Common Genetic Variants of the Human Steroid 21-Hydroxylase Gene (CYP21A2) Are Related to Differences in Circulating Hormone Levels

Doleschall, Márton; Szabó, J.; Pázmándi, Júlia; Szilágyi, Ágnes; Klara, Koncz; Farkas, Henriette; Tóth, Miklós; Igaz, Péter; Gláz, Edit; Prohászka, Zoltán; Korbonits, Márta; Rácz, Kàroly; Füst, George; Patócs, Attila

doi:10.1371/journal.pone.0107244

Cited by 12 publications

(12 citation statements)

References 43 publications

(67 reference statements)

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“…Although 21-DF is a known marker of 21-hydroxilase deficiency, in our SH patients several aspects, such as low ACTH, increased basal and stimulated F, and 17-OHP values comparable with NS adenomas, argue against this possibility. Our results are in contrast with previous studies highlighting some degrees of dysregulation of CYP21 in adrenocortical adenomas (37,38). The main reason for this difference relies on the different methods of 17-OHP determination, which are not comparable with our highly accurate LC-MS/MS.…”

Section: Discussioncontrasting

confidence: 99%

Steroid Profiling by LC-MS/MS in Nonsecreting and Subclinical Cortisol-Secreting Adrenocortical Adenomas

Dalmazi¹,

Fanelli²,

Mezzullo³

et al. 2015

The Journal of Clinical Endocrinology & Metabolism

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Context: Long-term follow-up studies revealed that patients with subclinical hypercortisolism (SH) due to adrenocortical adenomas have an increased incidence of cardiovascular diseases and mortality. No studies have yet investigated the steroid profile and its implications in patients with SH.Objective: The objective of the study was to analyze the steroid profile by liquid chromatographytandem mass spectrometry in sera from patients with unilateral adrenocortical adenomas.Design: This was a cross-sectional study. Setting:The study was conducted at an outpatient clinic. Participants:Patients with adrenocortical adenomas (nonsecreting, n ϭ 66; SH, n ϭ 28) and 188 ageand sex-matched controls drawn from the general population participated in the study. Main Outcome Measures:Cortisol, 21-deoxycortisol, 11-deoxycortisol, 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, T, progesterone, 11-deoxycorticosterone, and corticosterone in the basal condition and after a 1-24 ACTH test, and clinical data were measured. Results:Patients with SH showed lower basal and 1-24 ACTH-stimulated levels of dehydroepiandrosterone and androstenedione than those with nonsecreting adenomas and controls. T was also lower in SH females. Receiver-operating characteristic curves showed that androgens had good accuracy in predicting SH (sensitivity and specificity were 71% and 76% for dehydroepiandrosterone and 69% and 61% for androstenedione, respectively). Increased cortisol and reduced dehydroepiandrosterone levels were independently associated with increased waist circumference. Cortisol was also independently associated with increased number of cardiovascular risk factors in SH patients. After 1-24 ACTH stimulation, the SH patients also showed increased production of 21-deoxycortisol and 11-deoxycorticosterone. Conclusions:Liquid chromatography-tandem mass spectrometry steroid profile performed for the first time in sera from patients with adrenocortical adenomas showed impaired secretion of several steroids in SH patients. This fingerprint can help in better characterizing the functional status of these tumors. (J Clin Endocrinol Metab 100: 3529 -3538, 2015)

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Section: Discussioncontrasting

confidence: 99%

Steroid Profiling by LC-MS/MS in Nonsecreting and Subclinical Cortisol-Secreting Adrenocortical Adenomas

Dalmazi¹,

Fanelli²,

Mezzullo³

et al. 2015

The Journal of Clinical Endocrinology & Metabolism

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“…In fact, in studies of patients with uni-or bilateral adrenal adenomas, 16 % were CYP21A2 carriers and 2-6 % had undiagnosed CAH [179][180][181][182]. In contrast, others have only found 0.5 % of the patients with adrenal incidentalomas to be affected by CAH [183], and some have reported that their finding of 9.6 % CYP21A2 carriers with nonfunctioning adrenal incidentaloma was not different from that in healthy controls [184]. How frequently an adrenal incidentaloma presents symptoms of NCAH is unclear, but there are several reports of NCAH diagnoses as the result of the work-up of these tumors [24,29,[180][181][182]185].…”

Section: Adrenal Tumorsmentioning

confidence: 99%

Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency: clinical presentation, diagnosis, treatment, and outcome

2015

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Nonclassic congenital adrenal hyperplasia (NCAH) is one of the most frequent autosomal recessive disorders in man with a prevalence ranging from 0.1 % in Caucasians up to a few percent in certain ethnic groups. Most cases are never diagnosed due to very mild symptoms, misdiagnosing as polycystic ovary syndrome, or ignorance. In contrast to classic CAH, patients with NCAH present with mild partial cortisol insufficiency and hyperandrogenism and will survive without any treatment. Undiagnosed NCAH may result in infertility, miscarriages, oligomenorrhea, hirsutism, acne, premature pubarche, testicular adrenal rest tumors, adrenal tumors, and voice problems among other symptoms. A baseline measurement of 17-hydroxyprogesterone can be used for diagnosis, but the ACTH stimulation test with measurement of 17-hydroxyprogesterone is regarded as the golden standard. The diagnosis can be verified by CYP21A2 mutation analysis. Treatment is symptomatic and usually with glucocorticoids alone. The lowest possible glucocorticoid dose should be used. Long-term treatment with glucocorticoids will improve the symptoms but will also result in iatrogenic cortisol insufficiency and may also lead to long-term complications such as obesity, insulin resistance, hypertension, osteoporosis, and fractures. Although the complications seen in NCAH patients have been assumed to be related to the glucocorticoid treatment, some may, in fact, be associated with prolonged hyperandrogenism. Different risk factors and negative consequences should be monitored regularly in an attempt to improve the clinical outcome. More research is needed in this relatively common disorder.

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“…For the subjects with the c.955C4T variant, 96 healthy subjects (50% women) from a family study, 21 68 healthy subjects (65.2% women) and 125 patients (76.0% women) with NFAI from a recent study, 22 and 100 patients (58.0% women) with classical CAH due to 21-hydroxylase deficiency from the Second Department of Internal Medicine, Semmelweis University (Budapest, Hungary) and the Second Department of Pediatrics, Semmelweis University (Budapest, Hungary) were screened. In addition, one patient with supposed classical CAH was referred to us by the Department of Pediatrics, University of Pecs (Pecs, Hungary) for reexamination of the original genetic diagnosis.…”

Section: Subjects and Clinical Datamentioning

confidence: 99%

“…The exclusion criteria for NFAI patients were described recently. 22 The diagnosis was confirmed in all CAH patients by hormonal and genetic testing (except for the one who was reexamined) as described. 23,24 Furthermore, 34 adrenocortical tumor specimens of NFAI patients were obtained as described, 25 and screened for the c.955C4T variant.…”

Section: Subjects and Clinical Datamentioning

confidence: 99%

A unique haplotype of RCCX copy number variation: from the clinics of congenital adrenal hyperplasia to evolutionary genetics

et al. 2017

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There is a difficulty in the molecular diagnosis of congenital adrenal hyperplasia (CAH) due to the c.955C>T (p.(Q319*), formerly Q318X, rs7755898) variant of the CYP21A2 gene. Therefore, a systematic assessment of the genetic and evolutionary relationships between c.955C>T, CYP21A2 haplotypes and the RCCX copy number variation (CNV) structures, which harbor CYP21A2, was performed. In total, 389 unrelated Hungarian individuals with European ancestry (164 healthy subjects, 125 patients with non-functioning adrenal incidentaloma and 100 patients with classical CAH) as well as 34 adrenocortical tumor specimens were studied using a set of experimental and bioinformatic methods. A unique, moderately frequent (2%) haplotypic RCCX CNV structure with three repeated segments, abbreviated to LBSASB, harboring a CYP21A2 with a c.955C>T variant in the 3'-segment, and a second CYP21A2 with a specific c.*12C>T (rs150697472) variant in the middle segment occurred in all c.955C>T carriers with normal steroid levels. The second CYP21A2 was free of CAH-causing mutations and produced mRNA in the adrenal gland, confirming its functionality and ability to rescue the carriers from CAH. Neither LBSASB nor c.*12C>T occurred in classical CAH patients. However, CAH-causing CYP21A2 haplotypes with c.955C>T could be derived from the 3'-segment of LBSASB after the loss of functional CYP21A2 from the middle segment. The c.*12C>T indicated a functional CYP21A2 and could distinguish between non-pathogenic and pathogenic genomic contexts of the c.955C>T variant in the studied European population. Therefore, c.*12C>T may be suitable as a marker to avoid this genetic confound and improve the diagnosis of CAH.

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Common Genetic Variants of the Human Steroid 21-Hydroxylase Gene (CYP21A2) Are Related to Differences in Circulating Hormone Levels

Cited by 12 publications

References 43 publications

Steroid Profiling by LC-MS/MS in Nonsecreting and Subclinical Cortisol-Secreting Adrenocortical Adenomas

Steroid Profiling by LC-MS/MS in Nonsecreting and Subclinical Cortisol-Secreting Adrenocortical Adenomas

Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency: clinical presentation, diagnosis, treatment, and outcome

A unique haplotype of RCCX copy number variation: from the clinics of congenital adrenal hyperplasia to evolutionary genetics

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