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Congenital Adrenal Hyperplasia-Other Rare Forms

What is CAH?>>Types of CAH>>Rare Forms of CAH

Rare Forms of Congenital Adrenal Hyperplasia (CAH)

Introduction
Genetic Causes of Rare Forms of CAH
            11b-Hydroxylase Deficiency
            17a-Hydroxylase Deficiency
            3b-Hydroxylase Dehydrogenase Deficiency
            Congenital Lipoid Adrenal Hyperplasia
Clinical Presentation of Rare Forms of CAH
            Clinical Presentation of 11b-Hydroxylase Deficiency
            Clinical Presentation of 17a-Hydroxylase Deficiency
            Clinical Presentation of 3b-Hydroxylase Dehydrogenase Deficiency
            Clinical Presentation of Lipoid CAH
Diagnosis of Rare Forms of CAH
            Diagnosis of 11b-Hydroxylase Deficiency
            Diagnosis of 17a-Hydroxylase Deficiency
            Diagnosis of 3b-Hydroxylase Dehydrogenase Deficiency
            Diagnosis of Lipoid CAH
            Genetic Diagnosis of all Types of CAH
Treatment of Rare Forms of CAH
References

Frequently Used Abbreviations: ACTH: adrenocorticotropic hormone; AIRE: autoimmune regulator; CAH: congenital adrenal hyperplasia; DSD: disorder of sexual development; 3β-HSD: 3β-hydroxysteroid dehydrogenase; 17-OHP: 17-hydroxy-progesterone; STAR: steroid acute regulatory;

Introduction

Congenital Adrenal Hyperplasia (CAH) refers to a family of inherited disorders caused by enzymatic defects in adrenal steroid biosynthesis. In patients with CAH, reduced cortisol synthesis interrupts feedback inhibition of adrenocorticotropic-hormone (ACTH) release from the pituitary, leading to continual stimulation of the adrenals by ACTH and, consequently, adrenal hyperplasia. Incidence of “classic” CAH, which presents in infancy with signs of adrenal insufficiency and/or ambiguous genitalia, has been estimated at 1:15,000. Prevalence of the “non-classic” form of CAH, which typically presents later in life and with much milder symptoms, may be as high as 1:100 (1-4).

The three major types of adrenal steroid hormones, glucocorticoids, mineralocorticoids, and adrenal androgens, are each produced through a separate biosynthetic pathway. All three pathways, however, share common precursor molecules. If an enzymatic block occurs in any of the three biosynthetic pathways, precursor molecules are shunted into the remaining functional pathway(s). Therefore, defects in a specific biosynthetic enzyme can simultaneously lead to deficiency in one or two types of adrenal steroids and overproduction of the remaining type(s). Presentation and treatment of CAH depend on 1) which of the three major biosynthetic pathways is/are affected by the enzymatic defect in adrenal steroid synthesis, 2) the severity of the enzymatic defect, and 3) whether gonadal steroid synthesis is also affected. The pattern of elevated biosynthetic precursor molecules is highly diagnostic of the type of CAH. Genetic testing can also be used for the differential diagnosis of CAH, since the genes coding for the enzymes involved in steroid biosynthesis have been identified. Loss-of-function mutations in the gene CYP21A2 account for about 90% of all cases of CAH. Other, rarer forms of CAH are due to loss-of-function mutations in the genes CYP11B1, CYP17A1, HSD3B2, or STAR (lipoid CAH). All known forms of CAH show autosomal recessive inheritance. Genetic testing may be more sensitive than biochemical testing in cases of mild enzymatic defects. In addition, genetic testing can facilitate carrier detection, genetic counseling, and the early diagnosis and treatment of affected family members.

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Genetic Causes of Rare Forms of CAH

Figure 1 shows the normal biosynthetic pathways for mineralocorticoids, glucocorticoids, and adrenal androgens. Each step is catalyzed by a specific enzyme. In Figure 1, the genes coding for these enzymes are indicated in red. CAH can be caused by a defect in any one of several of these genes.
Figure1-Genes in the Adrenal Cortex

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11β-Hydroxylase Deficiency

Loss-of-function mutations in the gene CYP11B1 account for about 5-8% of all cases of CAH in Western Europe and the US (4,5). CYP11B1 codes for the cytochrome P-450 enzyme 11β-hydroxylase, which catalyzes the conversion of 11-deoxycortisol to cortisol in the glucocorticoid biosynthetic pathway. Defects in 11β-hydroxylase disrupt glucocorticoid synthesis, and precursors accumulating “upstream” of the enzymatic block are shunted into the biosynthetic pathways for mineralocorticoids and adrenal androgens. Patients are protected from an adrenal crisis by presence of corticosterone, which possesses glucocorticoid activity. However, increased levels of deoxycorticosterone can give rise to hypertension, since this intermediate product in the mineralocorticoid biosynthetic pathway shows weak mineralocorticoid activity. Overproduction of adrenal androgens leads to prenatal and/or postnatal virilization in genetic females and postnatal virilization in genetic males. The degree of virilization depends on the extent to which 11β-hydroxylase activity is impaired, which also determines the degree of excess mineralocorticoid activity. In the classic form of 11β -hydroxylase deficiency, which accounts for about two thirds of all cases, genetic females are born with ambiguous genitalia, and both males and females undergo premature adrenarche if untreated [Figure 3A]. Hypertension due to excessive salt retention may also be present. The non-classic form of 11β-hydroxylase deficiency is characterized by mild adrenal androgen excess only [Figure 3B].
Figure3-Beta Hydroxylase Deficiency-Classical CAH
Figure3-Beta Hydroxylase Deficiency-Classical CAH

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17α-Hydroxylase Deficiency

Loss-of-function mutations in the gene CYP17A1 account for about 1% of CAH in most populations, but represent the second most common cause of CAH in Brazil (6). CYP17A1 codes for a cytochrome P-450 enzyme with both 17α-hydroxylase and 17,20-lyase activities, which performs a gatekeeper function for the entry of precursor molecules into the glucocorticoid and adrenal androgen biosynthetic pathways: 17α-hydroxylase activity controls the branch point from the mineralocorticoid to the glucocorticoid biosynthetic pathway, and 17,20-lyase activity regulates the branch point from the glucocorticoid to the adrenal androgen biosynthetic pathway [see Fig. 4]. Defects in CYP17A1 that disrupt both the hydroxylase and the lyase activity affect the synthesis of glucocorticoids and androgens in the adrenal cortex as well as steroid synthesis in the gonads (7). Mineralocorticoid synthesis is not affected, but the block in the entry point to the glucocorticoid biosynthetic pathway leads to an increase in mineralocorticoid precursors such as deoxycorticosterone and corticosterone. This increase in the concentration of corticosterone, which exhibits glucocorticoid activity, compensates for the absence of cortisol and protects patients from an adrenal crisis. Increases in the levels of deoxycorticosterone and corticosterone are also believed to be the cause of the hypertension frequently observed in patients with 17α-hyproxylase deficiency, since both intermediates possess weak mineralocorticoid activity. Disruption of adrenal androgen production and gonadal steroid synthesis causes female or ambiguous external genitalia in 46XY males, sexual infantilism, and primary or, more rarely, secondary amenorrhea in 46XX females.

Figure4-Alpha-Hydrolyase Deficiency

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3β-Hydroxysteroid Dehydrogenase Deficiency

Loss-of-function mutations in the gene HSD3B2 account for about 1% of CAH (8). HSD3B2 codes for the enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD), which catalyzes the conversion of pregnenolone to progesterone in the mineralocorticoid biosynthetic pathway and the conversion of 17OH-pregnenolone to 17OH-progesterone in the glucocorticoid biosynthetic pathway. 3β-Hydroxysteroid dehydrogenase is also necessary for conversion of dehydroepiandrosterone to androstenedione in the adrenals and for the biosynthesis of sex steroids in the gonads. In 46XY males, 3β-HSD deficiency is associated with ambiguous genitalia due to impaired testosterone synthesis in the gonads. In genetic females, 3β-HSD deficiency may lead to premature adrenarche, amenorrhea, or ambiguous genitalia due to conversion of androgen precursors to androgens in peripheral tissues. Severe defects in 3β-HSD activity also cause deficiency in both mineralocortocoids and glucocorticoids and lead to salt wasting and primary adrenal insufficiency in males and females (salt-wasting form) [Figure 5].

Fig5-3Beta Hydroxysteroid Dehydrogenase Deficiency-Salt Wasting

                 Fig5-3Beta Hydroxysteroid Dehydrogenase Deficiency-Non Salt Wasting

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Congenital Lipoid Adrenal Hyperplasia

Loss-of-function mutations in the gene STAR, which are associated with congenital lipoid adrenal hyperplasia (lipoid CAH), account for a small percentage of CAH in most populations, but appear to be more common in individuals of Japanese, Korean, or Palestinian ancestry (9). STAR codes for the steroid acute regulatory protein, which fulfills a gatekeeper function for all of steroid biosynthesis by catalyzing the transfer of cholesterol from the cytosol into mitochondria, where the initial steps of steroidogenesis take place. Absence of functional StAR protein reduces cholesterol import into mitochondria by a factor of about ten, leading to impaired biosynthesis of all steroids and accumulation of cholesterol lipid droplets in the cytoplasm of affected cells. However, StAR-protein independent cholesterol import may allow for enough steroid synthesis to prevent acute symptoms in the absence of functional StAR protein, and only the gradual accumulation of lipid droplets leads to complete cessation of all steroidogenesis through generalized damage to the affected cells. For this reason, defects in STAR cause damage to steroidogenic target organs such as the adrenals and the gonads only if they are stimulated to produce steroids.

This “two hit” model of lipoid CAH explains why 46XY infants with lipoid CAH are born as phenotypic females, while onset of acute primary adrenal insufficiency and salt wasting may not occur until several weeks or even months after birth.

The fetal testis is stimulated and thus damaged by absence of functional StAR early in gestation, leading to lack of testosterone and preventing development of male external genitalia. In the adrenals, in contrast, stimulation prior to birth affects primarily the fetal zone; the definitive zone, which postnatally develops into the zona glomerulosa and zona fasciculata, may therefore remain partially functional for several weeks or months after birth in individuals with reduced StAR-protein activity. Similarly, the ovaries in 46XX individuals remain hormonally silent until puberty, when individual ovarian follicles are stimulated and, in individuals with lipoid CAH, thus damaged during each cycle. However, while 46XX individuals with lipoid CAH can spontaneously enter puberty and may undergo menarche, their cycles remain anovulatory because lack of StAR-protein activity prevents the progesterone surge necessary for ovulation.

To learn more about the genetics of CAH, please visit out CAH Overview page.

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Clinical Presentation of Rare Forms of CAH

Presentation of CAH depends on the underlying genetic defect and the severity of the enzymatic impairment (Table 1).

Table 1: Symptoms Associated with CAH

Table1-Symptoms Associated with CAH

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Clinical Presentation of 11β-Hydroxylase Deficiency

11β-Hydroxylase deficiency presents in both classic and non-classic forms. The classic form is associated with ambiguous genitalia in genetically female infants. In both male and female children, poorly treated 11β-hydroxylase deficiency can lead to hypertension due to excessive salt retention, rapid growth and advanced bone age, resulting in reduced adult height, and premature adrenarche. Continued postnatal virilization may cause premature penile (but not testicular) growth in genetic boys and clitoral growth in genetic girls.

The non-classic form of 11β-hydroxylase deficiency is not associated with hypertension or ambiguous genitalia and presents in girls or women with milder symptoms of androgen excess, such as hirsutism, cystic acne, or oligomenorrhea.

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Clinical Presentation of 17α-Hydroxylase Deficiency

17α-hydroxylase deficiency is associated with a 46XY disorder of sexual development (DSD) and typically presents with low-renin hypertension and lack of pubertal progression in adolescent phenotypic females. In cases of partial 17α-hydroxylase deficiency, 46XY individuals may present with ambiguous genitalia at birth and 46XX individuals with primary or secondary amenorrhea or ovarian cysts in adolescence or early adulthood. Hypertension may or may not be present with partial 17α-hydroxylase deficiency. Both 46XX and 46XY individuals with 17α-hydroxylase deficiency are typically infertile.

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Clinical Presentation of 3β-Hydroxysteroid Dehydrogenase Deficiency

3β-HSD deficiency presents in salt-wasting and a non-salt-wasting forms. Both forms are associated with ambiguous genitalia in genetic males and with premature adrenarche, amenorrhea, or ambiguous genitalia in genetic females. The salt-wasting form also causes renal sodium wasting and primary adrenal insufficiency. The severity of female virilization or male undervirilization is not correlated to the presence or absence of the salt-wasting phenotype.

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Clinical Presentation of Lipoid CAH

Lipoid CAH is associated with a 46XY DSD and is seen almost exclusively in phenotypic females. Symptoms of primary adrenal insufficiency and/or salt wasting typically become apparent within the first days or weeks of life, but may be delayed for up to several months after birth. Lipoid CAH may be associated with massive adrenal enlargement, since lack of cortisol biosynthesis prevents feedback inhibition of corticotropin releasing hormone and adrenocorticotropic hormone (ACTH) release from hypothalamus and pituitary, respectively, allowing continual stimulation of the adrenals.

In postpubertal 46XX females, lipoid CAH may also cause hyperplasia of the ovaries and can lead to large ovarian cysts. Both 46XX and 46XY individuals with lipoid CAH are infertile.

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Diagnosis of Rare Forms of CAH

Diagnosis of 11β-Hydroxylase Deficiency

The classic form of 11β-hydroxylase deficiency is suggested by ambiguous genitalia in infants or by low-renin hypertension in children. Detection of elevated deoxycorticosterone and/or 11-deoxycortisol levels also indicates 11β-hydroxylase deficiency.

The non-classic form of 11β-hydroxylase deficiency is suspected in girls or women with hirsutism or oligomenorrhea. Diagnostic steroid precursors are the same as for the classic form, although increases in concentration tend to be less dramatic.

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Diagnosis of 17α-Hydroxylase Deficiency

17α-Hydroxylase deficiency is indicated by low-renin hypertension in infants with ambiguous genitalia, 46XY infants with DSD, or sexually infantile adolescent females. Elevation in deoxycorticosterone and corticosterone, especially in response to cosyntropin stimulation, is diagnostic of 17α-hydroxylase deficiency. In 46XY individuals, it is important to differentiate 17α-hydroxylase deficiency from androgen insensitivity syndrome or 5α-reductase deficiency as the cause of ambiguous or female genitalia, since hypertension associated with 17α-hydroxylase deficiency can lead to life-threatening complications if left untreated.

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Diagnosis of 3β-Hydroxysteroid Dehydrogenase Deficiency

3β-HSD deficiency is indicated by salt-wasting and/or primary adrenal insufficiency in phenotypically female infants and by ambiguous genitalia in infants after exclusion of 21-hydroxylase and 11β-hydroxylase deficiency. 3β-HSD deficiency may also be considered as a cause of premature adrenarche or amenorrhea in females, after exclusion of the more common non-classic forms of CAH. Increased levels of pregnenolone, 17OH-pregnenolone, and dehydroepiandrosterone in response to cosyntropin stimulation are diagnostic of 3β-HSD deficiency.

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Diagnosis of Lipoid CAH

Diagnosis of lipoid CAH is suggested by massive adrenal enlargement in phenotypically female infants with symptoms and biochemical signs of primary adrenal insufficiency and/or salt wasting.

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Genetic Diagnosis of all Types of CAH

Since published studies have established a causal relationship between specific types of CAH and variants in CYP21A2, CYP11B1, HSD3B2, CYP17A1, or STAR, a differential diagnosis of CAH can be achieved through genetic testing. In the case of 21-hydroxylase deficiency, genetic testing can also suggest the form of 21-hydroxylase deficiency present, since certain mutations in CYP21A2 are found predominantly in association with a specific form of the disease.

In addition, genetic testing can be used to confirm a positive newborn screening test, identify carriers of CAH-associated mutations, and diagnose CAH in family members of patients at or before birth.

Additional information on genetic diagnosis can be found under Genetic Testing for CAH. For an international directory of genetic testing laboratories as well as genetics and prenatal diagnosis clinics visit: GeneTests.

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Treatment of Rare Forms of CAH

Glucocorticoid replacement therapy is used for all forms of CAH. Dosing has to be carefully calibrated, since excessive glucocorticoid treatment can result in significantly reduced adult height. Glucocorticoid treatment may also trigger true precocious puberty, which can be treated with long-acting gonadotropin-releasing-hormone analogues. In the case of the simple-virilizing form of 21-hydroxylase deficiency, addition of mineralocorticoid replacement may reduce the glucocorticoid dose required for maintaining acceptable 17-OHP levels.

Mineralocorticoid replacement is indicated for all salt-wasting forms of CAH (21-hydroxylase deficieny, 3β-HSD deficiency, and lipoid CAH). In young children, dietary sodium supplements may also be necessary.

Estrogen replacement can induce development of secondary female characteristics in phenotypically female individuals with 17α-hydroxylase deficiency, reduce adult height in 46XY phenotypically female individuals with 17α-deficiency, and prevent hypergonadotropic hypogonadism and ovarian cysts in 46XX individuals with 17α-hydroxylase deficiency or lipoid CAH.

Dexamethasone treatment during pregnancy has been shown to minimize genital virilization in fetuses affected with 21-hydroxylase or 11β-hydroxylase deficiency. Careful consideration of the benefits and risk of prenatal diagnosis and treatment should be given before initiating therapy.

In patients with ambiguous genitalia, families should receive appropriate counseling, sex should be assigned, and surgical correction of genital anomalies should be considered. Removal of dysgenic gonads may be recommended to reduce the risk of malignancy.

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References

  1. New MI (2004) An update of congenital adrenal hyperplasia. Ann NY Acd Sci 1038:14-43.
  2. White PC, Speiser PW (2000) Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocrine Reviews 21:245-291.
  3. Speiser PW, White PC (2003) Congenital adrenal hyperplasia. N Engl J Med 349:776-88.
  4. New MI (2003) Inborn errors of adrenal steroidogenesis. Mol Cell Endocrinol 211:75-83.
  5. Chemaitilly W, Wilson RC, New MI (2003) Hypertension and adrenal disorders. Current Hypertension Reports 5:498-504.
  6. Costa-Santos M, Kater CE, Auchus RJ, et al (2004) Two prevalent CYP17 mutations and genotype-phenotype correlations in 24 Brazilian patients with 17-hydroxylase deficiency. J Clin Endocrinol Metab 89:49-60.
  7. Auchus RJ (2001) The genetics, pathophysiology, and management of human deficiencies of P450c17. Endocrinol Metab Clin North Am 30:101-19,vii.
  8. Simard J, Ricketts M-L, Gingras S, Soucy P, Feltus AF, Melner MH (2005) Molecular biology of the 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase gene family. Endocrine Reviews 26:525-82.
  9. Miller WL (1997) Congenital lipoid adrenal hyperplasia: the human gene knockout for the steroidogenic acute regulatory protein. J Mol Endocrinol 19:227-40.

Portions of Rare Forms of Congenital Adrenal Hyperplasia reprinted with permission Correlagen Diagnostics, Inc. Copyright © 2005, 2006 Correlagen Diagnostics, Inc. All rights reserved.

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