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Hindawi Publishing CorporationInternational Journal of Pediatric EndocrinologyVolume 2010, Article ID 625105, 11 pagesdoi:10.1155/2010/625105Review ArticleNonclassic Congenital Adrenal HyperplasiaSelma Feldman Witchel1 and Ricardo Azziz2, 31 Division of Pediatric Endocrinology, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine,Pittsburgh, PA 15224, USA2 Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA3 Department of Obstetrics and Gynecology, and Medicine, The David Geffen School of Medicine at UCLA,Los Angeles, CA 90095, USACorrespondence should be addressed to Selma Feldman Witchel, selma.witchel@chp.eduReceived 3 March 2010; Accepted 5 April 2010Academic Editor: Peter Allen LeeCopyright © 2010 S. F. Witchel and R. Azziz. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.Nonclassic congenital adrenal hyperplasia (NCAH) due to P450c21 (21-hydroxylase deficiency) is a common autosomal recessivedisorder. This disorder is due to mutations in the CYP21A2 gene which is located at chromosome 6p21. The clinical featurespredominantly reflect androgen excess rather than adrenal insufficiency leading to an ascertainment bias favoring diagnosis infemales. Treatment goals include normal linear growth velocity and “on-time” puberty in affected children. For adolescent andadult women, treatment goals include regularization of menses, prevention of progression of hirsutism, and fertility. This paperwill review key aspects regarding pathophysiology, diagnosis, and treatment of NCAH.1. IntroductionNonclassic congenital adrenal hyperplasia (NCAH) due toP450c21 (21-hydroxylase) deficiency is a common autosomalrecessive disorder due to mutations in the CYP21A2 gene.This disorder was first described in 1957 by Decourt et al.[1]. Reported prevalences in women with androgen excessrange from 0.6% to 9% (Table 1). Higher prevalences havebeen reported in Ashkenazi Jewish, Mediterranean, Middle-Eastern and Indian populations. Reported gene frequenciesvary among ethnic groups and geographic region [2, 3].NCAH due to mutations in other steroidogenicenzyme genes, such as 11β-hydroxylase (CYP11B1) and3β-hydroxysteroid dehydrogenase (HSD3B2), is extremelyrare [4, 5]. The phenotypic spectrum for mutations in thecytochrome P450 oxidoreductase (POR) gene has beenexpanded to include amenorrhea, infertility, and low sexsteroid hormone levels [6]. Partial loss of function missensemutations in the steroidogenic acute regulatory protein(StAR) gene has been associated with nonclassic lipoidadrenal hyperplasia; mutations in the ACTH receptor(MC2R) gene or the melanocortin 2 receptor accessoryprotein (MRAP) gene are associated with phenotypes similarto nonclassic lipoid adrenal hyperplasia [7]. This review willfocus on NCAH due to CYP21A2 mutations.2. Molecular GeneticsTo date, 127 mutations have been reported in CYP21A2(http://www.hgmd.cf.ac.uk/); these mutations range fromcomplete loss of enzyme function to partial enzyme activity.Most of the mutations result from recombination betweenthe active gene, CYP21A2, and its highly homologous non-functional pseudogene, CYP21A1P (i.e., gene conversion),which is located in close proximity within the HLA regionon chromosome 6p21.3. Nevertheless, approximately 10–12 mutations account for the majority of the affectedalleles. The majority of the CYP21A2 mutations reportedto date are associated with simple virilizing or salt-wastingclassic congenital adrenal hyperplasia (CAH). Functionalstudies indicate that these mutations result in 0–5% residualenzymatic function [34].Functional analysis of mutations associated with NCAHgenerally indicates a 50–80% loss of enzymatic (21-hydroxylase) function. Individuals with NCAH are generally
Page 2 2International Journal of Pediatric EndocrinologyTable 1: Prevalence of NCAH due to 21-hydroxylase deficiency among hyperandrogenic women.CountryTotal # of Women# NCAH (%)CitationUSA (NE)22∗2 (9%)Emans et al., 1983 [8]USA (NE)1392 (1.4%)Cobin et al., 1985 [9]USA (NE)1644 (2.4%)Azziz and Zacur, 1989 [10]USA (SE)862 (2.3%)Azziz et al., 1993 [11]USA (SW)831 (1.2%)Chetkowski et al., 1984 [12]USA (SE)87318 (1.6%)Azziz et al., 2004 [13]Canada724 (5.5%)Innanen and Vale, 1990 [14]Puerto Rico1001 (1.0%)Romaguera et al., 2000 [15]Ireland966 (6.2%)McLaughlin et al., 1990 [16]England501 (2.0%)Turner et al., 1992 [17]France40024 (6.0%)Kuttenn et al., 1985 [18]France6916 (23%)Blanché et al., 1997 [19]Portugal12923 (17.8%)Pall et al., (in press) [20]Italy (South)37214 (4.0%)Carmina et al., 1987 [21]Italy (North)851 (1.1%)Motta et al., 1988 [22]Italy (Palermo)95041 (4.5%)Carmina et al., 2006 [23]Spain2706 (2.2%)Escobar-Morreale et al., 2008 [24]Czech Republic2988 (2.7%)Fanta et al., 2008 [25]Greece10710 (9.3%)Trakakis et al., 2008 [26]Turkey (Ankara)32∗1(3%)Akinci et al., 1992 [27]Turkey (Istanbul)6120 (33%)Yarman et al., 2004 [28]Turkey (Kayseri)2856 (2.1%)Unluhizarci et al., 2010 [29]Turkey (Central Anatolia)636 (9.5%)Kamel et al., 2003 [30]Israel17014 (8.2%)Eldar-Geva et al., 1990 [31]India603 (8.3%)Mithal et al., 1988 [32]India633 (5.7%)Khandekar et al., 1990 [33]∗adolescent girls.compound heterozygotes bearing different CYP21A2 muta-tions on each allele. The missense mutation, V281L, accountsfor at least one of the CYP21A2 alleles for most patientswith NCAH. This genetic variant is commonly identifiedamong Eastern Europeans especially those of AshkenaziJewish descent. Other missense mutations associated withNCAH include P30L, P453S, and R339H. Novel mutationsassociated with NCAH include R369W and I230T [35]. One-half to two-thirds of individuals with NCAH carry one alleleencoding for a severe defect in enzyme function (whichwould result in classic CAH if present on both alleles) andan allele encoding a mild defect in enzyme function on theother allele. Roughly, phenotype correlates with moleculargenotype and reflects the residual activity of the mildermutation [36–38]. Nevertheless, utilizing rigid criteria to dis-tinguish among salt wasting, simple virilizing and NCAH canbe problematic because impaired 21-hydroxylase functionrepresents a continuum of decreased enzyme activity.3. PathophysiologyIn broad terms, the virilizing forms (simple virilizing,salt-wasting, and nonclassic) of CAH are characterized bymutations that significantly impair cortisol biosynthesis andlead to the accumulation of steroid intermediates proximal tothe deficient enzyme. The resulting loss of cortisol negativefeedback inhibition leads to increased hypothalamic corti-cotrophin releasing hormone (CRH) and pituitary adreno-corticotrophic hormone (ACTH) secretion. With decreasedP450c21 activity, conversions of 17-hydroxyprogesterone(17-OHP) to 11-deoxycortisol, and progesterone (P4) todeoxycorticosterone, are impaired. Elevated 17-OHP, P4,and androstenedione concentrations are typically found.The excessive ACTH stimulation also results in fasciculata-reticularis zone hypertrophy, resulting in the adrenal hyper-plasia typical of the syndrome, and possibly increasedadrenocortical nodularity. Individuals with NCAH generallyhave adequate mineralocorticoid secretion.Unfortunately, the pathophysiology of NCAH (andCAH) is more complicated than this description wouldsuggest. For example, patients with NCAH usually have noevidence of ACTH or CRH excess. In fact, some have an over-responsive glucocorticoid response to ACTH stimulation,possibly reflective of subtle adrenal hyperplasia [39]. Anothermechanism resulting in excessive adrenal androgen secretionespecially in NCAH results from the alteration in enzymekinetics due to the CYP21A2 missense mutations [40]. Themutated enzyme protein is synthesized, but is less efficient
Page 3 International Journal of Pediatric Endocrinology3than the wild type. The net result is an increased precursorto product ratio, independent of ACTH levels. Hence, P4 and17-OHP levels in these patients may remain above normaleven in the presence of excessive glucocorticoid administra-tion [41]. In addition, genetic variations at other loci mayinfluence steroid metabolism and steroid responsiveness.Alterations in ovarian and gonadotropic function, withthe appearance of a polycystic ovary-like phenotype, alsocontribute to the androgen excess of these patients [42,43]. Functional ovarian abnormalities in patients with CAHand/or NCAH may relate to a number of etiologies, includingdisruption of the hypothalamic-pituitary-ovarian (HPO)axis by persistently elevated progesterones (e.g. P4 and/or17-OHP) or androgens, and/or a direct glucocorticoideffect. Androgen excess impairs hypothalamic sensitivity toprogesterone resulting in a persistently rapid GnRH pulsefrequency which favors LH hypersecretion [44]. This LHhypersecretion initiates and maintains a vicious cycle inwhich excessive ovarian androgen secretion intensifies theconsequences of the excessive adrenal androgen production.In fact, women with NCAH demonstrate higher LH concen-trations than normal women [42]. Prenatal programming ofthe hypothalamus due to excessive in utero androgen expo-sure may contribute to LH hypersecretion and reproductivedysfunction among women with classical forms of CAH[45, 46]. However, in utero exposure to excessive androgensis unlikely to play a major role in the pathophysiology amongwomen with NCAH.Finally, while the 17,20-lyase activity of P450c17 towardsΔ4 substrates (conversion of 17-OHP to androstenedione)is not significant in humans, it is possible that patientswith CAH and NCAH may experience increased androgenexcess due to a backdoor or alternative pathway convertingeither P4 or 17-OHP to more potent androgens suchas dihydrotestosterone (DHT) [47]. Enzymes involved inthis alternative pathway include 5α-reductases and 3α-hydroxysteroid dehydrogenases. The ovarian expression of5α-reductase may contribute to excessive ovarian androgensecretion in NCAH as well as PCOS [48].Overall, a more thorough understanding of the patho-physiologic mechanisms underlying the symptomatology ofNCAH will improve our ability to select effective therapeuticregimens and choose reliable markers indicative of therapeu-tic success. For example, available data would suggest that themeasurement of P4 or 17-OHP may not be the most accuratemarker of therapeutic efficacy, and suppression of excessiveandrogen secretion from both ovaries and adrenals may benecessary for optimum steroidogenic control.4. Clinical FeaturesIndividuals with NCAH generally present with signs andsymptoms of androgen excess rather than symptoms reflect-ing glucocorticoid deficiency. Children may present withpremature pubarche (i.e. the development of pubic hair,axillary hair, and/or increased apocrine odor prior to age8 years in girls and age 9 years in boys). In one study,4.2% of 238 French children with premature pubarchewere found to have NCAH; 17-OHP, androstenedione,and testosterone concentrations were significantly elevatedamong the children with NCAH compared to the remainder[49]. In a multicenter study including 220 individuals withNCAH, 92%, 8%, and 4% of patients diagnosed under theage of 10 years, 10–19 years, and 20–29 years, respectively,had a history of premature adrenarche [50].Additional features in children include tall stature,accelerated linear growth velocity, and advanced skeletalmaturation. Examination of the external genitalia may revealclitoral enlargement in some girls without genital ambiguity.Phallic enlargement with prepubertal testes may be notedin boys. Although tall as children, the accelerated skeletalmaturation promotes premature epiphyseal fusion leadingto short stature in adulthood. Typically, these symptoms aremore prominent among children with classic CAH.During adolescence and adulthood, an ascertainmentbias favors the diagnosis in females due to the nature of thehyperandrogenic symptoms. Symptoms include hirsutism,acne, alopecia, anovulation, and menstrual dysfunction. In amulticenter study, the most common symptoms among ado-lescent and adult women were hirsutism (59%), oligomen-orrhea (54%), and acne (33%) [50]. Presenting symptomsin 161 women with NCAH were hirsutism (78%), menstrualdysfunction (54.7%), and decreased fertility (12%) [51].Not all individuals with NCAH will be symptomatic. Astudy of the phenotype/genotype relationship in 330 familymembers revealed 9 symptomatic affected individuals, 42clinically asymptomatic affected individuals, 242 heterozy-gotic carriers, and 37 unaffected individuals [51]. As foundin this study, affected males are generally asymptomatic andusually identified following the diagnosis of a female fam-ily member. Peripubertal gynecomastia and adrenocorticalincidentaloma are extremely uncommon presenting features[52, 53].4.1. Acne. Acne can occur among patients with hyperandro-genism and may be the primary clinical manifestation ofCAH. Severe cystic acne refractory to oral antibiotics andretinoic acid has been attributed to NCAH.4.2. Alopecia. Additionally, male pattern baldness in youngwomen with this disorder has been noted as the sole present-ing symptom. Severe androgenic alopecia in association withmarked virilization has also been reported in older women.4.3. Hirsutism. Hirsutism is defined as the excessive growthof coarse terminal hairs in androgen-dependent areas.Hirsutism must be distinguished from hypertrichosis whichis defined as generalized excessive growth of androgen-independent hair, and may be related to the use of certainmedications (e.g., phenytoin, minoxidil, diazoxide, gluco-corticoids, and cyclosporine), familial factors, or metabolicdisorders (e.g., thyroid disturbances and anorexia nervosa).The modified Ferriman-Gallwey score provides a semi-subjective method to assess the magnitude of hair growthin nine androgen-dependent areas such as the mustachearea, chin, upper chest, abdomen, and back [54]. Although
Page 4 4International Journal of Pediatric Endocrinologya modified Ferriman-Gallwey score of 6 to 8 is usuallyconsidered to indicate hirsutism, variation among ethnicgroups occurs. Cosmetic treatments may reduce the ability toclinically detect hirsutism. Whereas hirsutism is uncommonin children or young adolescents, the prevalence of hirsutismand alopecia tends to increase over time [55]. Virilization andmasculinization are terms used to describe the presence ofmore severe symptoms of androgen excess. Specifically, theseterms refer to the presence of clitoromegaly, masculine bodyhabitus, male pattern hair loss, and voice changes. Thesefeatures, with the exception of occasional mild clitoromegaly,are not typically present in NCAH patients.4.4. Ovulation, Menstruation and Reproductive Function.Women with NCAH often present with amenorrhea (pri-mary or secondary), chronic anovulation, and infertility.Ultrasonography may demonstrate ovarian morphologyreminiscent of polycystic ovary syndrome (PCOS). Polycysticovary morphology may be present in about half of womenwith NCAH [56].Many women with NCAH are relatively fertile [57, 58].However, NCAH carries a greater risk of subfertility, inpart due to the prevailing ovulatory dysfunction. Reports inwomen with classic CAH suggest that elevated progesteroneconcentrations play an important role in preventing men-strual cyclicity and fecundity [59, 60]. Likewise, persistentlyelevated levels of progesterones during the follicular phasein women with NCAH may interfere with the quality ofcervical mucus, impeding penetration by sperm. In addition,elevated levels of 17-OHP and/or P4 during the preovulary(follicular) phase of the menstrual cycle may result ininadequate endometrial maturation and impaired embryoimplantation.Among 203 pregnancies in 101 women with NCAH,138 pregnancies preceded the mother’s diagnosis of NCAH.Spontaneous miscarriages were more common in the preg-nancies prior to NCAH diagnosis [57]. Another series ofwomen with NCAH desiring pregnancy reported similarfindings with a decrease in spontaneous miscarriages duringglucocorticoid treatment [61]. Potential limitations of thesestudies are that both are retrospective and largely includewomen ascertained by reproductive endocrinologists.Since 21-hydroxylase deficient NCAH is an autosomalrecessive disorder, the recurrence risk is 25% for pregnanciesof the biological parents of the proband. Thus, siblings of theproband may benefit from diagnostic evaluation for NCAH.For women with NCAH, the risk of having a child with salt-losing or simple virilizing classical forms of CAH dependsin part on the probability that the father is a carrier andmother’s genotype. Moran et al. found that the prevalenceof 21-OH-deficiency among liveborn children was 2.5%which was higher than the 0.2% calculated prevalence. Inaddition, at the time of the study 15% of children of motherswith NCAH had been also diagnosed with NCAH [57].Bidet et al. also found the prevalence of CAH to be greaterthan anticipated [61]. The suggested explanation for thehigher than expected prevalence of CAH and NCAH in thesepopulations may be the tendency for affected individualsto marry within their own ethnic background; some ethnicgroups are enriched for CYP21A2 variants.5. Other Considerations5.1. Precocious Puberty. Although more commonly observedin children with classic CAH, skeletal maturation may besignificantly advanced among children with NCAH andmay be associated with gonadotropin-dependent precociouspuberty [62]. Typically, the signs and symptoms of pubertybecome conspicuous after the initiation of glucocorticoidtreatment. In this situation, the hypothalamic GnRH pulsegenerator prematurely resumes pulsatile GnRH secretionleading to increased LH and FSH secretion resultingin increased gonadal steroid production. The precociouspuberty is considered to be secondary to the excessive adrenalsteroid secretion and advanced skeletal maturation associ-ated with NCAH. Some children with secondary GnRH-dependent precocious puberty benefit from treatment withGnRH-super agonists such as leuprolide acetate or histrelin.5.2. Bone Mineral Density. Glucocorticoids influence bonemetabolism by suppressing osteoblast activity, promotingincreased bone resorption by osteoclasts, and interferingwith calcium absorption from the gastrointestinal tract[63]. Thus, the need for chronic glucocorticoid therapyleads to concerns regarding bone density for individualswith CAH. Since DXA is based on a two-dimensionaltechnique, interpretation of areal bone mineral densityassessed by DXA scan can be confounded by bone widthand height. Thus, DXA can underestimate bone mineraldensity in shorter individuals [64]. Available data, derivedfrom outcome reports for individuals with classic CAH, areinconsistent due to varying glucocorticoid doses, potentialcompliance issues, and subject heterogeneity [65, 66]. Intheory, inadequate treatment would lead to androgen excessthat would be anticipated, in turn, to increase BMD. On theother hand, excessive glucocorticoid replacement treatmentwould be expected decrease BMD. At this time, outcomedata regarding BMD in NCAH are limited. Nevertheless, ithas been suggested that maintaining vitamin D sufficiencyshould be a goal for individuals with CAH [67].5.3. Gonadal Rest Tumors. During early gestation, cellsdestined to become the steroid producing cells of the adrenalcortex and gonads differentiate from neighboring regionsof the coelomic epithelium. Subsequently, some adrenalprecursor cells migrate, descend into the scrotum with thetestes, retain ACTH responsiveness, and can develop intotesticular adrenal rest tumors (TARTs) [68]. Such tumorshave generally been described in boys or men with classicCAH and poor compliance [69]. Incomplete detection andunderdiagnosis of NCAH in men hinders accurate ascertain-ment of the frequency of TARTs in men with NCAH.5.4. Adrenal Tumors. Adrenal tumors have rarely been iden-tified among individuals with NCAH. Following discoveryof an adrenal incidentaloma, an 88 year old women was
Page 5 International Journal of Pediatric Endocrinology5diagnosed with NCAH; her genetic analysis showed V281Land I172N [70]. A 57 year old man ascertained by findingan adrenal incidentaloma was diagnosed with NCAH; hehad elevated serum 17-OHP concentrations and urinary 17-ketosteroid excretion [71]. Adrenal myelolipomas have beenreported among untreated adults with NCAH [72].5.5. Contiguous Gene Deletion Syndrome. The CYP21A2 andCYP21A1P genes map to the HLA complex at chromosome6p21. Another gene located in this region of the genomeencodes for tenascin-X (TNXB). Tenascin-X is a largeextracellular matrix protein which is expressed in the dermisof the skin, and cardiac and skeletal connective tissue. Loss offunction TNXB mutations are associated with hypermobilityEhlers-Danlos syndrome [73]. Individuals with CYP21A2deletions may have haploinsufficiency for TNXB and maymanifest joint hypermobility, joint subluxations, and chronicmusculoskeletal pain [74]. A girl with classic CAH was foundto have a quadricuspid aortic valve, single kidney, bicornuateuterus, and vesicoureteral reflux [75]. Thus, it is possible thatthe Ehlers-Danlos phenotype could occur among patientswith NCAH who carry a continuous gene deletion involvingthis region on one allele and V281L on the other allele.Nevertheless, to date, no such case has been reported.5.6. Metabolic Consequences. Factors associated with in-creased risk for metabolic consequences cluster in womenwith NCAH. These factors include obesity, hypertension, andinsulin resistance. The androgen excess may independentlycontribute to this risk due to atherogenic lipid profiles. Usingthe minimal model to assess insulin sensitivity, insulin sensi-tivity was found to be decreased in six untreated nonobesewomen with NCAH compared to control subjects [76].Comparison of metabolic parameters in women with PCOS,women with NCAH, and healthy control women showed thatmetabolic parameters were comparable among women withNCAH, lean women with PCOS, and healthy control womenwhereas metabolic dysfunction was evident in the obesewomen with PCOS [20]. Available studies regarding insulinsensitivity have provided inconsistent results and generallyinvolve women with classical forms of CAH [77, 78].Platelet dysfunction is another feature that can beassociated with insulin resistance. To distinguish betweenthe consequence of hyperandrogenism and hyperinsulinism,agonist-induced platelet function was studied. Whereasplatelet aggregation in samples from women with PCOSwas high, platelet aggregation in samples from women withNCAH was comparable to the healthy controls [79].6. Psychosocial Considerations andQuality of LifeGender role develops as a result of society’s expectationsconcerning behavior. Prenatal factors such as hormonesand environmental exposures are hypothesized to influencegender role. Yet, the specific details regarding how prenatalandrogen exposure affects gender identity of girls with classicCAH remain to be clarified [80, 81]. Most women withadrenal hyperplasia, both CAH and NCAH, demonstrateheterosexual preferences [82]. Despite the impression thatwomen with NCAH primarily have postnatal androgenexcess, the frequency of homosexuality and bisexuality wasslightly increased in one study compared to non-CAHcontrols [82]. Limitations of this study include small samplesize and cross-sectional design. It is also unclear howrepresentative the subjects are relative to other women withNCAH.Infertility is inextricably related to self-esteem andpsychosocial adjustment. The anatomic concerns related towomen with classic CAH such as pain with vaginal pene-tration are generally not germane for women with NCAH[83]. As surgical, medical, and psychological treatmentshave improved, more women with classic and NCAH havesuccessfully completed pregnancies and given birth [84].7. DiagnosisIndividuals with the salt-wasting and simple virilizing formsof CAH are generally recognized in the newborn period, andmost affected females are detected by the genital ambiguity.Without a family history, males with classic CAH areidentified through newborn screening programs. In general,newborn screening programs fail to detect individuals withNCAH [85].Newborn screening programs measure of 17-OHP inwhole blood spots collected on filter paper. The 17-OHPresults for infants with NCAH are often not as elevatedas those for infants with classic CAH. Another confounderis that preterm infants, heterozygotic carriers, and sickinfants have 17-OHP concentrations which overlap theconcentrations measured in infants with NCAH. Thus,imperfect recall occurs almost by design because of the needto avoid excessive numbers of false positive results whiletrying to maintain adequate sensitivity and specificity todetect infants with classic CAH. Given the comparativelymild course of NCAH during childhood and the anxiety andcosts involved in false positive results, treatment based solelyon elevated hormone levels in the absence of symptoms mayonly increase the risk for iatrogenic adrenal insufficiencywithout any clear therapeutic benefit. Thus, risk/benefitanalysis of confirming the diagnosis of NCAH in a neonateprior to the development of symptoms is unresolved due tothe lack of outcome data [86].The clinical features of NCAH in postpubertal adultsmay be difficult to differentiate from those of the polycysticovary syndrome (PCOS) or, in children, from prematureadrenarche. Although random 17-OHP concentrations areusually diagnostic in classical forms of CAH, random 17-OHP concentrations may be within the normal range forindividuals with NCAH. Thus, the acute ACTH stimulationtest remains the gold standard to confirm decreased 21-hydroxylase activity. Following collection of a blood sampleto measure baseline hormone concentrations, syntheticACTH (Cortrosyn, 0.25 mg) is administered. A second bloodsample is collected 30–60 minutes later. Correlation ofhormone concentrations with genetic analyses has suggested
Page 6 6International Journal of Pediatric Endocrinologythat mutations are likely to be identified on both alleles whenthe ACTH-stimulated 17-OHP value exceeds 1500ng/dL,although a few NCAH patients, particularly if older, willdemonstrate ACTH-stimulated 17-OHP levels between 1000and 1500ng/dL. In one study, among 123 women withNCAH confirmed by molecular CYP21A2 analysis, meanbasal 17-OHP and mean ACTH-stimulated 17-OHP concen-trations were 1300 ± 1420ng/dL and 4080 ± 2040 ng/dL,respectively [51].In general, it is impractical to perform an acute ACTHstimulation test in all women suspected of NCAH (e.g.those with hyperandrogenic features or ovulatory/menstrualdysfunction). Various investigators have suggested the useof unstimulated levels of 17-OHP as a predictor of NCAH[24, 57, 87, 88]. Levels of 170–300ng/dL have been foundto be useful as a screening tool, best if obtained in themorning and, most importantly (to reduce false positives),in the follicular (preovulatory) phase of the menstrual cycleAmong 129 Portuguese women with hyperandrogenism andmenstrual dysfunction, 87% of women with NCAH, 25% oflean women with PCOS, 20% of obese women with PCOS,and 7% of control women had basal 17-OHP concentrations>200ng/dL [20]. In childhood, NCAH may present withpremature adrenarche. In a sample of 238 French childrenwith premature pubic hair, of which 4.2% had NCAH, theuse of a 17-OHP cut-off value of greater than 200ng/dLprovided a 100% sensitivity and 99% sensitivity for thedetection of NCAH in this cohort [49].Genetic testing should not be considered a first-linediagnostic study in individuals suspected of NCAH. How-ever, genetic studies may be useful in those patients (menor women) who are considering future fertility. Genetictesting can identify those individuals who are compoundheterozygotes and may carry an allele encoding a severedefect in CYP21A2. Overall, screening using morning 17-OHP concentrations, obtained in the follicular phase inreproductive-aged females, and followed, if positive, by anacute ACTH stimulation remain the essential clinical tools todiagnose NCAH.8. Laboratory AnalysisLaboratory techniques used to measure 17-OHP includeradioimmunoassays (RIA), enzyme-linked immunosorbentassays (EIA) and time-resolved fluoroimmunoassays (FIA).While there may be variability between the laboratories,our studies indicate a high degree of correlation betweenlaboratories [50]. As noted above, the presence of cross-reacting steroids of fetal adrenal origin may hinder theinterpretation of 17-OHP concentrations in preterm andterm infants. Recent technical improvement involve tandemmass spectrometry (MS) linked to liquid chromatography(LC) [89]. Detection of 17-OHP from dried whole bloodspots using LC followed by tandem mass spectrometry(LC/MS/MS) has been reported [90]. The use of LC/MS/MSmay improve the sensitivity and specificity of newbornscreening. The use of LC/MS/MS is not only limited tonewborns, the sensitivity and specificity of this techniquemake it applicable for 17-OHP determinations for children,adolescents, and adults.When considering genetic testing, an important limita-tion is that molecular genetic analysis can be confoundedby the complexity of the CYP21A2-CYP21A1P loci. Multiplemutations can occur on one allele so that the identificationof two mutations does not always signify CAH becauseboth mutations may occur on the same allele (cis). Copynumber variation involving the CYP21A2-CYP21A1P regionmay result in multiple copies of CYP21A2 on a single allele. Inaddition, most commercially available screening panels assayfor the 10–12 most common mutations, and may not be ableto detect all mutations [91]. Inclusion of a DNA sample fromat least one parent and/or a child may discriminate betweenvariants on the same (cis) or different (trans) alleles.9. TreatmentTreatment needs to be directed towards the symptoms. Inother words, treatment should not be initiated merely todecrease abnormally elevated hormone concentrations. Clin-ical goals of treatment include normal linear growth velocity,normal rate of skeletal maturation, “on-time” puberty, andappropriate weight status for children and adolescents.For adolescent and adult women, goals of therapy includeregularization of menstrual cycles, prevention of progressivehirsutism and acne, and fertility. For each child, adolescent,and adult with NCAH, the benefits of treatment shouldbe weighed against the potential risks of acute adrenalinsufficiency secondary to iatrogenic adrenal suppressiondue to glucocorticoid treatment. Treatment of hirsutism mayalso necessitate adjunctive cosmetic methods such as laser,electrolysis, and depilatories.Glucocorticoid treatment can be utilized for children andadolescents with significantly advanced skeletal maturation.Although treatment with oral contraceptives alone maybe sufficient in oligomenorrheic, acneic, or mildly hirsuteadolescents and adult women not seeking fertility, earlyglucocorticoid treatment may be beneficial to decrease therisk of persistent anovulation. In a crossover design involvingeight women with NCAH, oral contraceptive therapy wasassociated with increased SHBG and decreased free testos-terone concentrations. As would be anticipated, menstrualcyclicity was restored with oral contraceptive therapy [92].The use of anti-androgens (e.g. flutamide, cyproteroneacetate, or finasteride) should also be considered in womencomplaining of excess unwanted hair growth or scalp hairloss (androgenic alopecia). Despite minimal changes intestosterone and androstenedione concentrations, greaterimprovement in hirsutism was noted with the use of cypro-terone acetate compared to hydrocortisone among womenwith NCAH [93]. Thus, for adolescent and adult womenwith NCAH who are taking glucocorticoids, the addition oforal contraceptives or anti-androgens may allow for lowerglucocorticoid dosage.Among adults, treatment is generally reserved for symp-tomatic individuals, as the risks of iatrogenic adrenal sup-pression with glucocorticoid treatment need to be balanced
Page 7 International Journal of Pediatric Endocrinology7against the potential benefits of treatment. Most untreatedindividuals with NCAH manifest an adequate response tostress. One effective regimen involves hydrocortisone, 6–15 mg/m2/day divided into three daily doses. Many clinicianssuggest that reverse circadian dosing with the highest hydro-cortisone dose at night provides improved control, but noconsensus exists regarding how to divide the doses [56, 94].All individuals on glucocorticoid therapy require instructionregarding stress doses, including parenteral therapy, andshould wear medical alert identifying badges/jewelry.For daily treatment, prednisone, prednisolone, or dex-amethasone may also be used in adults. Because of the poten-tial detrimental effect of glucocorticoids on the fetus [95],various practitioners suggest that a glucocorticoid that isinactivated by placental 11β-hydroxysteroid dehydrogenasetype II (e.g. hydrocortisone, prednisone, and prednisolone)should be used in sexually active females who are not on ahighly effective contraceptive [95] or who become pregnant,unless specifically intending to suppress the fetal adrenal (seebelow). As the androgen secretory potential of the adrenalcortex declines with age [96], the demand for glucocorticoidsto suppress adrenal androgen secretion in NCAH mayameliorate with age. Stress doses of hydrocortisone are essen-tial for affected individuals maintained on glucocorticoidtreatment. For emergency situations, including labor anddelivery and surgery, the empiric stress dose is parenteralhydrocortisone (Solu-Cortef), 100 mg, IV or IM.Laboratory goals include normalization of androstene-dione and testosterone levels; alternatively, suppression ofDHEAS levels occurs with minimal doses of glucocorticoids.Normalization of 17-OHP or P4 concentrations indicatesexcessive hormone replacement therapy, unless so intendedin patients seeking fertility (see below).Women seeking fertility may benefit from the use ofovulatory agents (clomiphene or menotropins). Preliminar-ily, the preconception use of concomitant glucocorticoidsappears to reduce the risk of miscarriages in NCAH patientsconceiving [57]. In addition, in this setting maximumsuppression of 17-OHP and P4 could potentially allow max-imum endometrial proliferation and improve implantation.In addition, all women with NCAH desiring to conceiveshould undergo genetic screening to determine the presenceof severe CYP21A2 mutations (and, hence, the risk of havinga child with CAH), and if a severe allele is present thengenetic screening of the father should also be undertaken.Many of these patients benefit from preconception geneticcounseling.In patients who conceive and whose child is consideredat high risk for intrauterine virilization (i.e. a femaleinfant) consideration may be given to using high dosedexamethasone suppression in early gestation, before 10weeks gestational age [97, 98], until definitive diagnosisand chromosomal sex can be obtained using chorionic villisampling or early amniocentesis (by 10–13 weeks gestationalage). However, this experimental therapy is associated withsignificant risk of Cushingoid features and glucose intoler-ance in the mother [99]. The effects on the fetus particularlyrelated to brain development are unknown. In addition, sinceall “at-risk” fetuses are treated until the definitive diagnosisand chromosomal sex are known, 7/8 fetuses are needlesslyexposed to prenatal dexamethasone [100]. Overall, the risk ofa patient with NCAH of having a child with CAH is relativelylow (2.5%) [57]. Therefore, couples who conceive and whosegenetic diagnosis is not known should not be considered forprenatal dexamethasone suppression, unless they have had aprior child with salt-losing or simple virilizing CAH. Thosechoosing to use prenatal dexamethasone should do so onlyas participants of IRB-approved research studies [101].10. ConclusionsNonclassic congenital adrenal hyperplasia is a common auto-somal recessive disorder that can present in childhood, ado-lescence, and adulthood. 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