Congenital Adrenal Hyperplasia (CAH) refers to a number of autosomal recessive disorders that are associated with abnormal cortisol production 137.
CAH is primarily due to 21-hydroxylase deficiency, which is responsible for roughly 95% of cases 137. Therefore, this chapter focuses primarily on 21-hydroxylase deficiency-associated CAH.
CAH occurs due to mutations in the CYP21A2 gene, which encodes the adrenal steroid 21-hydroxylase enzyme 138. This enzyme converts 17-hydroxyprogesterone to 11-deoxycortisol (the precursor for cortisol) and progesterone to 11-deoxycorticosterone (the precursor for aldosterone) 137. Therefore, CAH results in the inability to make cortisol and aldosterone, leading to adrenal insufficiency and the accumulation of cortisol precursors that, in turn, lead to an excess of T-like hormones (androgens) in both sexes.
The global incidence of CAH in newborns is roughly 1:16,000 to 1:20,000 139. The incidence in the US is approximately 1:16,000 to 1:18,000 140,141.
There are two types of classic (or classical) CAH, salt-wasting (SW) and simple virilizing. The SW form represents 70% of the classic CAH 142. Untreated infants with SW CAH are at risk for developing life-threatening adrenal crisis from severe cortisol and aldosterone deficiency. Because newborn females with classic CAH undergo prenatal virilization, resulting in sexual ambiguity at birth, they are more likely to get diagnosed in the early days after birth, before the development of an adrenal crisis. In milder or simple virilizing forms of enzyme deficiency, classic CAH might not be recognized and treated early because patients do not develop adrenal insufficiency. Symptoms often occur later, when increased androgen production in affected girls and boys results in rapid growth or early signs of puberty 137.
There is a non-classic form of CAH that is less severe because affected and/or unaffected enzymes are capable of producing enough cortisol and aldosterone to avoid adrenal insufficiency, but the affected enzymes cause a backup of the precursors that result in an excess of T-like hormones. Girls or women present with symptoms of excess T-like hormones, such as unwanted hair growth and severe acne. They might also develop early puberty and/or irregular periods and infertility 137.
While girls with classic CAH usually have ambiguous genitalia (as noted above), boys appear normal. Therefore, in the US and many other countries, clinicians usually screen newborn babies for classic CAH 139. Screening can greatly reduce morbidity and mortality by identifying the severe, SW classic form of the disease before patients develop adrenal crises, particularly among affected boys 139. Males with mild CAH, even those with the SW form, might not be diagnosed until later childhood, when they experience growth problems (or when clinicians diagnose CAH in a younger sibling) 143.
Precise data is lacking regarding the cost of classic CAH. However, it has been estimated that adults with classic CAH would implement “sick day rules” 171 times over their lifetime, doubling or tripling the use of glucocorticoid and/or injectable steroid therapy. These patients might also need hospital treatment for adrenal crisis approximately 11 times over a lifetime 144. It has also been estimated that 20% of patients will die of complications associated with adrenal crisis, resulting in loss of 7 years of life on average 144.
Additional health-related complications are associated with excess corticosteroid use over a lifetime 145. Those with CAH might also experience more illness associated with CVD. In addition, CAH patients using glucocorticoid therapy have nearly twice the risk of bone fractures. Over a lifetime, this will result in an additional 0.8 fractures per CAH patient 144.
6.3.1 Classic Congenital Adrenal Hyperplasia
Table 18 shows the estimated incidence of classic CAH for various populations around the world. Based on New York newborn screening program data, the incidence of CAH in the US is lower in black infants and higher in Hispanic infants than non-Hispanic infants 140 (Table 19).
|US||1:16,000 – 1:18,000|
|Southwestern Alaska (Yupik Eskimos)||1:282|
|La Reunion, France||1:2,141|
Source: Adapted from Pang et al. 1988 146
|CAH Incidence||Total Tested (%)||Referred (%)||Confirmed (%)|
|Male||1:18,280||1,005,444 (51.2)||1,432 (57.8)||55 (50.9)|
|Female||1:18,050||956,856 (48.8)||1,044 (42.2)||53* (49.1)|
|White||1:15,610||874,066 (44.5)||767 (31.0)||56* (51.9)|
|Native American||–||3,009 (0.2)||1 (0.04)||0|
|Asian||1:15,250||137,269 (7.0)||104 (4.2)||9 (8.3)|
|Black||1:24,840||298,057 (15.2)||618 (25.0)||12 (11.1)|
|Hispanic||1:17,450||331,589 (16.9)||552 (22.3)||19 (17.6)|
Source: Pearce et al. 2016 140
CAH is an autosomal recessive disorder. Therefore, males and females are affected equally. However, in the absence of screening, there are reports of CAH diagnosed in more female than male infants (due to ambiguous genitalia present at birth in females). The higher female-to-male ratio of CAH infants without newborn screening is thought to result from unrecognized male infants with CAH who died from adrenal crisis before CAH could be diagnosed 143.
6.3.2 Non-Classic Congenital Adrenal Hyperplasia
Non-classic CAH occurs more frequently in the population, affecting as many as 0.1 to .2 % of Caucasians and 1 to 2% of Ashkenazi Jews 147.
The SW form affects 70% of cases of classic CAH identified by newborn screening programs. These cases are at risk for failure to thrive, and potentially fatal hypovolemia and shock within the first 4 weeks of life 139,142.
Without newborn screening for CAH, it is estimated that the infant mortality rate for the SW classic CAH is as high as 11.9%, 5-fold higher than the general population 148.
A review by Grosse and Vliet reported that the infant SW CAH mortality rates are estimated between 0 to 1.5% in cohorts with newborn screening 143. However, due to a lack of global screening, undiagnosed cases, and unrecognized deaths from CAH, the actual SW CAH mortality rate could be higher 143.
|Study||Screening||Birth Years||Prevalence SW-CAH||F-M ratio||Deaths|
|Thilen and Larson, 1990||No||1969-1986||1:18,600*||2||2.2|
|Van der Kamp et al. 2001||No||1988-1999||1:13,100||0||0|
|Van der Kamp et al. 2001||Yes||1988-1999||1:13,600||0||0|
|Brosnan et al. 1999||No||1989-1994||1:20,000||0||0|
|Brosnan et al. 1999||Yes||1989-1994||1:21,800||1||1.4|
Source: Grosse et al. 143
18.104.22.168 Feminizing Surgery
Clinicians still debate the optimal timing of surgical procedures, such as vaginoplasty, perineal reconstruction, and clitoroplasty. Vaginal reconstruction might be technically easier in the neonatal period with recent estrogen exposure from the placenta during pregnancy. However, delayed surgery results in a possible lower risk of vaginal stenosis and the need for vaginal dilation 137. For patients and their families, considerations include the effects on their mental health and the patient’s mental health if surgery is delayed; although, the delay would allow for patient participation in decision-making about surgery that might impair sexual function. Currently, pediatric endocrinologists work with families, and also (ideally) with a team of mental health professionals, social workers, and experienced surgeons 149. There is a great need for studies of outcomes for techniques and other issues, such as optimal timing and how to individualize the approach to the patient.
Targeted areas for improvement in the treatment of CAH include therapies that will limit the risks associated with exposure to excess corticosteroids. There are current clinical trials of drug therapies for CAH, such as Chronocort® 150 and a solucortef cortisol pump 151. Both of these medications attempt to limit side effects of excess corticosteroids by utilizing different corticosteroid formulations or delivery methods that are more physiologic.
A second group of drugs reduce the androgen production precursor backup before the enzyme block. In addition to avoiding the use of excess corticosteroids usually needed to treat or control elevated androgens in children, adolescents, and adult women, these new treatments could avoid the need for expensive treatments, such as GnRH agonists to delay early puberty and/or growth hormone treatments to help optimize height potential for children. These drugs include orally administered ATR-101 152 and abiraterone. A recent study reported that 100-250 mg/day of abiraterone acetate combined with replacement hydrocortisone normalized several measures of androgen excess in women who had classic CAH and elevated serum androstenedione 153. Currently, abiraterone acetate is in the first Phase 1 trial for pre-pubescent children with classic CAH 154.
22.214.171.124.1 Prenatal Treatment
For women who have previously had a child born with CAH and become pregnant again with the same partner, the fetus has a one in four chance of also having CAH. Because of the significant impact of ambiguous genitalia for the patient and their families, researchers have studies and developed experimental use of dexamethasone during pregnancy to normalize fetal androgens. The earliest time to perform a genetic test for CAH via chorionic villus sampling would be after excess fetal androgens have already affected fetal genital development in a female (10- to 12-weeks). Therefore, while early dexamethasone treatment is necessary as soon as pregnancy is diagnosed, it introduces the risk of unnecessary fetal and maternal steroid-exposure in infants without CAH and male infants with CAH who would not benefit from this treatment.
There are a few small cohort studies regarding outcomes of prenatal treatment for CAH. Although they generally agree that virilization is reduced in 80-85% of treated pregnancies, future studies are needed before prenatal treatment can be recommended 137.
Fetal dexamethasone treatment could be associated with reduced birth weight or other cognitive or behavioral problems. However, no studies (to date) regarding children with CAH treated with dexamethasone during pregnancy have reported any significant adverse outcomes 137,155-158. Maternal exposure to dexamethasone steroid treatment can also increase the risk for pregnancy-associated weight gain, hypertension in pregnancy, preeclampsia, and gestational diabetes. Although studies do not report that prenatal dexamethasone steroid treatment is associated with serious health risks for pregnant mothers, there have been reports of side effects that could be attributed to dexamethasone and weight gain; although the reports often did not include a control group 137,155-158.
6.5.2 Health Outcomes
In patients with CAH, elevated androgens in early puberty and prematurely advanced bone age results in lower achieved height than predicted (based on parental heights). Excess corticosteroid exposure might also be responsible for impaired growth 137.
According to a meta-analysis that included data from patients with classic CAH at 18 centers worldwide, mean adult height of was 1.37 SD (10 cm) below the mean. The meta-analysis also reported that patients diagnosed before reaching 1 year of age had increased adult height (0.54 SD) 159. Adolescents with classic CAH have an attenuated pubertal growth spurt 160. In spite of this, patients with classic CAH who strictly adhere to thrice-daily medication and monitoring every 3 months can reach approximate target heights 160-162. Therefore, vigilance regarding treatment is important during the first 2 years of life and during puberty to optimize height. Patients who have NCCAH can also experience reduced adult height, but the height deficit is not as severe as with classic CAH.
Important to note, there is limited evidence that initiation glucocorticoid treatment before puberty will improve adult height in those with NCCAH 163,164. Similarly, there are limited studies evaluating drugs that enhance growth in children with classic CAH.
We need studies of newer agents that limit androgen excess and/or new strategies utilizing currently available agents to promote growth or delay puberty to help optimize height potential.
Studies on fertility in CAH males are inconclusive 165-168. One study reported substantially reduced fertility (243) and another reported normal fertility 165.
As males with CAH age, there is an increase in testicular adrenal rest tumors, which impairs fertility. Depending on the study population, the reported prevalence of these tumors ranges from 0-94%, 165,166,169.
The suppression of gonadotropin secretion by adrenal steroids may also impair fertility in males with CAH if they do not receive adequate doses of glucocorticoids 168. In addition, men with CAH had fewer steady heterosexual relationships, compared to age-matched controls, which might point to psychosocial factors that affect fertility 167.
In a fertility study of women with CAH conducted by Hagenfeldt et al., pregnancy and delivery rates are significantly lower, despite fertility treatments 170. The percentage of women with CAH who tried to become pregnant was 30% compared to 66% of controls,; in addition, 50% of women with NCCAH, 30% of women with simple virilizing CAH, and 7% of women with SW CAH had children 170.
126.96.36.199 Cardiometabolic Risk
A study by Finkielstain et al. reported the adolescents and adults with CAH had a high prevalence of overweight, obesity, insulin resistance, high body mass index, and hypertension (elevated blood pressure was more present in classic CAH than non-classic CAH patients). In additional, 18% of adults had MetS 171.
The UK cohort study of adults with CAH (referenced above) reported that CAH patients had a higher body mass index in comparison with matched controls 172. The reported prevalence of comorbidities included obesity (41%), hypercholesterolemia (46%), and insulin resistance (29%), but there was no comparison to a matched control group for the latter two conditions 172.
Future studies should examine how types of treatment or adjusting treatment protocols could prevent the development of cardiometabolic conditions and risk factors.
188.8.131.52 Additional Comorbidities
Finkielstain et al. reported that 61% of CAH patients had low vitamin D and 37% of CAH adults had low bone mineral density 171. The UK cohort noted the osteopenia was present in 40% of adults and osteoporosis in 7% 172. Thirty-two percent of classic CAH and 59% of non-classic CAH women had hirsutism, and 33% of boys and 44% of adult men with classic CAH had testicular adrenal rest tumors (which can impair fertility) 171.
Women with non-classic CAH were more likely to have irregular periods and insulin resistance (similar to women with PCOS) 171. Insulin resistance is also common in both children with classic CAH (27%) and adults with classic (38%) and non-classic CAH (20%) 171.
Future studies are needed to characterize both the risk factors for co-morbidities and the best treatment regimens to lower the risk for developing health conditions.
184.108.40.206 Mental Health
The study of 203 United Kingdom UK adults with CAH (referenced above) also measured anxiety and depression. Scores for anxiety and depression ranged from normal (0-7) to mild (8-10), moderate (11-14), and severe (15-21). Only females with classic and non-classic CAH suffered mild anxiety; neither males nor females suffered from depression (see Table 21) 172.
|Male classic CAH (n = 33/62, 51%)||Age- and sex- matched controls (n = 165)||Female classic CAH (n = 65/103, 63%)||Age- and sex- matched controls (n = 325)||Female non-classic CAH (n = 31/31, 100%)||Age- and sex- matched controls (n = 155)|
|HADS anxiety score|
|Median (IQR)||6.5 (3.3-8.0)||3.0 (2.0-4.3)||9.0 (6.0-12.5)||4.0 (2.0-6.0)||8.0 (5.0-11.0)||4.0 (2.0-7.0)|
|HADS depression score|
|Median (IQR)||2.0 (1.0-5.5)||2.0 (0.8-4.0)||5.0 (1.0-7.0)||2.0 (1.0-5.0)||4.0 (1.5-9.0)||3.0 (1.0-6.0)|
Source: Arlt et al. 2010 172
220.127.116.11.2 Psychosocial Problems Specific to Disorders of Sexual Development
The recommendation of existing clinical guidelines 149,173-177 is that patients with psychosocial problems specific to disorders of sexual development (DSD) receive care from interdisciplinary teams that include mental health staff with expertise in managing DSD.
CAH, while a subtype of DSD 177, is not equal to other forms of DSD that have less well-defined outcomes. Mental health clinicians can manage those general psychosocial and psychiatric problems that are not specific to CAH. However, patients who have CAH and are 46,XX are may also have to cope with problems that are more specific to DSD, such as 1) gender assignment at birth when there is marked genital virilization; 2) decisions concerning gender-confirming genital surgery in infancy and early childhood (that is not medically necessitated); 3) medical education and counseling regarding psychosocial prognosis and managing parental distress; and 4) referral to experts for psychological gender evaluation and counseling regarding potential gender reassignment of 46,XX CAH patients seeking gender change 178.
Additional issues specific to DSD that require patient/family counseling include: gender-atypical behavior, preparation for surgery, bisexual and homosexual attractions (increased in 46,XX CAH women, however limited to a minority) 179, social fit, sexual functioning, general quality of life, and concerns about inappropriate curiosity or frank stigmatization by family/peers/lovers regarding gender-atypical features. Ideally, mental health staff with DSD expertise should manage these DSD-related problems using educational websites 180, clinical guidelines 149,173-177,181,182, and long-distance consultation with specialists by e-mail or phone.