Real-World Estimates of Adrenal Insufficiency–Related Adverse Events in Children With Congenital Adrenal Hyperplasia

Ali, Salma; Bryce, Jillian; Haghpanahan, Houra; Lewsey, James; Tan, Li En; Birkebæk, Niels H; Blankenstein, Oliver; Neumann, Uta; Balsamo, Antonio; Ortolano, Rita; Bonfig, Walter; Grinten, Hedi L Claahsen–van der; Cools, Martine; Costa, Eduardo Corrêa; Darendelıler, Feyza; Poyrazoğlu, Şükran; Elsedfy, Heba; Finken, Martijn J J; Flück, Christa E.; Gevers, Evelien; Korbonits, M; Guaragna-Filho, Guilherme; Güran, Tülay; Güven, Ayla; Hannema, Sabine E.; Higham, Claire; Hughes, Ieuan A.; Tadokoro-Cuccaro, Rieko; Thankamony, Ajay; Iotova, Violeta; Krone, Nils; Krone, Ruth; Lichiardopol, Corina; Luczay, Andrea; Mendonça, Berenice Bilharinho; Bachega, Tânia A.S.S.; Miranda, Mirela C; Milenković, Tatjana; Mohnike, Klaus; Nordenström, Anna; Einaudi, Silvia; Kamp, H van; Vieites, Ana; Vries, Liat de; Ross, Richard; Ahmed, S Faisal

doi:10.1210/clinem/dgaa694

Cited by 29 publications

(29 citation statements)

References 44 publications

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“…Even though an adequate hormonal replacement would minimize complications and assure a normal quality of life, current therapies have failed to prevent co-morbidities, and adrenal crises still occur as a leading cause of death ( 15 , 18 , 76 ). This is partly due to the lack of adequate preparations, making it difficult to control the disease.…”

Section: Management Of Patients With Dsd Associated To Adrenal Dysfunctionmentioning

confidence: 99%

Disorders of Sex Development of Adrenal Origin

et al. 2021

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Disorders of Sex Development (DSD) are anomalies occurring in the process of fetal sexual differentiation that result in a discordance between the chromosomal sex and the sex of the gonads and/or the internal and/or external genitalia. Congenital disorders affecting adrenal function may be associated with DSD in both 46,XX and 46,XY individuals, but the pathogenic mechanisms differ. While in 46,XX cases, the adrenal steroidogenic disorder is responsible for the genital anomalies, in 46,XY patients DSD results from the associated testicular dysfunction. Primary adrenal insufficiency, characterized by a reduction in cortisol secretion and overproduction of ACTH, is the rule. In addition, patients may exhibit aldosterone deficiency leading to salt-wasting crises that may be life-threatening. The trophic effect of ACTH provokes congenital adrenal hyperplasia (CAH). Adrenal steroidogenic defects leading to 46,XX DSD are 21-hydroxylase deficiency, by far the most prevalent, and 11β-hydroxylase deficiency. Lipoid Congenital Adrenal Hyperplasia due to StAR defects, and cytochrome P450scc and P450c17 deficiencies cause DSD in 46,XY newborns. Mutations in SF1 may also result in combined adrenal and testicular failure leading to DSD in 46,XY individuals. Finally, impaired activities of 3βHSD2 or POR may lead to DSD in both 46,XX and 46,XY individuals. The pathophysiology, clinical presentation and management of the above-mentioned disorders are critically reviewed, with a special focus on the latest biomarkers and therapeutic development.

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Section: Management Of Patients With Dsd Associated To Adrenal Dysfunctionmentioning

confidence: 99%

Disorders of Sex Development of Adrenal Origin

et al. 2021

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“…Risk of adrenal death (AD) is significant with Standardised Mortality Ratio (SMR) at 9.6-17.4 ( 8 , 9 ) and 1 death per 205 patients years ( 9 ) in children with AI. Rates of both AD and AC are likely to be higher than the literature suggests with recent studies reporting a median of zero AC events per patient year ( 10 ).…”

Section: Introductionmentioning

confidence: 96%

Acute Illness and Death in Children With Adrenal Insufficiency

et al. 2021

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BackgroundAdrenal Insufficiency (AI) can lead to life-threatening Adrenal Crisis (AC) and Adrenal Death (AD). Parents are trained to prevent, recognise and react to AC but there is little available information on what parents are actually doing at home to manage symptomatic AI.MethodsThree approaches were taken: (A) A retrospective analysis of patient characteristics in children and young people with AD over a 13-year period, (B) An interview-aided questionnaire to assess the circumstances around AC in children currently in our adrenal clinic, and (C) a separate study of parent perceptions of the administration of parenteral hydrocortisone.ResultsThirteen patients died (median age 10 years) over a thirteen-year period resulting in an estimated incidence of one AD per 300 patient years. Those with unspecified adrenal insufficiency were overrepresented (P = 0.004). Of the 127 patients contacted, thirty-eight (30%) were identified with hospital attendance with AC. Responses from twenty patients (median age 7.5 years) with AC reported nausea/vomiting (75%) and drowsiness (70%) as common symptoms preceding AC. All patients received an increase in oral hydrocortisone prior to admission but only two received intramuscular hydrocortisone. Questionnaires revealed that 79% of parents reported confidence in the administration of intramuscular hydrocortisone and only 20% identified a missed opportunity for injection.ConclusionsIn children experiencing AC, parents followed ‘sick day’ guidance for oral hydrocortisone, but rarely administered intramuscular hydrocortisone. This finding is discrepant from the 79% of parents who reported confidence in this task. Local training programmes for management of AC are comprehensive, but insufficient to prevent the most serious crises. New strategies to encourage use of parenteral hydrocortisone need to be devised.

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“…Patients affected by CAH require life-long glucocorticoid (GC) and, where appropriate, mineralocorticoid replacement therapy. Cortisol deficiency results in adrenocorticotropic hormone (ACTH) over-secretion due to loss of negative feedback along the hypothalamic-pituitary-axis (1), consequently resulting in adrenal androgen excess (2). Accumulation of steroids upstream of the enzymatic blockade is a hallmark of the disease.…”

Section: Introductionmentioning

confidence: 99%

Salivary profiles of 11-oxygenated androgens follow a diurnal rhythm in patients with congenital adrenal hyperplasia

Nowotny

Auer

Lottspeich

et al. 2021

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Context: Several studies have highlighted the importance of the 11 oxygenated 19 carbon (11oxC19) adrenal derived steroids as potential biomarkers for monitoring patients with 21 hydroxylase deficiency (21OHD). Objective: To analyze circadian rhythmicity of 11oxC19 steroids in saliva profiles and evaluate their relevance as potential monitoring parameters in 21OHD. Design, Setting, and Participants: Cross-sectional single center study including 34 patients with classic 21OHD (men=14; women=20) and 32 BMI- and age matched controls (men=15; women=17). Outcome Measures: Salivary concentrations of the following steroids were analyzed by LC MS/MS: 17 hydroxyprogesterone (17OHP), androstenedione (A4), testosterone (T), 11β hydroxyandrostenedione (11OHA4) and 11 ketotestosterone (11KT). Results: Similar to the previously described rhythmicity of 17OHP, 11OHA4 and 11KT concentrations followed a distinct diurnal rhythm in both patients and controls with highest concentrations in the early morning and declining throughout the day (11-OHA4: male patients Δmean = 79 %; male controls Δmean = 81%; female patients Δmean = 33 %; female controls Δmean = 91 %; 11KT: male patients Δmean = 64 %; male controls Δmean = 60 %; female patients Δmean = 49 %; female controls Δmean = 81 %). Significant correlations between the area under the curve (AUC) for 17OHP and 11KT (r(p)male = 0.741**; r(p)female = 0.842****), and 11OHA4 (r(p)male = 0.385n.s.; r(p)female = 0.527*) were observed in patients but not in controls. Conclusions: Adrenal 11oxC19 androgens are secreted following a diurnal pattern. This should be considered when evaluating their utility for monitoring treatment control.

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Real-World Estimates of Adrenal Insufficiency–Related Adverse Events in Children With Congenital Adrenal Hyperplasia

Cited by 29 publications

References 44 publications

Disorders of Sex Development of Adrenal Origin

Disorders of Sex Development of Adrenal Origin

Acute Illness and Death in Children With Adrenal Insufficiency

Salivary profiles of 11-oxygenated androgens follow a diurnal rhythm in patients with congenital adrenal hyperplasia

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