Congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency
General Information (adopted from Orphanet):
Synonyms, Signs:
17-@
ALPHA-HYDROXYLASE/17,20-LYASE DEFICIENCY, COMBINED COMPLETE, INCLUDED
17-@
ALPHA-HYDROXYLASE/17,20-LYASE DEFICIENCY, COMBINED PARTIAL, INCLUDED
ADRENAL HYPERPLASIA V
17-@
ALPHA-HYDROXYLASE DEFICIENCY 17,20-@
LYASE DEFICIENCY, ISOLATED, INCLUDED
CAH due to 17-alpha-hydroxylase deficiency
Deficiency of adrenal 17-hydroxylation activity was first demonstrated in a single patient by Biglieri et al. (1966), who suggested a similar defect in the gonad. Production of excessive corticosterone and deoxycorticosterone resulted in hypertension and hypokalemic alkalosis. Aldosterone ... Deficiency of adrenal 17-hydroxylation activity was first demonstrated in a single patient by Biglieri et al. (1966), who suggested a similar defect in the gonad. Production of excessive corticosterone and deoxycorticosterone resulted in hypertension and hypokalemic alkalosis. Aldosterone synthesis was almost totally absent. The patient had normal stature and amenorrhea. Although there were no other cases in the family and parental consanguinity was not noted, recessive inheritance was possible. Biglieri (1997) reviewed the evolution of the clinical features and laboratory findings in this case over 3 years. Goldsmith et al. (1967) reported a second case in whom the defect in 17-alpha-hydroxylation may have been less complete than in the first case. The patient was a 26-year-old woman with hypertension, primary amenorrhea, and lack of secondary sexual characteristics. Mallin (1969) described congenital adrenal hyperplasia due to 17-hydroxylase deficiency in 2 sisters. New (1970) reported the first affected male. The clinical features were pseudohermaphroditism with ambiguous external genitalia and prominent breast development at puberty. Unlike the previously reported female cases, this male patient did not demonstrate severe hypertension or hypokalemia. Testicular feminization was simulated in a patient reported by Heremans et al. (1976). Yazaki et al. (1982) reported a Japanese phenotypic female, born of consanguineous parents, with generalized muscle weakness due to hypokalemic myopathy, primary amenorrhea, and lack of pubertal development. Laparoscopy showed intraabdominal testes and no uterus. Karyotype was 46,XY. Laboratory studies showed increased plasma progesterone, corticosterone, aldosterone, ACTH (see 176830), LH (see 152780), and FSH (see 136530). Glucocorticoid replacement normalized plasma levels of ACTH, 17-deoxysteroids, and potassium. This patient was later found to have a homozygous mutation in the CYP17A1 gene (609300.0011; Yamaguchi et al., 1997), consistent with combined complete 17-alpha-hydroxylase/17,20-lyase deficiency. Scaroni et al. (1991) reported a family in which 3 members, 2 adult females and 1 pubertal-aged genotypic male, had congenital adrenal hyperplasia due to 17-alpha hydroxylase deficiency. All presented as phenotypic females with lack of sexual development and hypokalemic hypertension. Baseline hormonal studies showed low glucocorticoid, androgen, and estrogen levels. As a consequence, ACTH, LH, and FSH concentrations were increased. Plasma renin and aldosterone were also decreased. Short-term dexamethasone treatment normalized potassium and reduced blood pressure and the abnormal mineralocorticoid levels. Martin et al. (2003) reported 11 patients from 6 Brazilian families with combined 17-alpha-hydroxylase/17,20-lyase deficiency. All patients had elevated basal serum levels of progesterone and suppressed plasma renin activity. The authors concluded that basal progesterone measurement is a useful marker of P450c17 deficiency and that its use should reduce the misdiagnosis of this deficiency in patients presenting with male pseudohermaphroditism, primary or secondary amenorrhea, and mineralocorticoid excess syndrome. - Combined Partial 17-alpha-Hydroxylase/17,20-Lyase Deficiency Oshiro et al. (1995) reported a 32-year-old Japanese woman with combined partial 17-alpha-hydroxylase/17,20-lyase deficiency caused by mutation in the CYP17A1 gene (609300.0008). The patient was referred because of hypertension and amenorrhea. She had menarche at the age of 14 years with irregular menstruation until the age of 20, but no menstruation thereafter. Hypertension had been known since the age of 20 years. She had a flat chest, infantile genitalia, and no pubic or axillary hair. Computed tomography revealed bilateral adrenal hyperplasia without tumors, uterine hypoplasia, and atrophy of the ovaries. The patient had hypokalemia, metabolic alkalosis, and positive Trousseau sign. Yanase et al. (1989) reported a Japanese woman with combined partial 17-alpha-hydroxylase/17,20-lyase deficiency caused by mutation in the CYP17A1 gene (609300.0002). Functional expression studies showed that 17-alpha-hydroxylase and 17,20-lyase activities were less than 37% and 8% of normal, respectively. On a visit to the hospital at the age of 20 because of occipital headache, the patient was found to have hypertension and hypokalemia. Menstruation was irregular. Physical examination showed hypoplastic breasts and no pubic or axillary hair. Miura et al. (1996) reported follow-up of the Japanese woman reported by Yanase et al. (1989). In 1968, she was reported as having glucocorticoid-responsive hyperaldosteronism. She was treated with dexamethasone, resulting in normal blood pressure and normokalemia for 28 years. Because of sustained vaginal bleeding, she had a total hysterectomy at age 42. No follicles or corpus luteum were detected in the ovarian specimen. At age 45 years, she had decreased levels of sex steroids and increased levels of gonadotropins. Miura et al. (1996) concluded that the disorder resulted in early reduction of gonadal function with increasing age. - Isolated 17,20-Lyase Deficiency Geller et al. (1997) reported 2 patients with isolated 17,20-lyase deficiency caused by different homozygous mutations in the CYP17A1 gene (609300.00012 and 609300.0013, respectively). The first patient had genital ambiguity at birth, but was assigned female gender. When seen at 13 months of age, the patient showed a 2.2-cm phallus, perineal hypospadias, bilateral gonads palpable in a bifid scrotum, and a blind vaginal pouch seen on urethrocystograms. The parents were first cousins. Serum cortisol and electrolytes and blood pressure were normal. Gonadotropins were at normal prepubertal level in this patient. Testicular stimulation with human chorionic gonadotropin elicited grossly subnormal responses of testosterone, DHEA, and androstenedione. Basal and hCG-stimulated progesterone was normal. The second patient had a 46,XY karyotype, but genital ambiguity at birth when male gender was assigned. Gynecomastia developed at 14 years of age, and at 16 years the breasts were Tanner stage V; pubic hair was Tanner stage IV, but there was minimal body hair. The genitalia were characterized by a 4.5-cm phallus, perineal hypospadias, bifid scrotum, small descended testis on the right and left in the inguinal canal, and a blind vaginal pouch detected by urethrocystography. The parents denied consanguinity. Biason-Lauber et al. (1997) reported a newborn male patient from Israel with micropenis, undescended testes, and a hormonal pattern consistent with isolated 17,20-lyase deficiency. They found compound heterozygosity for mutations in the CYP17A1 gene. Gupta et al. (2001) studied one of the mutations and was unable to demonstrate activity consistent with the diagnosis. Hershkovitz et al. (2008) restudied this patient along with 3 other affected male relatives. They found deficiency of cytochrome P450 oxidoreductase (POR) caused by homozygosity for a mutation in the POR gene (124015.0016) in these individuals. Sequencing of the CYP17A1 in 2 different laboratories failed to find the mutations reported by Biason-Lauber et al. (1997). Hershkovitz et al. (2008) concluded that POR deficiency (201750) can masquerade clinically as isolated 17,20-lyase deficiency.
In a patient with combined 17-alpha-hydroxylase/17,20-lyase deficiency, Kagimoto et al. (1988) identified a 4-base duplication in the CYP17A1 gene (609300.0001), resulting in the loss of both enzymatic activities.
In 2 patients with isolated 17,20-lyase deficiency from ... In a patient with combined 17-alpha-hydroxylase/17,20-lyase deficiency, Kagimoto et al. (1988) identified a 4-base duplication in the CYP17A1 gene (609300.0001), resulting in the loss of both enzymatic activities. In 2 patients with isolated 17,20-lyase deficiency from a small village in Brazil, Geller et al. (1997) identified 2 different homozygous mutations in the CYP17A1 gene (609300.0012; 609300.0013). When expressed in COS-1 cells, the mutants retained 17-alpha-hydroxylase activity, but had minimal 17,20-lyase activity. Yanase et al. (1991) stated that since the first description by Biglieri et al. (1966), at least 122 cases of 17-alpha-hydroxylase deficiency had been reported. Furthermore, 14 cases of 17,20-lyase deficiency had been reported in which 17-alpha-hydroxylase activity remained normal, this being a major reason that the 2 enzymes were long thought to be different. Yanase et al. (1991) reviewed 8 cases in which intragenic lesions had been identified. In 11 patients from 6 Brazilian families with combined 17-alpha-hydroxylase/17,20-lyase deficiency, Martin et al. (2003) identified mutations in the CYP17A1 gene (609300.0009; 609300.0023-609300.0026).