Shifting the landscape: Dominant C-terminal rare missense FOXL2 variants in non-syndromic primary ovarian failure etiology.

Pathogenic germline variants in the FOXL2 gene are associated with Blepharophimosis, Ptosis, and Epicanthus Inversus syndrome (BPES) in humans, an autosomal dominant condition. Two forms of BPES have emerged: (i) type I (BPES-I), characterized by ocular signs and primary ovarian failure (POI), and (ii) type II (BPES-II) with no systemic associations. This study aimed to compare the distribution of FOXL2 variants in idiopathic POI/DOR (diminished ovarian reserve) and both types of BPES, and to determine the involvement of FOXL2 in non-syndromic forms of POI/DOR. We studied the whole coding region of the FOXL2 gene using next-generation sequencing in 1282 patients with non-syndromic POI/DOR. Each identified FOXL2 variant was compared to its frequency in the general population, considering ethnicity. Screening of the entire coding region of the FOXL2 gene allowed us to identify 10 different variants, including nine missense variants. Of the patients with POI/DOR, 14 (1%) carried a FOXL2 variant. Significantly, six out of nine missense variants (67%) were overrepresented in our POI/DOR cohort compared to the general or specific ethnic subgroups. Our findings strongly suggest that five rare missense variants, mainly located in the C-terminal region of FOXL2 are high-risk factors for non-syndromic POI/DOR, though FOXL2 gene implication accounts for approximately 0.54% of non-syndromic POI/DOR cases. These results support the implementation of routine genetic screening for patients with POI/DOR in clinical settings.

Diagnostic and referral pathways in patients with rare lipodystrophy and insulin-resistance syndromes: key milestones assessed from a national reference center.

BACKGROUND: Rare syndromes of lipodystrophy and insulin-resistance display heterogeneous clinical expressions. Their early recognition, diagnosis and management are required to avoid long-term complications. OBJECTIVE: We aimed to evaluate the patients' age at referral to our dedicated national reference center in France and their elapsed time from first symptoms to diagnosis and access to specialized care. PATIENTS AND METHODS: We analyzed data from patients with rare lipodystrophy and insulin-resistance syndromes referred to the coordinating PRISIS reference center (Adult Endocrine Department, Saint-Antoine Hospital, AP-HP, Paris), prospectively recorded between 2018 and 2023 in the French National Rare Disease Database (BNDMR, Banque Nationale de Données Maladies Rares). RESULTS: A cohort of 292 patients was analyzed, including 208 women, with the following diagnosis: Familial Partial LipoDystrophy (FPLD, n = 124, including n = 67 FPLD2/Dunnigan Syndrome); Acquired lipodystrophy syndromes (n = 98, with n = 13 Acquired Generalized Lipodystrophy, AGL); Symmetric cervical adenolipomatosis (n = 27, Launois-Bensaude syndrome, LB), Congenital generalized lipodystrophy (n = 18, CGL) and other rare severe insulin-resistance syndromes (n = 25). The median age at referral was 47.6 years [IQR: 31-60], ranging from 25.2 (CGL) to 62.2 years old (LB). The median age at first symptoms of 27.6 years old [IQR: 16.8-42.0]) and the median diagnostic delay of 6.4 years [IQR: 1.3-19.5] varied among diagnostic groups. The gender-specific expression of lipodystrophy is well-illustrated in the FPLD2 group (91% of women), presenting with first signs at 19.3 years [IQR: 14.4-27.8] with a diagnostic delay of 10.5 years [IQR: 1.8-27.0]. CONCLUSION: The national rare disease database provides an important tool for assessment of care pathways in patients with lipodystrophy and rare insulin-resistance syndromes in France. Improving knowledge to reduce diagnostic delay is an important objective of the PRISIS reference center.

Epigenetic/circadian clocks and PCOS.

Polycystic ovary syndrome (PCOS) affects 6-20% of reproductive-aged women. It is associated with increased risks of metabolic syndrome, Type 2 diabetes, cardiovascular diseases, mood disorders, endometrial cancer and non-alcoholic fatty liver disease. Although various susceptibility loci have been identified through genetic studies, they account for ∼10% of PCOS heritability. Therefore, the etiology of PCOS remains unclear. This review explores the role of epigenetic changes and modifications in circadian clock genes as potential contributors to PCOS pathogenesis. Epigenetic alterations, such as DNA methylation, histone modifications, and non-coding RNA changes, have been described in diseases related to PCOS, such as diabetes, cardiovascular diseases, and obesity. Furthermore, several animal models have illustrated a link between prenatal exposure to androgens or anti-Müllerian hormone and PCOS-like phenotypes in subsequent generations, illustrating an epigenetic programming in PCOS. In humans, epigenetic changes have been reported in peripheral blood mononuclear cells (PBMC), adipose tissue, granulosa cells (GC), and liver from women with PCOS. The genome of women with PCOS is globally hypomethylated compared to healthy controls. However, specific hypomethylated or hypermethylated genes have been reported in the different tissues of these women. They are mainly involved in hormonal regulation and inflammatory pathways, as well as lipid and glucose metabolism. Additionally, sleep disorders are present in women with PCOS and disruptions in clock genes' expression patterns have been observed in their PBMC or GCs. While epigenetic changes hold promise as diagnostic biomarkers, the current challenge lies in distinguishing whether these changes are causes or consequences of PCOS. Targeting epigenetic modifications potentially opens avenues for precision medicine in PCOS, including lifestyle interventions and drug therapies. However, data are still lacking in large cohorts of well-characterized PCOS phenotypes. In conclusion, understanding the interplay between genetics, epigenetics, and circadian rhythms may provide valuable insights for early diagnosis and therapeutic strategies in PCOS in the future.

Position statement on the diagnosis and management of congenital pituitary deficiency in adults: The French National Diagnosis and Treatment Protocol (NDTP).

Pituitary deficiency, or hypopituitarism, is a rare chronic disease. It is defined by insufficient synthesis of one or more pituitary hormones (growth hormone, TSH, ACTH, LH-FSH, prolactin), whether or not associated with arginine vasopressin deficiency (formerly known as diabetes insipidus). In adult patients, it is usually acquired (notably during childhood), but can also be congenital, due to abnormal pituitary development. The present study focuses on congenital pituitary deficiency in adults, from diagnosis to follow-up, including special situations such as pregnancy or the elderly. The clinical presentation is highly variable, ranging from isolated deficit to multiple deficits, which may be part of a syndromic form or not. Diagnosis is based on a combination of clinical, biological (assessment of all hormonal axes), radiological (brain and hypothalamic-pituitary MRI) and genetic factors. Treatment consists in hormonal replacement therapy, adapted according to the period of life and the deficits, which may be progressive. Comorbidities, risk of complications and acute decompensation, and the impact on fertility and quality of life all require adaptative multidisciplinary care and long-term monitoring.

Prognostic impact of hypothalamic perforation in adult patients with craniopharyngioma: a cohort study.

CONTEXT: Outcome of craniopharyngioma is related to its locoregional extension, which impacts resectability and the risk of surgical complications. To maximize resection and minimize complications, optic tract localization, temporal lobe extension and hypothalamic involvement are essential for surgical management. OBJECTIVE: To assess the outcome of craniopharyngiomas depending on their relation to the hypothalamus location. METHODS: We conducted a retrospective analysis of 79 patients with a craniopharyngioma who underwent surgery from 2007 to 2022. Craniopharyngiomas were classified in three groups, depending on the type of hypothalamus involvement assessed by preoperative MRI: infra-hypothalamic (type A, n=33); perforating the hypothalamus (type B, n=40); supra-hypothalamic (type C, n=6). Surgical strategy was guided by the type of hypothalamic involvement, favoring endonasal approaches for type A and type B, and transcranial approaches for type C. RESULTS: Long-term disease control was achieved in 33/33 (100%), 37/40 (92%) and 5/6 (83%) patients in type A, B and C respectively. In type B, vision was improved in 32/36 (89%) patients, while hypothalamic function was improved, stable or worsened in 6/40 (15%), 32/40 (80%) and 2/40 (5%) patients respectively. Papillary craniopharyngiomas were found in 5/33 (15%), 9/40 (22%) and 3/6 (50%) patients in types A, B and C respectively. In four patients, BRAF/MEK inhibitors were used, with significant tumor shrinkage in all cases. CONCLUSION: Craniopharyngiomas located below the hypothalamus or perforating it can be safely treated by transsphenoidal surgery. For supra-hypothalamic craniopharyngiomas, postoperative results are less favorable, and documenting a BRAF-mutation may improve outcome, if targeted therapy was efficient enough to replace surgical debulking.

Androgenic steroid excess in women.

Excessive use of anabolic-androgenic steroids (AAS) in sport occurs among professional athletes but increasingly also in amateurs. Prevalence of steroid use has been on the rise for a number of years. While the practice involves mostly men, it also occurs in women with an estimated prevalence of 1.6%. Since 2014, a 'steroid passport' has operated for sports people in competition that is based on longitudinal urinary and blood steroid levels, measured by liquid chromatography and mass spectrometry. Androgen excess stimulates muscle growth and improves muscle performance. However, their consumption carries numerous side effects, including myocardial hypertrophy; altered lipid metabolism and pro-thrombotic effects. The excess of AAS is associated with increased risk of atherosclerosis and cardiovascular events. Data for their effects in women is lacking. Perturbations of the menstrual cycle are common in female athletes, with spaniomenorrhea and even amenorrhea. This can be a consequence of gonadotropin insufficiency due to negative caloric balance, but may also be due to endogenous or exogenous hyperandrogenism. The use of AAS is probably underestimated as a public health issue, particularly in women, and thus presents a prevention challenge for healthcare professionals.

Stratification of the risk of ovarian dysfunction by studying the complexity of intermediate and premutation alleles of the FMR1 gene.

FMR1 premutation female carriers are at risk of developing premature/primary ovarian insufficiency (POI) with an incomplete penetrance. In this study, we determined the CGG repeat size among 1095 women with diminished ovarian reserve (DOR) / POI and characterized the CGG/AGG substructure in 44 women carrying an abnormal FMR1 repeat expansion number, compared to a group of 25 pregnant women carrying an abnormal FMR1 CGG repeat size. Allelic complexity scores of the FMR1 gene were calculated and compared between the two groups. In the DOR/POI cohort, 2.1% of women presented with an intermediate repeat size and 1.9% with a premutation. Our results suggest that the risk of POI is highest in the mid-range of CGG repeats. We observed that the allelic score is significantly higher in POI women compared to the pregnant women group (p-value = 0.02). We suggest that a high allelic score due to more than 2 AGG interspersions in the context of an intermediate number of repetitions could favor POI. Larger studies are still needed to evaluate the relevance of this new tool for the determination of the individual risk of developing POI in women with abnormal number of CGG repeats.

NOBOX gene variants in premature ovarian insufficiency: ethnicity-dependent insights.

PURPOSE: Premature ovarian insufficiency (POI) affects approximately 1% of women before the age of 40. Genetic contribution is a significant component of POI. The NOBOX gene was considered one of the major genetic causes of POI. However, the pathogenicity and the penetrance of NOBOX variants remain unclear. METHODS: We studied the whole coding region of the NOBOX gene by next generation sequencing in a cohort of 810 patients with POI, and we compared the frequency of each identified NOBOX variant to the general population taking into account the ethnicity of each individual. RESULTS: Screening of the whole coding region of the NOBOX gene allowed us to identify 35 different variants, including 5 loss-of-function variants. In total, 171 patients with POI (25%) carried out at least one NOBOX variant. Regarding missense variants, we observed a significant overrepresentation of the most frequent ones in our 810 POI patients as compared to the general, except for p.(Arg117Trp). However, taking into account the ethnic origin of the individuals, we observed no significant OR difference for p.(Arg44Leu) and p.(Arg117Trp) in African subgroup and for p.(Asp452Asn) in European subgroup. CONCLUSION: This population study suggests that the p.(Arg44Leu) variant could be considered benign variant and that the p.(Asp452Asn) and p.(Arg117Trp) variants could be considered moderate risk pathogenic variants with probably partial and very low penetrance and/or expressivity. In contrast, p.(Gly91Trp) and p.(Gly152Arg) variants could be considered pathogenic variants with a moderate functional impact.

Fertility care among people with primary ciliary dyskinesia.

INTRODUCTION: Fertility care is important for people living with primary ciliary dyskinesia (PCD) who are at increased risk of fertility problems. We investigated fertility care in an international participatory study. METHODS: Participants of the COVID-PCD study completed an online questionnaire addressing fertility issues. We used logistic regression to study factors associated with fertility specialist visits. RESULTS: Among 384 respondents (response rate 53%), 266 were adults (median age 44 years, interquartile range [IQR]: 33-54, 68% female), 16 adolescents, and 102 parents of children with PCD. Only half of adult participants (128; 48%) received care from fertility specialists at a median age of 30 years (IQR: 27-33)-a median of 10 years after PCD diagnosis. Only 12% were referred to fertility specialists by their PCD physician. Fertility specialist visits were reported more often by adults with pregnancy attempts (odds ratio [OR]: 9.1, 95% confidence interval [CI]: 3.8-23.6) and among people who reported fertility as important for them (OR: 5.9, 95% CI: 2.6-14.6) and less often by females (OR: 0.4, 95% CI: 0.2-0.8). Only 56% of participants who talked with healthcare professionals about fertility were satisfied with information they received. They expressed needs for more comprehensive fertility information and reported dissatisfaction with physician knowledge about PCD and fertility. CONCLUSION: People with PCD are inconsistently referred to fertility specialists. We recommend care from fertility specialists become standard in routine PCD care, and that PCD physicians provide initial fertility information either at diagnosis or no later than transition to adult care.

Pituitary surgery outcome in patients 75 years and older: a retrospective study.

BACKGROUND: As the population ages, the number of elderly patients with an indication for pituitary surgery is rising. Information on the outcome of patients aged over 75 is limited. This study reports a large series assessing the feasibility of surgical resection in this specific age range, focusing on surgical complications and postoperative results. METHODS: A retrospective cohort study of patients with pituitary adenomas and Rathke's cleft cysts was conducted. All patients were aged 75 years or over and treated by a single expert neurosurgical team. A control population included 2379 younger adult patients operated by the same surgeons during the same period. RESULTS: Between 2008 and 2022, 155 patients underwent surgery. Indication was based on vision impairment in most patients (79%). Median follow-up was 13 months (range: 3-96). The first surgery was performed with an endoscopic transsellar approach, an extended endonasal transtuberculum approach and a microscopic transcranial approach in 96%, 3%, and 1% of patients, respectively. Single surgery was sufficient to obtain volume control in 97% of patients. From Kaplan-Meier estimates, 2-year and 5-year disease control with a single surgery were 97.3% and 86.2%, respectively. Resection higher than 80% was achieved in 77% of patients. No vision worsening occurred. In acromegaly and Cushing's disease, endocrine remission was obtained in 90% of non-invasive adenomas. Surgical complications were noted in 5% of patients, with 30-day mortality, hematoma, cerebrospinal fluid leak, meningitis, and epistaxis occurring in 0.6%, 0.6%, 1.9%, 0.6%, and 1.3% respectively. New endocrine anterior deficits occurred in only 5%, while no persistent diabetes insipidus was noted. Compared with younger patients, the complication rate was not statistically different. CONCLUSIONS: Surgery beyond the age of 75, mainly relying on an endoscopic endonasal transsellar approach, is effective and safe, provided that patients are managed in tertiary centers.

Position statement on the diagnosis and management of acromegaly: The French National Diagnosis and Treatment Protocol (NDTP).

Acromegaly is a rare disease with prevalence of approximately 60 cases per million, slight female predominance and peak onset in adults in the fourth decade. Clinical diagnosis is often delayed by several years due to the slowly progressive onset of symptoms. There are multiple clinical criteria that define acromegaly: dysmorphic syndrome of insidious onset, symptoms related to the pituitary tumor (headaches, visual disorders), general signs (sweating, carpal tunnel syndrome, joint pain, etc.), complications of the disease (musculoskeletal, cardiovascular, pneumological, dental, metabolic comorbidities, thyroid nodules, colonic polyps, etc.) or sometimes clinical signs of associated prolactin hypersecretion (erectile dysfunction in men or cycle disorder in women) or concomitant mass-induced hypopituitarism (fatigue and other symptoms related to pituitary hormone deficiencies). Biological confirmation is based initially on elevated IGF-I and lack of GH suppression on oral glucose tolerance test or an elevated mean GH on repeated measurements. In confirmed cases, imaging by pituitary MRI identifies the causal tumor, to best determine management. In a minority of cases, acromegaly can be linked to a genetic predisposition, especially when it occurs at a young age or in a familial context. The first-line treatment is most often surgical removal of the somatotroph pituitary tumor, either immediately or after transient medical treatment. Medical treatments are most often proposed in patients not controlled by surgical removal. Conformal or stereotactic radiotherapy may be discussed on a case-by-case basis, especially in case of drug inefficacy or poor tolerance. Acromegaly should be managed by a multidisciplinary team, preferably within an expert center such as a reference or skill center for rare pituitary diseases.

Focus on Liver Function Abnormalities in Patients With Turner Syndrome: Risk Factors and Evaluation of Fibrosis Risk.

CONTEXT: Liver function abnormalities (LFAs) have been described in patients with Turner syndrome (TS). Although a high risk of cirrhosis has been reported, there is a need to assess the severity of liver damage in a large cohort of adult patients with TS. OBJECTIVE: Evaluate the types of LFAs and their respective prevalence, search for their risk factors, and evaluate the severity of liver impairment by using a noninvasive fibrosis marker. METHODS: This was a monocentric retrospective cross-sectional study. Data were collected during a day hospital visit. The main outcome measures were liver enzymes (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase), FIB-4 score, liver ultrasound imaging, elastography, and liver biopsies, when available. RESULTS: 264 patients with TS were evaluated at a mean age of 31.15 ± 11.48 years. The overall prevalence of LFAs was 42.8%. The risk factors were age, body mass index, insulin resistance, and an X isochromosome (Xq). The mean FIB-4 sore of the entire cohort was 0.67 ± 0.41. Less than 10% of patients were at risk of developing fibrosis. Cirrhosis was observed in 2/19 liver biopsies. There was no significant difference in the prevalence of LFAs between premenopausal patients with natural cycles and those receiving hormone replacement therapy (P = .063). A multivariate analysis adjusted for age showed no statistically significant correlation between hormone replacement therapy and abnormal gamma-glutamyl transferase levels (P = .12). CONCLUSION: Patients with TS have a high prevalence of LFA. However, 10% are at high risk of developing fibrosis. The FIB-4 score is useful and should be part of the routine screening strategy. Longitudinal studies and better interactions with hepatologists should improve our knowledge of liver disease in patients with TS.

18F-fluorocholine PET/CT detects parathyroid gland hyperplasia as well as adenoma: 401 PET/CTs in one center.

BACKGROUND: During the past decade, 18F-fluorocholine (FCH) PET/CT has been continuously performed at Tenon Hospital (Paris, France) for the detection of hyperfunctioning parathyroid glands (PT). METHODS: A cohort of 401 patients, deliberately referred for HPT since September 2012, has been analyzed. The aim of this real-life retrospective study was to determine the diagnostic utility of FCH in this setting, overall and in subgroups according to the type of hyperparathyroidism (HPT), the context of FCH in the imaging work-up and in the patient's history: initial imaging or persistence or recurrence after previous parathyroidectomy (PTX). The influence of the histologic type of resected PTs, hyperplasia or adenoma, on the preoperatory detection on FCH PET/CT has been studied as well. RESULTS: Four hundred one FCH PET/CTs were included in the cohort, performed in 323 patients with primary HPT (pHPT), including 18 with familial HPT (fHPT), and in 78 patients with secondary renal HPT (rHPT). The overall positivity rate in the 401 FCH PET/CTs was 73%. The PTX rate was twice greater in patients whose FCH PET/CT was positive than negative (73% vs. 35%). Abnormal PT(s) were pathology proven in 214 patients: only hyperplastic gland(s) in 75 cases and at least one adenoma in 136 cases; FCH PET/CT sensitivity was 89% and 92%, respectively. Similarly, there was no significant difference in patient-based sensitivity whether FCH PET/CT was performed as 1st line or later in the imaging work-up, or indicated for initial imaging or for suspicion of persistent or recurrent HPT. Gland-based sensitivity was significantly lower for hyperplasia than for adenoma (72% and 86%, respectively). The lowest gland-based sensitivity value was 65%, observed in case of hyperplasia and when FCH was performed late in the imaging work-up. FCH PET/CT correctly showed multiglandular HPT (MGD) in 36/61 proven cases, 59%. Results of ultrasonography (US) and 99mTc-sestaMIBI (MIBI) imaging were available in 346 and 178 patients, respectively. For both modalities, the corresponding sensitivity values were significantly less than those of FCH PET/CT (e.g., overall gland-based sensitivity 78% for FCH, 45% for US, 30% for MIBI) and MGD was detected in 32% of cases by US and 15% by MIBI. CONCLUSIONS: Although FCH PET/CT has been performed since 2017 as 1st line imaging for HPT at Tenon Hospital (Paris, France), a large majority of patients underwent prior US and/or MIBI in their preoperative work-up. Therefore, a selection bias is very likely, as most patients referred to FCH PET/CT had non-conclusive or discordant results of US and MIBI, explaining the low performance of those modalities in the present cohort compared to published results. Nevertheless, the superiority of FCH PET/CT over US and MIBI in detecting abnormal PTs reported in various comparative studies is definitely confirmed in this larger real-life cohort. The detection with FCH PET/CT of hyperplastic PTs was somewhat lower than that of adenomas but was better than using US or MIBI. The present results lead to recommend FCH PET/CT as the first line imaging modality in HPT when it is widely available or, if less available, at least in HPT with predominance of hyperplasia and/or MGD.

Polycystic ovary syndrome and adipose tissue.

Polycystic ovary syndrome (PCOS) is the most common endocrine metabolic disorder in women of reproductive age. Typically, it is associated with ovulatory dysfunction: dysovulation or anovulation, and symptoms of hyperandrogenism. It incurs risk of metabolic disorders such as diabetes, dyslipidemia and fatty liver. As a key endocrine organ in metabolic homeostasis, adipose tissue is often implicated in these complications. Studies of white adipose tissue (WAT) in PCOS have focused on the mechanism of insulin resistance in this tissue. Clinically, abnormalities in WAT distribution are seen, with decreased waist-to-hip ratio and increased ratio of adipose to lean mass. Such abnormalities are greater when total circulating androgens are elevated. At tissue level, white adipocyte hyperplasia occurs, along with infiltration of macrophages. Secretion of adipokines, cytokines and chemo-attractant proteins is increased in a pro-inflammatory manner, leading to reduced insulin sensitivity via alteration of glucose transporters, and hence decreased glucose uptake. The kinetics of non-esterified fatty acids (or free fatty acids) is also altered, leading to lipotoxicity. In recent years, brown adipose tissue (BAT) has been studied in women with PCOS. Although abundance is low in the body, BAT appears to play a significant role in energy expenditure and metabolic parameters. Both supra-clavicular skin temperature, which reflects BAT activity, and BAT mass are reduced in women with PCOS. Moreover, BAT mass and body mass index (BMI) are inversely correlated in patients. In the adipocyte, increased total circulating androgen levels reduce expression of uncoupling protein 1 (UCP1), a key protein in the brown adipocyte, leading to reduced biogenesis and mitochondrial respiration and hence a reduction in post-prandial thermogenesis. BAT is currently being investigated as a possible new therapeutic application.

Unraveling a case of 46,XY DSD due to 17ß-Hydroxysteroid Dehydrogenase type 3 mutations at the age of 49.

17-ß Hydroxysteroid dehydrogenase type 3 (17ß-HSD3) is an enzyme transforming Delta 4 androstenedione into testosterone. It is involved in the early development of the male genital tract. In this case report, we describe a 46,XY Difference of Sexual Development (DSD) individual with a female phenotype, primary amenorrhea, facial dysmorphia and mental retardation. Gene sequencing using a panel of genes involved in DSD revealed two heterozygous loss-of-function mutations in the HSD17B3 enzyme. Furthermore, a microarray analysis revealed a 37Mb segmental 3p duplication and a recurrent 16p13.11 microduplication. The large 3p duplication is responsible for her mental retardation and her facial dysmorphia. Interestingly, HSD17B3 mutations were identified only in adulthood, at the age of 49. Furthermore, the patient's severe mental retardation and facial dysmorphia are due to genetic abnormalities different from the ones involved in her DSD.

Prevalence and characteristics of gonadoblastoma in a retrospective multi-center study with follow-up investigations of 70 patients with Turner syndrome and a 45,X/46,XY karyotype.

Introduction: A gonadectomy is currently recommended in patients with Turner syndrome (TS) and a 45,X/46,XY karyotype, due to a potential risk of gonadoblastoma (GB). However, the quality of evidence behind this recommendation is low. Objective: This study aimed to evaluate the prevalence of GB, its characteristics, as well as its risk factors, according to the type of Y chromosomal material in the karyotype. Methods: Our study within French rare disease centers included patients with TS and a 45,X/46,XY karyotype, without ambiguity of external genitalia. Clinical characteristics of the patients, their age at gonadectomy, and gonadal histology were recorded. The regions of the Y chromosome, the presence of TSPY regions, and the percentage of 45,X/46,XY mosaicism were evaluated. Results: A total of 70 patients were recruited, with a median age of 29.5 years (21.0-36.0) at the end of follow-up. Fifty-eight patients had a gonadectomy, at a mean age of 15 ± 8 years. GB was present in nine cases. Two were malignant, which were discovered at the age of 14 and 32 years, without metastases. Neither the percentage of XY cells within the 45,X/46,XY mosaicism nor the number of TSPY copies was statistically different in patients with or without GB (P = 0.37). However, the entire Y chromosome was frequent in patients with GB (6/9). Conclusions: In our study, including a large number of patients with 45,X/46,XY TS, the prevalence of gonadoblastoma is 12.8%. An entire Y chromosome appears as the main risk factor of GB and should favor early gonadectomy. Significant statement: About 10% of patients with TS have a karyotype containing Y chromosomal material: 45,X/46,XY. Its presence is related to the risk of GB. Therefore, a prophylactic gonadectomy is currently recommended in such patients. However, the quality of evidence is low. Our objective was to evaluate the prevalence of GB according to the type of Y-chromosomal material. We found a prevalence of GB of 12.8% in a cohort of 70 TS patients. No sign of hyperandrogenism was observed. The entire Y chromosome was the most frequent type of Y-material in patients with GB. As the prognosis of these tumors was good, a delay of surgery might be discussed.

Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights.

CONTEXT: Premature ovarian insufficiency (POI) is a common form of female infertility that usually presents as an isolated condition but can be part of various genetic syndromes. Early diagnosis and treatment of POI can minimize comorbidity and improve health outcomes. OBJECTIVE: We aimed to determine the genetic cause of syndromic POI, intellectual disability, neutropenia, and cataracts. METHODS: We performed whole-exome sequencing (WES) followed by functional validation via RT-PCR, RNAseq, and quantitative proteomics, as well as clinical update of previously reported patients with variants in the caseinolytic peptidase B (CLPB) gene. RESULTS: We identified causative variants in CLPB, encoding a mitochondrial disaggregase. Variants in this gene are known to cause an autosomal recessive syndrome involving 3-methylglutaconic aciduria, neurological dysfunction, cataracts, and neutropenia that is often fatal in childhood; however, there is likely a reporting bias toward severe cases. Using RNAseq and quantitative proteomics we validated causation and gained insight into genotype:phenotype correlation. Clinical follow-up of patients with CLPB deficiency who survived to adulthood identified POI and infertility as a common postpubertal ailment. CONCLUSION: A novel splicing variant is associated with CLPB deficiency in an individual who survived to adulthood. POI is a common feature of postpubertal female individuals with CLPB deficiency. Patients with CLPB deficiency should be referred to pediatric gynecologists/endocrinologists for prompt POI diagnosis and hormone replacement therapy to minimize associated comorbidities.

[Worldwide contraception]. / La contraception à travers le monde.

The latest statistics concerning contraceptive use in the world have been published in 2019 by the United Nations. Among the 1.9 billion of women of reproductive age (15-49 years), 1.1 billion have a need for family planning. Among them, 190 millions are not using any contraception, although they wanted to avoid a pregnancy. There is a significant discrepancy among continents concerning the percentage of contraceptive use and the distribution of the different types of contraception. Female sterilization is the most widespread method of contraception since it represents 24% of all contraception methods used. Male condoms is used by 21% of couples. Thus, progress is still needed to disseminate effective, well tolerated and potentially reversible methods of contraception. Education of females, couples, medical and paramedical staff is one of the priority targets to improve contraception throughout the world.

Title: La contraception à travers le monde. Abstract: Les dernières données concernant la contraception à travers le monde ont été publiées en 2019 par l'Organisation des Nations unies (ONU). Parmi les 1,9 milliard de femmes en âge de procréer (entre 15 et 49 ans), 1,1 milliard souhaitaient une contraception. Pourtant, 10 % d'entre elles n'utilisaient pas de méthode contraceptive, essentiellement en raison d'un manque d'accès à ces méthodes. Selon les continents, une grande disparité est observée dans l'utilisation des différentes méthodes contraceptives. La stérilisation féminine, ou contraception définitive, reste cependant la méthode majoritairement utilisée puisqu'elle représente 24 % des contraceptions. Des progrès sont nécessaires, en particulier dans l'éducation, pour améliorer la diffusion d'autres méthodes également efficaces, qui sont bien tolérées et possiblement réversibles.