To update the congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency clinical practice guideline published by the Endocrine Society in 2010.
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.
Congenital adrenal hyperplasia (CAH) caused by steroid 21-hydroxylase deficiency occurs in 1:16,000-1:20,000 births. If not promptly diagnosed and treated, CAH can cause death in early infancy from ...shock, hyponatremia and hyperkalemia. Affected girls usually have ambiguous genitalia but boys appear normal; therefore, newborn babies are commonly screened for CAH in the US and many other countries. By identifying babies with severe, salt-wasting CAH before they develop adrenal crises, screening reduces morbidity and mortality, particularly among affected boys. Diagnosis is based on elevated levels of 17-hydroxyprogesterone, the preferred substrate for steroid 21-hydroxylase. Initial testing usually involves dissociation-enhanced lanthanide fluorescence immunoassay that has a low positive predictive value (about 1%), which leads to many follow-up evaluations that have negative results. The positive predictive value might be improved by second-tier screening using DNA-based methods or liquid chromatography followed by tandem mass spectrometry, but these methods are not widely adopted. Cost estimates for such screening range from US$20,000 to $300,000 per life-year saved. In babies with markedly abnormal screen results, levels of serum electrolytes and 17-hydroxyprogesterone should be immediately determined, but the most reliable way to diagnose CAH is measurement of levels of steroid precursors after stimulation with cosyntropin.
Background: Management of diabetic ketoacidosis (DKA) in pediatric patients is well established, but optimal management for hyperglycemic hyperosmolar state (HHS) and mixed DKA/HHS is uncertain.
...Aims: Develop a model to identify patients at increased risk of adverse events and identify management differences associated with adverse outcomes.
Methods: Retrospective chart review of 5,346 admissions from 3,104 unique patients with type 1 diabetes (T1D) or T2D at a large children’s hospital from 1/1/2010-7/1/2022 requiring IV insulin to manage DKA (pH <7.3, glucose > 200 mg/dl) and/or HHS (glucose >600 mg/dl). An ICU stay >48 hours (h) was a surrogate for severe adverse events. Risk of death or ICU stay >48 h (high risk HR group) was modeled using generalized estimating equations on a training dataset of 3,979 admissions from 2010-2019. Admissions 2020-2022 were the test dataset. Discrimination was assessed with receiver-operator-characteristic (ROC) curves. Using this predictive model, we selected a control (C) group at similar risk of adverse events to identify outcome-related management differences.
Results: There were 810 ICU admissions; 90 were >48 h. There were 8 diabetes-related deaths, 5 in 2020-2022. In the multivariate model, risk factors for severe adverse events included initial pH, glucose, absolute value of the deviation of glucose-corrected serum Na from 140, and a diagnosis of T2D. Discrimination was excellent; area under the ROC curve was 0.938 and 0.964 in the training and test datasets respectively. HR and C groups were similar for pH, glucose and sodium on admission, but altered mental status was more frequent in the HR group. Glucose and sodium corrected more slowly in the HR patients.
Conclusions: The prediction model accurately identified patients at increased risk of prolonged ICU stay or death. Rates of death and prolonged ICU stay increased during the Covid pandemic, correlated with more severe clinical presentation. Slower correction of metabolic abnormalities was associated with prolonged ICU stay.
Disclosure
M.Yousif: None. S.Adhikari: None. P.C.White: Consultant; Provention Bio, Inc.
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.
We review clinical studies on CAH treatment published in the last 18 months 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.
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.
This paper investigates the actual extrapolation capacity of three hydrological models in differing climate conditions. We propose a general testing framework, in which we perform series of ...split‐sample tests, testing all possible combinations of calibration‐validation periods using a 10 year sliding window. This methodology, which we have called the generalized split‐sample test (GSST), provides insights into the model's transposability over time under various climatic conditions. The three conceptual rainfall‐runoff models yielded similar results over a set of 216 catchments in southeast Australia. First, we assessed the model's efficiency in validation using a criterion combining the root‐mean‐square error and bias. A relation was found between this efficiency and the changes in mean rainfall (P) but not with changes in mean potential evapotranspiration (PE) or air temperature (T). Second, we focused on average runoff volumes and found that simulation biases are greatly affected by changes in P. Calibration over a wetter (drier) climate than the validation climate leads to an overestimation (underestimation) of the mean simulated runoff. We observed different magnitudes of these models deficiencies depending on the catchment considered. Results indicate that the transfer of model parameters in time may introduce a significant level of errors in simulations, meaning increased uncertainty in the various practical applications of these models (flow simulation, forecasting, design, reservoir management, climate change impact assessments, etc.). Testing model robustness with respect to this issue should help better quantify these uncertainties.
Key Points
Proposing methods to analyse model robustness in contrasted climate conditions
Quantifying robustness losses due to climate change in parameters transfer
Estimating homogeneity of results over a large number of catchments
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 11β-hydroxytestosterone (11OHT) and 11-ketotestosterone (11KT).
The objective of this study was to characterize the adrenal androgen biome contributing to adrenarche and PremA.
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).
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.
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.
Primary adrenal insufficiency is rare in childhood. Hypotension and hyponatremia are usually present at diagnosis, but only half of patients have hyperkalemia.
Context:
Primary adrenal insufficiency ...is usually diagnosed in infancy or adulthood, and cases presenting in childhood have not been systematically reviewed.
Objective:
Our objective was to determine etiologies, signs, and symptoms of primary adrenal insufficiency presenting in childhood.
Design and Setting:
We conducted a retrospective chart review at a tertiary-care pediatric hospital.
Patients:
Patients were children with corticoadrenal insufficiency, glucocorticoid deficiency, or mineralocorticoid deficiency.
Results:
Seventy-seven cases were identified in 1999–2010. Thirty-five had congenital adrenal hyperplasia (CAH) and were not reviewed further. Forty-two patients (20 diagnosed at our institution) had primary adrenal insufficiency. These had etiologies as follows: autoimmune (18), autoimmune polyendocrinopathy syndrome (an additional five), ACTH resistance (four), adrenoleukodystrophy (three), adrenal hypoplasia congenita (two), adrenal hemorrhage (two), IMAGe syndrome (one), and idiopathic (two). Of 20 patients diagnosed at our institution, two were being monitored when adrenal insufficiency developed and were not included in the analysis of presenting signs and symptoms: 13 of 18 patients were hypotensive; 12 of 18 had documented hyperpigmentation. Hyponatremia (<135 mEq/liter) occurred in 16 of 18. However, hyperkalemia (>5.0 mEq/liter) was noted in only nine. Hypoglycemia and ketosis were documented in four of 15 and four of six patients in whom it was sought, respectively. Fifteen patients underwent cosyntropin stimulation testing with median baseline and stimulated cortisol of 1.1 and 1.2 μg/dl, respectively. ACTH and renin were markedly elevated in all patients.
Conclusions:
Hyperkalemia is not a consistent presenting sign of primary adrenal insufficiency in childhood, and its absence cannot rule out this condition. A combination of chronic or subacute clinical symptoms, hypotension, and hyponatremia should raise suspicion of adrenal insufficiency.