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

Endocrine DOI 10.1007/s12020-015-0656-0

REVIEW

Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency: clinical presentation, diagnosis, treatment, and outcome Henrik Falhammar1,2 • Anna Nordenstro¨m3,4

Received: 22 April 2015 / Accepted: 3 June 2015 Ó Springer Science+Business Media New York 2015

Abstract 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

& Henrik Falhammar [email protected] 1

Department of Endocrinology, Metabolism and Diabetes, D2:04, Karolinska University Hospital, 171 76 Stockholm, Sweden

2

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

3

Department of Paediatric Endocrinology, Astrid Lindgren Children Hospital, Karolinska University Hospital, Stockholm, Sweden

4

Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden

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. Keywords 21-Hydroxylase deficiency Tumor Cardiovascular risk Fertility Mortality

Introduction Classic congenital adrenal hyperplasia (CAH) was first described in 1865 in a male in his 40s who had died during one of his frequent episodes of vomiting and diarrhea [1]. The autopsy revealed a 6-cm long penis with severe hypospadias, no testes, but normal vagina, uterus, tubes, and ovaries together with a normal prostate gland. Moreover, the adrenal glands were greatly enlarged. Ninety-two years later in 1957 the first case of a nonclassic CAH (NCAH) was reported [2]. The case described was a 26-year-old married woman with regular menstruation periods and normal genitals who presented with hirsutism and acne. Investigations showed increased androgens and steroid precursors, including the metabolite 17-hydroxyprogesterone (17OHP), which was further elevated by ACTH stimulation. After a 10 day course of cortisone a marked improvement was seen. In 1984, the gene encoding the 21-hydroxylase enzyme affected in CAH patients with 21-hydroxylase deficiency was reported [3]. In contrast to most patients with classic CAH requiring life-long

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glucocorticoid treatment for survival, most patients affected by NCAH have never been diagnosed and the treatment is only symptomatic. The present review will focus on clinical presentation, diagnosis, treatment, and clinical outcomes especially concerning quality of life, psychiatric morbidity, fertility, pregnancies and offspring, bone health, mortality, cardiometabolic systems, tumors, and voice. Final height and transition from childhood to adulthood have recently been reviewed elsewhere [4]. The review is based on articles found in PubMed published up to April 2015 using the search terms nonclassic/nonclassical congenital adrenal hyperplasia and/or 21-hydroxylase deficiency. Moreover, we reviewed selected references from articles retrieved in the initial search. Most studies have included either a mix of classic CAH and NCAH patients or only classic CAH patients, with only a few having exclusively NCAH individuals included. Data derived from classic CAH are sometimes presented when assumed to be similar in NCAH, but we have tried, as far as possible, to report data that include NCAH individuals and separated them from classic CAH individuals, if possible. In this review we have used CAH synonymously with 21-hydroxylase deficiency.

Physiology NCAH is an autosomal recessive disorder affecting adrenal steroid synthesis to some degree but does not, in contrast to classic CAH, cause genital ambiguity in 46XX infants [5, 6]. NCAH typically has 20–50 % residual 21-hydroxylase enzyme activity [7], leading to androgen excess [8], but also a mild cortisol and, to some extent, aldosterone deficiency [9]. The mildly reduced cortisol production stimulates ACTH secretion from the pituitary gland via the reduced negative feed-back, and the increased ACTH levels cause adrenocortical growth, resulting in adrenal hyperplasia. The steroid precursors directly proximal to the 21-hydroxylase block accumulation and are shifted into the different androgen pathways (Fig. 1). An adequate cortisol concentration is required for adequate adrenomedullary organogenesis and epinephrine production, and a correlation with the severity of the different classic CAH genotype groups has been demonstrated in both children and adults [10, 11]. The adrenomedullary function in NCAH was significantly better compared to classic CAH [12].

Clinical presentation CAH is clinically classified into classic and nonclassic forms. The former is then divided into salt-wasting (SW) and simple virilizing (SV) CAH. Females with classic CAH exhibit virilized external genitals at birth. Neither females nor males with the SW form will survive the first weeks of life unless

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adequately treated due to a severe aldosterone deficiency, resulting in salt loss and adrenal crisis. Males with the SV form usually present with early virilization at age 2–4 years [6]. NCAH individuals typically do not have virilized genitalia at birth and can present at any time postnatally with signs of androgen excess. According to the original clinical definition, the first symptoms should occur after 60 months of age. In a multicenter cohort study of 220 women with NCAH, only 11 % were diagnosed before 10 years of age, while the majority, 80 %, were diagnosed between 10 and 40 years of age. In those diagnosed before 10 years of age, 92 % had presented with premature pubarche. In contrast, those diagnosed later, the presenting symptoms had been hirsutism (59 %), oligomenorrhea (54 %), acne (33 %), infertility (13 %), alopecia (8 %), primary amenorrhea (4 %), and premature pubarche (4 %) [13]. In a single center study of 161 women with NCAH, the mean age at presentation was 23.4 years with a range of 13–52 years. The presenting symptoms were hirsutism (78 %), menstrual cycle disorders (55 %), and decreased fertility (12 %) [14]. In the most recent study including 280 NCAH individuals (84 % females), 40 % of the females presented before 8 years of age predominately with premature pubarche (88 %) and 60 % between age 14 and age 42 (median 21.4 years) with polycystic ovary syndrome (PCOS)-like symptoms (63 %), no symptoms (11 %, family screening), primary amenorrhea (7 %), secondary amenorrhea (6 %), subfertility (4 %), adrenal adenoma (3 %), acne (2 %), hair loss (2 %), and short stature (1 %) [15]. The males with NCAH, diagnosed between 0.8 and 52 years of age (median 24.5 years), presented with no symptoms (51 %, family screening), premature pubarche (29 %), hirsutism/ acne (11 %), subfertility (2 %), precocious/delayed puberty (4 %), and tall stature (2 %) [15]. As a consequence of chronic androgen excess on the hypothalamic-pituitaryovarian axis, by alteration of gonadotropin release or direct effects on the ovaries, women with CAH may develop a secondary PCOS-like physiology [16]. Women with both classic CAH [17] and NCAH [18, 19] may develop PCO. It has been estimated that around a quarter of NCAH women have PCO on ultrasound [19], and it should be noted that the clinical presentation of PCOS and NCAH can be identical [18, 19]; thus, in order to diagnose PCOS, it is a prerequisite that the latter has been excluded [20]. An overrepresentation of both undiagnosed patients with NCAH and female carriers (i.e., patients with only one CYP21A2 allele mutated) has been seen in clinics treating severe acne [21–23]. Some individuals are not diagnosed with NCAH until a very old age due to mild symptoms [24]. As a result of mild symptoms and doctors’ ignorance, most males and females with NCAH are probably never diagnosed. In the case of 330 parents, siblings, and children to women with NCAH, 51 (15 %) were diagnosed with

Endocrine Dehydroepiandrosterone sulfate (DHEAS) Cholesterol 17α-hydroxylase (CYP17)

Cholesterol desmolase (CYP11A) Pregnenolone

17,20-lyase (CYP17)

Sulfotransferase

17-hydroxypregnenolone

Dehydroepiandrosterone

17-hydroxyprogesterone

Androstenedione

3β-hydroxysteroid dehydrogenase Progesterone 21-hydroxylase (CYP21)

17β-hydroxysteroid dehydrogenase Deoxycorticosterone

11β-hydroxylase (CYP11B2)

11β-hydroxylase (CYP11B1) Corticosterone

Androstenediol

Testosterone

11-deoxycortisol

Cor tisol

5α-reductase type 2 Dihydrotestosterone

18-hydroxylase (CYP11B2)

Oxidative 3α-hydroxysteroid dehydrogenase Androstanediol

18-hydroxycorticosterone 18-oxidase (CYP11B2)

5α-reductase type 1 Androsterone Aldosterone 5α-pregnan17α-ol-3,20-dione

17β-hydroxysteroid dehydrogenase

17α-hydroxylase (CYP17) 17-hydroxyallopregnanolone

Reductive 3α-hydroxysteroid dehydrogenase

Fig. 1 Steroid synthesis in the adrenal cortex. The pathways of aldosterone, cortisol, and androgen synthesis and the enzymatic steps from the precursor cholesterol are shown. Within the brackets are the genes coding for some of the enzymes shown. In NCAH, 21-hydroxylase is the enzyme most often impaired and the corticosteroids, which are increased and usually measured clinically, are highlighted. In 21-hydroxylase deficiency, three different pathways may result in

increased androgen levels. Firstly, the normal way directly from 17-hydroxypregnenolone to dehydroepiandrosterone (DHEA). Secondly, when 17-hydroxyprogesterone levels are high, 17-hydroxyprogesterone is first converted to androstenedione. Thirdly, the proposed backdoor pathway, where 17-hydroxyprogesterone is first converted to 5a-pregnan-17a-ol-3,20-dione

NCAH when screened [14]. Since the introduction of neonatal screening in many countries, classic CAH is now usually diagnosed in the neonatal period, however, occasional classic CAH patients may still be missed in the neonatal screening [25, 26]. In contrast, NCAH is not usually identified in neonatal screening programs [27]. In our Swedish cohort of adult patients born before the introduction of neonatal screening, all diagnosed SW patients were diagnosed during the first weeks of life, SV females at age 0–15 years (almost all during infancy, one found late), and the NC females at 6–88 years of age, whereas the SV males were detected at age 3–67 years (only occasional patients being identified after 8 years of age), and males with NCAH at 13–30 years of age [10, 28, 29].

(Fig. 1). A concentration of 17OHP [ 240 nmol/L in a random blood sample is diagnostic of classic 21-hydroxylase deficiency, the reference level being \3 nmol/L at 3 days in a full-term infant [6]. Neonatal screening for CAH is performed in more than 30 countries [30]; thus, in those countries classic CAH is now mainly diagnosed by screening and not by symptoms alone. Neonatal screening in Sweden identifies all SWCAH but may miss some patients with SVCAH. The majority of individuals with NCAH will not be detected by screening [27]. Neonatal screening in the US only identified one baby with NCAH in 130,000 screened individuals [30]. Similarly, in Sweden only 12 NCAH cases were detected in 2.7 million screened babies [27]. Moreover, 24 of the 38 (63 %) diagnosed infants with NCAH were not detected in the screening [26]. When the diagnosis is suspected later in childhood and onwards, most experts advocate screening with an early morning 17OHP. A cut-off value of \2.5 nmol/L in children and \6.0 nmol/L in adults has been suggested to exclude CAH [6, 31]. The 17OHP sample should be taken in the early morning and in the follicular phase in

Diagnosis An elevated level of 17-OHP is used as a marker for CAH. It is the biochemical hallmark of 21-hydroxylase deficiency and the main substrate for the 21-hydroxylase enzyme

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menstruating women, or at any time in anovulatory individuals or males. It has been estimated that between 2 and 11 % of NCAH cases will be missed using this approach— at least in adults [14, 15, 32]. The next step if the clinical suspicion remains in spite of a normal basal 17OHP is the ACTH stimulation test (250 lg of cosyntropin i.v.), with a measurement of 17OHP at 60 min, which is the golden standard for the diagnosis. Traditionally, a basal 17OHP [15 nmol/L and/or ACTH-stimulated 17OHP[30 nmol/L has been used in males, and in females during the follicular phase, to diagnose NCAH [32]. In one study of 58 NCAH patients, the ACTH-stimulated 17OHP levels ranged from 51 to 363 nmol/L [32] and, consequently, it was suggested to increase the ACTH-stimulated cut-off value to [45 nmol/L, and to allow testing at any time of the day and on any day during the menstrual cycle [6]. However, two later studies have questioned this procedure because, among 140 and 160 genetically confirmed NCAH individuals, respectively, some were found to have a stimulated 17OHP of around 30 nmol/L [14, 15]. Some carriers may, however, have levels overlapping with those for NCAH [8], and some adrenal incidentalomas may also have levels of 17OHP above 30 nmol/L without a genetically confirmed carrier status or NCAH [29]. It should be noted that CAH is an autosomal recessive disorder and while 17OHP levels, basal and ACTH-stimulated, remain the gold standards for diagnosis, the expectation is that mutations will be identified on both CYP21A2 alleles (see Genetics below). In patients with classic CAH, basal and ACTHstimulated 17OHP will exceed 300 nmol/L [6, 33]. Measurements of the urinary metabolite of 17OHP, pregnanetriol in a 24-h sample, can be used to diagnose 21-hydroxylase deficiency [5], but normal values cannot completely rule out NCAH.

Prevalence Classic CAH due to 21-hydroxylase deficiency has been estimated to occur in one in 15,000 live-births according to data from 13 neonatal screening programs including more than 6.5 million newborns [6, 34–36]. This would indicate a carrier frequency of a classic CAH mutation of one in 60 individuals. In New York City, with a very heterogeneous population, one in 111 was affected by NCAH, but the prevalence varied widely between the different ethnicities and from 3.7 % in Ashkenazi Jews to 0.1 % in the remaining Caucasian population [37]. The high prevalence has led to claims of NCAH being the most frequent autosomal recessive disorder in man [8]. However, the high frequency has not been confirmed in all other populations (Table 1) [38–43].

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Genetics The gene encoding 21-hydroxylase is named CYP21A2 and has been well characterized [44]. Deletions and/or large gene conversions of the entire CYP21A2 and/or a limited number of point mutations comprise roughly 95 % of all mutations causing 21-hydroxylase deficiency [5, 45]. Most commercially available panels screen for these mutations. The CYP21A2 locus is complex and genetic testing should not be the first diagnostic test in the evaluation for NCAH (see Diagnosis above). The genotype-phenotype correlation in CAH is generally good [45, 46], especially for the genotypes for SW and NCAH, but the phenotypic variability is larger in the SV form [47, 48]. The phenotype is considered to be determined by the milder mutation of the two affected alleles. The most common mutations are ranked from the most severe to the mildest, i.e., null, I2 splice, I172N, P30L, and V281L (Fig. 2). V281L is the most frequent mutation among NCAH patients, comprising 73–87 % [14, 15, 48]. On the other hand, 98 % of V281L mutations have an NCAH phenotype [48]. The severity of the P30L genotype is in-between SV and NCAH, and the phenotype can be regarded as either one of these groups [5, 45, 48]. Occasional patients with the NCAH phenotype have been reported to have an SW or SV genotype [14, 48]. Moreover, in up to two-thirds of patients with NCAH, one of the two alleles carries a severe mutation [14, 15]. These patients had higher levels of both basal and stimulated 17OHP [14, 32], in addition to higher basal testosterone and androstenedione levels, compared to those with mild mutations on both alleles [14]. There was, however, no detectable difference in clinical symptoms [14, 32], except those of androgen excess presenting earlier in patients with a more severe mutation on the other allele [32]. The Endocrine Society Clinical Practice Guidelines from 2010 recommend genotyping for the purposes of genetic counseling and for confirmation of the diagnosis, especially in NCAH when the ACTH stimulation test is equivocal [33]. Still, we recommend all patients affected by CAH to be genotyped. Even though it has been estimated that only about 2 % of the general population are carriers, 8 % of partners to NCAH women carried a CYP21A2 mutation [14]. Moreover, the risk for an NCAH mother to give birth to a child affected by both classic CAH and NCAH is increased [49, 50] (Fig. 3). In addition, we have encountered patients diagnosed with NCAH and treated with glucocorticoids for years in whom we have not been able to identify any CYP21A2 mutations. Hence, the diagnosis has been changed to PCOS (although the opposite is far more common). This emphasizes the importance of genetically verifying the diagnosis of NCAH by CYP21A2 genotyping.

Endocrine Table 1 The prevalence of NCAH due to 21-hydroxylase deficiency in different ethnic populations Authors

Year

Location

Initial screening method

Total study population

Speiser et al. [37]

1985

New York City, US

HLA-B genotype data

278

Dumic et al. [38]

1990

Zagreb, Croatia and Beograd, Serbia

HLA genotype data Stimulated 17OHP

Zerah et al. [39]

1990

New York City, US

Salivary 17OHP

Fitness et al. [40]

1999

New Zealand

CYP21A2 mutation analysis

98 249 603

Ethnicity

Prevalence

Ashkenazi Jews

Estimated 3.7 %

Hispanics

Estimated 1.9 %

Yugoslavs Italians

Estimated 1.6 % Estimated 0.3 %

Other Caucasians

Estimated 0.1 %

Croatians and Serbs

Estimated 0.85 %

Ashkenazi Jews

2 of 62 (3.2 %)

Others

0 of 187 (0 %)

Caucasians (78 %)

0 of 603 (0 %)

Maori (13 %) Pacific Islanders (5 %)

Estimated 0.12 % (4.8 % carrier of CYP21A2 mutation, of which 2.0 % NCAH mutation)

Asians (4 %) Ezquieta et al. [41]

2005

Madrid, Spain

V281L mutation analysis

300

Spanish

Estimated 0.4 % (7.5 % carrier of NCAH mutation)

BaumgartnerParzer et al. [42]

2005

Vienna, Austria


200

Caucasians (50 % Yugoslavs)

Estimated 0.25 % (9.5 % carrier of CYP21A2 mutation, of which 4 % NCAH mutation)

Phedonos et al. [43]

2013

Nicosia, Cyprus


300

Greeks

Estimated 0.25 % (9.8 % carrier of CYP21A2 mutation)

Null

Clinical severity

Phenotype

Enzyme activity (in vitro) Percentage of normal

Deletion Del 8 bp E3 Cluster E6 L307insT Q318X R356W

SW

< 1%

I2 splice

SW/SV

Mutation

I172N

SV

P30L

SV/NCAH

V281L P453S

NCAH

2-10%

30-50%

Fig. 2 The most frequent mutations in the CYP21A2-genes, their phenotype and 21-hydroxylase enzyme activity in vitro. The rows relevant to NCAH are highlighted

Treatment Treatment is only warranted if the patient is symptomatic and desires treatment. In contrast to classic CAH, patients with NCAH do not require glucocorticoid treatment for

survival. Nevertheless, they have a partial cortisol insufficiency [14, 32, 51], mostly very mild, but up to one-third of them have an ACTH-stimulated cortisol level below 400 nmol/L and 60 % a level of less than 500 nmol/L. It has been suggested that a stimulated cortisol level of less than 500 nmol/L may justify daily glucocorticoid supplementation [52]. At least a liberal prescription of glucocorticoids for use during severe illness could be recommended for those with a suboptimal stimulated level. It should be noted that once daily glucocorticoids have been initiated, the hypothalamic–pituitary–adrenal (HPA) axis will be suppressed and thereby increase the risk of adrenal crisis. Thus, there is a need for higher glucocorticoid doses and sometimes i.v. administration during stress. Patient education regarding treatment is essential. Increased mortality has recently been reported in both classic CAH and NCAH, mainly due to adrenal crisis [53]. Gradually, during the last 20 years, the adverse long-term effects of supraphysiological glucocorticoid replacement dosing have come into focus [5, 6, 33, 54]. The dose should be as low as possible, but still control symptoms of androgen excess. Unfortunately, the dose required to

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Endocrine NCAH Unaffected (V281L/Null) (No/No)

NCAH Carrier (V281L/Null) (No/Null)

or

or

or

or

NCAH Carrier SWCAH Carrier (V281L/No) (Null/No) (V281L/Null) (Null/Null)

or

or

or

Carrier Carrier Carrier (V281L/No) (V281L/No) (No/Null)

or

Carrier (No/Null)

Fig. 3 Pedigree showing the genetic risk to the offspring of a patient with NCAH carrying a mild mutation (V281L) and a severe mutation (Null). If the partner is a carrier of a severe mutation (Null) (left panel), 50 % of the children will be affected by CAH (25 % NCAH,

25 % SWCAH) and 50 % will be carriers. If the partner is unaffected (no mutations on the two different alleles) (right panel), all children will be carriers (50 % carriers of a mild mutation, 50 % carriers of a severe mutation)

control the androgen levels will result in overtreatment and even subnormal androgen levels in many cases [28, 55]. Just how the newly developed extended-release hydrocortisone formulations will be used in the future in CAH remains to be elucidated [56]. In children, growth velocity, weight, and bone age are used to guide glucocorticoid treatment. However, in adults, there is no consensus on which laboratory and clinical parameters should be used to monitor therapy [57]. The Endocrine Society Guidelines recommend at least annual physical examination and appropriate hormone measurements, but optimal levels of the commonly used 17OHP and androstenedione are not stated [33]. In our experience, morning 17OHP levels vary widely and are not easy to use for guidance [28, 54]. Instead, we recommend, if available, diurnal 17OHP profiling with capillary dried blood spot samples, performed at home by the patient [54]. We also strive to keep androstenedione and testosterone (in females, a testosterone to sexual hormone globulin [SHBG] ratio of less than 0.05) within the normal reference range. DHEAS can only be utilized as a marker of nonadherence if above, or even within, the normal age-adjusted reference levels since it will be depressed below reference limits when regular doses of glucocorticoids are used [28, 55]. During childhood, hydrocortisone is the preferred choice due to the potential growth suppression of longer-acting preparations [58]. The recommended dose is 10–15 mg/ m2/day divided into three doses, but in some patients with NCAH, even lower doses may be required. Intermediateacting glucocorticoids, such as prednisolone (2.5– 7.5 mg/day divided into two doses) and long-acting glucocorticoids, such as dexamethasone (0.25–0.50 mg at bedtime or divided into two doses), may be an option near the completion of pubertal growth [6, 33, 54]. Intermediate- or

longer-acting glucocorticoids are usually preferred in adults because they may be taken once or twice daily. In Europe, prednisolone appears to be the preferred glucocorticoid [10, 28, 59–61] while, in the USA, prednisolone, dexamethasone, and hydrocortisone are each used in one-third of the cases [12]. Some clinicians advocate reverse circadian dosing to improve androgen control [62]; however, we and others normally try to avoid having the highest dose at nighttime because we believe it may affect sleep negatively and may possibly result in worse cardiovascular and metabolic longterm outcomes. A small study on six SW children showed that their 24-h blood pressure increased when the highest dose of hydrocortisone was given in the evening [63]. We sometimes give the largest dose of the glucocorticoid at bedtime to suppress nighttime ACTH secretion in order to improve fertility, but we only recommend this for short-term treatment. Cortisone acetate should not be used since it has to be converted to cortisol for biological activity and this conversion is dependent on 11b-hydroxysteroid dehydrogenase activity and can be impaired [6, 64].

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Mineralocorticoids Some degree of aldosterone insufficiency can be found in all individuals with 21-hydroxylase deficiency, and also in patients with NCAH [9]. Thus, fludrocortisone has sometimes also been used in NCAH cases [10, 18, 28, 60, 65], mainly to minimize the glucocorticoid doses required. The plasma renin or plasma renin activity should be aimed to range from high-normal to slightly increased [54]. Older NCAH adults normally do not benefit from fludrocortisone due to such side effects as hypertension and edema.

Endocrine

Other treatments Since most NCAH patients will have a good cortisol response to ACTH stimulation, other treatment options may be considered if they are symptomatic. Oral contraceptive pills inhibit androgen synthesis in the ovaries and increase the production of SHBG from the liver, resulting in a 40–60 % decrease in testosterone levels [66]. This may be enough to improve acne and hirsutism. Antiandrogens, such as spironolactone, flutamide, cyproterone acetate, and the 5-alpha-reductase inhibitor, finasteride, have also been used. In one study including 21 females with NCAH, 76 % received glucocorticoid therapy, 29 % were on oral contraceptive pills, and 14 % were on spironolactone [12]. In another study, the use of oral contraceptive pills was similar for CAH women and controls [67]. Hirsutism may also be treated with shaving, waxing, plucking, electrolysis, and laser therapy. Metformin has recently been shown to improve not only glycemic control, but also 17OHP, testosterone, androstenedione, and DHEAS in eight women with NCAH and T2DM [68]. Moreover, simvastatin also improved 17OHP, testosterone, androstenedione, and DHEAS in four women with NCAH and isolated hypercholesterolemia [69]. However, none of the two latter studies reported on improvement of symptoms. It should be emphasized that these two studies were based on a small number of NCAH women and that these medications did not improve symptoms, only biochemical parameters.

relatively frequently in women with classic CAH, but they have also been reported in NCAH women [67, 78–80]. A relationship between the severity of the CYP21A2 mutation and nonheterosexual orientation has been reported by us, but we found no case of homo- and bisexuality in NCAH (Fig. 4). A similar association was found between the genotype and living alone [79]. Pregnancies have been reported to be basically normal and uneventful in CAH women [67, 72, 75, 78]. In studies including only women with NCAH, the miscarriage rate was increased, but it normalized with glucocorticoid treatment [49, 50, 77, 81]. Otherwise, the pregnancies seemed to be normal, although they were not described in detail. In contrast, we reported gestational diabetes in about 20 % of a mixed cohort of classic and NCAH women, compared to none in the controls [28, 67]. One woman with NCAH and gestational diabetes has been reported on in detail [18]. Acute or elective cesarean section is common in CAH pregnancies (52–84 %), mostly due to previous genital surgery [67, 72, 75, 78]. None of the NCAH women in our study had a cesarean section [67].Yet, others have reported cesarean section also in NCAH women [72]. Pregnant women may need an increased glucocorticoid dose later on during pregnancy; however, there is no consensus [33]. Only 12 % in our cohort of mixed classic and NCAH pregnant women required a higher dose [67], which is similar to what has been reported by others. The majority do not need to change their regular glucocorticoid and mineralocorticoid doses [72]. Dexamethasone should be

Female fertility, pregnancy, and outcome of the offspring The pregnancy rate among women with classic CAH has been repeatedly found to be decreased, compared with both age-matched controls [67, 70–74] and fertility in the general population [60, 75]. Fertility has not been studied to the same extent in NCAH, but it appears to be less impaired [49, 50, 76, 77]. In a study including 56 women with NCAH, there was no difference in biological children compared to controls [74]. There is a clear relationship between the severity of the CYP21A2 mutation and the fertility rate, as we found no term pregnancy in the null genotype group, 13 % in I2 splice, 33 % in I172N, and 50 % in the group with NCAH mutations [67]. Polycystic ovaries and chronic anovulation secondary to androgen excess may be a contributing factor [17]. In our cohort of classic and NCAH women, the main reason for lower fertility was that few had tried to conceive. All who had tried to conceive had succeeded, occasionally after medical intervention, except for a few of the older patients [67]. It is important to suppress the progesterone levels to achieve pregnancy. Both homosexuality and bisexuality occur

Fig. 4 Bi- or homosexual orientation and having no partner among 62 adult women with a 21-hydroxylase deficiency, divided into different CYP21A2 genotype groups, and 62 age- and sex-matched controls. From Friseń et al. [79]. Copyright 2009, The Endocrine Society

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avoided because it is not inactivated by placental 11b-hydroxysteroid dehydrogenase type II [33] and may lead to a negative long-term effect on the offspring [82–84]. The Endocrine Society states that prenatal treatment of CAH with dexamethasone should only be administered in ethically approved clinical studies [33]. The outcome of the children to mothers with CAH is, in general, excellent [54]. One study found an increased frequency of small for gestational age (SGA) (16 %) in a cohort of both classic and NCAH babies [72]. When only the newborn to NCAH mothers were analyzed, the occurrence was even higher (2 out of 5, i.e., 40 %). In contrast, we found no case of SGA, malformation, or virilization in our cohort of both classic and NCAH mothers [67]. The preterm delivery rate of 3.0–4.3 % in NCAH and 1.0 % stillborn infants at term appears to be similar to population data [49, 50]. For unclear reasons, there may be more girls than boys born to mothers with CAH [67]. A review of several studies reported twice as many girls as boys [54]. The long-term follow-up of the offspring has shown normal physical and intellectual development [67, 72], but the risk of a mother with NCAH to have a child with classic CAH was reported to be 1.4–2.5 % and more than 14.8 % were affected with NCAH [49, 50] (Fig. 3). One explanation for this exceptionally high risk could be that these studies may have included populations in which the frequency of NCAH and consanguineous marriages within the ethnic subpopulation are common [54].

Male fertility Fertility in males with classic CAH has been reported to be compromised [60, 74, 85–87]. Impaired sperm quality occurs frequently, as well as low fecundity [86, 88–90]. There is, however, one report on CAH males with normal fertility, but it is from the 1970s when no genetic confirmation of the diagnosis was possible [91]. Fertility can be hampered by both undertreatment [92] and overtreatment with glucocorticoids [90]. The high frequency of testicular adrenal rest tumors (TARTs) in classic CAH males is considered to be the most important reason for fertility issues [92]. Nevertheless, CAH males with TARTs may father children [54, 86]. Fertility and TARTs have only been reported in a few patients affected by NCAH [86]. The largest study ever on CAH, including 253 males, 19 of which had NCAH, found an odds ratio of 0.4 for having children on comparing with 25,300 matched controls [74]. In males with NCAH, fertility did not differ significantly from controls; however, due to the low numbers of patients, this may have been caused by a lack of power. In summary, it is difficult to draw any conclusions about fertility in males with NCAH.

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Quality of life Reports on quality of life (QoL) in CAH are inconsistent. Varying degrees of impaired QoL have been described [59, 60, 74, 79, 93–96]. In a few publications, no difference from controls was found [97–99] and, in one study, even a better QoL compared to controls was reported [100]. Moreover, CAH patients were reported to have a better QoL compared to patients with primary adrenal insufficiency [94]. The likely explanation is that patients with congenital disorders have never experienced a time without their disorder, in contrast to patients with an acquired disorder [54]. The choice of glucocorticoid preparation has been reported to affect QoL, with prednisolone or dexamethasone resulting in a worse QoL in one study [101], while another including only males, showed worse outcomes with hydrocortisone/cortisone acetate than in controls and patients treated with prednisolone [99]. Both the CYP21A2 genotype group and the genital operative procedure affected the overall QoL in adult CAH females [102], with less sexual satisfaction being reported in the null genotype group compared to the other genotype groups [103]. However, all or the majority of CAH patients included in QoL studies have had the classical phenotype. NCAH individuals have not had genital surgery and have often been exposed to a long period of hyperandrogenism before diagnosis; hence, their QoL may differ from classic CAH. In an epidemiological study including 75 individuals with NCAH (56 females), the patients had worked during longer periods and had fewer sick leaves, but they had more disability pensions and social welfare benefits (only women) compared to 75,000 controls [74].

Psychiatric diseases Psychiatric morbidity has only been reported in one study on CAH individuals [104] in which only males were included. Generally, males with CAH had a higher occurrence of any psychiatric disorder, suicide or suicide attempts, and alcohol misuse. When NCAH males were analyzed separately only the frequency of psychotic disorders was raised compared to controls [104]. However, these results should be interpreted with caution, since the number of patients with psychiatric diagnoses was small.

Bone mineral density and fractures Supraphysiological glucocorticoid treatment is harmful to the preservation of bone mass via multiple mechanisms [105] and leads to osteopenia, osteoporosis, and,

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ultimately, fractures. Osteoporosis can be treated and measurements of bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) are important when estimating the fracture risk. Most studies using DXA have reported impaired BMD values in adult CAH [12, 55, 60, 96, 106–114], but a few have shown normal BMD [115– 118]. Longer-acting glucocorticoids seemed to result in a higher risk of negative effects on BMD than hydrocortisone [55, 109, 114], and the glucocorticoid dose appeared to be negatively correlated with BMD in some [107, 109, 110, 119], but not all studies [12, 55, 106, 111, 114–118]. Individuals with NCAH often are not started on glucocorticoids, if ever, until young adulthood when they are diagnosed, and thus have been exposed to elevated androgens for a prolonged period of time, which may lead to an increased BMD. In fact, adults with NCAH had a normal BMD and better values than adults with classic CAH [106, 112, 119]. This has also been demonstrated in children [120]. In contrast, some studies have shown a similar frequency of osteoporosis or decreased BMD in NCAH compared to classic CAH [12, 96, 116, 119]. Fracture prevalence has occasionally been reported in CAH [55, 106, 112, 114], and patients with NCAH seem to have experienced fewer fractures than those with the more severe forms [106, 112].

Mortality The apparent incidence of CAH has increased dramatically during the past century. According to a report from Sweden, it has increased from fewer than one CAH person per million live-births 100 years ago to more than one per 8800 live-births today [26]. The obvious reasons are the introduction of glucocorticoids at the beginning of the 1950s, better awareness of the disease, and introduction of neonatal screening. In the past, both male and female infants with the most severe pheno- and genotypes probably died undiagnosed [26]. Thus, the mortality was very high. Only two studies have reported on mortality in diagnosed CAH individuals [53, 121]. The first was from the UK and reported a mortality excess of 3 times than expected [121]. However, on analyzing subgroups, mortality was only significantly increased at ages 1 to 4 years, but not at older ages and only in CAH girls with an Indian subcontinent ethnicity. Only patients with SW CAH had an increased mortality and most of the deaths appeared to be due to adrenal crisis. The cohort was a mix of different variants of CAH, no CYP21A2 mutation analysis had been performed, and most were children, with only few adults included. The second study was recently published by us from Sweden [53]. A similar increase in the mortality rate was found, but the mortality was not concentrated over a

narrow age span. On average, CAH patients died 6.5 years earlier than matched controls, and the mortality was also increased in NCAH. The causes of death were adrenal crisis (42 %), cardiovascular events (32 %), cancer (16 %), and suicide (10 %). However, in some of the cardiovascular deaths, a severe infection was also reported on the death certificate; hence, perhaps at least 58 % were related to adrenal crisis. Two thirds of those with a known NCAH phenotype died of a cardiovascular condition and one-third of an adrenal crisis, but all cardiovascular cases had a concurrent severe infection, i.e., all may be related to adrenal crisis. This highlights the need for stress dosing of glucocorticoids also in NCAH patients on glucocorticoid treatment. The mean age at death increased successively over the decades. The risk for adrenal crisis in patients with NCAH never treated with glucocorticoids is, however, probably low, but an ACTH stimulation test should be performed to evaluate the cortisol response (see Treatment above).

Cardiovascular and metabolic complications The glucocorticoid doses required to suppress the androgens in CAH usually result in overtreatment and may lead to an increased risk of obesity, type 2 diabetes, dyslipidemia, and hypertension, i.e., the metabolic syndrome, and cardiovascular morbidity and mortality. To date, neither increased cardiovascular morbidity and mortality nor an increased prevalence of type 2 diabetes has been demonstrated in CAH patients [54]. This is to be expected since glucocorticoids have only been available since the 1950s and very few patients are older than 50 years of age [54]. We have previously reported an increased incidence of gestational diabetes, a strong predictor of future type 2 diabetes, in CAH women [28, 67]. In contrast, we could not demonstrate a significant increase in cardiovascular mortality in the Swedish patients, as compared to controls (32 vs. 27 %, P [ 0.05) [53]. Obesity A well-known risk factor for type 2 diabetes and cardiovascular morbidity and mortality is obesity, particularly visceral obesity. Most studies report an increased body mass index (BMI) in adults and children with CAH [12, 60, 87, 96, 110, 114, 117, 120, 122–126], but not in all [10, 65, 113, 127, 128]. Obesity was equally as prevalent in NCAH as in classic CAH in some studies [12, 65, 96, 107, 112, 120], while others showed a lower BMI in NCAH individuals [60]. The results should be interpreted with caution since estimating body fat using BMI can be unreliable, especially in CAH. Intense physical activity, common in

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CAH females [79], or hyperandrogenism due to undertreatment with glucocorticoids, may result in increased muscle mass and overestimating body fat if BMI is used. In contrast, physical inactivity or severe overtreatment with glucocorticoids may result in decreased lean mass and underestimation of fat mass when calculating BMI. DXA is a more precise and reliable method for assessing total and regional fat and also lean body mass than the anthropometric measurements. Most studies of CAH using DXA have found increased fat mass [110, 113, 117, 118, 128]. In contrast, fat mass was similar in younger CAH adult men and women when compared with agematched controls, but it was increased in CAH men over 30 years of age [10, 28]. CAH women over 30 years of age had, in spite of their currently suppressed androgens, increased lean mass [28], possibly reflecting previous undertreatment and/or their lifestyle. Due to the prolonged exposure to androgens, it could be suspected that NCAH would result in increased lean mass. In fact, it has been reported that children with NCAH had decreased fat mass, but increased lean mass, compared to children with classic CAH [65]. Insulin resistance and diabetes mellitus Most reports have shown decreased insulin sensitivity in CAH [10, 65, 125, 129–135], but none has so far reported increased type 2 diabetes [54]. We did, however, find an increased frequency of gestational diabetes, specifically in women with SV and NCAH [18, 28, 67]. Moreover, we demonstrated impaired insulin sensitivity only in patients over 30 year of age [10, 28, 136]. Even though obesity is a strong risk factor for insulin resistance also in CAH, some CAH studies have found increased insulin resistance also in nonobese individuals. When only nonobese women older than 30 were compared with nonobese controls, women with CAH still had increased insulin resistance [136]. In contrast, nonobese men with CAH had similar insulin sensitivity compared to nonobese controls [10]. Interestingly, in a study of children, only those with NCAH and not those with classic CAH were insulin-resistant even though the former had less fat mass [65]. This indicates that a postnatal androgen excess may have adverse metabolic effects on insulin sensitivity since the children with NCAH had been diagnosed 5 years later than those with classic CAH. This is also supported by a Chinese study in which 30 newly diagnosed and untreated nonoverweight young adult women with SV CAH had reduced insulin sensitivity compared to controls [126]. In addition, noncompliant adults showed insulin resistance, while none in the compliant groups did [96]. One study of females with NCAH found similar insulin sensitivity in patients and controls [137]. The diagnosis was not genetically verified,

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however, and none of these patients were on glucocorticoid treatment. Another study showed more insulin resistance in the children with classic CAH, but not in NCAH and no differences were found between the phenotype groups in adults [12]. Supraphysiological glucocorticoid doses are often claimed to be the reason for insulin resistance in CAH, but high androgen levels in females and low testosterone levels in males can result in insulin resistance [138, 139]. Hence, it is possible that too low glucocorticoid doses may also lead to insulin resistance (Fig. 5). Lipids In most studies, the lipid profiles in CAH, in both children and adults on glucocorticoid treatment, have been similar to those in controls [10, 28, 65, 129]. The same is true for untreated children [65] and adults with NCAH [137]. In contrast, Arlt et al. reported that many CAH adults, some obese, had dyslipidemia [60], but this study had no controls, which makes interpretation difficult. Increased triglycerides in nonobese children [140] and lower HDL in children and adults [132], compared to controls, have also been reported. Untreated nonoverweight women with the SV form had higher triglycerides and lower HDL than controls, probably due to severe hyperandrogenism [126]. Liver function tests Mildly elevated liver function test results, still within the normal range, but higher than in controls, particularly tests for gamma-glutamyl transpeptidase (GGT), have been reported in CAH adults [10, 136]. This may indicate nonalcoholic fatty liver disease (NAFLD), but others have not been able to confirm this finding [113]. NAFLD has been found in endogenous Cushing’s syndrome [141], long-term glucocorticoid therapy [142], and PCOS [143]. This suggests that not only glucocorticoids, but also elevated androgens, may lead to NAFLD. Blood pressure Blood pressure has not been shown to be severely affected in 21-hydroxylase deficiency, although studies have shown partly contradictory results [10, 12, 28, 60, 65, 87, 113, 126, 129, 144–151]. In children with classic CAH, blood pressure was normal during the first year of life [150]. In children and adolescents, 6.6 % were reported to have hypertension in a retrospective chart review [148], and ambulatory 24-h blood pressure measurements were elevated overall [145, 149]. Modest blood pressure elevations still within the normal range during daytime [146] and during hospital admission have been reported [147]. Blood pressure levels

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ACTH

Fat mass Glucococoid treatment

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PCOS risk Insulin resistance

and females had higher diastolic blood pressures, but not systolic, compared to the general population [113] and SV patients had higher diastolic blood pressures than the SW group (only one NC included in the study). Otherwise, no correlation was found between blood pressure and genotype groups, glucocorticoid doses, BMI, or fat mass [113]. How the dose was divided over the day in the adults was not reported. Heart rate

Fig. 5 NCAH is, via multiple mechanisms, associated with insulin resistance. In combination with increased androgens, this increases the risk of developing PCOS. While glucocorticoid treatment can lead to increased fat mass and increased insulin resistance, glucocorticoids also inhibit ACTH, resulting in decreased androgens and decreased insulin resistance

correlated with the degree of obesity in some studies [145, 149], whereas obesity was not able to predict hypertension in another study [148]. In children and adolescents with NCAH, single measurements of blood pressure were increased, compared to controls, while the levels in classic CAH were similar to those in controls [65]. In contrast, one study showed that children with classic CAH were more likely to have increased blood pressure compared to NCAH children [12]. The treatment regimen, not only the total dose per day, may be important in this context. A reversed circadian dosing, with the highest dose in the evening, resulted in a mean 24-hour blood pressure that was 1 SDS higher than when the same children were given the highest dose in the morning [63]. In CAH adults, single blood pressure measurements were normal and equal to those in controls in 29 young patients [129] and 61 adult females [28]. Patients and controls younger than 30 years of age were all reported to be normotensive, while in older patients and controls, the percentage with high blood pressure or on antihypertensive medication was similar [10, 28]. Moreover, in 219 adult classic CAH males single blood pressure measurements were lower than national data [87]. In contrast, in a UK national survey (n = 201), the subgroup of females with the classic phenotype showed increased diastolic pressures compared to national data [60]. In 30 untreated SV adult females, mainly systolic, but also diastolic (trend), blood pressures were elevated [126]. Ambulatory 24-h blood pressure measurements in 30 males were similar to those in controls [10], but were found to be generally elevated in 27 CAH adults, compared to BMI-matched controls [144]. Elevated blood pressure was more frequent in classic CAH than in NCAH [12]. In this latter study, the factors that were associated with a raised blood pressure were elevated 17OHP and male gender, but no associations were found with obesity, fludrocortisone dose, BMI, renin, or a family history of hypertension [12]. In another study, both males

An elevated heart rate, a risk factor for cardiovascular and noncardiovascular death independent of other cardiovascular risk factors [152–154], has been shown to be increased in a cohort of classic CAH and NCAH males C30 years, compared to controls [10]. The heart rate was correlated with other cardiovascular risk factors and it was concluded that decreased testosterone levels and increased HbA1c explained half of the increase [10]. In contrast, heart rate was found to be normal in young individuals with CAH [10, 155– 157]. An increased heart rate, with 24-h ambulatory monitoring, has also been found in adults (only one NCAH included), compared to BMI-matched controls [144]. Intima-media thickness In both children and young adults with CAH, intima-media thickness, a predictor of clinical arteriosclerosis and associated with cardiovascular risk, has been found to be increased compared to controls [129, 135]. However, in a cohort of CAH adolescents, no increased intima-media thickness was seen, but, instead, another surrogate marker for atherosclerosis, vascular endothelial and smooth muscle dysfunction, was demonstrated [151]. In none of these studies were individuals with NCAH included.

Tumors A high prevalence of benign tumors has been found mostly in classic CAH, but sometimes also in NCAH, mainly of adrenal and testicular origin [29, 86–88, 90, 158–160]. It has been speculated that individuals with CAH may have an increased risk for malignant tumors [161, 162], but cancer mortality has not been shown to be increased, compared to controls [53]. Testicular adrenal rest tumors, TARTs The testes and aberrant adrenal cells descend together during the embryological period in most, but not all, males. If these aberrant cells are stimulated, TARTs can occur. Undertreatment with both glucocorticoids and mineralocorticoids in

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CAH may stimulate the growth of TARTs since they have receptors for both ACTH and angiotensin II [163]. CAH patients without aberrant adrenal cells within their testes will never develop TART, which explains why some patients with poor compliance never develop TARTs. However, a recent study found both adrenocortical and Leydig cell features in TARTs, suggesting a totipotent embryonic cell origin [164]. TARTs are usually located in the rete testis, which makes them difficult to detect by palpation if \2 cm and increases the risk of obstruction of the seminal ducts, with subsequent permanent testicular damage [92]. TARTs have been reported in all ages, down to children 6 years of age [165, 166] and have even been noted at autopsy in newly born CAH boys [167]. There seems to be an increase in the prevalence during childhood and adolescence [168]. The highest prevalence of TARTs reported was 86–94 % [86, 88], while others have reported lower frequencies, probably reflecting differences in the mode of detection (palpation, ultrasound, or MRI) and the age of patients [60, 85, 87, 89– 91, 158, 169–172]. TARTs have mostly been reported in classic CAH and may be more prevalent in the more severe pheno- and genotypes [158, 170], but males with NCAH have been reported to have them as well [86]. Ultrasound and MRI demonstrated TARTs equally well down to a size of 0.2 cm [173]. TARTs are considered to be the most important cause of CAH male infertility [86, 92]. In order to improve fertility and diminish the size of the TARTs, increased doses of corticoids can be tried. As a last resort, testis-sparing surgery might be considered in order to improve fertility. The results of surgery on fertility have been highly variable [174–176] and, in one of these studies, the recommendation was that surgery is only indicated for relief of pain and discomfort caused by the TARTs [176]. Surgery should probably only be considered for long-standing TARTs when testicular biopsies have demonstrated viable testicular tissue since surgery to improve fertility is uncertain. It is essential to increase awareness of these benign tumors among clinicians and pathologists in order to avoid unnecessary orchidectomy for a suspected malignancy. In two different studies on adults, 6–7 % had previously undergone unnecessary testicular surgery for a suspected malignancy [60, 86]. Adrenal tumors Long-standing exposure to elevated ACTH secretion may lead to hyperplasia of the adrenal cortex [5], and subsequently tumor formation [29, 160, 177]. If computer tomography (CT) or MRI are performed, adrenal tumors are often detected with a frequency of 11–82 % [158–160], and with less than a third of the adrenals being normal. More than half of the tumors have been reported to be myelolipomas [158], which, occasionally, can be huge [178]. The size of the tumor, but also of

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both the adrenals, correlated positively with current elevated hormone levels [158, 159]. Adrenal tumors are also seen in 45 % of CAH carriers [160], i.e., individuals with CYP21A2 mutations on only one allele. Thus, undiagnosed CAH individuals and CAH carriers may be overrepresented in cohorts of patients with adrenal incidentalomas. In fact, in studies of patients with uni- or bilateral adrenal adenomas, 16 % were CYP21A2 carriers and 2–6 % had undiagnosed CAH [179– 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, 180–182, 185]. In some of these cases, the diagnosis of CAH, both classic and NCAH, was made on the urinary steroid profile sampled in the work-up of suspected adrenocortical cancer [24, 29, 185]. Even though adrenocortical cancer is rare in CAH, there are occasional case reports on previously both diagnosed and undiagnosed classic CAH [162, 186] and on undiagnosed NCAH [187, 188]. Thus, when tumors are found, a conventional evaluation should be performed to exclude other types of tumors that demand treatment.

Clinical outcome of vocal pathology in females The laryngeal tissue mass is increased by elevated androgen levels, with longer and thicker vocal folds resulting in a lower fundamental frequency of the voice. Women with CAH had more issues with their voice in their daily life and spoke with a lower mean, lower minimum, and lower maximum fundamental frequency, in addition to having a deeper voice compared to controls [189]. Voice problems were related to a late CAH diagnosis and poor compliance; however, there were a few patients who had a normal voice despite compliance issues and a late diagnosis [189]. Among women with CAH, 7 % had voice problems related to virilization, but, according to the patients’ own ratings of dark voice, 45 % were affected [190]. Half of the women with NCAH had a subjectively dark voice [190]. Long periods of high androgen levels must be avoided, also in NCAH, to prevent irreversible voice changes and a referral for voice assessment should be considered.

Conclusion NCAH is a common disorder, but most cases are probably never diagnosed, or they may be misdiagnosed as PCOS. Undiagnosed NCAH may result in hirsutism,

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oligomenorrhea, acne, infertility, miscarriage, alopecia, voice problems, and adrenal and testicular tumors, among other symptoms, in men and women, respectively. A baseline measurement of 17OHP can be used for diagnosis, but the ACTH stimulation test with measurement of 17OHP is the gold standard. We advocate CYP21A2 mutation analysis to verify the diagnosis and for genetic counseling. In addition, it can give prognostic and treatment guidance. Treatment is symptomatic and glucocorticoids are usually used, which will lead to a secondary cortisol insufficiency. Glucocorticoids will improve fertility and other symptoms, but they may result in long-term complications, such as obesity, insulin resistance, hypertension, osteoporosis, and fractures. Complications seen in NCAH patients have been assumed to be related to glucocorticoid treatment, but some may, in fact, be associated with prolonged hyperandrogenism. Monitoring of various risk factors and negative consequences should be performed regularly in an attempt to improve the clinical outcome. However, much of the information regarding, among other things, insulin resistance, obesity, blood pressure, cardiovascular disease, and mortality are quite limited because this information is derived from small nonrandomized control studies. More studies focusing on the particular difficulties patients with NCAH are facing, both in cases with a late clinical diagnosis and those with a neonatal diagnosis through screening, are warranted.

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Acknowledgments This study was supported by the Magnus Bergvall Foundation, Karolinska Institutet, and the Stockholm County Council. Conflict of interest The authors declare that they have no conflicts of interest. 15.

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Congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency.

Comments about the need for prenatal treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Prenatal diagnosis of 11beta-hydroxylase deficiency congenital adrenal hyperplasia.

Classic congenital adrenal hyperplasia: A delayed presentation.

First trimester prenatal treatment and molecular genetic diagnosis of congenital adrenal hyperplasia (21-hydroxylase deficiency).

Congenital adrenal hyperplasia: issues in diagnosis and treatment in children.

Comments to "A rational, non-radioactive strategy for the molecular diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency"

Concurrence of Meningomyelocele and Salt-Wasting Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency.

Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Recent advances in biochemical and molecular analysis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Genetic basis of endocrine disease 2: congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: a review of current knowledge.

Non-Classic Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency that Developed into Symptomatic Severe Hyponatremia.

Increased psychiatric morbidity in men with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Cortical bone mineral density in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Unusual heterozygotes of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Congenital adrenal hyperplasia: Treatment and outcomes.

Prevalence of nonclassic congenital adrenal hyperplasia in Turkish children presenting with premature pubarche, hirsutism, or oligomenorrhoea.

Images in clinical medicine. Congenital adrenal hyperplasia.

Novel treatment strategies in congenital adrenal hyperplasia.

Monitoring treatment in congenital adrenal hyperplasia.

Prenatal treatment of congenital adrenal hyperplasia.

Dexamethasone treatment for congenital adrenal hyperplasia.