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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BibTeX
@misc{dsilva2026comprehensive,
title = {{Comprehensive review of the genotype-phenotype spectrum and treatment for biallelic insulin receptoropathy based on 259 affected people}},
author = {Sheldon D'Silva and Bruno Donadille and Jingxiang Xu and Christine Bellanné-Chantelot and Vahid Aslanzadeh and Delphine Collin-Chavagnac and Jamal Al Jubeh and Rakesh Amin and Jacques Beltrand and Jean-Paul Beressi and Frédéric Beziaud and Elise Bismuth and Geremia Bolli and Jean-Claude Carel and Kate Chandler and Elaine Cochran and Marc de Kerdanet and Annalisa Deodati and Valeria Grasso and Siri Greeley and Iva Gueorguieva and Tulay Guran and Sekar Kanthimathi and Louis Lebreton and Mariangela Martino and Viswanathan Mohan and Benjamin Moreau and Sze May Ng and Marc Nicolino and Marek Niedziela and Kevin Perge and Michel Polak and Radha Venkatesan and Rachel Reynaud and Megan Startzell and A Kemal Topaloglu and Amaia Vela Desojo and Carine Villanueva and Rachel Williams and Michael Witsch and Khalid Hussain and Anna Stears and David Savage and Mehul Dattani and Loredana Marcovecchio and Stephen O'Rahilly and Camille Vatier and Isabelle Jéru and Kevin Colclough and Fabrizio Barbetti and Corinne Vigouroux and Rebecca Brown and Robert Semple},
howpublished = {Research Square},
year = {2026},
month = nov,
doi = {10.21203/rs.3.rs-11296131/v1},
url = {https://doi.org/10.21203/rs.3.rs-11296131/v1},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - Comprehensive review of the genotype-phenotype spectrum and treatment for biallelic insulin receptoropathy based on 259 affected people
AU - Sheldon D'Silva
AU - Bruno Donadille
AU - Jingxiang Xu
AU - Christine Bellanné-Chantelot
AU - Vahid Aslanzadeh
AU - Delphine Collin-Chavagnac
AU - Jamal Al Jubeh
AU - Rakesh Amin
AU - Jacques Beltrand
AU - Jean-Paul Beressi
AU - Frédéric Beziaud
AU - Elise Bismuth
AU - Geremia Bolli
AU - Jean-Claude Carel
AU - Kate Chandler
AU - Elaine Cochran
AU - Marc de Kerdanet
AU - Annalisa Deodati
AU - Valeria Grasso
AU - Siri Greeley
AU - Iva Gueorguieva
AU - Tulay Guran
AU - Sekar Kanthimathi
AU - Louis Lebreton
AU - Mariangela Martino
AU - Viswanathan Mohan
AU - Benjamin Moreau
AU - Sze May Ng
AU - Marc Nicolino
AU - Marek Niedziela
AU - Kevin Perge
AU - Michel Polak
AU - Radha Venkatesan
AU - Rachel Reynaud
AU - Megan Startzell
AU - A Kemal Topaloglu
AU - Amaia Vela Desojo
AU - Carine Villanueva
AU - Rachel Williams
AU - Michael Witsch
AU - Khalid Hussain
AU - Anna Stears
AU - David Savage
AU - Mehul Dattani
AU - Loredana Marcovecchio
AU - Stephen O'Rahilly
AU - Camille Vatier
AU - Isabelle Jéru
AU - Kevin Colclough
AU - Fabrizio Barbetti
AU - Corinne Vigouroux
AU - Rebecca Brown
AU - Robert Semple
PY - 2026
DA - 2026/11/01
PB - Research Square
DO - 10.21203/rs.3.rs-11296131/v1
UR - https://doi.org/10.21203/rs.3.rs-11296131/v1
AB - 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.
SN - 2693-5015
ER -