7 research outputs found
Non-classic cytochrome P450 oxidoreductase deficiency strongly linked with menstrual cycle disorders and female infertility as primary manifestations.
Can cytochrome P450 oxidoreductase deficiency (PORD) be revealed in adult women with menstrual disorders and/or infertility?
PORD was biologically and genetically confirmed in five adult women with chronically elevated serum progesterone (P) who were referred for oligo-/amenorrhea and/or infertility.
PORD is an autosomal recessive disease typically diagnosed in neonates and children with ambiguous genitalia and/or skeletal abnormalities. It is responsible for the decreased activity of several P450 enzymes, including CYP21A2, CYP17A1 and CYP19A1, that are involved in adrenal and/or gonadal steroidogenesis. Little is known about the optimal way to investigate and treat patients with adult-onset PORD.
In this series, we report five adult females who were evaluated in three tertiary endocrine reproductive departments between March 2015 and September 2018.
Five women aged 19-38 years were referred for unexplained oligo-/amenorrhea and/or infertility. Genetic testing excluded 21-hydroxylase deficiency (21OH-D), initially suspected due to the increased 17-hydroxyprogesterone (17-OHP) levels. Extensive phenotyping, steroid profiling by mass spectrometry, pelvic imaging and next-generation sequencing of 84 genes involved in gonadal and adrenal disorders were performed in all patients. IVF followed by frozen embryo transfer (ET) under glucocorticoid suppression therapy was performed for two patients.
All patients had oligomenorrhea or amenorrhea. None had hyperandrogenism. Low-normal serum estradiol (E2) and testosterone levels contrasted with chronically increased serum P and 17-OHP levels, which further increased after adrenocorticotrophic hormone (ACTH) administration. Despite excessive P, 17OH-P and 21-deoxycortisol rise after ACTH stimulation suggesting non-classic 21OH-D, CYP21A2 sequencing did not support this hypothesis. Basal serum cortisol levels were low to normal, with inadequate response to ACTH in some women, suggesting partial adrenal insufficiency. All patients harbored rare biallelic POR mutations classified as pathogenic or likely pathogenic according to the American College of Medical Genetics and Genomics standards. Pelvic imaging revealed bilateral ovarian macrocysts in all women. IVF was performed for two women after retrieval of a normal oocyte number despite very low E2 levels during ovarian stimulation. Frozen ET under glucocorticoid suppression therapy led to successful pregnancies.
The number of patients described here is limited and these data need to be confirmed on a larger number of women with non-classic PORD.
The diagnosis of PORD must be considered in infertile women with chronically elevated P and 17OH-P levels and ovarian macrocysts. Differentiation of this entity from non-classic 21OH-D is important, as the multiple enzyme deficiency requires a specific management. Successful fertility induction is possible by IVF, providing that P levels be sufficiently suppressed by glucocorticoid therapy prior to implantation.
No specific funding was used for this study. There are no potential conflicts of interest.
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Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia
International audienceAnophthalmia and microphthalmia (AM) are the most severe malformations of the eye, corresponding respectively to reduced size or absent ocular globe. Wide genetic heterogeneity has been reported and different genes have been demonstrated to be causative of syndromic and non-syndromic forms of AM. We screened seven AM genes [GDF6 (growth differentiation factor 6), FOXE3 (forkhead box E3), OTX2 (orthodenticle protein homolog 2), PAX6 (paired box 6), RAX (retina and anterior neural fold homeobox), SOX2 (SRY sex determining region Y-box 2), and VSX2 (visual system homeobox 2 gene)] in a cohort of 150 patients with isolated or syndromic AM. The causative genetic defect was identified in 21% of the patients (32/150). Point mutations were identified by direct sequencing of these genes in 25 patients (13 in SOX2, 4 in RAX, 3 in OTX2, 2 in FOXE3, 1 in VSX2, 1 in PAX6, and 1 in GDF6). In addition eight gene deletions (five SOX2, two OTX2 and one RAX) were identified using a semi-quantitative multiplex polymerase chain reaction (PCR) [quantitative multiplex PCR amplification of short fluorescent fragments (QMPSF)]. The causative genetic defect was identified in 21% of the patients. This result contributes to our knowledge of the molecular basis of AM, and will facilitate accurate genetic counselling
Identification of two homozygous mutations, in the male reproductive tract specific beta-defensin 126/128 genes, potentially underlie a severe sperm dysfunction
Introduction: Hereditary breast and ovarian cancer (HBOC) is estimated to represent 5-10% of all breast and ovarian cancer cases. Pathogenic germline variants in BRCA1 and BRCA2 account for 25% of familial cases. The identification of genetic defects in HBOC patients allows detection of carriers that can benefit from cancer risk management protocols, and predictive genetic testing to at-risk family members, after appropriate genetic counseling.
Two female patients with a personal and family history of cancer were studied by next-generation sequencing (NGS).
Methods: NGS using TruSight Cancer Panel (Illumina) followed by bioinformatic analysis of 18 genes associated with HBOC was performed. Pathogenic variants were confirmed by Sanger sequencing.
Results: A rare event of double heterozigosity for pathogenic variants was identified in both patients: patient A was heterozygous for BRCA1:c.2037delinsCC, p.(Lys679Asn*4) and ATM:c.3802delG, p.(Val1268*) and patient B carried both BRCA2:c.6001dupT, p.(Ser2001Phefs*2) and ATM:3435_3436delTGinsA, p.(Asp1145Glufs*11). After genetic counseling, three relatives of patient A were analyzed: while one of her two healthy sons was heterozygous for the ATM variant, the other was a double heterozygote for BRCA1:c.2037delinsCC and ATM:c.3802delG; a female cousin, recently diagnosed with breast cancer, was a carrier of ATM:c.3802delG only.
Conclusions: The identification of these two rare cases of double heterozigosity for pathogenic variants in BRCA1/BRCA2 and ATM genes, highlights the importance of using NGS-gene panel testing in HBOC. If molecular analysis had been restricted to BRCA genes only, the pathogenic ATM variants would have been missed in both families, depriving them of appropriate genetic counseling and cancer risk management.info:eu-repo/semantics/publishedVersio
A Sensitive and Selective Fluorescent Coumarin-Based Probe for Detection of Hypochlorite ion and its Application to Cellular Imaging
Selective, sensitive fluorescent probes for ClO- are desirable due to the importance of ClO- in biological processes. Herein, a readily available turn-off fluorescent probe for ClO- is reported, which displays highly selectivity and sensitivity over other common anions and reactive oxygen/nitrogen. Moreover, it is able to detect ClO- in Ramos cells via cellular imagingclose
MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype
International audienceMolecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition