Letter by Kim Regarding Article, "A Patient with Partial 17α-Hydroxylase Deficiency Initially Diagnosed with Asherman Syndrome and Pheochromocytoma".

This study present a case of a 49-year-old woman who suffered from resistant hypertension, hypokalemia, hypomenorrhea, and infertility. She was hospitalized 6 years earlier for hypomenorrhea and abdominal pain at the Xiamen Maternity and Child Health Hospital, where she was diagnosed with Asherman syndrome. During hospitalization, a computed tomography examination revealed an adrenal mass. She was referred to Xiamen University Affiliated Zhongshan Hospital for pheochromocytoma and underwent surgical resection of the left adrenal gland. The adrenal cortex adenoma was confirmed by pathological biopsy. Six years later, the patient also presented with hypertension and hypokalemia to our emergency department. A diagnosis of 17α-hydroxylase deficiency was established through the analysis of clinical and laboratory characteristics. The genetic analysis of CYP17A1 revealed compound heterozygous mutations, 1 of which was a mutation of c.1226 C>G, and the other c.297+2T>C.

Abstract. Five women with post pubertal hirsutism due to a partial 21-hydroxylase deficiency were studied. These patients had no abnormalities of the external genitalia. They were compared to 3 adult women with a complete defect in 21-hydroxylase. The diagnosis of 21-hydroxylase deficiency was substantiated by the dramatic increase in 17-hydroxyprogesterone (17-OHP) after im injection of 250 μg synthetic ACTH (22 ± 12 nmol/l to 349 ± 153 nmol/l). However, in adult women with 21-hydroxylase deficiency recognized at birth and presenting abnormalities of the external genitalia, plasma 17-OHP was elevated in basal conditions (512 ± 106 nmol/l) and only slightly increased after ACTH administration (657 ± 133 nmol/l). Plasma cortisol levels determinated at 08.00 h were lower than normal in both groups but only slightly in groups with partial 21-hydroxylase deficiency. After ACTH stimulation, plasma cortisol levels remained lower than normal in all patients but with a noticeable increase in patients with partial defect. The differences noted between precocious and delayed onset virilization gave an indication of the importance of the enzyme defect. Plasma testosterone (T) and androstenedione (Δ4) levels were elevated both in basal conditions and after ACTH administration. However, in patients with delayed onset of hirsutism most circulating T seems to originate from peripheral conversion of Δ4 to T. Plasma ACTH values were strongly elevated in patients with a complete defect in 21-hydroxylase (260 ± 50 pg/ml) but normal in patients with partial deficiency (< 40 pg/ml). In vitro testosterone 5α-reductase activity was determined in pubic skin homogenates from 4 patients with partial 21-hydroxylase deficiency. The amount of dihydrotestosterone + androstanediols formed from incubated [3H]testosterone was in the normal range for women. Virilization of patients with partial 21-hydroxylase deficiency therefore seems to be essentially due to an increase in active androgen production and not to exaggerated skin 'utilization' of pre-androgens as observed in idiopathic hirsutism.

Congenital adrenal hyperplasia (CAH) due to 17α-hydroxylase deficiency, a rare CAH syndrome, is characterised by failure to synthetise cortisol, adrenal androgens and gonadal steroids. The partial deficiency is much rarer,...

The aims of this study were to determine the frequency of late-onset adrenal hyperplasia due specifically to 21-hydroxylase deficiency in a group of Irish women who presented at a Dublin Clinic with symptoms of hyperandrogenism, including hirsutism, menstrual irregularities and/or cystic acne, and to determine if those with 21-hydroxylase deficiency showed particular HLA associations. 119 women had blood samples taken basally and 1 h after an injection of 0.25 mg synacthen with the following hormones profiled: 17-hydroxyprogesterone, 11-deoxycortisol, androstenedione, testosterone, DHEAS and cortisol. Blood sampling was carried out between 0900 and 1000 h during the early follicular phase of the menstrual cycle (when applicable). Ninety-six subjects were new referrals to the Clinic for investigation of hyperandrogenism and 23 were acting as controls. In this study, 6% of patients showed evidence of partial 21-hydroxylase deficiency. In addition, 3 of the 6 with partial 21-hydroxylase deficiency had normal baseline levels of 17-hydroxyprogesterone, with the biochemical abnormality becoming manifest only on synacthen stimulation. Late-onset adrenal hyperplasia due to partial deficiency of this enzyme should always be considered as a possible diagnosis in women who present with symptoms of hyperandrogenism. Synacthen stimulation is an important diagnostic tool in elucidating partial enzyme deficiency as baseline 17-hydroxyprogesterone may be normal in such patients.

Attenuated or partial 21-hydroxylase deficiency is one of several biochemical defects in steroid metabolism that can lead to hirsutism in young women after puberty. The diagnosis is made through the exaggerated response of 17 alpha-hydroxyprogesterone (17-OH) to adrenocorticotrophic hormone (ACTH). To provide reference data 72 mild to moderately hirsute patients aged 18 to 35 were studied (over two years) with the ACTH test. Four patients with an exaggerated response were found. The mean (+/- 1SD) for zero time was 2.4 (0.96) nmol/l and for the 60 minute time was 7.2 (2.04) nmol/l. A subpopulation was found with a significantly higher baseline at 6.2 (1.3) nmol/l but a blunted 60 minute response at 8.7 (2.5) nmol/l. This is important because of the potential confusion arising from the known variability in baseline values in previously reported patients with partial 21-hydroxylase deficiency. Extending the test to 90 minutes did not show further increase in the 17-OH response to ACTH, thus confirming the validity of the 60 minutes ACTH test. The cortisol response to ACTH was also studied. One patient with presumptive partial 21-hydroxylase deficiency overlapped in cortisol response with eight of the reference population. Theoretically, a blunted cortisol response would be expected because of the postulated enzyme block, and these results suggest that other steroid enzyme defects should also be considered when an exaggerated 17-OH response to ACTH is seen.

Of 218 women with hirsutism 16 (7%) were found to have partial 21-hydroxylase deficiency, while 38 (17%) had partial 3 beta-hydroxysteroid dehydrogenase deficiency. Six women (3%) had a steroid constellation which resembled that of an augmented adrenarche. In the women with enzyme deficiency over-weight and abnormal menstruations were more frequent (50%) than in those without such deficiency (33%). The degree of hirsutism and age at diagnosis were similar in those with and those without partial enzyme deficiency. Furthermore, the diagnosis of partial enzyme deficiency could only be made with certainty by the ACTH stimulation test, because with sole measurement of basal levels (17-hydroxyprogesterone and 21-desoxycortisol in 21-hydroxylase deficiency, and 17-hydroxypregnenolone and dehydroepiandrosterone in 3 beta-hydroxysteroid dehydrogenase deficiency) the enzyme defects are in most instances not revealed.

In this family, two affected boys have perineal hypospadias and bifid scrotum, and two affected girls have slight clitoral enlargement with otherwise normal genitalia. All are mild ‘salt-losers’ with spontaneous crises occurring late (3 months and 2 years) in the boys. The girls had negative Na+ balance only when stressed by salt deprivation at ages 2 months and 4 years. All had elevated 17-ketosteroid excretion when diagnosed and, in the 2 youngest, urinary DHA > androsterone. Cortisol production and/or 17-OH-corticosteroid excretions were normal. Steroid excretion patterns showed an increase of 3β-HSD activity with increased age, but with a persisting high excretion of Δ4-pregnanetriol (Δ5-p′triol). At 2 months, one girl excreted per 24 h: pregnanetriol (p′triol)-0.23 mg, Δ5-p′triol-1.2 mg, 17α-OH-pregnenolone-2.6 mg, 16α-OH-pregnenolone-8.2 mg, 16α-OH-DHA-5.4 mg, DHA-0.5 mg. Her sister, at age 10 years, during withdrawl of cortisone therapy, excreted per 24 h: p′triol-24 mg, Δ5-p′triol-14 mg, DHA-1.2 mg, no 16α-OH-pregnenolone or 16α-OH-DHA. We conclude that these cases have partial 3β-HSD deficiencies, on the basis of the inadequate fetal virilization and persistent post-natal excretion of large amounts of Δ5-′triol; and partial 21-hydroxylase deficiencies, on the basis of the high p′triol excretions. The low post-natal excretion of DHA, relative to Δ5-p′triol and 17α-OH-pregnenolone, may be due to a late fetal appearance of the 3β-HSD for DHA or may be due to an underactivity of the 17–20 desmolase (side-chain splitting) enzyme.

We performed molecular genetic analysis of 24 subjects from 19 families with 17-hydroxylase deficiency in Brazil. Of 7 novel CYP17 mutations, 2 (W406R and R362C) account for 50% and 32% of the mutant alleles, respectively. Both mutations were completely inactive when studied in COS-7 cells and yeast microsomes; however, phenotypic features varied among subjects. Some 46,XY individuals with these genotypes had ambiguous genitalia, and other subjects had normal blood pressure and/or serum potassium. We found mutations W406R and R362C principally in families with Spanish and Portuguese ancestry, respectively, suggesting that two independent founder effects contribute to the increased prevalence of 17-hydroxylase deficiency in Brazil. Mutations Y329D and P428L retained a trace of activity, yet the two individuals with these mutations had severe hypertension and hypokalemia. The 46,XX female with mutation Y329D reached Tanner stage 5, whereas the 46,XY subject with mutation P428L remained sexually infantile. The severity of hypertension, hypokalemia, 17-deoxysteroid excess, and sex steroid deficiency varied, even among patients with completely inactive CYP17 protein(s). Spontaneous sexual development occurred only in 46,XX females with partial deficiencies. We conclude that other factors, in addition to CYP17 genotype, contribute to the phenotype of individual patients with 17-hydroxylase deficiency.

Congenital adrenal hyperplasia (CAH) is an inherited recessive disorder of adrenal steroidogenesis, generally caused by a total or partial deficiency in 21-hydroxylase, due to a deletion of or mutations in the CYP21 gene (the gene that codes for 21-hydroxylase). Impaired cortisol biosynthesis results in corticotropin hypersecretion, which leads to overproduction of intermediate metabolites and androgens. To describe for the first time, to our knowledge, a patient with CAH and multiple sclerosis (MS). Case report. A 22-year-old woman, diagnosed at birth as having a salt-losing 21-hydroxylase deficiency, had sudden visual loss in the right eye and pyramidal, sensory, and cerebellar signs. Repeated brain magnetic resonance images showed focal white matter lesions in periventricular areas, the corpus callosum, the cerebellum, and the brainstem. A cerebrospinal fluid examination revealed several oligoclonal bands. Thereafter, she had 2 relapses, characterized by ataxia and diplopia, and recovered after corticosteroid treatment. The reported case fulfills the diagnostic criteria for CAH and MS. Some clues suggest that the association between CAH and MS could be nonincidental: a possible MS susceptibility locus is on chromosome 6p21, on which the CYP21 gene is located; the CYP21 gene and the CYP21P pseudogene alternate in tandem with the C4 genes (the genes that code for the homonym complement protein) (C4AQ0 is particularly frequent in patients with relapsing-remitting MS); and, in previous studies, brain magnetic resonance imaging showed T2-hyperintense focal areas in the white matter of CAH patients. Our observation should alert neurologists to the presence of signs and symptoms suggestive of late-onset CAH in MS patients and, in turn, endocrinologists to the appearance of neurological signs and symptoms in CAH patients.

A woman with a schizophreniform syndrome, drug-induced dyskinetic movements, and partial adrenocortical 21-hydroxylase deficiency was given short-term treatment with naloxone, which ameliorated the psychiatric symptoms and eliminated the dyskinetic movements.

Patients with late-onset congenital adrenal hyperplasia (LOCAH) due to partial 21-hydroxylase deficiency have no clinical or biochemical evidence of hypocortisolism. In contrast, patients with the classical forms of CAH frequently develop adrenal insufficiency, characterized by elevated plasma ACTH and low serum cortisol levels. To examine the various components of the hypothalamic-pituitary-adrenal axis in patients with LOCAH, we studied 12 patients with this disorder (10 females and 2 males; age range, 51/2-36 yr). Plasma ACTH and serum cortisol, 17-hydroxyprogesterone (17-OHP), and androstenedione (Adione) concentrations were measured after administration of ovine CRH (oCRH); 1 micrograms/kg at 2000 h) and in the unstimulated state (every 30-60 min for 24 h). The patients' oCRH-stimulated ACTH, cortisol, and Adione responses did not differ from those of normal subjects, whereas their serum 17-OHP concentrations were elevated both basally and after oCRH (P less than 0.05). The patients' unstimulated 24-h ACTH and cortisol levels were normal and exhibited normal diurnal variability. Cortisol pulse frequency was normal. The patients' unstimulated serum 17-OHP levels exceeded those in the normal subjects at all times (P less than 0.01) and exhibited diurnal variability paralleling that of ACTH and cortisol. Unstimulated serum Adione levels in 4 adult women were in the normal or low normal range, except between 0200-0730 h when they were moderately elevated (P less than 0.05). We conclude that the ACTH-cortisol component of the hypothalamic-pituitary-adrenal axis is in normal equilibrium in this group of patients with LOCAH. Because serum Adione levels were elevated only briefly, we suggest that peripheral tissue conversion of 17-OHP to androgens may be the primary cause of the hirsutism and acne in these patients.

P450 oxidoreductase (POR) deficiency is an autosomal recessive disorder of steroidogenesis with multiple clinical manifestations. POR is the electron donor for all microsomal P450 enzymes, including the three steroidogenic enzymes P450c17 (17α-hydroxylase/17,20-lyase), P450c21 (21-hydroxylase), and P450aro (aromatase). Since the first description of POR mutations in 2004, about 50 patients have been reported. Serum steroid profiles indicate partial deficiencies in 21-hydroxylase, 17α-hydroxylase and 17,20-lyase. The 17-OH progesterone levels are elevated, as in 21-hydroxylase deficiency, while androgen levels are low; cortisol may be normal but is poorly responsive to adrenocorticotropic hormone. Most patients also have associated skeletal malfor- mations (craniosynostosis, radio-ulnar synostosis, midface hypoplasia, bowed femora) termed Antley-Bixler syndrome. Antley-Bixler syndrome with normal steroidogenesis is caused by autosomal dominant gain-of-function mutations in fibroblast growth factor receptor 2. Males with POR deficiency are often undervirilized, while females can be virilized. The prognosis for patients with POR deficiency appears to depend on the severity of the bony malformations and their timely treatment. The potential impact of POR mutations on drug metabolism by other hepatic P450 enzymes requires further investigation. Given the varied physical and biochemical phenotype of POR deficiency and the risk of adrenal insufficiency, clinicians should be alert to this potential diagnosis.

Congenital adrenal hyperplasia due to 3 beta-ol-hydroxysteroid dehydrogenase (3 beta-ol) deficiency is usually lethal. A partial deficiency in 3 beta-ol has been suggested in some women presenting with androgen excess. In this study, 24 women were investigated who had hirsutism and oligomenorrhea and high serum delta 5 androgens compared to delta 4 androgens. Of these women, 9 had significantly elevated 17-hydroxypregnenolone (17 Preg) to 17-hydroxyprogesterone (17 Prog) ratios when compared to controls under basal conditions. On further testing of 9 women with ACTH, 4 had significantly elevated 17 Preg to 17 Prog ratios. Eight women had elevated ratios of dehydroepiandrosterone sulfate to androstenedione, 4 had elevations of androstenediol (Adiol) to testosterone (T), and 4 had abnormal 17 Preg to cortisol ratios. Only 3 women out of the original 24 selected for study had elevated ratios for all 4 different steroid pairs measured. 17 Prog was normal in these women with 3 beta-ol deficiency in contradistinction to the high levels normally observed in women with congenital adrenal hyperplasia due to 21- or 11-hydroxylase deficiency. It is suggested that the cause of androgen excess in these women is high circulating levels of Adiol and, in part, the slightly elevated unbound T levels in these women. In conclusion, a subtle, incomplete form of 3 beta-ol deficiency may exist in adult women and is manifest by high delta 5 androgens such as dehydroepiandrosterone sulfate and Adiol and normal delta 4 androgens such as androstenedione and T.

Steroid 17alpha-hydroxylase deficiency is characterized by failed sexual development and mineralocorticoid hypertension. Female patients usually exhibit primary amenorrhea. Some patients with partial deficiency are reported to have menses, yet they have hypertension and hypokalemia. We describe here a normotensive, infertile female patient with menses and minimal defects in secondary sex characteristics. The patient experienced menarche at age 13, and her menstrual cycles were regular until age 18 and irregular thereafter. Pubic hair was present (Tanner stage 3), and breast maturation was within normal range (Tanner stage 5). The patient's resting blood pressure was normal, and hypokalemia was not observed despite high blood corticosterone levels and reduced plasma renin activity. Analysis of the CYP17 gene revealed that the patient was homozygous for the Y201N mutation. In vitro expression of the mutated Y201N enzyme revealed reduced activities of both 17alpha-hydroxylase and 17,20-lyase; however, these reductions were less than those of the F53/54DEL mutation, which also shows mild clinical deficiency of 17alpha-hydroxylase/17,20-lyase. Thus, the 17alpha-hydroxylase/17,20-lyase deficiency in the present case is very mild both clinically and enzymatically. This case raises the possibility that there are infertile, menstruating women with undiagnosed 17alpha-hydroxylase deficiency.

17α-Hydroxylase deficiency is rare autosomal recessive disorder that manifested by hypertension, hypokalemia, delayed sexual development, primary amenorrhea and infertility. The information regarding infertility care and conception in women with this disorder are extremely limited. We report a 24-year-old Japanese woman with primary amenorrhea who was diagnosed as partial 17α-hydroxylase deficiency caused by homozygous 3 bp deletion in exon 1 of 17α-hydroxylase gene. In vitro fertilization with controlled ovarian stimulation was carried out and all viable embryo were frozen. During ovarian stimulation, serum progesterone levels were markedly elevated, and endometrial growth was impaired. Utilizing frozen-thaw embryo transfer under hormonal replacement (glucocorticoid, estradiol and progesterone), she had successfully given two consecutive live birth. Women with 17α-hydroxylase deficiency with residual ovarian reserve can afford reproductive success by appropriate diagnosis and treatment by assisted reproductive technology.