetes. We also describe the possible role of metformin in treating individuals with type A insulin resistance syndrome due to INSR gene variants.

Learning points

Insulin receptor (INSR) gene variants can be a cause of monogenic diabetes in children and adolescents.
Genetic evaluation should be considered in children and adolescents with type 2 diabetes (T2D), particularly where there is an atypical presentation and/or positive family history.
Metformin may have a role in the treatment of type A insulin resistance syndrome due to heterozygous mutation of the INSR gene.

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Most cited references 22

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Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

Sue Richards, Nazneen Aziz, Sherri Bale … (2015)

The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants. 1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence (e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.

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Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth.

Catherine Pihoker, Lisa K Gilliam, Sian Ellard … (2013)

Our study aims were to determine the frequency of MODY mutations (HNF1A, HNF4A, glucokinase) in a diverse population of youth with diabetes and to assess how well clinical features identify youth with maturity-onset diabetes of the young (MODY).

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Sex differences in the burden of type 2 diabetes and cardiovascular risk across the life course

Amy Huebschmann, Rachel Huxley, Wendy Kohrt … (2019)

By 2017 estimates, diabetes mellitus affects 425 million people globally; approximately 90–95% of these have type 2 diabetes. This narrative review highlights two domains of sex differences related to the burden of type 2 diabetes across the life span: sex differences in the prevalence and incidence of type 2 diabetes, and sex differences in the cardiovascular burden conferred by type 2 diabetes. In the presence of type 2 diabetes, the difference in the absolute rates of cardiovascular disease (CVD) between men and women lessens, albeit remaining higher in men. Large-scale observational studies suggest that type 2 diabetes confers 25–50% greater excess risk of incident CVD in women compared with men. Physiological and behavioural mechanisms that may underpin both the observed sex differences in the prevalence of type 2 diabetes and the associated cardiovascular burden are discussed in this review. Gender differences in social behavioural norms and disparities in provider-level treatment patterns are also highlighted, but not described in detail. We conclude by discussing research gaps in this area that are worthy of further investigation.

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Author and article information

Journal

Journal ID (nlm-ta): Endocrinol Diabetes Metab Case Rep

Journal ID (iso-abbrev): Endocrinol Diabetes Metab Case Rep

Journal ID (hwp): EDM

Title: Endocrinology, Diabetes & Metabolism Case Reports

Publisher: Bioscientifica Ltd (Bristol )

ISSN (Electronic): 2052-0573

Publication date (Electronic): 01 December 2021

Publication date Collection: 2022

Volume: 2022

Electronic Location Identifier: 21-0114

Affiliations

[1 ]Department of Endocrinology and Diabetes , Perth Children’s Hospital, Perth, Western Australia, Australia

[2 ]Department of Clinical Biochemistry , PathWest Laboratory Medicine WA, Royal Perth Hospital and Fiona Stanley Hospital Network, Perth, Australia

[3 ]School of Medicine , University of Western Australia, Perth, Australia

Author notes

Correspondence should be addressed to E E Sanderson; Email: Elaine.E.Sanderson@ 123456gmail.com

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Elaine E Sanderson http://orcid.org/0000-0002-2823-0006

Article

Publisher ID: EDM210114

DOI: 10.1530/EDM-21-0114

PMC ID: 8789010

PubMed ID: 35000900

SO-VID: 8b9a88e4-dfef-4314-985a-8ed74cc75901

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License..

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Monogenic diabetes due to an INSR mutation in a child with severe insulin resistance

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Bioscientifica Open Endocrinology

Most cited references 22

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth.

Sex differences in the burden of type 2 diabetes and cardiovascular risk across the life course

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