Lessons Learned from 17 Years of Multidisciplinary Care for DSD Patients at A Single Indonesian Center.

BACKGROUND: Our Multidisciplinary Team (MDT) is a large specialized team based in Semarang, Indonesia that cares for a wide variety of pediatric and adult individuals with Differences of Sex Development (DSD) from across Indonesia. Here we describe our work over the last 17 years. METHODS: We analyzed phenotypic, hormonal and genetic findings from clinical records for all patients referred to our MDT during the period 2004 to 2020. RESULTS: Among 1184 DSD patients, 10% had sex chromosome DSD, 67% had 46,XY DSD and 23% had 46,XX DSD. The most common sex chromosome anomaly was Turner syndrome (45,X) (55 cases). For patients with 46,XY DSD under-masculinization was the most common diagnosis (311 cases) and for 46,XX DSD a defect of Müllerian development was most common (131 cases) followed by Congenital Adrenal Hyperplasia (CAH) (116 cases). Sanger sequencing, MLPA and targeted gene sequencing of 257 patients with 46,XY DSD found likely causative variants in 21% (55 cases), with 13 diagnostic genes implicated. The most affected gene coded for the Androgen Receptor. Molecular analysis identified a diagnosis for 69 of 116 patients with CAH, with 62 carrying variants in CYP21A2 including four novel variants, and seven patients carrying variants in CYP11B1. In many cases these genetic diagnoses influenced the clinical management of patients and families. CONCLUSIONS: Our work has highlighted the occurrence of different DSDs in Indonesia. By applying sequencing technologies as part of our clinical care, we have delivered a number of genetic diagnoses and identified novel pathogenic variants in some genes, which may be clinically specific to Indonesia. Genetics can inform many aspects of DSD clinical management, and whilst many of our patients remain undiagnosed, we hope that future testing may provide answers for even more.

Corrigendum: Challenges in the treatment of late-identified untreated congenital adrenal hyperplasia due to CYP11B1 deficiency: Lessons from a developing country.

[This corrects the article DOI: 10.3389/fendo.2022.1015973.].

Pituitary Macroadenoma in a Girl with Male Karyotype: A Rare Case Study.

Macroadenoma is a tumor that typically develops in the epithelial cells of the pituitary gland. Patients suffering from the condition are often asymptomatic with complaints that are caused by hormonal imbalance. Therefore, chromosome analysis needs to be done to females aged >16 years presenting with amenorrhea. Karyotype 46,XY is a disorder of sex development (DSD) that is caused by the complex process of gene interactions, androgen synthesis, and hormone regulation. The patient initially came to the hospital for a scheduled transsphenoidal surgery due to pituitary macroadenoma, and later complained of primary amenorrhea and atypical external genital. Furthermore, physical examination of genitalia revealed mild clitoromegaly without obvious introitus vagina. Laboratory testing showed elevated prolactin and testosterone level, while ultrasonography imaging revealed the absence of the uterus and ovaries. The brain magnetic resonance imaging (MRI) demonstrated a pituitary adenoma, and cytogenetic analysis showed 46,XY karyotype. Subsequently, hyperprolactinemia, imaging, and histopathology examination were used to confirm pituitary macroadenoma in the patient. It was assumed that the undermasculinized genitalia was caused by hormonal disorders including the deficiency of androgen action or 5-alpha-reductase enzyme. 46,XY DSD has many different symptoms, hence, clinicians need to be aware of potential multifactorial aetiologies. Imaging of internal genitalia, hormonal and chromosomal analysis should be carried out to assess patients with unknown causes of the disorder. Molecular analysis needs to be carried to exclude the possible gene mutation.

Challenges in the treatment of late-identified untreated congenital adrenal hyperplasia due to CYP11B1 deficiency: Lessons from a developing country.

Background: Congenital Adrenal Hyperplasia (CAH) due to CYP11B1 is a rare autosomal recessive adrenal disorder that causes a decrease in cortisol production and accumulation of adrenal androgens and steroid precursors with mineralocorticoid activity. Clinical manifestations include cortisol deficiency, ambiguous genitalia in females (differences of sex development (DSD)), and hypertension. Medical treatment recommendations are well defined, consisting of glucocorticoid treatment to substitute glucocorticoid deficiency and consequently normalize adrenal androgen and precursors levels. Current guidelines also emphasize the need for specialized multidisciplinary DSD teams and psychosocial support. In many developing countries, care for DSD patients, especially when caused by an adrenal disease, is challenging due to the lack of infrastructure, knowledge, and medication. Objective: The study aims to report the conflicting decision-making process of medical treatment and sex assignment in late-identified CAH patients in developing countries. Methods: We describe the clinical and biochemical findings and the psychological assessment of five affected but untreated family members with CAH due to CYP11B1 deficiency. Results: All patients had a 46,XX karyotype, ambiguous genitalia, low cortisol levels, and hypertension. Two identified as males, two as females, and one had undecided gender. The patients were counselled that refusing treatment will lead to infertility and the potential risk of developing Addisonian crisis and severe hypertension. However, all 46,XX CAH males refused treatment with glucocorticoids due to the expected lowering of adrenal androgens as their main source of testosterone. None of the patients developed Addisonian crisis, probably due to some residual cortisol activity and glucocorticoid activity of elevated adrenal steroid precursors. Conclusion: Medical treatment and sex assignment in late-identified 46,XX CAH patients in Indonesia may often depend on local and cultural factors. The management of DSD conditions may have to be individualized and integrated into the psychological and social context of the affected family.

Phenotypic Variation of 46,XX Late Identified Congenital Adrenal Hyperplasia among Indonesians.

OBJECTIVES: To describe the phenotype variation in Indonesian 46,XX late-identified congenital adrenal hyperplasia (CAH) and the correlation between 17-hydroxyprogesterone (17-OHP) and genital virilization. METHODOLOGY: Retrospective study of 39 cases with five salt-wasting (SW) and 34 simple virilizing (SV) types. RESULTS: The median age of the patients was 9.83 years (range, 0.58 to 44 years) with Prader score 2 to 5. Clitoromegaly (100%) and skin hyperpigmentation (87%) were the most common features. Lack of breast development (Tanner 1 to 2) and menstrual disorders occurred in 9 patients (teenagers and adults). Short stature (6), low voice (14), prominent Adam's apple (9) and hirsutism (4) were found only in SV types. Rapid growth (7) and precocious puberty (8) were identified in children. Male gender on admission was found in 13 patients. The mean of 17-OHP level was 304.23 nmol/L [standard deviation (SD) 125.03 nmol/L]. There was no correlation between 17-OHP levels and virilization (r=0.19, p>0.05). CONCLUSION: Late-identified CAH showed severe virilization and irreversible sequelae, with clitoromegaly and skin hyperpigmentation as the most commonly seen features. Masculinization of CAH females created uncertainty with regard to sex assignment at birth, resulting in female, male and undecided genders. There is no significant correlation between 17-OHP levels with the degree of virilization in CAH females.

Hormonal evaluation in relation to phenotype and genotype in 286 patients with a disorder of sex development from Indonesia.

OBJECTIVE: The objective of this study was to determine the aetiological spectrum of disorders of sex development (DSD) in a large cohort of underprivileged and undiagnosed patients from Indonesia. METHODS: A total of 286 patients with atypical external and/or internal genitalia were evaluated using clinical, hormonal, molecular genetic and histological parameters. RESULTS: The age (years) at presentation was 0-0·5 in 41 (14·3%), >0·5-12 in 181 (63·3%) and >12 in 64 cases (22·4%). 46,XY DSD was most common (68·2%, n = 195), 46,XX DSD was found in 23·4% (n = 67) and sex chromosomal DSD in 8·4% (n = 24). In 61·2% of 46,XX DSD patients, 17·9% of 46,XY DSD patients and all sex chromosome DSD patients (29·4% in total), a final diagnosis was reached based on genetic or histological gonadal tissue evaluation. 17-hydroxyprogesterone and androstenedione levels were the most distinctive parameters in 46,XX DSD patients. In 46,XY DSD, diagnostic groups were identified based on the external masculinization score: androgen action disorder (AAD), unknown male undermasculinization (UMU), and gonadal dysgenesis (GD). LH, FSH and testosterone levels were most informative especially in the older age group. HCG tests were of no additional value as no patients with androgen synthesis disorders were found. Hormonal profiles of patients with sex chromosome DSD and a Y-chromosome sequence containing karyotype showed high levels of LH and FSH, and low levels of AMH, inhibin B and testosterone compared with the normal male range. Gene mutations were found in all patients with CAH, but in only 24·5% and 1·8% of patients with AAD and UMU. In 32% of 46,XY GD patients, copy number variants of different genes were found. CONCLUSION: A stepwise diagnostic approach led to a molecularly or histologically proven final diagnosis in 29·4% of the patients. The most informative parameters were serum levels of 17-hydroxyprogesterone and androstenedione in 46,XX DSD patients, and serum LH, FSH and testosterone levels in 46,XY DSD patients.