ESPE Yearbook of Paediatric Endocrinology

J Clin Endocrinol Metab. 2022; dgac271. PMID: 35512387 https://pubmed.ncbi.nlm.nih.gov/35512387/

Brief Summary: This study, in a series of independent patient cohorts, developed and validated a clinical score, based on the circulating concentrations of 13 major steroid hormones, to detect and subtype Congenital Adrenal Hyperplasia (CAH).

Steroidogenesis is a complex process that plays a pivotal role in numerous cellular/physiological functions (1). A total of 14 enzymes or cofactors are required for adrenal steroidogenesis, producing 16 major steroid metabolites (3). Genetic deficiencies in steroidogenesis enzymes impair glucocorticoid biosynthesis, and lead to Congenital Adrenal Hyperplasia (CAH), which includes 9 subtypes (2). CAH is one of the most common autosomal recessive disorders. The presentation of CAH is extremely variable, mostly owing to the complexity of the steroidogenesis pathway and the numerous disorder subtypes (1, 2). Each steroidogenesis enzyme or cofactor catalyzes multiple reactions. Individual subtypes may show overlapping presentations. Moreover, as mutant enzyme activity can be either mildly affected or completely inactivated, a continuum of disease phenotypes have been reported, from potentially life-threatening to infertility, and in some cases, individuals are completely asymptomatic (2).

The diagnosis of CAH often includes a tedious and uncertain workup. For the most common form of CAH, 21α-hydroxylase deficiency (21OHD), an ACTH stimulation test is usually required to confirm the diagnosis, especially for non-classic 21OHD (3, 4). Diagnostic criteria are lacking for other forms of CAH, such as 17α-hydroxylase/17,20-lyase deficiency (17OHD) and 11β-hydroxylase deficiency (11βOHD), even when genetic data are available, and no guidelines or consensus statements have been published. These challenges may result in misdiagnosis or delayed diagnosis of CAH. Profiling of multiple steroids by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in patients with steroid-hormone disorders has revealed distinctive steroid patterns associated with these disorders (4-6).

These authors describe a multi-classifier system to diagnose CAH by measuring a panel of 13 steroid hormone levels by LC-MS/MS in a single baseline blood sample. A cascade logistic regression model was performed to generate the "Steroidogenesis Score" to distinguish the three most common CAH subtypes 11βOHD, 17OHD and 21OHD in a discovery cohort (N=226). This was then validated in an independent cohort (N=111) and finally applied in a prospective cohort of 256 patients, where the Steroidogenesis Score showed high diagnostic accuracy: 11βOHD (AUC, 0.994), 17OHD (AUC, 0.993) and 21OHD (AUC, 0.979). For patients with non-classic 21OHD, the system had higher sensitivity than basal 17α-hydroxyprogesterone (17OHP) (AUC, 0.973 vs 0.840, p=0.005) and was non-inferior to basal and ACTH-stimulated 17OHP (AUC, 0.973 vs 0.947, p=0.681).

In summary, this biochemically steroidogenesis score showed high diagnostic accuracy, and will be especially useful for patients with the non-classic form of the disease. The test is easily conducted with a single blood draw. The use of data-learning approaches, such as the steroidogenesis score, may greatly increase the diagnostic accuracy and efficiency for this rare disease and possibly others.

References: 1. Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011; 32(1): 81–151. 2. Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, Arlt W, Auchus RJ, Falhammar H, Flück CE, Guasti L, Huebner A, Kortmann BBM, Krone N, Merke DP, Miller WL, Nordenström A, Reisch N, Sandberg DE, Stikkelbroeck NMML, Touraine P, Utari A, Wudy SA, White PC. Congenital Adrenal Hyperplasia-Current Insights in Pathophysiology, Diagnostics, and Management. Endocr Rev. 2022; 43(1): 91–159. 3. Speiser PW, Arlt W, Auchus RJ, et al. Congenital adrenal hyper- plasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018; 103(11): 4043–4088. 4. Rauh M. Steroid measurement with LC-MS/MS in pediatric endocrinology. Mol Cell Endocrinol. 2009; 301(1–2): 272–281. 5. Bancos I, Taylor AE, Chortis V, et al. Urine steroid metabolomics for the differential diagnosis of adrenal incidentalomas in the EURINE-ACT study: a prospective test validation study. Lancet Diabetes Endocrinol. 2020; 8(9): 773–781. 6. 24. Chortis V, Bancos I, Nijman T, et al. Urine steroid metabolomics as a novel tool for detection of recurrent adrenocortical carcinoma. J Clin Endocrinol Metab. 2020; 105(3): 307–e318.