A Rare Variant of Turner Syndrome (the X Isochromosome-X Syndrome): A Case Report

Background: Turner syndrome occurs in nearly one in every 2000-5000 female births. This syndrome is a genetic problem in the female phenotype and the most common sex chromosome anomaly. It is diagnosed based on clinical manifestations and cytogenetic examinations. The classic syndrome (i.e., monosomy X) makes up 50% of the cases while other forms contain X chromosome variants, which do not typically manifest as the classic X phenotype. Case Presentation: This study, presents a rare variant of Turner syndrome reported in a 20-year-old woman presenting with primary amenorrhea, hypothyroidism, and short stature who had hypergonadotropic hypogonadism with hypoplastic ovaries while without the clinical manifestations of the classic Turner syndrome. The karyotype was determined as X isochromosome-X syndrome [46 XXi (Xq)]. Conclusion: This rare syndrome occurs in approximately 7% of the cases of Turner syndrome. Rare variants of the syndrome should also be considered in female patients without the classic manifestations of Turner syndrome.

A Long Contiguous Stretch of Homozygosity Disclosed a Novel STAG3 Biallelic Pathogenic Variant Causing Primary Ovarian Insufficiency: A Case Report and Review of the Literature

Primary ovarian insufficiency (POI) refers to an etiologically heterogeneous disorder characterized by hypergonadotropic hypogonadism that represents a major cause of infertility in women under 40 years of age. Most cases are apparently sporadic, but about 10–15% have an affected first-degree relative, indicating a genetic etiology. Pathogenic variations in genes involved in development, meiosis and hormonal signaling have been detected in the hereditary form of the disorder. However, most cases of POI remain unsolved even after exhaustive investigation. A 19-year-old Senegalese female affected by non-syndromic POI presented with primary amenorrhoea and answered well to the hormonal induction of puberty. In order to investigate the presence of a genetic defect, aCGH-SNP analysis was performed. A 13.5 Mb long contiguous stretch of homozygosity (LCSH) was identified on chromosome 7q21.13-q22.1 where the exome sequencing revealed a novel homozygous 4-bp deletion (c.3381_3384delAGAA) in STAG3. Pathogenic variants in this gene, encoding for a meiosis-specific protein, have been previously reported as the cause of POI in only eight families and recently as the cause of infertility in a male. The here-identified mutation leads to the truncation of the last 55 amino acids, confirming the important role in meiosis of the STAG3 C-terminal domain.

Lutetium-177 DOTATATE Therapy Is Associated With Biochemical Endocrine Abnormalities in the Immediate Post-Treatment Period

Introduction: Lutetium-177(177Lu) DOTATATE is a form of peptide receptor radionuclide therapy (PRRT) targeting somatostatin receptor-2 (SSTR2), that is utilized in the treatment of neuroendocrine tumors. As various endocrine glands express SSTR2, 177Lu-DOTATATE can potentially disrupt endocrine function. The immediate post-treatment effects of 177Lu-DOTATATE on endocrine function are not known. Methods: We performed a retrospective analysis of data obtained from patients (≥18 years) enrolled under the 177Lu-DOTATATE trial (NCT03206060) for treatment of SSTR2 positive inoperable/metastatic pheochromocytoma/paraganglioma. 177Lu-DOTATATE (200 mCi) was administered intravenously every 8 weeks, for a total of 4 cycles. Endocrine evaluation was performed on blood samples obtained through an indwelling intravenous catheter during each cycle of PRRT on day 1 (pre-PRRT), day 2 (post-PRRT day 1), day 3 (post-PRRT day 2), day 30 (post-PRRT day 29), and day 60 (day 1 of the next cycle). Hormonal evaluation included ACTH, cortisol, TSH, free T4, GH, FSH, LH, testosterone, estradiol, and prolactin. Baseline abnormal hormonal values, and gonadotrophs in premenopausal women were excluded. Results: Data from 27 subjects (age: 54 ± 12.7 years; 13 female, 14 male) were analyzed. Three out of 27 patients (11.1%) developed clinically significant persistent endocrinopathies - secondary adrenal insufficiency (AI): (n=1 male), primary hypothyroidism: (n=1 male) and hypergonadotropic hypogonadism: (n=1 female). Compared to day 1, there were significant reductions in 1) ACTH (pg/mL) levels on day 2 (36.8 ± 34.1 vs. 23.1 ± 21; p<0.0001), day 3 (36.8 ± 34.1 vs. 24.3 ± 19.4; p<0.0001), and day 30 (36.8 ± 34.1 vs. 27.7 ± 19.1; p=0.01), without significant changes in average cortisol level, apart from 1 patient with undetectable cortisol, who developed secondary AI after 2nd cycle 2) LH (IU/L) levels on day 3 (16.4 ± 13.5 vs. 15.4 ± 13.5; p=0.014), 3) prolactin (ng/mL) on day 2 (9.9 ± 7.0 vs. 7.1 ± 5.7; p<0.0001), day 3 (9.9 ± 7.0 vs. 7.1 ± 5.4; p<0.0001), and day 30 (9.9 ± 7.0 vs. 7.6 ± 5.7; p=0.005), without significant changes in average estrogen and testosterone levels, apart from 1 woman with low estrogens developing hypergonadotropic hypogonadism after 3rd cycle 4) TSH (microIU/L) on day 2 (2.2 ± 1.4 vs. 1.4 ± 0.9; p<0.0001), and day 3 (2.2 ± 1.4 vs. 1.7 ± 1.3; p=0.001), and 5) free T4 (ng/dL) on day 2 (1.1 ± 0.2 vs. 1 ± 0.2; p=0.002). Hormonal values on day 60 were not significantly different from those on day 1, suggesting that majority of these changes were transient. Conclusions:177Lu-DOTATATE can be associated with transient endocrine disruption in the immediate post-treatment period. However, some of these changes may lead to persistent endocrinopathies which are likely associated with radiation exposure to the tissues expressing SSTR2. It is therefore important to periodically assess endocrine function during PRRT.

Features of sexual development in girls with general and genital infantilism in the early reproductive period

Purpose — study of the severity of secondary sexual characteristics in girls with general and genital infantilism in the early reproductive period. Materials and methods. 150 girls with general and genital infantilism were examined. All examined girls underwent clinical, functional, hormonal, biochemical, radiological, genetic and laboratory tests. The average age of girls was 19.56±0.13 (17–22) years. The average weight of the examined was within 55.37±1.56 (32–98) kg, height 1.57±0.13 (1.36–1.71) m. The body-mass index was 22.5±0.48 (15–48). The severity of secondary sexual characteristics was assessed according the J. Tanner scale. Results and conclusions. It was found that adolescents with general infantilism (hypogonadotropic hypogonadism) have a significant delay in the development of secondary sexual characteristics against the background of mild hirsutism (р<0.05). In Patients with genital infantilism (hypergonadotropic hypogonadism), significant axillary and suprapubic hair growth at the background of poor development of the mammary glands was noted. Also the moderate degree of hirsutism was confirmed. With normogonadotropic hypogonadism, the development of secondary sexual characteristics corresponds to similar indicators of practically healthy girls. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of these Institutes. The informed consent of the patient was obtained for conducting the studies. The authors declare no conflicts of interests. Key words: general infantilism, genital infantilism, hypogonadotropic hypogonadism, normogonadotropic hypogonadism, hypergonadotropic hypogonadism, hirsutism.

Moxibustion against Cyclophosphamide-Induced Premature Ovarian Failure in Rats through Inhibiting NLRP3-/Caspase-1-/GSDMD-Dependent Pyroptosis

Premature ovarian failure (POF) is a clinical term used to describe a condition in which women present with amenorrhoea, hypergonadotropic hypogonadism, and infertility under 40 years old, which are mainly characterized by ovarian granulosa cell inflammation and death. Pyroptosis is a proinflammatory form of programmed cell death. However, the roles of pyroptosis in POF and moxibustion (Mox) on pyroptosis in POF have not been elucidated. The aim of the present study was to investigate the protective effect of moxibustion against cyclophosphamide- (CP-) induced POF and to determine the underlying mechanisms. The results indicated that Mox could decrease the follicle-stimulating hormone (FSH) and luteotropic hormone (LH) and increase estradiol (E2) in serum, which indicated that it could improve ovarian reserve capacity. Mox also ameliorated CP-induced ovarian injury accompanied by decreased levels of interleukin-1β (IL-1β), IL-18, and gasdermin D (GSDMD), which are key features of pyroptosis. Further investigation showed that Mox alleviated POF through NLRP3-mediated pyroptosis. On the one hand, Mox directly inhibited TXNIP/NLRP3/caspase-1 signaling-induced pyroptosis, and on the other hand, it indirectly decreased NLRP3, pro-IL-1β, and pro-IL-18 through inhibiting TLR4/MyD88/NF-κB signaling. Our results show that Mox might be a new therapeutic strategy for the treatment of POF.

ENDO-ERN expert opinion on the differential diagnosis of pubertal delay

The differential diagnoses of pubertal delay include hypergonadotropic hypogonadism and congenital hypogonadotropic hypogonadism (CHH), as well as constitutional delay of growth and puberty (CDGP). Distinguishing between CDGP and CHH may be challenging, and the scientific community has been struggling to develop diagnostic tests that allow an accurate differential diagnosis. Indeed, an adequate and timely management is critical in order to enable optimal clinical and psychosocial outcomes of the different forms of pubertal delays. In this review, we provide an updated insight on the differential diagnoses of pubertal delay, including the available tests, their meanings and accuracy, as well as some clues to effectively orientate towards either constitutional pubertal delay or pathologic CHH and hypergonadotropic hypogonadism.