Additional evidence for the role of chromosomal imbalances and SOX8, ZNRF3 and HHAT gene variants in early human testis development.

BACKGROUND: Forty-six ,XY Differences/Disorders of Sex Development (DSD) are characterized by a broad phenotypic spectrum ranging from typical female to male with undervirilized external genitalia, or more rarely testicular regression with a typical male phenotype. Despite progress in the genetic diagnosis of DSD, most 46,XY DSD cases remain idiopathic. METHODS: To determine the genetic causes of 46,XY DSD, we studied 165 patients of Tunisian ancestry, who presented a wide range of DSD phenotypes. Karyotyping, candidate gene sequencing, and whole-exome sequencing (WES) were performed. RESULTS: Cytogenetic abnormalities, including a high frequency of sex chromosomal anomalies (85.4%), explained the phenotype in 30.9% (51/165) of the cohort. Sanger sequencing of candidate genes identified a novel pathogenic variant in the SRY gene in a patient with 46,XY gonadal dysgenesis. An exome screen of a sub-group of 44 patients with 46,XY DSD revealed pathogenic or likely pathogenic variants in 38.6% (17/44) of patients. CONCLUSION: Rare or novel pathogenic variants were identified in the AR, SRD5A2, ZNRF3, SOX8, SOX9 and HHAT genes. Overall our data indicate a genetic diagnosis rate of 41.2% (68/165) in the group of 46,XY DSD.

Small supernumerary marker chromosomes (sSMC) and male infertility: characterization of five new cases, review of the literature, and perspectives.

PURPOSE: To characterize small supernumerary marker chromosomes (sSMC) in infertile males RESEARCH QUESTION: Are molecular cytogenetic methods still relevant for the identification and characterization of sSMC in the era of next-generation sequencing? METHODS: In this paper, we report five males with oligoasthenozoospermia or azoospermia with a history of recurrent pregnancy loss in partnership in four cases. R-banding karyotyping and fluorescence in situ hybridization (FISH) analysis were performed and showed sSMC in all five cases. Microdissection and reverse-FISH were performed in one case. RESULTS: One sSMC, each, was derived from chromosome 15 and an X-chromosome; two sSMC were derivatives of chromosome 22. The fifth sSMC was a ring chromosome 4 complemented by a deletion of the same region 4p14 to 4p16.1 in one of the normal chromosomes 4. All markers were mosaics except one of sSMC(22). CONCLUSION: Through this study, we emphasize the necessity of a proper combination of high-throughput techniques with conventional cytogenetic and FISH methods. This could provide a personalized diagnostic and accurate results for the patients suffering from infertility or RPL. We also highlight FISH analyses, which are essential tools for detecting sSMC in infertile patients. In fact, despite its entire composition of heterochromatin, sSMC can have effects on spermatogenesis by producing mechanical perturbations during meiosis and increasing meiotic nondisjunction rate. This would contribute to understand the exact chromosomal mechanism disrupting the natural and the assisted reproduction leading to offer a personalized support.

The influence of gonadotropins on clinico-biological ICSI outcome: a retrospective comparative study rFsH vs HP-hmg.

Objective To investigate the difference in the outcome of ICSI-ET cycles among respondents patients, taking into account the molecule inducer of controlled ovarian stimulation: HP-hMG ou rFSH. Patients and Methods A comparative retrospective study over 62 months including a total of 1005 infertile couples, divided into two groups: HP-HMG (n=125) and rFSH (n=880). Results - The average numbers of retrieved oocytes and matures oocytes were significantly higher in rFSH group rFSH (7,94 ± 2,49, HP-HMG vs 9,05 ± 3,40, rFSH, p=0.0001and  3±2,68, HP-HMG vs 6,65±3,05 , rFSH, p=0,02 respectively). There was no statistically significant difference in the endometrial thickness and estradiol level on hCG injection day, the total amount of administrated gonadotropin and the duration of stimulation. In addition, we did not find a significant difference between the two groups regarding the fertilization, the maturation, the cleavage, top quality embryo, implantation, clinical pregnancy, multiple pregnancies, live birth and miscarriage rates. There was no case of severe ovarian hyperstimulation syndrome. Conclusion - Inspite of a higher number of retrieved and mature oocytes obtained with rFSH, the latter showed no superiority over HP-hMG which seem to be equally efficient and safe for ICSI treatment cycles.

Office hysteroscopy before first in vitro fertilization. A randomized controlled trial.

BACKGROUND: Implantation failure remains a mystery since decades. This procedure needs a "top quality embryo" and a "normal" uterine cavity. To assess uterine cavity before first in vitro fertilization (IVF), many diagnostic tools could be used. Hysteroscopy remains the gold standard to diagnose and treat intra-uterine anomalies. However, it is not clearly recommanded to offer an office hysteroscopy before first IVF when transvaginal ultrasound (TVUS) and hysterosalpingography (HSG) were normal. PURPOSE: This study aimed to assess the role of office hysteroscopy before first IVF when no intra-uterine anomalies are suspected. BASIC PROCEDURES: We conducted a randomized controlled trial including 171 women scheduled for their first IVF. Women were assigned to either Group I: office hysteroscopy before IVF or Group II: immediate IVF. We included women aged less than 40 years, having regular cycles, FSH levels less than10UI/l, antral follicular count ≥12, normal TVUS and HSG. Their body mass index (BMI) ranged from 19 to 30 kg/m2. We excluded patients known having severe endometriosis, polycystic ovarian syndrome (PCOS) and oocyte receivers. The primary outcome were livebirth rate and clinical pregnancy rate. MAIN FUNDINGS: Between january 2016 and september 2017, we randomly assigned 171 women to either Group I (n = 84) or Group II (n = 87). Hysteroscopy was done in the mid-follicular phase immediately before IVF. Baseline characteristics and IVF features were comparable between groups except for the IVF protocol. Live birth rate was 23,9% in Group I versus 19,3% in Group II. (p = 0,607). Clinical Pregnancy rate was 32,4% in Group I versus 21,7% in Group II. (p = 0,326). No statistical significance was observed for neither miscarriage rate nor multiple pregnancy rate. Hysteroscopy showed 30% unsuspected intra-uterine anomalies: 11 intra-uterine adhesions, 7 polyps, 7 clinical endometritis and one fibroid print. Therapeutic hysteroscopy was done only for 6 intra-uterine adhesions and 3 polyps. Other anomalies did not require operative hysteroscopy. Visual analog score during hysteroscopy was 4,69 +/-2,892. 5 women (6%) of Group I experienced discomfort during diagnostic hysteroscopy. Only one patient had vagal syncope. No further complications were observed. PRINCIPAL CONCLUSIONS: Office hysteroscopy before first IVF seems not improve IVF results. Minimal intra-uterine anomalies not diagnosed by transvaginal ultrasound and hysterosalpingography do not seem to reduce IVF results.

Indocyanine Green Fluorescence-Guided Sentinel Node Biopsy in Breast Cancer Within a North African Population: A Retrospective Study.

OBJECTIVE: Radio isotopes and blue dyes alone or in combination are the most commonly used tracer agents in sentinel node (SN) biopsy for early breast cancer. Recent studies have found fluorescence method using indocyanine green (ICG) as a promising technology with fewer disadvantages. MATERIALS AND METHODS: Retrospective analysis of our database that included patients with clinically node-negative breast cancer scheduled for breast surgery and SN biopsy between 2016 and January 2021. Patients who underwent detection using fluorescence-ICG were included in this study. RESULTS: A total of 47 patients were included. Median age was 50 (range: 24-78) years. Mean tumor size was 3.4 ± 1.5 cm. All patients received ICG injection and 11 received a combination of ICG and blue dye. Forty-five successful SN identifications with ICG were performed and 99 nodes retrieved. Eleven procedures were undertaken after initial systemic therapy. Twenty-four patients had at least one positive SN for malignancy. Mean follow up was 29.2 months and no axillary recurrence was noted during the study period. CONCLUSION: ICG appears to be a feasible and accurate method for SN biopsy with high identification rate. This is the first study of ICG in sentinel node biopsy in a North African population.

[Conserving surgery for breast cancer]. / Le Traitement Conservateur du Cancer du Sein.

Breast cancer is the first women's cancer. Conserving surgery associated with radiotherapy, is in progress. Her indications are frequent. The result for local control and global survival are the same as radical surgery.

Asymptomatic horn rudimentary pregnant uterine rupture with a viable fetus.

BACKGROUND: Rupture of pregnant rudimentary horn in a pseudounicornuate uterus is usually resulting in severe and dramatic haemoperitoneum at the beginning of the second trimester of gestation. Advanced abdominal pregnancy due to horn rudimentary uterine rupture with delivery of a viable fetus is exceptional. AIM: To analyse obstetrical entailments, diagnosis and current concepts of management of advanced abdominal pregnancy secondary to rudimentary horn rupture. CASE: An asymptomatic ruptured rudimentary horn pregnancy in a 31-year-old, second gravida, is reported. She was referred to our maternity for anhidramnios at estimated gestational age of 30 weeks. An advanced abdominal pregnancy was diagnosed with sonographic features suggestive of horn rudimentary uterine rupture. Elective laparotomy was performed and a healthy infant was delivered. Excision of the rudimentary horn was done and an uneventful recovery followed. CONCLUSION: An unusual sonographic appearance of the placenta with anhidramnios must first lead to consider the diagnosis of advanced abdominal pregnancy in time to save the surgeon from an unpleasant and dangerous surprise and to increase the chance of materno-fetal survival.

Subtelomeric Rearrangements in Patients with Recurrent Miscarriage.

BACHGROUND: The subtelomeric rearrangements are increasingly being investigated in cases of idiopathic intellectual disabilities (ID) and congenital abnormalities (CA) but are also thought to be responsible for unexplained recurrent miscarriage (RM). Such rearrangements can go unnoticed through conventional cytogenetic techniques and are undetectable even with high-resolution molecular cytogenetic techniques such as array comparative genomic hybridization (aCGH), especially when DNA of the stillbirth or families are not available. The aim of the study is to evaluate the rate of subtelomeric rearrangements in patients with RM. MATERIALS AND METHODS: In this cross-sectional study, fluorescent in situ hybridization (FISH), based on ToTelVysion telomeric probes, was undertaken for 21 clinically normal couples exhibiting a "normal" karyotype with at least two abortions. Approximately 62% had RM with a history of stillbirth or CA/ID while the other 38% had only RM. RESULTS: FISH detected one cryptic rearrangement between chromosomes 3q and 4p in the female partner of a couple (III:4) [46,XX,ish t(3;4)(q28-,p16+;p16-,q28+)(D3S4559+,D3S4560-,D4S3359+; D3S4560+, D4S3359- ,D4S2930+)] who presented a history of RM and family history of ID and CA. Analysis of the other family members of the woman showed that her sisters (III:6 and III:11) and brother (III:8) were also carriers of the same subtelomeric translocation t(3;4)(q28;p16). CONCLUSION: We conclude that subtelomeric FISH should be undertaken in couples with RM especially those who not only have abortions but also have had at least one child with ID and/or CA, or other clinically recognizable syndromes. For balanced and cryptic anomalies, subtelomeric FISH still remains the most suitable and effective tool in characterising such chromosomal rearrangements in RM couples.

Array Characterization of Prenatally Diagnosed 15q26 Microdeletion and 2q37.1 Duplication: Report of a New Case with Multicystic Kidneys and Review of the Literature.

We report on a molecular cytogenetic characterization of 15q26 deletion and 2q37.1 duplication in a fetus presenting with intrauterine growth restriction (IUGR), diaphragmatic hernia, multicystic kidneys, left kidney pyelectasis, and clubfeet. A terminal 15q26 deletion and a terminal 2q duplication of at least 10 and 9 Mb, respectively, derived from a maternal translocation, were found. The 15q26 deletion represents a contiguous gene deletion syndrome mainly characterized by IUGR, congenital diaphragmatic hernia, and less frequently kidney defects. This deletion encompasses the IGF1R and COUPTF2 genes, known to lead to fetal growth retardation syndrome. However, kidney malformations are less well known in such conditions, and to the best of our knowledge, no candidate gene has been proposed to date. Here, we review the literature of the 15q26 deletion syndrome and suggest that hypoplastic and multicystic kidneys, the most commonly observed anomalies in this condition, should be considered in the prenatal diagnosis setting. Based on COUPTF2 protein function, we hypothesize that its haploinsufficiency might be responsible for the renal pathology.

[Recurrent hydatidiform mole. Case report of 9 successive molar pregnancies]. / La mole hydatiforme recidivante. A propos d'un cas avec 9 grossesses molaires successives.

The recurrent hydatiform mole is rare, its frequency is lower to 1%. We report the observation of a 28 years old women. without antecedents of molar pregnancy in the family and without considerable pathological antecedents. She had 9 successive molar pregnancies, without inset normal pregnancies and without living children. The delay of at least 1 year between the gestations has been respected in 6 pregnancies. The etiologic balance in particular the caryotypes of parents is normal. The authors debate the étiopathogénic and prognostic factors of this pathology.

[Ovary teratoma. Report of 91 cases]. / Teratomes de l'ovaire. A propos de 91 cas.

OBJECTIVE: To analyse the clinical and anatomic aspects of cystic teratomas of the ovary, caracteristics of patients having cystic teratomas and the management trends at our institution. STUDY DESIGN: Retrospective study of 91 cases of cystic teratomas of the ovary diagnosed and treated at Farhat -Hached Hospital (Sousse) between 1 january 1995 and 30 june 2003. RESULTS: Cystic teratomas constituted 12.13% of all ovarian tumors diagnosed and treated at our institution during the study period. The median of age was 33.35 ans. Abdominal or pelvic pain was the most frequent symptom for presentation in 67% of the cases. In addition; incidental finding was noted in 25.3% of the cases and swelling in 23% of the cases. The mean tumor diameter was 10 cm. The rate of bilateral cystic teratomas of the ovary was 14.3%. 19.8% of cystic teratomas has occurred in pregnancy. The operative video-laparoscopy was employed in 9 cases, laparotomy was employed in82 cases. Histopathological evaluation has detected 96.7% cases of mature teratomas, and 3.3% cases of immature teratomas. CONCLUSION: Cystic tertomas are the most common ovarian neoplasms, that occurs most commonly during the reproductive years. The operative laparoscopy is the most common modality of treatment of mature cystic teratomas. Immature teratomas must be treated by laparotomy associated if necessary to chimiothrapiy.

[Prognosis of local recurrence of breast cancer in Tunisia]. / Les recidives loco-regionales du cancer du sein dans le Centre Tunisien (etude anatomo-clinique et facteurs pronostiques).

OBJECTIVE: To evaluate locoregional recurrence rate of breast cancer, determine its anatomoclinical characteristies and discuss the available therapeutic alternatives. PATIENTS AND METHODS: A retrospective study including 41 patients with LRR following modified radical mastectomy or conservative surgery of invasive breast carcinoma without metastasis, between January 1993 and December 2002. RESULTS: 38 cases of LRR occurred after mastectomy and 3 cases after conservative surgery. LRR rate was 4.84%, mean follow-up 44.7 months. Mean age of patients was 45 years and LRR mean occurrence time-interval 22.4 months. Recurrence was parietal in 25 cases, mammary in 2 cases, and nodal in 14 cases. 18 patients had to be operated on. CONCLUSION: Prognosis of breast cancer depends on distant metastasis. LRR constitutes the second major risk liable to influence the overall prognosis.

Novel homozygous nonsense mutations in the luteinizing hormone receptor (LHCGR) gene associated with 46,XY primary amenorrhea.

OBJECTIVE: To determine the genetic cause of 46,XY primary amenorrhea in three 46,XY girls. DESIGN: Whole exome sequencing. SETTING: University cytogenetics center. PATIENT(S): Three patients with unexplained 46,XY primary amenorrhea were included in the study. INTERVENTION(S): Potentially pathogenic variants were confirmed by Sanger sequencing, and familial segregation was determined where parents' DNA was available. MAIN OUTCOME MEASURE(S): Exome sequencing was performed in the three patients, and the data were analyzed for potentially pathogenic mutations. The functional consequences of mutations were predicted. RESULT(S): Three novel homozygous nonsense mutations in the luteinizing hormone receptor (LHCGR) gene were identified:c.1573 C→T, p.Gln525Ter, c.1435 C→T p.Arg479Ter, and c.508 C→T, p.Gln170Ter. CONCLUSION(S): Inactivating mutations of the LHCGR gene may be a more common cause of 46,XY primary amenorrhea than previously considered.

[Knowledge, attitude and behavior about the inherited predisposition to cancer. A survery of a population without any history of cancer in central Tunisia]. / Connaissances, attitudes et comportements vis a vis de la predisposition hereditaire aux cancers. Enquete aupres d'une population indemne de cancers dans le centre Tunisien.

The genetic bases of inherited predisposition to cancer are now established. The aim of our study is to value the knowledge, attitude and behavior of the general population about the inherited predisposition to cancer. Our study involved a population of 200 individuals. Without any history of cancer. The mean age of our population was 37.5 years (18 to 74 years). The education level was low in 62.5% of cases (illiterate or primary education). About knowledge: heredity was considered a predisposing factor to cancer by 42.5% of the respondents. About attitude: we noted a cancerophobia in 82% of cases. 86.5% of our respondents trought that an early diagnosis increased the chance of recovery. About behavior: 72.5% of the studied population wishd to know if they were predisposed to develop cancer. In case of pregnancy, 79% wished to know if the foetus wasa cancer gene predisposition carrier. 28% would keep this foetus in case of positive genetic testing. These results are encouraging to develop oncogenetic counselling in Tunisia.

The effect of placental removal method at cesarean delivery on perioperative hemorrhage: a randomized clinical trial ISRCTN 49779257.

OBJECTIVES: To evaluate whether the method of placental removal during cesarean section has an impact on perioperative hemorrhage and maternal infectious morbidity. STUDY DESIGN: Three hundred and two patients admitted for abdominal delivery were recruited in a prospective randomized clinical intention-to-treat trial. Participants were assigned to have their placenta removed either manually or spontaneously. The drop in hematocrit was the primary outcome; postpartum maternal infectious morbidity was also assessed. RESULTS: Two patients were excluded for incomplete data. One-hundred-fifty-one were randomized to the manual removal group and 149 to the spontaneous group. The demographic characteristics of the two populations were similar. The mean drop (%) in the manual removal group was greater than in the spontaneous group (5.57+/-3.86 and 2.65+/-2.67, respectively; P<0.01). the incidence of postpartum infectious morbidity was also significantly greater in the manual group (RR 15.8, 95% CI 2.19-117.5). CONCLUSION: Routine manual removal of placenta at cesarean section significantly increases perioperative blood loss and postpartum maternal infectious morbidity.

[Fetal thoraco-omphalopagus. Prenatal ultrasonographic diagnosis at 15 weeks]. / Foetus omphalo-thoracopages. Diagnostic échographique à 15 semaines d'aménorrhée.

A case of ultrasonographic prenatal diagnosis of conjoined thoraco-omphalopagus twins is reported at the fifteenth week of amenorrhea. Ultrasonography is the only mean of antepartum diagnosis of conjoined twins; Several diagnostic criteria are recalled as well as etiopathogenic and epidemiological considerations of this rare malformation which may concern 1/15.000 to 1/100.000 pregnancies.

[Breast cancer in elderly women in Tunisia. Retrospective study of 106 patients older than 65 years]. / Le cancer du sein chez la femme âgée en Tunisie. Etude rétrospective à propos de 106 patientes de plus de 65 ans.

OBJECTIVE: To report the epidemiological profile, anatomo - clinic, prognostic and therapeutic of breast cancers in aged woman from the region of the Center of Tunisia. Our retrospective study concern 106 patients with mammary cancers treated between January 1990 and December 1997 at the Farhat Hached Hospital in Sousse (Tunisia). The mean age was 71 years (extremes 65-91), 66% of the patients had an age more than 75 years, the mean age at the menopause was of 50 years. The size middle clinic was of 50 mm, 45.3 % of tumors was classed T4, 39.6 % T3. 39.6% of patients have a clinical axillary adenopathis. 14.2% of patients have metastases at diagnostics. 62.5% of the cases have a high histo-pronostic grading. The prognostic factor analysis recovered in multivary survey two parameters significatifs for the survival: the size tumoral (p <0.005) and the presence of metastases at the time of the diagnosis (p <0.001). The biologic and evolutionary features of the cancer of the breast in the aged woman bring to consider the hormonal approach like the most logical, especially for the patients bearers of hormonosensibles tumors, of or the interest of the systematic dosage of the hormonal receptors.

The uterine choriocarcinoma in postmenopausal women: specificities of diagnosis and treatment.

Choriocarcinoma is a gestational trophoblastic tumor that mainly affects women of childbearing age. Cases of choriocarcinoma in postmenopausal women are exceptional. Through an observation and literature review, we propose to study the specific diagnosis and treatment features of this tumor in menopausal women. We report the observation of a pure uterine choriocarcinoma, which occurred in post-menopause. The diagnosis was made on the analysis of surgical specimens confirmed by measurement of hCG. Chemotherapy was started after a total hysterectomy and bilateral salpingo-oophorectomy first. The improvement was dramatic after 3 courses of chemotherapy and the patient is in complete remission after five years of monitoring. The primitive forms of pure choriocarcinoma in postmenopausal women are exceptional. Their etiology is poorly understood and their treatment based on chemotherapy.

Unusual gestational choriocarcinoma arising in an interstitial pregnancy.

INTRODUCTION: Choriocarcinoma is a highly malignant trophoblastic neoplasm. Its association with ectopic pregnancy is very rare and usually with aggressive behavior. PRESENTATION OF CASE: We report a new case arising in an interstitial pregnancy occurring in a 46-year-old woman. The patient was admitted for severe pelvic pain and abundant metrorrhagia. One month ago, she had had a laparoscopic resection of an interstitial pregnancy subsequent to failure of chemotherapy by methotrexate. The raise of serum ßhCG level and the hyperechoic intrauterine mass were in favor of gestational trophoblastic disease. Urgent laparotomy was performed for circulatory collapse. Hysterectomy was done. Histological examination revealed a choriocarcinoma. The patient underwent chemotherapy. Two years later, neither metastasis nor recurrence was detected. DISCUSSION: Clinical diagnosis of primary interstitial choriocarcinoma is difficult, since it is rare and manifesting by non-specific abnormal vaginal bleeding. Imaging findings are also not helpful in ectopic location. The frequency of metastasis is related to the delayed diagnosis. Serial measurement of ßhCG level was the most useful marker of diagnosis and follow up. Histopathological examination remains the only tool of the precise diagnosis. Choriocarcinoma has a very good prognosis even in advanced stages, since it is very chemosensitive. CONCLUSION: The current trend of the treatment of ectopic pregnancy by conservative surgery requires adequate monitoring of ßhCG and careful examination of pathologic specimens to avoid misdiagnosis of ectopic gestational trophoblastic disease.