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The aim of the study is to encourage a critical debate on the use of normality in the medical literature on DSD or intersex. For this purpose, a scoping review was conducted to identify and map the various ways in which “normal” is used in the medical literature on DSD between 2016 and 2020. We identified 75 studies, many of which were case studies highlighting rare cases of DSD, others, mainly retrospective observational studies, focused on improving diagnosis or treatment. The most common use of the adjective normal was in association with phenotypic sex. Overall, appearance was the most commonly cited criteria to evaluate the normality of sex organs. More than 1/3 of the studies included also medical photographs of sex organs. This persistent use of normality in reference to phenotypic sex is worrisome given the long-term medicalization of intersex bodies in the name of a “normal” appearance or leading a “normal” life. Healthcare professionals should be more careful about the ethical implications of using photographs in publications given that many intersex persons describe their experience with medical photography as dehumanizing.

Study question Whether empty follicle syndrome (EFS) in a patient has a genetic basis. Summary answer Our findings would expand the mutational spectrum of LHCGR, in patients with GEFS What is known already The LHCGR gene (OMIM #52790) is located on chromosome 2p21 has 11 exons The LHCGRs present in gonadal cells; granulosa, theca and luteal cells in women and Leydig cells in menandplays a critical role in male sexual differentiation, female ovarian development and fertility (folliculogenesis, ovulation, corpus luteum formation and progesterone secretion) Inactivating mutations in males can lead to Leydig cell hypoplasia, which causes disorders in sexual development (MIM #238 320). Phenotype of women is less severe and variable and has no effect on the secondary sex characteristics, but it could cause amenorrhoea and infertility Study design, size, duration: In the context of clinical genetics, Next Generation Sequencing libraries were prepared in line with the manufacturer’s orders using QIASeq™ Targeted DNA Custom Panel (Qiagen) targeting exons and 20 bp exon-intron boundaries of selected genes (AR, BMP15, CATSPER1, CFTR, CYP21A2, FSHB, FSHR, HESX1, LHB, LHCGR, NR5A1, POU1F1, SRY, ZP1). The variant detected in NGS analysis was further confirmed using Sanger sequencing (MiSeq, Illumina, San Diego, CA). Participants/materials, setting, methods A 27 years old Turkish women with 6 year history of primary unexplained infertility underwent controlled ovarian hyperstimulation and IVF with an antagonist protocole in Ankara City Hospital. Although normal follicular development, E2 levels, and bioavailable β-hCG plasma levels, no oocytes or cumulus-corona complexes were retrieved by follicular aspiration. Main results and the role of chance A novel heterozygous mutation on Exon 5 of LHCGR (NM_000233.4):c.453C>G (p.Phe151Leu). This variant has not been reported in GnomAD database and is a novel variant as per controlled from ClinVar and HGMD mutation databases Also coagulation tests were done Patient was heterozygote for the prothrombin mutation (FXIII) and homozygote for MTHFR C677T mutation. The patient has normal pubertal development and female karyotype (46,XX). Gonadotropin and E2 levels were normal, nor any history of anosmia, primary amenorrhoea, polycystic ovaries, hyperandrogenism, systemic disorder, or neurologic defect. According to ACMG 2015 and HGMD detected variant was classified as unknown clinical significance (VUS) variant In 22nd World Congress COGI in 2015 we have presented another recurrent GEFS case with compound heterozygous frameshift mutations in exon 5 and 11 of LHCGRgene(c.1764_1765insT) and (c.430G>T, p.V144F) who developed premature ovarian failure at the end The different types of LHCGR mutations would lead to the different functional effects and clinical phenotypes in different ages; primary amenorrhea with high levels of LH, poor ovarian response (Poesidon group1), GEFS and secondary amenorrhea (premature ovarian failure) GEFS may be a gradual biological occurrence related to ovarian ageing. Long term follow up is important, since some clinical manifestations appear later in life. Limitations, reasons for caution LH resistance in females were always found due to their effected brothers and only 10 GEFS cases of 46, XX females with LHCGR gene defect reported in literature. Patient was heterozygous for indicated mutation; therefore segregation study should be done in family members and in vitro studies should be performed. Wider implications of the findings: Screening for mutations in the LHCGR gene in Poseidon group 1 and in patients GEFS especially the recurrent ones will provide valuable information and time for clinical management, corresponding treatment and give the opportunity of wise and cost effective counseling of patients about their future reproductive choices. Trial registration number it is a case report

Leydig cell aplasia/hypoplasia is an autosomal recessive condition. In its complete form, these patients are 46XY but are cryptorchid and phenotypically female. Most cases reported in literature presented with in adolescence with pubertal delay. We reported a case with a predefined mutation in the LHCGR gene, presenting with swelling in the inguinal region and therefore diagnosed in early childhood. We wanted to emphasize the necessity of keeping Leydig cell hypoplasia in mind in the differential diagnosis of sexual development disorders in early childhood.

Objective: To evaluate the association between preeclampsia and three single nucleotide polymorphisms (rs13405728 in LHCGR gene; rs13429458 in THADA gene, and rs2479106 in DENND1A gene) whi...

Background: Luteinizing hormone receptor gene shows four nonsynonymous polymorphisms within the exons. Three of these polymorphisms, i.e. rs4539842 (an insertion of 6bp CTGCAG at nucleotide position 54), rs12470652 (c.827A>G/p.Asn 291Ser), and rs2293275(c.935G>A/p.Ser312Asn) have been studied more frequently. Beside other hormones, LH and FSH have an important role in production of competent oocyte and female fertility. Therefore, the objective of the current study was to investigate the prevalence of exons 1(rs4539842) and 10(rs12470652, rs2293275) polymorphisms of the LHCGR gene and its relationship with successful IVF in Iranian infertile women. Methods: SNPs in exons 1 and 10 were analyzed in 100 women of two equally sized groups of IVF failure and IVF success women using genomic DNA. For polymorphisms in exon 10, PCR and direct sequencing were used and for the polymorphism in exon 1, RFLP technique was used. The RFLP technique is confirmed by sequencing. Results: Our results showed significant difference in allelic frequency of SNP rs2293275 among IVF successful and IVF failure groups (p=0.001). For this variation, AA genotype (A allele) was shown to have protective effect against IVF failure (p=0.03 and OR=0.04), while GG genotype (G allele) was a susceptive genotype to IVF failure (p=0.003 and OR=3.88).Allelic frequency of SNP rs4539842 also showed significant difference between the two groups (p=0.0025). For this SNP, subjects with no 6bp insertion (homozygote deletion genotype) were susceptible to failure in IVF (p=0.009 and OR=2.93). Conclusion: It has been revealed that two common SNPs (rs4539842 and rs2293275) in the LHCGR gene are associated with the outcome of IVF in Iranian infertile women. Thus, these two SNPs can be suggested to be used as predictors for IVF outcome in Iranian population.

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Introduction: Testotoxicosis is a rare gonadotropin-independent form of precocious puberty. Herein we discuss a uniquely severe case of severe testotoxicosis in infant male with a c.1732G>C (p.ASP578His) LHCGR gene mutation requiring surgical intervention. Case Description: This 9-month-old male initially presented with extremely elevated levels of testosterone (1383 ng/dl) and undetectable ultrasensitive LH and FSH titers. On physical exam he was Tanner stage 3. Scrotal ultrasound showed multiple bilateral nodular hypoechoic lesions. A genomic DNA 1732G->C mutation within the LHCGR gene leading to a p.Asp578His amino acid change was confirmed on genetic testing. Combination medical therapy with an androgen receptor blocker and aromatase inhibitor was initiated for testotoxicosis; however, his condition worsened on medical therapy with a further rise in testosterone levels (2177 ng/dl). He subsequently underwent 2 sequential orchiectomies for his condition with both pathologies demonstrating diffuse nodular Leydig cell hyperplasia. Conclusions Herein we report the youngest case of medically refractory testotoxicosis associated with progressive bilateral diffuse nodular Leydig cell hyperplasia requiring aggressive surgical intervention. The germline c.1732G>C (p.ASP578His) mutation found in this case was previously described as somatic mutations in 3 boys with benign nodular adenoma of the testes.

Premature ovarian failure (POF) is a frequent pathology affecting 1-1.5% of women under 40 years old. Despite advances in diagnosing and treating human infertility, POF is still classified as being idiopathic in 50-80% of cases, strongly suggesting a genetic origin for the disease. Different types of autosomal and X-linked genetic anomalies can originate the phenotype in syndromic and non-syndromic POF cases. Particular interest has been focused on research into non-syndromic POF causative coding variants during the past two decades. This has been based on the assumption that amino acid substitutions might modify the intrinsic physicochemical properties of functional proteins, thereby inducing pathological phenotypes. In this case, a restricted number of mutations might originate the disease. However, like other complex pathologies, POF might result from synergistic/compensatory effects caused by several low-to-mildly drastic mutations which have frequently been classified as non-functional SNPs. Indeed, reproductive phenotypes can be considered as quantitative traits resulting from the subtle interaction of many genes. Although numerous sequencing projects have involved candidate genes, only a few coding mutations explaining a low percentage of cases have been described. Such apparent failure to identify aetiological coding sequence variations might have been due to the inherent molecular complexity of mammalian reproduction and to the difficulty of simultaneously analysing large genomic regions by Sanger sequencing.The purpose of this review is to present the molecular and cellular effects caused by non-synonymous mutations which have been formally associated, by functional tests, with the aetiology of hypergonadotropic non-syndromic POF. Considerations have also been included regarding the polygenic nature of reproduction and POF, as well as future approaches for identifying novel aetiological genes based on next generation sequencing (NGS). © 2015 The Author.

Objective To identify new molecular actors involved in nonsyndromic premature ovarian failure (POF) etiology. Design This is a retrospective case-control cohort study. Setting University research group and IVF medical center. Patient(s) Twelve women affected by nonsyndromic POF. The control group included 176 women whose menopause had occurred after age 50 and had no antecedents regarding gynecological disease. A further 345 women from the same ethnic origin (general population group) were also recruited to assess allele frequency for potentially deleterious sequence variants. Intervention(s) Next generation sequencing (NGS), Sanger sequencing, and bioinformatics analysis. Main Outcome Measure(s) The complete coding regions of 70 candidate genes were massively sequenced, via NGS, in POF patients. Bioinformatics and genetics were used to confirm NGS results and to identify potential sequence variants related to the disease pathogenesis. Result(s) We have identified mutations in two novel genes, ADAMTS19 and BMPR2, that are potentially related to POF origin. LHCGR mutations, which might have contributed to the phenotype, were also detected. Conclusion(s) We thus recommend NGS as a powerful tool for identifying new molecular actors in POF and for future diagnostic/prognostic purposes. © 2015 American Society for Reproductive Medicine.

Review on LHCGR (luteinizing hormone/choriogonadotropin receptor), with data on DNA, on the protein encoded, and where the gene is implicated.

Testotoxicosis is a rare disorder which presents as isosexual peripheral precocious puberty in males. Despite the pattern of autosomal dominant inheritance, sporadic cases also may occur. Due to activating mutation in luteinizing hormone (LH))/choriogonadotropin receptor (LHCGR) gene, early virilization and advancement in bone age are common with increased serum testosterone levels above adult ranges, despite low LH and follicular-stimulating hormone (FSH) levels. There are different treatment regimens, such as combination of bicalutamide (antiandrogen agent) and a third-generation aromatase inhibitor, that are reported to be well-tolerated and successful in slowing bone age advancement and preventing progression of virilization. We report here two patients who presented with peripheral precocious puberty and an activating mutation in the LHCGR gene: one with a family history and previously determined mutation and the other without family history and with a novel mutation (c.830G>T). Combination of bicalutamide+anastrozole was ineffective in slowing pubertal progression and bone age. Short-term results were better with ketoconazole.