Congenital adrenal hyperplasia

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This page contains general information about Congenital adrenal hyperplasia. For more information on specific types, please visit the pages on 21-hydroxylase deficiency, 17 alpha-hydroxylase deficiency, 11β-hydroxylase deficiency, 3 beta-hydroxysteroid dehydrogenase deficiency, Cytochrome P450-oxidoreductase (POR) deficiency (ORD), congenital lipoid adrenal hyperplasia.

Congenital adrenal hyperplasia main page

Overview

Classification

21-hydroxylase deficiency
11β-hydroxylase deficiency
17 alpha-hydroxylase deficiency
3 beta-hydroxysteroid dehydrogenase deficiency
Cytochrome P450-oxidoreductase (POR) deficiency (ORD)
Lipoid congenital adrenal hyperplasia

Differential Diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

Synonyms and Keywords: Congenital adrenal hyperplasia, CAH, Adrenal hyperplasia

Overview

Congenital adrenal hyperplasia consists of several disorders result from defective enzymes and proteins involving in steroid and cortisol biosynthesis. Defects in steroid biosynthesis is caused by several genetic mutations. Decreasing cortisol levels leads to releasing the inhibitory feedback on corticotropin (ACTH) production. High ACTH level causes cortisol precursor accumulation and overproduction of other steroids. The most common cause of congenital adrenal hyperplasia is 21-hydroxylase deficiency, which accounts for more than 95% of cases. Other causes are 17 alpha-hydroxylase deficiency, 11β-hydroxylase deficiency, 3 beta-hydroxysteroid dehydrogenase deficiency, Cytochrome P450-oxidoreductase (POR) deficiency (ORD), and congenital lipoid adrenal hyperplasia.

Classification

Congenital adrenal hyperplasia is classified into seven types based on the genetic causes that lead to hyperplasia and hormonal imbalance. There are three zones of hormonal synthesis in the adrenal cortex that are shown below, and impairment of each pathway and enzyme may lead to a specific subtype of congenital adrenal hyperplasia such as 21-hydroxylase deficiency, 17 alpha-hydroxylase deficiency, 11β-hydroxylase deficiency, 3 beta-hydroxysteroid dehydrogenase deficiency, Cytochrome P450-oxidoreductase (POR) deficiency (ORD), and congenital lipoid adrenal hyperplasia.


Adrenal steroid synthesis pathways in adrenal cortex and related enzymes [1]
Disease History and symptoms Laboratory findings Defective gene
Blood pressure Genitalia Cortisol Aldosterone Androgens Estrogens Increased hormone precursors Potassium levels
21-hydroxylase deficiency Classic type, salt-wasting
  • Male: Normal or scrotal pigmentation and large phallus
↓↓ Relatively low

CYP21A1 and CYP21A2 gene

Classic type, non-salt-wasting Normal
  • Male: normal or scrotal pigmentation and large phallus
Relatively low Normal CYP21A1 and CYP21A2 gene
Non-classic type Normal Normal Normal Relatively low Normal

CYP21A1 and CYP21A2 gene

17-α hydroxylase deficiency Normal corticosterone

Normal cortisol

CYP17A1
11-β hydroxylase deficiency
  • Male: Normal or scrotal pigmentation and large phallus
Relatively low CYP11B1
3 beta-hydroxysteroid dehydrogenase deficiency Male:↓

Female:↑

HSD3B2
Cytochrome P450-oxidoreductase (POR) deficiency (ORD) Normal Normal Normal Mutations in the flavoprotein co-factor of the enzymes CYP17A1, CYP21A2, and CYP19A1 (aromatase).
Congenital lipoid adrenal hyperplasia None of precursors increased Gene mutations on chromosome 8, codes for a protein called steroid acute regulatory protein (StAR)

Differential Diagnosis

Congenital adrenal hyperplasia must be differentiated from diseases that cause ambiguous genitalia:[2][3]

Disease name Steroid status Important clinical findings
Increased Decreased
Classic type of 21-hydroxylase deficiency
11-β hydroxylase deficiency
17-α hydroxylase deficiency
3 beta-hydroxysteroid dehydrogenase deficiency
Gestational hyperandrogenism

Congenital adrenal hyperplasia must be differentiated from diseases that cause virilization and hirsutism in female:[4][3][5]

Disease name Steroid status Other laboratory Important clinical findings
Non-classic type of 21-hydroxylase deficiency Increased:
  • No symptoms in infancy and male
11-β hydroxylase deficiency Increased:

Decreased:

3 beta-hydroxysteroid dehydrogenase deficiency Increased:

Decreased:

Polycystic ovary syndrome
Adrenal tumors
  • Variable levels depends on tumor type
  • Older age
  • Rapidly progressive symptoms
Ovarian virilizing tumor
  • Variable levels depends on tumor type
  • Older age
  • Rapidly progressive symptoms
Cushing's syndrome
Hyperprolactinemia

Some types of congenital adrenal hyperplasia must be differentiated from diseases with primary amenorrhea and female external genitalia.[6][7][8][9][10][11][12][13]

Disease name Cause Differentiating
Findings Uterus Breast development Testosterone LH FSH Karyotyping
3-beta-hydroxysteroid dehydrogenase type 2 deficiency

Yes in female

Yes in female

Low

Normal

Normal

XY and XX

17-alpha-hydroxylase deficiency

No

No

Low

Normal

Normal

XY

Gonadal dysgenesis
  • Mutations in SRY, FOG2/ZFPM2, and WNT1

Yes

Yes

Low

High

High

XY

Testicular regression syndrome
  • Loss of testicular function and tissue early in development

No

No

Low

High

High

XY

LH receptor defects

No

No

Low

High

High

XY

5-alpha-reductase type 2 deficiency

No

No

Normal male range

High to normal

High to normal

XY

Androgen insensitivity syndrome 

No

Yes

Normal male range

Normal

Normal

XY

Mullerian agenesis

No

Yes

Normal female range

Normal

Normal

XX

Primary ovarian insufficiency

Yes

Yes

Normal female range

High

High

XX

Hypogonadotropic hypogonadism
  • Functional, sellar masses

Yes

No

Normal female range

Low

Normal

XX

Turner syndrome

  • Chromosomal

Yes

Yes

Normal female range

High

High

45 XO

References

  1. "File:Adrenal Steroids Pathways.svg - Wikimedia Commons". 
  2. Hughes IA, Nihoul-Fékété C, Thomas B, Cohen-Kettenis PT (2007). "Consequences of the ESPE/LWPES guidelines for diagnosis and treatment of disorders of sex development". Best Pract. Res. Clin. Endocrinol. Metab. 21 (3): 351–65. PMID 17875484. doi:10.1016/j.beem.2007.06.003. 
  3. 3.0 3.1 White PC, Speiser PW (2000). "Congenital adrenal hyperplasia due to 21-hydroxylase deficiency". Endocr. Rev. 21 (3): 245–91. PMID 10857554. doi:10.1210/edrv.21.3.0398. 
  4. Hohl A, Ronsoni MF, Oliveira M (2014). "Hirsutism: diagnosis and treatment". Arq Bras Endocrinol Metabol. 58 (2): 97–107. PMID 24830586.  Vancouver style error: initials (help)
  5. Melmed, Shlomo (2016). Williams textbook of endocrinology. Philadelphia, PA: Elsevier. ISBN 978-0323297387. =
  6. Maimoun L, Philibert P, Cammas B, Audran F, Bouchard P, Fenichel P, Cartigny M, Pienkowski C, Polak M, Skordis N, Mazen I, Ocal G, Berberoglu M, Reynaud R, Baumann C, Cabrol S, Simon D, Kayemba-Kay's K, De Kerdanet M, Kurtz F, Leheup B, Heinrichs C, Tenoutasse S, Van Vliet G, Grüters A, Eunice M, Ammini AC, Hafez M, Hochberg Z, Einaudi S, Al Mawlawi H, Nuñez CJ, Servant N, Lumbroso S, Paris F, Sultan C (2011). "Phenotypical, biological, and molecular heterogeneity of 5α-reductase deficiency: an extensive international experience of 55 patients". J. Clin. Endocrinol. Metab. 96 (2): 296–307. PMID 21147889. doi:10.1210/jc.2010-1024. 
  7. Moreira AC, Leal AM, Castro M (1990). "Characterization of adrenocorticotropin secretion in a patient with 17 alpha-hydroxylase deficiency". J. Clin. Endocrinol. Metab. 71 (1): 86–91. PMID 2164530. doi:10.1210/jcem-71-1-86. 
  8. Heremans GF, Moolenaar AJ, van Gelderen HH (1976). "Female phenotype in a male child due to 17-alpha-hydroxylase deficiency". Arch. Dis. Child. 51 (9): 721–3. PMC 1546244Freely accessible. PMID 999330. 
  9. Biglieri EG (1979). "Mechanisms establishing the mineralocorticoid hormone patterns in the 17 alpha-hydroxylase deficiency syndrome". J. Steroid Biochem. 11 (1B): 653–7. PMID 226795. 
  10. Saenger P (1996). "Turner's syndrome". N. Engl. J. Med. 335 (23): 1749–54. PMID 8929268. doi:10.1056/NEJM199612053352307. 
  11. Bastian C, Muller JB, Lortat-Jacob S, Nihoul-Fékété C, Bignon-Topalovic J, McElreavey K, Bashamboo A, Brauner R (2015). "Genetic mutations and somatic anomalies in association with 46,XY gonadal dysgenesis". Fertil. Steril. 103 (5): 1297–304. PMID 25813279. doi:10.1016/j.fertnstert.2015.01.043. 
  12. Imperato-McGinley J, Guerrero L, Gautier T, Peterson RE (1974). "Steroid 5alpha-reductase deficiency in man: an inherited form of male pseudohermaphroditism". Science. 186 (4170): 1213–5. PMID 4432067. 
  13. Schnitzer JJ, Donahoe PK (2001). "Surgical treatment of congenital adrenal hyperplasia". Endocrinol. Metab. Clin. North Am. 30 (1): 137–54. PMID 11344932. 

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