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OBJECTIVE: Develop a multivariable model to identify children with diabetic ketoacidosis (DKA) and/or hyperglycemic hyperosmolar state (HHS) at increased risk of adverse outcomes, and apply it to analyze adverse outcomes during and after the COVID-19 pandemic. DESIGN: Retrospective review of clinical data from 4565 admissions (4284 with DKA alone, 31 [0.7%] only HHS, 250 [5.4%] hyperosmolar DKA) to a large academic children's hospital from January 2010-June 2023. 2010-2019 data (N=3004) were used as a training dataset, and 2020-2021 (N=903) and 2022-2023 (N=658) data for validation. Death or intensive care unit stays >48 hours comprised a composite "Adverse Outcome" group. Risks for this composite outcome were assessed using generalized estimating equations. RESULTS: There were 47 admissions with Adverse Outcomes (1.5%) in 2010-2019, 46 (5.0%) in 2020-2021, and 16 (2.4%) in 2022-2023. Eight patients died (0.18%). Maximum serum glucose, initial pH and diagnosis of type 2 diabetes most strongly predicted Adverse Outcomes. The proportion of patients with type 2 diabetes was highest in 2020-2021. A multivariable model incorporating these factors had excellent discrimination (area under receiver operator characteristic curve [AUC] of 0.948) for the composite outcome in the training dataset, and similar predictive power (AUC 0.960 and 0.873) in the 2020-2021 and 2022-2023 validation datasets, respectively. In the full dataset, AUC for death was 0.984. CONCLUSIONS: Type 2 diabetes and severity of initial hyperglycemia and acidosis are independent risk factors for Adverse Outcomes, and explain the higher frequency of Adverse Outcomes during the COVID-19 pandemic. Risks decreased in January 2022-June 2023.
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The adrenal is a small, anatomically unimposing structure that escaped scientific notice until 1564 and whose existence was doubted by many until the 18th century. Adrenal functions were inferred from the adrenal insufficiency syndrome described by Addison and from the obesity and virilization that accompanied many adrenal malignancies, but early physiologists sometimes confused the roles of the cortex and medulla. Medullary epinephrine was the first hormone to be isolated (in 1901), and numerous cortical steroids were isolated between 1930 and 1949. The treatment of arthritis, Addison's disease, and congenital adrenal hyperplasia (CAH) with cortisone in the 1950s revolutionized clinical endocrinology and steroid research. Cases of CAH had been reported in the 19th century, but a defect in 21-hydroxylation in CAH was not identified until 1957. Other forms of CAH, including deficiencies of 3ß-hydroxysteroid dehydrogenase, 11ß-hydroxylase, and 17α-hydroxylase were defined hormonally in the 1960s. Cytochrome P450 enzymes were described in 1962-1964, and steroid 21-hydroxylation was the first biosynthetic activity associated with a P450. Understanding of the genetic and biochemical bases of these disorders advanced rapidly from 1984 to 2004. The cloning of genes for steroidogenic enzymes and related factors revealed many mutations causing known diseases and facilitated the discovery of new disorders. Genetics and cell biology have replaced steroid chemistry as the key disciplines for understanding and teaching steroidogenesis and its disorders.
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Enfermedades de las Glándulas Suprarrenales , Investigación Biomédica , Humanos , Hiperplasia Suprarrenal Congénita/genética , Hormonas , Oxigenasas de Función Mixta , Biología Molecular , Esteroides , Enfermedades de las Glándulas Suprarrenales/genética , Enfermedades de las Glándulas Suprarrenales/historia , Enfermedades de las Glándulas Suprarrenales/patología , Enfermedades de las Glándulas Suprarrenales/terapia , Glándulas Suprarrenales/anatomía & histología , Investigación Biomédica/historiaRESUMEN
The adrenal has played a major role in the history of pediatric endocrinology. Cases of congenital adrenal hyperplasia (CAH) were reported in the 19th century, leading to the understanding that the adrenal influenced sexual phenotypes as well as being mysteriously required for survival. Numerous adrenal steroids were isolated in the early 20th century, and bioassays eventually distinguished glucocorticoids, mineralocorticoids, and androgens. Treatment of CAH with cortisone in 1950 by Wilkins and by Bartter and Albright revolutionized clinical endocrinology and launched a productive era of pediatric adrenal research. Through careful clinical studies, Wilkins established the contemporary approach to treating CAH. Alfred Bongiovanni identified defective 21-hydroxylation in CAH in 1957, followed by deficiencies of 3ß-hydroxysteroid dehydrogenase and 11ß-hydroxylase. P450 enzymes were described in 1962-1964, and 21-hydroxylation was the first activity ascribed to a P450. Accurate assays for 17OH-progesterone in newborns and in response to ACTH permitted the diagnosis of CAH in children and families. Application of the techniques of molecular genetics elucidated genetic and biochemical bases of these disorders from 1984 to 2004. Pediatric endocrinologists played central roles in identifying the genes responsible for both common and rare forms of congenital adrenal hyperplasia and determining their most appropriate treatments.
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Hiperplasia Suprarrenal Congénita , Endocrinología , Humanos , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/genética , Mineralocorticoides , Glucocorticoides/uso terapéutico , AndrógenosRESUMEN
Objective: To evaluate the insulin-only configuration of the iLet® bionic pancreas (BP) in youth 6-17 years old with type 1 diabetes (T1D). Research Design and Methods: In this multicenter, randomized, controlled trial, 165 youth with T1D (6-17 years old; baseline HbA1c 5.8%-12.2%; 35% using multiple daily injections, 36% using an insulin pump without automation, 4% using an insulin pump with low glucose suspend, and 25% using a hybrid closed-loop system before the study) were randomly assigned 2:1 to use BP (n = 112) with insulin aspart or insulin lispro (BP group) or to a control group (n = 53) using their personal standard care insulin delivery (SC group) plus real-time continuous glucose monitoring (CGM). The primary outcome was HbA1c at 13 weeks. Results: Mean HbA1c decreased from 8.1% ± 1.2% at baseline to 7.5% ± 0.7% at 13 weeks with BP versus 7.8% ± 1.1% at both baseline and 13 weeks with SC (adjusted difference = -0.5%, 95% CI -0.7% to -0.2%, P < 0.001). Participants with baseline HbA1c ≥9.0% (n = 34) decreased mean HbA1c from 9.7% ± 0.8% to 7.9% ± 0.6% after 13 weeks with BP compared with 9.7% ± 0.5% to 9.8% ± 0.8% with SC. Over 13 weeks, mean time in range (TIR) 70-180 mg/dL increased by 10% (2.4 h per day) and mean CGM glucose was reduced by 15 mg/dL with BP compared with SC (P < 0.001). Analyses of time >180 mg/dL, time >250 mg/dL, and standard deviation of CGM glucose favored BP (P < 0.001). Time <54 mg/dL was low at baseline (median 0.2%) and not significantly different between groups over 13 weeks (P = 0.24). A severe hypoglycemia event occurred in 3 (2.7%) participants in the BP group and in 1 (1.9%) in the SC group. Conclusions: In youth 6-17 years old with T1D, use of insulin-only configuration of BP improved HbA1c, TIR, and hyperglycemic metrics without increasing CGM-measured hypoglycemia compared with standard of care. Improvement in glycemic metrics was most pronounced in participants with high baseline HbA1c levels. Clinical Trial Registry: clinicaltrials.gov; NCT04200313.
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Diabetes Mellitus Tipo 1 , Hipoglucemia , Adolescente , Biónica , Glucemia/análisis , Automonitorización de la Glucosa Sanguínea , Niño , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hemoglobina Glucada/análisis , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemia/prevención & control , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Insulina Aspart/uso terapéutico , Sistemas de Infusión de Insulina , Insulina Lispro/uso terapéutico , Insulina Regular Humana/uso terapéutico , PáncreasRESUMEN
Context: Autosomal dominant and rarely de novo gain-of-function variants in the LHCGR gene are associated with precocious male puberty, while somatic LHCGR variants have been found in isolated Leydig cell adenomas and Leydig cell hyperplasia. Bilateral diffuse Leydig cell tumor formation in peripheral precocious male puberty has not been reported. Case Description: We present a boy with gonadotropin-independent precocious puberty and rapid virilization beginning in infancy resistant to standard therapy. Treatment with abiraterone in addition to letrozole and bicalutamide proved effective. Bilateral diffuse Leydig cell tumors were identified at age 5 years. Results: Whole-genome sequencing of tumor and blood samples was performed. The patient was confirmed to have bilateral, diffuse Leydig cell tumors harboring the somatic, gain-of-function p.Asp578His variant in the LHCGR gene. Digital droplet polymerase chain reaction of the LHCGR variant performed in tumor and blood samples detected low levels of this same variant in the blood. Conclusion: We report a young boy with severe gonadotropin-independent precocious puberty beginning in infancy who developed bilateral diffuse Leydig cell tumors at age 5 years due to a somatic gain-of-function p.Asp578His variant in LHCGR. The gain-of-function nature of the LHCGR variant and the developmental timing of the somatic mutation likely play a role in the risk of tumor formation. Abiraterone (a CYP17A1 inhibitor), in combination with an antiandrogen, aromatase inhibitor, and glucocorticoid, appears to be an effective therapy for severe peripheral precocious puberty in boys.
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BACKGROUND: Currently available semiautomated insulin-delivery systems require individualized insulin regimens for the initialization of therapy and meal doses based on carbohydrate counting for routine operation. In contrast, the bionic pancreas is initialized only on the basis of body weight, makes all dose decisions and delivers insulin autonomously, and uses meal announcements without carbohydrate counting. METHODS: In this 13-week, multicenter, randomized trial, we randomly assigned in a 2:1 ratio persons at least 6 years of age with type 1 diabetes either to receive bionic pancreas treatment with insulin aspart or insulin lispro or to receive standard care (defined as any insulin-delivery method with unblinded, real-time continuous glucose monitoring). The primary outcome was the glycated hemoglobin level at 13 weeks. The key secondary outcome was the percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter; the prespecified noninferiority limit for this outcome was 1 percentage point. Safety was also assessed. RESULTS: A total of 219 participants 6 to 79 years of age were assigned to the bionic-pancreas group, and 107 to the standard-care group. The glycated hemoglobin level decreased from 7.9% to 7.3% in the bionic-pancreas group and did not change (was at 7.7% at both time points) in the standard-care group (mean adjusted difference at 13 weeks, -0.5 percentage points; 95% confidence interval [CI], -0.6 to -0.3; P<0.001). The percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter did not differ significantly between the two groups (13-week adjusted difference, 0.0 percentage points; 95% CI, -0.1 to 0.04; P<0.001 for noninferiority). The rate of severe hypoglycemia was 17.7 events per 100 participant-years in the bionic-pancreas group and 10.8 events per 100 participant-years in the standard-care group (P = 0.39). No episodes of diabetic ketoacidosis occurred in either group. CONCLUSIONS: In this 13-week, randomized trial involving adults and children with type 1 diabetes, use of a bionic pancreas was associated with a greater reduction than standard care in the glycated hemoglobin level. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT04200313.).
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Diabetes Mellitus Tipo 1 , Hipoglucemiantes , Insulina Aspart , Sistemas de Infusión de Insulina , Insulina Lispro , Adolescente , Adulto , Anciano , Biónica/instrumentación , Glucemia/análisis , Automonitorización de la Glucosa Sanguínea/instrumentación , Automonitorización de la Glucosa Sanguínea/métodos , Niño , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Insulina/administración & dosificación , Insulina/efectos adversos , Insulina/uso terapéutico , Insulina Aspart/administración & dosificación , Insulina Aspart/efectos adversos , Insulina Aspart/uso terapéutico , Sistemas de Infusión de Insulina/efectos adversos , Insulina Lispro/administración & dosificación , Insulina Lispro/efectos adversos , Insulina Lispro/uso terapéutico , Persona de Mediana Edad , Adulto JovenRESUMEN
PURPOSE OF REVIEW: Although the basic treatment of congenital adrenal hyperplasia (CAH) is well established, there are active clinical research projects to more closely mimic the normal diurnal rhythm of cortisol secretion and to reduce total glucocorticoid doses to minimize adverse metabolic effects. RECENT FINDINGS: We review clinical studies on CAH treatment published in the last 18âmonths or currently underway according to ClinicalTrials.gov listings. These can be grouped into several broad themes: alternative dosing forms of hydrocortisone with altered pharmacokinetics or easier dose titration; corticotropin-releasing hormone receptor antagonists that reduce corticotropin (ACTH) secretion and thereby reduce adrenal androgen secretion; androgen biosynthesis inhibitors; a first clinical trial of a gene therapy vector. SUMMARY: Alternative dosing forms of hydrocortisone are, or will shortly be, marketed, but cost may be a barrier to utilization, at least in the US market. Trials of corticotropin releasing hormone receptor antagonists and androgen biosynthesis inhibitors are currently underway. The author believes that trials of gene therapy for CAH are premature.
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Hiperplasia Suprarrenal Congénita , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Hormona Adrenocorticotrópica , Andrógenos/uso terapéutico , Glucocorticoides/uso terapéutico , Humanos , Hidrocortisona/uso terapéuticoRESUMEN
BACKGROUND: The coronavirus disease-2019 (COVID-19) pandemic had widespread impacts on the lives of parents and children. We determined how the pandemic affected Type 1 diabetes patients at a large urban pediatric teaching hospital. METHODS: We compared patient characteristics, glycemic control, PHQ-9 depression screen, in person and virtual outpatient encounters, hospitalizations and continuous glucose monitor (CGM) utilization in approximately 1600 patients in 1 year periods preceding and following the local imposition of COVID-related restrictions on 3/15/2020 ("2019" and "2020" groups, respectively). RESULTS: In a generalized linear model, increasing age, non-commercial insurance, Black and Hispanic race/ethnicity, and non-utilization of CGMs were all associated with higher hemoglobin A1c (HbA1c), but there was no difference between the 2019 and 2020 groups. The time in range in CGM users was lower with non-commercial insurance and in Black and Hispanic patients; it improved slightly from 2019 to 2020. CGM utilization by patients with non-commercial insurance (93% of such patients were in government programs, 7% uninsured or "other") increased markedly. In 2020, patients with commercial insurance (i.e., private-pay or provided by an employer) had fewer office visits, but insurance status did not influence utilization of the virtual visit platform. There was no change in hospitalization frequency from 2019 to 2020 in either commercially or non-commercially insured patients, but patients with non-commercial insurance were hospitalized at markedly higher frequencies in both years. PHQ-9 scores were unchanged. CONCLUSIONS: Hospitalization frequency, glycemic control and depression screening were unchanged in our large urban pediatric teaching hospital during the COVID pandemic. Increased utilization of CGM and rapid adoption of telemedicine may have ameliorated the impact of the pandemic on disease management.
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COVID-19 , Diabetes Mellitus Tipo 1 , Adolescente , COVID-19/epidemiología , Niño , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/terapia , Humanos , Cobertura del Seguro , Pandemias , SARS-CoV-2RESUMEN
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH is caused by steroid 21-hydroxylase deficiency due to mutations in CYP21A2. Since the last publication summarizing CAH in Endocrine Reviews in 2000, there have been numerous new developments. These include more detailed understanding of steroidogenic pathways, refinements in neonatal screening, improved diagnostic measurements utilizing chromatography and mass spectrometry coupled with steroid profiling, and improved genotyping methods. Clinical trials of alternative medications and modes of delivery have been recently completed or are under way. Genetic and cell-based treatments are being explored. A large body of data concerning long-term outcomes in patients affected by CAH, including psychosexual well-being, has been enhanced by the establishment of disease registries. This review provides the reader with current insights in CAH with special attention to these new developments.
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Hiperplasia Suprarrenal Congénita , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Hiperplasia Suprarrenal Congénita/terapia , Humanos , Hidrocortisona , Recién Nacido , Mutación , Tamizaje Neonatal , Esteroide 21-Hidroxilasa/genéticaRESUMEN
OBJECTIVE: To develop a multivariable prediction model to identify patients with type 1 diabetes at increased risk of hospitalization for diabetic ketoacidosis or hyperglycemia with ketosis in the 12 months following assessment. METHODS: Retrospective review of clinical data from patients with type 1 diabetes less than 17 years old at a large academic children's hospital (5732 patient years, 652 admissions). Data from the previous 12 months were assessed on October 15, 2015, 2016, 2017, and 2018, and used to predict hospitalization in the following 12 months using generalized estimating equations. Variables that were significant predictors of hospitalization in univariate analyses were entered into a multivariable model. 2014 to 2016 data were used as a training dataset, and 2017 to 2019 data for validation. Discrimination of the model was assessed with receiver operator characteristic curves. RESULTS: Admission in the preceding year, hemoglobin (Hb)A1c, non-commercial insurance, female sex, and non-White race were all individual predictors of hospitalization, but age, duration of diabetes and number of office visits in the preceding year were not. In multivariable analysis with threshold P < .0033, admissions in the previous 12 months, HbA1c, and non-commercial insurance remained as significant predictors. The model identified a subset of ~8% of the patients with a collective 42% risk of hospitalization, thus increased 5-fold compared with the 8% risk of hospitalization in the remaining 93% of patients. Similar results were obtained with the validation dataset. CONCLUSION: Our multivariable prediction model identified patients at increased risk of admission in the 12 months following assessment.
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Diabetes Mellitus Tipo 1/complicaciones , Cetoacidosis Diabética/etiología , Hospitalización , Hiperglucemia/etiología , Adolescente , Niño , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/terapia , Cetoacidosis Diabética/diagnóstico , Cetoacidosis Diabética/terapia , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hiperglucemia/diagnóstico , Hiperglucemia/terapia , Seguro de Salud , Masculino , Valor Predictivo de las Pruebas , Curva ROC , Estudios Retrospectivos , Factores de RiesgoRESUMEN
OBJECTIVE: We aimed to determine the reproducibility of TSH testing in pediatric patients referred to pediatric endocrinologists and to identify the threshold TSH levels that would predict the presence of antithyroid autoantibodies and inform decisions by pediatric endocrinologists to initiate or continue treatment with levothyroxine. STUDY DESIGN: We analyzed a retrospective case series of 325 children aged 1 to 18 years referred for hypothyroidism to the endocrinology clinic at a tertiary care children's hospital. The receiver operating characteristic area under curve (AUC) determined the ability of the initial TSH level to predict pediatric endocrinologists' treatment decisions, presence of thyroid autoantibodies, and reproducibility of elevated TSH on repeat testing. RESULTS: Of 325 patients, 191 were treated. The treated patients were more likely to have had a higher referral TSH, positive autoantibodies, and abnormal thyroid gland examination findings. An initial TSH of 5 had a specificity of only 14% for a repeat TSH of ≥5. An initial TSH level of 11 had a specificity of 90% for a repeat TSH of ≥11, with sensitivity of 90%. TSH was a relatively poor predictor (AUC, 0.711) of the presence of autoantibodies with optimal classification at TSH >8.8 mIU/L. It was better (AUC, 0.878) at predicting whether endocrinologists started or continued treatment with levothyroxine, with optimal classification at 8.2 mIU/L. TSH levels combined with antibody status and thyroid examination findings had the best ability to predict treatment (AUC, 0.930). CONCLUSIONS: TSH levels slightly above the reference range should not prompt referral to pediatric endocrinologists unless another basis for clinical concern is present.
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BACKGROUND/OBJECTIVES: Children attending diabetes camp are more active, increasing the risk of hypoglycemia. Decreasing initial insulin doses may reduce this risk. The objectives of our study were to compare glycemic control between campers receiving multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII), and analyze the impact of decreasing basal insulin by 10%. METHODS: We analyzed 849 camp sessions (599 children, 5-19 years old) from Camp Sweeney's 2016/2017 summers. Campers were separated into groups by year and insulin route (MDI_2016, MDI_2017, CSII_2016, and CSII_2017). The MDI_2016 group had initial basal insulin decreased 10%, while CSII_2016, MDI_2017, and CSII_2017 did not. Time spent in blood glucose ranges and area under the curve (AUC) were compared by year and insulin route using ANOVA. We also performed repeated measures ANOVA using campers who attended both years. RESULTS: No significant differences in time spent in any glucose range could be attributed to the initial 10% basal decrease, including on paired analysis. MDI_2017 had more decreases to basal insulin than the other groups. CSII campers had higher AUC and more hyperglycemia than MDI campers. CONCLUSIONS: Campers on MDI may benefit from decreasing basal insulin, either at the beginning of camp or during the first week. Future research is needed to optimize glycemic control in the camp setting.
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Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 1/rehabilitación , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Adolescente , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Femenino , Humanos , Masculino , Tratamiento DomiciliarioRESUMEN
OBJECTIVE: To examine (a) changes in parental involvement across early emerging adulthood, (b) whether yearly fluctuations in parental involvement were associated with adherence and glycated hemoglobin (HbA1c) over time, and (c) whether higher involvement was more beneficial for those with poorer executive function (EF). METHODS: A total of 228 high school seniors (M age = 17.76) with type 1 diabetes reported on mothers' and fathers' acceptance, knowledge of diabetes activities, disclosure to mothers and fathers regarding diabetes, and adherence at four yearly time points. At baseline, participants completed performance-based measures of EF. HbA1c was collected from assay kits. RESULTS: Growth curve models revealed significant declines in disclosure to fathers and mothers' and fathers' knowledge of diabetes activities; no changes were found in mothers' or fathers' acceptance nor disclosure to mothers. Multilevel models indicated significant between-person effects for nearly all aspects of parental involvement with more acceptance, knowledge, and disclosure associated with better HbA1c and adherence. Within-person effects for disclosure to fathers, and mothers' and fathers' knowledge indicated that in years when emerging adults perceived higher amounts of these types of involvement (compared with their own average), HbA1c was lower. Within-person effects were found for acceptance to mothers, disclosure to mothers and fathers, and mothers' diabetes knowledge for adherence. Disclosure to fathers and mothers' knowledge of diabetes activities were especially beneficial for HbA1c for those with poorer EF performance. CONCLUSIONS: Parental involvement in diabetes management remains important during the high-risk time of emerging adulthood, especially for those with poorer EF.
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Disfunción Cognitiva/etiología , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/terapia , Función Ejecutiva , Responsabilidad Parental , Padres , Cooperación del Paciente , Adolescente , Adulto , Función Ejecutiva/fisiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Adulto JovenRESUMEN
During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins.
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Insuficiencia Suprarrenal/genética , ADN Polimerasa II/genética , Retardo del Crecimiento Fetal/genética , Mutación/genética , Osteocondrodisplasias/genética , Proteínas de Unión a Poli-ADP-Ribosa/genética , Anomalías Urogenitales/genética , Adolescente , Adulto , Alelos , Niño , Preescolar , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Replicación del ADN/genética , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Fenotipo , Adulto JovenRESUMEN
Objective: To update the congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency clinical practice guideline published by the Endocrine Society in 2010. Conclusions: The writing committee presents updated best practice guidelines for the clinical management of congenital adrenal hyperplasia based on published evidence and expert opinion with added considerations for patient safety, quality of life, cost, and utilization.
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Hiperplasia Suprarrenal Congénita/terapia , Endocrinología/normas , Sociedades Médicas/normas , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/economía , Hiperplasia Suprarrenal Congénita/genética , Análisis Costo-Beneficio , Femenino , Terapias Fetales/economía , Terapias Fetales/métodos , Terapias Fetales/normas , Asesoramiento Genético/economía , Asesoramiento Genético/métodos , Asesoramiento Genético/normas , Glucocorticoides/uso terapéutico , Humanos , Recién Nacido , Cuidados a Largo Plazo/economía , Cuidados a Largo Plazo/métodos , Cuidados a Largo Plazo/normas , Tamizaje Neonatal/economía , Tamizaje Neonatal/normas , Seguridad del Paciente/normas , Calidad de Vida , Terapias en Investigación/economía , Terapias en Investigación/métodos , Terapias en Investigación/normasRESUMEN
Context: Adrenarche refers to the rise of dehydroepiandrosterone sulfate (DHEA-S) associated with the development of a functional adrenal zona reticularis. Clinical features of adrenarche include onset of body odor, axillary hair, and pubic hair, which reflect increased androgen action. An early rise in adrenal androgens, or premature adrenarche (PremA), is a risk factor for adverse metabolic profiles in adolescence and adulthood. The bioactive androgens associated with adrenarche and PremA remain poorly understood. The adrenal gland is a potential source of testosterone (T) and the 11-oxygenated derivatives 11ß-hydroxytestosterone (11OHT) and 11-ketotestosterone (11KT). Objective: The objective of this study was to characterize the adrenal androgen biome contributing to adrenarche and PremA. Participants and Methods: With the use of mass spectrometry, 19 steroids including the 11-oxygenated derivatives of T were measured in sera obtained from girls with PremA (n = 37; 4 to 7 years) and age-matched girls (n = 83; 4 to 10 years). Results: In reference population girls, dehydroepiandrosterone, DHEA-S, androstenediol-3-sulfate, T, and 11KT all increased at the onset of adrenarche (6 to 8 years) and beyond (9 to 10 years) (P < 0.05 vs younger subjects 4 to 5 years). T, 11OHT, and 11KT were further elevated in PremA vs age-matched girls (P < 0.001). Circulating concentrations of 11KT during adrenarche and PremA exceeded those of T and 11OHT (11KT > T ≥ 11OHT). Androgen receptor activity and nuclear translocation studies demonstrated that 11KT is a potent androgen similar to T. Conclusions: Our findings suggest that 11KT is the dominant bioactive androgen in children during adrenarche and PremA. Its androgenic capacity suggests that it may be responsible for the phenotypic changes seen in these phenomena.
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Adrenarquia/sangre , Andrógenos/sangre , Pubertad Precoz/sangre , Testosterona/análogos & derivados , Niño , Preescolar , Estudios de Cohortes , Sulfato de Deshidroepiandrosterona/sangre , Sulfato de Deshidroepiandrosterona/metabolismo , Femenino , Humanos , Espectrometría de Masas , Testosterona/sangre , Zona Reticular/metabolismoRESUMEN
OBJECTIVE: The objective of this study was to examine 1) whether teens' glycemic control and adherence to type 1 diabetes treatment regimen worsen during the transition from late adolescence to emerging adulthood, and 2) whether teens' executive function (EF), as measured by performance and self-reported problems with EF, is predictive of these changes (after controlling for general intelligence). RESEARCH DESIGN AND METHODS: High school seniors with type 1 diabetes (N = 236; mean age 17.74 years) were assessed at three yearly time points. At baseline, during the senior year of high school, participants completed a self-report measure of problems with EF and performance-based measures of EF and general intelligence (IQ). Glycemic control was determined on the basis of results collected from HbA1c assay kits, and teens reported their adherence at all three time points. RESULTS: HbA1c increased significantly across the three time points and adherence declined. EF performance was not associated with adherence or HbA1c at baseline, nor with changes in adherence over time. However, better EF performance predicted slower increases in HbA1c over time (i.e., slope) while controlling for IQ. Teens' self-reported problems with EF were associated with worse glycemic control and poorer adherence at baseline (i.e., intercept), but they did not predict changes in either HbA1c or adherence over time (i.e., slope). CONCLUSIONS: Abilities involved in performance on EF tests may be one resource for maintaining better glycemic control during the transition to emerging adulthood. Assessment of such EF abilities may allow for the identification of individuals who are most at risk for deterioration of glycemic control during this transition.