Genotype-Specific Cortisol Reserve in a Cohort of Subjects With Nonclassic Congenital Adrenal Hyperplasia (NCCAH)

Author:

Koren Ilana12ORCID,Weintrob Naomi3,Kebesch Rebekka1,Majdoub Hussein1,Stein Nili4,Naor Shulamit5,Segev-Becker Anat36

Affiliation:

1. Pediatric Endocrinology Unit, Carmel Medical Center, Clalit Health Services , Haifa 3436212 , Israel

2. Faculty of Medicine, Technion-Israel Institute of Technology , Haifa 3200003 , Israel

3. Pediatric Endocrinology and Diabetes Unit, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center , Tel Aviv 6423906 , Israel

4. Statistics Unit, Carmel Medical Center, Clalit Health Services , Haifa 3436212 , Israel

5. Endocrine laboratory, Clalit Health Services , Haifa 3688847 , Israel

6. Faculty of Medicine, Tel Aviv University , Tel Aviv 6997801 , Israel

Abstract

Abstract Context Recent guidelines suggest that patients with nonclassic congenital adrenal hyperplasia (NCCAH) stop glucocorticoid therapy after achieving adult height. However, these guidelines do not differentiate between NCCAH genotype groups. Objective Compare ACTH-stimulated cortisol and 17-hydroxyprogesterone (17OHP) levels, and the rate of partial cortisol insufficiency in subjects with NCCAH carrying one mild and one severe (mild/severe) mutation vs subjects with biallelic mild (mild/mild) mutations. Methods Retrospective evaluation of the medical records of 122 patients who presented with postnatal virilization and were diagnosed with NCCAH. Patients underwent standard intravenous 0.25 mg/m2 ACTH stimulation testing. Those with stimulated 17OHP level ≥40 nmol/L were screened for the 9 most frequent CYP21A2 gene mutations followed by multiplex ligation-dependent probe amplification. A stimulated cortisol level below 500 nmol/L was defined as partial cortisol deficiency. Results Patients were subdivided into 3 genotype groups: 77 carried the mild/mild genotype, mainly homozygous for p.V281L mutation; 29 were compound heterozygous for mild/severe mutation, mainly p.V281L/p.I2Splice, and 16 were heterozygous for p.V281L, and were excluded from statistical evaluation. Stimulated cortisol levels were significantly lower in the mild/severe than in the mild/mild group (mean ± SD, 480 ± 90 vs 570 ± 125 nmol/L, P < .001). The mild/severe group exhibited a significantly higher rate of partial cortisol insufficiency (21/28, 75% vs 28/71, 39%, P = .004). Peak 17OHP was significantly higher in the mild/severe group (198 ± 92 vs 118 ± 50 nmol/L, P < .001). Conclusion The high rate of partial adrenal insufficiency in the mild/severe group underscores the need to carefully consider the value of glucocorticoid therapy cessation and the importance of stress coverage in this group.

Publisher

The Endocrine Society

Subject

Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

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