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.
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.
Abstract
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 3β-hydroxysteroid dehydrogenase, 11β-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.
Graphical Abstract
Graphical Abstract
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a relatively common inherited disorder of cortisol biosynthesis that can be fatal if untreated.
The basic biochemistry and ...genetics of CAH have been known for decades but continue to be refined by the discoveries of an alternative 'backdoor' metabolic pathway for adrenal androgen synthesis and the secretion of 11-hydroxy and 11-keto analogs of known androgens, by the elucidation of hundreds of new mutations, and by the application of high-throughput sequencing techniques to noninvasive prenatal diagnosis. Although hydrocortisone is a mainstay of treatment, overtreatment may have adverse effects on growth, risk of obesity, and cardiovascular disease; conversely, undertreatment may increase risk of testicular adrenal rest tumors in affected men.
Refinements to screening techniques may improve the positive predictive value of newborn screening programs. Alternative dosing forms of hydrocortisone and additional therapeutic modalities are under study. Although surgical treatment of virilized female genitalia is widely accepted by families and patients, it is not without complications or controversy, and some families choose to defer it.
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