Inherited Insulin Resistance Syndromes (INSR) Genetic Testing

Inherited Insulin Resistance Syndromes (INSR) Sequencing 2006274
Method: Polymerase Chain Reaction/Sequencing

Confirm diagnosis of inherited insulin resistance syndromes in individuals with clinical and/or biochemical evidence

Not intended for evaluation of individuals with nonsyndromic forms of insulin resistance, such as isolated diabetes mellitus with no other physical features

Extreme insulin resistance is characterized by the inability of insulin receptors to bind to insulin, leading to ketoacidosis. Donohue syndrome (leprechaunism), Rabson-Mendenhall syndrome, and Type A insulin resistance are all caused by INSR gene variants. Severity of symptoms and survival rates vary greatly between syndromes.

Disease Overview

Incidence

Unknown, but estimated to be rare

Clinical Presentation

Syndromes and Associated Symptoms Caused by INSR Variants
Donahue Syndrome (Most Severe) Rabson-Mendenhall Syndrome (Intermediate Phenotype) Type A Insulin Resistance Syndrome (Least Severe)

Intrauterine growth restriction

Failure to thrive

Loss of glucose homeostasis

Hyperinsulinemia

Enlarged heart and kidneys

Dysmorphic features (prominent eyes, thick lips, upturned nostrils, low-set and posteriorly rotated ears)

Thick skin with lack of subcutaneous fat

Distended abdomen

Enlarged genitalia

Polycystic ovaries in females

Death often occurs before 1 yr of age

Growth retardation

Hyperinsulinemia

Acanthosis nigricans

Diabetes mellitus

Dysmorphic features (premature or dysplastic teeth, gingival hyperplasia, pineal hyperplasia)

Survival ranges from early childhood to adolescence

Hirsutism

Reduced subcutaneous fat

Diabetes mellitus

Acanthosis nigricans

Hyperinsulinemia

Amenorrhea and polycystic ovaries in females

Survival often beyond middle age

Pathophysiology

Insulin resistance occurs through the following process:

  • Insulin receptors are unable to bind to insulin
  • Insulin action on target organs decreases
  • Pancreas compensates for decreased insulin action by increasing insulin release
  • Pancreatic beta cells eventually unable to compensate
  • Glucose production by the liver and lipolysis of adipose tissue increases
  • Ketoacidosis results

Diagnosis

Inherited insulin resistance syndrome is often diagnosed based on:

  • Clinical features
  • Glucose and insulin levels
  • Fibroblast studies for insulin binding
  • Genetic testing

Genetics

Gene

INSR

Inheritance

  • Donohue syndrome: autosomal recessive
  • Rabson-Mendenhall syndrome: autosomal recessive
  • Type A insulin resistance syndrome: autosomal recessive or autosomal dominant
    • Recessive forms are more severe
    • Dominant forms may require contribution of other genetic or environmental factors to produce phenotype

Penetrance

Unknown, but expected to be reduced for individuals with a dominant variant

Test Interpretation

Sensitivity/Specificity

Clinical sensitivity: predicted to be >90% in individuals with a clinical diagnosis

Analytical sensitivity/specificity: 99%

Results

Result Variant Detection Interpretation

Positive

One pathogenic INSR gene variant detected

Predicts carrier status for an inherited insulin resistance syndrome

Depending on other genetic and environmental factors, may indicate an increased likelihood for developing type A insulin resistance

Two pathogenic INSR gene variants detected

Predicts a diagnosis of an inherited insulin resistance syndrome

Negative

No pathogenic variants detected

Reduced likelihood of being a carrier of or affected with an inherited insulin resistance syndrome

Inconclusive

INSR gene variants of unknown clinical significance may be detected by this test

n/a

n/a, not applicable

Limitations

  • Diagnostic errors can occur due to rare sequence variations
  • Regulatory region and deep intronic variants and large deletions/duplications are not detected
  • Genes other than INSR will not be evaluated
  • Medical management of patient should rely on clinical and/or biochemical findings

Last Update: October 2019