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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.


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].

Virilization
  • Persistent virilization and high testosterone levels led to right oophorectomy and completion left oophorectomy 6 months later.[ncbi.nlm.nih.gov]
  • Simple virilizing AS may cause precocious puberty in boys, who are also more prone to develop testicular tumors. Adult patients are usually of short stature.[symptoma.com]
  • Abstract We describe here a typical case of virilizing adrenocortical tumor. A 23-year-old Japanese woman had her male-like musculature, hirsutism, the absence of breast development and marked clitoromegaly.[ncbi.nlm.nih.gov]
  • She was first observed in the newborn period with marked degree virilization and clinical findings suggestive of salt-losing congenital adrenal hyperplasia.[ncbi.nlm.nih.gov]
  • Clinically, the children may present in two forms: “simple virilization” or “salt wasting.” At birth, female infants appear virilized with clitoral enlargement, labial fusion, and/or urogenital sinus.[accessanesthesiology.mhmedical.com]
Poor Feeding
  • Poor feeding or vomiting Dehydration Electrolyte changes (abnormal levels of sodium and potassium in the blood) Abnormal heart rhythm Girls with the milder form will usually have normal female reproductive organs (ovaries, uterus, and fallopian tubes)[medlineplus.gov]
  • Infants with salt-wasting CAH usually show some of the following features within the first few weeks of life: Poor feeding Listlessness and drowsiness Vomiting Diarrhea Dehydration Weight loss Low blood pressure Low blood salt (low blood sodium level)[newbornscreening.info]
Italian
  • Among American Caucasians, the incidence is approximately 1 15,000 ). [4] Continued treatment and wellness is enhanced by education and follow up. [15] History [ edit ] Before 20th century [ edit ] An Italian anatomist, Luigi De Crecchio (1832-1894) provided[en.wikipedia.org]
Hypertension
  • Deficiency of 17-hydroxylase leads to deficiency of estrogens and androgens and to excess deoxycorticosterone, causing sexual infantilism and hypertension.[britannica.com]
  • Thus, infants with 11-beta-hydroxylase deficiency will present with hypertension, differentiating this disorder from classical CAH.[visualdx.com]
  • An episode of hypertension occurred in each case, but was preceded and followed by periods of normal blood pressure. These episodes may have been due to accelerated release of desoxycorticosterone from implanted DOCA pellets.[pediatrics.aappublications.org]
  • One 11beta-OHD patient with sexual precocity symptoms and hypertension became normal after the hormone treatment, and six 17-OHD patients maintained their female sexuality after the hormone treatment and operation.[ncbi.nlm.nih.gov]
Advanced Bone Age
  • Advanced bone age may be diagnosed employing plain radiography. In patients with ambiguous genitalia, karyotyping should be carried out. Diagnostic imaging is recommended to assess the condition of internal reproductive organs.[symptoma.com]
Hirsutism
  • A 23-year-old Japanese woman had her male-like musculature, hirsutism, the absence of breast development and marked clitoromegaly.[ncbi.nlm.nih.gov]
  • Marked regression of hirsutism, advanced somatic and muscular development, deep voice and elevated urinary 17-ketosteroids followed removal of an adrenocortical adenoma.[pediatrics.aappublications.org]
  • In young women, the disease is associated with early pubarche, hirsutism, amenorrhea, and polycystic ovaries. Acne is commonly observed. Simple virilizing AS may cause precocious puberty in boys, who are also more prone to develop testicular tumors.[symptoma.com]
  • Polycystic ovarian syndrome can present with hirsutism, acne, and menstrual irregularities, but these patients will not have increased serum 17-hydroxyprogesterone, classical electrolyte abnormalities (hyponatremia, hyperkalemia), or increased urine 17[visualdx.com]
  • 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[women-info.com]
Amenorrhea
  • This 27-year-old patient, first evaluated at the age of 18, had a masculine figure, abnormal external genitalia, and primary amenorrhea. Clitoridectomy was performed.[journals.lww.com]
  • Girls with Adrenogenital Syndrome usually have amenorrhea (absence of periods) or rare irregular periods which could be a cause of infertility . Abnormal female external genitals during Adrenogenital syndrome should be operated in childhood.[women-info.com]
  • In young women, the disease is associated with early pubarche, hirsutism, amenorrhea, and polycystic ovaries. Acne is commonly observed. Simple virilizing AS may cause precocious puberty in boys, who are also more prone to develop testicular tumors.[symptoma.com]
  • Females present with delayed puberty, amenorrhea, and failure to develop breasts and pubic hair. These patients will have low urine 17-ketosteroid and high urine gonadotropin levels.[visualdx.com]
Clitoromegaly
  • Abstract For preservation of postoperative sensitivity of the glans clitoris, clitoroplasty for clitoromegaly due to adrenogenital syndrome is reported.[ncbi.nlm.nih.gov]
  • A 23-year-old Japanese woman had her male-like musculature, hirsutism, the absence of breast development and marked clitoromegaly.[ncbi.nlm.nih.gov]
  • […] 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[en.wikipedia.org]
  • La femei apare amenoree insotita de semne de exces de androgeni care duc la virilizare: hirsu-tism, clitoromegalie, ingrosarea vocii, modificarea raportului biacromial/bitrohanterian etc.[mediculmeu.com]
Testicular Pain
  • The only indication of surgery in stage 5 is testicular pain. Copyright 2017 Elsevier Masson SAS. All rights reserved.[ncbi.nlm.nih.gov]
  • Most patients present with bilateral testicular pain or masses. Gross: well-circumscribed, unencapsulated, solid and lobulated brown tumor.[auanet.org]
Primary Amenorrhea
  • This 27-year-old patient, first evaluated at the age of 18, had a masculine figure, abnormal external genitalia, and primary amenorrhea. Clitoridectomy was performed.[journals.lww.com]
Cryptorchidism
  • CONCLUSIONS: This case illustrates an unusual presentation of a testicular tumor in a patient with the adrenogenital syndrome as well as with myelolipoma and seminoma in a cryptorchid testis.[ncbi.nlm.nih.gov]

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.
Lymphocytic Infiltrate
  • TTAGS was characterized histologically by sheets of polygonal cells separated by dense fibrous tissue with focal lymphocyte infiltration.[ncbi.nlm.nih.gov]
  • infiltration Several small tumors within the rete testis will conflate, forming a single lobulated tumor, separated from the residual testicular tissue by fibrous strands Differentiation of adrenal cells with loss of ACTH and angiotensin II receptors[pathologyoutlines.com]

Treatment

  • In stages 2 and 3, intensified glucocorticoid treatment is recommended as a first step treatment. Sparing surgical approach is preferred for tumors of stage 4 and steroid unresponsive masses. Magnetic resonance imaging is recommended before surgery.[ncbi.nlm.nih.gov]
  • OBJECTIVE: To discuss the treatment of male adrenogenital syndrome.[ncbi.nlm.nih.gov]
  • RESULTS: Testicular neoplasia continue to grow despite adequate hormonal treatment and a bilateral orchiectomy was performed. The histopathological examination of the specimen ultimately confirmed the diagnosis of bilateral Leydig-cell tumour.[ncbi.nlm.nih.gov]
  • Treatment can be stopped if prenatal testing finds that the baby is male or is an unaffected female, otherwise treatment continues until birth.[encyclopedia.com]
  • Later the main treatment for Adrenogenital Syndrome will be hormonal compensation and hormonal replacement therapy – the main goal of treatment is to return hormone levels to normal.[women-info.com]

Prognosis

  • Benign prognosis. (Despite atypical nuclei with pleomorphism) DDX: Leydig cell tumor: usually painless, unilateral, most lacks nuclear pleomorphism, and a third has Reinke crystalloid.[auanet.org]
  • This case serves to emphasize the need for a guarded prognosis and alert observation even years after an uneventful course following removal of an adrenocortical tumor.[pediatrics.aappublications.org]
  • Prognosis If appropriately treated, the prognosis for CAH and particularly CAH21 is good and most people have a normal life span.[encyclopedia.com]

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

  • "in ways so slipshod as to breach professional standards of medical ethics" [13] and "there were no data on long-term follow-up of physical and metabolic outcomes in children exposed to dexamethasone". [14] Epidemiology [ edit ] The incidence varies geographically[en.wikipedia.org]
  • Epidemiological data: There were significantly fewer males (43%) than females (57%), and the percentage of males did not increase during the observation period. Salt wasters (SW) totalled 64.7%, whereas 35.3% had simple virilizing (SV) CAH.[thedoctorsdoctor.com]
Sex distribution
Age distribution

Pathophysiology

  • Congenital adrenal hyperplasia, which also dates to the first half of the century, has become the preferred term to reduce ambiguity and to emphasize the underlying pathophysiology of the disorders.[en.wikipedia.org]
  • Adrenogenital syndrome (TTAGS) Also know as Testicular adrenal rest tumors (TARTs) Biologically, the lesions represent hyperplasia of aberrant rests rather than a true neoplastic tumor Sites Normaly descended testis and adjacent tissues Etiology and Pathophysiology[pathologyoutlines.com]

Prevention

  • Dispareunia is prevented by total excision of the corpora cavernosa, including the crura.[ncbi.nlm.nih.gov]
  • Due to advances in modern medicine, those couples with the recessive CAH genes have an option to prevent CAH in their offspring through preimplantation genetic diagnosis (PGD).[en.wikipedia.org]
  • Virilism and addisonian crises were prevented with fair success in both by cortisone and DOCA.[pediatrics.aappublications.org]
  • In this form of CAH21 enough enzyme is present to prevent abnormally low levels of salt in the body and to prevent an adrenal crisis.[encyclopedia.com]
  • […] of the testis Only indication for surgery is the relief of pain and discomfort caused by TTAGS This staging system has not been validated Early treatment of CAH with adequate suppression of ACTH levels by glucocorticoid treatment from childhood, may prevent[pathologyoutlines.com]

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].

References

Article

  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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Last updated: 2018-06-22 00:40