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European Journal of Endocrinology Aug 2007Severe insulin resistance resulting from known or putative genetic defects affecting the insulin receptor or post-insulin receptor signalling represents a clinical... (Review)
Review
Severe insulin resistance resulting from known or putative genetic defects affecting the insulin receptor or post-insulin receptor signalling represents a clinical spectrum ranging from Donohue's and Rabson-Mendenhall syndrome, where the genetic defect is identified, through to the milder phenotype of type A insulin resistance, where a genetic defect can only be detected in around 10% of cases. Paradoxically, subjects with these conditions may present with hypoglycaemia due to mismatch of post-prandial glucose excursion and compensatory hyperinsulinaemia. Ultimately, treatment with insulin and insulin sensitisers will be unsuccessful and subjects may succumb to diabetes or its complications. Recombinant human IGF-I alone or combined with its binding protein (IGFBP-3) provides an alternative therapy as IGF-I receptor shares structural and functional homology with the insulin receptor and recombinant human insulin-like growth factor I (rhIGF-I) therapy could improve glucose disposal by signalling through the IGF-I receptor, whilst reducing the adverse effects of high insulin concentrations. There are also data which indicate that IGF-I signalling through the IGF-I receptor on the pancreatic beta-cell may be important in maintaining insulin secretion. Pilot studies confirmed that rhIGF-I could reduce glucose and insulin levels in subjects with type A insulin resistance and those with Rabson-Mendenhall syndrome with sustained beneficial effects on HbA1c. Continued study has confirmed efficacy of rhIGF-I when combined with IGFBP-3 in the treatment of Donohue's and type A insulin resistance subjects. Observations that IGF-I treatment can improve C-peptide levels in these subjects may indicate that it might be more valuable as a first line intervention to preserve beta-cell function, rather than its current use as a medication of last resort in subjects where all other therapies have failed.
Topics: Drug Therapy, Combination; Humans; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Receptor, Insulin; Recombinant Proteins; Severity of Illness Index; Signal Transduction
PubMed: 17785698
DOI: 10.1530/EJE-07-0271 -
The Lancet. Digital Health Jul 2024Pulmonary complications are the most common cause of death after surgery. This study aimed to derive and externally validate a novel prognostic model that can be used...
A prognostic model for use before elective surgery to estimate the risk of postoperative pulmonary complications (GSU-Pulmonary Score): a development and validation study in three international cohorts.
BACKGROUND
Pulmonary complications are the most common cause of death after surgery. This study aimed to derive and externally validate a novel prognostic model that can be used before elective surgery to estimate the risk of postoperative pulmonary complications and to support resource allocation and prioritisation during pandemic recovery.
METHODS
Data from an international, prospective cohort study were used to develop a novel prognostic risk model for pulmonary complications after elective surgery in adult patients (aged ≥18 years) across all operation and disease types. The primary outcome measure was postoperative pulmonary complications at 30 days after surgery, which was a composite of pneumonia, acute respiratory distress syndrome, and unexpected mechanical ventilation. Model development with candidate predictor variables was done in the GlobalSurg-CovidSurg Week dataset (global; October, 2020). Two structured machine learning techniques were explored (XGBoost and the least absolute shrinkage and selection operator [LASSO]), and the model with the best performance (GSU-Pulmonary Score) underwent internal validation using bootstrap resampling. The discrimination and calibration of the score were externally validated in two further prospective cohorts: CovidSurg-Cancer (worldwide; February to August, 2020, during the COVID-19 pandemic) and RECON (UK and Australasia; January to October, 2019, before the COVID-19 pandemic). The model was deployed as an online web application. The GlobalSurg-CovidSurg Week and CovidSurg-Cancer studies were registered with ClinicalTrials.gov, NCT04509986 and NCT04384926.
FINDINGS
Prognostic models were developed from 13 candidate predictor variables in data from 86 231 patients (1158 hospitals in 114 countries). External validation included 30 492 patients from CovidSurg-Cancer (726 hospitals in 75 countries) and 6789 from RECON (150 hospitals in three countries). The overall rates of pulmonary complications were 2·0% in derivation data, and 3·9% (CovidSurg-Cancer) and 4·7% (RECON) in the validation datasets. Penalised regression using LASSO had similar discrimination to XGBoost (area under the receiver operating curve [AUROC] 0·786, 95% CI 0·774-0·798 vs 0·785, 0·772-0·797), was more explainable, and required fewer covariables. The final GSU-Pulmonary Score included ten predictor variables and showed good discrimination and calibration upon internal validation (AUROC 0·773, 95% CI 0·751-0·795; Brier score 0·020, calibration in the large [CITL] 0·034, slope 0·954). The model performance was acceptable on external validation in CovidSurg-Cancer (AUROC 0·746, 95% CI 0·733-0·760; Brier score 0·036, CITL 0·109, slope 1·056), but with some miscalibration in RECON data (AUROC 0·716, 95% CI 0·689-0·744; Brier score 0·045, CITL 1·040, slope 1·009).
INTERPRETATION
This novel prognostic risk score uses simple predictor variables available at the time of a decision for elective surgery that can accurately stratify patients' risk of postoperative pulmonary complications, including during SARS-CoV-2 outbreaks. It could inform surgical consent, resource allocation, and hospital-level prioritisation as elective surgery is upscaled to address global backlogs.
FUNDING
National Institute for Health Research.
Topics: Humans; Elective Surgical Procedures; Postoperative Complications; Female; Prognosis; Middle Aged; Male; Prospective Studies; Aged; COVID-19; Risk Assessment; Adult; Machine Learning; Risk Factors; Lung Diseases; Cohort Studies
PubMed: 38906616
DOI: 10.1016/S2589-7500(24)00065-7 -
Primary Care Diabetes Feb 2021To report on Rabson-Mendenhall Syndrome (RMS) diagnosed in Kuwait.
AIM
To report on Rabson-Mendenhall Syndrome (RMS) diagnosed in Kuwait.
METHODS
A toddler (18 months old) was referred with high plasma insulin and dysmorphic features suggestive of RMS including coarse facial features with globular nose, full lips and furrowed tongue. His skin was hyperkeratotic with hypertrichosis. His sister (aged 13.5 years) was diagnosed with diabetes at 9 years of age and treated with metformin and insulin. She presented with similar dysmorphic features, extensive acanthosis nigricans, dental abnormalities and bilateral nephrocalcinosis. The children were born to non-consanguineous parents. Blood samples were sent for genetic testing in a reference laboratory.
RESULTS
Both children were found to be homozygous for the p.Arg141Trp missense variant (p.Arg114Trp if numbered according to pro-receptor sequence) in the alpha subunit of the insulin receptor.
CONCLUSIONS
These cases demonstrate the importance of raising awareness among healthcare professionals to ensure rapid referral of patients with characteristic physical features of RMS and severe insulin resistance for genetic testing. Unfortunately, treatment of RMS patients remains a challenge with poor prognosis and short life expectancy usually caused by diabetes-related complications. Genetic testing confirms the diagnosis and allows informed genetic counseling of parents considering future pregnancies.
Topics: Acanthosis Nigricans; Donohue Syndrome; Female; Follow-Up Studies; Humans; Infant; Insulin Resistance; Kuwait; Male; Siblings
PubMed: 32843252
DOI: 10.1016/j.pcd.2020.07.012 -
Diabetology International Jan 2021Whereas the genetic basis of insulin sensitivity is determined by variation in multiple genes, mutations of single genes can give rise to profound changes in such...
Whereas the genetic basis of insulin sensitivity is determined by variation in multiple genes, mutations of single genes can give rise to profound changes in such sensitivity. Mutations of the insulin receptor gene ()-which trigger type A insulin resistance, Rabson-Mendenhall, or Donohue syndromes-and those of the gene for the p85α regulatory subunit of phosphoinositide 3-kinase (), which give rise to SHORT syndrome, are the most common and second most common causes, respectively, of single-gene insulin resistance. Loss-of-function mutations of the genes for the protein kinase Akt2 () or for TBC1 domain family member 4 () have been identified in families with severe insulin resistance. Gain-of-function mutations of the gene for protein tyrosine phosphatase nonreceptor type 11 (), which negatively regulates insulin receptor signaling, give rise to Noonan syndrome, and some individuals with this syndrome manifest insulin resistance. Gain-of-function mutations of the gene for the p110α catalytic subunit of phosphoinositide 3-kinase () have been identified in individuals with segmental overgrowth or megalencephaly, some of whom also manifest spontaneous hypoglycemia. A gain-of-function mutation of was also found in individuals with recurrent hypoglycemia. Loss-of-function mutations of the gene for phosphatase and tensin homolog (), another negative regulator of insulin signaling, give rise to Cowden syndrome in association with exaggerated metabolic actions of insulin. Clinical manifestations of individuals with such mutations of genes related to insulin signaling thus provide insight into the essential function of such genes in the human body.
PubMed: 33479580
DOI: 10.1007/s13340-020-00455-5 -
BMC Pediatrics May 2024Donohue syndrome (DS), also referred to as leprechaunism, is a remarkably uncommon autosomal recessive disorder that primarily affects the endocrine system. Its...
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.
Topics: Humans; Male; Hypertension, Pulmonary; Infant; Donohue Syndrome
PubMed: 38773407
DOI: 10.1186/s12887-024-04714-1 -
European Journal of Pediatrics Aug 2013Donohue syndrome (leprechaunism; OMIM *246200) is a rare, recessively inherited disorder of extreme insulin resistance due to mutations in the insulin receptor gene...
Severe progressive obstructive cardiomyopathy and renal tubular dysfunction in Donohue syndrome with decreased insulin receptor autophosphorylation due to a novel INSR mutation.
UNLABELLED
Donohue syndrome (leprechaunism; OMIM *246200) is a rare, recessively inherited disorder of extreme insulin resistance due to mutations in the insulin receptor gene (INSR) causing either defects in insulin binding or receptor autophosphorylation and tyrosine kinase activity. We report a patient with pronounced clinical picture of leprechaunism who developed severe progressive hypertrophic obstructive cardiomyopathy (HOCM) and renal tubular dysfunction which improved on continuous subcutaneous infusion of recombinant human insulin-like growth factor-1 (rhIGF-I). INSR gene molecular analysis and insulin receptor (IR) autophosphorylation on cultured fibroblasts were performed. A novel homozygous missense mutation p.Leu795Pro was found, located in the extracellular portion of the β subunit of the insulin receptor. The post-binding defect of the insulin receptor signaling in cultured fibroblasts demonstrated decreased insulin receptor autophosphorylation.
CONCLUSION
Treatment with rhIGF-I partially reversed severe progressive HOCM and renal tubular dysfunction in a patient with Donohue syndrome associated with a novel p.Leu795Pro INSR gene mutation causing a severe decrease in IR autophosphorylation.
Topics: Cardiomyopathy, Hypertrophic; Donohue Syndrome; Fatal Outcome; Growth Disorders; Humans; Insulin Resistance; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Mutation, Missense; Propranolol; Receptor, Insulin
PubMed: 23229189
DOI: 10.1007/s00431-012-1901-7 -
Pediatrics Feb 2023The American Academy of Pediatrics National Registry for the Surveillance and Epidemiology of Perinatal coronavirus disease 2019 (COVID-19) (NPC-19) was developed to...
OBJECTIVES
The American Academy of Pediatrics National Registry for the Surveillance and Epidemiology of Perinatal coronavirus disease 2019 (COVID-19) (NPC-19) was developed to provide information on the effects of perinatal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
METHODS
National Registry for the Surveillance and Epidemiology of Perinatal COVID-19 participating centers entered maternal and newborn data for pregnant persons who tested positive for SARS-CoV-2 infection between 14 days before and 10 days after delivery. Incidence of and morbidities associated with maternal and newborn SARS-CoV-2 infection were assessed.
RESULTS
From April 6, 2020 to March 19, 2021, 242 centers in the United States centers reported data for 7524 pregnant persons; at the time of delivery, 78.1% of these persons were asymptomatic, 18.2% were symptomatic but not hospitalized specifically for COVID-19, 3.4% were hospitalized for COVID-19 treatment, and 18 (0.2%) died in the hospital of COVID-related complications. Among 7648 newborns, 6486 (84.8%) were tested for SARS-CoV-2, and 144 (2.2%) were positive; the highest rate of newborn infection was observed when mothers first tested positive in the immediate postpartum period (17 of 125, 13.6%). No newborn deaths were attributable to SARS-CoV-2 infection. Overall, 15.6% of newborns were preterm: among tested newborns, 30.1% of polymerase chain reaction-positive and 16.2% of polymerase chain reaction-negative were born preterm (P < .001). Need for mechanical ventilation did not differ by newborn SARS-CoV-2 test result, but those with positive tests were more likely to be admitted to a NICU.
CONCLUSIONS
Early in the pandemic, SARS-CoV-2 infection was acquired by newborns at variable rates and without apparent short-term effects. During a period that preceded widespread availability of vaccines, we observed higher than expected numbers of preterm births and maternal in-hospital deaths.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Child; COVID-19; SARS-CoV-2; Pregnancy Outcome; COVID-19 Drug Treatment; Pregnancy Complications, Infectious; Premature Birth; Infectious Disease Transmission, Vertical
PubMed: 36995183
DOI: 10.1542/peds.2022-059595 -
The Turkish Journal of Pediatrics 1993Features of leprechaunism, including low-birth weight, a grotesque elfin face with clubbed nose, hirsutism, large low-set ears, enlarge external genitalia, distended...
Features of leprechaunism, including low-birth weight, a grotesque elfin face with clubbed nose, hirsutism, large low-set ears, enlarge external genitalia, distended abdomen with emaciated extremities, and growth and motor retardation were present in a 3-month-old girl. Because of parental consanguinity in this patient, a recessive mode of inheritance seems likely.
Topics: Abnormalities, Multiple; Face; Female; Genitalia, Female; Growth Disorders; Hirsutism; Humans; Infant; Mental Disorders; Syndrome
PubMed: 8160285
DOI: No ID Found -
Endocrinology Feb 2003An infant with Donohue's syndrome (leprechaunism) was found to be homozygous for an in-frame trinucleotide deletion within the insulin receptor gene resulting in the...
Deletion of V335 from the L2 domain of the insulin receptor results in a conformationally abnormal receptor that is unable to bind insulin and causes Donohue's syndrome in a human subject.
An infant with Donohue's syndrome (leprechaunism) was found to be homozygous for an in-frame trinucleotide deletion within the insulin receptor gene resulting in the deletion of valine 335. When transiently transfected into Chinese hamster ovary cells, mutant receptor was produced in a mature form, but at significantly lower levels compared with wild-type receptor. Cell surface biotinylation experiments revealed that significant amounts of the DeltaV335 receptor were expressed on the cell surface. Despite this, cells expressing this receptor showed no significant insulin binding or ligand-induced receptor autophosphorylation. Although the DeltaV335 receptor was capable of being immunoprecipitated with antibodies directed against the beta-subunit of the receptor, the mutant receptor could not be recognized by a panel of antibodies directed against different epitopes of the alpha-subunit, suggesting that the loss of V335 results in a major conformational alteration in the receptor alpha-subunit. This would be predicted by the positioning of V335 at a critical location within a strand that provides the main rigid scaffold for the two beta-sheet faces of the L2 domain of the receptor. The severe biochemical and clinical consequences of this novel mutation, which occur despite substantial expression on the cell surface, emphasize the crucial role of the L2 domain in ligand binding by the insulin receptor.
Topics: Abnormalities, Multiple; Animals; Antibodies, Monoclonal; Base Sequence; CHO Cells; Cricetinae; Female; Gene Deletion; Growth Disorders; Humans; Infant; Insulin; Male; Molecular Sequence Data; Mutagenesis, Site-Directed; Phosphorylation; Protein Structure, Tertiary; Receptor, Insulin; Structure-Activity Relationship; Transfection
PubMed: 12538626
DOI: 10.1210/en.2002-220815 -
National Journal of Maxillofacial... 2021Insulin Resistance syndromes (IR's), are a group of genetic disorders caused due a functional defect in chromosome 19p13. It is an autosomal recessive condition. Donohue...
Insulin Resistance syndromes (IR's), are a group of genetic disorders caused due a functional defect in chromosome 19p13. It is an autosomal recessive condition. Donohue Syndrome was initially described by Donohue and Uchida in 1948 and 1954, a case of sisters born to parents with a first-degree consanguineous marriage. Infants presented with typical facial features that resembled the Leprechaun elves of Irish fairy tales. The following is a report of a rare case of dental complications of Severe Insulin Resistance Syndrome. An eight year old female child, with characteristic features of severe insulin resistance syndrome, reported to the Department of Pediatric and Preventive Dentistry, Pravara Institute of Medical Sciences, Loni, presenting with cariously destructed molars and a previous history of dental treatment under local anaesthesia. Given her condition, it was decided to reduce the multiple appointments, to one appointment with all procedures done under general anaesthesia. The following case report discusses the advantages, disadvantages and post operative complications faced when forming a treatment strategy for Severe Insulin Resistance Syndrome.
PubMed: 34188410
DOI: 10.4103/njms.NJMS_55_20