Cytogenomic Investigation of Syndromic Brazilian Patients with Differences of Sexual Development.

BACKGROUND: Cytogenomic methods have gained space in the clinical investigation of patients with disorders/differences in sexual development (DSD). Here we evaluated the role of the SNP array in achieving a molecular diagnosis in Brazilian patients with syndromic DSD of unknown etiology. METHODS: Twenty-two patients with DSD and syndromic features were included in the study and underwent SNP-array analysis. RESULTS: In two patients, the diagnosis of 46,XX SRY + DSD was established. Additionally, two deletions were revealed (3q29 and Xp22.33), justifying the syndromic phenotype in these patients. Two pathogenic CNVs, a 10q25.3-q26.2 and a 13q33.1 deletion encompassing the FGFR2 and the EFNB2 gene, were associated with genital atypia and syndromic characteristics in two patients with 46,XY DSD. In a third 46,XY DSD patient, we identified a duplication in the 14q11.2-q12 region of 6.5 Mb associated with a deletion in the 21p11.2-q21.3 region of 12.7 Mb. In a 46,XY DSD patient with delayed neuropsychomotor development and congenital cataracts, a 12 Kb deletion on chromosome 10 was found, partially clarifying the syndromic phenotype, but not the genital atypia. CONCLUSIONS: The SNP array is a useful tool for DSD patients, identifying the molecular etiology in 40% (2/5) of patients with 46,XX DSD and 17.6% (3/17) of patients with 46,XY DSD.

Is there an association between prostate-specific antigen and androgen levels in 46, XX patients with congenital adrenal hyperplasia?

INTRODUCTION: Congenital adrenal hyperplasia (CAH), a genetic disease characterized by defective cortisol synthesis and excessive levels of sex hormones, can cause precocious puberty in both sexes in untreated individuals and virilization in female patients with a 46, XX karyotype. The female paraurethral (Skene's) gland has been reported as prostate analogous. Growth of prostate tissue is associated with androgen production; therefore, prostate-specific antigen (PSA) levels may represent a marker of virilization in 46, XX patients with CAH. OBJECTIVES: To describe PSA levels in 46, XX patients and evaluate whether higher PSA levels are associated with androgenization and the severity of the disease. STUDY DESIGN: Sixty-six patients with CAH and a 46, XX karyotype were included, irrespective of age. Serum PSA, testosterone, 17-hydroxyprogesterone (17-OHP) and androstenedione levels were measured. Patients' age, age at diagnosis, forms of the disease, Prader classification, bone age assessment, sex of rearing, surgery, and the presence of clinical complications were obtained from their medical records. RESULTS: The mean age of patients was 11.45 ± 10.74 years. Forty-three patients (65%) were diagnosed neonatally at a median of 0.08 years (mean 1.47 ± 2.34 years), with registers of 17-OHP measurements (Guthrie test) being available in 51%. Testosterone, 17-OHP and androstenedione were significantly high. PSA was detectable in 25% of cases (levels >0.01 ng/ml), with a mean of 0.03 ± 0.09 ng/ml, and only in patients over five years of age. A correlation was found between PSA and age (p < 0.001), age at diagnosis (p = 0.002), testosterone (p = 0.001) and androstenedione (p = 0.023). There was no correlation between PSA and the forms of CAH or Prader classification. A sub-analysis of the patients over five years of age in whom PSA was detectable also showed that there was a correlation between PSA (p < 0.05) and age at analysis, age at diagnosis, testosterone and androstenedione levels. DISCUSSION: Limitations of this study include the small sample size due to the rareness of the disease, its retrospective nature, the absence of a control group, the fact that the sample was selected at two referral centers, which could have resulted in a selection bias, and the use of different reference values in the different laboratories conducting the PSA tests. CONCLUSIONS: PSA is detectable in 25% of 46, XX patients with CAH, only after five years of age. PSA level increases significantly with age, age at diagnosis, and testosterone and androstenedione levels, confirming a correlation between PSA levels and elevated androgen levels.

Impact of schooling in the HIV/AIDS prevalence among Brazilian transgender women.

Objective Discrimination and bullying are common conditions among LGBT people. During schooling, these practices compromising education. The aim of this study is to evaluate educational attainment among Brazilian transgender women (TW) and how their education level affects the risk of HIV infection. Study design a cross-sectional population-based study. Subjects and methods 95 adult TW were selected. Information concerning verbal and physical aggression, school dropout, school years (SY), and educational level were assessed. HIV status was screened using a fourth-generation immunoassay followed by western blot testing. Results The mean of SY was 9.1 ± 3.8 ys. The mean age at school dropout was 16.3 ± 3.4 ys old. Verbal aggression was reported by 83%, physical by 48%, and 18% of the TW dropped out school immediately after being physically assaulted. Participants who suffered physical aggression attended school for almost 4 years less than those participants who did not suffer this abuse (OR = -3.96, p < 0.0001). A similar result was found for verbal aggression (OR = -4.35; p < 0.0001). HIV/AIDS prevalence was 18% (n = 17). The mean of SY among HIV/AIDS positive and negative individuals were 6.8 ± 43 versus 9.7 ± 3, respectively (p = 0.004). Lower education was associated with higher frequency of HIV/AIDS among TW and this relationship was sustained after adjustment for injectable drug use and sex work (OR = 0.79, p = 0.04). Conclusion Among Brazilian TW, lower education level was a risk factor associated with HIV. The reasons for low schooling among TW are multifactorial, but verbal and physical harassment strongly contribute for it.

Psychosexual Aspects, Effects of Prenatal Androgen Exposure, and Gender Change in 46,XY Disorders of Sex Development.

CONTEXT: In 46,XY disorders of sexual development (DSD) patients, several factors may affect psychosexual development, leading to gender identity discrepancy and gender change later in life. Prenatal sexual steroid exposure and external genital virilization are considered to influence human psychosexual development, but their roles not completely understood yet. DESIGN: A total of 144 individuals (18 to 60 years of age) with a clinical/molecular diagnosis of 46,XY DSD from a single tertiary center were enrolled. Psychosexual outcomes (gender role, gender identity, and sexual orientation) were assessed using questionnaires and psychological test. The Sinnecker score was used for genital virilization measurement. Prenatal androgen exposure was estimated according to 46,XY DSD etiology. RESULTS: We found a positive association between prenatal androgen exposure and male psychosexual outcomes. Alternatively, prenatal estrogen exposure, age of gonadectomy, and the degree of external genital virilization did not influence any psychosexual outcome. There were 19% (n = 27) with gender change, which was associated with prenatal androgen exposure (P < 0.001) but not with the external genital virilization. The median age of gender change was 15 years, but most of the patients reported the desire for gender change earlier. CONCLUSIONS: Prenatal androgen exposure influenced psychosexual development in 46,XY DSD favoring male psychosexuality in all psychosexual outcomes, whereas the degree of external genital virilization did not influence these outcomes. The organizational effect of sexual steroids on psychosexuality at puberty appears to be weak in comparison with the prenatal effects. Prenatal androgen exposure also influenced female-to-male gender change frequency. All 46,XY DSD conditions with prenatal androgen exposure must be followed for gender issues in their management.

Androgen insensitivity syndrome: a review.

Androgenic insensitivity syndrome is the most common cause of disorders of sexual differentiation in 46,XY individuals. It results from alterations in the androgen receptor gene, leading to a frame of hormonal resistance, which may present clinically under 3 phenotypes: complete (CAIS), partial (PAIS) or mild (MAIS). The androgen receptor gene has 8 exons and 3 domains, and allelic variants in this gene occur in all domains and exons, regardless of phenotype, providing a poor genotype - phenotype correlation in this syndrome. Typically, laboratory diagnosis is made through elevated levels of LH and testosterone, with little or no virilization. Treatment depends on the phenotype and social sex of the individual. Open issues in the management of androgen insensitivity syndromes includes decisions on sex assignment, timing of gonadectomy, fertility, physcological outcomes and genetic counseling.

A recurrent synonymous mutation in the human androgen receptor gene causing complete androgen insensitivity syndrome.

Androgen insensitivity syndrome (AIS) is the most common cause of 46,XY disorders of sex development (46,XY DSD). This syndrome is an X-linked inheritance disease and it is caused by mutations in the human androgen receptor (AR) gene. Non-synonymous point AR mutations are frequently described in this disease, including in the complete phenotype. We present a novel synonymous mutation in the human AR gene (c.1530C > T) in four 46,XY patients from two unrelated families associated with complete androgen insensitivity syndrome (CAIS). The analysis of mRNA from testis showed that synonymous AR mutation changed the natural exon 1 donor splice site, with deletion of the last 92 nucleotides of the AR exon 1 leading to a premature stop codon 12 positions ahead resulting in a truncate AR protein. Linkage analyses suggested a probable founder effect for this mutation. In conclusion, we described the first synonymous AR mutation associated with CAIS phenotype, reinforcing the disease-causing role of synonymous mutations.

[Elevated levels of leptin and LDL-cholesterol in patients with well controlled congenital adrenal hyperplasia]. / Valores elevados de leptina e LDL-colesterol em pacientes com hiperplasia adrenal congênita bem controlados.

OBJECTIVE: The objective of this study was to evaluate patients with classic CAH before and after treatment with glucocorticoids/mineralocorticoid and compare the metabolic profile of the well controlled (WC) and poorly controlled (PC) group. SUBJECTS AND METHODS: We selected newly diagnosed patients and patients monitored for CAH, classical form, regularly using or not glucocorticoids/mineralocorticoid in the Genetics Service Hupes-UFBA, seen from March/2004 to May/2006. All patients underwent detailed clinical evaluation and laboratory tests (glucose, sodium and potassium; total cholesterol, HDL, LDL, triglycerides and uric acid; leptin, 17-hydroxyprogesterone, total testosterone, C peptide, and insulin). Patients with normal androgens were classified as well controlled (WC), and those with high levels of androgens either using or not glucocorticoids/mineralocorticoids were classified as poorly controlled (PC). RESULTS: We studied 41 patients with CAH: 11 in the WC group and 30 in PC group. Leptin and LDL cholesterol levels were higher in WC than in the PC group (p < 0.05). Uric acid values were lower in WC compared with the PC group (p < 0.05). CONCLUSION: Adequate control of CAH with steroids seems safe, as it is associated with only mild changes in lipid profile and leptin values. No other metabolic abnormality was associated with glucocorticoid use. The reason for lower uric acid levels found in WC CAH patients is unknown and should be further studied.