RARE DISEASE
Leprechaunism
Leprechaunism
Leprechaunism
Synonyms: Donohue syndrome
Synonyms: Donohue syndrome
Synonyms: Donohue syndrome
Drug discovery
0
drugs
With orphan designations
Overview
Leprechaunism (Donohue syndrome) is a rare autosomal recessive disorder caused by biallelic INSR gene mutations, leading to extreme insulin resistance. Characterized by severe intrauterine/postnatal growth retardation, dysmorphic facies (elfin features, hypertrichosis), lipoatrophy, acanthosis nigricans, and metabolic instability (hyperinsulinemia, hypo-/hyperglycemia). Mortality exceeds 80% in infancy due to infections or metabolic crises, though recombinant IGF-1 therapy may extend survival in rare cases [1][2][5][9].
Categories: rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases, rare skin diseases
Research Papers
57 drug discovery papers about Leprechaunism, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
57 drug discovery papers about Leprechaunism, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-06-01 | A REVIEW ON RARE GENETIC INSULIN RESISTANCE DISORDER: LEPRECHAUNISM / DONOHUE SYNDROME
Insulin resistance caused by rare genetic conditions are the group of inherited metabolic disorders that are characterized by the fact that the body does not respond to insulin properly although there are normal or very high levels of insulin in the blood. These disorders are mainly caused by mutations in the insulin receptor or in the signalling molecules that are involved after the receptor and they are accompanied by severe metabolic complications. Leprechaunism or Donohue syndrome is the most extreme phenotype in this group of disorders and it is significantly due to homozygous or compound heterozygous mutations in the INSR gene. Affected Patients mostly represents with intrauterine growth retardation (IUGR), dysmorphic features, severe hyperinsulinemia, multi-organ involvement in the neonatal period and there is a high mortality rate during the first few years of life. This review mainly focuses on classification, molecular genetics, and clinical manifestations of rare genetic insulin resistance disorders, particularly Leprechaunism. Diagnostic approaches, management strategies in vogue, and emerging therapies are also discussed. The understanding of these rare disorders will not only assist in early diagnosis, proper genetic counselling, and targeted therapy but will also grant new insights into the disease mechanisms. Furthermore, Research is required to enhance the clinical outcomes and quality of life in the affected patients.
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.
2025-05-22 | Bilateral ovarian juvenile granulosa cell tumor in a neonate with Donohue syndrome: a case report and review of literature
Abstract Background Hereditary severe insulin resistance syndrome (H-SIRS) is a group of disorders classified into four principal categories: primary insulin receptor defects, lipodystrophies, complex genetic syndromes, and obesity-related H-SIRS. Donohue syndrome represents the most extreme insulin receptoropathy with autosomal recessive inheritance. This gene is located on 19p13. Case presentation We report a case of a neonate with Donohue syndrome who had congenital bilateral juvenile granulosa cell tumor. She was treated surgically and by an insulin-sensitizing agent (metformin). On day 30 of life, she developed sudden fulminant necrotizing enterocolitis and unfortunately died on the same day despite aggressive resuscitation. Conclusion This is a unique case of congenital bilateral juvenile granulosa cell tumor in a neonate with Donohue syndrome. The tumor may constitute the natural progression of the syndrome rather than a complication of treatment. Surgery may be required when there is an increasing size of the ovaries leading to respiratory distress or when there is a concern of ovarian torsion. Given the potential for severe gastrointestinal complications in Donohue syndrome, clinicians must maintain a high index of suspicion and implement proactive monitoring strategies to ensure timely intervention and improve patient outcome.
2024-05-01 | 39 A Donhue’s syndrome case : rare severe syndromic insuline resistance
Background
Donohue Syndrome is the most severe form of the rare genetic severe insulin resistance syndromes caused by mutation in the insulin gene receptor (INSR) with a lifespan under 2 years mainly because of intercurrent infections. Resulting from a homozygous or compound heterozygous mutations of the INSR (INSR; 19p13.3– p13.2). It associates severe growth retardation beginning prenatally, hyperinsulinism with hyperglycemia and dysmorphic features.We report this case due to the extreme rarity of the syndrome and to present its clinical, biological findings and the underlying genetics.
Case Report(s)
The case is an Algerian female infant born to consanguineous parents via caesarian section at 37weeks gestation due to severe intrauterine growth restriction. She was admitted in our department at 4months old showing septic signs (high fever, tachycardia) with severe growth stunt (over -7DS), lipoatrophy, cholestasis, abdominal distension and dysmorphic features: craniofacial abnormalities with elfin facies and large low set ears, hypertrichosis and clitoromegaly. Laboratory results showed hyperinsulinism with high insulin, peptic C and fasting hypoglycemia; postprandial hyperglycemia ; cholestatic hyperbilirubinemia and low triglyceride and cholesterol levels. C-reactive protein was high. This presentation suggested DS which was confirmed by finding of a homozygous deletion in 19 p13.2 encompassing exon 2 of INSR. Antibiotics were immediately put and growth hormone therapy was initiated (0,35 mg/kg/d); unfortunately, 3 days later she died from apparent septicemia. Our patient had no opportunity for treatment with recombinant IGF-1.
Conclusion(s)
Our case shows a classic presentation of DS, with a fatal prognosis. Treatment is only symptomatic and requires a multidisciplinary team. Recombinant IGF-1 shows promise but the benefit is yet to be established. Majority of cases are found where consanguineous marriages prevail, thus genetic counseling and discouraging inbreeding should be done as preventive measures awaiting optimal treatment protocol.
2023-01-13 | INSR novel mutations identified in a Chinese family with severe INSR-related insulin resistance syndromes: A case report.
Severe insulin receptor gene (INSR)-related insulin resistance syndromes (SIR) include Donohue syndrome (DS), Rabson-Mendenhall syndrome (RMS), and type A insulin resistance. The incidence of DS is about 1 in 4 million births. We identified novel INSR mutations (c.2246delG and c.2646 + 5G > A) in a patient with SIR, which expanded the variant spectrum and helped to improve the understanding of the diagnosis and treatment of this condition. A 10-year-old Chinese boy was admitted to the hospital for deepening skin color. He presented with growth retardation, peculiar facial features, acanthosis nigricans, hypertrichosis, extremely high insulin levels, fasting hypoglycemia, and postprandial hyperglycemia, Whole-exome gene testing suggested compound heterozygous mutations in INSR (c.2246delG and c.2646 + 5G > A). The diagnosis was SIR. What's more, based on the phenotypic and biographical results, this child did not present typical RMS and DS but rather an intermediate phenotype between the 2 conditions. On the basis of a sensible diet and exercise, the patient was prescribed metformin (250 mg) at breakfast and lunch, which was increased to 500 mg after 1 month. After 2 months of treatment, the patient's glycated hemoglobin (HbA1c) levels decreased to 6% but his insulin resistance did not improve significantly. In children who are not obese but with severe insulin resistance, growth retardation, hirsutism, and hyperglycemia, genetic testing should be performed for early diagnosis, active treatment, and follow-up.
2026-06-01 | A REVIEW ON RARE GENETIC INSULIN RESISTANCE DISORDER: LEPRECHAUNISM / DONOHUE SYNDROME
Insulin resistance caused by rare genetic conditions are the group of inherited metabolic disorders that are characterized by the fact that the body does not respond to insulin properly although there are normal or very high levels of insulin in the blood. These disorders are mainly caused by mutations in the insulin receptor or in the signalling molecules that are involved after the receptor and they are accompanied by severe metabolic complications. Leprechaunism or Donohue syndrome is the most extreme phenotype in this group of disorders and it is significantly due to homozygous or compound heterozygous mutations in the INSR gene. Affected Patients mostly represents with intrauterine growth retardation (IUGR), dysmorphic features, severe hyperinsulinemia, multi-organ involvement in the neonatal period and there is a high mortality rate during the first few years of life. This review mainly focuses on classification, molecular genetics, and clinical manifestations of rare genetic insulin resistance disorders, particularly Leprechaunism. Diagnostic approaches, management strategies in vogue, and emerging therapies are also discussed. The understanding of these rare disorders will not only assist in early diagnosis, proper genetic counselling, and targeted therapy but will also grant new insights into the disease mechanisms. Furthermore, Research is required to enhance the clinical outcomes and quality of life in the affected patients.
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.
2025-05-22 | Bilateral ovarian juvenile granulosa cell tumor in a neonate with Donohue syndrome: a case report and review of literature
Abstract Background Hereditary severe insulin resistance syndrome (H-SIRS) is a group of disorders classified into four principal categories: primary insulin receptor defects, lipodystrophies, complex genetic syndromes, and obesity-related H-SIRS. Donohue syndrome represents the most extreme insulin receptoropathy with autosomal recessive inheritance. This gene is located on 19p13. Case presentation We report a case of a neonate with Donohue syndrome who had congenital bilateral juvenile granulosa cell tumor. She was treated surgically and by an insulin-sensitizing agent (metformin). On day 30 of life, she developed sudden fulminant necrotizing enterocolitis and unfortunately died on the same day despite aggressive resuscitation. Conclusion This is a unique case of congenital bilateral juvenile granulosa cell tumor in a neonate with Donohue syndrome. The tumor may constitute the natural progression of the syndrome rather than a complication of treatment. Surgery may be required when there is an increasing size of the ovaries leading to respiratory distress or when there is a concern of ovarian torsion. Given the potential for severe gastrointestinal complications in Donohue syndrome, clinicians must maintain a high index of suspicion and implement proactive monitoring strategies to ensure timely intervention and improve patient outcome.
2024-05-01 | 39 A Donhue’s syndrome case : rare severe syndromic insuline resistance
Background
Donohue Syndrome is the most severe form of the rare genetic severe insulin resistance syndromes caused by mutation in the insulin gene receptor (INSR) with a lifespan under 2 years mainly because of intercurrent infections. Resulting from a homozygous or compound heterozygous mutations of the INSR (INSR; 19p13.3– p13.2). It associates severe growth retardation beginning prenatally, hyperinsulinism with hyperglycemia and dysmorphic features.We report this case due to the extreme rarity of the syndrome and to present its clinical, biological findings and the underlying genetics.
Case Report(s)
The case is an Algerian female infant born to consanguineous parents via caesarian section at 37weeks gestation due to severe intrauterine growth restriction. She was admitted in our department at 4months old showing septic signs (high fever, tachycardia) with severe growth stunt (over -7DS), lipoatrophy, cholestasis, abdominal distension and dysmorphic features: craniofacial abnormalities with elfin facies and large low set ears, hypertrichosis and clitoromegaly. Laboratory results showed hyperinsulinism with high insulin, peptic C and fasting hypoglycemia; postprandial hyperglycemia ; cholestatic hyperbilirubinemia and low triglyceride and cholesterol levels. C-reactive protein was high. This presentation suggested DS which was confirmed by finding of a homozygous deletion in 19 p13.2 encompassing exon 2 of INSR. Antibiotics were immediately put and growth hormone therapy was initiated (0,35 mg/kg/d); unfortunately, 3 days later she died from apparent septicemia. Our patient had no opportunity for treatment with recombinant IGF-1.
Conclusion(s)
Our case shows a classic presentation of DS, with a fatal prognosis. Treatment is only symptomatic and requires a multidisciplinary team. Recombinant IGF-1 shows promise but the benefit is yet to be established. Majority of cases are found where consanguineous marriages prevail, thus genetic counseling and discouraging inbreeding should be done as preventive measures awaiting optimal treatment protocol.
2023-01-13 | INSR novel mutations identified in a Chinese family with severe INSR-related insulin resistance syndromes: A case report.
Severe insulin receptor gene (INSR)-related insulin resistance syndromes (SIR) include Donohue syndrome (DS), Rabson-Mendenhall syndrome (RMS), and type A insulin resistance. The incidence of DS is about 1 in 4 million births. We identified novel INSR mutations (c.2246delG and c.2646 + 5G > A) in a patient with SIR, which expanded the variant spectrum and helped to improve the understanding of the diagnosis and treatment of this condition. A 10-year-old Chinese boy was admitted to the hospital for deepening skin color. He presented with growth retardation, peculiar facial features, acanthosis nigricans, hypertrichosis, extremely high insulin levels, fasting hypoglycemia, and postprandial hyperglycemia, Whole-exome gene testing suggested compound heterozygous mutations in INSR (c.2246delG and c.2646 + 5G > A). The diagnosis was SIR. What's more, based on the phenotypic and biographical results, this child did not present typical RMS and DS but rather an intermediate phenotype between the 2 conditions. On the basis of a sensible diet and exercise, the patient was prescribed metformin (250 mg) at breakfast and lunch, which was increased to 500 mg after 1 month. After 2 months of treatment, the patient's glycated hemoglobin (HbA1c) levels decreased to 6% but his insulin resistance did not improve significantly. In children who are not obese but with severe insulin resistance, growth retardation, hirsutism, and hyperglycemia, genetic testing should be performed for early diagnosis, active treatment, and follow-up.
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