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Background The Congenital Adrenal Hyperplasia due to 21 hydroxylase deficiency is the most common cause of genital ambiguity in persons with XX sexual chromosomes. Genital ambiguity among persons with XY sexual chromosomes comprises diverse and rare etiologies. The deficiency of 17-beta-hydroxysteroid dehydrogenase type 3 enzyme (HSD17B3) is a rare autosomal recessive disorder due to functionally altered variants of the HSD17B3 gene. In this disorder/difference of sex development, the conversion of androstenedione into testosterone is impaired. The appearance of external genitalia of 46,XY individuals varies from typically male to almost female. Case presentation We report on a child presenting severe ambiguous genitalia. Due to access constraints, specialized care did not start until the child was 10 months old. Parents are consanguineous and were born in an area of high isonymy that is a cluster for rare recessive diseases. A new homozygous missense variant c.785G > T was found in exon 10 of the HSD17B3 gene. Conclusions Researchers-clinicians and researchers-researchers collaborative efforts to elucidate the genetic basis of this disease were critical since this etiologic investigation is not available through the public health system. This case exemplifies the families’ pilgrimage in cases of genital ambiguity due to a rare genetic condition. Recognizing the etiology was the baseline to provide information on prognosis and treatment options, and to shelter family and child doubts and hopes in order to better support their decisions.

In this study, we present 3 cases of Down syndrome (DS) associated with disorders/differences of sex development (DSD) and review the literature on this topic. Case 1: 1-year-old child with male genitalia and DS phenotype, 47,XX,+21 karyotype and testicular DSD. Case 2: 11-month-old child with male genitalia and few DS dysmorphisms, 45,X/47,XY,+21 karyotype, and mixed gonadal dysgenesis. Case 3: 4-month-old child with female genitalia and DS phenotype, 47,XY,+21 karyotype and XY complete gonadal dysgenesis. In the literature, among 188 patients, 107 (57%) had Klinefelter syndrome and 61 (33%) Turner syndrome, 12 (6%) had mixed gonadal dysgenesis, 2 (1%) had partial androgen insensitivity, 2 (1%) ovotesticular DSD, and the others had congenital adrenal hyperplasia, XY partial gonadal dysgenesis, XY complete gonadal dysgenesis, and complete androgen insensitivity (1 case each). A typical DS phenotype was found in all individuals of the revision, with the exception of one case, but DSD features were not always reported. In conclusion, the association of DS with sex chromosome DSD is the most frequently observed, whereas associations with 46,XX and 46,XY DSD is extremely rare.

Objective: To evaluate, in a sample of patients with disorders of sex development (DSD), data related to the age at referral and their correlation with the initial complaints, gender at referral, defined gender after diagnosis and etiological diagnosis. Methods: Retrospective review of the age at the first consultation and the reason for it, initial social gender and gender after the diagnosis, karyotype and etiological diagnosis of all cases treated at a DSD outpatient clinic between 1989 and 2016. Cases that did not involve DSD and DSD diagnoses that do not usually involve ambiguous genitalia, thus not requiring specialized monitoring, were excluded. Results: Of the 1793 treated cases, 1139 were diagnosed with some type of DSD. This study excluded 430 cases (272 with Turner's syndrome, 66 with Klinefelter syndrome, and 92 with pure gonadal dysgenesis), thus a total 709 individuals were included. Of these, 82.9% were referred due to ambiguous genitalia; only one-quarter were still in the first month of life, and 6.6% were referred due to pubertal delay, with most of them aged 10 years or older. Of these patients, 68.6% had a diagnosis of XY DSD, 22.4% of XX DSD, and 9% of sex chromosome abnormalities. Conclusions: This study presents the largest series in the literature of patients with DSD treated in a single center. The time of referral of the majority of patients with ambiguous genitalia fell short of the ideal, and milder cases of ambiguous genitalia and many with pubertal manifestations were referred even later. The results reinforce the importance of continuing education for professionals who will have the first contact with these patients, mainly pediatricians and neonatologists. Resumo Objetivo: Avaliar em uma amostra de pacientes com distúrbios da diferenciação do sexo (DDS), dados relacionados à idade, ao encaminhamento e sua correlação com as queixas iniciais, ao sexo ao encaminhamento e ao sexo final e diagnóstico etiológico. Métodos: Revisão retrospectiva da idade por ocasião da primeira consulta e motivo dela, sexo social inicial e após definição do diagnóstico, cariótipo e diagnóstico etiológico de todos os casos atendidos em um ambulatório especializado em DDS entre 1989 e 2016. Foram excluídos casos que não compreendiam DDS e diagnósticos de DDS que não cursam comumente com ambiguidade genital, não necessitam de acompanhamento especializado. Resultados: Dos 1.793 casos atendidos, 1.139 foram diagnosticados com algum DDS. Excluíram-se 430 (272 síndrome de Turner, 66 síndrome de Klinefelter e 92 disgenesia gonadal pura), totalizando 709. Desses, 82,9% foram encaminhados por ambiguidade genital, somente um quarto ainda no primeiro mês de vida e 6,6% por atraso puberal, a maioria com 10 anos ou mais; 68,6% tiveram diagnóstico de DDS XY; 22,4% DDS XX e 9% de anomalias dos cromossomos sexuais. Conclusões: Este estudo apresenta a maior casuística na literatura de pacientes com DDS atendidos em um único serviço. O momento de encaminhamento da maioria dos pacientes com ambiguidade genital foi aquém do ideal e casos mais leves de ambiguidade e muitos com manifestações puberais foram encaminhados ainda mais tardiamente. Os resultados reforçam a importância do ensino continuado a profissionais que terão o primeiro contato com esses pacientes, principalmente pediatras e neonatologistas.

Historically, the terms partial (PGD) and mixed gonadal dysgenesis (MGD) have been used to describe incomplete testicular differentiation in individuals with 46,XY or 45,X/46,XY karyotypes, respectively. However, it is currently unclear to what extent clinical features actually differ between these individuals. The aim of this study was to compare clinical, laboratory, and histological findings in these 2 groups. Patients with testicular dysgenesis seen in our service between 1989 and 2013 were selected. Sixty-one patients met the inclusion criteria. Individuals with 46,XY and 45,X/46,XY karyotypes were compared regarding genital features, gonadal histology and function, growth, and associated conditions. Twenty-five had mosaicism with a 45,X cell line (MGD), while a 46,XY karyotype (PGD) was found in 36 cases belonging to 32 families. Mutations in NR5A1, WT1, and SRY genes associated with testicular dysgenesis were found in 12 families. There were no significant differences regarding parental consanguinity, degree of external androgenization, gonadal location, histology, and function, and associated conditions. However, in the MGD group, the presence of a uterus, lower birth weight and length, and short stature were more often observed. Therefore, the use of histological features to classify PDG and MGD should be abandoned and replaced by classification based on karyotype.

Background: Partial Androgen Insensitivity Syndrome (PAIS) (OMIM # 312300) is one of the causes of Disorders/Differences of Sex Development with 46,XY karyotype and normal or increased testosterone secretion that results in atypical genitalia. In general, it is caused by inactivating mutations on AR gene (Xq12 - OMIM * 313700), therefore it presents an X-linked recessive inheritance. Individuals raised as males have incomplete puberty with micropenis, sparse hairs, gynecomastia and increased LH, testosterone and estradiol serum levels. Therefore, the use of aromatase inhibitor in these cases becomes a logical indication aiming to increase testosterone levels in the tentative of supplanting its peripheral resistance and decreasing estrogen levels. Objective: To present clinical and laboratory data during the first year of use of aromatase inhibitor in puberty of three boys with confirmed molecular diagnosis of PAIS. Results: All subjects used letrozole (2.5 mg daily during 12 months). None reported significant side effects. Cases 1 and 2 are brothers (p.Ala596Tre). Case 1: Onset of treatment at age 12; height changed from 158 cm (z = +1.15) to 166 cm (z = +1.21), Tanner from G2P2T2 to G3P3T1, penis from 4.0 to 6.5 cm, LH from 7.5 to 18.3 IU/L (NR: 1.5 to 9.3 IU/L), testosterone from 361 to 1,347 ng/dL (NR: 165 to 763 ng/dL), estradiol from 35 to

A retrospective cross-sectional study was performed in a DSD clinic at a tertiary service (University Hospital) to estimate the frequency of disorders of sex development (DSD) among men who seek medical care because of infertility. The sample included 84 men >20 years of age referred from 2010-2017 due to oligozoospermia or nonobstructive azoospermia of unknown etiology. Twelve cases (14%) were diagnosed as DSD, including Klinefelter Syndrome, 46,XX testicular DSD, and mild androgen insensitivity syndrome. Y chromosome microdeletions were detected in 2 patients. Among the remaining 70 cases there were patients with chromosome abnormalities which are not included in the DSD classification as well as rare NR5A1 variants of uncertain significance and hypergonadotropic hypogonadism and microorchidism in 46,XY subjects. In conclusion, the frequency of DSD in this study was 14%, consisting mainly of sex chromosome abnormalities but also 46,XX and 46,XY DSD. However, this figure may increase as further investigations are conducted in idiopathic cases with signs of primary testicular failure, which may present partial gonadal dysgenesis.