SAT-277 Re-Evaluation of the 17-Hydroxyprogesterone (17-OHP) Screening Threshold for Diagnosing Nonclassic Congenital Adrenal Hyperplasia (NCCAH) in the Era of Liquid Chromatography Tandem-Mass Spectrometry (LC-MS/MS)

Background: NCCAH is characterized by reduced 21-hydroxylase activity leading to elevations in adrenal androgens. It may be associated with an inadequate cortisol response to ACTH stimulation. Clinical diagnosis is problematic as signs and symptoms overlap with more common conditions such as premature adrenarche and polycystic ovarian syndrome. A screening 17-OHP >6 nmol/L (200 ng/dL) based on immunoassay prompts NCCAH diagnostic testing with an ACTH stimulation test. Peak 17-OHP <30 nmol/L (1000 ng/dL) post-ACTH excludes NCCAH. In 2011, we replaced immunoassay with LC-MS/MS for 17-OHP quantification which has greater specificity. A method comparison revealed a negative bias between LC-MS/MS and immunoassay measurements prompting us to evaluate the accuracy of the 17-OHP thresholds (1). Aims: To evaluate the 17-OHP thresholds that predict genetically-confirmed NCCAH. A secondary objective was to determine the prevalence of adrenal insufficiency (AI) in this population. Methods: A retrospective chart review was performed of clinical and genetic data for all patients <18 years who underwent ACTH stimulation tests with measurement of cortisol and 17-OHP from 2011 to 2018. NCCAH was genetically confirmed; other adrenal pathologies were excluded. AI was defined as peak cortisol < 500 nmol/L (18 µg/dL), measured by immunoassay. Using correlation data between immunoassay and LC-MS/MS, a new 17OHP threshold of 3.3 nmol/L (110 ng/dL) was calculated for the LC-MS/MS method and was considered equivalent to 6 nmol/L by immunoassay; similarly, 20 nmol/L (666 ng/dL) was considered equivalent to 30 nmol/L (1). Results: 188 patients met inclusion criteria. 23 (12%) had NCCAH of which 21/23 had genetic confirmation; the remaining 2 had peak 17-OHP >30 nmol/L by LC-MS/MS. Baseline 17-OHP > 6 nmol/L most accurately diagnosed NCCAH (sensitivity and specificity 96%) with no improvement using 17-OHP >3.3 nmol/L. 20/21 genetically confirmed NCCAH had peak 17-OHP >30 nmol/L. Of three with 17-OHP peak 20-30 nmol/L, one was a CAH carrier, one had other adrenal pathology, and another with unknown diagnosis. 87% with NCCAH had biochemical AI. Baseline 17-OHP >6 nmol/L predicted all with AI. Conclusion: Despite increased specificity of LC-MS/MS for steroid measurements, a baseline 17-OHP >6 nmol/L remained the most accurate predictor of NCCAH. This threshold also predicts all with AI, notably prevalent in our cohort. Analysis is limited by a small cohort, low NCCAH incidence and lack of genetic data in those presumed without NCCAH. However, this re-evaluation of screening and diagnostic thresholds is important in the era of evolving assays and these results support current practice guidelines. Reference: 1. Kyriakopoulou L. et al. Clin Biochem. 2013;46:642-651