The synthesis of steroid hormones in the adrenal cortex is dependent on the coordinated action of numerous enzymes. Congenital adrenal hyperplasia (CAH) is a group of recessive conditions in which genetic alterations in the enzymes involved in steroid syn thesis result in impaired glucocorticoid production. Depending on the enzyme involved and the point at which steroidogenesis is disrupted this is associated with excess or inadequate androgen production, accompanied by varying degrees of mineralocorticoid deficiency.
CAH is the most common genetic cause of primary adrenal in sufficiency in childhood with mutations in CYP21A2 accounting for 95% of cases of CAH. The carrier rate of 21- hydroxylase deficiency (21OHD) is estimated to be around 1 in 50, but is higher in certain ethnicities. CYP21A2 is located in a tandemly duplicated sequence within the human leukocyte antigen (HLA) cluster on chromosome 6. The region contains the C4A and C4B genes, which encode complement factor 4 as well as CYP21A2 and its pseudogene CYP21A1P. The tandem arrangement of these genes with a high degree of sequence similarity makes this region susceptible to misalignment during meiosis which can result in deletions and duplications as well as gene conversion events. The tenascin X gene, TNXB, which encodes an important constituent of the connective tissue, is located next to CYP21A2. Deletions of CYP21A2 together with part or all of TNXB lead to connective tissue disease. The high sequence similarly between CYP21A2 and its pseudogene precludes the use of direct sequencing approaches in cell- free DNA analysis as part of non- invasive prenatal diagnosis for CAH. Relative haplotype dosage analysis has now been successfully developed for this purpose.
The genetics of CAH is covered in detail in Chapter 5.9.1, here we will focus on those genes that have been identified in studies of FGD.
The first step in steroid synthesis in the adrenal gland involves the rate- limiting step of cholesterol transport from the outer mitochondrial membrane to the inner mitochondrial membrane by the steroidogenic acute regulatory protein (StAR). Defects in the STAR gene have long been known to cause lipoid CAH, whereby both glucocorticoid and mineralocorticoid deficiency are present together with defective gonadal steroidogenesis, the latter presenting as 46,XY DSD or gonadal insufficiency. In 46,XX females, lipiod CAH can present as progressive hypogonadism. However, it is now clear that 5– 10% of FGD patients harbour partial loss- of- function mutations in StAR which result in non- classical lipoid CAH and isolated glucocorticoid deficiency.
Once transported, cholesterol is converted to pregnenolone by the P450 side- chain cleavage enzyme (CYP11A1). Recessive genetic defects in the CYP11A1 gene are known to cause a similar phenotype to lipoid CAH. Partial loss- of- function mutations, with retention of up to 20% of wild type function can lead to delayed onset adrenal insufficiency with minor malformations of the external genitalia such as hypospadias. A relatively common variant in CYP11A1 among European populations, traditionally characterized as a benign variant, has recently been shown to affect splicing, thus demonstrating the difficulties in assigning pathogenicity to variants and the limited utility in using population frequencies to inform pathogenicity in recessive disease.
