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| __NOTOC__
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| {{Congenital adrenal hyperplasia}}
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| {{CMG}}; '''Associate Editor-In-Chief:''' {{CZ}}
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| ==Overview==
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| == Pathophysiology ==
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| In patients with 21-hydroxylase deficiency, there is a defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol which results in decreased cortisol synthesis and therefore increased corticotropin (ACTH) secretion and as a consequence of rising ACTH there is an increased production of androgens.<ref name="pmid10857554">{{cite journal |vauthors=White PC, Speiser PW |title=Congenital adrenal hyperplasia due to 21-hydroxylase deficiency |journal=Endocr. Rev. |volume=21 |issue=3 |pages=245–91 |year=2000 |pmid=10857554 |doi=10.1210/edrv.21.3.0398 |url=}}</ref>
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| More than 95% of all cases of CAH are caused by 21-hydroxylase deficiency (21-OHD);
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| Adrenal steroidogenesis occurs by a series of steps facilitated by adrenal zone-specific enzyme expression, and in different types of congenital adrenal hyperplasia this process is interrupted at distinct points. In addition to the classic well established steroidogenesis pathway, an alternative pathway to active androgen biosynthesis exists (termed the backdoor pathway),<sup>30 ; 31</sup> which might play a role in the pathophysiology of congenital adrenal hyperplasia (figure 2). The clinical manifestation of congenital adrenal hyperplasia is closely related to the type and severity of impairment.
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| == Genetics ==
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| Congenital adrenal hyperplasia subtypes are all autosomal recessive and monogenetic. The disease manifestation follows the allele that results in a more functional enzyme, and generally correlation between genotype and phenotype is good.<ref name="pmid20926536">{{cite journal |vauthors=Finkielstain GP, Chen W, Mehta SP, Fujimura FK, Hanna RM, Van Ryzin C, McDonnell NB, Merke DP |title=Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency |journal=J. Clin. Endocrinol. Metab. |volume=96 |issue=1 |pages=E161–72 |year=2011 |pmid=20926536 |pmc=3038490 |doi=10.1210/jc.2010-0319 |url=}}</ref><ref name="pmid23359698">{{cite journal |vauthors=New MI, Abraham M, Gonzalez B, Dumic M, Razzaghy-Azar M, Chitayat D, Sun L, Zaidi M, Wilson RC, Yuen T |title=Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=110 |issue=7 |pages=2611–6 |year=2013 |pmid=23359698 |pmc=3574953 |doi=10.1073/pnas.1300057110 |url=}}</ref>
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| 21 OH deficiency
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| Responsible gene for 21 OH deficiency is CYP21A. This gene has two types one is one is an active gene called ''CYP21A2'' and the other gene is a non-functional pseudogene named ''CYP21A1'' or ''CYP21P''
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| , is the gene for 21OH which is located within the [[Human leukocyte antigen|human leucocyte antigen]] class III region of chromosome 6. CYP21A2 and a homologous pseudogene'','' CYP21A1P, lie about 30 kb apart. Meiotic recombination events are common in this genomic region because of the high degree of sequence homology between duplicated genes. Approximately 95% of ''CYP21A2'' disease causing mutations are ''CYP21A1P''-derived variants or deletions due to recombination events.
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| Humans have two ''CYP21A'' genes, a non-functional pseudogene (''CYP21A1'' or ''CYP21P'') and the active gene (),
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| Conventionally, classic 21OH deficiency is subclassified into salt wasting and simple virilising forms, which reflect the severity of aldosterone deficiency. Mutations that completely inactivate ''CYP21A2'' result in the salt-wasting phenotype, which, without neonatal screening, presents in the first 2 weeks of life with a life-threatening adrenal crisis ( table 2).<sup>23</sup> Patients with classic simple virilising congenital adrenal hyperplasia have mutations that retain 1–2% of 21OH activity and minimal aldosterone production prevents a neonatal crisis.<sup>40</sup> Excess fetal adrenal androgen exposure results in virilisation of external genitalia of 46,XX patients with classic 21OH deficiency (salt wasting and simple virilising; figure 3A). Without neonatal screening, male toddlers with the simple virilising form of the disorder are diagnosed with signs and symptoms of androgen excess. Postnatal excess androgen presence leads to premature growth of pubic hair and rapid skeletal growth in children. Patients with the non-classic form retain up to 50% of enzyme activity and mostly do not have adrenal insufficiency, but might have partial glucocorticoid deficiency, and female patients have normal genitalia.<sup>41</sup> Patients might present with mild androgen excess or have few or no symptoms. In fact, the term cryptic congenital adrenal hyperplasia was created to define patients with non-classic congenital adrenal hyperplasia who are identified by family genetic studies, but are otherwise asymptomatic.<sup>42</sup>
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| ==References==
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| {{Reflist|2}}
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| [[Category:Disease]]
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| [[Category:Pediatrics]]
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| [[Category:Endocrinology]]
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| [[Category:Genetic disorders]]
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