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The CYP17A1 gene encodes the enzyme P450c17, which mediates both 17α-hydroxylase and 17,20-lyase activities and is essential for production of cortisol and sex steroids. Loss-of-function mutations of this gene cause 17α-hydroxylase/17,20-lyase deficiency, characterized by hypertension, hypokalemia and sexual infantilism. A 6-year-old phenotypically female patient presented with hypertension and hyperpigmentation. Her blood test results showed low cortisol and high adrenocorticotropic hormone (ACTH), progesterone, deoxycorticosterone and gonadotropin levels and were consistent with the diagnosis of 17α-hydroxylase/17,20-lyase deficiency. Her karyotype was 46XY. Genetic studies of the patient revealed a novel homozygous point mutation, c.1307G>A, within the coding sequence of the CYP17A1 gene. 17α-hydroxylase/17,20-lyase deficiency should be considered in the differential diagnosis of hypertension in children and adolescents, and physical examination of these patients should be done very carefully.

Background: Testicular microlithiasis (TM) is characterized by calcium deposits within the seminiferous tubules and is associated with benign and malign conditions., Aim: To determine TM prevalence in patients with congenital adrenal hyperplasia (CAH) and its association with testicular adrenal rest tumors (TART)., Patients and Methods: Scrotal ultrasound using a high-frequency linear transducer (12 MHz) was performed in 41 patients aged 12.1 +/- 4.7 (range 3.5-23.3) years and 49 healthy similarly aged controls. TM was classified with respect to the number of microliths per ultrasound field as limited (LTM, <5 microliths) and classic (CTM, > or = 5 microliths). CTM was graded as grade 1 (5-10 microliths), grade 2 (11-20 microliths), and grade 3 (>20 microliths)., Results: TM was detected bilaterally in 9 (21.9%) patients and 2 (4.1%) control cases (1 bilateral, 1 unilateral). Four patients had LTM, one evaluated as grade 1, one as grade 2, and three as grade 3. There were 9 patients with TART. Four patients had TM and TART concomitantly., Conclusion: Because TM is frequently found in patients with CAH and may also exist concomitantly with TART, we recommend that these patients be followed annually by testicular ultrasound., (Copyright 2010 S. Karger AG, Basel.)

Background/aims: Congenital adrenal hyperplasia (CAH) is characterized by adrenal insufficiency with or without salt wasting. It is also accompanied by adrenomedullary hypofunction. The aim of the present study was to investigate adrenomedullary function in patients with CAH due to 21-hydroxylase and 11beta-hydroxylase deficiencies and in age-matched normal subjects., Methods: We measured plasma catecholamines (epinephrine and norepinephrine) and urine metanephrine in 44 patients with CAH, 32 due to 21-hydroxylase deficiency (17 patients with the salt-wasting form and 15 patients with the simple virilizing form), and 12 due to 11beta-hydroxylase deficiency, and in 25 healthy controls., Results: Plasma epinephrine and urine metanephrine levels were significantly higher in the controls than in patients with CAH (p = 0.02 and p < 0.001, respectively). Plasma norepinephrine levels were significantly lower in the controls than in patients with CAH (p < 0.001). Interestingly, patients with the salt-wasting form had lower norepinephrine levels in comparison to the other subgroups of CAH., Conclusion: Despite the fact that CAH patients have insufficient epinephrine secretion, these patients have the ability to increase compensatory norepinephrine. However, this increase is much lower in patients with the salt-wasting form. These findings need to be confirmed by other studies.

Background: Congenital adrenal hyperplasia (CAH) due 21-hydroxylase deficiency (21-OHD) is a common autosomal recessive disorder. It is caused by defects in the CYP21A2 gene., Objective: Our aim was to determine the frequency of common gene mutations and to evaluate genotype-phenotype correlations in Turkish 21-OHD patients., Methods: Molecular analysis of the CYP21A2 gene was performed for the detection of the eight most common point mutations [p.P30L, IVS2-13C>G (IVS-2), p.I172N, exon 6 mutation cluster (p.I236N, p.V237E, p.M239K), p.V281L, p.Q318X, p.R356W, 8-bp-deletion], of large deletion and conversion by southern blotting, allele specific semi-quantitative PCR/enzyme restriction method and sequencing, in 56 patients with 21-OHD, from 52 families., Results: Disease-causing mutations were identified in 77 out of 91 alleles (84.6%) of the patients. Mutations were found in 34 of 43 alleles (79.1%) in salt wasting (SW; n=26), 32 of 36 alleles (88.8%) in simple virilizing (SV; n=24) and 11 of 12 alleles (91.6%) in non-classical (NC; n=6) form of CAH. The most frequent mutations were IVS-2 (22.0%), large conversion (14.3%), p.I172N (9.9%) p.R356W (8.8%), and large deletion (6.6%). In the SW form, the most frequent genotypes were homozygous for IVS-2 (11.5%) and homozygous for large conversion of the gene (11.5%). In the SV form, the most frequent genotype was homozygous for IVS-2 (20%), followed by compound heterozygous for p.I172N/8-bp del (10%). Homozygous for p.V281L (16.7%) was most common in NC. In most cases there was good correlation between genotype and phenotype. In the SW and NC forms, genotypes of all the patients correlated with their phenotypes., Conclusions: This is the first comprehensive study on the molecular basis of CAH patients in the Turkish population. Based on these results, we propose a modified screening strategy to facilitate molecular testing of CAH patients in our population.

21-Hydroxylase deficiency is a recessively inherited disorder resulting from mutations in the CYP21 gene. The CYP21 gene is located along with the CYP21P pseudogene in the human leukocyte antigen major histocompatibility complex region on chromosome 6. Molecular diagnosis is difficult due to the 98% similarity of CYP21 and CYP21P genes and the fact that almost all frequently reported mutations reside on the pseudogene. Allele-specific PCR for the 8 most frequently reported point mutations was performed in 31 Turkish families with at least a single 21-hydroxylase-deficient individual. The allele frequencies of the point mutations were as follows: P30L, 0%; IVS2 (AS,A/C-G,-13), 22.5%; G110delta8nt, 3.2%; I172N, 11.4%; exon 6 cluster (I236N, V237E, M239K), 3.2%; V281L, 0%; Q318X, 8%; and R356W, 9.6%. Large deletions and gene conversions were detected by Southern blot analysis, and the allele frequencies were 9.6% and 22.5%, respectively. Sequence analysis of the gene, performed on patients with only 1 mutated allele, revealed 2 missense mutations (R339H and P435S). A novel semiquantitative PCR/enzyme digestion-based method for the detection of large scale deletions/conversions of the gene was developed for routine diagnostic purposes, and its accuracy was shown by comparison with the results of Southern blot analysis.

To determine the glucocorticoid receptor (GC-R) status in congenital adrenal hyperplasia (CAH) we examined 11 patients (5 female, 6 male) with 21-hydroxylase deficiency and 3 patients (2 female, 1 male) with 11beta-hydroxylase deficiency. The mean age at investigation was 8.9+/-3.5 yr. Age of diagnosis was 4.4+/-3.2 yr and all patients were being treated with hydrocortisone. The control group included 10 (5 female, 5 male) age-matched healthy children. Blood samples were drawn at 0800 a.m. after an overnight fast in all subjects and after 5 days off treatment in patients with CAH. Serum cortisol (in all children), and serum 17-hydroxyprogesterone and androstenedione (in the patient group) were measured by radioimmunoassay. Mononuclear leukocytes were isolated from peripheral blood and the binding of [3H]dexamethasone to GC-R was examined. GC-R number and the dissociation constant (Kd), which is inversely proportional to its binding affinity, were determined. Mean GC-R numbers were 5814+/-1574 and 6816+/-1647; mean Kd values were 3.6+/-1.5 nM and 4.2+/-0.7 nM in patient and control groups, respectively. There were no significant differences in these parameters between the two groups. Neither receptor number nor binding affinity correlated with basal serum cortisol levels in either group. In the patient group, no correlation was observed between replacement hydrocortisone doses and either morning serum cortisol levels or GC-R number. The higher binding affinity and requirement of higher hydrocortisone dose might have been due to a compensatory response to increased clearance of glucocorticoids. In conclusion, GC-R parameters are not changed in patients with CAH and the variability of glucocorticoid replacement doses may be related to other functional defects of GC-R and glucocorticoid pharmacokinetics.

An 8.7 year-old patient, raised as a boy, presented with premature appearance of pubic hair and accelerated growth since 2 years of age and ambiguous genitalia noted at birth. There was first degree consanguinity between his parents. A similar problem was reported in a cousin. Examination of the external genitalia revealed complete scrotal fusion, a 5 cm long phallus, urogenital sinus at base of phallus with no gonads palpable. Pigmentation was increased. His blood pressure was 150/100 mm Hg. Pubic and axillary hair were at stage 3. Bone age was 17 years. Adrenal ultrasound was normal. Pelvic ultrasound showed relatively enlarged uterus and ovaries with normal echogenicity. Karyotype was 46,XX. Hormone profile was compatible with congenital adrenal hyperplasia (CAH) due to 11beta-hydroxylase deficiency (11-deoxycortisol: 11.5 nmol/l [400 ng/dl] [normal: 0.6-4.5 nmol/l [20-155 ng/ml]], androstenedione: 17.4 nmol/l [5 ng/ml] [normal: 0.1-1.2 nmol/l [0.03-0.35 ng/ml]]). Prednisolone and antihypertensive drugs were started. The patient underwent bilateral salpingo-oophorectomy and hysterectomy at 9.1 years. Histopathological examination of both ovaries revealed steroid cell tumor. The type of the tumor was "not otherwise specified" (NOS). Basal hormone levels and ACTH test performed 10 months after the operation and 7 days off treatment reconfirmed the diagnosis of 11beta-hydroxylase deficiency. Steroid cell tumors are extremely rare forms of steroid hormone-reducing ovarian neoplasms in childhood and may coexist with or imitate virilizing CAH.