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Context 46,XY Gonadal dysgenesis (GD) is a heterogeneous group of disorders with a wide phenotypic spectrum, including embryonic testicular regression syndrome (ETRS). Objective To report a gene for 46,XY GD etiology, especially for ETRS. Design Screening of familial cases of 46,XY GD using whole-exome sequencing and sporadic cases by target gene-panel sequencing. Setting Tertiary Referral Center for differences/disorders of sex development (DSD). Patients and Interventions We selected 87 patients with 46,XY DSD (17 familial cases from 8 unrelated families and 70 sporadic cases); 55 patients had GD (among them, 10 patients from 5 families and 8 sporadic cases had ETRS), and 32 patients had 46,XY DSD of unknown etiology. Results We identified four heterozygous missense rare variants, classified as pathogenic or likely pathogenic in the Asp-Glu-Ala-His-box (DHX) helicase 37 (DHX37) gene in five families (n = 11 patients) and in six sporadic cases. Two variants were recurrent: p.Arg308Gln (in two families and in three sporadic cases) and p.Arg674Trp (in two families and in two sporadic cases). The variants were specifically associated with ETRS (7/14 index cases; 50%). The frequency of rare, predicted-to-be-deleterious DHX37 variants in this cohort (14%) is significantly higher than that observed in the Genome Aggregation Database (0.4%; P < 0.001). Immunohistochemistry analysis in human testis showed that DHX37 is mainly expressed in germ cells at different stages of testis maturation, in Leydig cells, and rarely in Sertoli cells. Conclusion This strong genetic evidence identifies DHX37 as a player in the complex cascade of male gonadal differentiation and maintenance.

Molecular diagnosis is rarely established in 46,XX testicular (T) disorder of sex development (DSD) individuals with atypical genitalia. The Wilms' tumour factor‐1 (WT1) gene is involved in early gonadal development in both sexes. Classically, WT1 deleterious variants are associated with 46,XY disorders of sex development (DSD) because of gonadal dysgenesis. We report a novel frameshift WT1 variant identified in an SRY‐negative 46,XX testicular DSD girl born with atypical genitalia. Target massively parallel sequencing involving DSD‐related genes identified a novel heterozygous WT1 c.1453_1456del; p.Arg485Glyfs*14 variant located in the fourth zinc finger of the protein which is absent in the population databases. Segregation analysis and microsatellite analysis confirmed the de novo status of the variant that is predicted to be deleterious by in silico tools and to increase WT1 target activation in crystallographic model. This novel and predicted activating frameshift WT1 variant leading to the 46,XX testicular DSD phenotype includes the fourth zinc‐finger DNA‐binding domain defects in the genetic aetiology of 46,XX DSD.

Appropriate management of disorders of sex development (DSD) has been a matter of discussion since the first guidelines were published in the 1950s. In the last decade, with the advent of the 2006 consensus, the classical methods, especially regarding timing of surgery and sex of rearing, are being questioned. In our culture, parents of DSD newborns usually want their children to undergo genital surgery as soon as possible after sexual assignment, as surgery helps them to confirm the assigned sex. Developmental psychology theories back this hypothesis. They state that anatomic differences between sexes initiate the very important process of identification with the parent of the same sex. Sex-related endocrinological issues also demand early care. For example, using dihydrotestosterone cream to increase penile length or growth hormone treatment to improve final height require intervention at young ages to obtain better results. Although the timing of surgery remains controversial, recent evidence suggests that male reconstruction should be performed between 6 and 18 months of age. Feminizing surgery is still somewhat controversial. Most guidelines agree that severe virilization requires surgical intervention, while no consensus exists regarding mild cases. Our perspective is that precocious binary sex assignment and early surgery is a better management method. There is no strong evidence for delays and the consequences can be catastrophic in adulthood.

Purpose: To evaluate the accuracy of the uterine artery pulsatility index (PI) for the diagnosis of pubertal onset in girls.Methods: Cross-sectional study of girls with normal pubertal development. Puberty was diagnosed by the presence of Tanner breast development score ≥2. All girls underwent pelvic ultrasound and Doppler imaging of the uterine arteries. We evaluated the uterine artery PI and uterine, endometrial, and ovarian measurements. We used ROC curves with cutoffs determined by Youden index for data analysis.Results: We included 169 girls aged 5-16 years who underwent 202 pelvic ultrasound examinations. Prepubertal girls had a signi cantly higher mean PI (mean, 6.70; SD, 2.15) than girls in initial puberty (mean, 4.14; SD, 1.55) and in late puberty (mean, 2.81; SD, 1.05) (P<0.001 for all comparisons), which re ects a progressive increase in blood ow to the uterus with the progression of puberty. ROC curve analysis showed that the PI was able to identify the onset of puberty with a mean area under the curve of 0.838 (SD, 0.04) (P<0.001), and the PI cutoff point of 5.05 had a sensitivity of 77%, speci city of 85%, positive predictive value (PPV) of 92%, and accuracy of 79%. The combination of PI <5.05 plus uterine volume >3.75 cm³ had a sensitivity of 73%, speci city of 95%, PPV of 97%, and accuracy of 79% to detect initial puberty.Conclusions: The signi cant reduction in the PI during pubertal development combined with increasing uterine volume can be a valuable, highly speci c, noninvasive tool to con rm the onset of puberty.

Wilms’ tumor suppressor gene 1 (<i>WT1</i>) plays an essential role in urogenital and kidney development. Heterozygous germline pathogenic allelic variants of <i>WT1</i> have been classically associated with Denys–Drash syndrome (DDS) and Frasier syndrome (FS). Usually, exonic pathogenic missense variants in the zinc finger region are the cause of DDS, whereas pathogenic variants affecting the canonic donor lysine-threonine-serine splice site in intron 9 cause FS. Phenotypic overlap between <i>WT1</i> disorders has been frequently observed. New <i>WT1</i> variant-associated phenotypes, such as 46,XX testicular/ovarian-testicular disorders of sex development (DSD) and primary ovarian insufficiency, have been reported. In this report, we describe the phenotypes and genotypes of 7 Brazilian patients with pathogenic <i>WT1</i> variants. The molecular study involved Sanger sequencing and massively parallel targeted sequencing using a DSD-associated gene panel. Six patients (5 with a 46,XY karyotype and 1 with a 46,XX karyotype) were initially evaluated for atypical genitalia, and a 46,XY patient with normal female genitalia sought medical attention for primary amenorrhea. Germ cell tumors were identified in 2 patients, both with variants affecting alternative splicing of <i>WT1</i> between exons 9 and 10. Two pathogenic missense <i>WT1</i> variants were identified in two 46,XY individuals with Wilms’ tumors; both patients were &#x3c;1 year of age at the time of diagnosis. A novel <i>WT1</i> variant<i>,</i> c.1453_1456 (p.Arg485Glyfs*14), was identified in a 46,XX patient with testicular DSD. Nephrotic proteinuria was diagnosed in all patients, including 3 who underwent renal transplantation after progressing to end-stage kidney disease. The expanding phenotypic spectrum associated with <i>WT1</i> variants in XY and XX individuals confirms their pivotal role in gonadal and renal development as well as in tumorigenesis, emphasizing the clinical implications of these variants in genetic diagnosis.

RESUMOo emprego das diversas metodologias diagnósticas da deficiência de hormônio de crescimento (dgH) em crianças é controverso. neste artigo serão analisadas estas alternativas revisando a literatura e apresentando dados prospectivos obtidos pelos autores, sugerindo que a dgH seja diagnosticada empregando-se testes de triagem seguidos de testes de confirmação. Assim, recomenda-se que crianças com baixa estatura sejam avaliadas clíni-ca e laboratorialmente para exclusão de doenças crônicas e genéticas. naquelas com estatura < 3º percentil ou velocidade de crescimento (vc) < percentil 25, dosar igF-1 como triagem. se igF-1 < -1 desvio-padrão (dP), a dgH deve ser confirmada pela ausência de resposta do hormônio de crescimento (gH) a dois testes de estímulo (pico < 5 mcg/l). em paciente com fatores de risco, igF-1 < -1 dP e um teste não-responsivo também é diagnóstico de dgH. As crianças com igF-1 > -1 dP, devem ter a vc acompanhada e, se alterada, pode-se indicar reavaliação do eixo gH/igF-1 excluindo ou confirmando a dgH. the diagnostic approach to growth hormone deficiency (gHd) in children with short stature (ss) is controversial. Here we review the available methodology and present prospective data obtained in a cohort of patients with ss suggesting the use of screening test followed by the confirmation test. thus, the children with ss should be submitted to clinical and laboratorial evaluation to exclude of chronic and genetic diseases. in addition patients with height < 3 percentil or growth velocity < percentil 25, igF-1 levels should be measured. if the igF1 levels < -1 standard deviation (sd) compared to the age, gHd should be confirmed by two gH-stimulations tests (peak < 5 mcg/l). in risk factor patients, igF-1 < -1 sd and one non-responsible gH-test, the gHd was confirmed. children with igF-1 > -1 sd, the growth velocity should have observed and gH/igF-1 axis re-evaluated if the growth pattern is not satisfactory.

Granulosa-stromal tumors comprise 5 to 8% of all primary ovarian neoplasms. The first clinical manifestation is precocious puberty in most prepuberal patients. We report a case of mixed germ cell-cord stromal tumor of ovary in a 7.2 years old girl, who presented with isosexual pseudo-precocious puberty of progressive outcome. Serum testosterone, estradiol and 17alphaOH-progesterone levels were increased. Abdominal-pelvic ultrasound revealed a right ovarian mass. Unilateral salpingo-oophorectomy was performed with complete resection of the tumor. The patient is well 7 years after surgery with normal pubertal and growth development and no signs of tumor relapse. We review the clinical manifestations of ovarian tumors, classification and staging of sex cord-stromal tumors, follow-up, tumor markers, treatment and prognosis.