-
Frontiers in Endocrinology 2022Nuclear receptor subfamily 0 group B member 1 gene () encodes an orphan nuclear receptor that plays a critical role in the development and regulation of the adrenal...
Nuclear receptor subfamily 0 group B member 1 gene () encodes an orphan nuclear receptor that plays a critical role in the development and regulation of the adrenal gland and hypothalamic-pituitary-gonadal axis. In this study, we report a novel mutation in that led to adult-onset adrenal hypoplasia congenita (AHC) and pubertal development failure in a male adult. Clinical examinations revealed hyponatremia, elevated adrenocorticotropic hormone levels, reduced testosterone and gonadotropin levels, and hyper-responses to gonadotropin-releasing hormone and human chorionic gonadotropin stimulation tests. Whole-exome sequencing and Sanger sequencing were performed to identify the potential causes of AHC. Candidate variants were shortlisted based on the X-linked recessive models. Sequence analyses identified a novel hemizygous variant of c.1034delC in exon 1 of at Xp21.2, resulting in a frameshift mutation and premature stop codon formation. The c.1034delC/p.Pro345Argfs*27 in the gene was detected in the hemizygous state in affected males and in the heterozygous state in healthy female family carriers. These results expand the clinical features of AHC as well as the mutation profile of the causative gene . Further studies are needed to elucidate the biological effects of the mutation on the development and function of the adrenal gland and the hypothalamic-pituitary-gonadal axis.
Topics: Adrenal Insufficiency; Adult; DAX-1 Orphan Nuclear Receptor; Female; Genetic Diseases, X-Linked; Humans; Hypoadrenocorticism, Familial; Hypogonadism; Male; Testosterone
PubMed: 35784540
DOI: 10.3389/fendo.2022.897069 -
Frontiers in Pediatrics 2022Pubertal delay in males is frequently due to constitutional delay of growth and puberty, but pathologic hypogonadism should be considered. After general illnesses and...
Pubertal delay in males is frequently due to constitutional delay of growth and puberty, but pathologic hypogonadism should be considered. After general illnesses and primary testicular failure are ruled out, the main differential diagnosis is central (or hypogonadotropic) hypogonadism, resulting from a defective function of the gonadotropin-releasing hormone (GnRH)/gonadotropin axis. Ciliopathies arising from defects in non-motile cilia are responsible for developmental disorders affecting the sense organs and the reproductive system. WDR11-mediated signaling in non-motile cilia is critical for fetal development of GnRH neurons. Only missense variants of have been reported to date in patients with central hypogonadism, suggesting that nonsense variants could lead to more complex phenotypes. We report the case of a male patient presenting with delayed puberty due to Kallmann syndrome (central hypogonadism associated with hyposmia) in whom the next-generation sequencing analysis identified a novel heterozygous base duplication, leading to a frameshift and a stop codon in the N-terminal region of WDR11. The variant was predicted to undergo nonsense-mediated decay and classified as probably pathogenic following the American College of Medical Genetics and Genomics (ACMG) criteria. This is the first report of a variant in the WDR11 N-terminal region predicted to lead to complete expression loss that, contrary to expectations, led to a mild form of ciliopathy resulting in isolated Kallmann syndrome.
PubMed: 35722485
DOI: 10.3389/fped.2022.887658 -
Transplantation and Cellular Therapy Aug 2022Male gonadal dysfunction is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT) that can lead to disturbances in pubertal development,...
Male gonadal dysfunction is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT) that can lead to disturbances in pubertal development, sexual dysfunction, and infertility. However, no systematic review exists regarding prevalence and risk factors in relation to different treatment regimens. We aimed to systematically evaluate the current evidence regarding the prevalence of male gonadal dysfunction after pediatric HSCT, related risk factors, and the diagnostic value of surrogate markers of spermatogenesis in this patient group. We searched PubMed and Embase using a combination of text words and subject terms. The eligibility screening was conducted using predefined criteria. Data were extracted corresponding to the Leydig cell compartment involved in testosterone production and the germ cell compartment involved in spermatogenesis, respectively. Subsequently, data synthesis was performed. Of 2369 identified records, 25 studies were eligible. The studies were heterogeneous in terms of included diagnoses, gonadotoxic therapy, follow-up time, and definitions of gonadal dysfunction. The data synthesis revealed a preserved Leydig cell function in patients treated with non-total body irradiation (TBI) regimens, whereas the evidence regarding the impact of TBI conditioning on Leydig cell function was conflicting. Based on surrogate markers of spermatogenesis and only limited data on semen quality, the germ cell compartment was affected in half of the patients treated with non-TBI regimens and in nearly all patients treated with TBI conditioning. Testicular irradiation as part of front-line therapy before referral to HSCT led to complete Leydig cell failure and germ cell failure. Evidence regarding the impact of diagnosis, pubertal stage at HSCT, and chronic graft-versus-host disease is limited, as is the evidence of the diagnostic value of surrogate markers of spermatogenesis. Testicular irradiation as part of front-line therapy and TBI conditioning are the main risk factors associated with male gonadal dysfunction after pediatric HSCT; however, impaired spermatogenesis is also observed in half of the patients treated with non-TBI regimens. Methodological shortcomings limit existing evidence, and future studies should include semen quality analyses, follow-up into late adulthood, and evaluation of the cumulative exposure to gonadotoxic therapy.
Topics: Adult; Child; Gonadal Disorders; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Semen Analysis; Transplantation Conditioning; Whole-Body Irradiation
PubMed: 35644480
DOI: 10.1016/j.jtct.2022.05.036 -
Journal of Gynecology Obstetrics and... Sep 2022Patients with mosaic Turner syndrome who have normal phenotype and pubertal development may be diagnosed based on karyotype examination which is performed due to...
BACKGROUND
Patients with mosaic Turner syndrome who have normal phenotype and pubertal development may be diagnosed based on karyotype examination which is performed due to recurrent abortion or recurrent implantation failure; but according to the literature review, reproductive and obstetric consequences of these cases are based on case reports. There are contradictory publications on this subject recommending pre-implantation genetic testing (PGT) may be a solution to reduce the high risk for the fetus and perform normal embryo transfer.
AIM
In this study, our aim was to evaluate the results of in vitro fertilization and preimplantation genetic diagnosis in patients with low-grade and high-grade mosaic Turner syndrome.
METHODS
We collected data of patients between 2012 and 2018 from a single center retrospectively. The study analyzed 36 mosaic Turner syndrome patients, of whom, 10 patients were evaluated as high, 26 patients were evaluated as low-grade mosaic pattern for Turner syndrome.
RESULTS
Mean age (35,46±0,87 vs. 36,2 ± 1,85) body mass index (25,26±0,74 vs. 30,8 ± 0,63) baseline follicle stimulating hormone (5,73±0,74 vs. 6,70±1,17) basal luteinizing hormone (4,78±0,43 vs. 4,92±0,99) were similar between two groups. In the high-grade mosaic Turner Syndrome patients, duration of stimulation (7,60±0,16 vs. 8,0 ± 0,28, p<0,001), total gonadotrophin dose (1540,0 ± 165,12 vs. 2046,15± 111,47, p<0,001) and the number of normal karyotype embryos was statistically significantly higher (1,58±0,17 vs. 2,00±0,55, p<0,001). The Pregnancy rates in the low-grade and high-grade mosaic Turner syndrome patients' cycles were 30,8% versus 30%, (p = 0.76) respectively. IVF results were also evaluated by the presence of triploidy were accompanying Turner syndrome or not. In the presence of one or 2 X chromosomes, none of the included in the study could achieve live birth. The most common abnormality in the embryos was monosomy and trisomy of the chromosome13. In 30% of the cases, there were 2 or 3 abnormalities present together. In embryos with 2 abnormal chromosomes, the most common 2 abnormalities were monosomy 13 and trisomy 21, while trisomy 13, trisomy X and monosomy 18 were found in 3 or more abnormalities, respectively.
CONCLUSION
In vitro fertilization and Preimplantation genetic diagnose should be considered in the infertility treatment of the patient with mosaic Turner Syndrome.
Topics: Female; Fertilization in Vitro; Humans; Live Birth; Monosomy; Pregnancy; Preimplantation Diagnosis; Referral and Consultation; Retrospective Studies; Turner Syndrome
PubMed: 35569796
DOI: 10.1016/j.jogoh.2022.102405 -
Andes Pediatrica : Revista Chilena de... Feb 2022The increased survival of children and adolescents after Stem Cell Transplantation (SCT) has allowed us to gain a better understanding of the late effects that this...
INTRODUCTION
The increased survival of children and adolescents after Stem Cell Transplantation (SCT) has allowed us to gain a better understanding of the late effects that this procedure might have.
OBJECTIVE
to measure ovarian function and reserve after SCT.
PATIENTS AND METHOD
A descriptive, observatio nal, and cross-sectional study of girls and adolescents with SCT between 1999 and 2011. External gynecologic examination, hormone tests, and abdominal gynecologic ultrasound were performed, observing pubertal development pre-SCT. The following data from the clinical record were recorded: baseline pathology, type of conditioning, use of radiotherapy in conditioning, age at the time of SCT, and history of acute or chronic graft-versus-host disease (GVHD). Hormonal tests included follicle- stimulating hormone (FSH), luteinizing hormone (LH), estradiol, prolactin (PRL), thyroid-stimula ting hormone (TSH), free thyroxine, total testosterone, sex hormone-binding globulin (SHBG), and anti-Müllerian hormone (AMH). Statistical analysis included the chi-square or Fisher's Exact test with a p-value < 0.05.
RESULTS
41 patients were evaluated. The median age at the time of SCT was 6.8 years (1.5-14.1) and the median age at evaluation was 14.8 years (range: 4-25.4 years). 93% of the transplants were in patients with oncological disease and with myeloablative conditioning regimens. All patients presented decreased ovarian reserve, and 72% showed Premature Ovarian Failure (POF).
CONCLUSIONS
All patients had decreased ovarian reserve and most of them had a high prevalence of POF. Before SCT, a gynecological evaluation and subsequent follow-up for hormone monitoring and initiation of hormone replacement are essential.
Topics: Adolescent; Anti-Mullerian Hormone; Child; Cross-Sectional Studies; Female; Follicle Stimulating Hormone; Hematopoietic Stem Cell Transplantation; Humans; Menopause, Premature; Ovarian Reserve; Primary Ovarian Insufficiency
PubMed: 35506772
DOI: 10.32641/andespediatr.v93i1.3693 -
Future Oncology (London, England) Jun 2022To develop a predictive model for ovarian failure (OF) after chemotherapy in young post-pubertal women with cancer. Retrospective, monocentric cohort study including...
To develop a predictive model for ovarian failure (OF) after chemotherapy in young post-pubertal women with cancer. Retrospective, monocentric cohort study including 348 patients referring to the Oncofertility Unit of San Raffaele Hospital (Milan, Italy) from August 2011 to January 2020. A predictive model was constructed by multivariate logistic regression and receiver operating characteristic analysis. Data about menstrual function resumption were available for 184 patients. The best predictive model for OF was identified by the combination of age; number of chemotherapy lines; vincristine, adriamycin, ifosphamide/adriamycin, ifosphamide; capecitabine; adriamycin, bleomycine, vinblastine, doxorubicin (area under the curve = 0.906; CI 95% 0.858-0.954; p = 0.0001). The model predicts the probability of loss of ovarian function at cancer diagnosis and with every change of treatment.
Topics: Cohort Studies; Doxorubicin; Female; Fertility Preservation; Humans; Neoplasms; Prognosis; Retrospective Studies
PubMed: 35469452
DOI: 10.2217/fon-2022-0078 -
International Journal of Molecular... Apr 2022Congenital hypogonadotropic hypogonadism (CHH) is a rare reproductive endocrine disorder characterized by complete or partial failure of pubertal development and...
Congenital hypogonadotropic hypogonadism (CHH) is a rare reproductive endocrine disorder characterized by complete or partial failure of pubertal development and infertility due to deficiency of the gonadotropin-releasing hormone (GnRH). CHH has a significant clinical heterogeneity and can be caused by mutations in over 30 genes. The aim of this study was to investigate the genetic defect in two siblings with CHH. A woman with CHH associated with anosmia and her brother with normosmic CHH were investigated by whole exome sequencing. The genetic studies revealed a novel heterozygous missense mutation in the Fibroblast Growth Factor Receptor 1 (FGFR1) gene (NM_023110.3: c.242T>C, p.Ile81Thr) in the affected siblings and in their unaffected father. The mutation affected a conserved amino acid within the first Ig-like domain (D1) of the protein, was predicted to be pathogenic by structure and sequence-based prediction methods, and was absent in ethnically matched controls. These were consistent with a critical role for the identified missense mutation in the activity of the FGFR1 protein. In conclusion, our identification of a novel missense mutation of the FGFR1 gene associated with a variable expression and incomplete penetrance of CHH extends the known mutational spectrum of this gene and may contribute to the understanding of the pathogenesis of CHH.
Topics: Female; Humans; Hypogonadism; Kallmann Syndrome; Male; Mutation; Mutation, Missense; Portugal; Receptor, Fibroblast Growth Factor, Type 1
PubMed: 35457241
DOI: 10.3390/ijms23084423 -
American Journal of Physiology. Heart... Jun 2022Sex is increasingly emerging as determinant of right ventricular (RV) adaptation to abnormal loading conditions. It is unknown, however, whether sex-related differences...
Sex is increasingly emerging as determinant of right ventricular (RV) adaptation to abnormal loading conditions. It is unknown, however, whether sex-related differences already occur in childhood. Therefore, this study aimed to assess sex differences in a juvenile model of early RV pressure load by pulmonary artery banding (PAB) during transition from pre to postpuberty. Rat pups ( = 57, 3 wk old, 30-45 g) were subjected to PAB or sham surgery. Animals were euthanized either before or after puberty (4 and 8 wk postsurgery, respectively). Male PAB rats demonstrated failure to thrive already after 4 wk, whereas females did not. After 8 wk, female PAB rats showed less clinical symptoms of RV failure than male PAB rats. RV pressure-volume analysis demonstrated increased end-systolic elastance after 4 wk in females only, and a trend toward preserved end-diastolic elastance in female PAB rats compared with males ( = 0.055). Histology showed significantly less RV myocardial fibrosis in female compared with male PAB rats 8 wk after surgery. Myosin heavy chain 7-to-6 ratio switch and calcineurin signaling were less pronounced in female PAB rats compared with males. In this juvenile rat model of RV pressure load, female rats appeared to be less prone to clinical heart failure compared with males. This was driven by increased RV contractility before puberty, and better preservation of diastolic function with less RV myocardial fibrosis after puberty. These findings show that RV adaptation to increased loading differs between sexes already before the introduction of pubertal hormones. In this study, we describe sex differences in our unique weanling rat model of increased RV pressure load by pulmonary artery banding. We are the first to assess temporal sex-related differences in RV adaptation during pubertal development. Female rats show superior RV function and less diastolic dysfunction and fibrosis compared with male rats. These differences are already present before puberty, indicating that the differences in RV adaptation are not only determined by sex hormones.
Topics: Animals; Female; Fibrosis; Heart Failure; Heart Ventricles; Male; Rats; Ventricular Dysfunction, Right; Ventricular Function, Right; Ventricular Pressure
PubMed: 35333114
DOI: 10.1152/ajpheart.00071.2022 -
Wellcome Open Research 2022Endstage kidney failure rates are higher in South Asians than in White Europeans. Low birth weight is associated with adult chronic kidney disease and is more common in...
Endstage kidney failure rates are higher in South Asians than in White Europeans. Low birth weight is associated with adult chronic kidney disease and is more common in South Asians. Foetal kidney size was smaller in South Asians in the Born in Bradford (BiB) birth cohort. As part of BiB follow up, we aimed to investigate if there were ethnic differences in kidney function and blood pressure in early childhood and whether this was different by foetal kidney size. Serum creatinine, cystatin C, urea, and urinary albumin to creatinine ratio (ACR), protein to creatinine ratio (PCR) and retinol binding protein (RBP) were analysed in blood and urine samples from those who participated in the BiB follow-up at 7-11 years. Ethnicity was categorised by parental self-report as White European and South Asian. Estimated glomerular filtration rate (eGFR) was calculated using Schwartz, and cystatin C Zappitelli and Filler equations. Linear regression was used to examine the association between ethnicity and eGFR, PCR and blood pressure. 1591 children provided blood (n=1403) or urine (n=625) samples. Mean eGFR was 92 ml/min/1.73m (standard deviation (SD) 9) using Schwartz (n=1156) and 94 (SD 11) using Zappitelli (n=1257). CKD prevalence was rare (1 with eGFR <60 ml/min/1.73m , 14 (2.4%) had raised ACR (>2.5 mg/mmol in boys/3.5 mg/mmol in girls). Diastolic blood pressure was higher in South Asian children (difference 2.04 mmHg, 95% CI 0.99 to 3.10) but was not significant in adjusted analysis. There was no evidence of association in adjusted models between ethnicity and any eGFR or urinary measure at this age. There was no evidence of significant ethnic differences in kidney function at pre-pubertal age despite differences in kidney volume at birth. Longitudinal follow-up is required to track ethnic patterns in kidney function and blood pressure as children develop through puberty.
PubMed: 37274450
DOI: 10.12688/wellcomeopenres.17796.1 -
Journal of Pediatric Surgery Jun 2022Pediatric intestinal failure (PIF) affects nutrition, metabolism, and endocrine development, but its downstream impact on puberty is unknown.
BACKGROUND
Pediatric intestinal failure (PIF) affects nutrition, metabolism, and endocrine development, but its downstream impact on puberty is unknown.
METHODS
A retrospective review was performed of patients age >8 years with PIF managed at an intestinal rehabilitation program. Outcomes of interest were peak height velocity (PHV), age at PHV, and age at pubertal onset (Tanner stage 2). Outcomes were stratified by sex and compared to established norms.
RESULTS
Of 110 patients with PIF, 54.5% were male. Compared to the CDC 50th percentile, PHV in PIF patients was similar for females (8.09±2.36 vs. 7.37 cm/yr;p = 0.23) but significantly higher for males (9.27±2.56 vs. 7.91 cm/yr;p = 0.038). Age at PHV in PIF patients was significantly younger for both males (12.31±2.14 vs. 13.38 years;p = 0.049) and females (10.70±1.06 vs. 11.71 years;p = 0.001). PIF patients reached pubertal onset earlier than published norms; this was significant for males (12.41±1.80 vs. 13.44 years;p = 0.014), but not for females (10.45±1.81 vs. -11.15 years;p = 0.13). The mean height-for-age Z-score was -1.2, with 20% of patients having a Z-score less than -2.
CONCLUSIONS
Pubertal onset and growth are neither delayed nor diminished in patients with PIF. The high incidence of short stature, however, highlights the importance of optimizing prepubertal linear growth to attain full height potential.
TYPE OF STUDY
Prognosis study (Retrospective cohort study).
Topics: Body Height; Child; Female; Humans; Intestinal Failure; Male; Puberty; Retrospective Studies
PubMed: 35287963
DOI: 10.1016/j.jpedsurg.2022.01.057