RARE DISEASE
Rabson-Mendenhall syndrome
Rabson-Mendenhall syndrome
Rabson-Mendenhall syndrome
Drug discovery
2
drugs
With orphan designations
Overview
Rabson-Mendenhall syndrome (RMS) is a rare autosomal recessive disorder caused by mutations in the INSR gene, leading to severe insulin resistance and dysregulated glucose metabolism [1][6][7]. Characterized by growth retardation, acanthosis nigricans, dental dysplasia, and dysmorphic features, RMS manifests in early childhood with paradoxical hypoglycemia progressing to persistent hyperglycemia and diabetic ketoacidosis [2][4][12]. Prognosis remains poor due to limited treatment efficacy, with life expectancy typically <20 years [1][6][17].
Burden
High morbidity from metabolic instability, recurrent ketoacidosis, and end-organ complications [3][12][17]
Requires intensive daily management with frequent glucose monitoring and complex care coordination [9][12]
Limited treatment response: HbA1c often remains >10% despite aggressive therapy [3][16]
Therapies
Glycemic control: High-dose insulin (up to 4.6 U/kg/day), SGLT2 inhibitors (e.g., empagliflozin), and insulin sensitizers (metformin/pioglitazone) [3][9][16]
Adjunctive therapies: Recombinant IGF-1 (mecasermin) and leptin analogues show partial efficacy [2][16][18]
Supportive care: Surgical correction of dental/facial anomalies and multidisciplinary management [1][4]
Categories: rare endocrine diseases, rare genetic diseases, rare skin diseases
Research Papers
41 drug discovery papers about Rabson-Mendenhall syndrome, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
41 drug discovery papers about Rabson-Mendenhall syndrome, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-01-29 | Clinical spectrum of extreme insulin resistance syndromes treated with rhIGF-1: A single-center experience.
Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS) are extreme forms of insulin resistance (IR) caused by biallelic mutations in the insulin receptor gene. Recombinant human insulin-like growth factor-1 (rhIGF-1) treatment is often used but its long-term benefits and risks are still poorly delineated. We describe rhIGF-1 treatment outcomes of a cohort of patients with DS and RMS, and compare them to previously published patients. A single-center retrospective observational study with case note review was conducted. A literature search was performed for previously published DS and RMS patients treated with rhIGF-1. rhIGF-1 outcomes beyond 4 months have been reported for only 11 patients with DS and RMS to date. We provide outcome data for 3 more males, and report the long-term clinical course of a patient already described. Metabolic benefits of rhIGF-1 included improved glycemic control and fasting tolerance in early years of life, and some growth enhancement. Two patients exhibited poor response or intolerance to rhIGF-1 and died in infancy. The 2 longest-lived patients had progressive decompensation to diabetes mellitus, in 1 case despite long-term uninterrupted rhIGF-1 therapy. We also describe new features associated with severe insulin receptoropathies, such as cataract, liver hemangioma, and impaired hepatic protein synthesis. The phenotypes of DS and RMS are heterogeneous. Current treatment options remain unsatisfactory as high-dose rhIGF-1 exerts only limited beneficial effects and does not prevent decompensation to diabetes mellitus. More research is needed to identify alternative treatment strategies for extreme forms of IR.
2025-12-22 | The Use of Dapagliflozin in the Treatment of Children With Severe Insulin Resistance.
Managing severe insulin resistance (IR) is challenging, necessitating a multifaceted approach, including dietary restriction, exercise, and pharmacotherapy. This paper will detail our utilization of dapagliflozin in a series of cases involving patients with severe IR of various etiology and inadequate glycemic control. We describe six cases of extreme IR with distinct clinical diagnoses: four with Rabson-Mendenhall syndrome (RMS), one with IR type 1A, and a patient with type 1 diabetes mellitus (T1DM) and severe subcutaneous (SC) IR. These cases exhibit the observable characteristics of IR, characterized by an inability to effectively manage blood glucose (BG) with a standard treatment plan. Every case had a remarkable response to dapagliflozin. Subsequent assessment demonstrated improved HgbA1C, fasting glucose, insulin, and C-peptide concentrations. Furthermore, several cases demonstrated improvement in the clinical manifestations of IR following the administration of dapagliflozin, while others showed a reduction in the frequency of diabetic ketoacidosis (DKA). There were no documented adverse reactions with the use of dapagliflozin for a duration of 2-4 years in these patients. Dapagliflozin appeared both safe and effective as a standalone treatment or when used alongside other antidiabetes medications such as insulin in a case series of children with T1DM and severe IR or IR syndromes (IRS).
2025-08-24 | Rabson-Mendenhall syndrome: A rare case with severe insulin resistance
A rare hereditary cause of insulin resistance, Rabson-Mendenhall syndrome (RMS) is manifested by extreme insulin resistance caused by mutations in the insulin receptor (INSR) gene. The characteristics of RMS are retarded growth, dysmorphisms, hirsutism, enlarged genitalia, acanthosis nigricans, dysplastic dentition, hyperglycemia, elevated insulin level, and hyperplasia of the pineal gland. RMS patients usually present in childhood, and most affected patients usually survive till the second decade of life. We are presenting here a unique case of a 10-year-old girl with very high blood sugar and crowding of teeth. She developed classical symptoms of diabetes for the last three years. On examination, she had syndromic coarse facies, prognathism, gingival hyperplasia, larger lower lip, hyperdontia, hyperpigmented skin, hypertrichosis, severe acanthosis nigricans & dystrophic nails. Biochemical investigations revealed insulin resistance by high fasting insulin, and high normal C-peptide with very high Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). She was treated with insulin with insulin sensitizer-Metformin & Pioglitazone, but her blood glucose was still poorly controlled. J Assoc Clin Endocrinol Diabetol Bangladesh, July 2025;4(2): 80-84
2025-04-17 | 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.
We present a patient with Rabson-Mendenhall syndrome with unsatisfactory glycemic control of diabetes despite the use of metformin, pioglitazone, and sitagliptin. We investigated the long-term effects of treatment with an empagliflozin. After one year of empagliflozin therapy, an improvement in metabolic control of diabetes was detected. However, eleven months after implementation of empagliflozin, the patient was diagnosed with an early form of nephrocalcinosis. The empagliflozin dose was reduced, maintaining metabolic control and reducing hypercalciuria. We discuss the probable causes of nephrocalcinosis as well as the potential impact of SGLT-2 inhibitor therapy on the occurrence and progression of renal calcium deposition.
2025-01-29 | Insulin resistant diabetes mellitus in a girl with mild Rabson-Mendenhall syndrome: efficacy of sodium glucose co-transporter 2 inhibitor.
We report a beneficial effect of a sodium glucose co-transporter 2 (SGLT2) inhibitor in the management of insulin resistant diabetes mellitus (IRDM) in a Japanese girl with mild Rabson-Mendenhall syndrome (RMS). At 10 2/12 years of age, she was referred to us because of glucosuria, and was found to have marked acanthosis nigricans and RMS-like facial features such as proptosis, large ears, full lips, and gingival hypertrophy, but not other clinical features frequently found in RMS. At 11 9/12 years of age, her blood HbA1c level, though it remained ~ 6.5% until then, increased to 7.9% with pubertal development. She was treated with an SGLT2 inhibitor and metformin, which ameliorated overt hyperglycemia in the afternoon and the evening (postprandial time) as well as obvious hypoglycemia in the early morning (before breakfast), and reduced her blood HbA1c to 5.5%. Whole exome sequencing revealed probably disease-causing c.2465 T > C:p.(Leu822Pro) of paternal origin and c.3038C > T:p.(Pro1013Leu) of maternal origin in INSR. These findings imply the usefulness of SGLT2 inhibitor in the treatment of IRDM. It is likely that SGLT2 inhibitor mitigated hyperglycemia by increasing the urine glucose excretion and prevented severe hypoglycemia probably because of attenuated hyperinsulinemia in the absence of overt hyperglycemia.
2026-01-29 | Clinical spectrum of extreme insulin resistance syndromes treated with rhIGF-1: A single-center experience.
Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS) are extreme forms of insulin resistance (IR) caused by biallelic mutations in the insulin receptor gene. Recombinant human insulin-like growth factor-1 (rhIGF-1) treatment is often used but its long-term benefits and risks are still poorly delineated. We describe rhIGF-1 treatment outcomes of a cohort of patients with DS and RMS, and compare them to previously published patients. A single-center retrospective observational study with case note review was conducted. A literature search was performed for previously published DS and RMS patients treated with rhIGF-1. rhIGF-1 outcomes beyond 4 months have been reported for only 11 patients with DS and RMS to date. We provide outcome data for 3 more males, and report the long-term clinical course of a patient already described. Metabolic benefits of rhIGF-1 included improved glycemic control and fasting tolerance in early years of life, and some growth enhancement. Two patients exhibited poor response or intolerance to rhIGF-1 and died in infancy. The 2 longest-lived patients had progressive decompensation to diabetes mellitus, in 1 case despite long-term uninterrupted rhIGF-1 therapy. We also describe new features associated with severe insulin receptoropathies, such as cataract, liver hemangioma, and impaired hepatic protein synthesis. The phenotypes of DS and RMS are heterogeneous. Current treatment options remain unsatisfactory as high-dose rhIGF-1 exerts only limited beneficial effects and does not prevent decompensation to diabetes mellitus. More research is needed to identify alternative treatment strategies for extreme forms of IR.
2025-12-22 | The Use of Dapagliflozin in the Treatment of Children With Severe Insulin Resistance.
Managing severe insulin resistance (IR) is challenging, necessitating a multifaceted approach, including dietary restriction, exercise, and pharmacotherapy. This paper will detail our utilization of dapagliflozin in a series of cases involving patients with severe IR of various etiology and inadequate glycemic control. We describe six cases of extreme IR with distinct clinical diagnoses: four with Rabson-Mendenhall syndrome (RMS), one with IR type 1A, and a patient with type 1 diabetes mellitus (T1DM) and severe subcutaneous (SC) IR. These cases exhibit the observable characteristics of IR, characterized by an inability to effectively manage blood glucose (BG) with a standard treatment plan. Every case had a remarkable response to dapagliflozin. Subsequent assessment demonstrated improved HgbA1C, fasting glucose, insulin, and C-peptide concentrations. Furthermore, several cases demonstrated improvement in the clinical manifestations of IR following the administration of dapagliflozin, while others showed a reduction in the frequency of diabetic ketoacidosis (DKA). There were no documented adverse reactions with the use of dapagliflozin for a duration of 2-4 years in these patients. Dapagliflozin appeared both safe and effective as a standalone treatment or when used alongside other antidiabetes medications such as insulin in a case series of children with T1DM and severe IR or IR syndromes (IRS).
2025-08-24 | Rabson-Mendenhall syndrome: A rare case with severe insulin resistance
A rare hereditary cause of insulin resistance, Rabson-Mendenhall syndrome (RMS) is manifested by extreme insulin resistance caused by mutations in the insulin receptor (INSR) gene. The characteristics of RMS are retarded growth, dysmorphisms, hirsutism, enlarged genitalia, acanthosis nigricans, dysplastic dentition, hyperglycemia, elevated insulin level, and hyperplasia of the pineal gland. RMS patients usually present in childhood, and most affected patients usually survive till the second decade of life. We are presenting here a unique case of a 10-year-old girl with very high blood sugar and crowding of teeth. She developed classical symptoms of diabetes for the last three years. On examination, she had syndromic coarse facies, prognathism, gingival hyperplasia, larger lower lip, hyperdontia, hyperpigmented skin, hypertrichosis, severe acanthosis nigricans & dystrophic nails. Biochemical investigations revealed insulin resistance by high fasting insulin, and high normal C-peptide with very high Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). She was treated with insulin with insulin sensitizer-Metformin & Pioglitazone, but her blood glucose was still poorly controlled. J Assoc Clin Endocrinol Diabetol Bangladesh, July 2025;4(2): 80-84
2025-04-17 | 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.
We present a patient with Rabson-Mendenhall syndrome with unsatisfactory glycemic control of diabetes despite the use of metformin, pioglitazone, and sitagliptin. We investigated the long-term effects of treatment with an empagliflozin. After one year of empagliflozin therapy, an improvement in metabolic control of diabetes was detected. However, eleven months after implementation of empagliflozin, the patient was diagnosed with an early form of nephrocalcinosis. The empagliflozin dose was reduced, maintaining metabolic control and reducing hypercalciuria. We discuss the probable causes of nephrocalcinosis as well as the potential impact of SGLT-2 inhibitor therapy on the occurrence and progression of renal calcium deposition.
2025-01-29 | Insulin resistant diabetes mellitus in a girl with mild Rabson-Mendenhall syndrome: efficacy of sodium glucose co-transporter 2 inhibitor.
We report a beneficial effect of a sodium glucose co-transporter 2 (SGLT2) inhibitor in the management of insulin resistant diabetes mellitus (IRDM) in a Japanese girl with mild Rabson-Mendenhall syndrome (RMS). At 10 2/12 years of age, she was referred to us because of glucosuria, and was found to have marked acanthosis nigricans and RMS-like facial features such as proptosis, large ears, full lips, and gingival hypertrophy, but not other clinical features frequently found in RMS. At 11 9/12 years of age, her blood HbA1c level, though it remained ~ 6.5% until then, increased to 7.9% with pubertal development. She was treated with an SGLT2 inhibitor and metformin, which ameliorated overt hyperglycemia in the afternoon and the evening (postprandial time) as well as obvious hypoglycemia in the early morning (before breakfast), and reduced her blood HbA1c to 5.5%. Whole exome sequencing revealed probably disease-causing c.2465 T > C:p.(Leu822Pro) of paternal origin and c.3038C > T:p.(Pro1013Leu) of maternal origin in INSR. These findings imply the usefulness of SGLT2 inhibitor in the treatment of IRDM. It is likely that SGLT2 inhibitor mitigated hyperglycemia by increasing the urine glucose excretion and prevented severe hypoglycemia probably because of attenuated hyperinsulinemia in the absence of overt hyperglycemia.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Rabson-Mendenhall syndrome.
2 orphan drug designations for Rabson-Mendenhall syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Mecasermin rinfabate [Iplex] | proteins | EMA | 2004-10-21 | — | [INACTIVE] Insmed Europe Limited |
rhIGF-I/rhIGFBP-3 | proteins | FDA | 2003-12-09 | — | Insmed, Inc. |
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