ESPE Yearbook of Paediatric Endocrinology

Brief summary: This comprehensive narrative review provides a “Seminar” on congenital adrenal hyperplasia (CAH). The authors performed a thorough comprehensive qualitative summary of articles published mainly in Cochrane Library, MEDLINE, and Embase in English between Jan 1, 2005, and June 30, 2021, while not excluding commonly referenced and highly regarded older publications.

Congenital adrenal hyperplasia (CAH) is an ‘umbrella’ clinical term comprising a group of autosomal recessive disorders leading to multiple complex hormonal imbalances caused by various enzyme deficiencies in the adrenal steroidogenic pathway (1). Research in the past decades has advanced our understanding of disease genetics and pathophysiology (2). These complex hormonal imbalances can manifest with potentially life-threatening consequences, while disease-related and treatment-related morbidity and mortality are increased. After the introduction of life-saving hormone replacement therapy in the 1950s and neonatal screening programmes in many countries, nowadays neonatal survival rates in patients with congenital adrenal hyperplasia are high (3).

Alternative steroid pathways have been identified and a multitude of novel treatment approaches are being developed (1). Optimising diagnostic and treatment strategies, a successful transition process to adult services, patient empowerment, and continuous psychological support throughout the lifespan are key factors for improved outcome and quality of life and reduced long-term sequelae in patients with CAH (4).

The most common type of CAH is due to steroid 21-hydroxylase (21OH) deficiency; the classic (severe) form of 21OH deficiency is characterised by life-threatening adrenal crises and is the most common cause of atypical genitalia in neonates with 46,XX karyotype (5). Non-classic (mild) forms of CAH caused by 21OH deficiency are more common than the classic ones; they are detected clinically and primarily identified in female patients with hirsutism or impaired fertility (6). Finally, disease-related mortality in CAH remains increased and therapeutic management challenging, with multiple long-term complications related to treatment and disease affecting growth and development, metabolic and cardiovascular health, and fertility. Novel treatment approaches are required that they either mimick physiologic circadian cortisol secretion or reduce adrenal hyperandrogenism without the adverse effects of supraphysiologic glucocorticoid treatment (7).

References: 1. Miller WL. Steroidogenic electron-transfer factors and their diseases. Ann Pediatr Endocrinol Metab. 2021 Sep;26(3):138–148. 2. Krone N, Rose IT, Willis DS, et al. Genotype–phenotype correlation in 153 adult patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: analysis of the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) cohort. J Clin Endocrinol Metab. 2013; 98: E346–54. 3. Miller WL, White PC. A brief history of congenital adrenal hyperplasia. Horm Res Paediatr. 2022;95(6):529–545. 4. Gleeson H, Davis J, Jones J, O’Shea E, Clayton PE. The challenge of delivering endocrine care and successful transition to adult services in adolescents with congenital adrenal hyperplasia: experience in a single centre over 18 years. Clin Endocrinol (Oxf). 2013 Jan;78(1):23–8. 5. Ogilvy-Stuart AL, Brain CE. Early assessment of ambiguous genitalia. Arch Dis Child. 2004 May;89(5):401–7. 6. Ng JL, Lim EM, Zhang R, Beilby JP, Watts GF, Brown SJ, Stuckey BGA. Serum 21-deoxycortisol for diagnosis of non-classic congenital adrenal hyperplasia in women with androgen excess. J Clin Endocrinol Metab. 2023 Jun 26:dgad377. 7. Tschaidse L, Reisch N, Arlt W, Brac de la Perriere A, Linden Hirschberg A, Juul A, Mallappa A, Merke DP, Newell-Price JDC, Perry CG, Prete A, Rees DA, Stikkelbroeck NMML, Touraine PA, Coope H, Porter J, Ross RJM, Quinkler M. Modified-release hydrocortisone is associated with lower plasma renin activity in patients with salt-wasting congenital adrenal hyperplasia. Eur J Endocrinol. 2023 Jan 10;188(1):lvac006.