Non-classical Congenital Hyperplasia Research Articles

Differences in hormonal levels between heterozygous CYP21A2 pathogenic variant carriers, non-carriers, and females with non-classic congenital hyperplasia.

CYP21A2 mutation heterozygote carriers seem to have an increased risk of hyperandrogenism. However, the clinical relevance of the heterozygote carrier status and the reliability of hormonal testing in discriminating a carrier from a non-carrier are puzzling questions. We aimed to characterize a population of Portuguese females suspected of having non-classic congenital adrenal hyperplasia (NC-CAH) due to clinical and biochemical criteria and who have undergone CYP21A2 molecular analysis. Retrospectively, we have analyzed the clinical records of 131 females (32 girls aged 3-9 and 99 adolescents and premenopausal women aged 13-49) who underwent complete CYP21A2 molecular analysis due to suspicion of NC-CAH. We divided included participants into three groups according to the CYP21A2 molecular analysis: NC-CAH females (46), heterozygous carriers (49), and wild type (36). We then compared clinical signs and symptoms as well as biochemical and molecular data between carriers and NC-CAH individuals and between carriers and wild type females. We measured 17OHP by electrochemiluminescence immunoassay. Clinical features were similar between groups. Heterozygous carriers presented higher basal and post-cosyntropin 17-hydroxyprogesterone (17OHP) than wild type individuals (p < 0.05) and lower basal and stimulated 17OHP levels than NC-CAH patients (p < 0.05). We discovered a considerable overlap between 17OHP levels among groups. The most common pathogenic variant we identified was p.Val282Leu. In this population of hyperandrogenic women and children, heterozygous carriers showed higher basal and stimulated 17OHP than non-carriers although normal basal and stimulated 17OHP responses do not exclude heterozygosity for CYP21A2 pathogenic variants. In this study, only the molecular analysis presented good sensitivity in identifying heterozygotes.

SAT-210 When Acne, Hirsutism and Menstrual Irregularities Are More Than PCOS

Background: Polycystic ovarian syndrome (PCOS) mimics non-classic congenital hyperplasia (NCCAH), presenting with hyperandrogenic symptoms. NCCAH is usually diagnosed later in life, where 21-hydroxylase (21OHD) is the most common deficiency. There are more than 300 mutations in 21OHD, being V281L one of the described mutations. Clinical Case: 23 y/o female patient G0P0 comes to the office complaining of irregular periods, frontal hair loss, weight gain, acne and hirsutism. She has had noticed these changes since menarche; however, her acne was getting worse. Was seen 2 months prior to presentation by her gynecologist who order a free Testosterone that was elevated (6.4 pg/mL, n<4.2 pg/mL), with normal TSH (1.1 uIU/mL, n,0.45-4.5). She was not taking any medication. Her mother has history of 2 spontaneous abortions and her sister has acne and hirsutism as well. On physical exam BMI was 26, it was noticed comedones and papules on her face, back and shoulders. Ferriman-Gallwey scale was >8. At the initial visit due to the clinical scenario, it was thought that she had hyperandrogenic syndrome, probably secondary to PCOS. Serum blood test were ordered and showed an elevated total testosterone (71 ng/dL, n,8-48ng/dL), free testosterone (8.4 pg/mL, n<4.2 pg/mL), 17- OH pregnenolone performed by liquid chromatography-tendem mass spectrometry (LC-MS/MS) was (429 ng/dL, n, 35-290 ng/dL luteal phase) and androstenedione LC-MS/MS (1941 ng/dL, n, 41-262 ng/dL) which confirmed NCCAH diagnosis due to 21OHD. She had no desire to become pregnant at the time of evaluation; however, was concern about fertility and genetics. Was started on OCPs and genetic testing was positive for V281L mutation in the CYP21A2 gene, being homozygous for this mutation. Three months after, her acne and frontal hair loss were better, and a trial of spironolactone 50 mg daily, was prescribed. For her sister and mother was suggested to consult endocrinology, due to possible same disease. Conclusion: this case highlights the importance of recognizing NCCAH as a cause of hyperandrogenism. Molecular genetic analysis should be offered with genetic counseling to patients, since they can carry a severe allele which can affect their progeny. Clinicians should be aware of the importance of family history when diagnosing NCCAH on their patients; for detection, treatment and genetic counseling of NCCAH on family members as well, as found in this case.

Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women.

Non-classic congenital hyperplasia (NCAH) due to 21-hydroxylase deficiency is a common autosomal recessive disorder characterized by androgen excess. We conducted a systematic review and critical assessment of the available evidence pertaining to the epidemiology, pathophysiology, diagnosis and management of NCAH. A meta-analysis of epidemiological data was also performed. Peer-reviewed studies evaluating NCAH published up to October 2016 were reviewed. Multiple databases were searched including MEDLINE, EMBASE, Cochrane, ERIC, EBSCO, dissertation abstracts, and current contents. The worldwide prevalence of NCAH amongst women presenting with signs and symptoms of androgen excess is 4.2% (95% confidence interval: 3.2-5.4%). The clinical consequences of NCAH expand from infancy, i.e. accelerated growth, to adolescence and adulthood, i.e. premature pubarche, cutaneous symptoms and oligo-ovulation in a polycystic ovary syndrome (PCOS)-like clinical picture. The diagnosis of NCAH relies on serum 17-hydroxyprogesterone (17-OHP) concentrations. A basal 17-OHP concentration ≥2 ng/ml (6 nmol/l) should be used for screening if more appropriate in-house cut-off values are not available. Definitive diagnosis requires a 17-OHP concentration ≥10 ng/ml (30 nmol/l), either basally or after cosyntropin-stimulation. Molecular genetic analysis of the CYP21A2 gene, which is responsible for 21-hydroxylase activity, may be used for confirmation purposes and should be offered to all patients with NCAH along with genetic counseling because these patients frequently carry alleles that may result in classic CAH, the more severe form of the disease, in their progeny. Treatment must be individualized. Glucocorticoid replacement therapy may benefit pediatric patients with accelerated growth or advanced bone age or adult women seeking fertility, whereas adequate control of menstrual irregularity, hirsutism and other cutaneous symptoms is best served by the use of oral contraceptive pills and/or anti-androgens. Some women may need ovulation induction or assisted reproductive technology to achieve pregnancy. Patients with NCAH have a higher risk of miscarriage and may benefit from glucocorticoid treatment during pregnancy. Evidence-based diagnostic and treatment strategies are essential for the proper management of women with NCAH, especially considering that these patients may need different therapeutic strategies at different stages during their follow-up and that appropriate genetic counseling may prevent the occurrence of CAH in their children.

Routine screening for Cushing's syndrome is not required in patients presenting with hirsutism

Prevalence of Cushing's syndrome (CS) in patients presenting with hirsutism is not well known. Screening of CS in patients with hirsutism. Referral hospital. This study was carried out on 105 patients who were admitted to the Endocrinology Department with the complaint of hirsutism. All the patients were evaluated with low-dose dexamethasone suppression test (LDDST) for CS. Response to LDDST in patients presenting with hirsutism. All the patients had suppressed cortisol levels following low-dose dexamethasone administration excluding CS. The etiology of hirsutism was polycystic ovary syndrome in 79%, idiopathic hirsutism in 13%, idiopathic hyperandrogenemia in 6%, and nonclassical congenital hyperplasia in 2% of the patients. Routine screening for CS in patients with a referral diagnosis of hirsutism is not required. For the time being, diagnostic tests for CS in hirsute patients should be limited to patients who have accompanying clinical stigmata of hypercortisolism.