Atendendo mulheres com cariótipo 46, XY / Attending women with 46, XY karyotype

As diferenças ou distúrbios do desenvolvimento sexual (DDS) compreendem um grupo heterogêneo de condições congênitas que resultam na discordância entre os cromossomos sexuais, as gônadas e/ou o sexo anatômico de um indivíduo. A classificação desses distúrbios é baseada no cariótipo conforme o Consenso de Chicago de 2006 e substitui os termos pseudo-hermafroditismo, hermafroditismo e intersexo. O objetivo desta revisão é fornecer ao ginecologista conhecimentos básicos sobre a etiologia, fisiopatologia e orientações das principais anormalidades de DDS para uma avaliação diagnóstica e terapêutica no atendimento de mulheres na infância, adolescência e em idade adulta com cariótipo 46,XY. O diagnóstico deve ser realizado pela interação entre o exame clínico as dosagens hormonais, os exames de imagem e a análise genética, desde o cariótipo até o estudo de alterações dos genes por técnicas de biologia molecular. O tratamento é realizado de acordo com a etiologia e inclui intervenções cirúrgicas como a gonadectomia e plásticas sobre a genitália externa, terapia de reposição hormonal e apoio psicológico. São necessárias a individualização dos casos e uma equipe interdisciplinar, para um atendimento adequado às mulheres com cariótipo 46,XY.(AU)

Differences or disorders of sexual development (DSDs) comprise a heterogeneous group of congenital conditions that result in the disagreement between an individual's sex chromosomes, gonads and/or anatomic sex. The classification of these disorders is based on the karyotype according to the 2006 Chicago Consensus and replaces the terms pseudohermaphroditism, hermaphroditism and intersex. The aim of this review is to provide the gynecologist with basic knowledge about the etiology, pathophysiology and guidelines of the main abnormalities of DDS for a diagnostic and therapeutic evaluation in the care of women in childhood, adolescence and adulthood with a karyotype 46,XY. The diagnosis must be made by the interaction between clinical examination hormonal measurements, imaging and genetic analysis from the karyotype to the study of gene alterations by molecular biology techniques. Treatment is carried out according to the etiology and includes surgical interventions such as gonadectomy and plastic surgery on the external genitalia, hormone replacement therapy and psychological support. Individualization of cases and an interdisciplinary team are required to provide adequate care for women 46,XY karyotype.(AU)

POI after chemotherapy and bone marrow transplant may mimic disorders of sexual differentiation - a case report of a patient with primary amenorrhea and 46, XY karyotype.

Cytogenetic examination may be useful in determining the reason for primary amenorrhea in phenotypically female patients. The result 46, XY usually indicates two syndromes: complete androgen insensitivity or pure gonadal dysgenesis. We report a case of a patient, who due to acute lymphoblastic leukemia in childhood was treated with total body irradiation and bone marrow transplantation. Later on the patient presented with symptoms typical for premature ovarian failure and male karyotype in peripheral lymphocytes. The cytogenetic examination for peripheral cells showed normal female karyotype. Therefore, it has been concluded that ovarian function impairment resulted rather from the gonadotoxic effect of oncological treatment than as a disorder of sexual differentiation. The survival rates of childhood cancer are very high and some of the patients will experience premature ovarian failure. It must be remembered that after bone marrow transplantation karyotype of peripheral lymphocytes may be misleading.

A unique case of aggressive uterine cancer in a 45-year-old man with persistent Müllerian duct syndrome.

OBJECTIVE: Persistent Müllerian Duct Syndrome (PMDS), one of the causes of male pseudohermaphroditism, is a rare syndrome characterized by the presence of internal female genitalia (uterus, fallopian, tubes, cervix and upper vagina) in otherwise phenotypically and normally virilized men. METHODS: We present the 4th documented case of uterine malignancy in a 45-year-old man with PMDS presenting with lower abdominal protuberance and hematuria. RESULTS: Although testicular malignancies are common in undescended testis associated with PMDS, very few cases of müllerian duct malignancies have been reported. CONCLUSIONS: Persistent mullerian duct syndrome can be associated with aggressive non-testicular malignancies, especially uterine cancer, in normally virilized males.

OBJETIVOS: El síndrome de persistencia del Conducto de Müller (SPCM), una de las causas de pseudohermafroditismo masculino, es un síndrome raro caracterizado por la presencia de genitales internos femeninos (útero, trompas de falopio, cervix y fondo vaginal) en pacientes varones fenotipicamente y con virilización normal. MÉTODOS: Presentamos el 4º caso documentado de tumor maligno uterino en un hombre de 45 años con SPCM que presenta protuberancia abdominal inferior y hematuria. RESULTADOS: Aunque los tumores malignos testiculares son frecuentes en testículos no descendidos asociados con SPCM, se han comunicado muy pocos casos de tumores malignos del conducto de Müller. CONCLUSIONES: El síndrome de persistencia del Conducto de Müller se puede asociar con tumores malignos no testiculares agresivos, especialmente cáncer uterino en hombres normalmente virilizados.

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.

In Vivo Verification of the Pathophysiology of Lipoid Congenital Adrenal Hyperplasia in the Adrenal Cortex.

A two-hit hypothesis has been proposed to describe the pathophysiology of lipoid congenital adrenal hyperplasia. In previous studies using conventional steroidogenic acute regulatory protein (Star) gene knockout (KO) mice, adrenocortical lipid accumulation was already prominent at birth. Thus, the two-hit hypothesis was verified in the gonads of Star KO mice but not in the adrenal cortices. We generated time-dependent conditional Star KO mice induced by tamoxifen (TAM) injections and analyzed the adrenal cortices of the mice histologically and endocrinologically before, 24 hours after, and 8 weeks after TAM. We performed RNA sequencing analyses of the adrenal glands before and 8 weeks after TAM and histologically analyzed autologous adrenal cortices of TAM-induced Star KO mice with transplantation of wild-type adrenal gland. Lipid accumulation was scattered 24 hours after TAM and was prominent 8 weeks after TAM. Steroidogenic capacity decreased sequentially after TAM. Gene expression related to steroid biosynthesis significantly decreased 8 weeks after TAM compared with that before TAM. TAM-induced Star KO mice with adrenal transplantation showed normal ACTH levels and mild lipid accumulation. These results showed that the steroidogenic capacity decreased without histological change (the first hit) and declined with histological change (the second hit). Thus, we visualized the two-hit hypothesis in the adrenal cortex. The key feature of the secondary decline of steroidogenic capacity might be the decreased gene expression related to steroid biosynthesis after lipid accumulation exacerbated by ACTH hypersecretion.

MIRAGE syndrome is a rare cause of 46,XY DSD born SGA without adrenal insufficiency.

BACKGROUND: MIRAGE syndrome, a congenital multisystem disorder due to pathogenic SAMD9 variants, describes a constellation of clinical features including 46,XY disorders of sex development (DSD), small for gestational age (SGA) and adrenal insufficiency (AI). It is poorly understood whether SAMD9 variants underlie 46,XY DSD patients born SGA (46,XY DSD SGA) without AI. This study aimed to define the frequency and phenotype of SAMD9 variants in 46,XY DSD SGA without AI. METHODS: Forty-nine Japanese patients with 46,XY DSD SGA (Quigley scale, 2 to 6; gestational age-matched birth weight percentile, <10) without history of AI were enrolled. The single coding exon of SAMD9 was PCR-amplified and sequenced for each patient. Pathogenicity of an identified variant was verified in vitro. Placenta tissues were obtained from the variant-carrying patient, as well as from another previously described patient, and were analyzed histologically. RESULTS: In one 46,XY DSD SGA patient, a novel heterozygous SAMD9 variant, p.Phe1017Val, was identified. Pathogenicity of the mutant was experimentally confirmed. In addition to DSD and SGA, the patient had neonatal thrombocytopenia, severe postnatal grow restriction, chronic diarrhea and susceptibility to infection, all features consistent with MIRAGE, leading to premature death at age 14 months. The patient did not have any manifestations or laboratory findings suggesting AI. Placenta tissues of the two variant-carrying patients were characterized by maldevelopment of distal villi without other findings of maternal underperfusion. CONCLUSIONS: MIRAGE syndrome is a rare cause of 46,XY DSD SGA without AI. This study exemplifies that AI is a common feature of MIRAGE syndrome but that the absence of AI should not rule out a diagnosis of the syndrome.

Genetic testing of XY newborns with a suspected disorder of sex development.

PURPOSE OF REVIEW: The current review focuses on the neonatal presentation of disorders of sex development, summarize the current approach to the evaluation of newborns and describes recent advances in understanding of underlying genetic aetiology of these conditions. RECENT FINDINGS: Several possible candidate genes as well as other adverse environmental factors have been described as contributing to several clinical subgroups of 46,XY DSDs. Moreover, registry-based studies showed that infants with suspected DSD may have extragenital anomalies and in 46,XY cases, being small for gestational age (SGA), cardiac and neurological malformations are the commonest concomitant conditions. SUMMARY: Considering that children and adults with DSD may be at risk of several comorbidities a clear aetiological diagnosis will guide further management. To date, a firm diagnosis is not reached in over half of the cases of 46,XY DSD. Whilst it is likely that improved diagnostic resources will bridge this gap in the future, the next challenge to the clinical community will be to show that such advances will result in an improvement in clinical care.

Disorders of sex development in children in KwaZulu-Natal Durban South Africa: 20-year experience in a tertiary centre.

BACKGROUND: The objective of the study was to describe the prevalence, clinical characteristics and aetiological diagnosis in children with disorders of sex development (DSDs) presenting to a tertiary referral centre. METHODS: This is a retrospective review of all cases of DSD referred to the Paediatric Endocrine Unit in Inkosi Albert Luthuli Central Hospital (IALCH) from January 1995 to December 2014. RESULTS: A total of 416 children (15.1%; CI: 13.8%-16.5%) were diagnosed with DSD. The aetiological diagnosis based on the current classification [Lawson Wilkins Paediatric Endocrine Society (LWPES) and European Society for Paediatric Endocrinology (ESPE)] was sex chromosome DSD in 9.5% (n=33), 46 XX DSD in 33% (n=114) and 46 XY DSD in 57.5% (n=199). The most common diagnoses in descending order were a disorder in androgen synthesis and action (not classified) in 53% (n=182), ovotesticular DSD in 22% (n=75) and congenital adrenal hyperplasia (CAH) in 10% (n=36). Overall the median age of presentation was 10 months (IQR: 1 month-4.5 years). There was a significant relationship (p<0.001) between the age of presentation and aetiological diagnosis. The majority (97%) of African patients had a diagnosis of 46 XX DSD. Prematurity was present in 47% (n=83) of children with 46 XY DSD (p<0.001). CONCLUSIONS: DSD is not an uncommon diagnosis in African patients in sub-Saharan Africa. The most common aetiological diagnosis is 46 XY DSD in androgen synthesis and action, followed by ovotesticular DSD. CAH is only the third most common disorder.

Clinical profile of 93 cases of 46, XY disorders of sexual development in a referral center.

The term DSD refers to disorders that affect the normal process of sexual development causing disagreement between chromosomal, gonadal and phenotypic sex, and this study aimed to describe the clinical profile of a group with DSD 46, XY joined on DSD Clinic of Hospital of Salvador, Bahia Clinics. It was a retrospective study of medical records of survey data of 93 patients with DSD 46, XY. Among the patients studied 50.5% had no defined etiology and 20.4% had androgen insensitivity syndrome (AIS), 63.4% had been initially recorded in males, 31 (33.3%) in females, being that in two it was necessary to reassignment. All patients with complete AIS pure gonadal dysgenesis and had female genitalia. Others have been diagnosed with genital ambiguity or severe hypospadias and cryptorchidism. The gonads were palpable at the first consultation in 75.3% of patients. It is important to establish an active surveillance program for these patients. The first assessment took place before the age of ten in more than 50% of cases, which shows that much needs to be done for medical education and community about the DSD. Because the phenotypic variability of sexual development disorders was noted that the clinical profile of patients studied ranged between different etiologies, including hindering the diagnostic conclusion of these individuals.

Aetiological bases of 46,XY disorders of sex development in the Hong Kong Chinese population.

OBJECTIVE: Disorders of sex development are due to congenital defects in chromosomal, gonadal, or anatomical sex development. The objective of this study was to determine the aetiology of this group of disorders in the Hong Kong Chinese population. SETTING: Five public hospitals in Hong Kong. PATIENTS: Patients with 46,XY disorders of sex development under the care of paediatric endocrinologists between July 2009 and June 2011. MAIN OUTCOME MEASURES: Measurement of serum gonadotropins, adrenal and testicular hormones, and urinary steroid profiling. Mutational analysis of genes involved in sexual differentiation by direct DNA sequencing and multiplex ligation-dependent probe amplification. RESULTS: Overall, 64 patients were recruited for the study. Their age at presentation ranged from birth to 17 years. The majority presented with ambiguous external genitalia including micropenis and severe hypospadias. A few presented with delayed puberty and primary amenorrhea. Baseline and post-human chorionic gonadotropin-stimulated testosterone and dihydrotestosterone levels were not discriminatory in patients with or without AR gene mutations. Of the patients, 22 had a confirmed genetic disease, with 11 having 5α-reductase 2 deficiency, seven with androgen insensitivity syndrome, one each with cholesterol side-chain cleavage enzyme deficiency, Frasier syndrome, NR5A1-related sex reversal, and persistent Müllerian duct syndrome. CONCLUSIONS: Our findings suggest that 5α-reductase 2 deficiency and androgen insensitivity syndrome are possibly the two most common causes of 46,XY disorders of sex development in the Hong Kong Chinese population. Since hormonal findings can be unreliable, mutational analysis of the SRD5A2 and AR genes should be considered the first-line tests for these patients.

Etiological diagnosis of undervirilized male/XY disorder of sex development.

OBJECTIVE: To do clinical, hormonal and chromosomal analysis in undervirilized male / XY disorder of sex development and to make presumptive etiological diagnosis according to the new Disorder of Sex Development (DSD) classification system. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Endocrine Unit at National Institute of Child Health, Karachi, Pakistan, from January 2007 to December 2012. METHODOLOGY: Patients of suspected XY DSD / undervirilized male visiting endocrine clinic were enrolled in the study. Criteria suggested XY DSD include overt genital ambiguity, apparent female/male genitalia with inguinal/labial mass, apparent male genitalia with unilateral or bilateral non-palpable testes, micropenis and isolated hypospadias or with undescended testis. The older children who had delayed puberty were also evaluated with respect to DSD. As a part of evaluation of XY DSD, abdominopelvic ultrasound, karyotype, hormone measurement (testosterone, FSH, LH), FISH analysis with SRY probing, genitogram, laparoscopy, gonadal biopsy and HCG stimulation test were performed. Frequencies and percentages applied on categorical data whereas mean, median, standard deviation were calculated for continuous data. RESULTS: A total of 187 patients met the criteria of XY DSD. Age ranged from 1 month to 15 years, 55 (29.4%) presented in infancy, 104 (55.6%) between 1 and 10 years and 28 (15%) older than 10 years. Twenty five (13.4%) were raised as female and 162 as (86.6%) male. The main complaints were ambiguous genitalia, unilateral cryptorchidism, bilateral cryptorchidism, micropenis, delayed puberty, hypospadias, female like genitalia with gonads, inguinal mass. The karyotype was 46 XY in 183 (97.9%), 46 XX in 2 (1.1%), 47 XXY in 1 (0.5%), 45 X/46 XY in 1 (0.5%) patient. HCG stimulation test showed low testosterone response in 43 (23 %), high testosterone response in 62 (33.2%), partial testosterone response in 32 (17.1%) and normal testosterone response in 50 (26.7%). Genitogram was carried out in 86 (45.98%) patients. Presumptive etiological diagnosis of androgen sensitivity syndrome/ 5-alpha reductase deficiency, testicular biosynthetic defect/ leydig cell hypoplasia, partial gonadal dysgenesis, ovotesticular DSD, XX testicular DSD, mixed gonadal dysgenesis, testicular vanishing syndrome, klinefelter syndrome, hypogonadotropic hypogonadism, isolated hypospadias and isolated micropenis was made. CONCLUSION: Clinical, chromosomal and hormonal assessment may help in making the presumptive etiological diagnosis. Further molecular genetics analysis are needed in differentiating these abnormalities and to make a final diagnosis.

Review and management of 46,XY disorders of sex development.

Disorders of sex development (DSD) among 46,XY individuals are rare and challenging conditions. Abnormalities of karyotype, gonadal formation, androgen synthesis, and androgen action are responsible for the multiple disorders that result in undervirilization during development. Phenotypic appearance and timing of presentation are quite variable. The focus of treatment has shifted from early gender assignment and corrective surgery to careful diagnosis, proper education of patients and their families, and individualized treatment by a multi-disciplinary team. The modern management of these patients is difficult and controversial. Conflicting data on long-term outcomes of these individuals have been reported in the literature. The various etiologies of 46,XY DSD, current approaches to diagnosis and treatment, and reported long-term results are reviewed.

Disorders of sex development among Sudanese children: 5-year experience of a pediatric endocrinology clinic.

BACKGROUND: The birth of a child with disorders of sex development (DSDs) is considered a medical and psychosocial emergency. Management of these cases requires facilities and a multidisciplinary team. In developing countries, this is made difficult by the lack of facilities in addition to sociocultural and religious factors that can affect management. This is the first experience to be published from Sudan. OBJECTIVE: The aim of this study was to see the prevalence, etiological factors, management, and problems faced in handling these cases. METHODS: This is a retrospective descriptive study reviewing the records of all cases referred to a pediatric endocrinology clinic over a 5-year period. Cases were managed by a multidisciplinary team. RESULTS: One hundred fifty-six cases were seen, of which 122 were included in the study. A total of 79 (64.8%) were born at home, whereas 59 (52.2%) of the cases were not observed at birth by health-care providers. The average cost of investigating a case was $250-300. The investigations showed that 69 had XX DSD and 45 had XY DSD. The most common cause of XX DSD was congenital adrenal hyperplasia and that of XY DSD was androgen insensitivity syndrome. Twenty-three (19%) needed sex reassignment. There was a preference for the male sex. CONCLUSION: DSDs are not uncommon in Sudan. Because of lack of awareness and sociocultural reasons cases are referred late. Investigating these cases is expensive and has to be supported, and more multidisciplinary teams have to be trained to make services accessible and affordable.