SCIENTIFIC BACKGROUND

CYP11B1, CYP11B2, CYP17A1, CYP21A2, HSD3B2

Congenital adrenal hyperplasia (CAH), also known as adrenogenital syndrome (AGS), is an autosomal recessively inherited deficiency of cortisol and possibly aldosterone with a prevalence of about 1:10,000–1:16,000 (CAH) or 1:500–1:1,000 (late-onset CAH). The disease is predominantly caused by pathogenic variants in the 21-hydroxylase gene (CYP21A2) on chromosome 6p21.3. A clinical distinction is made between congenital or classic CAH and late‑onset or non-classic CAH.

 

Classic CAH is caused by variants that lead to an extreme reduction in 21-hydroxylase enzyme activity, which in turn leads to a reduction in enzymatic hydroxylation of 17-OH-progesterone and therefore to a lack of cortisol. In the presence of a very severe enzyme deficiency, the progesterone hydroxylation disturbance also leads to aldosterone deficiency. The metabolic block leads via negative feedback to the increased release of ACTH, which results in secondary adrenal cortex hyperplasia with the formation of male steroid metabolites and disturbances of female sex differentiation. In affected girls, there is virilization and the prenatal formation of intersexual genitals. Additional aldosterone deficiency leads to a life-threatening salt wasting syndrome if left untreated. Affected boys may also have salt wasting syndrome, and precocious puberty. Affected children stand out as the disease progresses due to accelerated skeletal maturation, which makes them too large initially, but later they are of small stature due to premature epiphyseal closure. If the parents are known to be carriers of the disease, the virilization of female fetuses can be prevented by administering dexamethasone during pregnancy.

 

Non-classic or late-onset CAH is characterized by less pronounced hyperandrogenemism, which can appear for the first time in adult women with symptoms including hirsutism, menstrual cycle disorders, low voice pitch, and acne. Late-onset CAH is caused by homozygosity of a "mild mutation" or by combined heterozygosity of a "mild" and a "severe mutation" or two "mild mutations" in the 21-hydroxylase gene.

 

Pathogenic variants in the 11-ß-hydroxylase gene (CYP11B1) cause about 5-8% of all classic cases of CAH. The resulting metabolic block also leads to the increased formation of male steroid metabolites and to disturbances of female sex differentiation. Salt wasting syndrome does not usually occur. Variants in the CYP11B1 gene have also been detected in women with late-onset CAH in individual cases.

 

In addition, CYP11B2 (aldosterone synthase), HSD3B2 (3ß-hydroxysteroid dehydrogenase), and CYP17A1 (steroid 17α-hydroxylase) genes can be analyzed.

 

  • Congenital adrenal hyperplasia  (CAH) due to 3ß-hydroxysteroid dehydrogenase deficiency (HSD3B2)
  • Congenital adrenal hyperplasia  (CAH) due to 11ß-hydroxylase deficiency (CYP11B1)
  • Congenital adrenal hyperplasia  (CAH) due to 21-hydroxylase deficiency (CYP21A2)
  • Hypoaldosteronism type 1 (CMOI) due to aldosterone synthase deficiency (CYP11B2)
  • Hypoaldosteronism type 2 (CMOII) due to aldosterone synthase deficiency (CYP11B2)
  • Adrenal hyperplasia due to 17α-hydroxylase deficiency (CYP17A1)

 

References

Nimkarn S, Gangishetti PK, Yau M, et al. 2002 [Updated 2016 Feb 4]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019 / New et al. 2013, Proc Natl Acad Sci USA 110:2611 / Speiser & White 2003, N Engl J Med 349:776

GENES

CYP11B1, CYP11B2, CYP17A1, CYP21A2, HSD3B2
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