17 alpha-hydroxylase deficiency pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]
Overview
17 alpha-hydroxylase deficiency is an uncommon form of congenital adrenal hyperplasia resulting from a defect in the gene CYP17A1, which encodes for the enzyme 17 alpha-hydroxylase and 17,20-lyase. 17 alpha-hydroxylase deficiency is transmitted in an autosomal recessive pattern. Mineralocorticoid excess and lack of androgens are two main features in this disease.
Pathogenesis
- CYP17A1 gene defects can cause two type of enzyme deficiencies. 17α-hydroxylase enzyme deficiency and 17,20-lyase deficiency. The dual activities mediate key transformations in cortisol and sex steroid synthesis:
- 17α-hydroxylase mediates the pathway: pregnenolone → 17-hydroxypregnenolone, also progesterone → 17-hydroxyprogesterone.
- 17,20-lyase mediates pathway 17-hydroxypregnenolone → Dehydroepiandrosterone, also 17-hydroxyprogesterone → androstenedione
- Mineralocorticoid excess is the major clinical clue distinguishing the 17α-hydroxylase deficiency from the 17,20-lyase deficiency, which only affects the sex steroids.
- In 17 alpha-hydroxylase deficiency steroid biosynthesis will be limited to progesterone, 11-deoxycorticosterone (DOC), and corticosterone.
- 11-deoxycorticosterone (DOC) binds to the mineralocorticoid receptor and its excess amounts in 17 alpha-hydroxylase deficiency causes aldosterone effects such as volume expansion, hypertension, and hypokalemia. Also, 11-deoxycorticosterone (DOC) effects will suppress renin and aldosterone production.
- The most important features of 17 alpha-hydroxylase deficiency include hypertension, hypokalemia and sexual infantilism.
- Hypertension and hypokalemia result from accumulation of cortisol precursors, that they have mineralocorticoid characteristics.
- Sexual infantilism results from inability of adrenal cortex to synthesize androgens and estrogens.[1][2][3][4][5]
Genetics
- 17 alpha-hydroxylase deficiency is an inherited disease with an autosomal recessive pattern, which means both copies of the gene in each cell have gene mutations.
- Commonly, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
Associated Conditions
Gross Pathology
Gross pathology findings in patients with 17 alpha-hydroxylase deficiency are:[7][8]
- Enlarged adrenal glands
- Wrinkled surface adrenal glands
- Cerebriform pattern adrenal glands (pathognomonic sign)
- Normal ultrasound appearances may also be seen
- Testicular masses may be identified representing adrenal rest tissue
Microscopic Pathology
In 17 alpha-hydroxylase deficiency microscopic findings may include:
- Diffuse cortical hyperplasia with smaller cells
- The cell cytoplasm can be vacuolated, and often more basophilic
- Rare mitotic figures may be present
- The hyperplastic cells typically lack features of cellular atypia.[9]
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References
- ↑ Kater CE, Biglieri EG (1994). "Disorders of steroid 17 alpha-hydroxylase deficiency". Endocrinol. Metab. Clin. North Am. 23 (2): 341–57. PMID 8070426.
- ↑ 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 1546244. PMID 999330.
- ↑ Auchus RJ, Lee TC, Miller WL (1998). "Cytochrome b5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer". J. Biol. Chem. 273 (6): 3158–65. PMID 9452426.
- ↑ Griffing GT, Wilson TE, Holbrook MM, Dale SL, Jackson TK, Ullrich I, Melby JC (1984). "Plasma and urinary 19-nor-deoxycorticosterone in 17 alpha-hydroxylase deficiency syndrome". J. Clin. Endocrinol. Metab. 59 (5): 1011–5. doi:10.1210/jcem-59-5-1011. PMID 6332824.
- ↑ Simsek E, Ozdemir I, Lin L, Achermann JC (2005). "Isolated 17,20-lyase (desmolase) deficiency in a 46,XX female presenting with delayed puberty". Fertil. Steril. 83 (5): 1548–51. doi:10.1016/j.fertnstert.2004.11.063. PMID 15866602.
- ↑ Hannah-Shmouni F, Chen W, Merke DP (2017). "Genetics of Congenital Adrenal Hyperplasia". Endocrinol. Metab. Clin. North Am. 46 (2): 435–458. doi:10.1016/j.ecl.2017.01.008. PMID 28476231.
- ↑ Congenital adrenal hyperplasia. Dr Henry Knipe and Dr M Venkatesh . Radiopaedia.org 2015.http://radiopaedia.org/articles/congenital-adrenal-hyperplasia
- ↑ Teixeira SR, Elias PC, Andrade MT, Melo AF, Elias Junior J (2014). "The role of imaging in congenital adrenal hyperplasia". Arq Bras Endocrinol Metabol. 58 (7): 701–8. PMID 25372578.
- ↑ 9.0 9.1 9.2 "Adrenal Gland - Hyperplasia - Nonneoplastic Lesion Atlas".