The Rare Genetic Steroid Disorders Consortium
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Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders caused by mutations in genes which encode the enzymes involved in one of the steps of adrenal steroid synthesis. These defects result in the absence or the decreased synthesis of cortisol from its cholesterol precursor. Depending on the specific enzyme defect, there is androgen excess or androgen deficiency. Aldosterone deficiency is also dependent on the specific enzyme defect. Symptoms due to CAH can vary from mild to severe depending on the degree of the enzymatic defect. For a summary of the typical findings of the forms of CAH studied by the RGSDC, see: Table 1.

Figure 1: Steroid Pathway Diagram
Figure 1. Scheme of Adrenal Steroid Synthesis. Click on the image to see a larger view.

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Disorders of Androgen Excess

21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia

Over 90% of cases of congenital adrenal hyperplasia (CAH) are the result of 21-hydroxylase deficiency (21-OHD). 21-OHD CAH is divided into two groups: the more severe "classical" forms and the milder "nonclassical" form, both of which are due to mutations in the CYP21 gene. In both forms, the 21-hydroxylase enzyme activity is decreased or absent, which results in accumulation of cholesterol precursors that are converted instead to sex steroids, which do not require 21-hydroxylation for synthesis. Classical CAH is composed of two forms: salt-wasting and simple virilizing. The salt-wasting form exhibits aldosterone deficiency, which affects the ability to retain salt, while both forms demonstrate virilization as a result of androgen excess. Due to prenatal exposure to high levels of testosterone, classically affected female fetuses experience virilization (masculinization) of the genitalia prenatally and present with genital ambiguity at birth; however, prenatal treatment of CAH with dexamethasone to prevent genital ambiguity has been successfully utilized for over a decade.

In the less severe, late-onset form of CAH, prenatal virilization does not occur.  This milder enzyme deficiency was termed "nonclassical" 21-hydroxylase deficiency (NC21OHD) in 1979. It is associated with distinct genetic mutations, and was found to be the most common autosomal recessive disorder in humans. Disease frequency of NC21OHD varies among ethnic groups, with the highest ethnic-specific disease frequency in Ashkenazi Jews at 1/27. In the heterogeneous population of New York City, the frequency is 1/100. Similar to classical CAH, nonclassical 21-hydroxylase deficiency may cause premature development of pubic hair, advanced bone age, accelerated growth velocity and diminished final height in both males and females. Women may present with symptoms of androgen excess, including hirsutism, acne, temporal baldness, and infertility. Menarche in females may be normal or delayed, and secondary amenorrhea is a frequent occurrence. Polycystic ovary syndrome may also be seen in these patients. In males, early beard growth, acne, and growth spurt may prompt the diagnosis of NC21OHD. Although many males appear to be asymptomatic, they may present with oligozoospermia, or diminished fertility and fecundity. Individuals presenting to dermatology and infertility clinics with symptoms of hyperandrogenemia are rarely screened for NC21OHD. Children under 5 with unusually fast growth (ultimately causing premature bone closure and short stature) or with premature adrenarche or pubarche are at risk for nonclassical CAH. Thus, tall stature, body odor, or pubic hair in prepubertal children should prompt consideration of this diagnosis. With hormonal and molecular genetic screening, adult and pediatric patients may be identified and treated with glucocorticoids, which have been shown to reverse symptoms within 3 months. This mild disorder is underdiagnosed.

Figure 2. Clinical spectrum of classical and nonclassical 21-hydroxylase deficiency
Figure 2. Clinical spectrum of classical and nonclassical 21-hydroxylase deficiency. Click on the image to see a larger view.

Diagnosis

All individuals who have classical CAH are at risk of life-threatening adrenal crisis unless they receive proper treatment. However, even people with nonclassical CAH may experience adrenal crisis following stress; therefore it is important to make the diagnosis and counsel the patient.

Classical and nonclassical 21-OHD CAH are diagnosed by serum elevations of the hormone 17-hydroxyprogesterone before and after a 60-minute adrenocorticotropin (ACTH) stimulation test (Figure 3). Confirmation by molecular genetic analysis of the CYP21 gene is advised.

<b>Figure 3. </b>Nomogram relating baseline to ACTH-stimulated serum concentrations of 17-hydroxyprogesterone (17-OHP). The scales are logarithmic. A regression line for all data points is shown.
Figure 3. Nomogram relating baseline to ACTH-stimulated serum concentrations of 17-hydroxyprogesterone (17-OHP). The scales are logarithmic. A regression line for all data points is shown. Click on the image to see a larger view.

Prenatal diagnosis : Prenatal diagnosis and treatment are available. Prenatal diagnosis is done by analysis of fetal DNA obtained by amniocentesis or chorionic villus sampling (CVS). Prenatal treatment with the drug dexamethasone prevents virilization of the genitalia of classically affected females and must be started prior to the 9th week of pregnancy, as outlined in the algorithm below (Figure 4).

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Figure 4. Algorithm for prenatal diagnosis and treatment of CAH. Click on the image to see a larger view.

Newborn Screening

Newborn screening for 21-hydroxylase deficiency congenital adrenal hyperplasia is now mandated or conducted in 33 states: Alaska, Alabama, Arizona, Colorado, Connecticut, Delaware, Florida, Georgia, Hawaii, Illinois, Indiana, Iowa, Maine, Maryland, Massachusetts, Michigan, Minnesota, Mississippi, Missouri, Montana, Nevada, New Jersey, New Mexico, New York, North Carolina, North Dakota, Oklahoma, Ohio, Oregon, Pennsylvania, Rhode Island, South Carolina, Tennessee, Texas, Vermont, Virginia, Washington, Wisconsin, and Wyoming.

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11b-Hydroxylase Deficiency Congenital Adrenal Hyperplasia

The second most common cause of congenital adrenal hyperplasia (CAH) is 11b-hydroxylase deficiency (11b-OHD), representing 5-8% of cases, though it was found to be more common in an Israeli population of Moroccan Jewish origin. Like 21-hydroxylase deficiency, 11b-OHD causes shunting of cortisol precursors into pathways of androgen biosynthesis, producing genital ambiguity in affected girls and postnatal hyperandrogenism in both sexes. Unlike 21-OHD, 11b-OHD is characterized by hypertension. Like 21OHD, there are both severe and mild, late-onset forms.

Diagnosis

Like 21OHD, 11b-OHD is diagnosed following an ACTH stimulation test, though in this case, the important diagnostic hormones are deoxycorticosterone (DOC) and 11-deoxycortisol, both of which are elevated, while plasma renin activity is markedly suppressed. Confirmation by molecular genetic analysis is available but not routine. Prenatal diagnosis and treatment are also available for this form of congenital adrenal hyperplasia.

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Disorders of Androgen Synthesis or Action

17a-Hydroxylase Deficiency (17a-OHD) Congenital Adrenal Hyperplasia

This form of congenital adrenal hyperplasia involves an enzyme that catalyzes more than one reaction, namely both the 17a-hydroxylation and 17,20-lyase reactions (see Figure 1), and both reactions are commonly impaired in the disorder. Affected individuals cannot produce cortisol but synthesize large amounts of corticosterone (a weak glucococorticoid, which mitigates the adrenal insufficiency) and deoxycorticosteroid, which causes hypertension and hypokalemia. Deficiency of 17,20-lyase impairs the ability to synthesize androgens and estrogens and causes male pseudohermaphroditism at birth and failure to virilize at puberty. Affected females have primary amenorrhea and clinical hypogonadism . The typical features of complete deficiency include hypertension and hypokalemia with associated sexual infantilism in genetic females and pseudohermaphroditism and sexual infantilism in genetic males. Nevertheless, there is considerable variability in the clinical and biochemical features, including a few mutations that cause isolated 17,20-lyase deficiency. The age of onset of hypertension and the severity of hypokalemia are highly variable, even among individuals with the same mutations.

This disorder has an estimated frequency in most countries of about 1:50,000 newborns and accounts worldwide for only about 1% of all cases of congenital adrenal hyperplasia. However, in Brazil 17a-OHD deficiency is the second most common cause of CAH, and this remarkable frequency is the result of two founder effects in areas with high coefficients of inbreeding so that two mutations account for more than 80% of cases in that country.

Diagnosis

Nearly 50 different mutations causing 17a-OH and 17,20-lyase deficiency have been described in the CYP17 gene.

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17b-Hydroxysteroid Dehydrogenase 3 Deficiency

17b-Hydroxysteroid dehydrogenase 3 deficiency is a very rare autosomal recessive form of male pseudohermaphroditism. Affected (46,XY) individuals are insufficiently virilized at birth to be raised as boys, and hence most are raised as girls. At the time of expected puberty, plasma testosterone levels increase, and considerable virilization occurs, similar to steroid 5a-reductase 2 deficiency. Thus, these patients, who are raised as girls initially, often request reassignment to male gender during puberty.

Diagnosis

Plasma androstenedione levels are elevated 10-fold or more, whereas testosterone and dihydrotestosterone levels are in the low or low normal range for normal males. The diagnosis can be made at birth due to genital ambiguity based on the high androstenedione/testosterone ratio (basal or after hCG stimulation). Otherwise, the diagnosis is made at puberty when virilization occurs. Molecular genetic diagnosis is often required to distinguish PAIS, steroid 5a-reductase 2 deficiency, and 17b-Hydroxysteroid dehydrogenase 3 deficiency, due to the similarities and difficulties in establishing these diagnoses.

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Androgen Receptor Disorders: Androgen Insensitivity Syndromes

While complete androgen insensitivity syndrome is a relatively straightforward diagnosis if entertained, the other disorders in this group present difficult diagnostic challenges.

The androgen insensitivity syndromes (AIS) are a family of X-linked disorders in which the fundamental defect is impairment of the function of the androgen receptor (AR) protein causing inability to respond to androgens. Such defects cause a spectrum of abnormalities in genetic males, depending on the severity of the underlying mutations, varying from phenotypic women (complete AIS [CAIS]) to phenotypic women with partial virilization of the external genitalia or men with hypospadias and gynecomastia (partial AIS [PAIS]) to men with infertility and/or minor degrees of undervirilization. Estimates of incidence of CAIS vary from 1 in 20,000 to 1 in 64,000 individuals with a 46,XY karyotype, and the disorder is the third most common form of primary amenorrhea after gonadal dysgenesis and congenital absence of the uterus in phenotypic women. The incidence of PAIS is estimated to be 1 in 30,000 individuals with a 46,XY karyotype. The incidence of AR mutations in men with unexplained infertility has not been established. In summary, the overall incidence of AR mutations may approximate 1 in 10,000 live births with 46,XY karyotype.

Diagnosis

In the phenotypic female, the diagnosis of AIS may be made by the finding of amenorrhea or inguinal hernias containing testes. Chromosomal analysis will reveal a 46,XY karyotype. The diagnosis is confirmed by genetic molecular analysis of the AR gene on the long arm of the X chromosome. Diagnosis of PAIS may be made in the newborn due to ambiguous genitalia.

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5a-Reductase 2 Deficiency

Steroid 5a-reductase 2 deficiency is a rare autosomal recessive form of male pseudohermaphroditism in which affected 46,XY males are born with ambiguous genitalia. Sex assignment and sex of rearing is usually female. Virilization at the time of expected puberty, which can be striking, is either mediated by the circulating dihydrotestosterone derived from the unaffected 5 a -reductase isoenzyme (type 1) or by high testosterone concentrations over a long period of time. Often, patients request reassignment to male gender when they virilize during puberty. The fact that the disorder is due to deficient formation of dihydrotestosterone was deduced in 1974 in studies of families in Dallas and the Dominican Republic. Studies of 5a-reductase activity in cultured skin fibroblasts documented that the disorder was due to loss-of-function mutations that impair only one of the two isoenzymes that perform this reaction, subsequently termed isoenzyme 2.

Diagnosis

The diagnosis is made in undervirilized 46,XY individuals in whom testosterone production is normal or elevated, but circulating dihydrotestosterone concentrations are low. Fourteen mutations in the SRD5A2 gene have been described.

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3b-Hydroxysteroid Dehydrogenase Deficiency

Classical (severe) and nonclassical (mild) forms of 3b-hydroxysteroid dehydrogenase deficiency (3b-HSD) CAH are known. In the classical form, steroid synthesis in both the adrenal cortex and the gonads (testes, ovary) is affected. Circulating androgen precursor steroids are converted outside the adrenal to androgens. Virilization of affected females can occur. In males, prenatal differentiation of the external genitalia is incomplete because of the gonadal defect. Thus, in this disorder genital ambiguity can affect individuals of both sexes. Only in the severe form has a gene for 3b-HSD been identified. The nonclassical form has no demonstrated genetic mutation and seems to wax and wane hormonally.

Diagnosis

3b-HSD is diagnosed following an ACTH stimulation test showing elevation of serum D5-17-hydroxypregnenolone, dehydroepiandrostenedione, and ratios of D5-17 hydroxypregnenolone/17-hydroxyprogesterone and D5-17-hydroxypregnenolone/cortisol. The disorder has an autosomal recessive inheritance. Some 40 mutations in 3ß-HSD type II gene already have been described.

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Low-Renin Hypertension

Apparent Mineralocorticoid Excess

Apparent mineralocorticoid excess (AME) is an extremely rare genetic disorder that causes severe hypertension in children, pre- and postnatal growth failure, low levels of potassium, renin, and aldosterone, and is caused by a deficiency of 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2). This enzyme is important for the conversion of cortisol to its inactive metabolite cortisone at the level of the kidney. This potentially fatal disease is caused by autosomal recessive mutations in the HSD11B2 gene. AME usually presents early in life; however, mild, clinically silent forms have been identified. Recently a mild form of this disorder with specific mutations has been described. This may be a cause of low-renin hypertension, which represents one-third of all forms of hypertension.

Diagnosis

Diagnosis is made by either demonstrating decreased conversion of cortisol to cortisone or by an elevated ratio of THF/THE, urinary metabolites of cortisol and cortisone, respectively. Since 1995, 21 mutations in the HSD11B2 gene have been identified in patients affected with AME.

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