Whole-exome sequencing in patients with maturation arrest: a potential additional diagnostic tool for prevention of recurrent negative testicular sperm extraction outcomes.

STUDY QUESTION: Could whole-exome sequencing (WES) be useful in clinical practice for men with maturation arrest (MA) after a first testicular sperm extraction (TESE)? SUMMARY ANSWER: WES in combination with TESE yields substantial additional information and may potentially be added as a test to predict a negative outcome of a recurrent TESE in patients with MA. WHAT IS KNOWN ALREADY: At present, the only definitive contraindications for TESE in men with non-obstructive azoospermia (NOA) are a 46,XX karyotype and microdeletions in the azoospermia factor a (AZFa) and/or AZFb regions. After a first negative TESE with MA, no test currently exists to predict a negative outcome of a recurrent TESE. STUDY DESIGN, SIZE, DURATION: In a cohort study, we retrospectively included 26 patients with idiopathic NOA caused by complete MA diagnosed after a first TESE. PARTICIPANTS/MATERIALS, SETTING, METHODS: Twenty-six men with MA at the spermatocyte stage in all seminiferous tubules, according to a histopathological analysis performed independently by two expert histologists, and a normal karyotype (i.e. no AZF gene microdeletions on the Y chromosome) were included. Single-nucleotide polymorphism comparative genomic hybridization array and WES were carried out. The results were validated with Sanger sequencing. For all the variants thought to influence spermatogenesis, we used immunohistochemical techniques to analyse the level of the altered protein. MAIN RESULTS AND THE ROLE OF CHANCE: Deleterious homozygous variants were identified in all seven consanguineous patients and in three of the 19 non-consanguineous patients. Compound heterozygous variants were identified in another 5 of the 19 non-consanguineous patients. No recurrent variants were identified. We found new variants in genes known to be involved in azoospermia or MA [including testis expressed 11 (TEX11), meiotic double-stranded break formation protein 1 (MEI1), proteasome 26s subunit, ATPase 3 interacting protein (PSMC3IP), synaptonemal complex central element protein 1 (SYCE1) and Fanconi anaemia complementation group M (FANCM) and variants in genes not previously linked to human MA (including CCCTC-binding factor like (CTCFL), Mov10 like RISC complex RNA helicase 1 (MOV10L1), chromosome 11 open reading frame 80 (C11ORF80) and exonuclease 1 (EXO1)]. LARGE SCALE DATA: Data available on request. LIMITATIONS, REASONS FOR CAUTION: More data are required before WES screening can be used to avoid recurrent TESE, although screening should be recommended for men with a consanguineous family background. WES is still a complex technology and can generate incidental findings. WIDER IMPLICATIONS OF THE FINDINGS: Our results confirmed the genetic aetiology of MA in most patients: the proportion of individuals with at least one pathologic variant was 50% in the overall study population and 100% in the consanguineous patients. With the exception of MEI1 (compound heterozygous variants of which were identified in two cases), each variant corresponded to a specific gene-confirming the high degree of genetic heterogeneity in men with MA. Our results suggest that WES screening could help to avoid recurrent, futile TESE in men with MA in general and in consanguineous individuals in particular, but these results need to be confirmed in future studies before clinical implementation. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Fondation Maladies Rares (Paris, France), Merck (Kenilworth, NJ, USA), IRSF (Montigny le Bretonneux, France) and Agence de la Biomédecine (Saint Denis, France). There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

[Update of Chlamydia trachomatis infection]. / Infection à Chlamydia trachomatis : mise au point.

Chlamydia trachomatis (CT) is the most common sexually transmitted bacterial infection worldwide. It is asymptomatic in most cases and mainly affects young women, with potential long term sequelae (pelvic inflammatory disease, tubal infertility, obstetric complications). The impact on male fertility is controversial. Screening methods as well as antibiotics use have recently been reassessed due to resistance phenomena and the negative effect on the urogenital microbiota. Positive CT serology may be indicative of tuboperitoneal pathology, which may not be noticed on hysterosalpingography. New research on single-nucleotide polymorphisms (SNPs) aims to establish a patient profile at higher risk of infectious tubal damage due to CT. CT seropositivity is also associated with decreased spontaneous pregnancy rates and is a predictive factor for obstetrical complications.

Leydig cell tumor of the testis with azoospermia and elevated delta4 androstenedione: case report.

BACKGROUND: Secreting interstitial cell (Leydig cell) tumors are rare. In adults, the clinical picture and steroid levels are variable. CASE PRESENTATION: This paper presents a case of left testicular tumor, showing azoospermia with normal serum level of total testosterone, collapsed FSH and LH, and high delta4 androstenedione. Histopathological investigation revealed a Leydig cell tumor. TESE allowed spermatozoa extraction and freezing. Testicular histology found hypospermatogenesis and germ-cell aplasia with interstitial fibrosis. Surgical resection of the tumor resulted in normalization of gonadotropins and fall in serum delta4 androstenedione to subnormal levels in the postoperative period confirming that the tumor was secreting delta4 androstenedione. It was hypothesized that high delta4 androstenedione resulted in intra tumoral 17 ß-HSD overtaken by delta4 androstenedione or that 17 ß-HSD activity in the tumor was different from that of normal Leydig cells. Three months after surgery sperm analysis found a complete recovery of spermatogenesis. A spontaneous pregnancy occurred 3 months after surgery and a girl was born. CONCLUSIONS: In this case, the diagnosis of testicular Leydig cell tumor secreting delta4 androstenedione was made in a context of azoospermia.

INTRODUCTION: Les tumeurs testiculaires interstitielles (ou tumeurs testiculaires à cellules de Leydig) à expression endocrine sont rares. Chez l'adulte le tableau clinique et le bilan hormonal sont variables. PRÉSENTATION DU CAS: Cet article présente le cas d'une tumeur testiculaire gauche dans un contexte d'azoospermie. Le bilan hormonal montre des gonadotrophines effondrées, une testostéronémie normale et une delta4 androstenedione augmentée. L'examen anatomopathologique a mis en évidence une tumeur à cellule de Leydig. La TESE a permis l'extraction et la congélation de spermatozoïdes. L'histologie a retrouvé un aspect mixte d'hypospermatogenèse diminuée incomplète et d'aplasie. Dans les suites de l'orchidectomie partielle gauche les taux de gonadotrophines se sont normalisés ainsi que le taux de delta4 androstenedione. L'hypothèse physiopathologique est que l'augmentation de la delta4 androstenedione résulte de la sursaturation de la 17 ß-HSD intra-tumoral ou que l'activité de la 17 ß-HSD intra-tumoral est différente de celle dans les cellules de Leydig normales. Trois mois après la chirurgie, le spermogramme a montré une normalisation des paramètres spermatiques et une grossesse spontanée est survenue permettant la naissance d'une petite fille. CONCLUSION: Dans ce cas clinique, le diagnostic de tumeur testiculaire à cellule de Leydig sécrétant de la delta4 androstenedione a été fait dans un contexte d'azoospermie.