Case Of 21-hydroxylase Deficiency Research Articles

Isotretinoin-unresponsive acne as a sign of a congenital disorder: a case of 21-hydroxylase deficiency.

Acne is a multifactorial and common disorder among young people and a frequent reason for dermatology consultation. When moderate-to-severe acne is not responsive to conventional treatments, oral isotretinoin is a very effective solution. However, there are cases in which this treatment fails to produce the expected results. In this case, an 18-year-old male patient with acne, unresponsive to traditional acne therapies, experienced only a partial benefit from oral isotretinoin. Endocrinology consultation and hormonal work-up revealed androgen metabolism anomalies suggestive of a non-classical form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. In this case report, the authors discuss when to suspect, how to diagnose, and how to manage similar cases.

A Case of 21-hydroxylase Deficiency with Massive Bilateral Adrenal Masses

Background: Congenital adrenal hyperplasia (CAH) can lead to bilateral adrenal tumors. Excess adrenocorticotropic hormone is thought to play a role in the development of adrenal nodules. Here we present a patient with a simple virilizing form of 21-hydroxylase deficiency, a married man, bilateral adrenal tumors, and 46-XX chromosomes.Case report: 39-year-old man suffered from abdominal pain and tension. Abdominal tomography showed macronodular hyperplasia in both adrenal glands, with the largest nodule reaching 4.2 cm on the left side. The patient's old records showed that CAH had been diagnosed at the age of 11 years, but the patient was not taking any medication. The patient was treated with glucocorticoid. Despite irregular use of the treatment, the size of the nodules remained stable for 3 years, and then a significant reduction in nodule size was observed.
 Conclusion: In patients with bilateral adrenal masses and incidentaloma, CAH should be considered to avoid unnecessary surgery or biopsy. A 17-hydroxyprogesterone test in a suspicious patient is a useful tool for diagnosis.

Screening for congenital adrenal hyperplasia in infertile women with high androgenemia during childbearing age

Objective The causes of infertility are complex and diverse, and congenital adrenal hyperplasia (CAH) is often overlooked in screening for infertility. In this study, CAH was diagnosed in women with high androgenemia who were infertile during childbearing age, and the diagnosis and treatment of CAH in pregnant women was investigated. Methods This study included 20 women with high androgenemia and infertility in the childbearing age who were referred to the Endocrinology Department after visiting the Reproductive Medicine Center of the First Affiliated Hospital of Nanjing Medical University from December 2016 to April 2019. All patients were tested for blood hormone levels, glucose, and lipid metabolism, underwent ACTH stimulation test, uterus and bilateral ovarian B-ultrasound, adrenal computed cosmography (CT), etc. Full-length sequencing of the CYP21A2 gene was performed as necessary. Results Among the 20 women with hyperandrogenism who were infertile, there were 7 cases of CAH (35.0%), including 6 cases of 21-hydroxylase deficiency (21-OHD) confirmed by gene sequencing; 10 cases of polycystic ovary syndrome (PCOS); 3 cases of idiopathic hyperandrogenemia (IHA). Sex hormone results showed that testosterone in CAH group was significantly higher than that in PCOS group and IHA group [(4.4±2.0 vs 2.9±0.4, 2.8±0.8) nmol/L, P 0.05]. However, the 17-OHP (60 min) in CAH group was significantly higher than that in PCOS group and IHA group [(200.1±80.8 vs 3.1±1.2, 3.4±0.2) ng/ml, P<0.05]. Glucocorticoid therapy was given to patients with CAH, and 4 patients had successful pregnancy. No clinical symptoms of CAH and external genital malformations were found in the offspring of patients who had been delivered. Conclusions The ACTH stimulation test is of great significance in the differential diagnosis of CAH, especially 21-OHD. Genetic testing helps to identify the type of mutation in CAH patients. On the one hand, glucocorticoid therapy may improve the pregnancy rate of CAH patients, on the other hand, it can help to reduce the status of maternal high androgen and avoid masculine manifestation of female offspring. Key words: Infertility; Hyperandrogenism; Congenital adrenal hyperplasia; ACTH stimulation test

A case of 21-hydroxylase deficiency in Turner′s syndrome and literature review

To improve the recognition and treatment of the combination of classical congenital adrenal hyperplasia (CAH) and Turner′s syndrome. A case of 21-hydroxylase deficiency (21-OHD) in 45, X[3]/46, XX[47] was reported, and the related literatures were reviewed. A 29-year-old woman with 45, X[3]/46, XX[47] was referred with clitorimegaly and primary amenorrhea. Her height was 150 cm with a weight of 56 kg. Physical examination revealed a Tanner stage Ⅵ for both breast development and pubic hair development. She showed a little signs of Turner′s syndrome, such as cubitus valgus. Lab findings: sex hormones are significantly increased, including progesterone, testosterone, dehydroepiandrosterone, 17 hydroxyprogesterone, dihydrotestosterone, and androstendione. Enhanced CT scan showed bilateral adrenal hyperplasia. Gynecological ultrasound showed that the size of the uterus and ovary were near normal and the endometrium was not clear. By gene mutation screening, two mutation sites were found in CYP21A2 gene, such as IVS2-13C/A→G and p. Ile173Asn(c.518T→A). Taken together, the patient was diagnosed as a combination of 21-OHD and Turner syndrome. A total of ten patients associated with CAH in Turner′s syndrome have been reported so far. The findings showed that routine karyotyping during investigations of patients presenting with ambiguous genitalia or with a diagnosis of CAH may reveal the concomitant presence of Turner′s syndrome. We should make a definite diagnosis and give early treatment as soon as possible. (Chin J Endocrinol Metab, 2017, 33: 760-764) Key words: Congenital adrenal hyperplasia; 21-hydroxylase deficiency; Turner′s syndrome; CYP21A2 gene mutation

An adult case of 21-hydroxylase deficiency complicated with azoospermia

An adult case of 21-hydroxylase deficiency complicated with azoospermia

Late Diagnosis of Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

Congenital adrenal hyperplasia results from 21-hydroxylase deficiency in more than ninety percent of cases. The classical form of 21-hydroxylase deficiency presents in the neonatal period with virilization or adrenal insufficiency, with or without concurrent salt wasting. We report on a rare case of classic 21-hydroxylase deficiency diagnosed in late adulthood. A 39-year-old male patient presented for workup of infertility. Urologic investigation revealed small testes, bilateral testicular masses, and asthenozoospermia. The patient's steroid metabolism showed markedly increased levels of adrenal androgens, in particular of 17-hydroxyprogesterone amd 21-deoxycortisol. The gas chromatographic-mass spectrometric (GC-MS) urinary steroid profile was dominated by metabolites of 17-hydroxyprogesterone, while the endogenous glucocorticoid production was subnormally low. ACTH levels in plasma were elevated. These hormonal findings were consistent with 21-hydroxylase deficiency. Therapy with dexamethasone was initiated. The CTP21A2 gene analysis revealed the mutation I172N (ATC --> AAC) in exon 4 of allele 1 and a large gene deletion in allele 2. Cases of 21-hydroxylase deficiency diagnosed in late adulthood are rare; however, clinicians should be alert of this possibility.

Prenatal diagnosis of 21-hydroxylase deficiency caused by gene conversion and rearrangements: pitfalls and molecular diagnostic solutions.

The present paper reports the prenatal diagnosis of congenital adrenal hyperplasia (CAH) in two cases of 21-hydroxylase deficiency. DNA diagnostic errors can be caused by the presence of the highly homologous 21-hydroxylase pseudogene, CYP21P, adjacent to the functional gene, CYP21. The present paper details how complex gene conversions and rearrangements between the CYP21 and CYP21P pose unique complications for prenatal diagnosis. Analysis of eight common mutations in the 21-hydroxylase gene as well as deletion of the entire gene is accomplished using polymerase chin reaction (PCR) followed by amplified created restriction site (ACRS) or allele-specific oligohybridization (ASO) and Southern blot followed by hybridization to a CYP21-specific probe. Linkage analysis was performed using microsatellite markers flanking the CYP21 gene. The direct mutation detection assay indicated a complicated gene conversion and rearrangement in the probands of both families. Interpretation of these rearrangements made it difficult to determine whether or not the fetuses would be affected with CAH. Linkage studies revealed that each fetus had inherited both parental disease chromosomes and was therefore predicted to be affected with CAH. As observed in the two reported cases, direct DNA analysis may provide limited information due to gene conversion or rearrangement between the CYP21 and CYP21P genes. These cases suggest that direct mutation detection should be supported by linkage analysis, whenever possible, to provide more comprehensive information for the family.

Urinary excretion of aldosterone metabolite Kelly-M1 in patients with adrenal dysfunction

Using tetrahydroaldosterone antibody a radioimmunoassay was developed to measure substance Kelly-M1 (K-M1) in human urine. The normal values were lower than observed by Kelly et al. who discovered the catabolite after giving large doses of exogenous aldosterone. While in essential hypertension the excretion of K-M1 was predominantly within the normal range, elevated values were found in most cases of 21-hydroxylase deficiency, both the simple virilizing and salt losing form, primary aldosteronism, renal hypertension and cystinosis. Our findings suggest that K-M1 may be formed from 21-deoxyaldosterone and/or by microbial intervention from aldosterone or its metabolites.

Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency

Specific 21-deoxycortisol (21-DF) antiserum was raised in New Zealand white rabbits using a 21-DF-3,20-oxime-bovine serum albumin complex. Plasma radioimmunoassay of 21-DF was developed and used together with a radioimmunoassay of 17-hydroxyprogesterone (17-OH-P) for diagnosis of patients with 21-hydroxylase deficiency of congenital and postpubertal forms. The assays were performed in plasma extracts after isolation by paper chromatography. The response of plasma 21-DF and 17-OH-P to i.v. ACTH (25 IU) was studied in 15 adult controls and compared to 8 women with the late onset form of 21-hydroxylase deficiency and 23 women with idiopathic hirsutism. Normal 21-DF values for women were 6.9 ± 3.6ng/dl and for men 9.71 ± 2.73 ng/dl. Newborn children (age: 3–10 days) had a value of 8.3 ± 4.8 ng/dl. These values are definitely lower than the lowest value ever published. This is possibly due to the specificity of the antibody. During the menstrual cycle the 21-DF values did not change. The baseline and post-stimulated concentrations of hormone were similar in controls and women with hirsutism but were significantly higher in women with the late onset form of 21-hydroxylase deficiency. In the congenital form of 21-hydroxylase deficiency the 21-DF values (baseline) were high. In general, the 21-DF and 17-OH-P values have shown parallel changes. However, one case of 21-hydroxylase deficiency with elevated 21-DF but normal 17-OH-P was observed. The use of 21-DF for the diagnosis of 21-hydroxylase deficiency is suggested.

K. Sexual steroids in the neonatal period

Specific 21-deoxycortisol (21-DF) antiserum was raised in New Zealand white rabbits using a 21-DF-3,20-oxime-bovine serum albumin complex. Plasma radioimmunoassay of 21-DF was developed and used together with a radioimmunoassay of 17-hydroxyprogesterone (17-OH-P) for diagnosis of patients with 21-hydroxylase deficiency of congenital and postpubertal forms. The assays were performed in plasma extracts after isolation by paper chromatography. The response of plasma 21-DF and 17-OH-P to i.v. ACTH (25 IU) was studied in 15 adult controls and compared to 8 women with the late onset form of 21-hydroxylase deficiency and 23 women with idiopathic hirsutism. Normal 21-DF values for women were 6.9 ± 3.6ng/dl and for men 9.71 ± 2.73 ng/dl. Newborn children (age: 3–10 days) had a value of 8.3 ± 4.8 ng/dl. These values are definitely lower than the lowest value ever published. This is possibly due to the specificity of the antibody. During the menstrual cycle the 21-DF values did not change. The baseline and post-stimulated concentrations of hormone were similar in controls and women with hirsutism but were significantly higher in women with the late onset form of 21-hydroxylase deficiency. In the congenital form of 21-hydroxylase deficiency the 21-DF values (baseline) were high. In general, the 21-DF and 17-OH-P values have shown parallel changes. However, one case of 21-hydroxylase deficiency with elevated 21-DF but normal 17-OH-P was observed. The use of 21-DF for the diagnosis of 21-hydroxylase deficiency is suggested.

DIFFICULTIES IN THE DIAGNOSIS OF THE ADRENOGENITAL SYNDROME IN INFANCY

Pregnanetriol was not excreted by an infant (7 days old) who was later shown to have a defect in steroid 21-hydroxylase. However, the excretion of this compound increased during the following days (1.2 mg on the thirteenth day of life). A high excretion of 3β-hydroxy-Δ steroids was the most noticeable abnormality in steroid excretion noted on the seventh day of life (e.g., 3β, 16α-dihydroxy-5-pregnen-20-one, 15 mg; 3β, 21-dihydroxy-5-pregnen-20-one, 1.4 mg and 3β, 16α-dihydroxy-5-androsten-17-one, 7.4 mg). This high 3β-hydroxy-Δ steroid excretion results in difficulties in distinguishing a defect in 3β-hydroxy steroid dehydrogenase from a 21-hydroxylase deficiency. At the age of 14 months the principal steroids excreted were those predominant in other cases of 21-hydroxylase deficiency, viz. pregnanetriol and 5β-pregnane-3α, 17α, 20α-triol-11-one (11-oxo-pregnanetriol).

Urinary steroidal patterns in adrenogential syndrome

The urinary steroidal pattern was reviewed in 7 cases of 21-hydroxylase deficiency (21-H) and 3 of 3β-hydroxysteroid dehydrogenase deficiency (3β-D). These were compared with 3 normals and 1 adrenal tumor of similar age. Pregnanetriol not only predominates in the urine of those with 21-H deficiency over Δ5-pregnene-3β, 17α, 21α-triol but in no instance did the latter substance exceed 0.9 mg./day and the ratio was 50:1 or greater. In 3β-D deficiency although pregnanetriol was found in each (in one case 34.6 mg/day) there was great elevation of pregnenetriol and the ratio was 2:1 or less. In one experiment 17-hydroxypregnenolone administered to a normal volunteer was converted exclusively into pregnanetriol. It is proposed that in 3β-D deficiency there may be peripheral conversion to pregnanetriol and careful measurement of these two triols can differentiate the two conditions. In addition pregnanetriolone was not found in 3β-D deficiency but was present in the 21-H deficiency. Gas chromatography was employed in these studies. The earlier hypothesis from this laboratory that pregnanetriol in 3β-D deficiency might represent a double defect no longer appears valid. (Drs. Maria I. New and Frederic M. Kenny kindly supplied specimens from 2 estalished cases).