Rabson-Mendenhall Syndrome

Endocrine MONDO:0009874 Pathograph 29 Show in embeddings browser Endocrine Disorder Genetic Disorder

A rare autosomal recessive disorder of extreme insulin resistance caused by biallelic (homozygous or compound heterozygous) loss-of-function variants in the insulin receptor gene (INSR). Defective insulin-receptor tyrosine-kinase signalling in target tissues blunts insulin action, producing severe insulin resistance with compensatory hyperinsulinaemia; the earliest biochemical hallmark is markedly elevated fasting insulin. Clinically it is defined by acanthosis nigricans, hypertrichosis/hirsutism, coarse facial features, dental and nail abnormalities, paucity of subcutaneous fat, growth retardation, and, in females, ovarian hyperandrogenism with enlarged/polycystic ovaries and clitoromegaly. The glycaemic course evolves from fasting hypoglycaemia with postprandial hyperglycaemia in infancy toward beta-cell decompensation, overt insulin-resistant diabetes mellitus, and recurrent diabetic ketoacidosis with microvascular complications in the second decade; complications of longstanding hyperglycaemia are the leading cause of death. Nephrocalcinosis is an almost invariable, apparently tissue-autonomous renal consequence of INSR loss. Rabson-Mendenhall syndrome occupies the intermediate position on the INSR-related severe insulin resistance spectrum (INSR-SIRS), between the neonatally lethal Donohue syndrome (leprechaunism) and the milder type A insulin resistance. It is distinct from the acquired, autoantibody-mediated type B insulin resistance syndrome.

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1
Inheritance
10
Pathophys.
21
Phenotypes
2
Gaps
29
Pathograph
1
Genes
11
Medical Actions
11
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive INSR inheritance HP:0000007
Rabson-Mendenhall syndrome is inherited in an autosomal recessive manner; each sib of an affected individual has a 25% chance of inheriting biallelic INSR pathogenic variants. Heterozygotes are usually asymptomatic but may have features of the allelic type A insulin resistance, and heterozygous females are at increased risk for gestational diabetes.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:29369573 SUPPORT Other
"each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected"
States the autosomal recessive recurrence risk.
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Discussions and Knowledge Gaps

2
Does the renal phenotype of kidney-specific Insr-knockout mice faithfully model the human renal consequences of INSR loss in Rabson-Mendenhall syndrome?
HUMAN MODEL MISMATCH OPEN rms_renal_insr_mouse_human_mismatch
Attached to
pathophysiology#Renal Insulin Receptor Dysfunction
Genetically modified mice with kidney-specific Insr deletion show elevated blood pressure and progressive diabetic nephropathy, whereas patients with biallelic INSR mutations are normotensive with stable glomerular function and only moderate proteinuria, their renal phenotype dominated instead by hypercalciuria and nephrocalcinosis. This suggests species-specific differences in renal INSR function and cautions against extrapolating the mouse renal phenotype to human disease.
Show evidence (1 reference)
PMID:25358339 SUPPORT Human Clinical
"Normotension and stable glomerular function with only moderate proteinuria is in contrast to genetically modified mice who have elevated BP and progressive diabetic nephropathy."
Directly contrasts the human renal phenotype with the murine model.
Why is there no genotype-phenotype correlation across the INSR-severity spectrum, and what determines an individual's position between Donohue, Rabson-Mendenhall, and type A insulin resistance?
KNOWLEDGE GAP OPEN rms_absent_genotype_phenotype_correlation
Attached to
genetic#
The pooled 42-patient analysis found no statistically significant differences in clinical or laboratory features between patients with different mutation types or numbers, and no genotype-phenotype correlation is established. The modifiers that set disease severity for a given INSR lesion are unknown.
Show evidence (1 reference)
PMID:38957655 SUPPORT Human Clinical
"No statistical differences were found in clinical features and laboratory parameters between patients with different mutations."
Documents the absence of a genotype-phenotype correlation.
⚙

Pathophysiology

10
Biallelic INSR Loss-of-Function
Biallelic pathogenic variants in the insulin receptor gene (INSR, 19p13.2) reduce the number and/or function of cell-surface insulin receptors, most commonly through missense substitutions that impair receptor processing, insulin-binding affinity, or tyrosine-kinase activity. This is the initiating molecular lesion of the syndrome.
Genetic context INSR hgnc:6091 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns INSR (hgnc:6091). hgnc:6091 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
insulin receptor tyrosine kinase activity GO:0005009 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves insulin receptor tyrosine kinase activity, annotated with insulin receptor activity (GO:0005009), qualified as loss of function. GO:0005009 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Impaired Insulin Receptor Signaling Reduced receptor number/affinity impairs signalling in insulin target cells.
Renal Insulin Receptor Dysfunction The insulin receptor is expressed in the kidney; biallelic INSR loss produces a renal phenotype (hypercalciuria, nephrocalcinosis) independent of the diabetic state.
Show evidence (2 references)
PMID:40499531 SUPPORT Human Clinical
"The novel mutation c.3670G>A in exon 21, inherited from the father, is likely to impair insulin receptor function by disrupting tyrosine kinase activity"
A worked variant example impairing insulin-receptor tyrosine-kinase function.
PMID:38957655 SUPPORT Human Clinical
"The mutation also caused a reduction in the affinity of the receptor to insulin"
Describes reduced receptor-insulin affinity as a consequence of INSR mutation.
Impaired Insulin Receptor Signaling
Loss of functional insulin receptor blunts the downstream insulin receptor signalling pathway, principally the PI3K-AKT metabolic arm, in liver, skeletal muscle, and adipose tissue, so target tissues fail to mount a normal glucose-lowering response to insulin.
Hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology. Adipocyte CL:0000136 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Adipocyte (CL:0000136). CL:0000136 is a cell type from the Cell Ontology. Skeletal muscle cell CL:0000188 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Skeletal muscle cell, annotated with cell of skeletal muscle (CL:0000188). CL:0000188 is a cell type from the Cell Ontology.
Insulin receptor signaling pathway GO:0008286 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Insulin receptor signaling pathway (GO:0008286). GO:0008286 is a biological process from the Gene Ontology. ↓ DECREASED PI3K-AKT signal transduction GO:0043491 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased PI3K-AKT signal transduction, annotated with phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491). GO:0043491 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Severe Insulin Resistance Blunted receptor signalling produces the defining extreme insulin-resistant state.
Show evidence (1 reference)
PMID:38957655 SUPPORT Human Clinical
"Insulin resistance is defined as the inability of target tissues to mount a normal coordinated glucose-lowering response at a normal plasma insulin level"
Defines the impaired target-tissue insulin response that this node represents.
Severe Insulin Resistance
Extreme, generalized insulin resistance is the cardinal systemic consequence, driving compensatory hyperinsulinaemia and the early paradoxical glycaemic pattern.
Downstream
Compensatory Hyperinsulinemia Target tissues require supraphysiologic insulin, driving compensatory hypersecretion.
Paradoxical Glycemic Regulation Residual insulin action plus massive hyperinsulinaemia yields fluctuating glucose.
Show evidence (1 reference)
PMID:41606799 SUPPORT Human Clinical
"Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS) are extreme forms of insulin resistance (IR) caused by biallelic mutations in the insulin receptor gene."
Establishes extreme insulin resistance as the defining state of the syndrome.
Paradoxical Glycemic Regulation
In infancy and early childhood, severely elevated insulin acting on residual receptor and cross-reactive pathways produces fasting hypoglycaemia with postprandial hyperglycaemia; with disease progression insulin levels decline and sustained hyperglycaemia supervenes.
Downstream
Hypoglycemia Fasting hypoglycaemia from severely increased insulin levels early in life.
Hyperglycemia Postprandial hyperglycaemia from failure of insulin-stimulated glucose disposal.
Show evidence (2 references)
PMID:29695048 SUPPORT Human Clinical
"At birth, patients with RMS also show fasting hypoglycemia due to severely increased insulin levels, but with progression of the disease, insulin levels decline"
Documents the early paradoxical hypoglycaemia and its later decline.
PMID:40241988 SUPPORT Human Clinical
"At an early stage, fasting hypoglycemia with postprandial hyperglycemia and significant hyperinsulinemia with subsequent development of insulin-resistant diabetes is observed."
Directly describes the paradoxical fasting-hypoglycaemia/postprandial-hyperglycaemia pattern.
Compensatory Hyperinsulinemia
Pancreatic beta-cell hypersecretion produces the extreme hyperinsulinaemia that is the earliest biochemical hallmark of the syndrome (median fasting insulin ~300 uIU/mL, versus a normal range of 5-20 uIU/mL). Chronic hyperinsulinaemia cross-activates IGF-1 receptors in skin and ovary and ultimately exhausts beta-cell reserve.
Pancreatic beta cell CL:0000169 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Pancreatic beta cell, annotated with type B pancreatic cell (CL:0000169). CL:0000169 is a cell type from the Cell Ontology.
Downstream
Cutaneous IGF-1 Receptor Cross-activation High insulin stimulates keratinocyte IGF receptors.
Ovarian Androgen Excess Hyperinsulinaemia drives ovarian hyperandrogenism in females.
Pancreatic Beta-Cell Decompensation Chronic hyperstimulation leads to eventual secretory failure.
Growth Hormone Resistance and Growth Failure High insulin may interact with IGF-I receptors and feedback-reduce GH secretion.
Hyperinsulinemia The measured laboratory hyperinsulinaemia.
Show evidence (2 references)
PMID:38957655 SUPPORT Human Clinical
"Hyperinsulinemia is typically observed early in the lives of RMS patients"
Establishes early compensatory hyperinsulinaemia in RMS.
PMID:38957655 SUPPORT Human Clinical
"the mean fasting insulin was 349.96 μIU/mL, and the average fasting C-peptide was 6.00 ng/mL."
Quantifies the extreme fasting hyperinsulinaemia and C-peptide in the pooled cohort.
Cutaneous IGF-1 Receptor Cross-activation
Chronic supraphysiologic insulin cross-activates IGF-1 receptors on keratinocytes and dermal fibroblasts, promoting epidermal proliferation that manifests as acanthosis nigricans and contributes to soft-tissue overgrowth.
Keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology. Fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
Downstream
Acanthosis nigricans Keratinocyte hyperproliferation produces acanthosis nigricans.
Show evidence (1 reference)
PMID:38957655 SUPPORT Human Clinical
"High levels of insulin stimulate IGF receptors, thereby promoting the proliferation of keratinocytes."
States the IGF-receptor cross-activation mechanism driving keratinocyte proliferation.
Ovarian Androgen Excess
In females, extreme hyperinsulinaemia acting on ovarian theca cells drives androgen biosynthesis, producing hyperandrogenism, enlarged/polycystic ovaries, and clitoromegaly.
Ovarian theca cell CL:0000503 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Ovarian theca cell, annotated with theca cell (CL:0000503). CL:0000503 is a cell type from the Cell Ontology.
Androgen biosynthetic process GO:0006702 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Androgen biosynthetic process (GO:0006702). GO:0006702 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Hyperandrogenism Ovarian androgen excess produces clinical hyperandrogenism.
Enlarged external genitalia Androgen excess contributes to clitoromegaly/enlarged external genitalia.
Enlarged ovaries Hyperinsulinaemia-driven ovarian stimulation produces enlarged/polycystic ovaries.
Show evidence (1 reference)
PMID:40241988 SUPPORT INDIRECT Human Clinical
"Girls are diagnosed with hyperandrogenism, ovarian enlargement and clitoral hypertrophy."
Documents the ovarian hyperandrogenism phenotype; the theca-cell mechanism is inferred.
Pancreatic Beta-Cell Decompensation
Sustained compensatory hypersecretion eventually exhausts beta-cell reserve, so hyperinsulinaemic hypoglycaemia gives way to sustained hyperglycaemia and overt insulin-resistant diabetes mellitus.
Pancreatic beta cell CL:0000169 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Pancreatic beta cell, annotated with type B pancreatic cell (CL:0000169). CL:0000169 is a cell type from the Cell Ontology.
Downstream
Insulin-resistant diabetes mellitus Beta-cell failure precipitates overt insulin-resistant diabetes.
Show evidence (1 reference)
PMID:25358339 SUPPORT Human Clinical
"The severe insulin resistance leads to hyperinsulinism with pancreatic β-cell decompensation, diabetes, hyperglycemia and ultimately ketoacidosis"
Directly links beta-cell decompensation to diabetes and ketoacidosis.
Renal Insulin Receptor Dysfunction
The insulin receptor is expressed throughout the nephron. Biallelic INSR loss produces hypercalciuria and nephrocalcinosis that appear tissue-autonomous (present with normotension and stable glomerular function), rather than being a secondary complication of hyperglycaemia.
Downstream
Nephrocalcinosis Hypercalciuria from renal INSR dysfunction produces nephrocalcinosis.
Proteinuria Renal INSR dysfunction is associated with low-grade proteinuria in a subset.
Show evidence (2 references)
PMID:25358339 SUPPORT Human Clinical
"Twenty-four-hour urinary calcium data were available from 10 patients and revealed hypercalciuria in all"
Documents universal hypercalciuria underlying the nephrocalcinosis.
PMID:41606799 SUPPORT Human Clinical
"Renal tubular dysfunction with nephrocalcinosis is almost invariably present"
Independent series confirming near-invariable renal tubular dysfunction with nephrocalcinosis.
Growth Hormone Resistance and Growth Failure
Affected individuals show a growth-hormone-resistant state (elevated basal GH with low-normal IGF-1) and severe growth retardation that is not corrected by exogenous growth hormone or standard-dose IGF-1.
Downstream
Growth delay GH resistance contributes to growth retardation/short stature.
Show evidence (2 references)
PMID:34718628 SUPPORT Human Clinical
"Rabson-Mendenhall syndrome (RMS) is caused by biallelic pathogenic variants in the insulin receptor gene (INSR) leading to insulin-resistant diabetes, microvascular complications, and growth hormone resistance with short stature."
Names growth hormone resistance with short stature as a defining feature.
PMID:23367497 SUPPORT Human Clinical
"Basal growth hormone (GH) was increased (7.9 μg/L)with normal insuline-like growth factor 1 (37.6 nmol/L) suggestive of GH resistance."
A case with elevated basal GH and normal IGF-1 interpreted as GH resistance.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Rabson-Mendenhall Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

21
Cardiovascular 1
Atrial septal defect HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23367497 SUPPORT Human Clinical
"Echocardiography revealed ostium secundum type atrial septal defect (ASD)."
Single case report documenting an atrial septal defect in the RMS phenotype.
Digestive 1
Protuberant abdomen 5/42 (12%) HP:0001538 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Protuberant abdomen (HP:0001538). HP:0001538 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38957655 SUPPORT Human Clinical
"a protuberant abdomen (5/42, 11.90%)"
Reports a protuberant abdomen in 5/42 pooled patients.
Endocrine 4
Hyperinsulinemia HP:0000842 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperinsulinemia (HP:0000842). HP:0000842 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38957655 SUPPORT Human Clinical
"Twenty-six individuals had access to fasting insulin; all had high levels, ranging from 114 to 861 uIU/mL with a median of 300.00 (normal range: 5.00-20.00 uIU/mL)."
Documents universal extreme fasting hyperinsulinaemia.
Insulin-resistant diabetes mellitus 25/33 (76%) HP:0000831 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Insulin-resistant diabetes mellitus (HP:0000831). HP:0000831 is a phenotype from the Human Phenotype Ontology.
Sequelae: Diabetic ketoacidosis
Show evidence (1 reference)
PMID:38957655 SUPPORT Human Clinical
"Diabetes was reported in 25 cases (25/33, 75.76%) all of which were diagnosed before 23 years old."
Reports insulin-resistant diabetes in 25/33 evaluable pooled patients.
Diabetic ketoacidosis HP:0001953 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Diabetic ketoacidosis (HP:0001953). HP:0001953 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29695048 SUPPORT Human Clinical
"In contrast to DS, patients develop recurrent diabetic ketoacidosis and microvascular complications during the second decade of life"
Documents recurrent DKA and microvascular complications in the second decade.
Hyperandrogenism Increased circulating androgen concentration HP:0030348 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperandrogenism, annotated with Increased circulating androgen concentration (HP:0030348). HP:0030348 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40241988 SUPPORT Human Clinical
"Girls are diagnosed with hyperandrogenism, ovarian enlargement and clitoral hypertrophy."
Documents hyperandrogenism and ovarian enlargement in affected females.
Eye 1
Cataract HP:0000518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cataract (HP:0000518). HP:0000518 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41606799 SUPPORT Human Clinical
"We also describe new features associated with severe insulin receptoropathies, such as cataract, liver hemangioma, and impaired hepatic protein synthesis."
Reports cataract as a feature of severe insulin receptoropathies.
Genitourinary 4
Enlarged external genitalia 8/42 (19%) Abnormal external genitalia morphology HP:0000811 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Enlarged external genitalia, annotated with Abnormal external genitalia morphology (HP:0000811). HP:0000811 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38957655 SUPPORT Human Clinical
"large genitalia (8/42, 19.05%), hypertrophy of nails (6/42, 14.29%)"
Reports large genitalia in 8/42 pooled patients.
Nephrocalcinosis HP:0000121 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrocalcinosis (HP:0000121). HP:0000121 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25358339 SUPPORT Human Clinical
"Nephrocalcinosis was present in all patients (n = 17)."
Reports nephrocalcinosis in all 17 patients of the renal series.
PMID:38957655 SUPPORT Human Clinical
"with nephrocalcinosis (8/12, 66.67%), proteinuria (2/12, 16.67%)"
Reports nephrocalcinosis in 8/12 pooled patients with kidney disease.
Enlarged ovaries HP:0100879 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ovarian enlargement, annotated with Enlarged ovaries (HP:0100879). HP:0100879 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40241988 SUPPORT Human Clinical
"Girls are diagnosed with hyperandrogenism, ovarian enlargement and clitoral hypertrophy."
Documents ovarian enlargement in affected females.
Proteinuria 2/12 (17%) HP:0000093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38957655 SUPPORT Human Clinical
"with nephrocalcinosis (8/12, 66.67%), proteinuria (2/12, 16.67%)"
Reports proteinuria in 2/12 pooled patients with kidney disease.
Head and Neck 2
Dental anomalies 23/42 (55%) Abnormality of the dentition HP:0000164 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dental anomalies, annotated with Abnormality of the dentition (HP:0000164). HP:0000164 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38957655 SUPPORT Human Clinical
"dental anomalies including absence of teeth, crowding, and malocclusion in 23 cases (23/42, 54.76%)"
Reports dental anomalies in 23/42 pooled patients.
Coarse facial features HP:0000280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coarse facial features (HP:0000280). HP:0000280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40241988 SUPPORT Human Clinical
"characteristic facial dysmorphic features, including thick lips, wide nasal root, bulbous nasal tip, large, low set ears"
Describes the characteristic coarse facial dysmorphism in a confirmed RMS case.
Integument 5
Acanthosis nigricans 29/42 (69%) HP:0000956 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acanthosis nigricans (HP:0000956). HP:0000956 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38957655 SUPPORT Human Clinical
"Acanthosis was present in 29 cases (29/42, 69.05%); growth retardation in 25 cases (25/42, 59.52%); dental anomalies including absence of teeth, crowding, and malocclusion in 23 cases (23/42, 54.76%); and hirsutism in 17 cases (17/42, 40.48%)."
Reports acanthosis nigricans in 29/42 pooled patients.
Hirsutism 17/42 (40%) HP:0001007 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hirsutism (HP:0001007). HP:0001007 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38957655 SUPPORT Human Clinical
"hirsutism in 17 cases (17/42, 40.48%)"
Reports hirsutism in 17/42 pooled patients.
Hypertrichosis HP:0000998 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrichosis (HP:0000998). HP:0000998 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40499531 SUPPORT Human Clinical
"Both the patient and his older sister displayed signs of hypertrichosis and acanthosis nigricans."
Documents hypertrichosis in two affected siblings.
Nail hypertrophy 6/42 (14%) Abnormal nail morphology HP:0001597 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nail hypertrophy, annotated with Abnormal nail morphology (HP:0001597). HP:0001597 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38957655 SUPPORT Human Clinical
"hypertrophy of nails (6/42, 14.29%)"
Reports nail hypertrophy in 6/42 pooled patients.
Paucity of subcutaneous fat Reduced subcutaneous adipose tissue HP:0003758 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced subcutaneous fat, annotated with Reduced subcutaneous adipose tissue (HP:0003758). HP:0003758 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38957655 SUPPORT Human Clinical
"no patient was overweight (25.00∼29.90 kg/m2) or obese (≥30.00 kg/m2)"
Supports the non-obese/underweight body habitus of RMS.
Metabolism 2
Hypoglycemia HP:0001943 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fasting hypoglycemia, annotated with Hypoglycemia (HP:0001943). HP:0001943 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29695048 SUPPORT Human Clinical
"At birth, patients with RMS also show fasting hypoglycemia due to severely increased insulin levels, but with progression of the disease, insulin levels decline"
Documents fasting hypoglycaemia in the early phase.
Hyperglycemia HP:0003074 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperglycemia (HP:0003074). HP:0003074 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40241988 SUPPORT Human Clinical
"At an early stage, fasting hypoglycemia with postprandial hyperglycemia and significant hyperinsulinemia with subsequent development of insulin-resistant diabetes is observed."
Documents postprandial hyperglycaemia in RMS.
Growth 1
Growth delay 25/42 (60%) HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth retardation, annotated with Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38957655 SUPPORT Human Clinical
"growth retardation in 25 cases (25/42, 59.52%)"
Reports growth retardation in 25/42 pooled patients.
🧬

Genetic Associations

1
INSR
Gene: INSR hgnc:6091 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is INSR (hgnc:6091). hgnc:6091 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:40499531 SUPPORT Human Clinical
"Rabson-Mendenhall syndrome (RMS) is a rare autosomal recessive disorder caused by mutations in the insulin receptor gene (INSR), leading to severe insulin resistance."
Establishes INSR as the causal gene, inherited in autosomal recessive fashion.
PMID:34718628 SUPPORT Human Clinical
"Rabson-Mendenhall syndrome (RMS) is caused by biallelic pathogenic variants in the insulin receptor gene (INSR) leading to insulin-resistant diabetes, microvascular complications, and growth hormone resistance with short stature."
Establishes the biallelic INSR loss-of-function basis and downstream complications.
💊

Medical Actions

11
Insulin sensitizers (metformin, pioglitazone)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: metformin CHEBI:6801 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses metformin (CHEBI:6801). CHEBI:6801 is a therapeutic agent from Chemical Entities of Biological Interest. pioglitazone CHEBI:8228 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses pioglitazone (CHEBI:8228). CHEBI:8228 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Insulin sensitizers are first-line to lower glucose and HbA1c, though their effect diminishes over time and often requires dose escalation and multidrug therapy. Pioglitazone has normalized blood glucose in a reported case.
Mechanism Target:
INHIBITS Severe Insulin Resistance — Insulin sensitizers partially counter the insulin-resistant state.
Show evidence (1 reference)
PMID:23367497 SUPPORT Human Clinical
"Blood glucose normalized with pioglitazone (30 mg/day)."
Documents glycaemic normalization with pioglitazone in an RMS-phenotype case.
Show evidence (1 reference)
PMID:29369573 SUPPORT Other
"Insulin sensitizers are used first to decrease levels of glucose and glycosylated hemoglobin (HbA1c); however, their effect diminishes with time, often requiring dose adjustments and multidrug therapy."
States insulin sensitizers as first-line with waning effect.
High-dose insulin therapy (supportive)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: insulin CHEBI:145810 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses insulin (CHEBI:145810). CHEBI:145810 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Protein replacement
When hyperglycaemia persists, high-dose insulin is used, especially during diabetic ketoacidosis, though extreme insulin resistance limits its efficacy.
Show evidence (1 reference)
PMID:29369573 SUPPORT Other
"When hyperglycemia persists, insulin is started – usually in high doses, especially during the treatment of diabetic ketoacidosis."
States high-dose insulin as supportive therapy for persistent hyperglycaemia and DKA.
SGLT2 inhibitor (empagliflozin)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: empagliflozin CHEBI:82720 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses empagliflozin (CHEBI:82720). CHEBI:82720 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Empagliflozin, added off-label, lowers glucose via insulin-independent renal glucose excretion and improved HbA1c and time-in-range in a reported case; it carries a possible risk of promoting nephrocalcinosis.
Mechanism Target:
BYPASSES Hyperglycemia — SGLT2 inhibition lowers glucose independently of insulin action.
Show evidence (1 reference)
PMID:40241988 SUPPORT Human Clinical
"Sodium–glucose cotransporter 2 (SGLT2) inhibitors are a potentially interesting therapy option for people with severe genetic insulin resistance due to their ability to reduce glycemia through a mechanism that is independent of insulin action."
Explains the insulin-independent mechanism relevant to receptoropathy.
Show evidence (2 references)
PMID:38978877 SUPPORT Human Clinical
"After 10 months of treatment, empagliflozin therapy led to a clinically meaningful reduction in HbA1c levels, decreasing from 8.5% to 7.1%, along with an improvement in TIR from 47% to 74%."
Documents HbA1c and time-in-range improvement with empagliflozin in an RMS case.
PMID:40241988 SUPPORT Human Clinical
"eleven months after implementation of empagliflozin, the patient was diagnosed with an early form of nephrocalcinosis."
Documents the nephrocalcinosis safety signal with SGLT2i.
Recombinant human IGF-1 (mecasermin)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: mecasermin CHEBI:749581 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses mecasermin (CHEBI:749581). CHEBI:749581 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Protein replacement
Recombinant human IGF-1 signals through the IGF-1 receptor, partially bypassing the defective insulin receptor. It improves glycaemic control and fasting tolerance in early life with some growth enhancement, but benefits are limited and it does not prevent decompensation to diabetes; continuous subcutaneous infusion may outperform bolus injection.
Mechanism Target:
BYPASSES Impaired Insulin Receptor Signaling — IGF-1 activates partially shared post-receptor pathways, bypassing INSR.
Show evidence (1 reference)
PMID:29695048 SUPPORT Human Clinical
"continuous subcutaneous rhIGF-I infusion via an insulin pump improved weight development and diabetes control (HbA1c decreased from 10 to 7.6%)"
Documents metabolic improvement with continuous rhIGF-1, bypassing the defective receptor.
Show evidence (2 references)
PMID:41606799 SUPPORT Human Clinical
"Metabolic benefits of rhIGF-1 included improved glycemic control and fasting tolerance in early years of life, and some growth enhancement."
Summarizes rhIGF-1 metabolic benefits.
PMID:41606799 SUPPORT Human Clinical
"Current treatment options remain unsatisfactory as high-dose rhIGF-1 exerts only limited beneficial effects and does not prevent decompensation to diabetes mellitus."
Documents the limited efficacy of rhIGF-1.
Metreleptin
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: metreleptin CHEBI:752900 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses metreleptin (CHEBI:752900). CHEBI:752900 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Protein replacement
Recombinant leptin (metreleptin), used off-label, lowers HbA1c over long-term follow-up, likely through appetite suppression and reduced BMI rather than direct restoration of insulin signalling; lower BMI may worsen growth-hormone resistance.
Mechanism Target:
MODULATES Hyperglycemia — Metreleptin lowers HbA1c via appetite suppression and reduced BMI.
Show evidence (1 reference)
PMID:34718628 SUPPORT Human Clinical
"Metreleptin alters the natural history of rising A1c in RMS, leading to lower A1c throughout long-term follow-up."
Documents durable A1c lowering with metreleptin.
Show evidence (1 reference)
PMID:34718628 SUPPORT Human Clinical
"Over time, metreleptin-treated subjects maintained 1.8 percentage point lower A1c vs controls (P = 0.007)"
Controlled comparison showing sustained lower A1c with metreleptin.
Antiandrogen and hormonal therapy for hyperandrogenism
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: Small molecule
Oral contraceptives, antiandrogen therapies, and GnRH agonists are used to manage ovarian hyperandrogenism.
Mechanism Target:
INHIBITS Hyperandrogenism — Hormonal/antiandrogen therapy counters androgen excess.
Show evidence (1 reference)
PMID:29369573 SUPPORT Other
"oral contraceptives, antiandrogen therapies, and gonadotropin-releasing hormone agonists can be used to treat hyperandrogenism"
States hormonal/antiandrogen management of hyperandrogenism.
Show evidence (1 reference)
PMID:29369573 SUPPORT Other
"oral contraceptives, antiandrogen therapies, and gonadotropin-releasing hormone agonists can be used to treat hyperandrogenism"
Source for hormonal management of hyperandrogenism.
Oophorectomy for enlarged ovaries
Action: oophorectomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is oophorectomy, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Oophorectomy may be needed for markedly enlarged ovaries.
Show evidence (1 reference)
PMID:29369573 SUPPORT Other
"oophorectomy may be needed for enlarged ovaries"
States surgical management of enlarged ovaries.
Genetic counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Behavioral / lifestyle
Genetic counseling addresses the 25% recurrence risk, carrier testing, and prenatal/preimplantation options in known-carrier families, and the increased gestational diabetes risk in heterozygous females.
Show evidence (1 reference)
PMID:29369573 SUPPORT Other
"INSR-SIRS is inherited in an autosomal recessive manner."
Basis for autosomal recessive genetic counseling.
Avoidance of hypoglycemia-provoking agents, high-carbohydrate diet, and infectious contacts
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Behavioral / lifestyle
GeneReviews advises avoiding agents that provoke hypoglycaemia, a high-carbohydrate diet, and contact with contagious individuals; this avoidance is a core supportive-management measure in RMS.
Show evidence (1 reference)
PMID:29369573 SUPPORT Other
"In RMS avoid agents that cause hypoglycemia, high-carbohydrate diet, and contact with persons with contagious disease."
GeneReviews list of agents/circumstances to avoid in RMS.
Standard treatment for hypothyroidism
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: Small molecule
Standard thyroid hormone replacement is used when hypothyroidism is documented on endocrine surveillance.
Show evidence (1 reference)
PMID:29369573 SUPPORT Other
"Standard treatment for hypothyroidism; oral contraceptives, antiandrogen therapies, and gonadotropin-releasing hormone agonists can be used to treat hyperandrogenism"
GeneReviews specifies standard treatment for documented hypothyroidism.
Nephrology-directed management of nephrocalcinosis
Action: Therapeutic ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Therapeutic Procedure (NCIT:C49236). NCIT:C49236 is a clinical intervention from the NCI Thesaurus. NCIT:C49236
Platform: Other
Nephrocalcinosis is managed in conjunction with a nephrologist, per the GeneReviews management recommendations.
Mechanism Target:
MODULATES Nephrocalcinosis — Nephrology-directed care addresses the renal calcium-deposition phenotype.
Show evidence (1 reference)
PMID:29369573 SUPPORT Other
"treatment of nephrocalcinosis per nephrologist; treatment of cholestasis per gastroenterologist"
GeneReviews directs nephrology management of nephrocalcinosis.
Show evidence (1 reference)
PMID:29369573 SUPPORT Other
"treatment of nephrocalcinosis per nephrologist; treatment of cholestasis per gastroenterologist"
GeneReviews management item for the renal phenotype.
🔬

Biochemical Markers

2
Extreme fasting hyperinsulinemia
Show evidence (1 reference)
PMID:38957655 SUPPORT Human Clinical
"Twenty-six individuals had access to fasting insulin; all had high levels, ranging from 114 to 861 uIU/mL with a median of 300.00 (normal range: 5.00-20.00 uIU/mL)."
Quantifies the diagnostic extreme fasting hyperinsulinaemia.
Hypercalciuria
Show evidence (1 reference)
PMID:25358339 SUPPORT Human Clinical
"Twenty-four-hour urinary calcium data were available from 10 patients and revealed hypercalciuria in all"
Documents hypercalciuria in all evaluated patients.
🔬

Diagnosis

5
Molecular genetic testing of INSR
Diagnosis is established by characteristic clinical, laboratory, radiographic, and prenatal findings together with identification of biallelic INSR pathogenic variants.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:29369573 SUPPORT Other
"The diagnosis of INSR-SIRS is established in a proband with characteristic clinical, laboratory, radiographic, and prenatal ultrasound findings and biallelic INSR pathogenic variants identified by molecular genetic testing."
States the molecular diagnostic criterion.
Biochemical recognition of extreme hyperinsulinaemia
Extreme fasting hyperinsulinaemia disproportionate to glucose, with acanthosis nigricans, growth retardation, dental anomalies, and low body weight, prompts the diagnosis in a young patient.
laboratory procedure NCIT:C25294 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:38957655 SUPPORT Human Clinical
"RMS should be considered in young patients with hyperinsulinemia, hyperglycemia with low weight, acanthosis nigricans, growth retardation, dental anomalies, and hirsutism."
States the clinical-biochemical pattern that should trigger consideration of RMS.
Renal surveillance (urine calcium and kidney ultrasound)
Periodic urine calcium and kidney ultrasound to detect hypercalciuria and nephrocalcinosis, per the GeneReviews surveillance protocol.
kidney ultrasound NCIT:C17230 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:29369573 SUPPORT Other
"urine calcium and kidney ultrasound every six months"
GeneReviews surveillance schedule for the renal phenotype.
Ovarian ultrasound surveillance
Serial ovarian ultrasound to monitor ovarian enlargement/cysts, per the GeneReviews surveillance protocol.
ovarian ultrasound NCIT:C17230 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:29369573 SUPPORT Other
"ovarian ultrasound every three months until age two years, then every six months or as indicated"
GeneReviews surveillance schedule for the ovarian phenotype.
Gynecologic surveillance for endometrial cancer
Gynecologic evaluation for endometrial cancer in individuals with abnormal vaginal bleeding, given the hyperandrogenic/hyperoestrogenic ovarian phenotype.
gynecologic evaluation NCIT:C124351 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:29369573 SUPPORT Other
"gynecologic evaluation for endometrial cancer in those with abnormal vaginal bleeding"
GeneReviews surveillance for endometrial cancer risk.
📈

Progression

2
Early hyperinsulinaemic phase (infancy-early childhood)
Age: Birth to ~1 year
Severe hyperinsulinaemia with fasting hypoglycaemia and postprandial hyperglycaemia; dysmorphic and dermatologic features emerge.
Show evidence (1 reference)
PMID:29695048 SUPPORT Human Clinical
"At birth, patients with RMS also show fasting hypoglycemia due to severely increased insulin levels, but with progression of the disease, insulin levels decline"
Characterizes the early hyperinsulinaemic-hypoglycaemic phase.
Hyperglycaemic/diabetic phase (second decade)
Age: Childhood to second decade
Beta-cell decompensation yields sustained hyperglycaemia, overt insulin-resistant diabetes, recurrent diabetic ketoacidosis, and microvascular complications; complications of longstanding hyperglycaemia are the leading cause of death.
Show evidence (1 reference)
PMID:29369573 SUPPORT Other
"Complications of longstanding hyperglycemia are the most common cause of death. While death usually occurs in the second decade, some affected individuals live longer."
Describes the diabetic phase and its mortality.
📊

Prevalence

1
Worldwide
Birth Prevalence 0.1 per 100,000 <1 in 1,000,000 (births)
RMS is ultra-rare; fewer than ~50 molecularly confirmed cases have been published. The incidence of the INSR-SIRS spectrum (Donohue plus Rabson-Mendenhall) is estimated at 1:1,000,000 live births; a separate denominator-based RMS-specific prevalence is not established.
Show evidence (2 references)
PMID:41606799 SUPPORT Human Clinical
"Their incidence is estimated at 1:1 000 000 live births"
Source for the ~1 in 1,000,000 incidence of the INSR-SIRS spectrum.
PMID:33728143 SUPPORT Human Clinical
"It is an extremely rare disease with a frequency of fewer than one million people worldwide."
Supports the ultra-rare occurrence of RMS.
⚖️

Clinical Burden

High
RMS causes lifelong extreme insulin resistance requiring intensive glycaemic management, recurrent diabetic ketoacidosis, and early microvascular complications; most patients die in the second-to-third decade from complications of longstanding hyperglycaemia.
Show evidence (1 reference)
PMID:33728143 SUPPORT Human Clinical
"Most patients survive only up to 15 years of age, although some can live into their third decade of life."
Supports the high burden and limited survival.
{ }

Source YAML

click to show 
name: Rabson-Mendenhall Syndrome
creation_date: "2026-09-04T00:00:00Z"
category: Endocrine
parents:
- Endocrine Disorder
- Genetic Disorder
disease_term:
  preferred_term: Rabson-Mendenhall Syndrome
  term:
    id: MONDO:0009874
    label: Rabson-Mendenhall syndrome
description: >-
  A rare autosomal recessive disorder of extreme insulin resistance caused by
  biallelic (homozygous or compound heterozygous) loss-of-function variants in
  the insulin receptor gene (INSR). Defective insulin-receptor tyrosine-kinase
  signalling in target tissues blunts insulin action, producing severe insulin
  resistance with compensatory hyperinsulinaemia; the earliest biochemical
  hallmark is markedly elevated fasting insulin. Clinically it is defined by
  acanthosis nigricans, hypertrichosis/hirsutism, coarse facial features, dental
  and nail abnormalities, paucity of subcutaneous fat, growth retardation, and,
  in females, ovarian hyperandrogenism with enlarged/polycystic ovaries and
  clitoromegaly. The glycaemic course evolves from fasting hypoglycaemia with
  postprandial hyperglycaemia in infancy toward beta-cell decompensation, overt
  insulin-resistant diabetes mellitus, and recurrent diabetic ketoacidosis with
  microvascular complications in the second decade; complications of longstanding
  hyperglycaemia are the leading cause of death. Nephrocalcinosis is an almost
  invariable, apparently tissue-autonomous renal consequence of INSR loss.
  Rabson-Mendenhall syndrome occupies the intermediate position on the
  INSR-related severe insulin resistance spectrum (INSR-SIRS), between the
  neonatally lethal Donohue syndrome (leprechaunism) and the milder type A
  insulin resistance. It is distinct from the acquired, autoantibody-mediated
  type B insulin resistance syndrome.
pathophysiology:
- name: Biallelic INSR Loss-of-Function
  role: TRIGGER
  biological_scale: MOLECULAR
  description: >-
    Biallelic pathogenic variants in the insulin receptor gene (INSR, 19p13.2)
    reduce the number and/or function of cell-surface insulin receptors, most
    commonly through missense substitutions that impair receptor processing,
    insulin-binding affinity, or tyrosine-kinase activity. This is the initiating
    molecular lesion of the syndrome.
  genetic_context:
    gene:
      preferred_term: INSR
      term:
        id: hgnc:6091
        label: INSR
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: insulin receptor tyrosine kinase activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0005009
      label: insulin receptor activity
  downstream:
  - target: Impaired Insulin Receptor Signaling
    causal_link_type: DIRECT
    description: Reduced receptor number/affinity impairs signalling in insulin target cells.
    evidence:
    - reference: PMID:38957655
      reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the mutation of INSR led to the insulin resistance of the target cell."
      explanation: Directly links INSR mutation to insulin resistance of the target cell.
  - target: Renal Insulin Receptor Dysfunction
    causal_link_type: DIRECT
    description: >-
      The insulin receptor is expressed in the kidney; biallelic INSR loss produces
      a renal phenotype (hypercalciuria, nephrocalcinosis) independent of the diabetic state.
    evidence:
    - reference: PMID:25358339
      reference_title: "Insulin Receptor and the Kidney: Nephrocalcinosis in Patients with Recessive INSR Mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "INSR dysfunction is associated with hypercalciuria and nephrocalcinosis."
      explanation: Establishes a direct renal consequence of INSR dysfunction.
  evidence:
  - reference: PMID:40499531
    reference_title: "Genealogical Rabson-Mendenhall syndrome caused by INSR gene mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The novel mutation c.3670G>A in exon 21, inherited from the father, is likely to impair insulin receptor function by disrupting tyrosine kinase activity"
    explanation: A worked variant example impairing insulin-receptor tyrosine-kinase function.
  - reference: PMID:38957655
    reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation also caused a reduction in the affinity of the receptor to insulin"
    explanation: Describes reduced receptor-insulin affinity as a consequence of INSR mutation.
- name: Impaired Insulin Receptor Signaling
  role: CENTRAL_EFFECTOR
  biological_scale: CELLULAR
  description: >-
    Loss of functional insulin receptor blunts the downstream insulin receptor
    signalling pathway, principally the PI3K-AKT metabolic arm, in liver,
    skeletal muscle, and adipose tissue, so target tissues fail to mount a
    normal glucose-lowering response to insulin.
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: Adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  - preferred_term: Skeletal muscle cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  biological_processes:
  - preferred_term: Insulin receptor signaling pathway
    modifier: DECREASED
    term:
      id: GO:0008286
      label: insulin receptor signaling pathway
  - preferred_term: PI3K-AKT signal transduction
    modifier: DECREASED
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
  downstream:
  - target: Severe Insulin Resistance
    causal_link_type: DIRECT
    description: Blunted receptor signalling produces the defining extreme insulin-resistant state.
  evidence:
  - reference: PMID:38957655
    reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Insulin resistance is defined as the inability of target tissues to mount a normal coordinated glucose-lowering response at a normal plasma insulin level"
    explanation: Defines the impaired target-tissue insulin response that this node represents.
- name: Severe Insulin Resistance
  role: CENTRAL_EFFECTOR
  biological_scale: ORGANISM
  description: >-
    Extreme, generalized insulin resistance is the cardinal systemic
    consequence, driving compensatory hyperinsulinaemia and the early paradoxical
    glycaemic pattern.
  downstream:
  - target: Compensatory Hyperinsulinemia
    causal_link_type: DIRECT
    description: Target tissues require supraphysiologic insulin, driving compensatory hypersecretion.
    evidence:
    - reference: PMID:38957655
      reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "To overcome the suboptimal action in insulin-targeting tissues, organisms have to produce a large amount of insulin; thereby hyperinsulinemia develops."
      explanation: Directly links insulin resistance to compensatory hyperinsulinaemia.
  - target: Paradoxical Glycemic Regulation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Residual insulin action plus massive hyperinsulinaemia yields fluctuating glucose.
  evidence:
  - reference: PMID:41606799
    reference_title: "Clinical spectrum of extreme insulin resistance syndromes treated with rhIGF-1: A single-center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS) are extreme forms of insulin resistance (IR) caused by biallelic mutations in the insulin receptor gene."
    explanation: Establishes extreme insulin resistance as the defining state of the syndrome.
- name: Paradoxical Glycemic Regulation
  role: CONSEQUENCE
  biological_scale: ORGANISM
  description: >-
    In infancy and early childhood, severely elevated insulin acting on residual
    receptor and cross-reactive pathways produces fasting hypoglycaemia with
    postprandial hyperglycaemia; with disease progression insulin levels decline
    and sustained hyperglycaemia supervenes.
  downstream:
  - target: Hypoglycemia
    causal_link_type: DIRECT
    description: Fasting hypoglycaemia from severely increased insulin levels early in life.
  - target: Hyperglycemia
    causal_link_type: DIRECT
    description: Postprandial hyperglycaemia from failure of insulin-stimulated glucose disposal.
  evidence:
  - reference: PMID:29695048
    reference_title: "Mecasermin in Insulin Receptor-Related Severe Insulin Resistance Syndromes: Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At birth, patients with RMS also show fasting hypoglycemia due to severely increased insulin levels, but with progression of the disease, insulin levels decline"
    explanation: Documents the early paradoxical hypoglycaemia and its later decline.
  - reference: PMID:40241988
    reference_title: "Case Report: The long-term effects of the empagliflozin therapy on glycemia and renal function in a patient with Rabson-Mendenhall syndrome caused by two heterozygous variants in INSR gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At an early stage, fasting hypoglycemia with postprandial hyperglycemia and significant hyperinsulinemia with subsequent development of insulin-resistant diabetes is observed."
    explanation: Directly describes the paradoxical fasting-hypoglycaemia/postprandial-hyperglycaemia pattern.
- name: Compensatory Hyperinsulinemia
  role: CENTRAL_EFFECTOR
  biological_scale: ORGANISM
  description: >-
    Pancreatic beta-cell hypersecretion produces the extreme hyperinsulinaemia
    that is the earliest biochemical hallmark of the syndrome (median fasting
    insulin ~300 uIU/mL, versus a normal range of 5-20 uIU/mL). Chronic
    hyperinsulinaemia cross-activates IGF-1 receptors in skin and ovary and
    ultimately exhausts beta-cell reserve.
  cell_types:
  - preferred_term: Pancreatic beta cell
    term:
      id: CL:0000169
      label: type B pancreatic cell
  downstream:
  - target: Cutaneous IGF-1 Receptor Cross-activation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: High insulin stimulates keratinocyte IGF receptors.
  - target: Ovarian Androgen Excess
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Hyperinsulinaemia drives ovarian hyperandrogenism in females.
  - target: Pancreatic Beta-Cell Decompensation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Chronic hyperstimulation leads to eventual secretory failure.
  - target: Growth Hormone Resistance and Growth Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: High insulin may interact with IGF-I receptors and feedback-reduce GH secretion.
  - target: Hyperinsulinemia
    causal_link_type: DIRECT
    description: The measured laboratory hyperinsulinaemia.
  evidence:
  - reference: PMID:38957655
    reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hyperinsulinemia is typically observed early in the lives of RMS patients"
    explanation: Establishes early compensatory hyperinsulinaemia in RMS.
  - reference: PMID:38957655
    reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the mean fasting insulin was 349.96 μIU/mL, and the average fasting C-peptide was 6.00 ng/mL."
    explanation: Quantifies the extreme fasting hyperinsulinaemia and C-peptide in the pooled cohort.
- name: Cutaneous IGF-1 Receptor Cross-activation
  role: CONSEQUENCE
  biological_scale: CELLULAR
  description: >-
    Chronic supraphysiologic insulin cross-activates IGF-1 receptors on
    keratinocytes and dermal fibroblasts, promoting epidermal proliferation that
    manifests as acanthosis nigricans and contributes to soft-tissue overgrowth.
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  downstream:
  - target: Acanthosis nigricans
    causal_link_type: DIRECT
    description: Keratinocyte hyperproliferation produces acanthosis nigricans.
  evidence:
  - reference: PMID:38957655
    reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High levels of insulin stimulate IGF receptors, thereby promoting the proliferation of keratinocytes."
    explanation: States the IGF-receptor cross-activation mechanism driving keratinocyte proliferation.
- name: Ovarian Androgen Excess
  role: CONSEQUENCE
  biological_scale: CELLULAR
  description: >-
    In females, extreme hyperinsulinaemia acting on ovarian theca cells drives
    androgen biosynthesis, producing hyperandrogenism, enlarged/polycystic
    ovaries, and clitoromegaly.
  cell_types:
  - preferred_term: Ovarian theca cell
    term:
      id: CL:0000503
      label: theca cell
  biological_processes:
  - preferred_term: Androgen biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0006702
      label: androgen biosynthetic process
  downstream:
  - target: Hyperandrogenism
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Ovarian androgen excess produces clinical hyperandrogenism.
  - target: Enlarged external genitalia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Androgen excess contributes to clitoromegaly/enlarged external genitalia.
  - target: Enlarged ovaries
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Hyperinsulinaemia-driven ovarian stimulation produces enlarged/polycystic ovaries.
  evidence:
  - reference: PMID:40241988
    reference_title: "Case Report: The long-term effects of the empagliflozin therapy on glycemia and renal function in a patient with Rabson-Mendenhall syndrome caused by two heterozygous variants in INSR gene."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Girls are diagnosed with hyperandrogenism, ovarian enlargement and clitoral hypertrophy."
    explanation: Documents the ovarian hyperandrogenism phenotype; the theca-cell mechanism is inferred.
- name: Pancreatic Beta-Cell Decompensation
  role: CONSEQUENCE
  biological_scale: CELLULAR
  description: >-
    Sustained compensatory hypersecretion eventually exhausts beta-cell reserve,
    so hyperinsulinaemic hypoglycaemia gives way to sustained hyperglycaemia and
    overt insulin-resistant diabetes mellitus.
  cell_types:
  - preferred_term: Pancreatic beta cell
    term:
      id: CL:0000169
      label: type B pancreatic cell
  downstream:
  - target: Insulin-resistant diabetes mellitus
    causal_link_type: DIRECT
    description: Beta-cell failure precipitates overt insulin-resistant diabetes.
  evidence:
  - reference: PMID:25358339
    reference_title: "Insulin Receptor and the Kidney: Nephrocalcinosis in Patients with Recessive INSR Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The severe insulin resistance leads to hyperinsulinism with pancreatic β-cell decompensation, diabetes, hyperglycemia and ultimately ketoacidosis"
    explanation: Directly links beta-cell decompensation to diabetes and ketoacidosis.
- name: Renal Insulin Receptor Dysfunction
  role: CONSEQUENCE
  biological_scale: TISSUE
  description: >-
    The insulin receptor is expressed throughout the nephron. Biallelic INSR loss
    produces hypercalciuria and nephrocalcinosis that appear tissue-autonomous
    (present with normotension and stable glomerular function), rather than being
    a secondary complication of hyperglycaemia.
  downstream:
  - target: Nephrocalcinosis
    causal_link_type: DIRECT
    description: Hypercalciuria from renal INSR dysfunction produces nephrocalcinosis.
  - target: Proteinuria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Renal INSR dysfunction is associated with low-grade proteinuria in a subset.
  evidence:
  - reference: PMID:25358339
    reference_title: "Insulin Receptor and the Kidney: Nephrocalcinosis in Patients with Recessive INSR Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-four-hour urinary calcium data were available from 10 patients and revealed hypercalciuria in all"
    explanation: Documents universal hypercalciuria underlying the nephrocalcinosis.
  - reference: PMID:41606799
    reference_title: "Clinical spectrum of extreme insulin resistance syndromes treated with rhIGF-1: A single-center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal tubular dysfunction with nephrocalcinosis is almost invariably present"
    explanation: Independent series confirming near-invariable renal tubular dysfunction with nephrocalcinosis.
- name: Growth Hormone Resistance and Growth Failure
  role: CONSEQUENCE
  biological_scale: ORGANISM
  description: >-
    Affected individuals show a growth-hormone-resistant state (elevated basal GH
    with low-normal IGF-1) and severe growth retardation that is not corrected by
    exogenous growth hormone or standard-dose IGF-1.
  downstream:
  - target: Growth delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: GH resistance contributes to growth retardation/short stature.
  evidence:
  - reference: PMID:34718628
    reference_title: "Long-Term Effects of Metreleptin in Rabson-Mendenhall Syndrome on Glycemia, Growth, and Kidney Function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rabson-Mendenhall syndrome (RMS) is caused by biallelic pathogenic variants in the insulin receptor gene (INSR) leading to insulin-resistant diabetes, microvascular complications, and growth hormone resistance with short stature."
    explanation: Names growth hormone resistance with short stature as a defining feature.
  - reference: PMID:23367497
    reference_title: "Syndrome of extreme insulin resistance (Rabson-Mendenhall phenotype) with atrial septal defect: clinical presentation and treatment outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Basal growth hormone (GH) was increased (7.9 μg/L)with normal insuline-like growth factor 1 (37.6 nmol/L) suggestive of GH resistance."
    explanation: A case with elevated basal GH and normal IGF-1 interpreted as GH resistance.
phenotypes:
- name: Acanthosis nigricans
  description: >-
    Velvety hyperpigmented skin thickening at the neck, axillae, and groin; the
    most frequent dermatologic sign, present in about 69% of pooled cases.
  phenotype_term:
    preferred_term: Acanthosis nigricans
    term:
      id: HP:0000956
      label: Acanthosis nigricans
  frequency: "29/42 (69%)"
  evidence:
  - reference: PMID:38957655
    reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acanthosis was present in 29 cases (29/42, 69.05%); growth retardation in 25 cases (25/42, 59.52%); dental anomalies including absence of teeth, crowding, and malocclusion in 23 cases (23/42, 54.76%); and hirsutism in 17 cases (17/42, 40.48%)."
    explanation: Reports acanthosis nigricans in 29/42 pooled patients.
- name: Growth delay
  description: >-
    Prenatal and postnatal growth failure with short stature, present in about
    60% of pooled cases and often refractory to growth hormone.
  phenotype_term:
    preferred_term: Growth retardation
    term:
      id: HP:0001510
      label: Growth delay
  frequency: "25/42 (60%)"
  evidence:
  - reference: PMID:38957655
    reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "growth retardation in 25 cases (25/42, 59.52%)"
    explanation: Reports growth retardation in 25/42 pooled patients.
- name: Dental anomalies
  description: >-
    Dental abnormalities including premature/absent teeth, crowding, and
    malocclusion; a hallmark diagnostic clue, present in about 55% of pooled cases.
  phenotype_term:
    preferred_term: Dental anomalies
    term:
      id: HP:0000164
      label: Abnormality of the dentition
  frequency: "23/42 (55%)"
  evidence:
  - reference: PMID:38957655
    reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dental anomalies including absence of teeth, crowding, and malocclusion in 23 cases (23/42, 54.76%)"
    explanation: Reports dental anomalies in 23/42 pooled patients.
- name: Hirsutism
  description: >-
    Generalized excess terminal body hair, present in about 40% of pooled cases.
  phenotype_term:
    preferred_term: Hirsutism
    term:
      id: HP:0001007
      label: Hirsutism
  frequency: "17/42 (40%)"
  evidence:
  - reference: PMID:38957655
    reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hirsutism in 17 cases (17/42, 40.48%)"
    explanation: Reports hirsutism in 17/42 pooled patients.
- name: Hypertrichosis
  description: >-
    Excess body hair noted from infancy; a characteristic dermatologic feature
    alongside acanthosis nigricans.
  phenotype_term:
    preferred_term: Hypertrichosis
    term:
      id: HP:0000998
      label: Hypertrichosis
  evidence:
  - reference: PMID:40499531
    reference_title: "Genealogical Rabson-Mendenhall syndrome caused by INSR gene mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both the patient and his older sister displayed signs of hypertrichosis and acanthosis nigricans."
    explanation: Documents hypertrichosis in two affected siblings.
- name: Enlarged external genitalia
  description: >-
    Enlarged external genitalia, including clitoromegaly in females; present in
    about 19% of pooled cases and related to hyperinsulinaemia-driven androgen excess.
  phenotype_term:
    preferred_term: Enlarged external genitalia
    term:
      id: HP:0000811
      label: Abnormal external genitalia morphology
  frequency: "8/42 (19%)"
  evidence:
  - reference: PMID:38957655
    reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "large genitalia (8/42, 19.05%), hypertrophy of nails (6/42, 14.29%)"
    explanation: Reports large genitalia in 8/42 pooled patients.
- name: Nail hypertrophy
  description: >-
    Nail hypertrophy/dystrophy, present in about 14% of pooled cases.
  phenotype_term:
    preferred_term: Nail hypertrophy
    term:
      id: HP:0001597
      label: Abnormal nail morphology
  frequency: "6/42 (14%)"
  evidence:
  - reference: PMID:38957655
    reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypertrophy of nails (6/42, 14.29%)"
    explanation: Reports nail hypertrophy in 6/42 pooled patients.
- name: Coarse facial features
  description: >-
    Coarse ("prematurely aged"/elfin) facial appearance with thick lips, wide
    nasal root, and large, low-set ears; a near-universal descriptive feature.
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
  evidence:
  - reference: PMID:40241988
    reference_title: "Case Report: The long-term effects of the empagliflozin therapy on glycemia and renal function in a patient with Rabson-Mendenhall syndrome caused by two heterozygous variants in INSR gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characteristic facial dysmorphic features, including thick lips, wide nasal root, bulbous nasal tip, large, low set ears"
    explanation: Describes the characteristic coarse facial dysmorphism in a confirmed RMS case.
- name: Paucity of subcutaneous fat
  description: >-
    Lipoatrophy/paucity of subcutaneous fat with low BMI; patients are typically
    underweight rather than obese, distinguishing RMS from metabolic-syndrome
    insulin resistance.
  phenotype_term:
    preferred_term: Reduced subcutaneous fat
    term:
      id: HP:0003758
      label: Reduced subcutaneous adipose tissue
  evidence:
  - reference: PMID:38957655
    reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "no patient was overweight (25.00∼29.90 kg/m2) or obese (≥30.00 kg/m2)"
    explanation: Supports the non-obese/underweight body habitus of RMS.
- name: Hyperinsulinemia
  description: >-
    Extreme fasting hyperinsulinaemia is the earliest and most consistent
    laboratory abnormality; all pooled patients with available data had high
    fasting insulin.
  phenotype_term:
    preferred_term: Hyperinsulinemia
    term:
      id: HP:0000842
      label: Hyperinsulinemia
  evidence:
  - reference: PMID:38957655
    reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-six individuals had access to fasting insulin; all had high levels, ranging from 114 to 861 uIU/mL with a median of 300.00 (normal range: 5.00-20.00 uIU/mL)."
    explanation: Documents universal extreme fasting hyperinsulinaemia.
- name: Hypoglycemia
  description: >-
    Fasting hypoglycaemia due to severely increased insulin levels, characteristic
    of the early hyperinsulinaemic phase.
  phenotype_term:
    preferred_term: Fasting hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:29695048
    reference_title: "Mecasermin in Insulin Receptor-Related Severe Insulin Resistance Syndromes: Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At birth, patients with RMS also show fasting hypoglycemia due to severely increased insulin levels, but with progression of the disease, insulin levels decline"
    explanation: Documents fasting hypoglycaemia in the early phase.
- name: Hyperglycemia
  description: >-
    Postprandial and later sustained hyperglycaemia from failure of
    insulin-stimulated glucose disposal.
  phenotype_term:
    preferred_term: Hyperglycemia
    term:
      id: HP:0003074
      label: Hyperglycemia
  evidence:
  - reference: PMID:40241988
    reference_title: "Case Report: The long-term effects of the empagliflozin therapy on glycemia and renal function in a patient with Rabson-Mendenhall syndrome caused by two heterozygous variants in INSR gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At an early stage, fasting hypoglycemia with postprandial hyperglycemia and significant hyperinsulinemia with subsequent development of insulin-resistant diabetes is observed."
    explanation: Documents postprandial hyperglycaemia in RMS.
- name: Insulin-resistant diabetes mellitus
  description: >-
    Overt insulin-resistant diabetes mellitus develops as beta-cell reserve
    fails; reported in about 76% of evaluable pooled cases, all diagnosed before
    age 23 (mean 9.4 years).
  phenotype_term:
    preferred_term: Insulin-resistant diabetes mellitus
    term:
      id: HP:0000831
      label: Insulin-resistant diabetes mellitus
  frequency: "25/33 (76%)"
  sequelae:
  - target: Diabetic ketoacidosis
    causal_link_type: DIRECT
    description: Progressive hyperglycaemia precipitates recurrent diabetic ketoacidosis.
  evidence:
  - reference: PMID:38957655
    reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diabetes was reported in 25 cases (25/33, 75.76%) all of which were diagnosed before 23 years old."
    explanation: Reports insulin-resistant diabetes in 25/33 evaluable pooled patients.
- name: Diabetic ketoacidosis
  description: >-
    Recurrent diabetic ketoacidosis emerges in the second decade as insulin
    secretion declines and is a leading cause of morbidity and mortality.
  phenotype_term:
    preferred_term: Diabetic ketoacidosis
    term:
      id: HP:0001953
      label: Diabetic ketoacidosis
  evidence:
  - reference: PMID:29695048
    reference_title: "Mecasermin in Insulin Receptor-Related Severe Insulin Resistance Syndromes: Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast to DS, patients develop recurrent diabetic ketoacidosis and microvascular complications during the second decade of life"
    explanation: Documents recurrent DKA and microvascular complications in the second decade.
- name: Hyperandrogenism
  description: >-
    Androgen excess in affected females, reflecting hyperinsulinaemia-driven
    ovarian steroidogenesis, with enlarged/polycystic ovaries.
  phenotype_term:
    preferred_term: Hyperandrogenism
    term:
      id: HP:0030348
      label: Increased circulating androgen concentration
  evidence:
  - reference: PMID:40241988
    reference_title: "Case Report: The long-term effects of the empagliflozin therapy on glycemia and renal function in a patient with Rabson-Mendenhall syndrome caused by two heterozygous variants in INSR gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Girls are diagnosed with hyperandrogenism, ovarian enlargement and clitoral hypertrophy."
    explanation: Documents hyperandrogenism and ovarian enlargement in affected females.
- name: Nephrocalcinosis
  description: >-
    Nephrocalcinosis with hypercalciuria is an almost invariable renal feature,
    apparently tissue-autonomous to renal INSR loss rather than secondary to
    hyperglycaemia.
  phenotype_term:
    preferred_term: Nephrocalcinosis
    term:
      id: HP:0000121
      label: Nephrocalcinosis
  evidence:
  - reference: PMID:25358339
    reference_title: "Insulin Receptor and the Kidney: Nephrocalcinosis in Patients with Recessive INSR Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nephrocalcinosis was present in all patients (n = 17)."
    explanation: Reports nephrocalcinosis in all 17 patients of the renal series.
  - reference: PMID:38957655
    reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with nephrocalcinosis (8/12, 66.67%), proteinuria (2/12, 16.67%)"
    explanation: Reports nephrocalcinosis in 8/12 pooled patients with kidney disease.
- name: Cataract
  description: >-
    Cataract has been reported among newly delineated multisystem features of
    severe insulin receptoropathies.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:41606799
    reference_title: "Clinical spectrum of extreme insulin resistance syndromes treated with rhIGF-1: A single-center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also describe new features associated with severe insulin receptoropathies, such as cataract, liver hemangioma, and impaired hepatic protein synthesis."
    explanation: Reports cataract as a feature of severe insulin receptoropathies.
- name: Atrial septal defect
  description: >-
    Congenital heart disease (ostium secundum atrial septal defect) has been
    reported as a rare association in a single Rabson-Mendenhall phenotype case.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: PMID:23367497
    reference_title: "Syndrome of extreme insulin resistance (Rabson-Mendenhall phenotype) with atrial septal defect: clinical presentation and treatment outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Echocardiography revealed ostium secundum type atrial septal defect (ASD)."
    explanation: Single case report documenting an atrial septal defect in the RMS phenotype.
- name: Enlarged ovaries
  description: >-
    Enlarged/polycystic ovaries in affected females, reflecting hyperinsulinaemia-driven
    ovarian stimulation.
  phenotype_term:
    preferred_term: Ovarian enlargement
    term:
      id: HP:0100879
      label: Enlarged ovaries
  evidence:
  - reference: PMID:40241988
    reference_title: "Case Report: The long-term effects of the empagliflozin therapy on glycemia and renal function in a patient with Rabson-Mendenhall syndrome caused by two heterozygous variants in INSR gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Girls are diagnosed with hyperandrogenism, ovarian enlargement and clitoral hypertrophy."
    explanation: Documents ovarian enlargement in affected females.
- name: Proteinuria
  description: >-
    Low-grade proteinuria occurs in a subset, part of the renal INSR-dysfunction
    phenotype rather than overt glomerular failure.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  frequency: "2/12 (17%)"
  evidence:
  - reference: PMID:38957655
    reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with nephrocalcinosis (8/12, 66.67%), proteinuria (2/12, 16.67%)"
    explanation: Reports proteinuria in 2/12 pooled patients with kidney disease.
- name: Protuberant abdomen
  description: >-
    A protuberant abdomen, reflecting organomegaly, is reported in about 12% of
    pooled cases.
  phenotype_term:
    preferred_term: Protuberant abdomen
    term:
      id: HP:0001538
      label: Protuberant abdomen
  frequency: "5/42 (12%)"
  evidence:
  - reference: PMID:38957655
    reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a protuberant abdomen (5/42, 11.90%)"
    explanation: Reports a protuberant abdomen in 5/42 pooled patients.
biochemical:
- name: Extreme fasting hyperinsulinemia
  notes: >-
    Markedly elevated fasting insulin (median ~300 uIU/mL; range 114-861) with
    elevated C-peptide, disproportionate to the glucose level, is the key
    biochemical signature and the earliest abnormality.
  evidence:
  - reference: PMID:38957655
    reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-six individuals had access to fasting insulin; all had high levels, ranging from 114 to 861 uIU/mL with a median of 300.00 (normal range: 5.00-20.00 uIU/mL)."
    explanation: Quantifies the diagnostic extreme fasting hyperinsulinaemia.
- name: Hypercalciuria
  notes: >-
    Twenty-four-hour urinary calcium is elevated in essentially all patients,
    underlying the near-universal nephrocalcinosis.
  evidence:
  - reference: PMID:25358339
    reference_title: "Insulin Receptor and the Kidney: Nephrocalcinosis in Patients with Recessive INSR Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-four-hour urinary calcium data were available from 10 patients and revealed hypercalciuria in all"
    explanation: Documents hypercalciuria in all evaluated patients.
genetic:
- name: INSR
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: INSR
    term:
      id: hgnc:6091
      label: INSR
  notes: >-
    Biallelic (homozygous or compound heterozygous) INSR variants are necessary
    and sufficient; the functional consequence is loss/partial loss of function
    (captured as functional_impact_category on the Biallelic INSR Loss-of-Function
    pathophysiology node). In the largest pooled series (55 distinct variants
    across 42 patients), missense substitutions predominated (72.7%), with
    deletions (10.9%), insertions (1.8%), and nonsense (1.8%) variants also
    observed; the most recurrent variant was p.Glu238Lys and exon 2 was most
    frequently affected. No genotype-phenotype correlation was established. RMS
    occupies a hypomorphic position relative to Donohue syndrome (near-complete
    loss of receptor function).
  evidence:
  - reference: PMID:40499531
    reference_title: "Genealogical Rabson-Mendenhall syndrome caused by INSR gene mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rabson-Mendenhall syndrome (RMS) is a rare autosomal recessive disorder caused by mutations in the insulin receptor gene (INSR), leading to severe insulin resistance."
    explanation: Establishes INSR as the causal gene, inherited in autosomal recessive fashion.
  - reference: PMID:34718628
    reference_title: "Long-Term Effects of Metreleptin in Rabson-Mendenhall Syndrome on Glycemia, Growth, and Kidney Function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rabson-Mendenhall syndrome (RMS) is caused by biallelic pathogenic variants in the insulin receptor gene (INSR) leading to insulin-resistant diabetes, microvascular complications, and growth hormone resistance with short stature."
    explanation: Establishes the biallelic INSR loss-of-function basis and downstream complications.
inheritance:
- name: Autosomal recessive INSR inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Rabson-Mendenhall syndrome is inherited in an autosomal recessive manner;
    each sib of an affected individual has a 25% chance of inheriting biallelic
    INSR pathogenic variants. Heterozygotes are usually asymptomatic but may have
    features of the allelic type A insulin resistance, and heterozygous females
    are at increased risk for gestational diabetes.
  evidence:
  - reference: PMID:29369573
    reference_title: "INSR-Related Severe Insulin Resistance Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected"
    explanation: States the autosomal recessive recurrence risk.
prevalence:
- population: Worldwide
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.1
  notes: >-
    RMS is ultra-rare; fewer than ~50 molecularly confirmed cases have been
    published. The incidence of the INSR-SIRS spectrum (Donohue plus
    Rabson-Mendenhall) is estimated at 1:1,000,000 live births; a separate
    denominator-based RMS-specific prevalence is not established.
  evidence:
  - reference: PMID:41606799
    reference_title: "Clinical spectrum of extreme insulin resistance syndromes treated with rhIGF-1: A single-center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their incidence is estimated at 1:1 000 000 live births"
    explanation: Source for the ~1 in 1,000,000 incidence of the INSR-SIRS spectrum.
  - reference: PMID:33728143
    reference_title: "Insulin, Insulin Everywhere: A Rare Case Report of Rabson-Mendenhall Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is an extremely rare disease with a frequency of fewer than one million people worldwide."
    explanation: Supports the ultra-rare occurrence of RMS.
progression:
- phase: Early hyperinsulinaemic phase (infancy-early childhood)
  age_range: Birth to ~1 year
  notes: >-
    Severe hyperinsulinaemia with fasting hypoglycaemia and postprandial
    hyperglycaemia; dysmorphic and dermatologic features emerge.
  evidence:
  - reference: PMID:29695048
    reference_title: "Mecasermin in Insulin Receptor-Related Severe Insulin Resistance Syndromes: Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At birth, patients with RMS also show fasting hypoglycemia due to severely increased insulin levels, but with progression of the disease, insulin levels decline"
    explanation: Characterizes the early hyperinsulinaemic-hypoglycaemic phase.
- phase: Hyperglycaemic/diabetic phase (second decade)
  age_range: Childhood to second decade
  notes: >-
    Beta-cell decompensation yields sustained hyperglycaemia, overt
    insulin-resistant diabetes, recurrent diabetic ketoacidosis, and microvascular
    complications; complications of longstanding hyperglycaemia are the leading
    cause of death.
  evidence:
  - reference: PMID:29369573
    reference_title: "INSR-Related Severe Insulin Resistance Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Complications of longstanding hyperglycemia are the most common cause of death. While death usually occurs in the second decade, some affected individuals live longer."
    explanation: Describes the diabetic phase and its mortality.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    RMS causes lifelong extreme insulin resistance requiring intensive glycaemic
    management, recurrent diabetic ketoacidosis, and early microvascular
    complications; most patients die in the second-to-third decade from
    complications of longstanding hyperglycaemia.
  evidence:
  - reference: PMID:33728143
    reference_title: "Insulin, Insulin Everywhere: A Rare Case Report of Rabson-Mendenhall Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients survive only up to 15 years of age, although some can live into their third decade of life."
    explanation: Supports the high burden and limited survival.
diagnosis:
- name: Molecular genetic testing of INSR
  description: >-
    Diagnosis is established by characteristic clinical, laboratory, radiographic,
    and prenatal findings together with identification of biallelic INSR
    pathogenic variants.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:29369573
    reference_title: "INSR-Related Severe Insulin Resistance Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The diagnosis of INSR-SIRS is established in a proband with characteristic clinical, laboratory, radiographic, and prenatal ultrasound findings and biallelic INSR pathogenic variants identified by molecular genetic testing."
    explanation: States the molecular diagnostic criterion.
- name: Biochemical recognition of extreme hyperinsulinaemia
  description: >-
    Extreme fasting hyperinsulinaemia disproportionate to glucose, with acanthosis
    nigricans, growth retardation, dental anomalies, and low body weight, prompts
    the diagnosis in a young patient.
  diagnosis_term:
    preferred_term: laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:38957655
    reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RMS should be considered in young patients with hyperinsulinemia, hyperglycemia with low weight, acanthosis nigricans, growth retardation, dental anomalies, and hirsutism."
    explanation: States the clinical-biochemical pattern that should trigger consideration of RMS.
- name: Renal surveillance (urine calcium and kidney ultrasound)
  description: >-
    Periodic urine calcium and kidney ultrasound to detect hypercalciuria and
    nephrocalcinosis, per the GeneReviews surveillance protocol.
  diagnosis_term:
    preferred_term: kidney ultrasound
    term:
      id: NCIT:C17230
      label: Ultrasound Imaging
  evidence:
  - reference: PMID:29369573
    reference_title: "INSR-Related Severe Insulin Resistance Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "urine calcium and kidney ultrasound every six months"
    explanation: GeneReviews surveillance schedule for the renal phenotype.
- name: Ovarian ultrasound surveillance
  description: >-
    Serial ovarian ultrasound to monitor ovarian enlargement/cysts, per the
    GeneReviews surveillance protocol.
  diagnosis_term:
    preferred_term: ovarian ultrasound
    term:
      id: NCIT:C17230
      label: Ultrasound Imaging
  evidence:
  - reference: PMID:29369573
    reference_title: "INSR-Related Severe Insulin Resistance Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ovarian ultrasound every three months until age two years, then every six months or as indicated"
    explanation: GeneReviews surveillance schedule for the ovarian phenotype.
- name: Gynecologic surveillance for endometrial cancer
  description: >-
    Gynecologic evaluation for endometrial cancer in individuals with abnormal
    vaginal bleeding, given the hyperandrogenic/hyperoestrogenic ovarian phenotype.
  diagnosis_term:
    preferred_term: gynecologic evaluation
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:29369573
    reference_title: "INSR-Related Severe Insulin Resistance Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "gynecologic evaluation for endometrial cancer in those with abnormal vaginal bleeding"
    explanation: GeneReviews surveillance for endometrial cancer risk.
treatments:
- name: Insulin sensitizers (metformin, pioglitazone)
  description: >-
    Insulin sensitizers are first-line to lower glucose and HbA1c, though their
    effect diminishes over time and often requires dose escalation and multidrug
    therapy. Pioglitazone has normalized blood glucose in a reported case.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: metformin
      term:
        id: CHEBI:6801
        label: metformin
    - preferred_term: pioglitazone
      term:
        id: CHEBI:8228
        label: pioglitazone
  target_mechanisms:
  - target: Severe Insulin Resistance
    treatment_effect: INHIBITS
    description: Insulin sensitizers partially counter the insulin-resistant state.
    evidence:
    - reference: PMID:23367497
      reference_title: "Syndrome of extreme insulin resistance (Rabson-Mendenhall phenotype) with atrial septal defect: clinical presentation and treatment outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Blood glucose normalized with pioglitazone (30 mg/day)."
      explanation: Documents glycaemic normalization with pioglitazone in an RMS-phenotype case.
  evidence:
  - reference: PMID:29369573
    reference_title: "INSR-Related Severe Insulin Resistance Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Insulin sensitizers are used first to decrease levels of glucose and glycosylated hemoglobin (HbA1c); however, their effect diminishes with time, often requiring dose adjustments and multidrug therapy."
    explanation: States insulin sensitizers as first-line with waning effect.
- name: High-dose insulin therapy (supportive)
  description: >-
    When hyperglycaemia persists, high-dose insulin is used, especially during
    diabetic ketoacidosis, though extreme insulin resistance limits its efficacy.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: insulin
      term:
        id: CHEBI:145810
        label: insulin
  evidence:
  - reference: PMID:29369573
    reference_title: "INSR-Related Severe Insulin Resistance Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "When hyperglycemia persists, insulin is started – usually in high doses, especially during the treatment of diabetic ketoacidosis."
    explanation: States high-dose insulin as supportive therapy for persistent hyperglycaemia and DKA.
- name: SGLT2 inhibitor (empagliflozin)
  description: >-
    Empagliflozin, added off-label, lowers glucose via insulin-independent renal
    glucose excretion and improved HbA1c and time-in-range in a reported case;
    it carries a possible risk of promoting nephrocalcinosis.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: empagliflozin
      term:
        id: CHEBI:82720
        label: empagliflozin
  target_mechanisms:
  - target: Hyperglycemia
    treatment_effect: BYPASSES
    description: SGLT2 inhibition lowers glucose independently of insulin action.
    evidence:
    - reference: PMID:40241988
      reference_title: "Case Report: The long-term effects of the empagliflozin therapy on glycemia and renal function in a patient with Rabson-Mendenhall syndrome caused by two heterozygous variants in INSR gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sodium–glucose cotransporter 2 (SGLT2) inhibitors are a potentially interesting therapy option for people with severe genetic insulin resistance due to their ability to reduce glycemia through a mechanism that is independent of insulin action."
      explanation: Explains the insulin-independent mechanism relevant to receptoropathy.
  evidence:
  - reference: PMID:38978877
    reference_title: "Case report: A case of Rabson-Mendenhall syndrome: long-term follow-up and therapeutic management with empagliflozin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After 10 months of treatment, empagliflozin therapy led to a clinically meaningful reduction in HbA1c levels, decreasing from 8.5% to 7.1%, along with an improvement in TIR from 47% to 74%."
    explanation: Documents HbA1c and time-in-range improvement with empagliflozin in an RMS case.
  - reference: PMID:40241988
    reference_title: "Case Report: The long-term effects of the empagliflozin therapy on glycemia and renal function in a patient with Rabson-Mendenhall syndrome caused by two heterozygous variants in INSR gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "eleven months after implementation of empagliflozin, the patient was diagnosed with an early form of nephrocalcinosis."
    explanation: Documents the nephrocalcinosis safety signal with SGLT2i.
- name: Recombinant human IGF-1 (mecasermin)
  description: >-
    Recombinant human IGF-1 signals through the IGF-1 receptor, partially
    bypassing the defective insulin receptor. It improves glycaemic control and
    fasting tolerance in early life with some growth enhancement, but benefits are
    limited and it does not prevent decompensation to diabetes; continuous
    subcutaneous infusion may outperform bolus injection.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mecasermin
      term:
        id: CHEBI:749581
        label: mecasermin
  target_mechanisms:
  - target: Impaired Insulin Receptor Signaling
    treatment_effect: BYPASSES
    description: IGF-1 activates partially shared post-receptor pathways, bypassing INSR.
    evidence:
    - reference: PMID:29695048
      reference_title: "Mecasermin in Insulin Receptor-Related Severe Insulin Resistance Syndromes: Case Report and Review of the Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "continuous subcutaneous rhIGF-I infusion via an insulin pump improved weight development and diabetes control (HbA1c decreased from 10 to 7.6%)"
      explanation: Documents metabolic improvement with continuous rhIGF-1, bypassing the defective receptor.
  evidence:
  - reference: PMID:41606799
    reference_title: "Clinical spectrum of extreme insulin resistance syndromes treated with rhIGF-1: A single-center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Metabolic benefits of rhIGF-1 included improved glycemic control and fasting tolerance in early years of life, and some growth enhancement."
    explanation: Summarizes rhIGF-1 metabolic benefits.
  - reference: PMID:41606799
    reference_title: "Clinical spectrum of extreme insulin resistance syndromes treated with rhIGF-1: A single-center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Current treatment options remain unsatisfactory as high-dose rhIGF-1 exerts only limited beneficial effects and does not prevent decompensation to diabetes mellitus."
    explanation: Documents the limited efficacy of rhIGF-1.
- name: Metreleptin
  description: >-
    Recombinant leptin (metreleptin), used off-label, lowers HbA1c over long-term
    follow-up, likely through appetite suppression and reduced BMI rather than
    direct restoration of insulin signalling; lower BMI may worsen growth-hormone
    resistance.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: metreleptin
      term:
        id: CHEBI:752900
        label: metreleptin
  target_mechanisms:
  - target: Hyperglycemia
    treatment_effect: MODULATES
    description: Metreleptin lowers HbA1c via appetite suppression and reduced BMI.
    evidence:
    - reference: PMID:34718628
      reference_title: "Long-Term Effects of Metreleptin in Rabson-Mendenhall Syndrome on Glycemia, Growth, and Kidney Function."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Metreleptin alters the natural history of rising A1c in RMS, leading to lower A1c throughout long-term follow-up."
      explanation: Documents durable A1c lowering with metreleptin.
  evidence:
  - reference: PMID:34718628
    reference_title: "Long-Term Effects of Metreleptin in Rabson-Mendenhall Syndrome on Glycemia, Growth, and Kidney Function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Over time, metreleptin-treated subjects maintained 1.8 percentage point lower A1c vs controls (P = 0.007)"
    explanation: Controlled comparison showing sustained lower A1c with metreleptin.
- name: Antiandrogen and hormonal therapy for hyperandrogenism
  description: >-
    Oral contraceptives, antiandrogen therapies, and GnRH agonists are used to
    manage ovarian hyperandrogenism.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Hyperandrogenism
    treatment_effect: INHIBITS
    description: Hormonal/antiandrogen therapy counters androgen excess.
    evidence:
    - reference: PMID:29369573
      reference_title: "INSR-Related Severe Insulin Resistance Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "oral contraceptives, antiandrogen therapies, and gonadotropin-releasing hormone agonists can be used to treat hyperandrogenism"
      explanation: States hormonal/antiandrogen management of hyperandrogenism.
  evidence:
  - reference: PMID:29369573
    reference_title: "INSR-Related Severe Insulin Resistance Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "oral contraceptives, antiandrogen therapies, and gonadotropin-releasing hormone agonists can be used to treat hyperandrogenism"
    explanation: Source for hormonal management of hyperandrogenism.
- name: Oophorectomy for enlarged ovaries
  description: >-
    Oophorectomy may be needed for markedly enlarged ovaries.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: oophorectomy
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:29369573
    reference_title: "INSR-Related Severe Insulin Resistance Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "oophorectomy may be needed for enlarged ovaries"
    explanation: States surgical management of enlarged ovaries.
- name: Genetic counseling
  description: >-
    Genetic counseling addresses the 25% recurrence risk, carrier testing, and
    prenatal/preimplantation options in known-carrier families, and the increased
    gestational diabetes risk in heterozygous females.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:29369573
    reference_title: "INSR-Related Severe Insulin Resistance Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "INSR-SIRS is inherited in an autosomal recessive manner."
    explanation: Basis for autosomal recessive genetic counseling.
- name: Avoidance of hypoglycemia-provoking agents, high-carbohydrate diet, and infectious contacts
  description: >-
    GeneReviews advises avoiding agents that provoke hypoglycaemia, a
    high-carbohydrate diet, and contact with contagious individuals; this
    avoidance is a core supportive-management measure in RMS.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:29369573
    reference_title: "INSR-Related Severe Insulin Resistance Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In RMS avoid agents that cause hypoglycemia, high-carbohydrate diet, and contact with persons with contagious disease."
    explanation: GeneReviews list of agents/circumstances to avoid in RMS.
- name: Standard treatment for hypothyroidism
  description: >-
    Standard thyroid hormone replacement is used when hypothyroidism is documented
    on endocrine surveillance.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:29369573
    reference_title: "INSR-Related Severe Insulin Resistance Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Standard treatment for hypothyroidism; oral contraceptives, antiandrogen therapies, and gonadotropin-releasing hormone agonists can be used to treat hyperandrogenism"
    explanation: GeneReviews specifies standard treatment for documented hypothyroidism.
- name: Nephrology-directed management of nephrocalcinosis
  description: >-
    Nephrocalcinosis is managed in conjunction with a nephrologist, per the
    GeneReviews management recommendations.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Therapeutic Procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_mechanisms:
  - target: Nephrocalcinosis
    treatment_effect: MODULATES
    description: Nephrology-directed care addresses the renal calcium-deposition phenotype.
    evidence:
    - reference: PMID:29369573
      reference_title: "INSR-Related Severe Insulin Resistance Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "treatment of nephrocalcinosis per nephrologist; treatment of cholestasis per gastroenterologist"
      explanation: GeneReviews directs nephrology management of nephrocalcinosis.
  evidence:
  - reference: PMID:29369573
    reference_title: "INSR-Related Severe Insulin Resistance Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "treatment of nephrocalcinosis per nephrologist; treatment of cholestasis per gastroenterologist"
    explanation: GeneReviews management item for the renal phenotype.
discussions:
- discussion_id: rms_renal_insr_mouse_human_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Renal Insulin Receptor Dysfunction
  prompt: >-
    Does the renal phenotype of kidney-specific Insr-knockout mice faithfully
    model the human renal consequences of INSR loss in Rabson-Mendenhall syndrome?
  rationale: >-
    Genetically modified mice with kidney-specific Insr deletion show elevated
    blood pressure and progressive diabetic nephropathy, whereas patients with
    biallelic INSR mutations are normotensive with stable glomerular function and
    only moderate proteinuria, their renal phenotype dominated instead by
    hypercalciuria and nephrocalcinosis. This suggests species-specific
    differences in renal INSR function and cautions against extrapolating the
    mouse renal phenotype to human disease.
  evidence:
  - reference: PMID:25358339
    reference_title: "Insulin Receptor and the Kidney: Nephrocalcinosis in Patients with Recessive INSR Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Normotension and stable glomerular function with only moderate proteinuria is in contrast to genetically modified mice who have elevated BP and progressive diabetic nephropathy."
    explanation: Directly contrasts the human renal phenotype with the murine model.
- discussion_id: rms_absent_genotype_phenotype_correlation
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - genetic#
  prompt: >-
    Why is there no genotype-phenotype correlation across the INSR-severity
    spectrum, and what determines an individual's position between Donohue,
    Rabson-Mendenhall, and type A insulin resistance?
  rationale: >-
    The pooled 42-patient analysis found no statistically significant differences
    in clinical or laboratory features between patients with different mutation
    types or numbers, and no genotype-phenotype correlation is established. The
    modifiers that set disease severity for a given INSR lesion are unknown.
  evidence:
  - reference: PMID:38957655
    reference_title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No statistical differences were found in clinical features and laboratory parameters between patients with different mutations."
    explanation: Documents the absence of a genotype-phenotype correlation.
notes: >-
  LUMP/SPLIT: Rabson-Mendenhall syndrome is kept as a separate entry from the
  other members of the INSR allelic series. It is the intermediate-severity form
  of INSR-related severe insulin resistance (INSR-SIRS), a continuum running from
  the neonatally lethal Donohue syndrome (leprechaunism; near-complete loss of
  receptor function) through Rabson-Mendenhall to the milder type A insulin
  resistance (PMID:29369573, PMID:29695048). Although the three share the same
  causal gene and are described by GeneReviews as one phenotypic continuum, they
  are curated separately here because they differ in onset, severity, survival,
  and (for type A) typical inheritance and are represented by distinct MONDO
  concepts. Keep-separate is the expected call. This entry is also deliberately
  distinct from the acquired, autoantibody-mediated type B insulin resistance
  syndrome (kb/disorders/Type_B_Insulin_Resistance_Syndrome.yaml), which shares
  the extreme-insulin-resistance clinical picture but has no INSR genetic lesion.
  CURATION SCOPE: Pineal hyperplasia is named in the OMIM title of RMS (262190)
  and reported in case series, but none of the abstracts fetched into the local
  reference cache carried a directly quotable statement of it, so it is described
  here without a separately evidenced phenotype rather than being asserted on a
  weaker citation. Emerging GLP-1/GIP-agonist (tirzepatide) case reports were
  identified in deep research but were not indexed in PubMed at curation time and
  could not be snippet-verified, so they are noted here rather than curated as a
  treatment.
review_notes: >-
  Created de novo from a claude_code deep-research report treated as leads. Two
  ontology bindings suggested by the report were hallucinated or Named-Entity
  confusions and were corrected during curation: HP:0000707 (suggested for
  "dentition") is actually "Abnormality of the nervous system" (used HP:0000164);
  NCIT:C77082 (suggested for metreleptin) is Tolvaptan and NCIT:C1966 (suggested
  for mecasermin) is Imaging Agent (used CHEBI:752900 metreleptin and
  CHEBI:749581 mecasermin). HP:0000857, initially considered for diabetes, is
  "Neonatal insulin-dependent diabetes mellitus"; HP:0000831
  (insulin-resistant diabetes mellitus) was used instead. All evidence snippets
  are exact substrings of PubMed abstracts/full text cached via just
  fetch-reference.
references:
- reference: PMID:38957655
  title: "Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients."
- reference: PMID:29369573
  title: "INSR-Related Severe Insulin Resistance Syndrome."
  tags: [GeneReviews]
- reference: PMID:40499531
  title: "Genealogical Rabson-Mendenhall syndrome caused by INSR gene mutation."
- reference: PMID:25358339
  title: "Insulin Receptor and the Kidney: Nephrocalcinosis in Patients with Recessive INSR Mutations."
- reference: PMID:41606799
  title: "Clinical spectrum of extreme insulin resistance syndromes treated with rhIGF-1: A single-center experience."
- reference: PMID:29695048
  title: "Mecasermin in Insulin Receptor-Related Severe Insulin Resistance Syndromes: Case Report and Review of the Literature."
- reference: PMID:34718628
  title: "Long-Term Effects of Metreleptin in Rabson-Mendenhall Syndrome on Glycemia, Growth, and Kidney Function."
- reference: PMID:38978877
  title: "Case report: A case of Rabson-Mendenhall syndrome: long-term follow-up and therapeutic management with empagliflozin."
- reference: PMID:40241988
  title: "Case Report: The long-term effects of the empagliflozin therapy on glycemia and renal function in a patient with Rabson-Mendenhall syndrome caused by two heterozygous variants in INSR gene."
- reference: PMID:23367497
  title: "Syndrome of extreme insulin resistance (Rabson-Mendenhall phenotype) with atrial septal defect: clinical presentation and treatment outcomes."
- reference: PMID:33728143
  title: "Insulin, Insulin Everywhere: A Rare Case Report of Rabson-Mendenhall Syndrome."
📚

References & Deep Research

References

11
PMID:38957655
Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients.
No top-level findings curated for this source.
PMID:29369573
INSR-Related Severe Insulin Resistance Syndrome.
No top-level findings curated for this source.
PMID:40499531
Genealogical Rabson-Mendenhall syndrome caused by INSR gene mutation.
No top-level findings curated for this source.
PMID:25358339
Insulin Receptor and the Kidney: Nephrocalcinosis in Patients with Recessive INSR Mutations.
No top-level findings curated for this source.
PMID:41606799
Clinical spectrum of extreme insulin resistance syndromes treated with rhIGF-1: A single-center experience.
No top-level findings curated for this source.
PMID:29695048
Mecasermin in Insulin Receptor-Related Severe Insulin Resistance Syndromes: Case Report and Review of the Literature.
No top-level findings curated for this source.
PMID:34718628
Long-Term Effects of Metreleptin in Rabson-Mendenhall Syndrome on Glycemia, Growth, and Kidney Function.
No top-level findings curated for this source.
PMID:38978877
Case report: A case of Rabson-Mendenhall syndrome: long-term follow-up and therapeutic management with empagliflozin.
No top-level findings curated for this source.
PMID:40241988
Case Report: The long-term effects of the empagliflozin therapy on glycemia and renal function in a patient with Rabson-Mendenhall syndrome caused by two heterozygous variants in INSR gene.
No top-level findings curated for this source.
PMID:23367497
Syndrome of extreme insulin resistance (Rabson-Mendenhall phenotype) with atrial septal defect: clinical presentation and treatment outcomes.
No top-level findings curated for this source.
PMID:33728143
Insulin, Insulin Everywhere: A Rare Case Report of Rabson-Mendenhall Syndrome.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record review notes

Created de novo from a claude_code deep-research report treated as leads. Two ontology bindings suggested by the report were hallucinated or Named-Entity confusions and were corrected during curation: HP:0000707 (suggested for "dentition") is actually "Abnormality of the nervous system" (used HP:0000164); NCIT:C77082 (suggested for metreleptin) is Tolvaptan and NCIT:C1966 (suggested for mecasermin) is Imaging Agent (used CHEBI:752900 metreleptin and CHEBI:749581 mecasermin). HP:0000857, initially considered for diabetes, is "Neonatal insulin-dependent diabetes mellitus"; HP:0000831 (insulin-resistant diabetes mellitus) was used instead. All evidence snippets are exact substrings of PubMed abstracts/full text cached via just fetch-reference.

Record notes

LUMP/SPLIT: Rabson-Mendenhall syndrome is kept as a separate entry from the other members of the INSR allelic series. It is the intermediate-severity form of INSR-related severe insulin resistance (INSR-SIRS), a continuum running from the neonatally lethal Donohue syndrome (leprechaunism; near-complete loss of receptor function) through Rabson-Mendenhall to the milder type A insulin resistance (PMID:29369573, PMID:29695048). Although the three share the same causal gene and are described by GeneReviews as one phenotypic continuum, they are curated separately here because they differ in onset, severity, survival, and (for type A) typical inheritance and are represented by distinct MONDO concepts. Keep-separate is the expected call. This entry is also deliberately distinct from the acquired, autoantibody-mediated type B insulin resistance syndrome (kb/disorders/Type_B_Insulin_Resistance_Syndrome.yaml), which shares the extreme-insulin-resistance clinical picture but has no INSR genetic lesion. CURATION SCOPE: Pineal hyperplasia is named in the OMIM title of RMS (262190) and reported in case series, but none of the abstracts fetched into the local reference cache carried a directly quotable statement of it, so it is described here without a separately evidenced phenotype rather than being asserted on a weaker citation. Emerging GLP-1/GIP-agonist (tirzepatide) case reports were identified in deep research but were not indexed in PubMed at curation time and could not be snippet-verified, so they are noted here rather than curated as a treatment.

Create: Rabson-Mendenhall syndrome · 2026-09-04T14:41:09Z · View source

De novo curation of Rabson-Mendenhall syndrome (MONDO:0009874), the intermediate-severity INSR-related severe insulin resistance syndrome. Pathograph: biallelic INSR loss-of-function -> impaired insulin receptor (PI3K-AKT) signalling -> severe insulin resistance -> compensatory hyperinsulinaemia branching to cutaneous IGF-1R cross-activation (acanthosis nigricans), ovarian androgen excess (hyperandrogenism), beta-cell decompensation (insulin-resistant diabetes -> DKA), GH resistance (growth failure), plus a tissue-autonomous renal INSR dysfunction node (nephrocalcinosis). 11 phenotypes with HP terms and cohort frequencies from the 42-patient pooled series (PMID:38957655); INSR genetic section (hgnc:6091, AR, LOSS_OF_FUNCTION functional_impact_category on the trigger node); treatments (insulin sensitizers, high-dose insulin, empagliflozin/SGLT2i, mecasermin/rhIGF-1, metreleptin, antiandrogens, oophorectomy, genetic counseling) using the therapeutic_agent pattern; HUMAN_MODEL_MISMATCH discussion on the murine-vs-human renal phenotype (PMID:25358339) and a KNOWLEDGE_GAP on the absent genotype-phenotype correlation. All 65 evidence snippets verified against cached references. Corrected two Named-Entity-Confusion NCIT codes (metreleptin/mecasermin) and two hallucinated HP codes suggested by the deep-research lead. Kept separate from Donohue and type A (INSR allelic series) and from autoimmune type B insulin resistance.

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Rabson-Mendenhall Syndrome: Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 25 citations 2026-09-04T14:09:53.057215

Rabson-Mendenhall Syndrome: Comprehensive Research Report

1. Disease Information

Overview. Rabson-Mendenhall syndrome (RMS) is an ultra-rare autosomal recessive disorder caused by biallelic (homozygous or compound heterozygous) loss-of-function variants in the insulin receptor gene (INSR), producing one of the most severe forms of genetically determined insulin resistance in humans. It sits in the middle of a phenotypic continuum of "INSR-related severe insulin resistance syndrome" (INSR-SIRS), between the neonatally lethal Donohue syndrome (leprechaunism, the most severe end) and the comparatively milder Type A insulin resistance syndrome (NBK476444). Clinically it is defined by extreme hyperinsulinemia, growth retardation, characteristic coarse ("elfin"/senile) facial features, acanthosis nigricans, hypertrichosis, dental and nail abnormalities, and pineal hyperplasia, with progression to insulin-resistant diabetes mellitus and recurrent diabetic ketoacidosis (DKA) in the first two decades of life.

Key identifiers: - OMIM: 262190 ("Pineal Hyperplasia, Insulin-Resistant Diabetes Mellitus, and Somatic Abnormalities") — OMIM 262190 - Gene locus (OMIM): INSR, 147670, chromosome 19p13.2 - Orphanet: ORPHA:769 — Orphanet: Rabson-Mendenhall syndrome - MONDO: MONDO:0009874 - UMLS/MedGen: C0271695 — MedGen - ICD-10: E13 (Other specified diabetes mellitus) is the commonly cross-referenced code (no RMS-specific ICD-10 code exists; it is typically coded under syndromic/other diabetes categories) - GeneReviews chapter: "INSR-Related Severe Insulin Resistance Syndrome" (covers both Donohue syndrome and RMS as one continuum) — GeneReviews NBK476444

Synonyms: Mendenhall syndrome; insulin resistance with acanthosis nigricans and pineal hyperplasia; INSR-related severe insulin resistance syndrome (intermediate/RMS phenotype).

Evidence basis. Nearly all available data derive from aggregated case reports and small case series (individual patients, not large registries or EHR cohorts) — fewer than ~50–100 molecularly confirmed cases have been published worldwide. The largest aggregation to date is a 2024 systematic review/meta-analysis of 42 patients pooled from 33 published articles (PMC11216847), which is the closest the literature has to a "disease-level" resource; otherwise virtually all information is from individual case reports, with GeneReviews and Orphanet providing curated syntheses of that case literature.

2. Etiology

Primary cause — genetic. RMS is caused by biallelic pathogenic variants in INSR (insulin receptor gene, 19p13.2), inherited in autosomal recessive fashion with variable expressivity. GeneReviews describes five functional classes of INSR pathogenic variants, all converging on loss of receptor function: 1. Impaired receptor biosynthesis 2. Impaired transport of the receptor to the plasma membrane 3. Impaired insulin binding affinity 4. Impaired tyrosine kinase activity 5. Accelerated receptor degradation

The 42-patient analysis (PMC11216847) found 55 distinct INSR variants: missense mutations were by far the most common class (72.7%), followed by deletions (10.9%), insertions (1.8%), and nonsense variants (1.8%); the most recurrent single variant was p.Glu238Lys (7.3%, 4/55), and exon 2 was the most frequently affected exon (7 occurrences). Compound heterozygosity is more common than true homozygosity; 52.4% of the 42 patients carried ≥2 distinct variants and 47.6% carried a single (presumed homozygous or the second allele undetected) variant.

Genotype-phenotype correlation. GeneReviews states explicitly: "There are no known genotype-phenotype correlations in INSR-SIRS" — variant type/location does not reliably predict Donohue vs. RMS vs. Type A severity, though broadly, variants that abolish receptor function completely tend toward the Donohue end and partial-function variants toward RMS/Type A.

Founder/recurrent variants documented in the literature: - c.167T>C (p.Ile56Thr) — founder variant reported in the Israeli Druze population - c.3003_3012del10insGGAAG (p.Ser1001ArgfsTer37) — reported in Tunisian families - A 2024 "genealogical" case series (PMID:40499531) describes a multi-generation kindred with RMS traced through a shared INSR variant.

Risk factors: - Genetic: biallelic INSR variants are necessary and sufficient; parental consanguinity substantially raises recurrence risk in families, and RMS pedigrees are frequently consanguineous (per case-series commentary; no population-based consanguinity rate is published). - Heterozygous carriers (parents/siblings) are generally asymptomatic but may show a mild phenotype overlapping with Type A insulin resistance syndrome, and heterozygous females are described as being at increased risk for gestational diabetes and require glucose monitoring in pregnancy (GeneReviews). - Environmental/lifestyle: no environmental, infectious, dietary, or occupational risk factor is implicated — this is a purely monogenic disorder; standard childhood metabolic stressors (illness, fasting, high-carbohydrate intake) precipitate the glycemic swings and DKA episodes that mark disease progression but do not cause the underlying condition.

Protective factors: None specific are described in the literature; there is no known modifier variant or environmental exposure shown to attenuate the phenotype. Because affected individuals retain some residual insulin receptor function (unlike Donohue syndrome), the RMS phenotype itself can be considered a "less severe" position along the allelic severity spectrum, but this is a genotype effect, not an independent protective factor.

Gene-environment interaction: Not established beyond the generic observation that infection, illness, and nutritional intake modulate glycemic control and precipitate ketoacidosis in the context of the underlying genetic lesion; no GxE database entries specific to RMS were identified.

3. Phenotypes

RMS phenotypes span dysmorphic/dermatologic signs, endocrine-metabolic laboratory abnormalities, and organ-specific complications. Frequencies below are drawn from the 42-patient pooled analysis (PMC11216847) unless otherwise noted.

Phenotype Frequency HPO term (suggested) Notes
Acanthosis nigricans 69.1% (29/42) HP:0000956 Early childhood onset; velvety hyperpigmented, thickened skin at neck, axillae, groin
Growth retardation / short stature 59.5% (25/42) HP:0001510 (Growth delay) / HP:0004322 (Short stature) Both prenatal (IUGR) and postnatal growth failure described
Dental anomalies (premature eruption, crowding, dysplastic teeth) 54.8% (23/42) HP:0000707 (Abnormality of the dentition) Early tooth eruption is a hallmark diagnostic clue
Hirsutism / hypertrichosis 40.5% (17/42) HP:0000998 (Hirsutism) / HP:0000998-adjacent HP:0001054 (Hypertrichosis) Generalized excess body hair, often noted from infancy
Enlarged genitalia (clitoromegaly in females; phallic enlargement) 19.0% (8/42) HP:0000027 (Abnormality of penis) / HP:0000138 (Ovarian cyst)-related Related to hyperinsulinemia-driven androgen excess
Nail hypertrophy/dystrophy 14.3% (6/42) HP:0001807 (Abnormal nail morphology)
Coarse/senile facial appearance, prominent jaw, full lips, large ears, furrowed tongue Common (qualitative, near-universal in case reports) HP:0000280 (Coarse facial features) Descriptive "elfin" or prematurely aged appearance
Fasting hypoglycemia with postprandial hyperglycemia Characteristic early feature HP:0001943 (Hypoglycemia) / HP:0003074 (Hyperglycemia) Paradoxical pattern from extreme hyperinsulinemia acting on residual receptor + non-receptor pathways
Diabetes mellitus (insulin-resistant) 75.8% of evaluable cases (25/33) developed by age 23 HP:0000857 (Insulin-resistant diabetes mellitus) Mean diagnostic age 9.41 years (range 0–23)
Diabetic ketoacidosis (recurrent) Frequent complication, leading cause of morbidity/mortality HP:0025187 (or generic) Emerges as insulin secretion declines in the second decade
Pineal hyperplasia Named in OMIM title; reported in multiple cases HP:0011912 (Pineal cyst)-adjacent; no exact HPO term for hyperplasia — closest is pineal gland abnormality Melatonin metabolite excretion is elevated, consistent with disordered pineal function
Polycystic/enlarged ovaries with hyperandrogenism Frequent in postpubertal/pubertal females HP:0000138 (Ovarian cyst) / HP:0000023 (Hyperandrogenism) Can require gonadectomy if causing mass effect or malignancy concern
Nephrocalcinosis / renal abnormality "Most individuals" per GeneReviews/GARD summaries HP:0000121 (Nephrocalcinosis) Distinct mechanism proposed relating INSR function in the kidney (PMC4369119)
Organomegaly (kidney, liver, spleen, tongue, external genitalia) Reported subset HP:0002240 (Hepatomegaly) etc.
Lipoatrophy / paucity of subcutaneous fat Common descriptive feature HP:0009125 (Lipodystrophy) Contrasts with obesity-associated insulin resistance; patients are typically underweight, not obese
Low BMI / underweight Mean BMI 16.0 kg/m²; 84.2% (16/19) underweight; no obese patients reported — Distinguishes RMS from acquired/metabolic-syndrome insulin resistance
Cardiac abnormalities (case reports) Uncommon but described (ASD, and hypertrophic remodeling in the allelic Donohue phenotype) HP:0001631 (ASD) One case report of RMS with atrial septal defect (PMC3628395); cardiomyopathy is more classically described in Donohue syndrome (30% of infants per GeneReviews)

Onset/progression pattern: Symptoms typically begin in infancy with failure to thrive and early dentition; acanthosis nigricans and hypertrichosis emerge in early childhood; the glycemic pattern evolves over time — GeneReviews notes that from birth to about age 1, severe hyperinsulinemia with fluctuating glucose predominates, while from roughly age 1 onward, insulin levels decline, glucose rises, hypoglycemic events lessen, and risk of ketoacidosis increases. Diabetes and its complications (retinopathy, nephropathy, DKA) are the dominant issues of the second decade.

Quality of life impact: Not formally studied with validated instruments (no EQ-5D/SF-36/PROMIS data identified for RMS specifically); qualitatively, disease burden is severe — recurrent hospitalizations for DKA, growth failure, dysmorphic features affecting social functioning, and early mortality risk dominate the clinical picture. No disease-specific QOL studies were found.

4. Genetic/Molecular Information

Causal gene: INSR (HGNC:6091; OMIM *147670), chromosome 19p13.2. Encodes a heterotetrameric receptor tyrosine kinase: preproprotein of 1,382 amino acids processed into two extracellular α-subunits (731 aa each, encoded by exons 1–11, insulin-binding) and two transmembrane β-subunits (620 aa each, encoded by exons 12–22, intracellular tyrosine kinase domain) linked by disulfide bonds into an α₂β₂ heterotetramer.

Variant classification (ACMG/AMP context): Pathogenic/likely pathogenic biallelic variants required for diagnosis per GeneReviews diagnostic criteria (clinical + molecular confirmation). Sequence analysis (missense, nonsense, splice-site, small indels) detects >90% of pathogenic variants; gene-targeted deletion/duplication analysis accounts for <10%.

Variant types observed (PMC11216847, n=55 variants across 42 patients): - Missense: 72.7% - Deletions: 10.9% - Insertions: 1.8% - Nonsense: 1.8% - (remainder: other/splice-site types not separately itemized in the search-derived summary) - Most recurrent: p.Glu238Lys (7.3%) - Exon 2 most frequently mutated

Allele frequency in population databases: RMS-causing variants are, as expected for an ultra-rare autosomal recessive disease, present at very low or absent frequencies in gnomAD/1000 Genomes/ExAC; specific allele frequencies were not retrieved in this search pass and should be confirmed per-variant via gnomAD/ClinVar at curation time (e.g., ClinVar entries such as NM_000208.4(INSR):c.2480_2487del (p.Gln827fs) and c.394G>A (p.Gly132Ser) are annotated for RMS — ClinVar RCV000015828, ClinVar RCV000240670).

Somatic vs. germline: Exclusively germline; no somatic mosaicism or acquired-mutation mechanism is described for RMS.

Functional consequence: Loss of function (LOF) — reduced receptor number at the cell surface and/or reduced receptor signaling function; GeneReviews' five-class mechanism list (above) captures the range from synthesis defects through accelerated degradation. This is a partial/hypomorphic LOF state compared to Donohue syndrome, which typically reflects near-complete loss of receptor function.

Modifier genes: None specifically validated; genotype-phenotype correlation is explicitly stated as absent in GeneReviews, implying that modifying genetic or environmental factors (not yet characterized) must account for phenotypic variability among carriers of similarly severe INSR lesions.

Epigenetic information: No RMS-specific DNA methylation, histone modification, or chromatin studies were identified in this search.

Chromosomal abnormalities: RMS is caused by point mutations/small indels in INSR, not by large-scale chromosomal rearrangements, aneuploidy, or translocation; no DECIPHER/ECARUCA structural variant entries specific to RMS were found in this pass.

Molecular signaling mechanism (downstream of INSR): Insulin binding to the extracellular α-subunits induces a conformational change that triggers β-subunit tyrosine kinase autophosphorylation. This recruits insulin receptor substrate (IRS) adaptor proteins, activating two principal downstream cascades: - PI3K/AKT pathway — via IRS docking, mediates the majority of insulin's metabolic effects (GLUT4 translocation, glycogen synthesis, lipogenesis, suppression of gluconeogenesis) - Ras/Raf/MEK/MAPK pathway — via IRS and Shc adaptors, mediates mitogenic/growth-regulatory effects and gene expression control

In RMS, loss-of-function INSR variants blunt this signaling cascade at its origin, producing profound peripheral (metabolic) insulin resistance while — paradoxically — some tissues (notably ovarian theca cells) retain enough residual insulin/IGF-1 receptor crosstalk to mediate hyperandrogenism: insulin (at pathologically elevated concentrations) and IGF-1 both stimulate ovarian theca-cell androgen synthesis via cytochrome P450c17α (CYP17A1) upregulation and synergy with LH, explaining the hyperandrogenic/polycystic ovarian phenotype despite systemic insulin resistance — a mechanism paralleled in the broader PCOS literature on "selective insulin resistance" in which the MAPK/mitogenic arm and ovarian steroidogenic insulin sensitivity are relatively preserved even as the PI3K/AKT metabolic arm is impaired.

5. Environmental Information

RMS is a fully penetrant monogenic disorder; no environmental toxin, occupational exposure, lifestyle factor, or infectious trigger is implicated in disease causation. Environmental/behavioral factors are relevant only as modulators of the clinical course: - Intercurrent infection and metabolic stress can precipitate diabetic ketoacidosis - Dietary carbohydrate load and fasting state drive the paradoxical postprandial hyperglycemia / fasting hypoglycemia pattern - No infectious agent is causally or precipitously linked to RMS in the literature surveyed

6. Mechanism / Pathophysiology

Causal chain (ordered)

  1. Biallelic loss-of-function variants in INSR (chromosome 19p13.2) → leads to reduced number and/or reduced function of cell-surface insulin receptors (via impaired receptor synthesis, membrane trafficking, insulin-binding affinity, tyrosine kinase activity, or accelerated degradation — GeneReviews' five mechanistic classes).
  2. Deficient functional insulin receptor at target tissues (adipocyte, myocyte, hepatocyte) → results in markedly reduced insulin-stimulated PI3K/AKT signaling → leads to impaired GLUT4-mediated glucose uptake in muscle/fat and failure to suppress hepatic gluconeogenesis — the core defect of severe peripheral insulin resistance (inferred from general INSR-IRS-PI3K-AKT pathway biology, extrapolated to RMS by the clinical response pattern).
  3. Peripheral insulin resistance → triggers compensatory pancreatic beta-cell hypersecretion of insulin → results in the extreme hyperinsulinemia that is a biochemical hallmark of RMS (median fasting insulin 300 μIU/mL in the pooled cohort, up to 861 μIU/mL, versus a normal range of 5–20 μIU/mL).
  4. In infancy/early childhood, residual insulin action combined with massive hyperinsulinemia produces a paradoxical glycemic pattern: fasting hypoglycemia (from insulin's residual/non-canonical suppressive effects, e.g., via IGF-1 receptor cross-activation at supraphysiologic insulin concentrations) alternating with postprandial hyperglycemia (from failure of insulin-stimulated glucose disposal) — this step is well described clinically but its precise molecular basis (differential receptor reserve across tissues/pathways) is partly inferred.
  5. Over the first decade, beta-cell secretory capacity declines (a form of "insulin resistance exhaustion" / relative beta-cell failure under chronic hyperstimulation) → leads to a shift from hyperinsulinemic hypoglycemia toward sustained hyperglycemia and overt insulin-resistant diabetes mellitus (diagnosed in ~76% of evaluable cases by a mean age of 9.4 years).
  6. Progressive hyperglycemia, especially with intercurrent illness or reduced caloric intake, → precipitates recurrent diabetic ketoacidosis, which is the leading proximate cause of death, typically in the second to third decade of life.
  7. Branch — ovarian axis: Extreme hyperinsulinemia, acting through residual insulin receptor and cross-reactive IGF-1 receptor signaling in ovarian theca cells (a tissue where the MAPK/steroidogenic arm of insulin/IGF-1 signaling is relatively preserved despite systemic PI3K/AKT-mediated resistance), → stimulates CYP17A1 (P450c17α) activity and synergizes with LH → results in ovarian hyperandrogenism, enlarged/polycystic ovaries, clitoromegaly, and hirsutism (mechanism extrapolated from the general PCOS/insulin-resistance literature; not RMS-specific mechanistic studies).
  8. Branch — growth axis: Loss of INSR function, combined with a state of growth hormone resistance (elevated basal GH with low-normal IGF-1 in reported cases, consistent with GH resistance), → contributes to severe growth retardation/short stature; IGF-1 receptor signaling (a partially redundant pathway to INSR) is insufficient to compensate fully, and neither exogenous growth hormone nor standard-dose IGF-1 corrects the growth deficit (documented specifically as "lack of effect of growth hormone and insulin-like growth factor-I" in a landmark natural-history report).
  9. Branch — dermatologic/soft tissue overgrowth: Chronic extreme hyperinsulinemia → cross-activates IGF-1 receptors on keratinocytes and dermal fibroblasts (which retain responsiveness to insulin at pathological concentrations) → produces acanthosis nigricans (epidermal hyperkeratosis/hyperpigmentation), hypertrichosis, gingival hyperplasia, and soft-tissue/dental overgrowth — the shared mechanistic explanation across the INSR-SIRS spectrum (Donohue, RMS, Type A), inferred from receptor cross-reactivity biology rather than RMS-specific mechanistic proof.
  10. Branch — pineal gland: Pineal hyperplasia with increased urinary melatonin metabolite excretion is reported, but the precise causal link between INSR loss-of-function and pineal overgrowth is not mechanistically established in the literature reviewed — this remains a descriptive association, not a demonstrated causal step.
  11. Branch — renal: Nephrocalcinosis and other renal abnormalities occur in a substantial proportion of patients; a dedicated study (PMC4369119, "Insulin Receptor and the Kidney: Nephrocalcinosis in Patients with Recessive INSR Mutations") proposes a direct role for insulin receptor signaling in renal tubular calcium handling, independent of the diabetic state — i.e., a tissue-autonomous consequence of INSR loss rather than a secondary complication of hyperglycemia (a distinguishing mechanistic claim worth flagging as its own pathophysiology node).

Molecular pathways

  • PI3K/AKT (KEGG insulin signaling pathway; GO:0043491 protein kinase B signaling) — principal metabolic arm, impaired in RMS
  • Ras/Raf/MEK/MAPK (GO:0000165 MAPK cascade) — mitogenic/growth arm, relatively spared, implicated in the paradoxical growth-promoting, hyperandrogenic, and soft-tissue overgrowth phenotypes
  • IGF-1 receptor (IGF1R) cross-signaling — proposed compensatory/pathogenic pathway at supraphysiologic insulin concentrations

Cellular processes

  • Compensatory pancreatic beta-cell hyperinsulin secretion, followed by secretory exhaustion (GO:0030073 insulin secretion)
  • Impaired GLUT4 translocation in adipocytes/myocytes (GO:0071384 cellular response to corticosteroid; more precisely GO:0035774 positive regulation of insulin secretion involved in cellular response to glucose stimulus is adjacent — GLUT4 translocation is GO:0071286-adjacent; suggest GO:0044381 glucose import in response to insulin stimulus)
  • Ovarian theca cell androgen biosynthesis (GO:0006702 androgen biosynthetic process)
  • Keratinocyte/fibroblast hyperproliferation underlying acanthosis nigricans

Cell types (CL terms, suggested)

  • CL:0000169 type B pancreatic cell (beta cell) — compensatory hyperinsulinemia/exhaustion
  • CL:0002327 mammary epithelial cell — not relevant; more relevant: CL:0000038 erythroid progenitor — not relevant
  • CL:0000499 stromal cell of ovary / theca cell (no precise CL ID retrieved in this pass; note as "ovarian theca cell" free text if no exact term validates)
  • CL:0000312 keratinocyte — acanthosis nigricans
  • CL:0000057 fibroblast — dermal/gingival overgrowth
  • CL:0000182 hepatocyte — hepatic glucose overproduction

Anatomical involvement (see Section 7 for detail)

Molecular profiling / omics

No transcriptomic, proteomic, metabolomic, lipidomic, single-cell, or spatial-omics studies specific to RMS patient tissue were identified in this search. This is consistent with the disease's rarity and the case-report-dominated evidence base; RMS mechanism is inferred largely from the well-characterized general insulin-signaling literature (PI3K/AKT, MAPK) rather than disease-specific omics data.

7. Anatomical Structures Affected

Organ level (primary): - Endocrine pancreas (compensatory beta-cell hyperfunction, later failure) - Adipose tissue (lipoatrophy/paucity of subcutaneous fat) - Skin/integument (acanthosis nigricans, hypertrichosis) - Reproductive system — ovaries (enlargement, polycystic change, hyperandrogenism), external genitalia (clitoromegaly/phallic enlargement) - Kidney (nephrocalcinosis, organomegaly) - Pineal gland (hyperplasia) - Dentition/oral cavity (premature/dysplastic teeth, gingival hyperplasia, furrowed tongue) - Skeletal system (growth retardation, short stature)

Secondary/complication-level organ involvement: - Cardiovascular system (rare congenital defects such as ASD reported; hypertrophic cardiomyopathy more classically part of the Donohue end of the spectrum) - Liver, spleen (organomegaly in some cases) - Eyes (diabetic retinopathy as a late microvascular complication)

Body systems involved: Endocrine, integumentary, reproductive, renal, dental/craniofacial, skeletal/growth, and (secondarily) cardiovascular and ophthalmologic systems.

Suggested UBERON terms: - UBERON:0001264 pancreas - UBERON:0001013 adipose tissue - UBERON:0002097 skin of body - UBERON:0000992 ovary - UBERON:0002113 kidney - UBERON:0002298 pineal gland - UBERON:0001091 tooth / UBERON:0001754 gingiva - UBERON:0000948 heart

Tissue/cell level: Epidermis/keratinocytes (acanthosis nigricans), ovarian theca cell layer, renal tubular epithelium (nephrocalcinosis), pancreatic islet beta cells, dermal fibroblasts and hair follicles (hypertrichosis).

Subcellular level: Plasma membrane insulin receptor (reduced density/trafficking defect — GO:0005886 plasma membrane; GO:0005899 insulin receptor complex); endoplasmic reticulum (receptor biosynthesis/folding defects in some variant classes — GO:0005783).

Localization/laterality: Not applicable — RMS manifestations are bilateral/systemic rather than lateralized.

8. Temporal Development

Onset: Congenital/neonatal-to-infantile onset of insulin resistance biochemistry and dysmorphic features; failure to thrive, early dentition, and acanthosis nigricans typically noted in infancy to early childhood. Onset pattern is insidious/chronic rather than acute, though DKA episodes are acute events superimposed on the chronic disease course.

Progression: - Early stage (infancy–early childhood): Predominantly hyperinsulinemic with fasting hypoglycemia/postprandial hyperglycemia; dysmorphic and dermatologic features become apparent. - Intermediate stage (childhood, mean age ~9.4 years): Overt diabetes mellitus manifests as beta-cell compensation begins to fail (diagnosed in ~76% of evaluable pooled cases by age 23, most well before that). - Late/advanced stage (second–third decade): Recurrent DKA, microvascular complications (nephropathy, retinopathy), and in females, hyperandrogenic ovarian disease; this stage carries the highest mortality risk. - Disease course is progressive rather than relapsing-remitting, though glycemic control fluctuates episodically (hypoglycemia early, hyperglycemia/DKA later) — a shifting rather than static progressive pattern. - Duration: Chronic, lifelong; RMS patients, unlike those with Donohue syndrome (who typically die before age 1), commonly survive into the second or third decade, with some reaching adulthood.

Remission patterns: No spontaneous remission is described; treatment (leptin, IGF-1, insulin, SGLT2 inhibitors) can improve glycemic control (partial biochemical "remission" of hyperglycemia) but does not cure or reverse the underlying receptor defect.

Critical periods: The transition around age ~1 year (from a hyperinsulinemic/hypoglycemia-predominant pattern to a hyperglycemia-predominant pattern) and the pubertal transition (onset of hyperandrogenic ovarian disease) are noted as clinically important inflection points warranting intensified monitoring per GeneReviews surveillance recommendations.

9. Inheritance and Population

Epidemiology: - RMS is exceptionally rare; NORD states "fewer than 50 patients have been reported in the medical literature," and other sources describe an incidence of "less than 1 in 1,000,000." No formal prevalence/incidence estimate from a population registry exists. Donohue syndrome, the more severe allelic disorder, is separately estimated at 1:1,000,000 births (GeneReviews); RMS prevalence is presumed similar or somewhat higher given its comparatively better survival (ascertainment bias toward RMS in the literature). - The pooled 42-patient cohort's geographic distribution: Asia 33.3%, Europe 33.3%, North America 26.2%, South America 4.8%, Oceania 2.4% — reflecting publication/ascertainment patterns rather than true population prevalence.

Inheritance pattern: Autosomal recessive. Siblings of an affected individual have (per GeneReviews) a 25% chance of being affected (biallelic), 50% chance of being heterozygous carriers, and 25% chance of inheriting neither variant.

Penetrance: Complete for the biallelic genotype (all reported biallelic INSR LOF carriers manifest disease), though severity is variable ("variable expressivity" per NORD).

Expressivity: Variable — phenotype ranges along the INSR-SIRS continuum even among patients with severe biallelic variants, and no genotype-phenotype correlation has been established.

Genetic anticipation: Not described/applicable (not a repeat-expansion disorder).

Germline mosaicism: Not specifically reported for RMS in this search pass.

Founder effects: Documented founder variants include c.167T>C (p.Ile56Thr) in the Israeli Druze population and c.3003_3012del10insGGAAG in Tunisian families (GeneReviews).

Consanguinity: RMS pedigrees are frequently consanguineous, consistent with autosomal recessive inheritance of an ultra-rare allele; several case reports explicitly note parental consanguinity.

Carrier frequency: Not established in population databases given the ultra-rarity and allelic heterogeneity of causal INSR variants; heterozygous carriers are generally asymptomatic but may show mild features of the allelic Type A insulin resistance phenotype, and heterozygous females have increased gestational diabetes risk.

Population demographics: - Sex ratio: roughly equal, slightly female-predominant in the pooled cohort — 57.1% female (24/42) vs. 42.9% male (18/42); NORD states the condition "affects males and females equally." - No specific ethnic/geographic endemicity beyond the founder populations noted above; cases have been reported across Asia, Europe, the Americas, and Oceania. - Age distribution of affected individuals in the literature: diagnosis from birth to early 20s, with a mean diagnostic age (for diabetes specifically) of 9.41 years.

10. Diagnostics

Clinical recognition: Diagnosis is suspected from the combination of extreme fasting hyperinsulinemia (often >100–300+ μIU/mL, orders of magnitude above the normal 5–20 μIU/mL range) with disproportionately modest or fluctuating glucose abnormalities, plus characteristic dysmorphic features (coarse facies, acanthosis nigricans, hypertrichosis, dental anomalies, growth retardation).

Laboratory tests: - Fasting glucose, insulin, C-peptide (markedly elevated insulin/C-peptide with hyperinsulinemia disproportionate to glucose level is the key biochemical signature) - HbA1c (mean 9.35% in the pooled cohort at diagnosis of diabetes; normal 4–6%) - Lipid panel — characteristically low triglycerides and elevated HDL (distinguishing RMS from acquired/lipodystrophy-type insulin resistance, which typically shows high triglycerides/low HDL) - Adiponectin — reported elevated in RMS - Thyroid function (surveillance for hypothyroidism) - Androgen panel in postpubertal females (testosterone, DHEA-S) for hyperandrogenism workup

Imaging: - Pelvic/ovarian ultrasound (surveillance for ovarian enlargement/cysts, malignancy risk) - Renal ultrasound (nephrocalcinosis surveillance) - Echocardiography/cardiac MRI (cardiac surveillance, alternating modalities per GeneReviews protocol) - Prenatal ultrasound findings (IUGR) can be an early clue in affected pregnancies

Genetic testing (per GeneReviews): - Diagnosis requires characteristic clinical/laboratory/radiographic/prenatal findings plus identification of biallelic INSR pathogenic variants - Sequence analysis of INSR detects >90% of pathogenic variants (missense, nonsense, splice-site, small indels) - Gene-targeted deletion/duplication analysis (e.g., MLPA) detects the remaining <10% (larger structural variants) - Multigene panels including INSR and phenocopy genes, or exome/genome sequencing, are used when the clinical presentation is ambiguous - Genetic Testing Registry (GTR) lists clinical/research testing for this condition — GTR C0271695

Differential diagnosis (per GeneReviews): - Donohue syndrome — more severe allelic disorder; distinguished by extreme prenatal growth restriction, cardiomyopathy (~30% of infants), and death typically before age 1 - Type A insulin resistance syndrome — milder allelic disorder, usually heterozygous INSR variant, later onset (puberty+), less severe diabetes, normal survival - Silver-Russell syndrome — IUGR and hypoglycemia but lacks hyperinsulinemia and RMS-characteristic facies - Familial hyperinsulinism — hyperinsulinemic hypoglycemia but lacks dysmorphism/severe growth deficiency, and insulin levels are much lower than in INSR-SIRS - Berardinelli-Seip congenital lipodystrophy — hyperinsulinemia and cardiomyopathy but with hyperlipidemia/hepatic steatosis and distinct fat-loss dysmorphism rather than INSR-driven features - IGF1R resistance — IUGR/developmental delay but no hyperinsulinemia, only mild glucose intolerance

Screening: No population-based newborn screening program exists for RMS (it is not detected by standard metabolic newborn screening panels); diagnosis relies on clinical suspicion. Cascade/family genetic testing is appropriate once a proband's biallelic INSR variants are identified, and prenatal/preimplantation testing can be offered in known-carrier families.

11. Outcome/Prognosis

Survival and mortality: RMS carries a poor but variable prognosis. Multiple sources converge on death typically occurring in the second to third decade of life, most commonly due to diabetic ketoacidosis and/or severe infection. In contrast to Donohue syndrome (death usually <1 year), RMS patients commonly survive into the teens or twenties, and some into their third decade — this is the key survival distinction between the two ends of the INSR-SIRS spectrum. Notably, the 42-patient pooled analysis reported that, aside from one 14-year-old who died of pulmonary hypertension, all other patients in that cohort were alive at time of reporting — though this reflects a survivorship/publication bias in a predominantly cross-sectional case-report literature rather than a true cohort-based mortality rate.

Morbidity/complications: - Recurrent diabetic ketoacidosis - Microvascular diabetic complications (retinopathy, nephropathy) emerging in the second decade - Nephrocalcinosis (renal, potentially INSR-intrinsic rather than purely diabetes-driven) - Ovarian complications — enlarged/polycystic ovaries, hyperandrogenism, and a documented concern for gynecologic malignancy (endometrial cancer surveillance recommended with abnormal vaginal bleeding per GeneReviews) - Growth failure/short stature, often refractory to growth hormone or standard IGF-1 therapy - Recurrent infections (a feature more prominent in Donohue syndrome but relevant across the spectrum)

Quality of life: Not formally quantified with validated instruments in the literature reviewed; disease burden is substantial given recurrent hospitalization, chronic dysmorphic features, and the psychosocial impact of a life-limiting rare disease in childhood/adolescence.

Prognostic factors: Degree of residual insulin receptor function (genotype severity) is the presumed principal driver of position along the Donohue–RMS–Type A severity spectrum, though no formal genotype-phenotype correlation has been validated. Access to advanced therapies (metreleptin, rhIGF-1, SGLT2 inhibitors) appears to improve glycemic control and may favorably influence long-term outcomes, though no controlled mortality-outcome data exist.

12. Treatment

There is no curative or disease-modifying therapy that restores insulin receptor function; management is supportive/symptomatic, aimed at glycemic stabilization, growth optimization, and complication prevention. NORD states plainly: "There is no specific treatment for individuals with Rabson-Mendenhall syndrome. The treatment of the disorder is directed toward the specific symptoms," and conventional high-dose insulin and standard insulin sensitizers are typically inadequate long-term.

Pharmacotherapy: - Insulin sensitizers (metformin, thiazolidinediones/pioglitazone) — first-line per GeneReviews to reduce HbA1c, though efficacy wanes over time, requiring dose escalation (NCIT:C15986 Pharmacotherapy; therapeutic_agent metformin/pioglitazone) - High-dose insulin therapy — required once oral agents fail; U-500 concentrated insulin recommended once doses exceed 200 units/day; extreme doses (up to 500 U/hour) documented during DKA in limited case reports - SGLT2 inhibitors (empagliflozin) — emerging off-label adjunct; case reports show HbA1c reduction (e.g., 8.5%→7.1% over 10 months in one 11-year-old, with time-in-range improving from 47% to 74%) and improved time-in-range independent of insulin receptor pathway, since SGLT2 inhibition works via renal glucose excretion — PMC11228259, PMC11999824 - GLP-1/GIP receptor agonists (tirzepatide) — a 2026 case report describes two genetically confirmed RMS patients treated with subcutaneous tirzepatide (2.5–3.3 mg weekly) for 3 months, reporting improved glycemic control — Frontiers in Endocrinology 2026

Advanced/targeted therapeutics: - Metreleptin (recombinant leptin) — FDA-approved for generalized lipodystrophy, used off-label in RMS. A controlled NIH natural-history comparison (9 metreleptin-treated vs. 7 untreated patients) found the metreleptin group maintained significantly lower HbA1c long-term (LSM difference 1.8%, P=0.007), with a 1.4% ± 1.1% A1c reduction at 12 months (P=0.006) versus a 0.2% increase in untreated controls; effect attributed to appetite suppression and lower BMI/weight (Δweight SDS −1.1±0.5, ΔBMI SDS −1.3±0.6, both P=0.0001) rather than direct insulin-pathway restoration. No significant renal-function benefit or harm was observed (24-hr urine protein/albumin, eGFR unchanged between groups). A tradeoff was noted: lower BMI after metreleptin may worsen growth hormone resistance, yielding a null effect on IGF-1/growth despite improved glycemia — JCEM 2022 - Recombinant human IGF-1 (rhIGF-1, mecasermin) — used particularly for DKA/severe metabolic decompensation and to bypass the defective insulin receptor via IGF1R signaling; benefits are variable and often modest, with continuous subcutaneous pump infusion reported as more effective than twice-daily injection in at least one case; does not prevent eventual progression to diabetes; potential adverse effects include theoretical malignancy risk from chronic IGF1R stimulation — PMC5983765 (mecasermin review), JCEM 2025 clinical spectrum with rhIGF-1 - Growth hormone therapy — an early natural-history study specifically documented "lack of effect of growth hormone and insulin-like growth factor-I" on the growth deficit in RMS, indicating GH resistance in this condition (JCEM, historical citation; PMID retrieval recommended at curation)

Hormonal/hyperandrogenism management: - Oral contraceptives, antiandrogens (flutamide, spironolactone), 5-alpha-reductase inhibitors (finasteride), and GnRH agonists for ovarian hyperandrogenism (NCIT:C15986 Pharmacotherapy; multiple agent classes) - Gonadectomy considered for markedly enlarged ovaries causing respiratory compromise or malignancy concern (NCIT:C15329 Surgical Procedure)

Endocrine surveillance-driven treatment: Standard levothyroxine replacement for documented hypothyroidism.

Supportive/rehabilitative care: Coordinated multidisciplinary management (pediatric endocrinology, dentistry, nutrition, cardiology) is recommended given the multisystem nature of the disease; dietary management (frequent feeding, protein-enriched evening feeds in infancy) mirrors strategies from the more severe Donohue syndrome end of the spectrum to prevent hypoglycemia.

Experimental/investigational: No RMS-specific gene therapy, CRISPR, cell therapy, or RNA-based (ASO/siRNA) therapeutic is in clinical development per the literature reviewed; anti-insulin receptor monoclonal antibody strategies have been explored preclinically in mouse models of human insulin receptoropathy (biorxiv preprint) but have not reached human RMS trials.

Treatment outcomes summary (from the 42-patient pooled cohort): Among 26 patients with treatment data — oral hypoglycemic agents alone in 57.7% (15/26), combined insulin + oral agents in 34.6% (9/26), and insulin monotherapy in 7.7% (2/26) — reflecting real-world heterogeneity in regimen choice.

Suggested NCIT terms: NCIT:C15986 (Pharmacotherapy), NCIT:C93352 (Targeted Therapy) for GLP-1/SGLT2/leptin agents, NCIT:C15329 (Surgical Procedure) for gonadectomy, NCIT:C15240 (Genetic Counseling).

13. Prevention

Primary prevention: Not applicable in the traditional sense — as a monogenic recessive disorder, primary prevention is limited to reproductive genetic counseling and carrier screening in at-risk (especially consanguineous or founder-population) families, rather than modifiable risk-factor reduction.

Secondary prevention: Early clinical recognition (dysmorphic features, hyperinsulinemia pattern) and prompt genetic confirmation allow earlier initiation of glycemic surveillance and treatment, potentially reducing the frequency/severity of DKA episodes; GeneReviews' structured surveillance protocol (glucose/HbA1c/insulin/C-peptide every 3 months; thyroid/androgen labs every 6 months; ovarian ultrasound every 3 months until age 2 then every 6 months; cardiac imaging every 6 months until age 2 then annually; renal assessment every 6 months; developmental assessment every 3 months) functions as a structured secondary-prevention framework to catch complications early.

Tertiary prevention: Aggressive glycemic management (insulin, adjunctive SGLT2i/GLP-1 agonists/metreleptin) aims to prevent progression to microvascular complications and recurrent DKA in patients who already have the disease.

Genetic counseling/screening: Carrier testing and prenatal/preimplantation genetic diagnosis are appropriate in families with a known proband, given the 25% recurrence risk per pregnancy in carrier x carrier matings; genetic counseling should also address the increased gestational diabetes risk in heterozygous INSR carrier females.

Public health/behavioral: No population-level public health intervention applies given the disease's extreme rarity and purely genetic etiology; there is no vaccine, environmental intervention, or lifestyle-based primary prevention strategy.

14. Other Species / Natural Disease

No naturally occurring veterinary or wildlife counterpart of RMS specifically was identified in this search (no OMIA entry located in this pass); INSR-related disease in domestic/companion animals was not surfaced by the queries run. This gap should be checked directly against OMIA (Online Mendelian Inheritance in Animals) at curation time, as spontaneous Insr loss-of-function disease in animals is not well documented in the general veterinary literature. Given the essential, highly conserved role of the insulin receptor across mammals, a naturally occurring biallelic-null phenotype would be expected to be severe/lethal (paralleling Donohue syndrome), which may explain the absence of reported natural veterinary cases (a plausible inference, not directly evidenced in this search).

Orthologous gene: Mouse Insr (MGI:96575), rat Insr (RGD:2916) — both extensively studied in engineered (not naturally occurring) knockout models (see Section 15).

15. Model Organisms

Genetically engineered mouse models (tissue-specific Insr knockouts) — these model components of insulin resistance but do not fully recapitulate the multisystem human RMS phenotype (dysmorphism, pineal hyperplasia, dental anomalies), since global germline Insr knockout in mice is neonatally lethal (paralleling Donohue syndrome severity) and most published models are conditional/tissue-specific:

  • Muscle-specific knockout (MIRKO): >90% decrease in insulin receptor kinase activity and reduced insulin-dependent glucose uptake in muscle, yet mice do not develop diabetes — illustrating compensation by other tissues (Physiological Reviews review, JCI review of knockout models)
  • Liver-specific knockout (LIRKO): Dramatic insulin resistance, severe glucose intolerance, failure of insulin to suppress hepatic glucose output, and marked hyperinsulinemia from both increased secretion and decreased clearance — the closest single-tissue model to the hyperglycemia/hyperinsulinemia biochemistry of RMS
  • Adipose-specific knockout (FIRKO): Protected from obesity and glucose intolerance — illustrating that adipose Insr loss alone does not reproduce human disease severity
  • Beta-cell-specific Insr/Igf1r double knockout: Develops diabetes, whereas single-gene knockouts show only mild phenotypes — demonstrating redundancy between insulin and IGF-1 receptor signaling in beta cells, mechanistically relevant to why IGF-1-based therapies (mecasermin) have been tried in human RMS
  • "Humanized" Insr knock-in models carrying patient-derived INSR variants have been used preclinically to test anti-insulin-receptor antibody therapeutics as a potential novel approach to insulin receptoropathy (bioRxiv preprint, "Anti-insulin receptor antibodies improve hyperglycaemia in a mouse model of human insulin receptoropathy") — this is the most disease-specific (as opposed to generic tissue-knockout) rodent model identified, though it remains preclinical.

Model limitations: No single mouse model reproduces the full RMS phenotype (growth retardation, acanthosis nigricans, pineal hyperplasia, dental/gingival overgrowth, ovarian hyperandrogenism, nephrocalcinosis) — tissue-specific knockouts isolate individual metabolic phenotypes (hepatic, muscle, adipose, beta-cell) but the integrated human syndrome (including its distinctive dermatologic and dysmorphic features driven by cross-reactive IGF1R signaling in skin/ovary/bone) has not been captured in a single validated animal model per the literature surveyed. Global germline Insr-null mice die perinatally from diabetic ketoacidosis, mirroring Donohue syndrome rather than the somewhat more viable RMS phenotype, and true patient-variant knock-in models recapitulating hypomorphic (partial-function) RMS-type alleles are not well represented in the literature retrieved.

Research applications: Tissue-specific knockout models remain the primary tool for dissecting which organ-specific consequences of INSR loss (hepatic glucose overproduction, muscle glucose uptake failure, adipose dysfunction, beta-cell secretory response) contribute to the integrated human phenotype, and knock-in/humanized models are beginning to support therapeutic antibody development as a potential future RMS treatment strategy.

Resource databases for follow-up: MGI (Mouse Genome Informatics) for Insr allele catalog; IMPC/KOMP for available knockout/conditional lines.

Summary of Key Ontology Term Suggestions for KB Curation

  • Gene: hgnc:6091 (INSR)
  • MONDO: MONDO:0009874
  • OMIM: 262190
  • ORPHA: 769
  • HP terms: HP:0000956 (Acanthosis nigricans), HP:0001510 (Growth delay), HP:0000707 (Dentition abnormality), HP:0000998 (Hirsutism), HP:0000121 (Nephrocalcinosis), HP:0000138 (Ovarian cyst), HP:0000023 (Hyperandrogenism), HP:0001943 (Hypoglycemia), HP:0003074 (Hyperglycemia), HP:0000857 (Insulin-resistant diabetes mellitus), HP:0000280 (Coarse facial features)
  • GO (biological process): insulin receptor signaling pathway (GO:0008286), PI3K/AKT signaling, MAPK cascade (GO:0000165), androgen biosynthetic process (GO:0006702)
  • CL: CL:0000169 (type B pancreatic cell), CL:0000312 (keratinocyte), CL:0000057 (fibroblast)
  • UBERON: UBERON:0001264 (pancreas), UBERON:0000992 (ovary), UBERON:0002113 (kidney), UBERON:0002298 (pineal gland), UBERON:0001013 (adipose tissue)
  • NCIT (treatment): NCIT:C15986 (Pharmacotherapy), NCIT:C15329 (Surgical Procedure), NCIT:C93352 (Targeted Therapy)

Sources

Note on evidence quality: This report is compiled from web search and web-fetch results, not from primary-source PDF retrieval or PMID-level abstract verification. Per dismech's evidence policy, every claim above should be treated as a lead requiring verification against the primary source (exact PMID, exact quoted snippet) before being entered into a KB YAML evidence block — several figures (e.g., specific percentages from the 42-patient meta-analysis, the metreleptin trial statistics) were extracted via WebFetch summarization rather than direct primary-text quotation and must be re-confirmed against the original PMC full text with just fetch-reference before citing.