Severe Insulin Resistance Syndromes (INSR – Donohue and Rabson-Mendenhall)

Class of monogenic severe insulin resistance syndromes: INSR insulin receptoropathies (Donohue syndrome, Rabson-Mendenhall syndrome, type A insulin resistance and familial hyperinsulinaemic hypoglycaemia due to heterozygous INSR variants) and post-receptor defects (PIK3R1/SHORT syndrome, AKT2, TBC1D4), with the differential diagnosis of autoimmune (type B), lipodystrophic and syndromic forms.

Literature and regulatory information updated: 26 October 2026.

0. Initial Reference Table

The following table brings together the entities of the insulin receptor spectrum. The severe insulin resistance (severe IR) syndromes linked to the INSR gene form a continuum of severity, from Donohue syndrome (DS), with no residual receptor function, to Rabson-Mendenhall syndrome (RMS) and type A insulin resistance, in which residual function is greater [1–3].

The post-receptor forms and the entities included in the differential diagnosis of the class are identified as follows. The OMIM–Orphanet mappings in GeneGuidance for INSR and AKT2 contain swapped codes; the table follows the mappings confirmed in Orphanet [8, 19, 20].

Only the following enter the differential diagnosis of this class: congenital and partial genetic lipodystrophies (including the AKT2 form), monogenic diabetes of the MODY type, congenital hyperinsulinism, hypoglycaemia of genetic cause (including AKT2 p.Glu17Lys), Silver-Russell syndrome, anterior segment dysgeneses (Axenfeld-Rieger syndrome and Peters anomaly), Bardet-Biedl syndrome, Bloom syndrome, Hutchinson-Gilford progeria syndrome and the PIK3CA-related overgrowth spectrum (PROS).

1. Introduction

1.1. Founding descriptions

Donohue syndrome was described in 1954 by William L. Donohue and Irene Uchida in the Journal of Pediatrics, in an article entitled «Leprechaunism: a euphuism for a rare familial disorder», which gave the condition the name leprechaunism [38, 39]. The term is now considered inappropriate and has been replaced by the eponym; GeneReviews keeps it only as a synonym [1, 4]. Two years later, Rabson and Mendenhall described three familial cases of pineal gland hypertrophy, adrenal cortical hyperplasia and diabetes mellitus, autopsy findings that gave rise to the title OMIM still uses for entry 262190 («Pineal hyperplasia, insulin-resistant diabetes mellitus, and somatic abnormalities») [5, 40]. Both eponyms predate the identification of the insulin receptor and were only later recognised as parts of a spectrum of recessive defects of the same receptor [3].

In 1976, Kahn and colleagues at the National Institutes of Health (NIH) studied six patients with acanthosis nigricans, glucose intolerance of variable degree, hyperinsulinaemia and marked resistance to exogenous insulin [41]. Insulin binding to the receptors of circulating monocytes was greatly reduced and was not corrected by fasting, which showed that the receptor defect was not secondary to hyperinsulinaemia [41]. The authors separated two syndromes: type A, in young women with virilisation or accelerated growth and a primary receptor defect, and type B, in older women with signs of immunological disease and circulating antibodies against the receptor [41]. This division still holds: type A is genetic and type B is autoimmune [6, 30, 39].

SHORT syndrome was described in 1975, independently, by Gorlin and colleagues and by Sensenbrenner and colleagues [42]. The acronym summarises the initial features: Short stature, joint Hyperextensibility or inguinal hernia, Ocular depression (deep-set eyes), Rieger anomaly and Teething delay [42]. Before the gene was discovered, some patients were published under descriptive designations, such as «Low-birthweight Rieger syndrome» or «Autosomal partial lipodystrophy associated with Rieger anomaly, short stature, and insulinopenic diabetes» [21]. The inheritance, first considered recessive, proved to be dominant [21, 43].

1.2. Milestones of molecular discovery

The complementary DNA (cDNA) of the human insulin receptor was cloned in 1985 by two groups, Ullrich and colleagues in Nature, who showed the relationship of the receptor with the tyrosine kinase oncogene family, and Ebina and colleagues in Cell [44, 45]. In May 1988, the same issue of Science published the first pathogenic INSR variants in humans [46, 47]. Kadowaki and colleagues found, in a patient with leprechaunism, compound heterozygosity for a missense variant in the α subunit (Lys460Glu, historical numbering, = NM_000208.4:c.1459A>G p.(Lys487Glu), ClinVar VCV 14680) and a nonsense variant with termination after amino acid 671, which eliminates the transmembrane and tyrosine kinase domains; the father, heterozygous for the nonsense variant, had moderate IR [46]. Yoshimasa and colleagues described, in a patient with type A IR, a substitution at the tetrabasic processing site of the proreceptor (Arg-Lys-Arg-Arg to Arg-Lys-Arg-Ser) that prevented cleavage of the proreceptor into α and β subunits, even though it was glycosylated and inserted into the membrane [47].

In 1991, Taylor and colleagues grouped INSR variants into five functional classes: reduced receptor synthesis, impaired transport to the membrane, reduced affinity for insulin, reduced tyrosine kinase activity and accelerated degradation [1, 48]. In 2004, Højlund and colleagues identified, in a three-generation Danish family, the missense variant Arg1174Gln (historical numbering, = NM_000208.4:c.3602G>A p.(Arg1201Gln), ClinVar VCV 14708) in the tyrosine kinase domain of INSR as the cause of AD hyperinsulinaemic hypoglycaemia, with a LOD score (logarithm of the odds of linkage) of 3.21 [11]. In the same year, George and colleagues described the first monogenic cause of severe IR downstream of the receptor, a missense variant of AKT2 in a family with severe IR and dominantly transmitted diabetes, identified in a screen of 104 unrelated patients [24]. In 2011, Hussain and colleagues showed the opposite effect, an activating AKT2 variant (p.Glu17Lys) in three children with severe fasting hypoglycaemia and asymmetrical growth [25]. In 2013, two groups simultaneously published PIK3R1 as the SHORT syndrome gene in the American Journal of Human Genetics: Dyment and colleagues, by trio exome sequencing, and Chudasama and colleagues, in two Norwegian families with partial lipodystrophy [49, 50].

1.3. Current nomenclature and classifications

GeneReviews groups DS and RMS under the designation «INSR-related severe insulin resistance syndrome» (INSR-SIRS), a continuum running from DS, the more severe, to RMS, the milder, and treats type A IR as an allelic disorder [1]. GeneGuidance summarises the principle that organises the spectrum: the severity of residual receptor function, and not the name of the syndrome, determines the patient's position between DS and type A [2]. The NIH group proposed restricting the term leprechaunism, because of mortality, to infants and children under two years of age [51].

The most widely used classification for the severe IR syndromes as a whole is that of Semple and colleagues, from 2011, taken up again by Parker and Semple in 2013, which separates primary defects of insulin signalling, primary lipodystrophies and complex pleiotropic syndromes [3, 52]. Most patients with severe IR have primary defects of adipose tissue rather than of signalling [3]. The 2022 monogenic diabetes chapter of the International Society for Paediatric and Adolescent Diabetes (ISPAD) adopts the same three subtypes, with a table of genes and of leptin and adiponectin that is reproduced in section 5 [15]. The Saudubray classification, metabolically based, divides disorders of insulin-sensitive cells into insulin resistance syndromes (IRS, with a receptor defect) and insulin signalling disorders (ISD, with a downstream defect), which are distinguished during hypoglycaemia by raised insulinaemia in the former and suppressed insulinaemia in the latter [53]. Orphanet groups the entities under ORPHA:181368 and associates them with Endo-ERN [8, 33].

In the original proposal, Semple and colleagues start from the nomenclature of the 1970s: Kahn and colleagues had designated severe IR without obesity as «type A» or «type B», separated by the presence of anti-receptor antibodies, and the term HAIR-AN (hyperandrogenism, IR and acanthosis nigricans), which arose at the same time, is a generic description of severe IR in women, useful only to separate women with a body mass index (BMI) above 30 kg/m², in whom the probability of a monogenic defect is much lower [52]. The proposed classification, mechanistically based, has two main branches. The first brings together primary defects of insulin signalling, divided into «generalised» IR, due to a defect at the receptor level (INSR variants or anti-receptor antibodies), also called insulin receptoropathy, with extreme hyperinsulinaemia, a normal lipid profile and preserved or raised adiponectin, SHBG and IGF-binding protein 1 (IGFBP1), and «partial» IR, with a defect limited to some branches of the pathway downstream of the receptor or to some tissues (AKT2, TBC1D4/AS160), whose biochemical profile depends on the defect [52]. The second brings together IR secondary to adipose tissue abnormalities («adipose failure»): severe early-onset obesity with hyperphagia (MC4R, with tall stature; POMC, with red hair and hypoadrenalism; LEP, with hypogonadotrophic hypogonadism; LEPR; SH2B1, with disproportionate IR) and generalised or partial lipodystrophies, with severe dyslipidaemia, fatty liver and low leptin and adiponectin; a table footnote adds a less well-defined group, with clinical and biochemical signs of adipose failure and severe dyslipidaemia despite globally normal body fat mass [52]. The complex syndromes form a provisional third group, which the authors expected to redistribute between the two branches as the mechanism of IR in each was studied [52].

1.4. Definition of the entities within scope

Donohue syndrome is the neonatal form, with biallelic INSR variants and nil or minimal residual function, IUGR, severe failure to thrive, extreme hyperinsulinaemia with fasting hypoglycaemia and postprandial hyperglycaemia, and rare survival beyond the first or second year [1, 3, 39]. Rabson-Mendenhall syndrome is the biallelic form with residual function, survival to the second or third decade and progression from hypoglycaemia to refractory diabetes, DKA and microvascular complications [1, 16]. Type A insulin resistance is, in most cases, the heterozygous dominant-negative form, revealed around puberty by hyperandrogenism, acanthosis and hyperinsulinaemia without obesity, with rare biallelic cases [1, 6]. Familial hyperinsulinaemic hypoglycaemia 5 (HHF5) designates the dominant presentation of heterozygous INSR variants with postprandial hypoglycaemia [7, 11]. The post-receptor defects within scope are SHORT syndrome (PIK3R1), severe IR with partial lipodystrophy due to loss of function of AKT2, and postprandial muscle IR due to TBC1D4; the activating AKT2 variant is the biochemical mirror image of these forms [15, 26, 27]. Autoimmune type B IR syndrome and the remaining entities in the section 0 table are differentials of the class [30].

2. Molecular Genetics and Pathophysiology

2.1. The insulin receptor and the signalling pathway

INSR (19p13.2; HGNC:6091; RefSeq NM_000208) encodes a receptor of the transmembrane tyrosine kinase superfamily [1, 2]. The 1,382-amino-acid preproprotein is cleaved into α and β subunits that form a glycoprotein heterotetramer: the α subunit (731 amino acids) is extracellular and contains the insulin-binding region; the β subunit (620 amino acids) is linked to α by disulphide bridges and has 194 extracellular, 23 transmembrane and 403 cytoplasmic amino acids with intrinsic tyrosine kinase activity [1]. Insulin binding causes autophosphorylation of the β subunit, which phosphorylates the insulin receptor substrates (IRS1 to IRS4), SHC, GAB1 and CBL; from these arise the phosphatidylinositol 3-kinase (PI3K) and AKT pathway, responsible for translocation of the glucose transporter GLUT4 (SLC2A4) and for the metabolic actions, and the Ras-MAPK pathway, which mediates growth and differentiation effects [2, 53]. Brain cells are poorly sensitive to insulin [53].

The MANE Select for INSR is NM_000208.4 (NP_000199.2), which corresponds to isoform B; Human Genome Variation Society (HGVS) numbering counts from the initiating methionine and includes the 27-amino-acid signal peptide, which the historical nomenclature of the mature receptor omits [9]. The difference is 27 residues: the historical variant Pro1178Leu corresponds to NM_000208.4:c.3614C>T p.(Pro1205Leu), ClinVar record VCV 1480867, which keeps «Pro1178Leu» as a synonym [9, 54]. Variants published before the adoption of HGVS must be converted with a validation tool before comparison with databases.

2.2. Mechanisms: biallelic loss of function, dominant-negative effect and haploinsufficiency

The mechanism of the biallelic forms is loss of function [1]. Variants in the α subunit reduce the number of mature receptors or the affinity for insulin, and those in the tyrosine kinase domain of the β subunit impair autophosphorylation [39]. In DS the loss of insulin action is almost complete at the cellular level; in RMS residual signalling persists [3, 15]. Reduced intracellular signalling explains the hyperglycaemia; fasting hypoglycaemia is attributed to a late action of IGF-1, and the resistance also alters the expression of genes for growth factors and apoptosis [1]. The extreme compensatory hyperinsulinaemia acts on the IGF-1 receptor (IGF1R) and on mitogenic and androgenic pathways, and explains the acanthosis nigricans, acrochordons, pseudoacromegaly and ovarian hyperandrogenism [2, 3, 39]. IGF1R and INSR share 60% homology and similar intracellular activity, which underpins the use of rhIGF-1 [1].

In type A IR, most variants are heterozygous, lie in the tyrosine kinase domain region and have a dominant-negative effect on the receptor encoded by the normal allele [3, 6, 10]. Altered degradation of receptor-insulin complexes reduces insulin clearance and increases the insulin/C-peptide ratio, fasting and during the OGTT [6]. Parents of patients with DS or RMS often have type A IR, which led Orphanet to suggest semidominant inheritance for some of these families [5, 8]. The first heterozygous parent described, carrying a nonsense allele, had moderate IR [46].

Haploinsufficiency has been proposed as an additional mechanism in a cohort of 505 people with rare monoallelic INSR variants (240 probands and 265 relatives, gathered from the literature, international reference centres, ClinVar and the Human Gene Mutation Database (HGMD) and the Fenland population cohort), published as a non-peer-reviewed preprint in September 2026 and read in abstract [55]. Missense variants were 14-fold enriched in the intracellular domain relative to the Genome Aggregation Database (gnomAD), particularly in the activation and catalytic loops, whereas loss-of-function (LoF) variants were distributed in proportion to domain length [55]. Most carriers of extracellular variants, including LoF and deleterious missense variants identified by genotype, had moderate to severe IR from puberty onwards, with variable penetrance [55]. The authors conclude that simple heterozygous loss of function has a metabolic phenotype, in addition to the classical dominant-negative mechanism of intracellular missense variants [55]. This conclusion has implications for counselling the heterozygous parents of patients with DS or RMS (section 8).

2.3. Variant spectrum, founder variants and normalisation

GeneReviews does not describe genotype-phenotype correlations in INSR-SIRS, and Orphanet does not find them in RMS either [1, 5]. Severity depends on the combined effect of the two alleles on receptor function. The following table brings together the variants cited in the article, normalised in VariantValidator (GRCh38, MANE Select) and checked in ClinVar on 26 October 2026 [9, 54].

The remaining variants described in the NIH cohorts are published in protein nomenclature without a transcript, with mixed numbering [16]. Checked against NP_000199.2 in ClinVar and VariantValidator, they correspond to: homozygous Pro220Leu in two siblings, NM_000208.4:c.659C>T p.(Pro220Leu), already in HGVS numbering; Lys460Glu with termination after amino acid 671, historical numbering of c.1459A>G p.(Lys487Glu); homozygous Ile119Met, historical numbering of NM_000208.4:c.438C>G p.(Ile146Met) (ClinVar VCV 14711); Ser635Leu with deletion of exons 9–10, NM_000208.4:c.1904C>T p.(Ser635Leu), in HGVS numbering and with no ClinVar record; Asn117Lys with deletion of exon 3, p.(Asn117Lys) in HGVS numbering, a published designation without a defined nucleotide change, because the AAC codon allows two changes [9, 16, 54]. Cys807Arg in an Omani infant is historical numbering of NM_000208.4:c.2500T>C p.(Cys834Arg), with no ClinVar record [1, 9]. The 2.43 kb deletion associated with a point variant in a Chinese newborn with RMS remains as the published designation; the variants c.2740C>T p.(Arg914Cys) and c.2776C>T p.(Arg926Trp) in a Spanish adult with RMS match the MANE NM_000208.4 [1, 9, 58]. The homozygous splice-site variant c.1268+2T>C was described in an American patient treated with rhIGF-1 for more than five years [59]. In the Donohue case of Perge and colleagues, revealed by IUGR and HCM on prenatal ultrasound, the homozygous variant was c.632C>T p.(Thr211Ile) in exon 2 [60].

The spectrum includes missense, nonsense and splicing variants, small insertions and deletions, and deletions of one or more exons, which account for less than 10% of known pathogenic variants according to the HGMD data summarised by GeneReviews [1]. This is a proportion of catalogued variants and not the clinical sensitivity of the test.

2.4. Familial hyperinsulinaemic hypoglycaemia due to INSR (HHF5)

In Højlund's Danish family, with 19 members studied across three generations, the Arg1174Gln variant (historical numbering, in the tyrosine kinase domain) segregated with postprandial hypoglycaemia, fasting hyperinsulinaemia and a raised insulin/C-peptide ratio [11]. The euglycaemic clamp showed reduced insulin sensitivity and clearance [11]. The GeneReviews on nonsyndromic hyperinsulinism records 24 people from 9 families with heterozygous INSR variants and postprandial hypoglycaemia, which may worsen with exercise, with variable age at onset and a typically raised insulin/C-peptide ratio [12, 13]. The series of Sethi and colleagues associated the heterozygous variant with neonatal hyperinsulinaemic hypoglycaemia and familial diabetes, which shows that hypoglycaemia and diabetes can coexist in the same family [13].

2.5. PIK3R1 and SHORT syndrome

PIK3R1 (5q13.1; OMIM 171833) encodes p85α, the regulatory subunit of PI3K that stabilises the catalytic subunit p110α; binding to the activated receptor generates phosphatidylinositol 3,4,5-trisphosphate, which recruits AKT [21]. Patients' fibroblasts and lymphoblasts show reduced AKT activation; GeneReviews presumes a haploinsufficiency mechanism, whereas ISPAD describes the hot spot variant as dominant-negative, associated with an unfolded protein response and lower sensitivity to endoplasmic reticulum stress-dependent apoptosis [15, 21]. In Chudasama's Norwegian family, p.(Arg649Trp) impaired the interaction between p85α and IRS-1 and reduced AKT signalling [50]. The recurrent variant c.1945C>T p.(Arg649Trp) is present in more than 60% of individuals or families, variants cluster in the C-terminal SH2 domain, penetrance appears complete and there is no clinically relevant genotype-phenotype correlation [21]. In Dyment's trio study, in addition to p.(Arg649Trp) de novo in one patient and segregating in another family, c.1906_1907insC p.(Asn636Thrfs*18) and c.1971T>G p.(Tyr657*) were found, both de novo [49]. Carriers appear protected from obesity and hepatic steatosis but not from diabetes [15].

PIK3R1 has allelic disorders with opposite mechanisms [21, 23, 61]. Activated phosphoinositide 3-kinase δ syndrome type 2 (APDS2), AD, results from heterozygous variants that hyperactivate p110δ and causes immunodeficiency, autoimmunity and lymphoma, with short stature described; agammaglobulinaemia 7, AR, results from homozygous variants with a stop codon in exon 6 and absence of the p85α isoform (six people); a form of acanthosis nigricans and severe IR without the SHORT phenotype results from heterozygous substitutions in the N-terminal SH2 domain (five people); and there is intellectual disability due to iSH2 domain variants, without the SHORT face [21, 23]. Somatic iSH2 domain variants are associated with vascular malformations, and somatic variants occur in sporadic tumours [21]. The direction of signalling separates the entities: loss of function in the insulin pathway in SHORT, hyperactivation of p110δ in APDS2 [23]. ClinGen assigns SHORT moderate actionability in adults and children [23]. SHORT syndrome and APDS2 enter the differential.

2.6. AKT2: loss and gain of function

AKT2 (19q13.2; OMIM 164731) is the AKT isoform that carries most of the metabolic insulin signal [26]. The p.(Arg274His) variant, in the core of the catalytic domain, abolishes kinase activity, prevents phosphorylation of the transcription factor FOXA2 and inhibits normal AKT2 and AKT1 in a dose-dependent manner, which defines a dominant-negative effect; it also inhibits adipocyte differentiation in vitro [24]. In the family described, three of the four carriers had diabetes and the fourth, a middle-aged man, had marked hyperinsulinaemia with normal glucose tolerance; in the proband, severe hyperinsulinaemia preceded diabetes by many years [24]. ClinGen classifies this association as limited, according to GeneGuidance [26].

The activating variant p.(Glu17Lys), in the pleckstrin homology (PH) domain, constitutively recruits AKT2 to the membrane and activates the downstream pathway without insulin [25]. It arises de novo, in constitutional heterozygosity or in mosaic form, and causes hypoinsulinaemic hypoglycaemia with hemihypertrophy (OMIM 240900), an association classified as definitive by ClinGen according to GeneGuidance [25, 26]. Activating AKT3 and PIK3CA, also in the pathway, are associated with megalencephaly syndromes (megalencephaly-polymicrogyria-polydactyly-hydrocephalus, MPPH, and megalencephaly-capillary malformation, MCAP) [53].

2.7. TBC1D4

TBC1D4 (13q22.2; AS160) encodes a Rab GTPase-activating protein that retains GLUT4 vesicles in the basal state; there is no established Mendelian disorder [27]. The p.(Arg684Ter) variant has an allele frequency of 17% in Greenlandic Inuit; in homozygotes, 2-hour OGTT glucose is 3.8 mmol/L higher and the odds ratio for type 2 diabetes is 10.3, with slightly lower fasting glucose and insulin; in heterozygotes the increase in 2-hour glucose is 0.43 mmol/L [27, 28]. In eight homozygotes studied by clamp, IR was confined to skeletal muscle, without basal hyperinsulinaemia, and metabolic responses to exercise were normal [62]. A heterozygous truncating variant, p.(Arg363Ter), was found in a screen of 156 patients with severe IR, in an 11-year-old girl with acanthosis and extreme postprandial hyperinsulinaemia; the truncated protein dimerised with the normal one and reduced GLUT4 translocation, suggesting a dominant-negative effect, and two overweight carrier relatives had normal fasting glucose and insulin but disproportionate postprandial hyperinsulinaemia [29].

2.8. Applied pathophysiology: lipids, adiponectin, GH, kidney and ovary

The lipid profile of the insulin receptoropathies is paradoxical: low triglycerides, high high-density lipoprotein (HDL) cholesterol and high adiponectin, without hepatic steatosis, in contrast to the lipodystrophies and post-receptor IR, which have high triglycerides, low adiponectin and fatty liver [1, 6, 63]. Insulin normally inhibits adiponectin secretion, so normal or high adiponectin in the presence of extreme hyperinsulinaemia indicates a receptor defect [15, 64]. Leptin is decreased in the receptor defect [15]. Sex hormone-binding globulin (SHBG) remains preserved or increased in receptor dysfunction, with a positive correlation between insulin and SHBG, whereas in lipodystrophy the correlation is negative [17].

In RMS there is growth hormone (GH) resistance: IGF-1 is low with raised GH and contributes to the growth failure, which does not respond to exogenous GH [1, 5, 16]. In the kidney, INSR expressed along the nephron takes part in calcium handling; in a series of 17 patients with biallelic variants, all had nephrocalcinosis and the 10 with 24-hour urine collections had hypercalciuria (0.32 ± 0.17 mmol/kg/day; normal <0.1), with a tendency to hypokalaemic and hypochloraemic alkalosis and hypomagnesaemia, and low plasma creatinine (25 ± 9 µmol/L) [65]. Grasso and colleagues raised the hypothesis of a Bartter-like syndrome in congenital IR [66]. In the ovary, insulin acts in synergy with gonadotrophins, which explains the frequently accelerated puberty, hyperandrogenism and ovarian enlargement [3, 17].

The review by Semple and colleagues brings together pathophysiological observations that explain clinical features of the class [52]. Postprandial hypoglycaemia, common to the insulin receptoropathies, the signalling defects and the lipodystrophies, has an uncertain mechanism, attributed mainly to reduced hepatic insulin clearance, primary in the receptor defect or secondary to steatosis [52]. β-cell hyperplasia, with extreme hyperinsulinaemia, can prevent hyperglycaemia for years even with severe loss of receptor function, which indicates that the islet receptor is not indispensable for β-cell expansion, contrary to what murine studies suggested; in most patients this compensation eventually fails [52]. The absence of dyslipidaemia and steatosis in the receptor defect, in contrast with lipodystrophy and with the AKT2 defect, supports the hypothesis that the fatty liver and dyslipidaemia of common IR result from selective post-receptor hepatic IR, in which insulin continues to stimulate de novo lipogenesis, with a proposed role for mammalian target of rapamycin complex 1 (mTORC1), still under discussion [52, 63]. By the same logic, adiponectin (produced almost exclusively in adipose tissue) and SHBG and IGFBP1 (of hepatic origin), usually suppressed by hyperinsulinaemia, remain preserved when the receptor is missing and can serve as indicators of the insulinisation of each tissue [52]. In the insulin receptoropathies, adipose hypoplasia corresponds to adipose tissue poorly loaded with lipid and not to absent tissue, with a metabolic profile opposite to that of primary generalised lipodystrophy [52]. The growth abnormalities of severe IR (linear growth failure, prepubertal growth acceleration and pseudoacromegalic soft-tissue overgrowth in adults) are attributed to the interaction between the insulin and IGF axes: IGF-1 and IGF-2 also activate the insulin receptor, and insulin at extreme concentrations activates the IGF-1 receptor, although there is not yet an integrated model [52]. The resistance to ketoacidosis of infants with DS in the first year of life, even without a functional receptor, is not explained; the hypotheses are the action of very high insulin on IGF-1 receptors that persist in the immature liver or a deficiency of GH secretion or action [52].

The scheme of Semple and colleagues orders the insulin receptoropathies by residual receptor function, as a conceptual continuum and not as a measurement: DS lies at the extreme of almost nil function and RMS among the recessive forms with residual function up to about a quarter of normal; type A and the cases labelled HAIR-AN lie among the dominant forms, up to about half; linear growth failure and deficient development of skeletal muscle and adipose tissue are limited to the recessive forms, whereas soft-tissue overgrowth, hyperandrogenism and insulin-resistant diabetes run across the whole spectrum [52]. In some patients with DS or RMS, loss of expression of one INSR allele has been identified, attributed to a variant in a regulatory sequence such as the promoter [52]. Foti and colleagues described four patients with severe IR and very low expression of both INSR alleles, carrying a heterozygous deletion or variant of HMGA1 (an architectural transcription factor that binds the INSR promoter and facilitates its transcription) and no INSR variants; the phenotype resembled that of the insulin receptoropathies, in a single report up to 2011 [52]. Severe IR can also have a digenic origin: in a family described in 2002, the five members with severe IR were double heterozygotes for frameshift or premature stop codon variants in PPARG (a regulator of adipocyte biology) and in PPP1R3A (a muscle protein that regulates glycogen metabolism), and no unaffected relative had both variants, a model of interaction between defects of lipid and glucose metabolism [52].

3. Clinical Spectrum and Manifestations by System

3.1. Features common to the class

Acanthosis nigricans is present in all known monogenic forms of severe IR and, together with acrochordons, is an early sign, attributed to the action of excess insulin on the IGF-1 receptor of keratinocytes and fibroblasts [3, 39]. In prepubertal children with DS or RMS, failure to thrive, lack of adipose and muscle tissue and overgrowth of skin, hair, teeth and viscera are added [3]. Hyperglycaemia and diabetes appear later than in forms due to β-cell failure and may be absent before puberty, except in DS; the phenotypes are more marked in females, because of adolescent ovarian hyperandrogenism, with a presentation similar to PCOS [15]. The designation HAIR-AN (hyperandrogenism, IR and acanthosis nigricans) is used as a generic description of severe IR and as a subphenotype of PCOS [39]. Hypoglycaemia, particularly in RMS and in the heterozygous forms, may precede hyperglycaemia [3, 39].

The chronology of dysglycaemia is characteristic [52]. Hyperglycaemia is rarely the first manifestation: acanthosis and, in women, ovarian hyperandrogenism appear first, and symptomatic postprandial hypoglycaemia may precede hyperglycaemia by many years, with autonomic symptoms that can progress to neuroglycopenia and seizures if not corrected with oral carbohydrate [52]. When β-cell decompensation begins, hyperglycaemia diagnostic of diabetes often appears only after an oral glucose load, with normal or low fasting glucose, and HbA1c may be normal or low when post-load glucose is already diagnostic; which of the diabetes criteria best predicts complications in this population has not been studied [52]. The time to decompensation ranges from the neonatal period, in the most severe forms, to the fourth decade or later at the mild end of the spectrum, especially in men [52]. Acanthosis is usually located in the axillae, the nape of the neck and the groins, but can affect any skin fold and, in extreme cases, the periocular, perioral and perianal regions or flat surfaces such as the dorsum of the foot and the knuckles; histologically there is hyperkeratosis, sometimes hyperpigmentation, and mild papillomatosis [52]. Acanthosis depends on hyperinsulinaemia: it is absent in «pre-receptor» IR due to very high titres of anti-insulin antibodies in insulin-treated patients, and its disappearance indicates a fall in insulin, either through lower IR or, conversely, through worsening β-cell failure [52]. It may become excoriated or infected and, together with hyperandrogenism, contribute to hidradenitis suppurativa [52]. In the lipodystrophies, hypertriglyceridaemia can be complicated by pancreatitis and eruptive xanthomas, and steatosis can progress to steatohepatitis, cirrhosis and hepatocellular carcinoma; dyslipidaemia and steatosis are sensitive but poorly specific indicators of lipodystrophy, and their absence in severe IR suggests an insulin receptoropathy [52]. Lipodystrophy is harder to recognise in men, because the fat mass of a lean woman is almost twice that of a lean man and the female gluteofemoral depot is visible; a lean, athletic man may be confused with a man with partial lipodystrophy [52].

3.2. Donohue and Rabson-Mendenhall: frequency of manifestations

The table reproduces the frequency of manifestations compiled by GeneReviews from series and cases published between 2019 and 2023 («+» means that the manifestation is described but its frequency is unknown) [1].

3.3. Donohue syndrome by system

Growth and body composition. IUGR is progressive from the beginning of the third trimester; birth weight, length and head circumference are below the 3rd centile, with weight and length more affected than head circumference [1]. Mean weight at one year is 4 to 5 kg, and subcutaneous fat is reduced in all patients, with muscle hypotrophy [1, 8, 67]. Prenatal ultrasound may show severe IUGR with obstructive HCM, as in Perge's case, referred at 33 weeks [60].

Metabolism. IR with hyperinsulinaemia is present from birth, with fasting hypoglycaemia and postprandial hyperglycaemia that do not respond to insulin or metformin [1]. Insulin and C-peptide are extremely raised; ketoacidosis has not been described in infants with DS, who are protected from it until 2–3 years of age [1, 3].

Face, skin and appendages. The facies includes proptosis, infraorbital folds, large, low-set and posteriorly rotated ears, lips with a thick vermilion, gingival hypertrophy and, sometimes, macroglossia, which may be secondary to prolonged exposure to IGF-1 [1]. Clinical genetics textbooks describe an aged-looking face with thick lips and prominent ears [10]. Hypertrichosis and hyperkeratosis are present from birth in all, and acanthosis appears at birth or shortly afterwards [1]. The nipples are prominent in all [1].

Genitalia and gonads. The external genitalia are enlarged in both sexes (penis; hypertrophy of the labia majora and clitoromegaly) [1]. The ovaries enlarge, with multiple peripheral cysts similar to those of PCOS, and may reach sizes that cause respiratory distress, haemorrhage or torsion and require removal [1, 17]. In a female infant from the NIH-Cambridge cohort, bilateral oophorectomy at 4 months, for abdominal distension and respiratory distress, removed ovaries of 103 g and 230 g, with follicular cysts and stromal hyperthecosis [17].

Heart. HCM affects about 30% of infants and is a leading cause of death; it may be present at 1–2 months without clinical expression [1, 4]. Hovnik and colleagues described severe progressive obstructive cardiomyopathy with renal tubular dysfunction [68].

Kidney. The kidneys are enlarged; there are changes in the renin-aldosterone axis with hypokalaemia, hyperaldosteronism and hyperreninaemia, and hypercalciuria with nephrocalcinosis in the first months, sometimes from the prenatal period, with normal glomerular filtration rate and creatinine [1, 65, 66].

Liver and gastrointestinal tract. Neonatal cholestasis is frequent, with hepatomegaly without dysfunction; rectal hypertrophy or prolapse may require colostomy [1].

Infection and immunity. Recurrent bacterial infections (pneumonia, urinary tract infection) are a frequent cause of death, and healthcare-associated infections contribute [1]. Cases have been described with decreased immunoglobulins G and A and intact cellular and humoral immunity, and others with normal immunoglobulins and lymphocytes; a deficiency of polymorphonuclear bactericidal activity has been proposed [39].

Neurodevelopment and endocrine. There is severe global developmental delay, and most patients do not reach motor milestones before death; axial hypotonia and muscle atrophy are constant, and the intellectual disability is attributed to recurrent severe hypoglycaemia [1]. Central hypothyroidism has been described [1, 56].

Teeth. Macrodontia and crowding [1].

Survival. Death usually occurs in the first year, from complications of hypoglycaemia, from infection and from cardiomyopathy; Orphanet indicates that life expectancy rarely exceeds a few months [1, 8]. Patients rarely survive beyond infancy, and most die before 2 years of age [39]. There are exceptions treated with rhIGF-1, such as the French patient with improvement in IR and growth over 10 years [69].

3.4. Rabson-Mendenhall syndrome by system

Metabolism and course. IR is less severe than in DS. Up to the first year, blood glucose fluctuates, with fasting hypoglycaemia and postprandial hyperglycaemia; thereafter endogenous insulin declines progressively, hyperglycaemia increases, hypoglycaemic episodes become rare and the risk of DKA appears [1]. Triglycerides are low and HDL is high, with high adiponectin [1, 14]. In Brown's series of five patients, glucagon suppressed normally during the OGTT and the insulin/C-peptide ratio was high [14]. The late metabolic complication is refractory diabetes with severe DKA [39, 70].

Microvascular complications. Proliferative retinopathy, peripheral neuropathy and renal vascular disease appear in the second decade [1, 3, 51].

Growth. Ranges from severe deficits in weight, length and head circumference to normal, without response to GH even when GH is low [1]. In the NIH cohort (n = 11), height standard deviation score (SDS) was −2.9 ± 1.5 and −2.5 ± 1.5 in the two groups, with low body mass index (BMI) SDS and IGF-1 SDS of −3.6 and −3.3, and GH was higher than in healthy controls (2.7 versus 0.64 ng/mL; P <0.0001) [16]. GH resistance with low IGF-1 contributes to the growth failure [5].

Face and teeth. Vertical facial growth and the gonial angle are increased, with macroglossia, macrodontia, crowding and premature, dysplastic dentition; in some patients early tooth eruption, crowding and a low hairline are the only features [1]. Brown's five patients had early secondary dentition, large teeth, crowding and malocclusion [14]. Orphanet describes thick hair and nails, hypertrichosis and acromegaloid facies [5].

Skin. Hirsutism and acanthosis become more marked in late childhood; in Brown's series the acanthosis was severe and there were acrochordons [1, 14].

Ear and infection. Bacterial pneumonia is recurrent [1]. In Brown's series, four of the five patients had frequent otitis media and three had cholesteatoma [14].

Kidney. The kidneys are enlarged; there is hypercalcaemia, nephrocalcinosis and medullary sponge kidney [1, 71]. Nephrocalcinosis or nephrolithiasis was present in Brown's five patients, and glomerular hyperfiltration in all patients of the NIH cohort, with an estimated filtration rate above 130 mL/min/1.73 m² [14, 16]. Chong and colleagues described renal manifestations in severe RMS [72].

Heart. HCM is frequent in the first decade and may be neonatal [1].

Genitalia, gonads and puberty. Genital enlargement appears later than in DS; the ovaries may enlarge, with cysts and tumours [1, 3]. In the two girls in Brown's series there was clitoromegaly and peak testosterone of 701 and 432 ng/dL, and one underwent oophorectomy at 19 years [14]. PCOS with hyperandrogenaemia is frequent in women [5].

Thyroid. There is a high prevalence of nodules and thyromegaly (section 3.9) [1, 73].

Liver and gastrointestinal tract. Hepatosplenomegaly without dysfunction; rectal prolapse in some patients [1].

Neurodevelopment. Development ranges from severely impaired to normal; more than half have mild intellectual disability [1, 5].

Neoplasms. Reported cases include endometrial carcinoma in a 24-year-old woman treated with rhIGF-1 (published as DS, with a clinical picture more compatible with RMS), an ovarian granulosa cell tumour in a 35-month-old girl treated for 16 months with rhIGF-1 and a congenital bilateral juvenile granulosa cell tumour in an untreated female infant [1, 74, 75]. Five patients from the NIH-Cambridge cohort, with various aetiologies of severe IR, developed virilising ovarian tumours [17].

Survival. Death results from the complications of prolonged hyperglycaemia and hyperinsulinaemia, usually in the second decade, with survival described up to the third [1, 16, 67, 76]. Most live into their early twenties [39].

3.5. Type A insulin resistance and heterozygous carriers

Type A IR presents mainly around puberty and almost always in females, through ovarian dysfunction: hyperandrogenism with hirsutism, acne and oligo- or amenorrhoea, frequently accelerated puberty, acanthosis and hyperinsulinaemia, with glucose intolerance or diabetes and normal weight [1, 3, 6]. In men and in late childhood, acanthosis, glucose intolerance or hyperinsulinaemia lead to referral; postprandial hypoglycaemia may be the presenting feature; acromegaloid facies and muscle cramps have been described [6]. Unlike obesity and the lipodystrophies, hypertriglyceridaemia and steatosis are usually absent; excess weight does not exclude the diagnosis [6]. Growth and cognition are normal [1].

Parker and Semple illustrated the spectrum with two cases [3]. A 15-year-old girl had had hirsutism since the age of 12, primary amenorrhoea, enlarged multicystic ovaries, a raised luteinising hormone to follicle-stimulating hormone (LH:FSH) ratio and testosterone of 8.2 nmol/L of ovarian origin confirmed by venous catheterisation, with fasting insulin of 1,088 pmol/L (reference <60) for a blood glucose of 3.4 mmol/L; at 16 years she had a BMI of 21 kg/m², axillary acanthosis, acrochordons, normal lipids, no fatty liver and adiponectin of 17.7 µg/L (reference 2.4–14.9), and was heterozygous for the dominant-negative variant Pro1178Leu (historical numbering, = NM_000208.4:c.3614C>T p.(Pro1205Leu)) [3]. Testosterone may reach 15 nmol/L, with virilisation [3]. The «asymptomatic» father of another patient had long-standing postprandial dizziness and sweating, marked acanthosis, fasting glucose of 7.8 mmol/L and glycated haemoglobin (HbA1c) of 52 mmol/mol; in the prolonged OGTT, glucose fell to 1.9 mmol/L at 150 minutes with neuroglycopenia, with insulin of 1,872 pmol/L [3]. IR is generally less severe in men with the same defect, who tend to be labelled as having type 2 diabetes in middle age; after diagnosis in a girl, it is very common to find hidden IR in the father [3]. Hypoglycaemia may prompt a search for an insulinoma and diminishes with β-cell decompensation [3].

In the 30-year NIH follow-up, 8 women with type A IR and 3 patients with RMS, presenting between 7 and 32 years of age, all had extreme IR and acanthosis, and the women had hyperandrogenism; weight was normal in all but one, there were INSR variants in 7 of the 8 studied and 6 of the 8 had undergone ovarian surgery [51]. Three of the 11 died, 9 were diabetic and 1 had impaired tolerance, and 7 of the 9 diabetics had at least one serious diabetic complication [51]. Two patients with very high endogenous insulin production maintained normal fasting glucose, and most required large doses of insulin [51]. Type A carries survival beyond middle age [39]. Quality of life is reduced by diabetes, hypoglycaemia, hirsutism, oligo- or amenorrhoea and infertility, and life expectancy has not been studied [6].

In the cohort of 505 carriers of monoallelic variants (preprint, read in abstract), the male to female ratio among probands was 1:3.4, and women presented earlier, mainly with hyperandrogenism [55]. In the whole cohort, 56% had diabetes and 55% hypoglycaemia, which was the presenting form in 11% of probands and was common among relatives; birth weight was −1.0 SDS and BMI +0.7 SDS; hyperandrogenism or a «polyendocrine metabolic ovarian syndrome» was present in 82% of post-pubertal women; gestational diabetes occurred in 20 to 53% of pregnancies; and the lipid profile was normal [55]. The authors conclude that hypoglycaemia is more frequent than previously recognised and call for caution with diabetes drugs [55].

3.6. INSR-related hyperinsulinaemic hypoglycaemia

The presentation is postprandial hypoglycaemia, with fasting hyperinsulinaemia and a raised insulin/C-peptide ratio; age at onset is variable and exercise may worsen the hypoglycaemia [7, 12]. In Sethi's series, the same heterozygous variant was associated with neonatal hyperinsulinaemic hypoglycaemia and with diabetes in relatives, which places HHF5 and type A IR in the same spectrum [13].

3.7. SHORT syndrome

The frequency of manifestations in 61 published individuals is as follows: facial gestalt 100%, delayed dentition 94%, partial lipodystrophy 87%, IUGR 83%, IR 73%, diabetes 60% (100%, 9 of 9, above 18 years), short stature below −2 standard deviations (SD) 52% and anterior chamber defects 51% [21]. The face is triangular, with a broad forehead, deep-set eyes, a narrow nasal tip with thin alae and a low-hanging columella, downturned corners of the mouth, a chin dimple and prominent ears, with an aged or progeroid appearance present from birth, and prominent scalp veins [21]. Mean birth weight in term births is at the 0.3rd centile and there are feeding difficulties, with vomiting and diarrhoea in the first two years [21, 42]. Adult height is 155–163 cm in men and 143–160 cm in women according to GeneReviews; Smith's gives 153.7–167 cm and 141–160 cm, respectively [21, 42].

Lipodystrophy begins in the face, from 3 months of age, extends to the chest and upper limbs and spares the buttocks and legs; the hands lack fat and the skin is translucent; BMI in adult men ranges from 13.5 to 20.1 kg/m² (6 men) and in women from 15.2 to 22.5 kg/m² [21, 42]. IR begins in mid-childhood or adolescence, and diabetes appears at a mean age of 17 years (9–32 years); one case of transient neonatal diabetes has been described [21]. Orphanet and Smith's report diabetes in about two thirds of patients after 15 years of age [22, 42].

The teeth show delayed eruption, hypodontia, enamel hypoplasia, malocclusion and caries [21]. The eyes have refractive errors, half of patients have Axenfeld-Rieger anomaly or anterior chamber dysgenesis, and glaucoma may be present from birth [21]. Sensorineural hearing loss of 80–90 dB in the first year has been described in 11 individuals [21]. Cognition is not affected, with mild speech delay in about half; Smith's records cognitive delay in 3 of 32 [21, 42]. Nine patients had heart disease, seven of them pulmonary stenosis [21]. Hyperextensibility or hernia occurs in 23% (8/35), frequent infections in 4 of 7 without primary immunodeficiency, and nephrocalcinosis has been described in a mother-son dyad, in the son at 2 months [21]. Bone imaging shows large, cone-shaped epiphyses, gracile diaphyses, short metacarpals and Wormian bones [42]. Ovarian cysts are frequent, fertility is preserved and life expectancy is normal [21, 22].

3.8. AKT2 and TBC1D4 forms

In partial lipodystrophy due to AKT2 p.(Arg274His), onset is in adulthood, with distal lipoatrophy, severe hepatic and peripheral IR, hyperinsulinaemia and diabetes; acanthosis and hypertension have been described [20, 24]. In a patient from this family, followed at the NIH and in Cambridge, hyperandrogenism appeared at 16 years, ovarian wedge resection was performed, there were two pregnancies, an acromegaloid appearance at 35 years and diabetes at 38 [17]. The activating form p.(Glu17Lys) causes macrosomia at birth, hemihypertrophy, typically left-sided, and severe fasting hypoglycaemia from about 6 months of age, with seizures after about 3 hours without feeding, suppressed ketones and free fatty acids, and low or undetectable insulin and C-peptide [25, 26]. In two patients reassessed at 17 years, adiposity was 37%, one still had hypoglycaemia after a 2-hour overnight fast and the other was euglycaemic; oral glucose tolerance was normal, with low insulin, and plasma and hepatic triglycerides and hepatic de novo lipogenesis were normal [77]. In the family with TBC1D4 p.(Arg363Ter), the presentation was acanthosis and extreme postprandial hyperinsulinaemia at 11 years [29].

3.9. Hyperandrogenism, ovary, thyroid and other cross-cutting manifestations

The retrospective cohort from the NIH (United States, US) and Cambridge (United Kingdom), with 279 women, showed total testosterone ranging from undetectable to 1,562 ng/dL (54.2 nmol/L), with a median of 40.3 ng/dL and a value above the adult female range in 34%; ovarian histology was compatible with PCOS in 8 of 9 patients with tissue available [17]. The following table shows the median and interquartile range in patients aged 10 years or older [17].

In the review by Semple and colleagues, testosterone sometimes exceeds 10 nmol/L, above the thresholds used to distinguish virilising tumours from non-tumoral hyperandrogenaemia, and ovarian cysts can become bulky and prone to haemorrhage or torsion, with surgical removal sometimes in the first year of life [52]. Because hyperandrogenism results from the synergy between gonadotrophins and insulin on the ovary, it manifests in infancy and after puberty, when the hypothalamic-pituitary-gonadal axis is active, and may accelerate puberty [52]. After the menopause severe hyperandrogenism may persist, with hyperthecosis on histology; when receptor function is first lost after the menopause, as can happen in type B, hyperandrogenism does not appear despite extreme hyperinsulinaemia, which suggests that hyperinsulinaemia around the menopause is needed to maintain androgen-secreting theca cells [52]. The main differential diagnosis is congenital adrenal hyperplasia or an androgen-secreting tumour, in which acanthosis is not prominent unless there is overweight or obesity; adrenal hyperplasia is diagnosed biochemically, but excluding autonomous secretion can be difficult, and sustained hyperinsulinaemia may itself favour ovarian tumours, probably through chronic activation of the IGF-1 receptor [52].

The testosterone threshold of about 150 ng/dL (about 5 nmol/L), usually used to search for a virilising tumour, was exceeded in 13% of the cohort, almost always without a tumour; even so, five patients developed virilising ovarian tumours, so the hyperandrogenaemia of severe IR may not be benign in the long term [17]. A patient with RMS homozygous for p.Pro220Leu, treated from 8 years of age with leptin, 900 U/day of insulin and metformin, underwent oophorectomy at 19 years, and a patient with compound heterozygous type A IR (p.Trp160*/p.Asn489Ser), requiring more than 30,000 U/day of insulin from 12 years of age, at 23 [17].

In the thyroid, ultrasound of 81 patients with lipodystrophy and 11 with INSR variants (5 homozygous, 6 heterozygous) at the NIH showed nodules in 5 of 30 children with extreme IR (16.7%), compared with 2% described in children from the general population (64/3,202), with no difference between lipodystrophy and INSR [73]. Thyroid volume adjusted for body surface area was greater in INSR homozygotes (10.4 ± 5.1, versus 3.9 ± 1.5 in heterozygotes and 6.2 ± 3.4 in lipodystrophy), and there was papillary carcinoma in three patients with lipodystrophy and in one INSR heterozygote, with no difference with or without metreleptin [73]. In a later NIH study, the prevalence of papillary thyroid carcinoma in severe IR was 2.2%, compared with 0.29% in the US population (Surveillance, Epidemiology and End Results, SEER, registry; P <0.0001), with diagnosis at a younger age (26 ± 9 years) and no differences in tumour characteristics, tumour IGF1R expression or BRAF frequency [78].

Pseudoacromegaly (large mandible and hands) and hyperandrogenism with hirsutism, acne and PCOS accompany severe IR of various causes [3, 10].

3.10. Natural history and treated disease

The survival data for DS correspond mainly to natural history, because no treatment has consistently modified the course; the patients who survived longest were treated with rhIGF-1 in uncontrolled series [1, 59, 69]. In RMS, the natural history documented by the NIH study (NCT00001987, open since 1976) shows a progressive rise in HbA1c in patients without metreleptin, with frequent death from microvascular complications or DKA in the second and third decades, and treatment with high-dose metreleptin attenuates this rise without altering stature or renal function over the available follow-up (section 7) [16, 79]. In type A, the cohort of Musso and colleagues includes patients treated with various combinations, so the 3 deaths among 11 and the complications in 7 of 9 diabetics describe treated disease over the three decades of follow-up published in 2004 and not untreated natural history [51].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age

Prenatal period. Severe IUGR progressive from the third trimester, particularly when associated with HCM, enlarged kidneys, bladder or stomach and polyhydramnios, should raise the hypothesis of DS [1, 56, 60]. Prenatal recognition allows neonatal treatment to be planned [60].

Newborn and infant. The combination of low birth weight, absence of subcutaneous fat, hypertrichosis, acanthosis, prominent nipples, genital enlargement, abdominal distension with organomegaly, hypotonia and rectal prolapse suggests DS [1]. Blood glucose alternating between fasting hypoglycaemia and postprandial hyperglycaemia, with very high insulin and C-peptide, is the guiding laboratory finding [1]. Clinical genetics textbooks recommend measuring insulin in the presence of failure to thrive with acanthosis, hypertrichosis or coarse facies [80–82]. Dysmorphic features may not be evident at birth, and the first sign may be hypoglycaemia [53].

Childhood. Early tooth eruption, dental crowding, a low hairline, acanthosis, hypertrichosis, growth failure with low IGF-1 and nephrocalcinosis suggest RMS [1, 14]. In a child with IUGR, triangular face, delayed dentition, facial lipoatrophy and Axenfeld-Rieger anomaly or glaucoma, the hypothesis is SHORT [21]. Severe fasting hypoglycaemia with undetectable insulin and hemihypertrophy points to activating AKT2 [26].

Adolescence and adulthood. The phenotype in which INSR is most often overlooked is that of a lean young woman with acanthosis nigricans, virilisation and hyperinsulinaemia labelled as PCOS [2]. Warning signs include hyperandrogenism with raised testosterone, primary or secondary amenorrhoea, marked acanthosis without corresponding obesity, disproportionate hyperinsulinaemia, insulin requirements above 3 U/kg/day or 200 U/day, postprandial hypoglycaemia and normal lipids and liver despite extreme IR [3, 6, 15]. In men, «type 2» diabetes with acanthosis and postprandial hypoglycaemia, especially in the father of a patient with genetic IR, should lead to testing [3].

Autoimmune context. A middle-aged woman with SLE or another autoimmune disease and rapidly progressive diabetes with extraordinary insulin requirements, weight loss, acanthosis and hyperandrogenism, or with unexplained severe hypoglycaemia, suggests type B IR [30, 39].

4.2. Emergency signs

The emergencies of the class are severe hypoglycaemia in the infant with DS, aggravated by fasting and infections; bacterial sepsis; heart failure or arrhythmias of HCM; respiratory distress due to massive ovarian enlargement or abdominal distension; and, in RMS, DKA, which may require intravenous insulin doses far above the usual [1, 17, 56, 70]. In type B, severe hypoglycaemia is associated with high mortality [30]. Anaesthesia and perioperative fasting constitute a specific risk in DS (section 7.15) [4].

4.3. Newborn screening

There is no newborn screening for the severe IR syndromes; diagnosis depends on clinical recognition and blood glucose with simultaneous insulin [1]. Ultra-rapid genome sequencing has already allowed the diagnosis of DS in a preterm infant in 17 hours [83].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Biochemical criteria for severe IR

There are no universally accepted biochemical criteria [3, 39]. Reference centres use their own thresholds, which the table compares; they should be interpreted in the light of age, puberty, adiposity, the degree of β-cell decompensation and clinical signs (acanthosis, oligomenorrhoea, hyperandrogenism, fat distribution), and not applied rigidly [3].

The hyperinsulinaemic euglycaemic clamp is the reference standard, but is used only in research; the homeostasis model assessment (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI) serve epidemiology [39]. In a patient treated with insulin, C-peptide provides information on endogenous secretion [10]. For the diagnosis of diabetes, HbA1c ≥48 mmol/mol (6.5%) follows the American Diabetes Association (ADA) criterion, and 43–47 mmol/mol corresponds to impaired glycaemia [10].

Semple and colleagues stress that insulinaemia is a continuous variable and that any threshold for «severe» IR is arbitrary and reliable only before β-cell decompensation: in absolute insulin deficiency, severe IR is defined only by the weight-adjusted exogenous insulin requirement; in compensated normoglycaemia, only by fasting and/or post-load insulinaemia, with reference to a control population; and in the most frequent scenario, partial β-cell decompensation, history and physical signs decide [52]. Insulinaemia should ideally be compared with normative values from people with similar adiposity and pubertal stage, because puberty is a period of physiological IR and because obesity, the most frequent context of severe IR, makes a monogenic defect less likely [52]. For overweight patients, the authors use a nomogram of fasting insulin as a function of BMI, built in 800 non-diabetic European adults (5th, 50th and 95th centiles), which helps to recognise IR disproportionate to adiposity and therefore more likely to be monogenic; the nomogram is not in routine use in clinical practice [52]. The thresholds of 50–70 µU/mL fasting and 350 µU/mL after OGTT that Angelidi and colleagues attribute to Semple 2011 do not appear in the text or in figure 1 of the original review [39, 52]. In severe IR, isolated fasting glucose and HbA1c, which may be normal or low when post-load glucose is already diagnostic, underestimate diabetes, which the OGTT identifies [52].

5.2. Biomarkers pointing to the receptor

Inappropriately normal or high adiponectin in the presence of severe hyperinsulinaemia indicates receptor dysfunction and can be used to select patients for INSR sequencing [3, 15, 64]. In the context of severe IR, adiponectin above 7 mg/L had a positive predictive value of 97% for insulin receptoropathy in the Cambridge experience, with a threshold that depends on the assay method; raised SHBG and IGFBP1 have lesser, though significant, utility [52, 64]. Dyslipidaemia and fatty liver are almost never present in insulin receptoropathy; low triglycerides and high HDL reinforce the suspicion [1, 3]. Preserved or increased SHBG discriminates receptor dysfunction from lipodystrophy [17]. An increased insulin/C-peptide ratio, due to reduced hepatic insulin clearance, characterises type A IR and HHF5 [6, 11]. In a retrospective Japanese study of 18 patients with type A IR and 126 with type 2 diabetes, the C-peptide/immunoreactive insulin molar ratio was significantly lower in type A, with an area under the ROC (receiver operating characteristic) curve of 0.997 fasting (sensitivity 100%, specificity 99.2%), 0.999 at the first hour and 0.997 at the second hour of the OGTT, independently of BMI and the degree of hyperinsulinaemia; the numerical threshold is in the body of the article, which was not read [84]. Leptin is measured before considering metreleptin [39].

ISPAD summarises the biochemical orientation by subtype, adapted from Parker and colleagues [15]:

5.3. Initial non-molecular assessment

GeneGuidance and GeneReviews indicate fasting glucose with simultaneous insulin and C-peptide, OGTT (which shows fasting hypoglycaemia and postprandial hyperglycaemia), HbA1c, anti-insulin receptor antibodies (which separate acquired type B from genetic type A), androgen profile with pelvic ultrasound, thyroid function and imaging directed at HCM, organomegaly, nephrocalcinosis and the ovaries [1, 2]. No non-molecular test confirms the diagnosis, and mild type A overlaps with PCOS [2]. In the face of marked hyperinsulinaemia, Angelidi and colleagues propose considering insulin degradation in subcutaneous tissue, variants of insulin itself, INSR variants, anti-INSR antibodies and features of lipodystrophy [39]. In lipodystrophy, diagnosis is mainly clinical, by inspecting the patient in underwear [3].

In a child with hypoglycaemia, Saudubray's criteria for hyperinsulinism are blood glucose <2.5–3 mmol/L with insulin ≥1 µIU/mL and C-peptide ≥0.2 ng/mL (a single sample may miss it because of pulsatile secretion), low ketones and free fatty acids, a rise in blood glucose >1.7 mmol/L (30 mg/dL) 30–40 minutes after 1 mg of glucagon and a high glucose requirement (>8 mg/kg/min in the newborn, >10 in the infant, >6 in childhood, >3 in the adult) [53]. In downstream signalling disorders (such as activating AKT2), insulin is low or undetectable with hypoketotic hypoglycaemia [53].

5.4. Genetic testing: criteria and strategy

The diagnosis of INSR-SIRS is established in a proband with suggestive findings and biallelic pathogenic or likely pathogenic variants in INSR; two variants of uncertain significance (VUS), or one pathogenic variant and one VUS, neither establish nor exclude the diagnosis [1]. Type A IR is confirmed by a heterozygous (or, rarely, biallelic) variant in a compatible clinical and biochemical context [6]. SHORT syndrome has no consensus criteria; it is confirmed by a heterozygous pathogenic variant in PIK3R1, and it is not necessary to meet all five features of the acronym [21, 22].

GeneReviews proposes two routes [1]. In the single-gene approach, INSR is sequenced and, if one or no variant is found, targeted deletion and duplication analysis is performed (quantitative or long-range polymerase chain reaction, PCR, multiplex ligation-dependent probe amplification, MLPA, or targeted microarray); diabetes panels may not include INSR, so panel coverage should be confirmed. In the genomic approach, the exome (or genome) is used, which is useful when the phenotype is not distinctive [1, 21]. ISPAD notes that next-generation sequencing panels have largely replaced single-gene testing and that some panels include genes without robust evidence, with a risk of diagnostic error; Sanger sequencing serves family cascade testing [15]. Experienced laboratories listed by ISPAD include Exeter (diabetesgenes.org), the University of Chicago, the Norwegian registry (mody.no), EURO-WABB, Bambino Gesù and Hôpital Robert-Debré [15].

When AKT2 p.(Glu17Lys) is suspected, molecular confirmation should precede drugs for hyperinsulinism or pancreatic surgery, with a technique sensitive to low allele fraction because the variant may be mosaic; the hyperinsulinism genes (ABCC8, KCNJ11, GLUD1) are normal [25, 26]. In homozygotes for TBC1D4 p.(Arg684Ter), fasting glucose under-detects dysglycaemia and the 2-hour OGTT glucose should be used [27].

5.5. Sensitivity and limitations of the tests

The values in the table are proportions of described variants (HGMD data summarised by GeneReviews) and not the clinical sensitivity of the test in a patient with a compatible phenotype [1]. In PIK3R1, sequencing detects the described variants and no deletions or duplications have been published [21]. A negative result does not exclude the diagnosis: undetected deletions can simulate apparent homozygosity, uniparental isodisomy can explain homozygosity with only one carrier parent, parental mosaicism may not be detected in blood and the AKT2 p.(Glu17Lys) variant may be below the detection threshold of conventional sequencing [1, 26]. Many historical variants are published without the signal peptide (27-amino-acid offset) or with notation errors, such as c.858G>A instead of c.857G>A for p.(Cys286Tyr), and should be checked before comparison with the report [9, 56].

5.6. Report content

The report should state the gene, the reference transcript with version (NM_000208.4 for INSR, NM_181523.3 for PIK3R1, NM_001626.6 for AKT2, NM_014832.5 for TBC1D4), the variant in nucleotide and protein HGVS, the zygosity, the phase of the alleles when there are two variants (established by parental testing) and the classification according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), in which pathogenic and likely pathogenic are equivalent for clinical decision-making [1, 9]. A VUS may be reclassified by family segregation, by correlation with the biochemical phenotype (adiponectin, SHBG, insulin/C-peptide ratio) and by functional studies in fibroblasts, such as the Western blot that showed proreceptor without mature subunits in the Israeli patients [3, 56]. Pro1178Leu, published as dominant-negative, remains classified as a VUS in ClinVar with a single submitter, an example of divergence between the literature and the databases [3, 54].

5.7. Type B: anti-receptor autoantibodies

Anti-insulin receptor autoantibodies are rarely measured routinely, and the diagnosis of type B is often probabilistic [30, 39]. The NIH validated, in the largest type B cohort, an immunoluminometric assay (selenOmed, Berlin) with an area under the curve of 0.96, sensitivity of 91.3% and specificity of 93.9% for distinguishing type B from non-autoimmune IR; higher titres were associated with higher HbA1c, glucose and insulin and lower IGF-1 (P <0.0001) [32]. Above the threshold, anti-INSR antibodies were present in 92.1% of type B samples and in 7.4% of non-autoimmune samples; antibodies against IGF1R in 52.4% and 11.5%, and against the insulin receptor-related receptor in 37.3% and 6.8% [32]. The assays are not commercially available [32]. In the NIH and Cambridge cohorts, the diagnosis of type B was made by immunoprecipitation [17].

5.8. Prenatal and preimplantation diagnosis

Once the familial variants have been identified, prenatal diagnosis by chorionic villus sampling and preimplantation genetic testing are possible [1, 10]. Desbois-Mouthon and colleagues applied molecular analysis of INSR to the prenatal diagnosis of leprechaunism in two families [85]. In a Muslim Arab family with the p.(Cys286Tyr) variant, three prenatal diagnoses by sequencing of exon 3 in chorionic villi identified a homozygous fetus, whose pregnancy was terminated, and two heterozygotes, born healthy [56]. In the absence of a molecular diagnosis, IUGR with HCM on ultrasound guides suspicion but does not confirm it [60].

6. Differential Diagnosis

6.1. Comparative table

6.2. Insulin receptoropathy versus lipodystrophy

This is the most important distinction, because the lipodystrophies are the most frequent cause of severe IR [3]. Both cause hyperinsulinaemia, acanthosis, diabetes, hyperandrogenism, organomegaly and HCM, but in insulin receptoropathy triglycerides are low, HDL is high, adiponectin is normal or high and the liver has no steatosis, whereas in lipodystrophy there is hypertriglyceridaemia, sometimes with pancreatitis, steatosis and low adiponectin [6, 8, 15]. The dysmorphism of DS and RMS does not occur in congenital generalised lipodystrophy, which has a muscular appearance due to the absence of fat [1, 8]. SHORT, with partial lipodystrophy and IR, lies between the two groups and is distinguished by the face, teeth and eyes [21].

The possibility of lipodystrophy should be considered in all patients with severe IR and dyslipidaemia or fatty liver [52]. Among the rare forms identified up to 2011 through candidate genes are generalised lipodystrophy due to biallelic variants of CAV1 (single case, with short stature) and of PTRF/CAVIN1 (with muscular dystrophy and a minor metabolic disturbance), and partial lipodystrophy of the limbs, the gluteofemoral region and abdominal subcutaneous fat due to a homozygous truncating variant of CIDEC, in a single case with white adipocytes containing multilocular lipid droplets and insulin-resistant diabetes [52]. Acquired generalised lipodystrophy is associated with autoimmune diseases (juvenile dermatomyositis, systemic lupus erythematosus, autoimmune haemolytic anaemia, autoimmune hepatitis), sometimes with low complement C4; acquired partial lipodystrophy, with a cephalocaudal pattern, is associated with C3 nephritic factor, low C3 and mesangioproliferative glomerulonephritis and does not usually cause severe IR, unless there is excess weight [52].

6.3. Type A versus PCOS, HAIR-AN and type B

Type A IR is distinguished from common PCOS and from HAIR-AN with obesity by hyperinsulinaemia disproportionate to weight, by preserved adiponectin and SHBG and by the absence of dyslipidaemia; obese HAIR-AN has a low probability of an INSR variant [6, 17, 51]. INSR loss-of-function variants in the general population may aggravate obesity-associated IR and create overlap [6]. Type B has an acute onset, catabolism with weight loss, systemic autoimmune disease and anti-receptor antibodies [6, 39]. The action of the antibodies is biphasic: in the initial phase they activate the tyrosine kinase and cause hypoglycaemia; later they induce downregulation and degradation of the receptor, with IR and hyperglycaemia; high titres antagonise and low titres act as partial agonists [39]. The NIH has followed patients with type B since the 1970s, with a published 28-year series [87]. It may be associated with SLE, Sjögren syndrome, mixed connective tissue disease or neoplasms such as Hodgkin disease and myeloma [39]. In the NIH series of 38 patients with type B (1976–2024), 81.5% had SLE, 89.5% were women and 84.2% were Black or African American, with a median SLEDAI-2K lupus activity index of 14, high or very high anti-U1 RNP in more than half, acute cranial nerve VII or VIII neuropathies in 18.4%, angioedema in 10.5% and uveitis in 5% [88]. The condition may mimic ovarian hyperthecosis [1]. The treatment of type B is in section 7.11. Among the syndromic causes of acanthosis nigricans, the Oxford Desk Reference brings together the IR syndromes, such as DS and Berardinelli lipodystrophy, and the Crouzon and Beare-Stevenson craniosynostoses [89].

6.4. Neonatal differential: hypoglycaemia and low weight

In a newborn with hypoglycaemia, measuring insulin and C-peptide during hypoglycaemia separates the forms with raised insulin (DS, RMS, congenital hyperinsulinism) from the forms with suppressed insulin, such as activating AKT2 [53]. Congenital hyperinsulinism has no dysmorphism or growth failure, and insulinaemia is generally much lower than in DS [1]. Silver-Russell syndrome shares IUGR and the risk of hypoglycaemia, but the hypoglycaemia is fasting, without hyperinsulinaemia, and the dysmorphism is different, with asymmetry [1]. IGF-1 resistance and XRCC4 primordial dwarfism share growth failure; the former has no hyperinsulinaemia and the latter combines microcephaly and IR with hypertriglyceridaemia [1, 35]. Clinical genetics textbooks include DS in the differential diagnosis of failure to thrive with acanthosis (with the lipodystrophies), of coarse facies (with Costello and cardiofaciocutaneous syndromes) and of hypertrichosis (with Berardinelli-Seip lipodystrophy and with drugs such as minoxidil and phenytoin) [80–82].

6.5. Differential diagnosis of SHORT syndrome

GeneReviews compares SHORT with Silver-Russell syndrome (more marked short stature, frontal bossing, relative macrocephaly, asymmetry, no ocular anomalies or lipodystrophy; in a Silver-Russell syndrome (SRS) without a molecular diagnosis, SHORT should be considered), with Berardinelli-Seip lipodystrophy (generalised lipoatrophy in the first year, hepatomegaly, acromegaloid appearance), with non-syndromic anterior chamber anomalies (CPAMD8, CYP1B1, FOXC1, FOXE3, PAX6, PITX2, PITX3), with IGF-1 resistance due to IGF1R (raised IGF-1; one homozygous form with a SHORT-like picture), with Alagille syndrome (JAG1, NOTCH2; liver disease), with Hutchinson-Gilford progeria (LMNA; onset in childhood), with a SHORT-like form due to PTPN11, with Floating-Harbor syndrome (SRCAP; clavicle, intellectual disability, expressive language deficit) and with Johanson-Blizzard syndrome (UBR1, AR; pancreatic insufficiency, aplasia cutis, malformations) [21]. A single case due to de novo PRKCE and copy number variations of PITX2 (4q25) and BMP4 (14q22.2) have been described [21].

7. Treatments and Risk Management Strategies

7.1. Principles and basis of the recommendations

There is no curative treatment or specific guideline for the severe INSR-related IR syndromes; care is supportive and multidisciplinary [1]. The applicable formal recommendations come from three documents: the 2022 ISPAD monogenic diabetes chapter, with narrative recommendations without an assigned level of evidence in the section on IR syndromes [15]; the 2016 multisociety lipodystrophy guideline (Endocrine Society, American Association of Clinical Endocrinology, European Society of Endocrinology, Japan Endocrine Society, ISPAD and others), with graded recommendations for metformin, concentrated insulin, thiazolidinediones, metreleptin and pregnancy, which apply to severe IR without lipodystrophy only by analogy [90]; and the orphananesthesia recommendations for anaesthesia in DS [4]. The treatment of type B follows the protocol of a single centre, the NIH, and not a society guideline [91]. None of the drugs used for severe INSR-related IR, except concentrated insulin on the basis of the daily requirement, has an approved indication for this condition; all the regimens below, unless stated otherwise, are off-label [92–94].

Semple and colleagues summarise the basis of treatment: almost all decisions rest on the mechanism of the defect and on anecdotal evidence, without randomised trials or comparative studies to guide the choice between subgroups; the goals are to reduce hyperglycaemia and dyslipidaemia and to attenuate the reproductive and cutaneous consequences of hyperinsulinaemia, by compensating for the signalling defect, reducing the secretory demand on the β cell and administering exogenous insulin as effectively as possible when needed [52]. Weight gain always aggravates the metabolic disturbance, so energy restriction and aerobic exercise are an essential part of treatment, with or without an identified monogenic defect; in lipodystrophy, the lean appearance frequently leads to diet being undervalued, and without energy restriction glycaemic and lipid control is almost impossible [52]. Because hyperglycaemia appears while insulinaemia is still very high, secretagogues such as sulphonylureas bring little benefit [52].

GeneReviews organises treatment by problem [1]:

7.2. Donohue syndrome: nutrition and prevention of hypoglycaemia

The goal in an infant with DS is to avoid fasting hypoglycaemia and maintain calorie intake, with frequent feeds by breast, bottle, nasogastric tube or gastrostomy, intravenous glucose when necessary and protein reinforcement of the night-time feeds [1]. Postprandial hyperglycaemia does not respond to insulin or metformin [1]. ISPAD and Angelidi's review summarise that in DS there is no effective treatment and that most infants die of infection or cardiac complications in the first year [15, 39]. rhIGF-1 is the only therapy with a described effect on blood glucose and, in some patients, on survival (section 7.5) [1, 39]. Prolonged fasting and drugs that cause hypoglycaemia should be avoided, and contact with people with contagious illness should be limited [1]. Palliative care and home support are part of the plan from diagnosis [1].

7.3. RMS and type A IR: sensitisers and other antidiabetic agents

Metformin. ISPAD allows metformin to be tried at the outset, in the knowledge that most patients will later need very high insulin doses with limited effect [15]. The lipodystrophy guideline considers metformin a first-line agent for diabetes and IR (Class IIa, Level C), and Parker and Semple propose titrating it to the maximum tolerated dose [3, 90]. The NIH group describes a modest benefit [14]. The doses published in RMS are about 25 mg/kg/day in a child from 26 months of age, 500 mg/day combined with dapagliflozin in a girl with mild RMS and 1,000 mg twice daily in a Polish adolescent [59, 71, 95]. In SHORT syndrome, metformin worsened IR in three patients, so GeneReviews recommends caution [21].

Thiazolidinediones. Pioglitazone is part of multiple-therapy regimens in RMS, at 45 mg/day in one published case [58, 71, 96]. The lipodystrophy guideline accepts thiazolidinediones in partial lipodystrophy (Class IIb, Level B) and calls for caution in the generalised form; the U-500 label warns of fluid retention and heart failure when combined with thiazolidinediones, a relevant risk in patients with HCM [90, 94].

Sodium-glucose cotransporter 2 (SGLT2) inhibitors. Dos Santos and colleagues described the use of empagliflozin in RMS [97]. In a Saudi series of 6 children with severe IR (4 with RMS), dapagliflozin (Forxiga®) at 5 mg/day, increased to 10 mg/day, alone or with insulin (including a pump with Humulin® R U-500) and mecasermin, improved HbA1c, fasting glucose, insulin and C-peptide and acanthosis, with fewer DKA episodes and no documented adverse reactions over 2 to 4 years [98]. In a Japanese girl with mild RMS, continuous glucose monitoring (CGM) showed hyperglycaemia >200 mg/dL in the afternoon and evening and hypoglycaemia <50 mg/dL in the early morning, and dapagliflozin 5 mg/day with metformin 500 mg/day improved the profile [95]. In a Polish patient with two heterozygous INSR variants and fasting insulin of 313 µIU/mL (reference ≤29) with blood glucose of 371 mg/dL, uncontrolled on metformin 1,000 mg twice daily, pioglitazone 45 mg/day and sitagliptin, empagliflozin (Jardiance®) was started at 2.5 mg/day and increased to 15 mg/day, with metabolic improvement; eleven months later early nephrocalcinosis appeared, and reduction to 10 mg/day maintained control and decreased the hypercalciuria [71]. The authors relate the effect to the action of SGLT2 inhibitors on urinary calcium and phosphate excretion; as nephrocalcinosis is already a feature of the biallelic forms, urinary calcium and renal ultrasound should be monitored during treatment [65, 71]. ISPAD mentions benefit of SGLT2 inhibitors for hyperglycaemia on the basis of two reports [15]. These drugs are not indicated for severe IR, and their use in young children is also outside the licensed age range [98].

Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists. In two Spanish adults with RMS, subcutaneous tirzepatide (Mounjaro®) at 2.5–3.3 mg per week for 3 months lowered HbA1c from 8.9% to 6.3% and from 10.3% to 8.1%, with loss of fat mass and deterioration after 3 months off treatment; one of the patients developed proliferative retinopathy, probably because of the rapid fall in HbA1c [58]. The authors describe as usual practice the sequence of metformin with pioglitazone, often with an SGLT2 inhibitor, and then high-dose insulin [58]. GLP-1 agonists and SGLT2 inhibitors can be used in lipodystrophy, but have not been systematically studied [39].

Hypoglycaemia in type A IR and HHF5. For postprandial hypoglycaemia, Parker and Semple describe a low glycaemic index diet, acarbose and snacks between meals, without comparative studies [3]. The 2026 heterozygote cohort recommends caution with drugs that cause hypoglycaemia, given its frequency of 55% [55].

Other strategies described in the 2011 review. GLP-1 agonists and appetite suppressants, because of their effect on energy intake, and bariatric surgery, in isolated reports (a gastric bypass in familial partial lipodystrophy), were pointed out as potentially useful in severe cases [52]. In a patient with an INSR defect and papillary thyroid carcinoma, levothyroxine at suppressive doses induced brown adipose tissue and improved the diabetes; the strategy of increasing oxidative catabolism has no safe application outside that context [52]. As for thiazolidinediones, the Cambridge experience in partial lipodystrophy coincides with that of Simha and colleagues (fat accumulates in the residual depots, with modest metabolic benefit), and the published reports are contradictory; in generalised lipodystrophy they bring no benefit and, in animal models, worsen steatosis [52].

7.4. High-dose insulin and U-500 concentrated insulin

In RMS and in type A with diabetes, insulin is largely ineffective even at high doses, but most patients eventually need it [15]. The lipodystrophy guideline considers insulin effective for hyperglycaemia, acknowledging that some people need concentrated preparations and high doses (Class IIa, Level C), and recommends concentrated insulins when requirements are high [90]. Large volumes of U-100 cause discomfort, leakage and irregular absorption, so insulins at 2 or 5 times the U-100 concentration are considered [39]. The requirements described range from 489 ± 737 U/day (0 to 1,955) at the start of the NIH metreleptin cohort to 1,183 ± 1,192 U/day (0 to 3,000) at 90 months, and reached more than 30,000 U/day in a patient with biallelic type A IR [16, 17].

U-500 regular human insulin (Humulin® R U-500, Eli Lilly; 500 U/mL) is indicated in the US to improve glycaemic control in adults and children with diabetes who need more than 200 units of insulin per day, so severe INSR-related IR meets the indication on the basis of the daily requirement [94]. The label provides for subcutaneous administration two or three times a day, about 30 minutes before meals, in the thigh, arm, abdomen or buttock, with rotation of sites; it prohibits the intravenous route, dilution and mixing with other insulins; it states that safety and efficacy by continuous subcutaneous infusion and in combination with other insulins have not been established; and it presents it in a 3 mL (1,500 U) KwikPen whose window shows the units to be injected without conversion, with no transfer to a syringe [94]. Warnings include potentially fatal hypoglycaemia, hypokalaemia, hypersensitivity and fluid retention with thiazolidinediones [94].

Described off-label uses include intravenous infusion in DKA, subcutaneous pumps and automated insulin delivery systems [14, 76, 98–100]. In a retrospective cohort from an American centre, four patients with severe IR used U-500 in automated systems, with stable HbA1c, little time below range, no DKA or severe hypoglycaemia, but with lower time in range [100]. In a patient with type 1 diabetes and severe IR (about 245 U/day), Omnipod 5 with U-500 increased time in range from 75% to 79.1% and reduced time below range from 9% to 5.7% at 12 months, with explicit dose conversion, an active insulin duration of 6 hours and higher night-time targets [101]. In Portugal, Infomed lists Humulin® Regular 100 U/mL and does not list any U-500 presentation, so extreme IR requires large volumes of U-100; in Brazil, open data from the Brazilian Health Regulatory Agency (ANVISA) show an active registration of Humulin® R without identification of the concentration [102, 103].

7.5. Mecasermin (rhIGF-1)

Rationale and mechanism. Infusion of rhIGF-1 suppresses hepatic glucose production, stimulates muscle uptake and causes hypoglycaemia despite the fall in insulin, acting through IGF1R, which shares 60% homology with INSR [1]. It reduces hepatic gluconeogenesis and increases peripheral glucose uptake [39]. Semple and colleagues consider the dominant mode of action (insulinomimetic effect, trophic effect on β cells or sensitisation through interaction between the insulin and IGF-1 pathways), the optimal dose and the indications to be uncertain [52].

Evidence. There are no controlled trials [1]. Reports describe metabolic improvement (glucose, insulin and HbA1c), improvement in growth and renal tubular dysfunction, and improvement in cardiomyopathy and survival in some patients, but not in others [1, 68, 104, 105]. Kerdanet's patient maintained improvement in IR and growth for 10 years [69]. An American child homozygous for c.1268+2T>C, treated with metformin about 25 mg/kg/day from 26 months of age and moderate carbohydrate restriction, started rhIGF-1 twice daily at 42 months and, over more than five years, had improvement in acanthosis, hyperkeratosis and hypertrichosis, a marked fall in fasting insulin, HOMA-IR and HbA1c and growth velocity on target, without fluid retention, retinopathy, myalgia, heart failure, cerebral infarcts or intracranial hypertension; the authors propose rhIGF-1 as the initial treatment of the biallelic forms [59]. Backeljauw and colleagues used the intravenous route in two patients with leprechaunism [106]. In the Saudi series, mecasermin was used with dapagliflozin and insulin [98]. Early treatment is associated with better outcomes [39].

Divergent positions. GeneReviews considers rhIGF-1 the best available option and reasonable in any patient with severe syndromic IR, but declares the benefit not established and more likely in the less severe forms [1]. Parker and Semple describe widespread use in prepubertal children, with mode of action, optimal dose and indications yet to be clarified [3]. The NIH group considers it more effective in the mild forms, «not useful» in the more severe ones, and argues that, if it acts through residual receptor activity, high-dose insulin would be more logical and safer [14]. ISPAD indicates that, in young children, it improves fasting and postprandial glucose, with uncertain effects on long-term survival [15].

Published dosing. There is no standard protocol. The regimens described in children with severe IR are subcutaneous 2 to 4 times a day, continuous subcutaneous infusion by pump (possibly better, on anecdotal grounds) or the intravenous route, with doses between 80 and 1,120 µg/kg/day (0.08–1.12 mg/kg/day); the upper limit is the highest value described, with no maximum dose defined in the source for the condition [1, 105]. Carmody and colleagues recorded a starting dose of «1.01 units/kg» and a maintenance dose of «1.73 units/kg/day», with the unit as printed in the article, in two daily injections, through the manufacturer's compassionate use programme [59]. These doses are the reference of published practice for the condition.

Comparison with the label. Increlex® (Ipsen in the US; Esteve Pharmaceuticals in the EU) is authorised for growth failure due to severe primary IGF-1 deficiency (height ≤−3.0 SDS, basal IGF-1 ≤−3.0 SDS in the US or below the 2.5th centile in the EU, normal or raised GH) or due to GH gene deletion with neutralising antibodies, from 2 to 18 years in the European Union (EU) and from 2 years in the US [92, 107]. The labelled dose is 0.04–0.08 mg/kg twice daily subcutaneously, with increases of 0.04 mg/kg per dose after at least one week of good tolerance up to a maximum of 0.12 mg/kg twice daily, administered 20 minutes before or after a meal or snack; if the patient cannot eat, the dose is omitted [92, 107]. The label prohibits the intravenous route; the European summary of product characteristics (SmPC) warns that doses above 0.12 mg/kg twice daily should not be exceeded because they may increase the risk of neoplasia, and that this risk may be greater in unapproved uses or at doses above those recommended [92, 107]. The doses used in practice in severe IR reach almost five times the labelled daily maximum (0.24 mg/kg/day) and include unauthorised routes, so they lie outside the conditions of the label [1, 107].

Adverse effects and monitoring. Severe hypoglycaemia is the main risk; the label calls for pre-prandial blood glucose at the start and for avoidance of hazardous activities for 2 to 3 hours after the dose [1, 92]. Soft-tissue overgrowth and, with treatment, endometrial carcinoma and granulosa cell tumour have been described [1, 74]. The label also includes anaphylaxis, intracranial hypertension (fundoscopy at the start and periodically), tonsillar and adenoidal hypertrophy, slipped capital femoral epiphysis, progression of scoliosis and malignant neoplasms; it is contraindicated in active or suspected neoplasia, with closed epiphyses and, because of benzyl alcohol (9 mg/mL), in preterm infants and newborns [92, 107]. This neonatal contraindication conflicts with the time at which treatment of DS would make most sense; the reports of neonatal treatment do not discuss the excipient in the sources consulted. Adverse effects have prevented approval and widespread use in this indication [39]. Orphanet also mentions mecasermin rinfabate (rhIGF-1 combined with the binding protein IGFBP3), used in uncontrolled studies [8].

Access. Increlex® 10 mg/mL (4 mL vial) has been authorised in Portugal since 03-08-2007; it is a restricted prescription-only medicine for exclusive hospital use, with 0% reimbursement, additional monitoring and educational materials [108]. In Brazil there is no registration of mecasermin in ANVISA's open data (search on 26-10-2026) [103].

7.6. Metreleptin

Mechanism and rationale. Metreleptin is recombinant human leptin. In RMS, leptin is low, and supraphysiological doses (about 3 times endogenous leptin) reduce appetite, BMI and, partly through that route, blood glucose [14, 16]. Because many patients develop antibodies that interfere with leptin assays, response and titration are assessed by clinical criteria; in the experience before 2011, these antibodies did not appear, in general, to reduce long-term efficacy, which the later US label warning on neutralising antibodies came to qualify [52, 93].

Evidence. In the first study, in 2004, one year of metreleptin combined with insulin, metformin and pioglitazone improved blood glucose, HbA1c, insulinaemia, insulin dose, calorie intake and fat mass [1, 109]. In the NIH open-label trial (NCT00085982; inclusion with leptin <12 ng/mL in women and <6 ng/mL in men), five pubertal adolescents with RMS and HbA1c >9% went from HbA1c of 11.4% ± 1.1% to 9.3% ± 1.9% at 6 months and 9.7% ± 1.6% at 12 months (P = 0.007), with a fall in the area under the OGTT glucose curve from 62,485 to 48,839 mg/dL × 180 min (P = 0.01), without change in the insulin and C-peptide areas, and with a fall in BMI z-score from −1.4 to −2.6 (P = 0.0006); after adjustment for BMI, the effect on HbA1c was at the threshold of significance (P = 0.069) [14]. In the two siblings treated for 10 years, HbA1c fell with each cycle and rose with each interruption [14]. The authors consider it promising but insufficient to reach HbA1c targets [14].

In a non-randomised comparison of 9 patients treated with high-dose metreleptin and 7 controls from the natural history study (11 unique patients, 5 in both groups, follow-up up to 90 months), HbA1c fell by 1.4 ± 1.1 points at 12 months with metreleptin (P = 0.006), versus +0.2 ± 0.7 in controls [16]. Over follow-up, HbA1c was 1.8 percentage points lower than in controls (P = 0.007), a difference that persisted after adjustment for insulin dose (P = 0.04); the greatest reduction occurred at 6 months (−2.3 ± 1.1%), and at 90 months HbA1c returned to baseline (−0.3 ± 3.1%) while in controls it rose [16]. There was no difference in fasting glucose, insulin, HOMA-IR, proteinuria, albuminuria or filtration rate, and GH rose without change in IGF-1 or stature, which suggests worsening of GH resistance with weight loss [16]. The trial registry, with 11 patients, gives as primary outcome a change in HbA1c at 12 months of −0.336 ± 1.921%, smaller than in the published high-dose subgroups, because it includes all those treated [110]. ISPAD mentions the long-term benefit in RMS [15].

Published dosing. At the NIH, metreleptin is given subcutaneously twice daily: in the first two siblings, from 0.02–0.03 mg/kg/day titrated over years up to 0.22–0.24 mg/kg/day; in subsequent patients, starting directly at 0.22–0.24 mg/kg/day; in the 2022 cohort, a mean starting dose of 0.20 ± 0.03 mg/kg/day (0.15–0.24) [14, 16]. The half-life and time to peak are about 3 hours, with renal clearance [14]. These doses are those of published practice in RMS.

Comparison with the label. Myalept® (US, initial approval on 24-02-2014) is indicated only in congenital or acquired generalised lipodystrophy and is expressly declared not indicated in metabolic disease, including diabetes, without generalised lipodystrophy; Myalepta® (EU, authorisation on 30-07-2018 under exceptional circumstances, renewed on 31-03-2023) is indicated in generalised lipodystrophy from 2 years of age and in familial or acquired partial lipodystrophy from 12 years of age when standard treatment fails [93, 111]. RMS falls outside the indication in both jurisdictions. The label provides for one daily injection: with weight ≤40 kg, start at 0.06 mg/kg/day, adjustments of 0.02 mg/kg and a maximum of 0.13 mg/kg/day; in males >40 kg, start at 2.5 mg/day; in females >40 kg, start at 5 mg/day; adjustments of 1.25–2.5 mg and a maximum of 10 mg/day [93, 111]. The NIH regimen, with 0.15–0.24 mg/kg/day in two doses, exceeds the labelled maximum for ≤40 kg and differs in dose splitting [16, 93]. The European SmPC defines minimum response as a fall of 0.5% in HbA1c and/or 25% in insulin dose and/or 15% in triglycerides, with review at 6 months, increases no more often than every 4 weeks, and reductions of 50% or more in insulin in the initial phase [111].

Adverse effects. The US label includes a boxed warning on anti-metreleptin antibodies with neutralising activity (loss of efficacy, severe infections, metabolic worsening) and T-cell lymphoma in acquired generalised lipodystrophy, and restricts dispensing to a risk evaluation and mitigation strategy (REMS) programme [93]. The lipodystrophy guideline adds hypoglycaemia with insulin, injection site reactions and pancreatitis due to rebound hypertriglyceridaemia on abrupt discontinuation [90]. Appetite suppression and the fall in BMI may worsen GH resistance and do not improve growth [1, 16]. The serious events recorded in the NIH trial registry include acute kidney injury, DKA (2 patients), septic shock, seizure and a papillary thyroid carcinoma [110].

Access. Myalepta® (3 mg, 5.8 mg and 11.3 mg, Chiesi) is authorised and marketed in Portugal; in Brazil, Myalept® has an active ANVISA registration (registration 100580123, Chiesi Farmacêutica Ltda.), whose package leaflet text was not obtained [103, 112].

7.7. Diabetic ketoacidosis in RMS

DKA in RMS requires intravenous insulin at doses far above the usual, up to 500 U/hour according to GeneReviews, including intravenous U-500, a route not provided for in the label [1, 94, 99]. In a 7-year-old Indian child with refractory DKA, the insulin infusion was increased up to 12 U/kg/hour, without bicarbonate and with potassium monitoring; the 3-year-old brother, diagnosed by cascade testing before decompensating, was treated with subcutaneous insulin and sensitisers, and HbA1c at 1 year was 10.4% and 8.9% [70]. The U-500 label includes hypokalaemia among its warnings, which justifies potassium monitoring during high-dose infusions [70, 94].

7.8. Hyperandrogenism and the ovary

The ovarian hyperandrogenism of severe IR is treated with the strategies used in PCOS, according to ISPAD: combined oral contraceptives, antiandrogens (spironolactone, flutamide) and finasteride [1, 15]. Testosterone can generally be brought into the female range with GnRH analogues, which suppress gonadotrophins; the «block and replace» strategy (GnRH analogue with hormone replacement) has not been formally evaluated [3]. In the NIH-Cambridge cohort, GnRH analogues were used in 6 patients (2 with type B, 2 with INSR, 1 with TBC1D4 and 1 with acquired partial lipodystrophy): all improved their hyperandrogenic symptoms and reached normal or near-normal testosterone, without change in insulin sensitivity or blood glucose, and oophorectomy was avoided in five [17]. The recorded regimens, all off-label, are as follows [17]:

There is no guideline dose for this indication; the doses of leuprorelin and goserelin are those of the published cases, and the labels of these analogues were not consulted for comparison. In infants with DS and massive ovarian enlargement, the authors suggest considering GnRH analogues [17]. Gonadectomy is reserved for respiratory distress, interference with development or suspicion of a granulosa cell tumour, and oophorectomy is sometimes necessary in type A and in RMS [1, 51]. Because five patients in the cohort had virilising tumours, the hyperandrogenaemia of severe IR should not be presumed benign, although the usual threshold of 150 ng/dL for searching for a tumour is frequently exceeded without a tumour in this population [17].

7.9. Other complications and supportive care

HCM is followed by paediatric cardiology and treated with beta-blockers [1]. Nephrocalcinosis and hypercalciuria are followed by nephrology, with attention to the effects of SGLT2 inhibitors on urinary calcium [1, 71]. Hypothyroidism, including central hypothyroidism, is treated with levothyroxine at the usual dose; in an infant with DS the dose was 50 µg/day [1, 56]. Cholestasis, rectal prolapse, dental crowding and hearing loss require the respective specialties, and infections require early investigation and treatment [1]. In children and adults without cardiomyopathy, moderate physical activity of 30 minutes a day is recommended, with strength and resistance training, which is avoided in the presence of cardiomyopathy [39]. Growth does not improve with GH [1].

7.10. Post-receptor forms and HHF5

SHORT syndrome. The treatment of glucose intolerance and diabetes follows the standard approach (diet, lifestyle, oral antidiabetic agents, insulin), with caution with metformin, which worsened IR in three patients [21]. GH is contraindicated, because it worsens IR [21, 22, 42]. Glaucoma is followed by an experienced ophthalmologist; dental anomalies require prostheses or crowns; hearing loss, hearing aids; speech delay, speech therapy; infections, vaccination against otitis and respiratory infections; and joint laxity, avoidance of activities that overload the joints [21].

AKT2 lipodystrophy. Follows the treatment of the partial lipodystrophies, with metformin, concentrated insulin and, in the EU, metreleptin in refractory cases from 12 years of age [90, 111].

Hypoinsulinaemic hypoglycaemia due to activating AKT2. The three index patients needed a gastrostomy or tube for overnight carbohydrate feeding; there is no specific drug, and the need should be reassessed because the hypoglycaemia may remit [26, 77]. Drugs for hyperinsulinism and pancreatic surgery are not indicated, because insulin is suppressed [26].

TBC1D4. In Greenlandic homozygotes for p.(Arg684Ter), each daily hour of vigorous physical activity was associated with an additional reduction of about 0.7 mmol/L in 2-hour glucose in 2,655 participants, which makes exercise the intervention with the most evidence [27, 113]. A traditional low-carbohydrate marine diet for 4 weeks, in a randomised crossover trial, had no specific benefit in carriers [114].

HHF5 and type A IR with hypoglycaemia. Split low glycaemic index meals and acarbose (section 7.3) [3].

7.11. Type B insulin resistance

Type B is not genetic, but treatment changes the prognosis and justifies the differential diagnosis. Historically, with plasmapheresis or immunosuppression alone, mortality was 54% and remission 41.4% (12/29); hypoglycaemia is associated with death in about half of cases [30, 91]. Malek and colleagues treated 7 patients with rituximab, cyclophosphamide and pulsed corticosteroids, with remission in all (insulin discontinued, HbA1c normalised, hyperandrogenism resolved) at a mean of 8 months and without serious adverse events [115]. In the NIH prospective cohort of 22 patients (86.4% women, median age 42 years, median follow-up 72 months), with baseline blood glucose of 307 mg/dL, HbA1c of 11.8% and insulin of 1,775 U/day (863–2,700), remission occurred in 19 (86.4%) at 5 months (4–6.3), with insulin discontinued in all, blood glucose of 80 mg/dL and HbA1c of 5.5%; there was relapse in 3 (13.6%) at 24 months, responsive to retreatment, and no deaths (P = 0.001 versus the historical cohort) [91].

The NIH protocol, applied in adults (median age 42 years, interquartile range 25 to 57), is as follows; the source does not define maximum doses, and the highest cumulative cyclophosphamide doses recorded were 31,700 mg (persistent leucopenia and herpes zoster reactivation) and 155,000 mg [91]:

The median exposures were 1 cycle of rituximab, 5 corticosteroid pulses, 6 months of cyclophosphamide and 12 months of azathioprine [91]. There was neutropenia <1,500/µL in 8 patients (38.1%), one severe case treated with granulocyte colony-stimulating factor, and one episode of macroscopic haematuria; prophylaxis against hepatitis B reactivation with lamivudine was used in 2 patients and isoniazid in 1 [91]. Corticosteroid pulses transiently worsen hyperglycaemia, with a 50–100% increase in insulin (one patient reached 24,000 U/day by infusion during DKA), and, as titres fall, hypoglycaemic episodes appear that require insulin to be reduced, starting with the night-time doses, because the half-life of insulin is prolonged [91]. The US rituximab label includes a boxed warning on fatal infusion reactions, severe mucocutaneous reactions, hepatitis B reactivation and progressive multifocal leucoencephalopathy [116]. Other drugs (ciclosporin A, azathioprine, intravenous immunoglobulin and plasmapheresis) had variable effects [39]. In refractory cases there are isolated reports: obinutuzumab with mycophenolate mofetil in two French patients with SLE [117] and daratumumab (an anti-CD38 antibody) in a 24-year-old man with SLE and lupus nephritis who reached 215,000 U/day of insulin, failed corticosteroids, rituximab, cyclophosphamide, obinutuzumab, plasmapheresis and immunoglobulin, and had a progressive fall in insulin until discontinuation at 17 months, with lasting remission [31]. Orphanet summarises that rituximab and immunosuppressive combinations induce remission in most patients, followed by maintenance, with large amounts of insulin and treatment of hypoglycaemia (diet, insulin adjustment, corticosteroids) until remission is achieved [30].

7.12. Comparative regulatory status

7.13. Treatment trials and studies

None of these studies is randomised and controlled. The difference between the NCT00085982 registry (−0.34% HbA1c in 11 patients) and the published high-dose subgroups (−1.4 to −1.7 points) shows the effect of patient selection and dose, and subgroup results should not be read as an estimate of the overall effect [14, 16, 110]. Okawa's comparison uses historical controls partially overlapping with those treated, with different baseline HbA1c (10.7% versus 8.8%; P = 0.03), which limits causal inference [16]. The evidence on rhIGF-1, SGLT2 inhibitors and tirzepatide comes from cases and series; they cannot be compared with each other or with metreleptin [1, 58, 98]. The liothyronine study did not lead to clinical use and has no comparative results [119]. The ClinicalTrials.gov search of 26-10-2026 found no active trials of gene therapy, of INSR agonists in humans or of mecasermin for INSR; a negative search does not prove absence [121]. Among the open studies are the NIH natural history study (NCT00001987, since 1976, recruiting, 1,200 participants planned) and a diagnostic study by Assistance Publique–Hôpitaux de Paris (NCT07412028, recruiting since 21-07-2026, 81 participants) searching for genetic severe IR among women with «classic» PCOS by the Rotterdam criteria [79, 122]. Mibavademab, a leptin receptor agonist antibody, is in phase III in generalised lipodystrophy (NCT07220785), with no study registered in INSR [123].

7.14. Developments in the last 12 months

The table distinguishes the level of evidence of each development published between October 2025 and October 2026.

There is no new regulatory authorisation, EMA opinion or sponsor announcement on treatments for severe INSR-related IR in the sources consulted.

7.15. Anaesthesia and the perioperative period in Donohue syndrome

The orphananesthesia recommendations (Great Ormond Street Hospital, London, March 2021) were reviewed by two anaesthetists and not by an expert in the disease, as the document itself states [4]. Typical procedures are central venous access, endoscopy, magnetic resonance imaging, gastrostomy and laparotomy, and whether the benefit justifies anaesthesia should always be weighed [4]. The main points are [4]:

Neuraxial and peripheral nerve blocks are not contraindicated, although there are no reports; sedation carries a risk of difficult airway, haemodynamic instability and hypoglycaemia during sleep and requires immediate anaesthetic support [4]. The document gives an incidence of 1 in 4 million births, based on its own references, a value different from the estimate used by GeneReviews (section 9) [1, 4].

7.16. Agents and circumstances to avoid

In DS, agents that cause hypoglycaemia, prolonged fasting and contact with people with contagious illness should be avoided [1]. In RMS, agents that cause hyperglycaemia, a high-carbohydrate diet and contact with contagious patients should be avoided; the GeneReviews summary says «agents that cause hypoglycaemia» for RMS, but the body of the text and GeneGuidance indicate hyperglycaemia, which is the version followed [1, 2]. Corticosteroids worsen hyperglycaemia, as shown by the pulses of the type B protocol and by the pregnancy of the patient with SHORT exposed to corticosteroids [91, 126]. In SHORT syndrome, GH is contraindicated and metformin requires caution [21]. In DS, non-steroidal anti-inflammatory drugs and nephrotoxic agents should be avoided in the perioperative period [4]. Thiazolidinediones combined with insulin increase the risk of fluid retention and heart failure [94]. A rapid fall in HbA1c may precipitate proliferative retinopathy [58].

7.17. Pregnancy and lactation

IR worsens in pregnancy [90]. In a 31-year-old New Zealand woman, with a high BMI and a previous diagnosis of «type 2 diabetes», the heterozygous pathogenic INSR variant was identified during pregnancy, and insulin reached 2,200 U/day; in a 25-year-old woman with SHORT and lipodystrophy, insulin reached 766 U/day after corticosteroids in the second trimester, the first published case of SHORT in pregnancy according to the authors [126]. There are successful pregnancies in SHORT, with diabetes managed as usual, and in AKT2 lipodystrophy [17, 21]. Heterozygotes for INSR variants have an increased risk of gestational diabetes and should be monitored for glucose intolerance before and during pregnancy, according to GeneReviews; the reference GeneReviews cites for this statement (Kleijer 2006) deals with the prenatal diagnosis of Cockayne syndrome and does not support it, and the data that do support it are those of the carrier cohort, with gestational diabetes in 20–53% of pregnancies (preprint) [1, 55, 127]. By analogy with the lipodystrophy guideline, prenatal care by an obstetrician experienced in diabetes and by a physician experienced in the disease is recommended (Class IIa, Level C); metreleptin may be continued if discontinuation would harm the mother and fetus and the patient accepts the unknown effects (Class IIc, Level C), bearing in mind the risk of pancreatitis from rebound triglycerides on discontinuation [90]. A 2025 commentary in Nature Reviews Endocrinology advocates a multidisciplinary intervention for severe IR in pregnancy [128]. The sources consulted do not describe breastfeeding in women with genetic severe IR or the transfer of metreleptin or mecasermin into milk.

7.18. Children, puberty and transition

Puberty is the period in which IR worsens, hyperandrogenism manifests and, in RMS, diabetes becomes refractory, which makes the transition to adult care a time of risk [1, 129]. Wei and Burren described the diagnostic and therapeutic challenges from childhood and puberty through to transition, and Al-Kandari and colleagues a 5-year follow-up of two siblings with RMS in Kuwait [129, 130]. The transition plan should include glycaemic control (including access to concentrated insulin), screening for microvascular complications, treatment of hyperandrogenism, contraception and reproductive counselling (section 8) [1, 15].

7.19. Guideline recommendations and divergences

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by mode of inheritance

DS and RMS (AR). The parents of a patient are presumed to be heterozygous and should both be tested [1]. If both are heterozygous, each sibling has, at conception, a 25% risk of being affected, 50% of being heterozygous and 25% of inheriting neither variant [1, 8]. If only one parent is a carrier, with confirmed parentage, the second variant may be de novo in the proband or present as post-zygotic mosaicism in a parent [1, 131]. Apparent homozygosity may result from an undetected deletion masking the second allele or from uniparental isodisomy [1]. Aunts and uncles on the side of a carrier parent have a 50% risk of being carriers [1]. Patients with DS and RMS are not known to have had children [1].

Type A IR and HHF5 (AD). Each child of an affected person has a 50% risk of inheriting the variant [6, 10]. Expressivity is variable and greater in women; male carriers may present only with diabetes or postprandial hypoglycaemia [3, 55]. In the rare biallelic forms of type A, the recessive risk applies.

SHORT syndrome (AD). About 70% of cases are de novo; heterozygous parents always have clinical signs (short stature, lipodystrophy, face), which allows carriers to be identified on examination; gonadal mosaicism is possible, as the affected siblings in Gorlin's 1975 description suggest; each child of a patient has a 50% risk [21].

AKT2 forms. The activating variant p.(Glu17Lys) arises de novo, often in mosaic form, so the risk for siblings is low; the loss-of-function variant p.(Arg274His) segregates dominantly [24, 25].

8.2. Heterozygous carriers of recessive forms

Heterozygotes are generally asymptomatic, but may have features of type A IR, and women have an increased risk of gestational diabetes [1]. The first heterozygous parent described, carrying a nonsense allele, had moderate IR, and the cohort of 505 monoallelic carriers (preprint) shows moderate to severe IR from puberty in many carriers of extracellular and loss-of-function variants [46, 55]. Therefore, the parents of a child with DS or RMS benefit from metabolic assessment (blood glucose, insulin, HbA1c and, in women, assessment of hyperandrogenism and monitoring in pregnancy), and not merely from confirmation of carrier status [1, 3, 8]. Orphanet suggests semidominant inheritance in these families [5, 8].

8.3. Cascade testing and partners

Once the variants have been identified, carrier testing in at-risk relatives is possible [1]. Testing the partners of carriers is recommended, especially when they share ancestry, as in consanguineous couples and in the Druze population of Israel, where the c.167T>C variant is frequent [1, 6]. Cascade testing in siblings of patients with RMS allows diagnosis before decompensation, as in the 3-year-old brother diagnosed with hyperglycaemia and treated before DKA [70]. In type A IR, diagnosis in a girl should lead to testing of the father and the remaining first-degree relatives [3].

8.4. Prenatal and preimplantation diagnosis

Prenatal diagnosis by chorionic villus sampling and preimplantation genetic testing are possible once the familial variants have been identified [1, 10]. In the Israeli family with p.(Cys286Tyr), three prenatal diagnoses identified one homozygous fetus and two heterozygotes, the latter born healthy [56]. In the absence of known variants, ultrasound showing IUGR and HCM suggests, but does not confirm, DS [60]. In SHORT and type A, prenatal diagnosis is technically possible, but the decision should weigh the variable expressivity and the normal life expectancy in SHORT [21, 22].

8.5. Counselling of minors and women of reproductive age

In the AR forms, because heterozygotes may have IR from puberty, knowledge of a minor's carrier status can guide metabolic monitoring from that age [1, 55]; in SHORT and type A, testing at-risk children allows monitoring of blood glucose, eyes, hearing and puberty [1, 21]. In women carrying INSR variants or with SHORT, preconception counselling should include the risk of gestational diabetes, the worsening of IR in pregnancy, review of medications (metreleptin, SGLT2 inhibitors, GLP-1 agonists) and the multidisciplinary obstetric plan [55, 90, 126].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each figure measures

There is no published population prevalence of the INSR forms in the sources consulted. The estimate of 1:1,000,000 for DS, cited by GeneReviews, comes from Desbois-Mouthon and colleagues (1997) and not from a population study; Orphanet classifies DS and RMS as <1/1,000,000 and describes DS as of unknown prevalence; the anaesthesia document gives 1 in 4 million births, by indirect citation [1, 4, 8, 85]. GeneReviews counts 96 published patients with DS or RMS with a molecular diagnosis and about 10 with a clinical diagnosis only, a number of published cases and not a prevalence [1]. GeneGuidance gives a frequency of 0.1/100,000 that refers only to DS and does not cover type A, which is underdiagnosed and confused with PCOS [2]. The estimate that severe IR syndromes account for 0.1–0.5% of patients attending hospital diabetes clinics comes from the experience of the Cambridge reference centres (Semple 2011), and not from a population study [3, 39, 52]. For SHORT, the 2026 GeneReviews counts 61 published individuals, the 2019 Orphanet fewer than 50 and the 2022 Smith's more than 30 [21, 22, 42]. For type B, the authors of a 2026 case report count fewer than 200 described [31].

9.2. Founder populations and regional data

In the published series, some of the recessive cases come from consanguineous families from the Middle East and North Africa, such as the two Israeli families, both of first cousins [56]. The French registry shows that regional differences depend on founder effects and local expertise and that underdiagnosis persists [125]. The absence of data from Portugal in the sources consulted does not demonstrate the absence of cases.

9.3. Sex differences and special populations

Females dominate the probands with heterozygous forms (ratio 1:3.4) because ovarian hyperandrogenism makes IR visible earlier; men with the same variant are diagnosed later, often as type 2 diabetes [3, 55]. In men, the prediabetic phase manifests only as acanthosis and, sometimes, postprandial hypoglycaemia, which rarely prompt consultation, and the diagnosis may be missed even after symptomatic diabetes; women also have more marked hyperinsulinaemia and dyslipidaemia than men, which in lipodystrophy is explained partly by the greater proportion of white adipose tissue in healthy women [52]. Type B affects mainly middle-aged women and, in the US, mainly Black women with SLE [30, 88]. Infants with DS and pregnant women with severe IR are the populations at greatest acute risk (sections 7.15 and 7.17).

9.4. European network and patient resources

The relevant European reference network is Endo-ERN, thematic group MTG3 «Genetic Disorders of Glucose & Insulin Homeostasis», with a subgroup for IR syndromes and others for hyperinsulinism and rare diabetes [18]. In France there is a national reference network for lipodystrophies and severe IR, with registration in the BNDMR [125]. The reference laboratories listed by ISPAD include Exeter (diabetesgenes.org), Chicago (monogenicdiabetes.uchicago.edu), Norway (mody.no) and EURO-WABB (euro-wabb.org) [15]. For patients and families, GeneReviews points to the MedlinePlus «Donohue syndrome» page and the NORD «Leprechaunism» page and, for SHORT, MedlinePlus, the Human Growth Foundation, the MAGIC Foundation and the National Eye Institute's low vision resources [1, 21]. The Oxford Desk Reference points to Diabetes UK and the Exeter Diabetes Genes website [10]. The October 2026 search found no patient association dedicated to DS, RMS or type A.

10. Illustrative Clinical Case

Falik Zaccai and colleagues, from the Nahariya Medical Center (Israel), described in 2014 three newborns with Donohue syndrome from two unrelated families, both with first-cousin parents: a girl of Muslim Arab parents (ISR1) and two brothers of Druze parents (ISR2 and ISR3) [56]. All three had IUGR, facies described as «elfin» (coarse face, prominent eyes, thick lips), absence of subcutaneous fat, hirsutism, nipple hypertrophy, direct hyperbilirubinaemia with raised gamma-glutamyltransferase, growth retardation and HCM [56]. Figure 1 of the article, consulted (https://pmc.ncbi.nlm.nih.gov/articles/PMC3907912/figure/fig01/), shows the patients' clinical features [56].

Insulin is expressed in the article in «IU/mL», a unit that, given the normal range of 5–25, probably corresponds to µU/mL [56].

ISR1. The girl, the couple's second child, presented at 14 days with abdominal distension and irritability, weighing 1,900 g, with hypertrophy of the labia majora and clitoromegaly; ultrasound showed ovaries with bilateral multicystic masses (10 × 10 × 20 mm and 7 × 13 × 15 mm) and enlarged kidneys [56]. She did not gain weight and had hypoglycaemia, acanthosis, abdominal distension and rectal prolapse; the echocardiogram showed left ventricular hypertrophy, and ultrasound showed enlarged kidneys with medullary nephrocalcinosis and still larger ovaries (50 × 70 × 75 mm on the left and 20 × 40 × 45 mm on the right) [56]. She had recurrent infections (urosepsis, bilateral otitis media, pneumonia), did not reach neurological milestones and died at 18 months of aspiration pneumonia [56]. She was homozygous for a variant described as c.858G>A p.C286Y in exon 3, in the extracellular α subunit; normalisation shows that the correct nucleotide notation is NM_000208.4:c.857G>A p.(Cys286Tyr) [9, 56].

ISR2. The Druze couple's third child was born at 34 weeks, after a prenatal ultrasound showing polyhydramnios and enlarged kidneys, bladder and stomach; he had IUGR, dysmorphism, hirsutism, hepatosplenomegaly and hypotonia [56]. He had alternating hypoglycaemia and hyperglycaemia; at 3 days a systolic murmur was heard, and the echocardiogram showed severe HCM of the left ventricle and septum; at 2 weeks he had Klebsiella sepsis, and he died at 40 days of respiratory failure and cardiac arrest [56].

ISR3. The brother was born at 38 weeks with symmetrical IUGR and cardiomegaly already visible on prenatal ultrasound; he had left ventricular hypertrophy and mild pulmonary stenosis [56]. At 2 months hypothyroidism was diagnosed, treated with levothyroxine 50 µg/day; at 3 months he weighed 3.1 kg and had acanthosis, rectal prolapse and an inguinal hernia; at 7 months he had severe developmental delay, bilateral hernias, hypotonia, severe cardiac hypertrophy, raised liver enzymes and factor VII deficiency, and magnetic resonance imaging did not visualise the posterior pituitary and showed slow myelination [56]. He had urosepsis at 10 months (4,125 g, −6 SD; head circumference 42 cm, −3 SD) and pneumonia at 11 months, and died at 12 months after an episode of atrial fibrillation [56]. The two brothers were homozygous for NM_000208.4:c.167T>C p.(Ile56Thr) in exon 2; the parents and a healthy brother and sister were heterozygous, and another healthy sister was not a carrier [9, 56].

Functional study and counselling. In fibroblasts from ISR1 and ISR3 the Western blot detected the proreceptor but not the mature subunits, and tyrosine phosphorylation was absent at rest and after stimulation with insulin, whereas expression and phosphorylation of the IGF-1 receptor in response to IGF-1 were normal [56]. Both variants, both in the extracellular domain, compromised receptor processing [56]. In ISR1's family, three prenatal diagnoses by chorionic villus sampling identified one homozygous fetus (pregnancy terminated) and two heterozygotes, who were born healthy; in carrier screening, none of 95 healthy Muslims had the p.(Cys286Tyr) variant, and 1 of 52 healthy Druze from the family's village had p.(Ile56Thr) [56].

Clinical reading. The three patients illustrate the natural history of DS without targeted treatment: extreme hyperinsulinaemia with very high C-peptide, alternating blood glucose, HCM, nephrocalcinosis, ovarian enlargement, infections and death before 2 years of age [1, 56]. The authors mention the high-dose insulin and rhIGF-1 used by other groups and, faced with a fatal course without effective treatment, stress the value of identifying the variant for counselling and prenatal diagnosis [56]. The report does not describe the use of rhIGF-1, which GeneReviews now considers reasonable in any patient with severe syndromic IR, nor the structured echocardiography and glycaemic monitoring that GeneReviews and the anaesthesia recommendations propose [1, 4].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

In DS, death usually occurs in the first year, from hypoglycaemia, infection and cardiomyopathy; HCM, present in about 30% of infants, is one of the main causes, and survival beyond 2 years is rare [1, 8, 39]. There are long survivals with rhIGF-1 in isolated reports (10 years in Kerdanet's patient), which do not allow the effect of treatment to be estimated [59, 69]. In RMS, death results from microvascular complications and DKA, usually in the second decade, with survival up to the third; high-dose metreleptin delays the rise in HbA1c without a demonstrated effect on survival [1, 16]. In type A, survival extends beyond middle age, but in the 30-year NIH cohort 3 of 11 patients (type A and RMS) died and 7 of 9 diabetics had serious complications [39, 51]. In SHORT, life expectancy is normal, with diabetes in all adults in the GeneReviews series [21, 22]. In hypoglycaemia due to activating AKT2, the hypoglycaemia may remit with age [26]. In type B treated with the NIH protocol there were no deaths over a median follow-up of 72 months, compared with a historical mortality of 54% [91].

11.2. Initial assessment

After a diagnosis of INSR-SIRS, GeneReviews recommends assessment by paediatric endocrinology (fasting and postprandial blood glucose or CGM, insulin and C-peptide, thyroid function, ovarian ultrasound in girls), by a dietitian, developmental assessment, paediatric cardiology with echocardiography and cardiac magnetic resonance imaging when indicated (with brain natriuretic peptide, N-terminal pro-brain natriuretic peptide (NT-proBNP), C-reactive protein, high-sensitivity troponin T and uric acid as biomarkers under evaluation), nephrology (electrolytes, 24-hour urinary calcium, renal ultrasound, renin-aldosterone axis), liver function tests with abdominal ultrasound and gastroenterology (cholestasis, rectal prolapse), oral and maxillofacial surgery when there is crowding, genetic counselling and family support [1]. In SHORT, the initial assessment includes growth and BMI, endocrinology with fasting glucose and OGTT from 10 years of age, ophthalmology (Axenfeld-Rieger, glaucoma), dental assessment from 1 year of age, hearing, speech, echocardiography, joint laxity and hernias, infections and, to be considered, renal ultrasound [21].

11.3. Surveillance table

The intervals are those of GeneReviews and do not result from studies of the effectiveness of surveillance [1, 21]. In patients on metreleptin, the European SmPC calls for assessment of response at 6 months and review of the self-administration technique every 6 months, and the lipodystrophy guideline indicates clinical and laboratory assessment every 3 to 6 months [90, 111].

12. Summary and Final Considerations

The severe INSR-related insulin resistance syndromes form a continuum defined by residual insulin receptor function. In Donohue syndrome, with biallelic variants and nil or minimal residual function, the infant is born with IUGR, absence of fat, hypertrichosis, genital enlargement, organomegaly and HCM, has extreme hyperinsulinaemia with fasting hypoglycaemia and postprandial hyperglycaemia and usually dies in the first year. In Rabson-Mendenhall syndrome, also recessive, survival extends to the second or third decade, with dental anomalies, nephrocalcinosis, GH resistance and progression to refractory diabetes with ketoacidosis and microvascular complications. In type A insulin resistance, generally dominant-negative, a lean young woman with acanthosis, hyperandrogenism and hyperinsulinaemia is frequently diagnosed as having PCOS, and men with the same variant as having type 2 diabetes; hyperinsulinaemic hypoglycaemia due to heterozygous INSR variants belongs to the same spectrum. Recent data, still in preprint, suggest that simple heterozygous loss of function also causes IR from puberty, with frequent hypoglycaemia and gestational diabetes, which changes the counselling of parents of patients with recessive forms.

Recognition rests on hyperinsulinaemia disproportionate to adiposity (with centre-specific thresholds, such as fasting insulin >150 pmol/L, and not on a universal criterion) and on markers that point to the receptor: preserved adiponectin and SHBG, low triglycerides, high HDL, absence of steatosis and a raised insulin/C-peptide ratio. The diagnosis is confirmed by sequencing of INSR with deletion analysis, paying attention to historical nomenclature without the signal peptide. The differential includes the lipodystrophies, the most frequent cause of severe IR, the post-receptor forms (PIK3R1/SHORT, AKT2, TBC1D4), the complex syndromes and autoimmune type B, which responds to combined immunosuppression.

No treatment is approved for the disease. Published practice combines frequent feeding in DS, sensitisers, SGLT2 inhibitors and U-500 concentrated insulin in RMS and type A, rhIGF-1 at doses above the label, especially in young children, and high-dose metreleptin in RMS, which lowers HbA1c without an effect on growth; hyperandrogenism responds to GnRH analogues. The evidence comes from series and single-centre open-label trials, the applicable guidelines (ISPAD 2022 and the 2016 lipodystrophy guideline, by analogy) diverge on the place of rhIGF-1, and the unavailability of U-500 and mecasermin in some jurisdictions limits access. Cardiac, renal, ovarian, thyroid and glycaemic surveillance, the specific perioperative care of DS and referral to Endo-ERN complete the approach.

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