Outcomes of one-stage feminizing genitoplasty in children with congenital adrenal hyperplasia and severe virilization.

PURPOSE: To present our surgical experience and outcomes in congenital adrenal hyperplasia (CAH) patients with severe virilization using a combined technique of total urogenital mobilization (TUM) and a modified pull-through vaginoplasty to perform a safe and effective one-stage feminizing genital reconstruction for these children. METHODS: Fourteen CAH patients with severe virilization, defined by a Prader IV and V rating of the external genitalia, underwent TUM followed by a limited vaginal pull-through procedure from June 2016 to December 2020. Postoperative anatomical and cosmetic outcomes, and urinary continence, were evaluated. RESULTS: Out of the 14 cases in this study, 8 were classified as prader IV and 6 as Prader V. The median age at surgery was 11 months (range 6-36 months), and the mean urethral length was 1.4 cm (range 1.2-1.8 cm). The median follow-up period was 4 years. Our cosmetic outcomes were good in 11 (78.5%), satisfactory in 2, and poor in one case. All patients achieved age-appropriate toilet training without urinary incontinence. CONCLUSION: Adopting our surgical approach of TUM with modified pull-through vaginoplasty has simplified feminizing surgical reconstruction in CAH cases with severe genital atypia and a very high vaginal confluence with short urethral length, yielding adequate introitus with good anatomical and cosmetic appearance and adequate urinary continence outcomes.

PUBERTAL VIRILIZATION IN AN ADOLESCENT WITH 46, XY DISORDER OF SEXUAL DEVELOPMENT: A NOVEL MUTATION IN NR5A1 GENE.

Background: NR5A1 [Steroidogenic factor 1 (SF1)] is a nuclear receptor that is essential for the development of gonads and adrenal glands as well as the establishment of steroidogenesis in these organs. The clinical findings of the mutations of NR5A1 gene in 46, XY individuals are variable. Virilization at puberty can be seen in some of the 46, XY children who have a female phenotype and are raised as female.A girl aged 13 years and 10 months old was brought by the family for deepening of her voice. On physical examination, her breast development was Tanner stage 2, axillary hair (+) and pubic hair was Tanner stage 4. She had labioscrotal fusion and 4.4 cm phallus (External Masculinisation Score was 6). Hypergonadotropic hypogonadism, low AMH and high testosterone levels were detected in laboratory tests. Uterus was not visualized in pelvic ultrasonography. Karyotype analysis was reported as 46, XY. Sequence analysis of the NR5A1 gene revealed a novel heterozygote c.1075_1089del (p.Leu359_Leu363del) variant. The patient was raised as a female and oestrogen replacement was started following gonadectomy. Conclusion: It should be kept in mind that virilization may develop at puberty in individuals with 46, XY disorder of sexual development due to NR5A1 mutation.

Antenatally Detected Functional Adrenocortical Adenoma: A Case Report and Review of Current Literature.

Pediatric adrenocortical tumors (ACTs) are rare entities with an incidence of 0.2% of all pediatric tumors. Only two cases of antenatally detected ACT have been reported in the literature. Our case is the first report of an antenatally detected suprarenal mass which manifested with postnatal virilizing features and was proven to be adrenocortical adenoma on histology.

Incidental Finding of Bilateral Ovarian Adrenal Rest Tumor in a Patient With Congenital Adrenal Hyperplasia: A Case Report and Brief Review.

Ovarian adrenal rest tumors (OART) are tumors that develop in females with congenital adrenal hyperplasia (CAH). In contrast to their counterpart in testicles, they are exceptional and few cases have been reported in the literature. In this report, we present clinicopathological findings of a female patient with CAH due to 21-hydroxylase deficiency who was incidentally diagnosed with OART with a review of the literature. The 14-year-old patient, who was raised as a boy, developed a virilizing syndrome with high testosterone levels that were attributed to non adherence to her replacement corticosteroid therapy. She consulted for sex reassignment surgery. Pelvic ultrasound was normal. She underwent hysterectomy and bilateral adnexectomy. No abnormalities were noticed during the operation. Grossly, both ovaries were variegated with well circumscribed and lobulated, brownish-yellow nodules. Histologically, the nodules were composed of nests of large polygonal cells with centrally located nuclei and prominent nucleoli. There was mild atypia and no crystals of Reinke. Thus, the findings of the histopathological examination were consistent with bilateral OART. Histological differential diagnosis of OART can be challenging particularly with leydig cell tumor, stromal luteoma and steroid cell tumors, not otherwise specified. OART must be considered in women with CAH and persistent virilizing symptoms despite negative imaging results.

Occult symptomatic bilateral pure Leydig cell tumors in a postmenopausal woman: a case report.

BACKGROUND: Pure Leydig cell tumors (LCTs) represent 0.1% of ovarian masses. Postmenopausal patients typically present with virilization. Although LCTs can be challenging to locate on conventional imaging, positron emission tomography (PET) has been demonstrated to be effective. CASE: A 64-year-old postmenopausal woman presented with alopecia, facial hirsutism, and clitoromegaly. Laboratory findings included elevated testosterone and androstenedione. Ultrasound, computed tomography, and magnetic resonance imaging showed no adnexal masses. PET did not demonstrate ovarian fludeoxyglucose-avidity. Histopathology after bilateral salpingo-oophorectomy revealed bilateral Leydig cell tumors. Her testosterone normalized 2 weeks postoperatively. CONCLUSION: We describe the occult, symptomatic, bilateral ovarian Leydig cell tumors, an occurrence that has not been described in the literature. Virilizing tumors must be considered in patients with evidence of hyperandrogenism, even without pelvic masses on imaging.

Case of fetal ovarian juvenile granulosa cell tumor: Complications and management.

A prenatal ovarian juvenile granulosa cell tumor (JGCT) is a rare entity which may present as an intra-abdominal cyst. Due to its low incidence, optimal management and timing for intervention remain uncertain. This report presents a case of an intra-abdominal cystic structure in a female fetus, one of the two fetuses in a dichorionic-diamniotic twin pregnancy, detected during routine fetal sonographic surveillance at 30 weeks of gestation. Further fetal evaluation detected the sonographic triad of an ovarian cystic mass, polyhydramnios and signs of fetal virilizations, requiring us to consider the presence of an atypical, ovarian androgen secreting tumor. Following delivery, acute ovarian torsion and intracystic hemorrhage required emergent surgical intervention, confirming the diagnosis of JGCT. Following surgical treatment, laboratory, clinical, and morphological features improved progressively.

Testosterone serum levels are not predictive of maternal virilization in hyperreactio luteinalis.

BACKGROUND: Elevated concentrations of circulating testosterone are present in hyperreactio luteinalis (HL), a pregnancy-specific, self-limited condition. HL is associated with maternal virilization in about 30% of cases. The correlation between testosterone levels and maternal virilization has not yet been quantified. Our aim was to identify a testosterone cut-off level which may allow to predict maternal virilization. METHODS: A literature research was performed. Publications were chosen if serum testosterone concentrations and presence or absence of maternal virilization was mentioned. Additionally, we report serial levels of steroids analyzed by Liquid chromatography-tandem mass spectrometry (LC-MS/MS) in one case of HL managed at our institution. RESULTS: In all, 31 cases fulfilled the search criteria. We found significant overlap between testosterone levels in asymptomatic women and women with signs of virilization (range 6.2-37.3 nmol/l and 13.7-197.5 nmol/l, respectively). The method applied for testosterone analysis was mentioned in three reports only. Peak serum testosterone concentration in our case was 120.3 nmol/l. CONCLUSION: From the available data, maternal virilization in HL cannot be predicted by the level of circulating testosterone. However, comparability of results is hampered by the analytical methods applied. LC-MS/MS should preferably be used for reporting concentrations of circulating testosterone.

[Neuroendorine paraneoplastic syndromes]. / Neuroendokrine paraneoplastische Syndrome.

Skin is commonly affected by neuroendorine paraneoplastic syndromes (PNS). This is due to the expression of receptors in the skin by which abnormally secreted neuroendocrine hormones and mediators elicit directly, and indirectly, cutaneous key signs and thus facilitate early diagnosis of these diseases. In acromegaly, induction of the growth hormone-insulin-like growth factor­1 axis results in trophic changes of the acral portions of the skin and mucosal membranes including cutis verticis gyrata. The skin signs of non-iatrogenic Cushing syndrome are identical with those of exogenous prolonged intake of glucocorticoids: centripetal accumulation of adipose tissue, plethora and striae distensae. Episodic flushing of the face and trunk (together with explosive diarrhea) is a key feature of carcinoid tumors. Fibrotic remodeling of the heart and retroperitoneal space, and less commonly of the skin, are important complications mediated by abnormally secreted 5­hydroxytryptamine (serotonin, 5­HT), the latter eliciting profibrotic responses on HT2B-receptor-expressing fibroblasts. Androgen-secreting tumors lead to well-established receptor-mediated cutaneous signs of peripheral hyperandrogenisms: seborrhea, acne, hirsutism, and androgenetic alopecia. In contrast, the pathogenesis of necrolytic migratory erythema as a key feature of glucagonoma remains incompletely understood and is thought to be related to hypoaminoacidemia. This review summarizes the clinical features of neuroendocrine PNS with skin involvement, elucidates its underlying pathophysiology, lists differential diagnoses, and explains key diagnostic steps and principal therapeutic options. An interdisciplinary approach is essential to provide the best care of all patients with neuroendocrine PNS.

A hemizygous mutation in the androgen receptor gene causes different phenotypes of androgen insensitivity syndrome in two siblings by disrupting the nuclear translocation.

The androgen insensitivity syndrome (AIS) is a congenital disease characterized by androgen resistance due to androgen receptor (AR) gene mutations, resulting in disorders of sex differentiation in 46,XY individuals. However, the underlying mechanisms in the majority of AR variants and the phenotype-genotype correlations are unclear. Here, we identified a p.Y764H variant of the AR gene that results in different phenotypes in a family. Structural analyses revealed that amino acid substitution affected protein properties and spatial conformation, and in vitro, functional studies showed impaired nuclear translocation ability of the mutated protein. Moreover, the extent to which this variant reduced nuclear translocation depends on the dihydrotestosterone (DHT) concentrations. Our results, for the first time, demonstrated a pathogenesis of the p.Y764H mutations in AR resulting in AIS phenotype, and indicated that AIS patients with p.Y764H mutation and preserved gonad might have residual AR activity at high androgen levels, putting patients at risk for pubertal virilization in the future. We provide an in-depth insight into the pathogenesis in AIS based on the amino acid substitution, which may help aid its precise diagnosis, personalized treatment, and organized follow-up to avoid gender dysphoria.

Efficacy and safety of prenatal dexamethasone treatment in offspring at risk for congenital adrenal hyperplasia due to 21-hydroxylase deficiency: A systematic review and meta-analysis.

OBJECTIVE: To assess the efficacy and safety of prenatal dexamethasone treatment in offspring at risk for congenital adrenal hyperplasia. METHODS: MEDLINE, EMBASE, the Cochrane Library, the clinicaltrials.gov website databases were systematically searched from inception through March 2019. WMD and SMD with 95%CIs were calculated using random or fixed effects models. RESULTS: There was a significant reduction in virilization in the DEX-treated group (WMD: -2.39, 95%CI: -3.31,-1.47). No significant differences were found in newborn physical outcomes for birth weight (WMD: 0.09, 95%CI: -0.09, 0.27) and birth length (WMD = 0.27, 95%CI: -0.68, 1.21). Concerning cognitive functions, no significant differences in the domains of psychometric intelligence (SMD: 0.05, 95%CI: -0.74, 0.83), verbal memory (SMD: -0.17, 95%CI: -0.58, 0.23), visual memory (SMD: 0.10, 95%CI: -0.14, 0.34), learning (SMD: -0.02, 95%CI: -0.27, 0.22) and verbal processing (SMD: -0.38, 95%CI: -0.93, 0.17). Regarding behavioural problems, no significant differences in the domains of internalizing problems (SMD: 0.16, 95%CI: -0.49, 0.81), externalizing problems (SMD: 0.07, 95%CI: -0.30, 0.43) and total problems (SMD: 0.14, 95%CI: -0.23, 0.51). With respect to temperament, no significant differences in the domains of emotionality (SMD: 0.13, 95%CI: -0.79, 1.05), activity (SMD: 0.04, 95%CI: -0.32, 0.39), shyness (SMD: 0.25, 95%CI: -0.70, 1.20) and sociability (SMD: -0.23, 95%CI: -0.90, 0.44). CONCLUSIONS: Prenatal DEX treatment reduced virilization with no significant differences in newborn physical outcomes, cognitive functions, behavioural problems and temperament. The results need to be interpreted cautiously due to the existence of limitations.

Case of ovarian steroid cell tumor diagnosed after presenting acute heart failure.

We report a rare case of an ovarian steroid cell tumor with a diagnosis prompted by heart failure symptoms. A 28-year-old Japanese nulligravida/nullipara with a chief complaint of respiratory discomfort during physical exertion and exhibiting heart failure symptoms was referred to our hospital. She also had signs of virilization, including secondary menorrhea since the age of 20, hirsutism and balding. Cushing's syndrome was suspected, and further examinations showed hypertestosteronemia and right ovarian tumor. Symptomatic treatment for heart failure with diuretics and antihypertensives was followed by abdominal right adnexectomy performed due to the androgen-producing ovarian tumor. The tumor was solid and larger than a fist, and confirmed as a steroid cell tumor through postoperative histopathology. Serum total testosterone levels normalized at day 3 postoperatively, and menstruation resumed 2 months later. Our case was diagnosed due to heart failure symptoms, and its treatment resulted in improvement in virilization signs.

Voice dissatisfaction in individuals with a disorder of sex development.

OBJECTIVE: Changes of sex hormone levels in disorders of sex development (DSD) can affect the body, including the vocal folds, during and after foetal development. The voice is a gender characteristic that may also be affected. There is a lack of knowledge on voice alteration in DSD. To explore this in different forms of DSD, we describe the prevalence of voice alterations and investigate patient satisfaction with voice. DESIGN: The study is part of dsd-LIFE, a multicentre cross-sectional clinical evaluation project assessing the long-term outcomes of surgical, hormonal and psychological interventions in individuals with DSD. PATIENTS: The study included 1040 individuals with different forms of DSD, that is Turner and Klinefelter syndromes, different degrees of gonadal dysgenesis and 46 XY DSD. Participants were recruited through patient advocacy groups and health care. MEASUREMENTS: Satisfaction with voice, Adam's apple, if patient's self-identified gender was mistaken on the phone leading to distress. RESULTS: A vast majority of the participants with DSD (between 58.3% to 82% in various groups) were not satisfied with their voice, and approximately 15% (n = 147) were mistaken on the phone in accordance with self-identified gender. For 102 participants, this caused distress. CONCLUSIONS: We have identified that voice problems are a cause of distress in all forms of DSD. This result needs to be confirmed and compared with controls. We recommend that evaluation of the voice should be included in future international guidelines for management of DSD.

Postmenopausal androgen-secreting ovarian tumors: challenging differential diagnosis in two cases.

Postmenopausal hyperandrogenism constitutes a very rare condition of tumoral or non-tumoral origin primarily residing either in the ovary or in the adrenal glands. We present herein two cases with this condition; one with abnormal postmenopausal genital bleeding and mild increase in facial hair, and the second with slow-developing hirsutism and virilization. Both cases shared a notorious increase in libido. The laboratory tests showed high levels of testosterone (>100 ng/ml). A normal value of dehydroepiandrosterone sulfate and a normal cortisol level at 9 am after 1 mg of dexamethasone administered at midnight (Nugent test) made an adrenal etiology very unlikely. On the other hand, a high level of inhibine B oriented to an ovarian source. Transvaginal sonography failed to demonstrate an ovarian tumor, but an abdominal and pelvic computed tomography scan or magnetic resonance imaging detected an ovarian tumor and normal adrenal glands. A laparoscopic oophorectomy was performed, and the histological study demonstrated a steroidal cell tumor in the first case and a Leydig cell tumor in the second.

Hepatoblastoma with Precocious Puberty.

Hepatoblastoma (HB), a primary liver tumor of childhood, is often accompanied by raised levels of alpha-fetoprotein (α-FP). Rarely, the beta-human chorionic gonadotropin (ß-hCG) levels may also be elevated, which can cause peripheral precocious puberty (PPP). We report a case of HB with precocious puberty wherein hormonal assays showed an increase in α-FP, ß-hCG, and testosterone levels, and suppression of follicle-stimulating and luteinizing hormone levels. After chemotherapy and surgery, α-FP, ß-hCG, and testosterone levels normalized, and the signs of virilization did not progress further. New therapeutic approaches have made a previously reported grim prognosis of virilizing HB, more favorable now. In the assessment of PPP, the possibility of a tumoral source for the hormones should also be considered.

[Feminizing genitoplasty in virilization of the external genitalia].

The review focuses on the feminizing genitoplasty of the external genitalia in patients with disorders of sex development. The opinions of various surgeons and surgical schools on the timing, stages and methods of performing feminizing genitoplasty in girls with the virilization of the genitalia are presented. The development and improvement of surgical techniques for performing clitoroloplasty in patients with virilization of genitalia are described, as well as different types of labioplasty. The main methods of reconstruction of the urogenital sinus are given.

Recurrent maternal virilization during pregnancy in patients with PCOS: two clinical cases.

BACKGROUND: Maternal virilization during pregnancy is a rare phenomenon. Polycystic ovary syndrome (PCOS), luteoma and luteinic cysts are the most frequent and benign etiologies. This article presents two cases of recurrent maternal virilization during pregnancy. CLINICAL CASES: Our reported cases were young women with Afro-Caribbean and Nigerian origins. Data were collected by history-taking, clinical examination, laboratory investigations, transabdominal ultrasonographic examination and Magnetic Resonance Imaging. Both patients were diagnosed with PCOS according to the Rotterdam criteria. During each of their pregnancies they both developed an explosive hirsutism, a deepening in the voice, a clitoromegaly. Gestational diabetes occurred during pregnancies. There was no fetal virilization, despite raising androgen levels, more than tenfold to normal. Improvement of hirsutism and normalization of androgens were described in postpartum. CONCLUSION: Only few cases of maternal virilization during pregnancy were reported in literature and even fewer concern recurrent and bilateral ovarian etiology. Hyperplasia of ovarian theca cells seems to be the most likely explanation, which would suggest that PCOS belongs to a spectrum of abnormal reactivity of the ovary to human Chorionic Gonadotrophin (hCG) stimulation along with luteoma and luteinic cyst of pregnancy.  Insulin resistance could worsen hyperandrogenism but is not enough to explain virilization. Treatment should focus on protecting the fetus of possible virilization as well as its mother, but also on preserving the subsequent fertility in both.

Testosterone- and Cortisol-secreting Oncocytic Adrenocortical Adenoma in the Pediatric Age-group.

Oncocytic tumors are epithelial neoplasms that occur in various organs, including adrenal glands. Oncocytic adrenocortical adenomas and carcinomas are uncommon but well-known pathological entities in adults. However, generally oncocytic tumors, particularly in the adrenal glands, are very rare in the pediatric age-group. Most oncocytic adrenal tumors are not functional. We present a rare case of right-sided, functional oncocytic adrenocortical adenoma in a 5-year-old boy, who presented with clinical manifestations of precocious puberty and Cushing syndrome. Laparoscopic adrenalectomy showed a well-defined mass weighing 8.4 g and measuring 3 cm in maximum dimension. Histological examination demonstrated no features suggestive of aggressive biological behavior. The patient showed no evidence of recurrent or metastatic disease and continued to have normal serum hormonal levels 28 months following the surgery. In this report, we discuss the clinicopathological characteristics of this rare pathological entity and briefly review the literature on functional oncocytic adrenal tumors in the pediatric population.

[Steroid 21-hydroxylase deficiency, the most frequent cause of congenital adrenal hyperplasia]. / Szteroid-21-hidroxiláz-deficientia, a congenitalis adrenalis hyperplasia leggyakoribb oka.

Congenital adrenal hyperplasia is a group of genetic diseases due to the disablement of 7 genes; one of them is steroid 21-hydroxylase deficiency. The genes of congenital adrenal hyperplasia encode enzymes taking part in the steroidogenesis of adrenal gland. Steroid 21-hydroxylase deficiency is an autosomal recessive disorder caused by mutations of the steroid 21-hydroxylase gene. The mutations of steroid 21-hydroxylase gene cause 95% of the congenital adrenal hyperplasia cases. Although the non-classic steroid 21-hydroxylase deficiency with mild symptoms is seldom diagnosed, the classic steroid 21-hydroxylase deficiency may lead to life-threatening salt-wasting and adrenal crises due to the insufficient aldosterone and cortisol serum levels. The classic type requires life-long steroid replacement which may result in cushingoid side effects, and typical comorbidities may be also developed. The patients' quality of life is decreased, and their mortality is much higher than that of the population without steroid 21-hydroxylase deficiency. The diagnosis, consequences and the patients' life-long clinical care require a multidisciplinary approach: the specialists in pediatrics, internal medicine, endocrinology, laboratory medicine, genetic diagnostics, surgery, obstetrics-gynecology and psychology need to work together. Orv Hetil. 2018; 159(7): 269-277.

MENOPAUSAL ANDROGEN EXCESS - ASSOCIATED CARDIO-METABOLIC RISK: CLUES FOR OVARIAN LEYDIG CELL TUMOUR (CASE REPORT AND MINI-REVIEW OF LITERATURE).

BACKGROUND: Ovarian Leydig cell tumour is a very rare steroid hormones producing mass, causing clinical and biochemical hyperandrogenism. Even if the level of evidence is based on case studies, many authors (but not all) agree that raised androgens increase the cardio-metabolic risk thus early diagnosis and treatment are necessary On the other hand, the endocrine features pointing an ovarian tumour source of testosterone do not indicate the specific histological finding which needs a post-operative conformation. CASE PRESENTATION: We report a case of a 60-year-old woman with a 4-year history of progressive virilisation in association with hypertension, high number of red blood cells, impaired glucose tolerance and dyslipidemia. Total testosterone was 20 times above normal with suppressed gonadotropins, inadequate for menopause. Trans-vaginal ultrasound and pelvic and abdominal computerized axial tomography imaging revealed a right ovarian solid nodule, and no evidence of alteration in the adrenal glands. Total hysterectomy and bilateral salpingo-oophorectomy were performed. Histopathology and immunohistochemistry confirmed the diagnosis of Leydig cell tumour. After surgery, androgen levels returned to normal and the doses of anti-hypertensive drugs were reduced. CONCLUSIONS: The hyperandrogenic state with elevated plasma testosterone and progressive signs of virilization raises suspicion of an ovarian androgen-secreting tumor. For a postmenopausal patient with hyperandrogenism the diagnosis of Leydig cell tumour should be considered. However, the exact diagnosis is provided by post-operative histological exam. Prolonged exposure to hyperandrogenism may generate cardiovascular abnormalities and metabolic syndrome which after tumor excision and removal of the source of androgen hormones are expected to significantly improve.

Virilizing oncocytic adrenocortical carcinoma: clinical and immunohistochemical studies.

CONTEXT: Oncocytic tumors of the adrenal cortex are rare, mostly nonfunctioning and benign. SETTING: Report virilizing oncocytic adrenocortical carcinoma in a 50-year-old woman. PATIENT: She presented a recent and progressive virilization syndrome, associated with high blood pressure. Hormonal evaluation showed elevated serum testosterone and delta-4-androstenedione levels, normal urinary free cortisol level and incomplete suppression of cortisol at the 1 mg dexamethasone suppression test. CT scan of the abdomen revealed a 35 mm left adrenal mass. INTERVENTION: The patient underwent a left adrenalectomy, and the histological study showed a 3 cm oncocytic adrenocortical carcinoma with signs of malignancy. RESULTS: Immunohistochemical study revealed that tumor cells expressed the steroidogenic enzymes involved into androgen synthesis (3ßHSD and P450c17α), P450 aromatase and luteinizing hormone (LH) receptors. Post-operatively, signs of virilization improved rapidly, serum testosterone and delta-4-androstenedione levels returned to normal, as did the dexamethasone suppression test. During follow-up CT-scan and 18-FDG PET/CT showed a right ovary mass, corresponding to a follicular cyst associated with hyperthecosis. The patient is alive with no recurrence 48 months after adrenal surgery. CONCLUSION: Oncocytic adrenocortical carcinomas, although extremely rare, should be considered in women with a virilization syndrome. In this woman immunohistochimical studies revealed the presence of steroidogenic enzymes involved into androgen synthesis and aromatization, and LH receptors could be implicated in this pathology.