Insulin Receptor Gene; INSR

Introduction
Loss-of-function mutations in the INSR Gene are well established as causes of severe insulin resistance. The spectrum of clinical phenotypes is continuous, but for historical reasons patients they are often classified as one of 3 discrete syndromes: Donohue syndrome (formerly leprechaunism) is caused by near complete loss or receptor function, and presents as severe intrauterine growth retardation, neonatal hypoglycaemia with post prandial hyperglycaemia, and characteristic dysmorphism including hypertrichosis and soft tissue overgrowth leading to coarse facial features. Death in the first year or two of life is the norm. Rabson Mendenhall Syndrome, due to around 70-80% loss or receptor function (to a first approximation) is compatible with survival into the second decade, and similarly features linear growth retardation, hypertrichosis, coarse facial features, premature eruption of dentition, organomegaly and lack of adipose tissue. Once beta cell decompensation occurs diabetes is ectremely resistant to insulin therapy and the prognosis is poor. Less severe degrees of insulin receptor loss of function give rise to Type A Insulin Resistance. This most commonly presents in post pubertal females as primary or secondary oligo/amenorrhoea with severe acanthosis nigricans and hyperandrogenism. It may or may not feature diabetes at diagnosis, though highly insulin resistant diabetes with attendant complications almost invariably supervenes. In men it usually present later as insulin resistant diabetes. Donohue and Rabson Mendenhall syndromes usually have autosomal recessive inheritance, while type A insulin resistance is commonly autosomal dominant.

Clinical Indications
1. Diagnosis of Donohue & Rabson Mendenhall syndromes
2. Prenatal diagnosis of Donohue syndrome if genotype of index case is available

Method Information
PCR -Dideoxy sequencing of DNA extracted from peripheral leukocytes

Patient Preparation
As for all genetic tests patients need to be counselled as results may impact on family members. The requesting clinician is responsible for provision of appropriate counselling.

Sample Requirements
5mls of EDTA anticoagulated blood are required.

Sample Handling
Please send the sample via first class post from UK locations

Interpretation
The laboratory will provide interpretation

Quality Assessment
UK EMQN.

Centres offering this assay
Cambridge Addenbrooke’s Hospital Endocrine Laboratory

References
OMIM #246200 *147670
Krook A, O’Rahilly S. Mutant insulin receptors in syndromes of insulin resistance. Baillieres Clin Endocrinol Metab. 1996 Jan;10(1):97-122

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