Congenital Adrenal Hyperplasia Clinical Presentation

The clinical phenotype of congenital adrenal hyperplasia depends on the nature and severity of the enzyme deficiency. The most common form is 21-hydroxylase deficiency (CYP21). Approximately 50% of patients with classic congenital adrenal hyperplasia due to CYP21A mutations or deletions have salt wasting due to inadequate aldosterone synthesis. Although the information below is presented according to chromosomal sex, the sex of a neonate with congenital adrenal hyperplasia is often initially unclear because of genital ambiguity.

Clinical presentation in females

Females with severe forms of adrenal hyperplasia due to deficiencies of 21-hydroxylase, 11-beta-hydroxylase or 3-beta-hydroxysteroid dehydrogenase have ambiguous genitalia at birth due to excess adrenal androgen production in utero. This is often called classic virilizing adrenal hyperplasia.

Mild forms of 21-hydroxylase deficiency in females are identified later in childhood because of precocious pubic hair, clitoromegaly, or both, often accompanied by accelerated growth and skeletal maturation due to excess postnatal exposure to adrenal androgens. This is called simple virilizing adrenal hyperplasia.

Still milder deficiencies of 21-hydroxylase or 3-beta-hydroxysteroid dehydrogenase activity may present in adolescence or adulthood with oligomenorrhea, hirsutism, and/or infertility. This is termed nonclassic adrenal hyperplasia. ^[4]

Females with 17-hydroxylase deficiency appear phenotypically female at birth but do not develop breasts or menstruate in adolescence because of inadequate estradiol production. They may present with hypertension.

Clinical presentation in males

21-hydroxylase deficiency in males is generally not identified in the neonatal period because the genitalia are normal. If the defect is severe and results in salt wasting, these male neonates present at age 1-4 weeks with failure to thrive, recurrent vomiting, dehydration, hypotension, hyponatremia, hyperkalemia, and shock (classic salt-wasting adrenal hyperplasia). Patients with less severe deficiencies of 21-hydroxylase present later in childhood because of the early development of pubic hair, phallic enlargement, or both, accompanied by accelerated linear growth and advancement of skeletal maturation (simple virilizing adrenal hyperplasia).

In male infants, the disease may be misdiagnosed as gastroenteritis or pyloric stenosis, with potentially disastrous consequences due to delayed treatment with glucocorticoids.

Males with steroidogenic acute regulatory (StAR) deficiency, classic 3-beta-hydroxysteroid dehydrogenase deficiency, or 17-hydroxylase deficiency generally have ambiguous genitalia or female genitalia because of inadequate testosterone production in the first trimester of fetal life.

Other findings

Hyponatremia, hyperkalemia, and/or hypoglycemia suggests the possibility of adrenal insufficiency.

Hypoglycemia and hypotension may, in part, be due to associated epinephrine synthesis in the adrenal medulla due to cortisol deficiency. Cortisol, perfusing the adrenal medulla from the cortex, normally stimulates phenylethanolamine N -methyltransferase, the last enzyme in epinephrine synthesis.

Children with simple virilizing 21-hydroxylase deficiency or 11-hydroxylase deficiency have early pubic hair, phallic enlargement, and accelerated linear growth and advanced skeletal maturation.

Two forms of adrenal hyperplasia (ie, 11-hydroxylase [CYP11B1] and 17-hydroxylase [CYP17] deficiency) result in hypertension due to the accumulation of supraphysiologic concentrations of deoxycorticosterone. ^[13] This weak mineralocorticoid has little consequence at physiologic concentrations but causes sodium retention and hypertension at the supraphysiologic concentrations that occur in these conditions. One form of adrenal hyperplasia results in isolated aldosterone deficiency without affecting the synthesis of cortisol or sex steroids. This form is due to a defect in enzymatic activities that have variously been termed CMO I, CMO II, 18-hydroxylase, or 18-hydroxycorticosterone dehydrogenase; however, it is currently thought to represent one protein called aldosterone synthetase (CYP11B2).

A study by Carvalho determined that in 46,XX patients with CAH resulting from CYP17A1 defects, diagnostic factors include amenorrhea, absence/sparseness of pubic hair, and ovarian macrocysts (risk factors for ovarian torsion), along with the aforementioned hypertension. CYP17A1 defects are also indicated by high basal progesterone levels in patients with hypergonadotropic hypogonadism. ^[14]

Other forms of adrenal hyperplasia are characterized by disordered genital development in utero, lack of secondary sexual characteristics development, or hypertension. For example, 17-hydroxylase deficiency in females is rarely identified at birth, but these females seek medical attention later in life because of hypertension or failure to develop secondary sexual characteristics at puberty due to an inability to synthesize estrogens. Male patients with this disorder have ambiguous or female genitalia and may be raised as girls and seek medical attention later in life because of hypertension or a lack of breast development.

Patients with aldosterone deficiency of any etiology may present with dehydration, hyponatremia, and hyperkalemia, especially with the stress of illness.

Male or female patients with 11-hydroxylase deficiency may present in the second or third week of life with a salt-losing crisis. However, these patients develop hypertension, hypokalemic alkalosis, or both later in life. This paradox is explained by resistance to mineralocorticoids in infancy and the inability of the elevated deoxycorticosterone levels to replace the deficient serum concentrations of aldosterone in infancy. Upon maturation, mineralocorticoid responsiveness increases, and the elevated concentrations of deoxycorticosterone are sufficient to cause sodium retention, potassium excretion, and hypertension.

Infants with StAR deficiency (lipoid adrenal hyperplasia) usually have signs of adrenal insufficiency (eg, poor feeding, vomiting, dehydration, hypotension, hyponatremia, hyperkalemia). Some patients do not receive medical attention until late infancy. Male patients with this form of adrenal hyperplasia have female or ambiguous genitalia. Female patients have normal female genitalia. A curious observation is that girls who survive develop breasts and menstruate at puberty, suggesting preservation of ovarian steroidogenesis.

Physical findings depend on the nature and severity of the deficient enzyme activity. See the image below.

Steroidogenic pathway for cortisol, aldosterone, and sex steroid synthesis. A mutation or deletion of any of the genes that code for enzymes involved in cortisol or aldosterone synthesis results in congenital adrenal hyperplasia. The particular phenotype that results depends on the sex of the individual, the location of the block in synthesis, and the severity of the genetic deletion or mutation.

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• Deficiencies of enzyme activity involved in cortisol synthesis result in elevations in concentrations of corticotropic hormone (previously adrenocorticotropic hormone [ACTH]) that often cause hyperpigmentation. This hyperpigmentation may be subtle and is best observed in the genitalia and areolae.

• In virilizing forms (ie, 21-hydroxylase deficiency, 11-beta-hydroxylase deficiency, and 3-beta-hydroxysteroid dehydrogenase deficiency), female patients have ambiguous genitalia at birth that range from complete fusion of the labioscrotal folds and a phallic urethra to clitoromegaly, partial fusion of the labioscrotal folds, or both, as shown in the images below.

• This virilization results from the abnormally high concentrations or steroidogenic precursors that are converted to potent androgens, testosterone, and dihydrotestosterone. Dihydrotestosterone is most potent in terms of virilizing the external genitalia and is synthesized from testosterone by 5-alpha reductase, an enzyme that resides in skin of genital tissue. Recently, human steroidogenic tissues have been shown to have the capability of converting precursors like progesterone and 17-OH progesterone to dihydrotestosterone through a "backdoor pathway" that does not involve testosterone in the pathway. ^{[15, 16, 17]}

  A female patient with the 46,XX karyotype with mild virilization due to congenital virilizing adrenal hyperplasia secondary to 21-hydroxylase deficiency. Despite the mild clitoromegaly, this patient has fusion of the labial-scrotal folds and salt wasting.

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  Severe virilization in a female patient with the 46,XX karyotype with congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency. This patient also has salt wasting.

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  • In relatively nonsevere forms, genitalia may be normal at birth, but early pubic hair and clitoromegaly (often accompanied by tall stature) may appear in childhood.

  • In mild forms, excess facial or body hair often appears.

• Male patients with 21-hydroxylase deficiency have normal genitalia but may develop signs of dehydration at age 1-4 weeks if they have salt wasting or may have no problems in infancy but develop a salt-wasting crisis with illness during childhood (classic salt-wasting adrenal hyperplasia). Less-severely affected males may present with precocious development of pubic hair, phallic enlargement, and accelerated growth and skeletal maturation in childhood (simple virilizing adrenal hyperplasia).

• Ambiguous genitalia or female genitalia are also observed in male patients with 3-beta-hydroxysteroid dehydrogenase deficiency, 17-hydroxylase deficiency, and StAR deficiency.

• High blood pressure and, sometimes, hypokalemia may be observed in individuals with 11-beta-hydroxylase deficiency and 17-hydroxylase deficiency. These findings are due to the accumulation of the mineralocorticoid deoxycorticosterone.

The defects that cause congenital adrenal hyperplasia are autosomal recessive disorders due to deficient activity of a protein involved in cortisol synthesis, aldosterone synthesis, or both.

• In most cases, this disorder is due to a mutation or deletion of the gene that codes for the involved protein. When both genes carry the same mutation or deletion, the condition is homozygous. When the 2 affected genes carry different mutations or deletions, the patient is said to be a compound heterozygote. In general, the clinical severity reflects the least affected allele. Carriers or heterozygotes who carry only one abnormal gene are asymptomatic.

• Many of the genes involved in cortisol and aldosterone synthesis code for CYP proteins. The best-studied gene is the 21-hydroxylase gene (CYP21, CYP21A). The 21-hydroxylase gene is located on chromosomal band 6p21.3 among genes that code for proteins that determine human leukocyte antigen (HLA) types. The gene for 21-hydroxylase has a pseudogene (CYP21P) 30 kb away from CYP21 that is 98% homologous in structure to CYP21A; however, it is rendered inactive because of minor differences in the gene. The proximity of CYP21P with CYP21A is thought to predispose the CYP21A gene to crossovers in meiosis between CYP21A and CYP21P, resulting in loss of genetic function.

• Other defects occur because of gene deletions or mutations. Among abnormalities of CYP21A, approximately 95% are thought to be due to recombinations with CYP21P, 20% are thought to represent deletions, and 70% are point mutations. The phenotype depends on the function of the less-severely affected gene rather than on the more severely affected gene because the former determines the level of enzyme activity. In general, genotype-phenotype correlations are strong, although exceptions occur. Because aldosterone secretion is approximately 1000-fold less than cortisol secretion, the enzyme activity required for aldosterone synthesis is less than that required for cortisol synthesis. Therefore, patients with only the most severe loss of function of CYP21A have salt wasting.

• The 11-beta-hydroxylase gene (CYP11B1) is on chromosomal band 8q21. CYP11B1 has no pseudogene, and no HLA association is found. CYP11B1 catalyzes the conversion of 11-deoxycortisol to cortisol in the glucocorticoid pathway and the conversion of deoxycorticosterone to corticosterone in the mineralocorticoid pathway. A neighboring gene codes for CYP11B2, or aldosterone synthetase, which catalyzes the conversion of corticosterone to aldosterone in the zona glomerulosa. Mutations and deletions of the CYP11B2 gene result in diminished aldosterone synthesis. Therefore, individuals with CYP11B2 deficiency develop hyponatremia, hyperkalemia, and dehydration. Sexual differentiation occurs normally because sex steroid synthesis and cortisol synthesis are not impaired. The genes for CYP11B1 and CYP11B2 share 95% sequence homology for coding sequences. Nonetheless, gene conversion from chromosomal crossover at meiosis does not appear to play a major role in the mutations and deletions thatrendereither gene inactive.

• Two tissue forms of 3-beta-hydroxysteroid dehydrogenase are described. Type I occurs primarily in the adrenal and gonad, whereas type II occurs primarily in the placenta and liver. The genes for both forms reside on chromosomal band 1p13. The classic form of 3-beta-hydroxysteroid dehydrogenase deficiency results from mutations or deletions in the gene for the adrenal form of the enzyme.

• Some patients appear to have nonclassic forms of this disease, as evidenced by symptoms and signs of virilization such as hirsutism, oligomenorrhea, and infertility. Laboratory studies may reveal mildly abnormal precursors-to-product ratios (ie, increased ratio of 17-hydroxypregnenolone to 17-hydroxyprogesterone and of dehydroepiandrosterone to androstenedione). These patients have not had mutations or deletions in any of the genes that code for adrenal 3-beta-hydroxysteroid dehydrogenase. The molecular basis for this disorder remains undefined. Clinical and hormonal findings of this condition and polycystic ovary disease overlap considerably. Some patients benefit from suppression of adrenal steroidogenesis with dexamethasone.

• 17-alpha-hydroxylase activity and 17,20-desmolase activities are thought to be due to a single protein (CYP17) with separate enzymatic activity sites.

• Some patients with lipoid adrenal hyperplasia, which was originally thought to be due to deficiency of CYP450 side-chain cleavage (scc) enzyme activity, have had mutations in a gene that codes for StAR. This protein appears to be involved in the transport of cholesterol across the mitochondrial membrane, where CYP450 scc can act on it. This enzyme converts cholesterol to pregnenolone, which is then processed in the various steroidogenic tissues into cortisol, aldosterone, or sex steroids. Thus, a deficiency of StAR results in a global steroid deficiency state. Affected 46 XY individuals may have female external genitalia, and affected 46 XX individuals have normal female genitalia. Both develop signs of adrenal insufficiency with onset from early infancy to age 6 months.

• A curious observation is that females with this disorder who survived as the result of early replacement of glucocorticoids and mineralocorticoid have developed breasts and spontaneous nonovulatory menses at puberty. Researchers postulate that the accumulation of cholesterol esters in steroidogenic cells, which results from StAR deficiency, is eventually toxic to the steroidogenic cells. According to this theory, some ovarian function is preserved because ovarian steroidogenesis does not occur until puberty, and then steroidogenesis occurs in only one follicle at a time, thereby allowing some preservation of steroidogenesis.

• Mutations in the gene that code for CYP oxidoreductase were recently found to cause deficiencies of several enzymes involved in steroidogenesis. CYP oxidoreductase facilitates electron transfer from nicotinamide adenine dinucleotide phosphate (NADPH) reduced form to the 21-hydroxylase and 17-hydroxylase enzymes required in steroidogenesis (Online Mendelian Inheritance in Man [OMIM] 201750 and 124015). ^[18] Some individuals with these mutations have craniosynostosis and skeletal abnormalities known as the Antley-Bixler syndrome (OMIM 207410). ^[19] However, mutations in the fibroblast growth factor receptor-2 can also cause the phenotypic picture of Antley-Bixler syndrome without problems in steroidogenesis.