Adrenogenital Syndrome

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.

The disease is related to the following processes:  congenital and has an incidence of about  0 / 100.000.

Overview

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].

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

Prognosis

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].

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.

Treatment

Prevention

Patient Information

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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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