"An unprecedented occurrence: a case report of pulmonary hypertension manifestation in Donohue syndrome".

INTRODUCTION: Donohue syndrome (DS), also referred to as leprechaunism, is a remarkably uncommon autosomal recessive disorder that primarily affects the endocrine system. Its incidence rate is exceedingly low, with only 1 case reported per 4 million live births. The syndrome is distinguished by a series of characteristic clinical features. CASE PRESENTATION: We present a case of a twenty-month-old male with DS who experienced a range of dysmorphic and clinical features with the involvement of multiple systems. These features include skin hyperpigmentation, hypertrichosis, distinct facial features, abdominal distension, and microcephaly, with the involvement of the endocrine, renal, respiratory, and cardiac systems. CONCLUSION: The primary features of DS involve severe insulin resistance and growth abnormalities, the association with pulmonary hypertension (PHTN) has not been reported before. This finding adds more complexity to the condition. To the best of the author's knowledge, this is the first report for a patient with DS who has PHTN. Further investigation is required since the mechanisms behind the development of PHTN in DS are not entirely understood. Shedding light on this association will contribute to better management strategies and outcomes for affected patients.

[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.

Clinical and Functional Characterization of Novel INSR Variants in Two Families With Severe Insulin Resistance Syndrome.

Objective: Defects in the insulin receptor (INSR) gene cause various severe insulin resistance conditions, including Donohue syndrome (DS), Rabson-Mendenhall syndrome (RMS) and type A insulin resistance (type A-IR). This study aimed to investigate the clinical characterization and molecular defects in three Chinese children with INSR-related insulin resistance syndrome. Methods: We reviewed the clinical data of three Chinese children with INSR-related insulin resistance syndrome from two unrelated kindreds. Genetic analysis was performed using whole-exome sequencing and the effects of the novel variants were further assessed by in vitro functional assays. Results: The proband with type A-IR presented with acanthosis nigricans, hypertrichosis, and euglycemia with mild insulin resistance in early childhood. His sister presented with features typical of type A-IR and was diagnosed with diabetes mellitus with severe insulin resistance at the age of 9.8 years. The proband with DS showed typical dysmorphic characteristics, severe intrauterine growth retardation, extreme insulin resistance, fasting hypoglycemia and postprandial hyperglycemia from birth. The heterozygote variants c.[3670G>A]; c.[3614C>T] were identified in both siblings with type A-IR; and c.[749_751del]; c.[3355C>T] in the patient with DS. In vitro studies showed that the novel variant c.749_751del [p.(Thr250del)] in the α-subunit, reduced expression of the mature INSR protein and severely impaired INSR function. In contrast, the novel variant c.3670G>A [p.(Val1224Met)] in the ß-subunit had no effect on total protein expression and phosphorylation of INSR and Akt, suggesting that the variant p.Val1224Met appeared to be tolerated and was not responsible for the severe insulin resistance. Conclusion: Our study detailed the clinical features of three patients with type A-IR and DS, and identified two novel variants in the INSR gene. Functional assays indicated the novel variant p.Thr250del was pathogenic. In contrast, the novel variant p.Val1224Met was suggested to be tolerated by our experimental data, even though bioinformatics analyses predicted the variant as deleterious.

Mutación del gen INSR. Insulinorresistencia poco prevalente en edad pediátrica. A propósito de un caso / INSR gene mutation. Insulin resistance with low prevalence in pediatrics. A case review

No disponible

Acantosis nigricans en los síndromes de resistencia grave a la insulina / Acantosis nigricans in severe insulin resistance syndromes

No disponible

Gastrointestinal dysmotility and pancreatic insufficiency in 2 siblings with Donohue syndrome.

Donohue syndrome is a rare congenital syndrome of insulin-resistance and abnormal glucose homeostasis, caused by mutations in the insulin receptor (INSR) gene. It is characterized by specific phenotypic and clinical features and the diagnosis is based on clinical, biochemical and genetic criteria. We report 2 siblings with Donohue syndrome (cases 1, 2) with multiple clinical and biochemical characteristics. Both patients shared the same mutation and presented with intra-uterine growth restriction, failure to thrive, fasting hyperinsulinaemic hypoglycaemia and episodic post-prandial hyperglycaemia. Less common clinical features were also present, such as atrial septal defect and biventricular hypertrophy, clotting disorders, abnormal liver function tests and nephrocalcinosis. Interestingly, 2 previously unrecognized manifestations of the syndrome were also identified: severe gastrointestinal dysmotility (case 1) and exocrine pancreatic insufficiency (case 2). The co-existence of all the above clinical features makes these cases extremely rare. Gastrointestinal dysmotility should always be considered as a potentially fatal feature in patients with the syndrome, due to the complexity of the possible co-morbidities. In addition, our clinical experience for the first time suggests that pancreatic exocrine insufficiency may offer a possible explanation for the growth retardation observed in some patients with this syndrome. Our finding that replacement treatment with pancreatic enzymes improved weight gain (case 2) implies that all patients with Donohue syndrome should be investigated for exocrine pancreatic insufficiency.

Treatment of Diabetic Ketoacidosis With Intravenous U-500 Insulin in a Patient With Rabson-Mendenhall Syndrome: A Case Report.

Rabson-Mendenhall syndrome is a rare genetic disorder resulting from mutations in the insulin receptor and is associated with high degrees of insulin resistance. These patients are prone to complications secondary to their hyperglycemia including diabetic ketoacidosis (DKA). We report the case of a 19-year-old male with Rabson-Mendenhall syndrome presenting with DKA who required doses of up to 500 U/h (10.6 U/kg/h) of insulin. The patient's insulin infusion was originally compounded with U-100 regular insulin, although to minimize volume, the product was compounded with U-500 insulin. The DKA eventually resolved requiring infusion rates ranging from 400 to 500 U/h. Although numerous opportunities for medication errors exist with the use of U-500 insulin, this case outlines the safe use of concentrated intravenous insulin when clinically indicated for patients requiring extremely high doses of insulin to control blood glucose.

Hypertrophic cardiomyopathy in Donohue syndrome.

We report the case of a patient with Donohue syndrome who died of heart failure due to obstructive hypertrophic cardiomyopathy. A literature survey revealed that hypertrophic cardiomyopathy was present in 30% of these patients and was often fatal. Therefore, every patient with Donohue syndrome should be screened for hypertrophic cardiomyopathy.

Donohue syndrome and use of continuous subcutaneous insulin pump therapy.

Donohue syndrome is a rare autosomal recessive condition caused by severe loss-of-function mutations in the insulin receptor (INSR) gene. The diagnosis is made on clinical, biochemical and genetic grounds. Mutations are found on chromosome 19p13.2, and code for mutations in the INSR gene. Treatment is challenging and often unsuccessful, and relies on maintaining normoglycaemia and avoiding fasting; in some patients, recombinant human insulin-like growth factor (rhIGF-1) has been trialled. The prognosis is poor, with most babies dying in infancy. Ethically, it is important to consider the benefit versus burden of treatment, the quality of life of the surviving patient and the parents' wishes, when making decisions regarding withholding or withdrawing care.

Donohue syndrome: a new case with a new complication.

Donohue syndrome (DS) is a very rare autosomal recessive disease affecting less than one in a million live births. It represents the most severe form of insulin resistance due to mutations involving the insulin receptor gene. DS is characterized by pre- and postnatal growth retardation with failure to thrive, lipoatrophy, muscle wasting, acanthosis nigricans, hypertrichosis, and dysmorphic features. Glucose homeostasis is affected with hyperinsulinemia, fasting hypoglycemia, and postprandial hyperglycemia. We report a Jordanian patient with genetically proven DS who had the classical physical features, progressive hypertrophic cardiomyopathy, cholestasis, and hyperglycemia, followed by hypoglycemia. In addition, the patient developed polyuria and uremia despite normal creatinine levels, hypernatremia, and hypertension. To our knowledge, these metabolic derangements were not previously reported in patients with DS.

A syndrome of insulin resistance resembling Donohue syndrome with patent ductus arteriosus.

Donohue syndrome, a rare autosomal recessive disorder, is associated with the mutation of the insulin receptor gene in the short arm of the 19th chromosome. It is very rare that a syndrome of insulin resistance resembles Donohue syndrome with patent ductus arteriosus. A 14-year-old girl, whose parents were consanguineous, was often admitted for abdominal pain over the past 8 years. She presented not only polydipsia, polyphagia, and weight loss but also small elfin face, distended abdomen, enlarged clitoris, hypertrichosis, acanthosis nigricans of the neck, decreased subcutaneous fat and 3/6 continuous murmur radiating to the right shoulder with thrill on 2nd to 3rd left sternal border. In addition, she had hyperglycemia, hyperinsulinism, and patent ductus arteriosus by laboratory examination and echocardiography, respectively. This child shows insulin resistance resembling Donohue syndrome with patent ductus arteriosus. Most of patients with Donohue syndrome die prematurely. The child surviving for a long time may have a milder form of Donohue syndrome and may be due to a less severe form of the defective gene. Chromosomal abnormalities may be also associated with this disease.

Identification of a novel insulin receptor gene heterozygous mutation in a patient with type A insulin resistance syndrome.

BACKGROUND: Several types of mutations in the insulin receptor gene have been identified in patients with genetic syndromes of insulin resistance. PATIENT REPORT: We describe a 12-year-old girl with type A insulin resistance with hyperandrogenism, hyperinsulinemia, and diabetes mellitus but without the dysmorphic characteristic of leprechaunism or Rabson-Mendenhall syndrome. The proband's mother had hyperinsulinemia and diabetes mellitus but did not show any common clinical features of type A insulin resistance. The proband's brother also had hyperinsulinemia but manifested neither glucose intolerance nor common clinical features of type A insulin resistance. A novel heterozygous mutation, p.Asn1164Thr, of the insulin receptor gene (INSR) was identified in this family. CONCLUSION: These cases illustrate the diversity of clinical phenotypes associated with mutations of the insulin receptor gene.

A case of Rabson-Mendenhall syndrome with a novel mutation in the tyrosine kinase domain of the insulin receptor gene complicated by medullary sponge kidney.

Rabson-Mendenhall syndrome (RMS) is a genetic disorder characterized by severe insulin resistance and somatic characteristics. Recombinant insulin-like growth factor 1 (r-IGF-1) is used to treat RMS, as the IGF-1 and insulin receptors share homology. However, the effect of r-IGF-1 varies in patients and it is difficult to manage metabolic status appropriately in r-IGF-1 resistant cases. We report a Japanese boy with RMS who showed resistance to r-IGF-1 therapy and a novel mutation in the insulin receptor in the tyrosine kinase domain. Mutations in this region disturb tyrosine kinase catalytic activity in IGF-1 receptors as a result of dominant negative effects. We consider this mutation to be the cause of resistance to r-IGF-1. The patient also exhibited radiographical features of medullary sponge kidney and had severe nephrocalcinosis and hypokalemia, indicating Bartter syndrome. However, analysis revealed no mutations in the responsible genes and the etiology of the renal abnormalities therefore remains unknown.

A novel mutation of the insulin receptor gene in a preterm infant with Donohue syndrome and heart failure.

Donohue syndrome (DS) is a rare autosomal recessive condition caused by mutations in the gene encoding the insulin receptor. It is characterised by severe metabolic and endocrine derangement, prenatal and postnatal linear growth impairment, soft tissue overgrowth, and poor development of adipose tissue and muscle. Causes of death, which is often within the first year of life, include intercurrent infection and, in some cases, heart failure. Management is currently based on case reports and very small case series only, and no formal guidelines or recommendations exist. We describe a preterm infant who had typical features of DS but who later developed hypertrophic cardiomyopathy with heart failure leading to death at 10 weeks old. Molecular genetic analysis revealed compound heterozygosity for the previously reported p.Arg890X nonsense mutation and the novel p.Tyr818Cys missense mutation in the INSR gene. Tyrosine 818 falls in an exquisitely conserved residue of the alphabeta fibronectin domain of the insulin receptor, whose structure and function are much less well understood than other parts of the receptor. We discuss management options for DS, including the therapeutic dilemma around whether recombinant human insulin-like growth factor 1, one of the few available treatments for the syndrome, may exacerbate hypertrophic cardiomyopathy and cardiac failure.

Areolar sebaceous hyperplasia with underlying primary duct carcinoma of the breast in a woman with Donohue syndrome (leprechaunism).

Areolar hyperplasia is only reported when exaggerated, and even so, exaggerated areolar sebaceous hyperplasia is rare. We have recently seen a case of areolar sebaceous hyperplasia in a 32-year-old woman with Donohue syndrome (leprechaunism), who also had an invasive ductal carcinoma in the same breast. The patient showed typical "elfin-like" face with wide nostrils and thick lips, large and low-set ears, and dysplastic nails. The areola showed a yellowish thickened plaque of 5-cm diameter that corresponded to a hyperplasia of the sebaceous glands. Immunohistochemistry for the mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) was performed on the sebaceous hyperplasia and on the breast carcinoma, and no lack of expression of the markers was evidenced. We have found no other reported case of areolar sebaceous hyperplasia either in cases of breast carcinoma or in cases of leprechaunism.

Rabson-Mendenhall syndrome: two case reports and a brief review of the literature.

Rabson-Mendenhall syndrome is a rare, autosomal recessive disorder characterized by insulin resistance syndrome, growth retardation, coarse and senile-looking faces, mental precocity, early dentition, and pineal hyperplasia. Mutations of the insulin receptor gene affecting insulin action appear to be the basic mechanism underlying this syndrome. We report on Rabson-Mendenhall syndrome in two siblings and briefly review the literature.