Adrenogenital Syndrome (Congenital Adrenal Hyperplasia)

In patients suffering from the adrenogenital syndrome, deficient corticosteroid release by the adrenal glands gives rise to an increased production of adrenocorticotropic hormone by the pituitary gland, which, in turn, causes an overproduction of sex steroids. The vast majority of cases is provoked by an inherited deficiency of 21-hydroxylase, an enzyme required for the biosynthesis of aldosterone, cortisol, and corticosterone.

Adrenogenital Syndrome results from the following process: congenital.

Presentation

The clinical manifestation of the disease is largely dependent on the type and degree of enzyme deficiency [4]. As has been indicated above, the majority of cases results from mutations of the gene encoding for 21-hydroxylase [2]. This enzyme is required for corticosteroid and aldosterone synthesis, and affected individuals present with combined deficiencies. In contrast, CYP11B1 defects causing the 11β-hydroxylase deficiency, an uncommon form of AS, are related to decreased levels of corticosteroids while the release of aldosterone is largely unaltered [3]. Accordingly, 21-hydroxylase deficiency is related to the so-called salt-losing form of AS, whereas reduced activity of 11β-hydroxylase provokes the simple virilizing form of the disease. Less common, non-classical forms of AS are associated with disturbances of sex steroid production.

About two-thirds of AS patients are classified as "salt wasters" [5]. These individuals usually present with symptoms of adrenal insufficiency shortly after birth or within the first month of life [6]. Lethargy, feeding difficulties, vomiting, and weight loss are common symptoms [7]. Further examinations may reveal dehydration, hyponatremia, and hyperkalemia. If left untreated, life-threatening metabolic decompensation and shock may occur. Moreover, female neonates typically have ambiguous genitalia comprising an enlarged clitoris, partly fused labia majora, and a common urogenital sinus instead of separated urethra and vagina [4]. Boys may show penile enlargement and hyperpigmentation.

Simple virilizing AS is less severe than salt-losing disease and may not manifest until puberty. In young women, the disease is associated with early pubarche, hirsutism, amenorrhea, and polycystic ovaries [4]. Acne is commonly observed. Simple virilizing AS may cause precocious puberty in boys, who are also more prone to develop testicular tumors [8] [9]. Adult patients are usually of short stature. In the long term, enhanced concentrations of sex steroids may cause hypogonadotropic hypogonadism [10] [11].

Entire body system
  • Italian Among American Caucasians, the incidence is approximately 1 15,000 ). [4] History [ edit ] Before 20th century [ edit ] An Italian anatomist, Luigi De Crecchio (1832-1894) provided the earliest known description of a case of probable CAH. [source] It appears to happen more often in people of Ashkenazi Jewish, Hispanic, Slavic and Italian background. [source]
  • Virilization 21-hydroxylase deficiency, virilizing, non salt wasting 21-hydroxylase deficiency, virilizing, salt losing 3 beta-hydroxysteroid dehydrogenase deficiency Adrenal hyperplasia, congenital Adrenal hyperplasia, congenital, simple virilizing Adrenal hyperplasia [source] hyperplasia, virilizing, salt-losing Gestational hyperandrogenism, virilized XX Late onset congenital adrenal hyperplasia Steroid 17-alpha-monooxygenase deficiency, undervirilized XY Steroid 21-monooxygenase deficiency, simple virilizing type Undervirilized [source] XY, 3-beta hydroxysteroid deficiency Undervirilized XY, congenital adrenal hyperplasis, Virilized female due to gestational hyperandrogenism Virilized XX, gestational hyperandrogenism 255.2 Excludes Applies To Adrenogenital syndromes, virilizing or feminizing [source]
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Skin
  • Hirsutism In young women, the disease is associated with early pubarche, hirsutism , amenorrhea , and polycystic ovaries [4]. [source] In young women, the disease is associated with early pubarche, hirsutism, amenorrhea, and polycystic ovaries. [source] Main symptoms of the disease include the following: Amenorrhea (absence of periods) or irregular rare periods; Changed voice (deep voice); Pre-puberty or puberty early appearance of pubic and armpit hairs; Excessive body and face hair growth ( hirsutism [source]
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respiratoric
musculoskeletal
urogenital
  • Amenorrhea This 27-year-old patient, first evaluated at the age of 18, had a masculine figure, abnormal external genitalia, and primary amenorrhea[source] Girls with Adrenogenital Syndrome usually have amenorrhea (absence of periods) or rare irregular periods which could be a cause of infertility . [source] Main symptoms of the disease include the following: Amenorrhea (absence of periods) or irregular rare periods; Changed voice (deep voice); Pre-puberty or puberty early appearance of pubic and armpit hairs; Excessive body and face hair growth ( hirsutism [source]
  • Clitoromegaly hair and rapid growth in childhood precocious puberty or failure of puberty to occur ( sexual infantilism : absent or delayed puberty ) excessive facial hair , virilization , and/or menstrual irregularity in adolescence infertility due to anovulation clitoromegaly [source]
  • Primary Amenorrhea This 27-year-old patient, first evaluated at the age of 18, had a masculine figure, abnormal external genitalia, and primary amenorrhea[source]
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Workup

  • Laboratory analyses of blood samples are required to determine electrolyte levels and concentrations of ACTH, 17-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, testosterone, cortisol, aldosterone, and renin. High levels of 17-hydroxyprogesterone in a randomly timed blood sample are diagnostic of 21-hydroxylase deficiency [4].
  • An ACTH stimulation test may be required to identify AS not related to the 21-hydroxylase deficiency.
  • Urine samples may be analyzed for their contents of adrenal hormones and metabolites like 17-ketosteroids, although these studies have been largely replaced by serum analyses.
  • Advanced bone age may be diagnosed employing plain radiography.
  • In patients with ambiguous genitalia, karyotyping should be carried out [12]. Diagnostic imaging is recommended to assess the condition of internal reproductive organs.
  • Genetic analyses are usually not required to diagnose AS. However, corresponding results greatly facilitate genetic counseling and possibly prenatal testing in family members.

Laboratory

Serum
Urine

Treatment

Prognosis

Complications

  • Adrenocortical Insufficiency Figure 9: Assessment of Adrenocortical Insufficiency (Hypercortisolism). [source]
  • Ambiguous Genitalia In patients with ambiguous genitalia, karyotyping should be carried out. [source] Moreover, female neonates typically have ambiguous genitalia comprising an enlarged clitoris, partly fused labia majora, and a common urogenital sinus instead of separated urethra and vagina. [source] Moreover, female neonates typically have ambiguous genitalia comprising an enlarged clitoris , partly fused labia majora, and a common urogenital sinus instead of separated urethra and vagina [4]. [source]
  • Gynecomastia tubulovesicular cristae, lipid droplets and lipofuscin granules in the polygonal cells No Reinke crystals Differential diagnosis Leydig cell tumor Less commonly bilateral (3% compared to 75% in TTAGS, Pathologica 1994;86:557 , Urol Clin North Am 2000;27:519 ) Gynecomastia [source] During the last 3 months he developed bilateral gynecomastia[source]
  • Hypertension Deficiency of 17-hydroxylase leads to deficiency of estrogens and androgens and to excess deoxycorticosterone, causing sexual infantilism and hypertension[source] Other, rarer forms of congenital adrenal hyperplasia result in varying degrees of hypertension or lack of sexual development, depending on the particular enzyme that is defective. [source] Deficiency of 11-hydroxylase, an enzyme that catalyzes the last step in the synthesis of cortisol, leads to virilization and hypertension, the latter of which is caused by excess production of deoxycorticosterone, a mineralocorticoid similar to aldosterone [source]
  • Hypokalemia Current Topic Differentials •Adrenal Hypoplasia •Adrenal Insufficiency •Ambiguous Genitalia and Intersexuality •Androgen Insensitivity Syndrome •Cystic Fibrosis •Denys-Drash Syndrome •Failure to Thrive •Familial Glucocorticoid Deficiency •Hyperkalemia •Hypokalemia [source] It is now thought that patients with hypertension and hypokalemia, regardless of presumed cause, and patients with treatment-resistant hypertension should be screened for primary aldosteronism. [source] Hyperaldosteronism (Conn's syndrome) Hypertension, hypokalemia, suppressed plasma renin activity and increased aldosterone characterized the syndrome of primary aldosteronism reported by Conn in 1955. [source]
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Etiology

Besides 21-hydroxylase deficiency, other enzyme defects may account for AS. All forms known to date are inherited as an autosomal recessive trait.

Epidemiology

Sex distribution
Age distribution

Pathophysiology

Prevention

Summary

The adrenal glands comprise distinct cell populations producing different hormones. In detail:

  • Catecholamines are released by cells located in the adrenal medulla.
  • Precursors of androgens and estrogens are synthesized by cells of the zona reticularis, the innermost layer of the adrenal cortex.
  • Glucocorticoids like cortisol and corticosterone originate from the zona fasciculata.
  • The outermost layer of the adrenal cortex, the zona glomerulosa, accounts for synthesis and release of aldosterone.

Adrenal hormone release is primarily controlled by superior centers like pituitary gland and hypothalamus and negative feedback loops assure the preservation of an equilibrium between demands and hormone synthesis. First and foremost, adrenal corticosteroids inhibit adrenocorticotropic hormone (ACTH) release by the pituitary gland. In the case of insufficient corticosteroid synthesis, the pituitary gland releases excess amounts of ACTH, which, in turn, stimulates the production of hormones by functional adrenal tissues [1]. Moreover, any disturbance of aldosterone production interferes with electrolyte balance. In patients suffering from adrenogenital syndrome (AS), both aldosterone and corticosteroid synthesis may be impaired, most commonly due to an inherited 21-hydroxylase deficiency [2]. Accordingly, AS is often referred to as congenital adrenal hyperplasia. The latter term, however, does not consider rare cases of acquired AS. These may be triggered by adrenal or gonadal neoplasms.

Of note, aldosterone release by zona glomerulosa cells is regulated by the renin-angiotensin system and is not part of the hypothalamic-pituitary-adrenal hormone axis [3].

Patient Information

Self-assessment

References

  1. Parsa AA, New MI. Steroid 21-hydroxylase deficiency in congenital adrenal hyperplasia. J Steroid Biochem Mol Biol. 2016.
  2. Yau M, Khattab A, Poppas D, Ghizzoni L, New M. Congenital Adrenal Hyperplasia: Unresolved Issues. Front Horm Res. 2016; 46:184-195.
  3. Peter M, Dubuis JM, Sippell WG. Disorders of the aldosterone synthase and steroid 11beta-hydroxylase deficiencies. Horm Res. 1999; 51(5):211-222.
  4. Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet. 2005; 365(9477):2125-2136.
  5. Padidela R, Hindmarsh PC. Mineralocorticoid deficiency and treatment in congenital adrenal hyperplasia. Int J Pediatr Endocrinol. 2010; 2010:656925.
  6. Al-Agha AE, Ocheltree AH, Al-Tamimi MD. Association between genotype, clinical presentation, and severity of congenital adrenal hyperplasia: a review. Turk J Pediatr. 2012; 54(4):323-332.
  7. Heather NL, Seneviratne SN, Webster D, et al. Newborn screening for congenital adrenal hyperplasia in New Zealand, 1994-2013. J Clin Endocrinol Metab. 2015; 100(3):1002-1008.
  8. Rich MA, Keating MA, Levin HS, Kay R. Tumors of the adrenogenital syndrome: an aggressive conservative approach. J Urol. 1998; 160(5):1838-1841.
  9. Claahsen-van der Grinten HL, Hermus AR, Otten BJ. Testicular adrenal rest tumours in congenital adrenal hyperplasia. Int J Pediatr Endocrinol. 2009; 2009:624823.
  10. Merke DP, Poppas DP. Management of adolescents with congenital adrenal hyperplasia. Lancet Diabetes Endocrinol. 2013; 1(4):341-352.
  11. Rohayem J, Tuttelmann F, Mallidis C, Nieschlag E, Kliesch S, Zitzmann M. Restoration of fertility by gonadotropin replacement in a man with hypogonadotropic azoospermia and testicular adrenal rest tumors due to untreated simple virilizing congenital adrenal hyperplasia. Eur J Endocrinol. 2014; 170(4):K11-17.
  12. Taboada M, Gagliardi P. The challenge of mistaken sex assignment in an 11-year-old with virilizing CAH. Adv Exp Med Biol. 2011; 707:163-168.

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