ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2006) 12 P46

A novel syndrome of extreme insulin resistance, primordial dwarfism, and gonadal failure

RK Semple1, F Finucane2, M O’Driscoll3, FM Regan4, MA Soos1, PR Stutchfield5, JH Davies6, DB Dunger4, PA Jeggo3, JJ Nolan2 & S O’Rahilly1


1University of Cambridge Dept.of Clinical Biochemistry, Cambridge, United Kingdom; 2Metabolic Research Unit, St James’s Hospital, Dublin, Ireland; 3Genome Damage and Stability Centre, University of Sussex, East Sussex, United Kingdom; 4University of Cambridge Dept.of Paediatrics, Cambridge, United Kingdom; 5Glan Clwyd Hospital, Rhyl, Denbighshire, United Kingdom; 6Southampton University Hospitals NHS Trust, Southampton, United Kingdom.


Single gene defects causing severe insulin resistance have been elucidated either by directed screening of candidate genes (INSR, AKT2, PPARG) or by detailed linkage mapping in large pedigrees (BSCL2, AGPAT2, LMNA), and study of patients harbouring these known defects continues to yield important insights into insulin’s action in health and disease. However a large proportion of the genetic defects leading to severe insulin resistance in slim subjects remains undiscovered. We now report in detail 3 patients with primordial dwarfism, extreme insulin resistance, characteristic bird-like facial dysmorphism, and primary gonadal failure. In addition, both patients investigated to date have evidence of significant chromosomal instability, and 2 of 3 have skeletal dysplasia. All 3 patients have normal insulin receptor sequence despite insulin resistance commensurate with that seen in insulin receptoropathies, and had neither biochemical evidence of growth hormone deficiency nor significant clinical response to exogenous growth hormone in childhood. The close similarities between these patients leads us to hypothesize that this syndrome is caused by defects in a gene or genes within a pathway which is integral both to the metabolic actions of insulin and to the sensing and/or repair of DNA damage. Such a link between responses to DNA damage and insulin action offers the intriguing possibility that elucidating the responsible genetic defect may for the first time provide an aperture in humans to the mechanisms governing the close relationship between longevity and insulin action which is consistently seen in model organisms from nematodes to mice, but which has been clouded to date in humans by the life-shortening metabolic consequences of impaired insulin action. Cellular studies are currently underway to localise this functional defect further and to refine selection of candidate genes.

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