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Cited by 264Genomics and Rare DiseasesSkin Diseases and DiabetesDiabetes, Cardiovascular Risks, and Lipoproteins

Clinical Course of Genetic Diseases of the Insulin Receptor (Type A and Rabson-Mendenhall Syndromes): A 30-Year Prospective

Musso, Carla, Cochran, Elaine, Moran, Stephanie Ann, Skarulis, Monica C., Oral, Elif Arioglu, Taylor, Simeon, Gorden, Phillip·2004·Medicine
DOI 10.1097/01.md.0000133625.73570.54
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Abstract

The interaction of insulin with its cell surface receptor is the first step in insulin action and the first identified target of insulin resistance. The insulin resistance in several syndromic forms of extreme insulin resistance has been shown to be caused by mutations in the receptor gene. We studied 8 female patients with the type A form of extreme insulin resistance and 3 patients (2 male and 1 female) with the Rabson-Mendenhall syndrome and followed the natural history of these patients for up to 30 years. The 11 patients ranged in age from 7 to 32 years at presentation. All 11 patients had extreme insulin resistance, acanthosis nigricans, and hyperandrogenism in the female patients, and all but 1 were of normal body weight. This phenotype strongly predicts mutations in the insulin receptor: of the 8 patients studied, 7 were found to have mutations. Similar results from the literature are found in other patients with type A and Rabson-Mendenhall syndromes and leprechaunism. The hyperandrogenic state resulting from hyperinsulinemia and insulin resistance in these patients was extreme: 6 of 8 patients had ovarian surgery to correct the polycystic ovarian syndrome and elevation of serum testosterone. By contrast, a larger group of insulin-resistant patients who were obese with hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN syndrome) did not have a high probability of mutations in the insulin receptor. The morbidity and mortality of these patients were high: 3 of 11 died, 9 of 11 were diabetic and 1 had impaired glucose tolerance, and 7 of 9 patients had 1 or more severe complication of diabetes. Our literature review revealed that the mortality of leprechaunism is so high that the term leprechaunism should be restricted to infants or young children under 2 years of age. Analogous to patients with the common forms of type 2 diabetes, these patients had a heterogeneous course. In 2 patients who were able to maintain extremely high endogenous insulin production, the fasting blood glucose remained normal even though post-glucose-challenge levels were elevated. Most patients, however, required large doses of exogenous insulin to ameliorate the severe hyperglycemia. Preliminary results of a recent study suggest that recombinant leptin administration may benefit these patients with severe insulin resistance.

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  • Patients with extreme insulin resistance as a result of receptor mutations or autoantibodies do not have NASH-associated findings such as hypertriglyceridemia, hepatomegaly, or abnormal liver function tests.

    “In our experience, patients with extreme insulin resistance as a result of receptor mutations 17,18 or autoantibodies 19 do not have NASH-associated findings such as hypertriglyceridemia, hepatomegaly, or abnormal liver function tests.”

    From Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy† (2005) · cites this paper as [18]

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Authors
Musso, C., Cochran, E., Moran, S. A., Skarulis, M. C., Oral, E. A., Taylor, S., & Gorden, P.
Affiliations
National Institutes of Health (US)
ORCID
Venue
Medicine
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2004-07
Volume
83
Issue
4
Pages
209-222
ISSN
0025-7974 (ISSN-L)
DOI
10.1097/01.md.0000133625.73570.54
OpenAlex
W2083986466
Cited by
264
References
100
Citations by year
2026: 8 · 2025: 9 · 2024: 12 · 2023: 13 · 2022: 15 · 2021: 18 · 2020: 8 · 2019: 8 · 2018: 18 · 2017: 9 · 2016: 13 · 2015: 10 · 2014: 19 · 2013: 11 · 2012: 11
FWCI
5.36
Type
journal article
Language
en
Open access
closed
Locations
  • Medicine (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Health Sciences › Medicine › Dermatology › Skin Diseases and Diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
insulin receptor mutations, Rabson-Mendenhall syndrome, leprechaunism, hyperandrogenism, acanthosis nigricans, polycystic ovary syndrome, hyperinsulinemia, diabetes complications, natural history (disease), leptin therapy, insulin receptor gene
MeSH terms
Acanthosis Nigricans, Adolescent, Adult, Child, Female, Follow-Up Studies, Hirsutism, Humans, Insulin Resistance, Male, Mutation, Polycystic Ovary Syndrome, Receptor, Insulin, Syndrome, Time Factors, Hyperandrogenism

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