Comprehensive review of the genotype-phenotype spectrum and treatment for biallelic insulin receptoropathy based on 259 affected people

Abstract Background Biallelic deleterious variants in the insulin receptor gene ( INSR ) cause severe insulin resistance (IR), historically partitioned into Donohue syndrome, Rabson–Mendenhall syndrome and type A IR. Case literature is scattered, and clinical management rests on uncontrolled case series. Genotype–phenotype relationships, natural history, prognosis and optimal management are only partially established. Methods We reviewed reports of biallelic INSR variants published over 40 years and supplemented these with cases from international referral centres, abstracting clinical, biochemical and genetic data from 259 affected individuals (226 unrelated probands; 210 distinct INSR variants). Variant burden was compared with the general population using gnomAD, and a Random Survival Forest-based prognostic model was developed, with cross-validation of feature importance. Results Complete loss-of-function (KO) variants affected 33.3% of patients vs 12.6% in gnomAD (p = 2.5×10⁻¹²), with no domain clustering. All biallelic KO patients presented in the first month of life. Disease was multi-system, encompassing profound IR with fasting hypoglycaemia, hyperglycaemia without dyslipidaemia, pre-/postnatal growth failure with soft-tissue overgrowth, cholestatic liver disease, nephrocalcinosis, cardiac hypertrophy, ovarian enlargement, coagulopathy and colonic overgrowth. Seventy-two individuals (28%) died at a median 0.36 years, most commonly from sepsis; all KO patients were deceased or censored by 36 months. The prognostic model discriminated survival beyond 2 years, stratifying the cohort into tertiles with 2-year survivals of 89.8%, 83.3% and 39.5%. Biallelic KO variants and low birthweight standard deviation score were the strongest negative predictors, with male sex also adverse. Evidence guiding therapy is weak: insulin and metformin remain pragmatic mainstays, SGLT2 inhibitors show encouraging benefit, and rhIGF-1, used in a third of cases, yielded mixed outcomes. Conclusions Biallelic insulin receptoropathy forms a clinical continuum. Routinely available presentation features permit data-driven prognostication, facilitating individualised risk assessment. Several stereotyped tissue-specific features remain poorly understood mechanistically. Strengthening of the therapeutic evidence base is urgently required.

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Research Square
Published
2026-11-01
DOI
https://doi.org/10.21203/rs.3.rs-11296131/v1
Primary Topic
Genomics and Rare Diseases
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preprint

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preprint

Comprehensive review of the genotype-phenotype spectrum and treatment for biallelic insulin receptoropathy based on 259 affected people

Elaine K. Cochran, Marc de Kerdanet, Iva Gueorguieva, Jean‐Claude Carel et al.
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Research Square
Genomics and Rare Diseases
preprint

Comprehensive review of the genotype-phenotype spectrum and treatment for biallelic insulin receptoropathy based on 259 affected people

Elaine K. Cochran, Marc de Kerdanet, Iva Gueorguieva, Jean‐Claude Carel, Rakesh Amin, Isabelle Jéru, Kevin Colclough, Delphine Collin‐Chavagnac, Marc P Nicolino, Fabrizio Barbetti, David B. Savage, Jamal Al Jubeh, Annalisa Deodati, Stephen O’Rahilly, Amaia Vela Desojo, Bruno Donadille, Ali Kemal Topaloglu, Kévin Perge, Mariangela Martino, Tülay Güran, Rachel Reynaud, Sekar Kanthimathi, Carine Villanueva, Sze May Ng, V. Grasso, Christine Bellanné‐Chantelot, Louis Lebreton, Corinne Vigouroux, Loredana Marcovecchio, B. Moreau, Anna J. Stears, Megan S Startzell, Michael Witsch, Geremia B. Bolli, Mehul Dattani, Camille Vatier, Frédéric Beziaud, Marek Niedziela, Vahid Aslanzadeh, Sheldon D’Silva, Élise Bismuth, Jean-Paul Beressi, Jacques Beltrand, Rebecca Brown, Radha Venkatesan, Khalid Hussain, Kate Chandler, Michel Polak, Jingxiang Xu, Viswanathan Mohan, Rachel Williams, Robert Semple, Siri Greeley
preprint en

Abstract

Abstract Background Biallelic deleterious variants in the insulin receptor gene ( INSR ) cause severe insulin resistance (IR), historically partitioned into Donohue syndrome, Rabson–Mendenhall syndrome and type A IR. Case literature is scattered, and clinical management rests on uncontrolled case series. Genotype–phenotype relationships, natural history, prognosis and optimal management are only partially established. Methods We reviewed reports of biallelic INSR variants published over 40 years and supplemented these with cases from international referral centres, abstracting clinical, biochemical and genetic data from 259 affected individuals (226 unrelated probands; 210 distinct INSR variants). Variant burden was compared with the general population using gnomAD, and a Random Survival Forest-based prognostic model was developed, with cross-validation of feature importance. Results Complete loss-of-function (KO) variants affected 33.3% of patients vs 12.6% in gnomAD (p = 2.5×10⁻¹²), with no domain clustering. All biallelic KO patients presented in the first month of life. Disease was multi-system, encompassing profound IR with fasting hypoglycaemia, hyperglycaemia without dyslipidaemia, pre-/postnatal growth failure with soft-tissue overgrowth, cholestatic liver disease, nephrocalcinosis, cardiac hypertrophy, ovarian enlargement, coagulopathy and colonic overgrowth. Seventy-two individuals (28%) died at a median 0.36 years, most commonly from sepsis; all KO patients were deceased or censored by 36 months. The prognostic model discriminated survival beyond 2 years, stratifying the cohort into tertiles with 2-year survivals of 89.8%, 83.3% and 39.5%. Biallelic KO variants and low birthweight standard deviation score were the strongest negative predictors, with male sex also adverse. Evidence guiding therapy is weak: insulin and metformin remain pragmatic mainstays, SGLT2 inhibitors show encouraging benefit, and rhIGF-1, used in a third of cases, yielded mixed outcomes. Conclusions Biallelic insulin receptoropathy forms a clinical continuum. Routinely available presentation features permit data-driven prognostication, facilitating individualised risk assessment. Several stereotyped tissue-specific features remain poorly understood mechanistically. Strengthening of the therapeutic evidence base is urgently required.

Research Square
University of Rome Tor Vergata (IT), Poznan University of Medical Sciences (PL), Hôpital Necker-Enfants Malades (FR), Nottingham University Hospitals NHS Trust (GB), Centre Hospitalier de Luxembourg (LU), Edge Hill University (GB), University of Cambridge (GB), University of Perugia (IT), Great Ormond Street Hospital (GB), Shaikh Khalifa Medical City (AE), Cambridge University Hospitals NHS Foundation Trust (GB), Centre Hospitalier Universitaire de Lille (FR), Sorbonne Université (FR), University of Chicago (US), Massachusetts General Hospital (US), National Institute of Diabetes and Digestive and Kidney Diseases (US), Madras Diabetes Research Foundation (IN), Manchester University NHS Foundation Trust (GB), Hospices Civils de Lyon (FR), Hôpital Saint-Antoine (FR), Hôpital Pellegrin (FR), Pitié-Salpêtrière Hospital (FR), Bambino Gesù Children's Hospital (IT), Hôpital Robert-Debré (FR), Sidra Medical and Research Center (QA), Centre de Recherche Saint-Antoine (FR), Hospital de Cruces (ES), Centre Hospitalier Universitaire de Rennes (FR), Centre Hospitalier de Versailles (FR), Hôpital de la Timone (FR), Royal Devon University Healthcare NHS Foundation Trust (GB), Marmara University (TR), University of Edinburgh (GB)
U.S. Department of Health and Human Services, Diabetes UK, Indian Council of Medical Research, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases
Good health and well-being
Genomics and Rare Diseases
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