small molecules

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.

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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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2017-08-01 | Structural Basis and Genotype–Phenotype Correlations of INSR Mutations Causing Severe Insulin Resistance

The insulin receptor (INSR) gene was analyzed in four patients with severe insulin resistance, revealing five novel mutations and a deletion that removed exon 2. A patient with Donohue syndrome (DS) had a novel p.V657F mutation in the second fibronectin type III domain (FnIII-2), which contains the α-β cleavage site and part of the insulin-binding site. The mutant INSR was expressed in Chinese hamster ovary cells, revealing that it reduced insulin proreceptor processing and impaired activation of downstream signaling cascades. Using online databases, we analyzed 82 INSR missense mutations and demonstrated that mutations causing DS were more frequently located in the FnIII domains than those causing the milder type A insulin resistance (P = 0.016). In silico structural analysis revealed that missense mutations predicted to severely impair hydrophobic core formation and stability of the FnIII domains all caused DS, whereas those predicted to produce localized destabilization and to not affect folding of the FnIII domains all caused the less severe Rabson-Mendenhall syndrome. These results suggest the importance of the FnIII domains, provide insight into the molecular mechanism of severe insulin resistance, will aid early diagnosis, and will provide potential novel targets for treating extreme insulin resistance.

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2009-12-23 | Downregulation of Wnt-Mediated ROS generation is causally implicated in leprechaunism

Although mutations in the insulin receptor have been causally implicated with leprechaunsim, the full pathophysiology of the syndrome cannot be accounted for by malfunction of this gene alone. We sought to characterize a connection between Wnt-mediated cell signaling and the production of reactive oxygen species (ROS) which revealed a novel mechanistic basis for understanding the pathogenesis of leprechaunism. To identify candidate genes involved in this process, a PCR-based subtractive hybridization was performed. Candidate genes were examined for interaction with the Wnt signaling pathway and ROS generation. We found that Dickkopf 1 (Dkk1), a Wnt inhibitor, is overexpressed in skin fibroblast cells derived from three leprechaunism patients and that the cells showed an impaired response to Wnt2 in terms of β-catenin-Tcf activation. Knockdown of Dkk1 in the patient cell lines rescued Wnt2-mediated Tcf activation. Concerted action of Wnt2 and knockdown of Dkk1 resulted in enhanced Nox4 expression and PDGF-induced ROS generation compared to parental patient cells. Furthermore, we found that NFATc2 was activated in response to Wnt2 stimulation and directly activates Nox4 expression. These data show a crosstalk between Wnt and ROS pathways which in turn provides new mechanistic insights at the molecular level into the pathogenesis of leprechaunism.

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2006-09-26 | A Patient With Extreme Insulin Resistance Syndrome Treated With Pioglitazone

Genetic types of extreme insulin resistance include type A insulin resistance syndrome, leprechaunism, congenital generalized lipodystrophy, and Rabson-Mendelhall syndrome (1). Acanthosis nigricans and ovarian masculinization are frequently associated with these syndromes. Genetic defects in insulin action at the receptor or postreceptor levels are responsible for insulin resistance. Since thiazolidinediones enhance insulin sensitivity in patients with insulin resistance, we administered pioglitazone to an insulin-resistant patient with a mutation of the insulin receptor. A 15-year-old Japanese female was referred to the hospital for an evaluation of hirsutism. Acanthosis nigricans was present in the axillary area and on the neck. She had been amenorrheic since menarche at the age of 12 years. She had …

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proteins

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.

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2024-05-01 | 39 A Donhue’s syndrome case : rare severe syndromic insuline resistance

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. 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. 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.

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2022-11-08 | [Donohue syndrome and use of continuous subcutaneous IGF1 pump therapy].

Donohue syndrome (DS), also called Leprechaunism, is the most severe form of insulin resistance associated with biallelic mutations in INSR gene (OMIM: 147670). The approximate incidence of this syndrome is 1 per 1000000 births. Patients are present with typical clinical features such as intrauterine growth retardation, facial dysmorphism, severe metabolic disturbances, hepatomegaly and hypertrophic cardiomyopathy. Most DS patients die within the first two years of life due to respiratory infections, severe hypoglycemia or progressive cardiomyopathy. Treatment options are limited and no specific therapy exist for DS. Given the similarities between insulin and insulin-like growth factor 1 (IGF-1) receptors, recombinant human IGF-1 (rhIGF-1) has been used to treat severe insulin resistance including DS.We report the case of a male patient with genetically confirmed Donohue syndrome, successfully treated with continuous subcutaneous IGF1 infusion via insulin pump. We observed improvement of glycemic control, liver function and cardiac hypertrophy regression following 15-month IGF1 therapy. Синдром Донохью (лепречаунизм) — это наиболее тяжелая форма инсулинорезистентности, возникающая вследствие мутаций в гене рецептора инсулина INSR (OMIM: 147670). Данное заболевание встречается с частотой 1:1 000 000 живых новорожденных. У пациентов отмечается типичная клиническая картина: выраженная задержка внутриутробного развития, дизморфизм, грубые метаболические нарушения, гепатомегалия, гипертрофия миокарда. Большинство пациентов погибают в течение первых двух лет жизни вследствие интеркуррентных инфекций верхних дыхательных путей, эпизодов тяжелых гипогликемий или кардиомиопатии. В настоящее время не существует специфической терапии для лечения синдрома Донохью, однако в мировой литературе имеется ряд описаний успешного применения рекомбинантного инсулиноподобного фактора роста 1 (ИФР1) для лечения тяжелой инсулинорезистентности, в том числе и лепречаунизма. В статье представлены клиническое описание пациента с синдромом Донохью и первый опыт применения непрерывной подкожной инфузии рекомбинантного ИФР1 при данном заболевании в России. По нашим наблюдениям, применение данной терапии оказалось эффективным. На фоне лечения в течение 15 мес отмечаются выраженная положительная динамика в отношении гликемического контроля, печеночной функции, а также регресс гипертрофической кардиомиопатии.

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2022-03-02 | Long-Term Effects of Metreleptin in Rabson-Mendenhall Syndrome on Glycemia, Growth, and Kidney Function.

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. Small, uncontrolled studies suggest that 1-year treatment with recombinant leptin (metreleptin) improves glycemia in RMS. This study aimed to determine effects of long-term metreleptin in RMS on glycemia, anthropometrics, the growth hormone axis, and kidney function. We compared RMS patients during nonrandomized open-label treatment with metreleptin (≥ 0.15 mg/kg/day) vs no metreleptin over 90 months (5 subjects in both groups at different times, 4 only in metreleptin group, 2 only in control group). Main outcome measures were A1c; glucose; insulin; 24-hour urine glucose; standard deviation scores (SDS) for height, weight, body mass index (BMI), and insulin-like growth factor 1 (IGF-1); growth hormone; and estimated glomerular filtration rate. Over time, metreleptin-treated subjects maintained 1.8 percentage point lower A1c vs controls (P = 0.007), which remained significant after accounting for changes in insulin doses. Metreleptin-treated subjects had a reduction in BMI SDS, which predicted decreased A1c. Growth hormone increased after metreleptin treatment vs control, with no difference in SDS between groups for IGF-1 or height. Reduced BMI predicted higher growth hormone, while reduced A1c predicted higher IGF-1. Metreleptin alters the natural history of rising A1c in RMS, leading to lower A1c throughout long-term follow-up. Improved glycemia with metreleptin is likely attributable to appetite suppression and lower BMI SDS. Lower BMI after metreleptin may also worsen growth hormone resistance in RMS, resulting in a null effect on IGF-1 and growth despite improved glycemia.

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2019-02-12 | Enteroinsular hormones in two siblings with Donohue syndrome and complete leptin deficiency.

The main biochemical hallmark of the rare and lethal condition of Donohue syndrome (DS) is hyperinsulinemia. The roles of the gut and other pancreatic hormones involved in glucose metabolism, satiety and energy expenditure have not been previously reported in DS. Two siblings with genetically confirmed DS and extremely low weight underwent a mixed meal (MM) test where pancreatic hormones insulin, C-peptide, glucagon, active amylin, pancreatic polypeptide (PP) as well as gut hormones active glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), ghrelin, peptide YY (PYY) and leptin were analyzed using a Multiplex assay. Results were compared to those of 2 pediatric controls. As expected, concentrations of insulin, C-peptide and amylin were very high in DS cases. The serum glucagon concentration was undetectable at the time of hypoglycemia. GIPs concentrations were lower in the DS, however, this was not mimicked by the other incretin, GLP-1. Ghrelin concentrations were mainly undetectable (<13.7 pg/mL) in all participants. DS cases had higher PYY and dampened PP concentrations. Leptin levels remained completely undetectable (<137.0 pg/mL). Patients with DS have extremely high amylin levels, completely undetectable serum glucagon and leptin levels with abnormal satiety regulating hormone PP with a relatively normal ghrelin response during a MM test. The low serum GIP might be acting as physiological brake on insulin secretion. The undetectable serum leptin levels suggest the potential of using leptin analogues as therapy for DS patients.

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antibodies

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.

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