CAH is a genetic disorder, which means it's inherited from parents and is present at birth. Arch Sex Behav. Congenital adrenal hyperplasia (CAH) refers to a group of genetic disorders that affect the adrenal glands, a pair of walnut-sized organs above the kidneys. Diaz A, Laufer MR Breech LLAA of PC on A, Care AC of O and GC on AH. Performance enhancement in the measurement of 5 endogenous steroids by LC-MS/MS combined with differential ion mobility spectrometry. Treatment should be initiated not only to address the main cause of the patient's visit but additionally to decrease abnormally elevated hormone concentrations. For example, in a series from Moran et al., among NCCAH women aged 10 to 19 years, oligomenorrhea was present in 56% of the cases in comparison to only 9% of adolescence with primary amenorrhea (12). CAH may sometimes be called 21-hydroxylase deficiency. Some people with nonclassic CAH never have symptoms. Is basal serum 17-OH progesterone a reliable parameter to predict nonclassical congenital adrenal hyperplasia in premature adrenarche? Very low levels of cortisol in the blood can cause diarrhea, vomiting, dehydration, low blood sugar levels, seizures and shock. Therefore, hydrocortisone should be considered the best form of treatment in cases of GC supplementation therapy. For affected adolescent and adult women, it is crucial to investigate any suspicion of NCCAH and determine a firm and accurate diagnosis. In most cases occurring under 8 years of age, the first symptom is premature pubarche. have pointed out, if the sum of basal and post-stimulation 17 OHP values exceeds 1.5 nmol/L, then the possibility of heterozygosity is exceptionally high (20). Kazmi D, Bailey J, Yau M, Abu-Amer W, Kumar A, Low M, et al. J Clin Endocrinol Metab. Excess androgen. doi: 10.1159/000369901, 26. Pediatr Endocrinol Rev. Simpson JL, et al. It is therefore crucial to educate the parents of young children, as well as to re-educate patients on their transition to adult care, about stress dosing. If OCPs fail as the first line approach, antiandrogens (spironolactone, flutamide, bicalutamide, cyproterone acetate, and finasteride) may be added to the treatment. Meanwhile, data regarding fertility in women with NCCAH have recently been assessed in detail and the estimated infertility incidence is 11% among NCCAH women, that is, relatively milder than in CAH, and in many cases is easily resolved. Merc Fernndez-Balsells M, Muthusamy K, Smushkin G, Lampropulos JF, Elamin MB, Abu Elnour NO, et al. Hoepffner W, Kaufhold A, Willgerodt H, Keller E. Patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency can achieve their target height: the Leipzig experience. Of note, the screening and diagnostic thresholds for LC-MS/MS quantified 17 OHP are yet to be defined. (2005) 90:331825. Female infants may have atypical genitalia appearance, such as an enlarged clitoris that may resemble a penis, and a partially closed labia resembling a scrotum. Glucocorticoid treatment regimen and health outcomes in adults with congenital adrenal hyperplasia. The nonclassic form of CAH doesn't cause adrenal crisis. In our group of 161 women with the disease 63% of the patient presented with a polycystic ovary-like phenotype (14). 18. (1994) 78:2416. https://www.nichd.nih.gov/health/topics/cah. doi: 10.1210/jcem-63-2-418. doi: 10.1210/jc.2005-1457, 36. Accessed Dec. 8, 2021. As a result, genetic testing of the partners of these women is essential to assess the risk of giving birth to a child with the classical form of CAH (64, 67). Livadas S, Dracopoulou M, Dastamani A, Sertedaki A, Maniati-Christidi M, Magiakou A-M, et al. (2009) 5:4908. According to other studies, a baseline value of 17 OHP between 5.1 and 9 nmol/L is sufficient for the diagnosis of NCCAH (13, 16, 17). Arch Sex Behav. The imbalance of hormones the body needs to function may mean too little cortisol, too little aldosterone, excess androgens or a combination of these imbalances. Ambroziak U, Kepczynska-Nyk A, Kuryowicz A, Wysouch-Cieszynska A, Maunowicz EM, Bartoszewicz Z, et al. The preferred GC treatment in children is usually hydrocortisone 1015 mg/m2, divided into three doses. (2005) 63:2704. (2001) 86:20713. Known gene abnormalities include insertions, deletions, missense/nonsense codons, and point mutations. Furthermore, in some cases, elevated androgen concentrations may lead to secondary stimulation of the GnRH axis, leading to premature puberty. doi: 10.1210/jc.2009-1383. Received: 09 January 2019; Accepted: 22 May 2019; Published: 06 June 2019. Lteif AN (expert opinion). Accessed Dec. 8, 2021. As far as the cortisol levels are concerned, generally a post-stimulation value of atleast 496 nmol/L is expected. 10:366. doi: 10.3389/fendo.2019.00366. Signs and symptoms of CAH vary, depending on which gene is affected and the level of enzyme deficiency. Horm Metab Res. Miller WL, Witchel SF. MICHAEL A. DEATON, PH.D., M.D., JOHN E. GLORIOSO, M.D., AND DAVID B. MCLEAN, M.D. Of course, this frequency depends on the reference population, a higher incidence occurring in populations with high intermarriage rates (36). J Clin Endocrinol Metab. Int J Pediatr Endocrinol. Clin Endocrinol. Besides, we should keep in mind that since the same patient will have changing requirements through the years, the attending physician should undertake a tailor-made approach in order to cover her specific needs at different stages of life. However, in our data derived from 280 subjects with the disease, six patients (2.1%) had a baseline 17 OHP value < 6 nmol/L (14). Clin Endocrinol (Oxf). These disorders are usually passed on by two carriers. (2010) 49:1395400. Mild congenital adrenal hyperplasia, however, is common, affecting one in 100 to 1,000 persons in the United States and frequently eluding diagnosis. (2018) 39:522. DHEAS values are decreased with very small doses, whereas the suppression of 17 OHP and progesterone levels requires very high GC doses. However, it should be noted that carrier status is 215% in different populations and half of these individuals carry a severe mutation. Even mild congenital adrenal hyperplasia can result in life-threatening sinus or pulmonary infections, orthostatic syncope, shortened stature and severe acne. Bonfig W, Bechtold S, Schmidt H, Knorr D, Schwarz HP. doi: 10.1016/j.ymgme.2006.12.005, 7. (2006) 118:224550. Treatment should be initiated immediately on confirmation of pregnancy.4,10 Dexamethasone readily crosses the placenta and suppresses the fetal adrenal gland. (1984) 63:44551. The progressive nature of the disease is highlighted by the fact that the prevalence of hirsutism has been shown to increase with age and has been observed to be rare before puberty. Merke DP, Poppas DP. During major life-threatening stress, surgery, or serious illness, patients with NCCAH who are glucocorticoid-treated may require larger or more frequent doses of glucocorticoids given that their adrenal function is iatrogenically suppressed. 5. found a lower than average Prader score in fetuses treated with dexamethasone prenatally, but no difference in long-term outcomes (72). Factors that increase the risk of having CAH include: People who have classic CAH are at risk of adrenal crisis. (1995) 80:23229. It is therefore advisable to consider CAH as a continuum of phenotypes, from severe to mild or else asymptomatic (3). Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, et al. (2013) 78:74750. Prenatal dexamethasone use for the prevention of virilization in pregnancies at risk for classical congenital adrenal hyperplasia because of 21-hydroxylase (CYP21A2) deficiency: a systematic review and meta-analyses. This is a life-threatening medical emergency that requires immediate treatment. Best Pract Res Clin Endocrinol Metab. (2015) 2015:296924. doi: 10.1155/2015/296924, 67. Arlt W, Willis DS, Wild SH, Krone N, Doherty EJ, Hahner S, et al. Int J Pediatr Endocrinol. (2018) 103:404388. Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. If the prospective father carry a NC mutation, then nothing else is needed. Further, in the case of discontinuation, patients should be informed about the possibility of infertility and should be encouraged to seek medical advice if they wish to conceive (19). Clin Endocrinol. They must also know that the probability that their child will suffer from the classical form of the disease is high, despite treatment. Witchel SF, Azziz R. Nonclassic congenital adrenal hyperplasia. New MI, Abraham M, Yuen T, Lekarev O. These women may also be hirsute and frequently present with oligomenorrhea, infertility or polycystic ovary syndrome.17. Specifically, a complete steroid profile should be performed in equivocal cases to confirm 21-hydroxylase deficiency and exclude other enzymatic detects. However, most women with NCCAH seek medical assistance when they experience symptoms of androgen excess and, when clinical suspicion prompts testing, elevated basal 17 OHP levels will more likely than not point to a diagnosis of NCCAH. The birth rate has been estimated at 17% in comparison to 65% of the control population (62). The combination of hyperandrogenic signs, menstrual disorders, and poor quality of life is well documented and it is particularly high in younger women. Gn EN, Ozn ZA, Alikaifoglu A, Engiz O, Bulum B, Kandemir N. (2011). Excess androgen hormones in females may result in facial hair, excessive body hair and a deepening voice. Drr HG. Moreover, specialists in fields involved in the treatment of this disorder, such as dermatologists, gynecologists, and psychologists, need in-depth understanding about the management of suspicious or already diagnosed cases of NCCAH. "Mayo," "Mayo Clinic," "MayoClinic.org," "Mayo Clinic Healthy Living," and the triple-shield Mayo Clinic logo are trademarks of Mayo Foundation for Medical Education and Research. Saygili F, Oge A, Yilmaz C. Hyperinsulinemia and insulin insensitivity in women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency: the relationship between serum leptin levels and chronic hyperinsulinemia. Some people with mild congenital adrenal hyperplasia can mount limited glucocorticoid stress responses and are thus never recognized as having the disorder. Cosmetic approaches such as laser application and depilatories can also be suggested for women complaining of excessive or unwanted hair growth or scalp hair loss (androgenic alopecia) (32, 34, 57). Kohn B, Levine LS, Pollack MS, Pang S, Lorenzen F, Levy D, et al. doi: 10.1210/jcem.86.1.7131, 68. The net result is increased production from the adrenal gland of cortisol precursors and androgens. On the other hand, an analysis of 45 males with NCCAH identified PP in only 29% of subjects (14). doi: 10.1210/jc.2006-2109, 49. Non-classical congenital adrenal hyperplasia (NCCAH) is considered to be a common monogenic inherited disease, with an incidence range from 1:500 to 1:100 births worldwide. In the young female, 2 years post menarche and if normal ovulatory cycles have been recorded, a patient-centered approach toward the hyperandrogenic symptoms that may appear is highly recommended. (2009) 10:7782. J Clin Endocrinol Metab. On the other hand, in cases where severe hirsutism and/or acne are present, prescription of oral contraceptives and/or antiandrogens may be advisable. The outcome of the pregnancy may even be successful without any glucocorticoid treatment in cases where NCCAH was not yet diagnosed, as also reported in a case report by Cuhaci et al. (2014) 9:e93805. If this procedure is widely implemented in clinical practice, unnecessary prenatal dexamethasone treatment will be avoided (73). Dewailly D, Vantyghem-Haudiquet MC, Sainsard C, Buvat J, Cappoen JP, Ardaens K, et al. https://www.uptodate.com/contents/search. Indeed, many false positive 17 OHP measurements were found when LC-MS/Ms measurements were compared with standard methods (21) Nevertheless, the latter procedures are not universally used, in the event of an uncertain diagnosis, they will provide more precise results. Regular growth pattern, a bone age compatible to chronological age, and absence of central obesity may also serve as clinical indices for appropriate management. Br J Dermatol. Classical congenital adrenal hyperplasia is rare, affecting only one in 14,000 patients, but mild forms of the disease may occur in one of every 100 to 1,000 persons.1,2 The condition is caused by a deficient synthesis of cortisol; most cases are related to 21-hydroxylase or 11- hydroxylase deficiency35 (Figure 1). Signs and symptoms of classic CAH may include: Atypical genitalia. Mayo Clinic. In our experience, the administration of bicalutamide has achieved significant improvement in cases of severe acne, but similar results were not obtained in cases with severe hirsutism. suggest that most but not all of the phenotypic variability in 21-hydroxylase deficiency results from allelic variation in CYP21A2 (26). White PC. Available studies indicate that adult height approached the expected target height in patients that were closely monitored and who strictly complied with medication plans (4850). Speiser PW, Serrat J, New MI, Gertner JM. Cortisol may be the only hormone that's deficient. For those women with symptomatic hyperandrogenism or with reported infertility but who wish to conceive, GC therapy is highly recommended. However, due to the perplexity of the disease and its multifaceted nature, there are no specific guidelines for the timing of regimen changes or cessation of glucocorticoid therapy in children. 54. Those who survive to adulthood experience premature puberty. The aim of prenatal treatment of CAH is the prevention of genital virilization of the fetus, but also alleviation of the stress felt by the parents who are likely to have a child with ambiguous genitalia (70). Working in this direction, novel studies point to the use of cell-free fetal DNA obtained from maternal plasma as a promising method that will allow the determination of fetal gender and the diagnosis of CAH at an early gestational age (<9 weeks). Falhammar H, Nordenstrm A. Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency: clinical presentation, diagnosis, treatment, and outcome. 2021; doi:10.1016/j.ecl.2020.10.008. doi: 10.1530/eje.0.1360188, 48. This content does not have an Arabic version. In borderline cases, it is advisable to obtain a complete adrenocortical profile after the ACTH stimulation test to differentiate 21-hydroxylase deficiency from other enzyme defects and establish a firm diagnosis. J Clin Endocrinol Metab. Planning of suggested procedures during pregnancy based on prospective parents genotype. Additionally, the administration of 2.57.5 mg of prednisolone, a dose considered as normal, exerts a longstanding negative impact on bone metabolism (45). Congenital adrenal hyperplasia in adults: a review of medical, surgical and psychological issues. Turk J Pediatr. doi: 10.1210/jcem-55-5-817, 12. It is reported that the first clinical presentation of NCCAH is in 11% of cases before the age of 10 years and in 80% between the ages of 10 and 40 years (12). Additionally, in a review by Merce Fernandez-Balsells et al., dexamethasone was shown to be associated with reduction in fetus virilization without significant maternal or fetal adverse effects (63). New developments in prenatal diagnosis of congenital adrenal hyperplasia. Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. Likewise, the incidence in France and Switzerland ranges between 1:15,472 and 1:23,000 and 1:10,749 and 1:11,661 when the different methods of screening are used (4). In ovarian ultrasound, 77% of them displayed polycystic ovaries and 41% increased ovarian size. (2004) 33:97104. A single copy of these materials may be reprinted for noncommercial personal use only. Azziz R, Hincapie LA, Knochenhauer ES, Dewailly D, Fox L, Boots LR. Levin JH, Carmina E, Lobo RA. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an endocrine society clinical practice guideline. Furthermore, women with NCCAH commonly experience subfertility, therefore, there will be analysis of the appropriate approach for these patients, including during pregnancy, based mainly on genotype. By contrast, in the event that the prospective mother is a compound heterozygote with one severe (C) and one NC mutation, then genetic testing of the future father is mandatory. This site complies with the HONcode standard for trustworthy health information: verify here. Simultaneous measurement of thirteen steroid hormones in women with polycystic ovary syndrome and control women using liquid chromatography-tandem mass spectrometry. Diagnosis of congenital adrenal hyerplasia in fetuses that are at risk for congenital adrenal hyperplasia can be determined using human leukocyte antigen haplotype or by demonstration of excess cortisol precursors in amniotic fluid. This content is owned by the AAFP. In comparison to the diagnosis of the classical form of the disease, which is made at birth or during the neonatal period because of genital ambiguity and/or salt-wasting symptoms or through screening programs employed in some countries most cases of NCCAH are not easily detectable (4, 10). Consultation with an endocrinologist is recommended for patients who require complex hormone regimens. have in several studies reported impaired psychological profile among patients with NCCAH due to 21OH deficiency. Endocrinol Metab Clin North Am. Women with mild congenital adrenal hyperplasia often present with hirsutism, oligomenorrhea or infertility. One may suggest the use of a Synacthen test, and if it is not compatible with heterozygosity (sum of basal and peak stimulated 17 OHP values < 1.5 nmol/L), then DNA testing could be avoided. J Bone Miner Res. Pediatrics. Finally, the fact that there is no consensus as to which GC should be used and the absence of long-term data regarding different modalities of GC administration further complicate attending physicians' decisions on and selection of the optimal choice for each patient. doi: 10.1172/JCI115897, 27. doi: 10.1159/000110587, 50. Most importantly, it should be clarified to parents that dexamethasone administration does not modify patient status but is directed toward reducing the need for surgery rather than preserving life or intellectual capacity. The disorder usually manifests in childhood. Heterozygotes carrying one CYP21A2 mutation exhibit slightly elevated 17 OHP levels post ACTH stimulation, though there is overlap in unaffected subjects (9). This content does not have an English version. This time interval suggests that all pregnancies at risk for virilizing CAH should be treated, even though only 1 out of 8 fetuses is affected and female (19, 34, 70). (2010) 73:43644. Mild congenital adrenal hyperplasia due to 11- hydroxylase deficiency is more common, however, and may be responsible for 1 to 2 percent of cases of hirsutism and oligomenorrhea in women.35, The classic form of congenital adrenal hyperplasia occurs when cortisol synthesis is extremely low. doi: 10.1210/jc.2010-0917, 42. Congenital adrenal hyperplasia is diagnosed by demonstration of excess cortisol precursors in the serum during an adrenal corticotropic hormone challenge.