17 alpha(a)-hydroxylase/17,20-lyase deficiency is a condition that affects the function of certain hormone-producing glands called the gonads (ovaries in females and testes in males) and the adrenal glands. The gonads direct sexual development before birth and during puberty and are important for reproduction. The adrenal glands, which are located on top of the kidneys, regulate the production of certain hormones, including those that control salt levels in the body. People with 17a-hydroxylase/17,20-lyase deficiency have an imbalance of many of the hormones that are made in these glands. 17a-hydroxylase/17,20-lyase deficiency is one of a group of disorders, known as congenital adrenal hyperplasias, that impair hormone production and disrupt sexual development and maturation.\n\nHormone imbalances lead to the characteristic signs and symptoms of 17a-hydroxylase/17,20-lyase deficiency, which include high blood pressure (hypertension), low levels of potassium in the blood (hypokalemia), and abnormal sexual development. The severity of the features varies. Two forms of the condition are recognized: complete 17a-hydroxylase/17,20-lyase deficiency, which is more severe, and partial 17a-hydroxylase/17,20-lyase deficiency, which is typically less so.\n\nMales and females are affected by disruptions to sexual development differently. Females (who have two X chromosomes) with 17a-hydroxylase/17,20-lyase deficiency are born with normal external female genitalia; however, the internal reproductive organs, including the uterus and ovaries, may be underdeveloped. Women with complete 17a-hydroxylase/17,20-lyase deficiency do not develop secondary sex characteristics, such as breasts and pubic hair, and do not menstruate (amenorrhea). Women with partial 17a-hydroxylase/17,20-lyase deficiency may develop some secondary sex characteristics; menstruation is typically irregular or absent. Either form of the disorder results in an inability to conceive a baby (infertility).\n\nIn affected individuals who are chromosomally male (having an X and a Y chromosome), problems with sexual development lead to abnormalities of the external genitalia. The most severely affected are born with characteristically female external genitalia and are generally raised as females. However, because they do not have female internal reproductive organs, these individuals have amenorrhea and do not develop female secondary sex characteristics. These individuals have testes, but they are abnormally located in the abdomen (undescended). Sometimes, complete 17a-hydroxylase/17,20-lyase deficiency leads to external genitalia that do not look clearly male or clearly female. Males with partial 17a-hydroxylase/17,20-lyase deficiency may have a small penis (micropenis), the opening of the urethra on the underside of the penis (hypospadias), or a scrotum divided into two lobes (bifid scrotum). Males with either complete or partial 17a-hydroxylase/17,20-lyase deficiency are also infertile.

Classic 3-beta-hydroxysteroid dehydrogenase deficiency is an autosomal recessive form of CAH characterized by a severe impairment of steroid biosynthesis in both the adrenals and the gonads, resulting in decreased excretion of cortisol and aldosterone and of progesterone, androgens, and estrogens by these tissues. Affected newborns exhibit signs and symptoms of glucocorticoid and mineralocorticoid deficiencies, which may be fatal if not diagnosed and treated early, especially in the severe salt-wasting form. Moreover, male newborns exhibit pseudohermaphroditism with incomplete masculinization of the external genitalia due to an impairment of androgen biosynthesis in the testis. In contrast, affected females exhibit normal sexual differentiation or partial virilization (summary by Rheaume et al., 1992).

ACTH-independent macronodular adrenal hyperplasia (AIMAH) is an endogenous form of adrenal Cushing syndrome characterized by multiple bilateral adrenocortical nodules that cause a striking enlargement of the adrenal glands. Although some familial cases have been reported, the vast majority of AIMAH cases are sporadic. Patients typically present in the fifth or sixth decade of life, approximately 10 years later than most patients with other causes of Cushing syndrome (Swain et al., 1998; Christopoulos et al., 2005). Approximately 10 to 15% of adrenal Cushing syndrome is due to primary bilateral ACTH-independent adrenocortical pathology. The 2 main subtypes are AIMAH and primary pigmented nodular adrenocortical disease (PPNAD; see 610489), which is often a component of the Carney complex (160980) and associated with mutations in the PRKAR1A gene (188830). AIMAH is rare, representing less than 1% of endogenous causes of Cushing syndrome (Swain et al., 1998; Christopoulos et al., 2005). See also ACTH-independent Cushing syndrome (615830) due to somatic mutation in the PRKACA gene (601639). Cushing 'disease' (219090) is an ACTH-dependent disorder caused in most cases by pituitary adenomas that secrete excessive ACTH. Genetic Heterogeneity of ACTH-Independent Macronodular Adrenal Hyperplasia AIMAH2 (615954) is caused by germline mutation on 1 allele of the ARMC5 gene (615549) coupled with a somatic mutation in the other allele. AIMAH3 (620990) is caused by germline mutation on 1 allele of the KDM1A gene (609132) coupled with a somatic mutation in the other allele.

21-hydroxylase deficiency (21-OHD) is the most common cause of congenital adrenal hyperplasia (CAH), a family of autosomal recessive disorders involving impaired synthesis of cortisol from cholesterol by the adrenal cortex. In 21-OHD CAH, excessive adrenal androgen biosynthesis results in virilization in all individuals and salt wasting in some individuals. A classic form with severe enzyme deficiency and prenatal onset of virilization is distinguished from a non-classic form with mild enzyme deficiency and postnatal onset. The classic form is further divided into the simple virilizing form (~25% of affected individuals) and the salt-wasting form, in which aldosterone production is inadequate (=75% of individuals). Newborns with salt-wasting 21-OHD CAH are at risk for life-threatening salt-wasting crises. Individuals with the non-classic form of 21-OHD CAH present postnatally with signs of hyperandrogenism; females with the non-classic form are not virilized at birth.

Any primary pigmented nodular adrenocortical disease in which the cause of the disease is a mutation in the PDE8B gene.

Familial hyperaldosteronism type I (HALD1), also referred to as glucocorticoid-remediable aldosteronism (GRA), is an autosomal dominant disorder characterized by hypertension, variable hyperaldosteronism, and abnormal adrenal steroid production, including 18-oxocortisol and 18-hydroxycortisol (Lifton et al., 1992). There is significant phenotypic heterogeneity, and some individuals never develop hypertension (Stowasser et al., 2000). Genetic Heterogeneity of Familial Hyperaldosteronism Familial hyperaldosteronism type II (HALD2; 605635) is caused by mutation in the CLCN2 gene (600570) on chromosome 3q27. Familial hyperaldosteronism type III (HALD3; 613677) is caused by mutation in the KCNJ5 gene (600734) on chromosome 11q24. Familial hyperaldosteronism type IV (HALD4; 617027) is caused by mutation in the CACNA1H gene (607904) on chromosome 16p13.

Hyperaldosteronism type III (HALD3) is characterized by hypertension secondary to massive adrenal mineralocorticoid production. Like patients with glucocorticoid-remediable aldosteronism (GRA, or HALD1; 103900), patients with HALD3 present with childhood hypertension, elevated aldosteronism levels, and high levels of the hybrid steroids 18-oxocortisol and 18-hydroxycortisol. However, hypertension and aldosteronism in HALD3 are not reversed by administration of exogenous glucocorticoids and patients require adrenalectomy to control hypertension (Geller et al., 2008).

Cushing syndrome is a clinical designation for the systemic signs and symptoms arising from excess cortisol production. Affected individuals typically show hypertension, impaired glucose tolerance, central obesity, osteoporosis, and sometimes depression. Corticotropin-independent Cushing syndrome results from autonomous cortisol production by the adrenal glands, often associated with adrenocortical tumors. Adrenocortical tumors are most common in adult females (summary by Cao et al., 2014; Sato et al., 2014).