Disorders of Sex Development in Indonesia: Natural course and the implications of a stepwise multidisciplinary approach

__Abstract__ This thesis elaborates the stepwise diagnostic procedure in DSD patients using a multidiscipline approach to obtain the diagnosis of these patients which includes clinical assessment, hormonal, genetic, and pathological investigations, so that it is beneficial as the background for decisions on the required therapy. Most of the patients in this research had a 46,XY karyotype where Androgen Action Disorder was found to affect the majority of the cases. In the majority of the 46,XX DSD cases, CAH required immediate comprehensive treatment because its nature often leads to a life threatening situation. In a developing country such as Indonesia, it is rare to have a complete diagnostic procedure where a molecular evaluation is needed for DSD confirmation. A health care center providing molecular analyses as its service is considered very rare, if not nonexistent. Such luxury is limited to a research center in a capital town. Early diagnosis and integrated treatment is vital for DSD patients, in order to obtain the proper outcome in terms of medical, psychological and social aspects. A stepwise practical diagnostic approach in a large cohort of DSD patients in Indonesia led to a genetically or histologically proven final diagnosis in 27 % of the patients. The most helpful parameters were serum levels of 17-hydroxyprogesterone and androstenedione in 46,XX DSD patients and LH, FSH and basal testosterone levels in 46,XY DSD patients. The long-term effects of 21-hydroxylase deficiency on phenotype in 15 patients with ages between 1 and 33 years who had not been treated for prolonged periods were studied to assess the correlation between genotype and phenotype. Results suggest that a correlation does exist between the concentration of androgens and the extent of virilization. Saliva of 24 CAH patients who received glucocorticoid replacement therapy was studied. The question was whether determination of salivary androstenedione and 17-hydroxyprogesteronein CAH patients would be a useful alternative to the measurement of these hormones in serum. The results suggest that this is indeed the case. A detailed gonadal histology study was undertaken on 16 Indonesian DSD patients using morphological studies and immunohistochemistry. The precursor lesions gonadoblastoma, carcinoma in situ, or GCC were diagnosed in four cases. A hormone producing ovarian Leydig cell tumor was identified in a 46,XX patient. In spite of the significantly lower risk of GCC in the general Asian population, DSD is a dominant risk factor

Quality of Life in Late-Treated Patients With Disorders of Sex Development: Insights for Patient-Centered Care

Background: Patients with a disorder of sex development (DSD) are born with atypical genitals or may develop atypical genitals and atypical body appearance, if left untreated. Health related quality of life (HRQoL) was assessed in Indonesian patients to whom diagnostic procedures and medical intervention had been delayed. Method: Comparison of 118 patients born with DSD, aged 6–41 years (60 children, 24 adolescents, and 34 adults) and 118 healthy control subjects matched for gender, age, and residential setting. HRQoL was measured using a translation of the TACQOL/TAAQOL. Results: According to parental and children’s report, children with DSD reported more problems in social functioning and had less positive moods. Girls, in particular, reported problems in cognitive functioning. Adult patients reported more depressive moods, especially women, who reported more anger. No differences were found between in the adolescent groups. Conclusion: The data suggest that Indonesian children with DSD experienced more problems in social contact than non-affected Indonesian children, whereas Indonesian adults with DSD suffered from negative emotions more often than non-affected Indonesians. These findings on HRQoL are in line with findings on emotional functioning

Whole exome sequencing combined with linkage analysis identifies a novel 3 bp deletion in NR5A1

Disorders of sex development (DSDs) encompass a broad spectrum of conditions affecting the development of the gonads and genitalia. The underlying causes for DSDs include gain or loss of function variants in genes responsible for gonad development or steroidogenesis. Most patients with DSD have an unknown genetic etiology and cannot be given an

Functional analysis of novel androgen receptor mutations in a unique cohort of Indonesian patients with a disorder of sex development

Mutations in the androgen receptor (AR) gene, rendering the AR protein partially or completely inactive, cause androgen insensitivity syndrome, which is a form of a 46,XY disorder of sex development (DSD). We present 3 novel AR variants found in a cohort of Indonesian DSD patients: p.I603N, p.P671S, and p.Q738R. The aim of this study was to determine the possible pathogenic nature of these newly found unclassified variants. To investigate the effect of these variants on AR function, we studied their impact on transcription activation, AR ligand-binding domain interaction with an FxxLF motif containing peptide, AR subcellular localization, and AR nuclear dynamics and DNA-binding. AR-I603N had completely lost its transcriptional activity due to disturbed DNA-binding capacity and did not show the 114-kDa hyperphosphorylated AR protein band normally detectable after hormone binding. The patient with AR-I603N displays a partial androgen insensitivity syndrome phenotype, which is explained by somatic mosaicism. A strongly reduced transcriptional activity was observed for AR-Q738R, together with diminished interaction with an FxxLF motif containing peptide. AR-P671S also showed reduced transactivation ability, but no change in DNA- or FxxLF-binding capacity and interferes with transcriptional activity for as yet unclear reasons

Gonadal malignancy in 13 consecutive collected patients with disorders of sex development (DSD) from Semarang (Indonesia)

Aims Caucasian patients with disorders of sex development (DSD) are at a high risk of developing germ cell cancer (GCC). GCC is prominent in young adults in Western countries, while the incidence is significantly lower in Asia. So far, the risk of GCC in Asian DSD patients is unknown. Methods and results A detailed study of gonad histology , morphology and immunohistochemistry (OCT3/4, testis-specific protein Y-encoded, VASA, SCF/ KITLG, SOX9, FOXL2) of 16 Indonesian DSD patients was undertaken. 13 cases could be analysed, including ovarian tissue (n=3), streak gonad (n=1), undifferentiat