Non-mosaic Patients Research Articles

Birth of a healthy child fathered by a man with Klinefelter`s syndrome after preimplantation genetic testing

Introduction. Most men with non-mosaic Klinefelter?s syndrome (KS; 47, XXY) have azoospermia, and were until recently considered completely infertile. However, it has been confirmed that some non-mosaic patients had spermatozoa in the ejaculate, although severe oliogasthenoterato-soospermia was present in all of them. Although a high fertilization rate with an intracytoplasmic sperm injection (IC-SI) procedure using sperm from a non-mosaic patient and the cumulative pregnancy rate following in vitro fertilization constitute 53%, the incidence of live births after ICSI using sperm of men with non-mosaic KS is very low: 1 in 8 cases. Case report. At the Clinical Centre of Vojvodina?s Department of Gynecology and Obstetrics, a successful in vitro fertilization treatment was conducted using the sperm of a man with KS non-mosaic syndrome. Preimplantation genetic testing was performed for the embryo selection, and an euploid embryo was transferred in the subsequent natural cycle. Delivery of male newborn was spontaneous, vaginal, with head presentation, after 40 weeks and 3 days. The newborn?s Apgar score was 10/10. His birth weight was 3,950 g, and his length was 55 cm. At 12 months of age, his psychomotor development was assessed as normal on the Brunet-L?zine psychomotor development scale. Conclusion. Due to an increased risk of chromosomal abnormalities (abnormalities of sex or autosomal chromosomes) in embryos from couples with KS males, preimplantation genetic testing is conducted to select a chromosomally normal embryo. This may help achieve pregnancy sooner, decrease the chance of multiple pregnancy and its potential complications, decrease the risk of miscarriage, and reduce the need for invasive prenatal diagnostic procedures and the risks of other complications, as well as the risk of late termination of pregnancy in case of pathological findings of the fetal karyo-type using conventional diagnostic procedures.

Clinical and genetic features of somatic mosaicism in facioscapulohumeral dystrophy

PurposeTo analyse the clinical spectrum, genetic features, specific D4Z4 hypomethylation status and genotype–phenotype correlations for somatic mosaicism in facioscapulohumeral dystrophy (FSHD).MethodsThis was a prospective, hospital-based, case–control, observational study of 35...

Blood Testis Barrier and Somatic Cells Impairment in a Series of 35 Adult Klinefelter Syndrome Patients.

Klinefelter Syndrome (KS) is the most common genetic cause of infertility in men. Degeneration of the testicular tissue starts in utero and accelerates at puberty with hyalinisation of seminiferous tubules, spermatogonia apoptosis and germ cell maturation arrest. Therefore, fertility preservation in young KS boys has been proposed, although this measure is still debated due to insufficient knowledge of the pathophysiology of the disease. To better understand the underlying mechanisms of testicular failure and germ cell loss, we analysed functional and morphological alterations in the somatic compartment of KS testis, i.e., Sertoli cells, including the blood–testis barrier (BTB) and Leydig cells (LC). We compared three populations: 35 KS 47,XXY non-mosaic patients, 28 Sertoli-cell-only (SCO) syndrome patients and 9 patients with normal spermatogenesis. In KS patients the expression of BTB proteins connexin-43 and claudin-11 assessed with a semi-quantitative scoring system appeared significantly reduced with a disorganised pattern. A significant reduction in seminiferous tubules expressing androgen receptors (AR) was observed in KS compared to normal spermatogenesis controls. INSL3 expression, a marker of LC maturation, was also significantly reduced in KS compared to patients with normal spermatogenesis or SCO. Hence, the somatic compartment impairment in KS could be involved in degeneration of seminiferous tubules.

Comorbidity landscape of the Danish patient population affected by chromosome abnormalities

PurposeMost chromosome abnormality patients require long-term clinical care. Awareness of mosaicism and comorbidities can potentially guide such health care. Here we present a population-wide analysis of direct and inverse comorbidities affecting patients with chromosome abnormalities. MethodsWe extracted direct and inverse comorbidities for the 11 most prevalent chromosome abnormalities from the Danish National Patient Registry (covering 6.9 million patients hospitalized between 1994 and 2015): trisomy 13, 18, and 21, Klinefelter (47,XXY), triple X, XYY, Turner (45,X), Wolf–Hirschhorn, Cri-du-chat, Angelman, and Fragile X syndromes (FXS). We also performed four sub-analyses for male/female Down syndrome (DS) and FXS and non-mosaic/mosaic DS and Turner syndrome. ResultsOur data cover 9,003 patients diagnosed with at least one chromosome abnormality. Each abnormality showed a unique comorbidity signature, but clustering of their profiles underlined common risk profiles for chromosome abnormalities with similar genetic backgrounds. We found that DS had a decreased risk for three inverse cancer comorbidities (lung, breast, and skin) and that male FXS and non-mosaic patients have a much more severe phenotype than female FXS and mosaic patients, respectively. ConclusionOur study underlines the importance of considering mosaicism, sex, and the associated comorbidity profiles of chromosome abnormalities to guide long-term health care of affected patients.

Clinical aspects of infertile 47,XYY patients: a retrospective study

47,XYY syndrome is a sex chromosomal anomaly in men, which may be associated with infertility and has an incidence of 0.1% of male births. The clinical and paraclinical characteristics of men suffering from this anomaly have not been fully described. In this retrospective study, we present 37 cases of 47,XYY infertile men with sperm counts varying from normal to azoospermia, referred to the Genetics Laboratory at the Royan Institute, Iran. Thirteen individuals were mosaic and 24 non-mosaics. Non-mosaic patients were classified as azoospermic (nine cases) and normospermic/oligozoospermic men (15 cases). Two of the non-mosaic and three mosaic patients had secondary infertility. In addition, 13 of them underwent IUI, IVF or ICSI, and in seven cases, there was a biochemical pregnancy. The remaining 14 patients did not have ART. The 47,XYY syndrome is relatively unusual and can be missed clinically because of the lack of symptoms and of diverse phenotypes. Diagnosis of this aneuploidy can provide valuable data for counselling and early management of the patients who undergo fertility evaluation.

Ring chromosome 20

Ring Chromosome 20 syndrome is a rare chromosomal disorder characterized by refractory epilepsy, with seizures in wakefulness and sleep, behavioral problems and mild to severe cognitive impairment. Facial dysmorphism or other congenital malformations are rarely reported making it difficult to diagnose the syndrome based on clinical findings alone. Therefore, diagnosis requires cytogenetic testing. More than 100 cases have been published since the initial report in 1972. In some patients, the ring (20) is found in all cells analyzed and in these cases, the ring is almost always accompanied by deletions of 20pter and/or 20qter. However, in the majority of cases the ring is present in only a proportion of cells, with two normal 20's in the remaining cells (mosaicism), and in these cases, no deletions of chromosome 20 have been observed. Patients with supernumerary r(20) chromosomes have also been identified, but these individuals do not generally have seizures and are not discussed in this review. Characterization by fluorescence in situ hybridization and array-based analysis has shed insight into the molecular composition and possible mechanisms of ring formation, in both the mosaic and non-mosaic patients. The age of onset of seizures correlates with the percentage of cells with the ring in mosaic patients. While the underlying etiology of the phenotype is still not understood, evidence is accumulating which suggests the deletion of candidate genes on chromosome 20 is not responsible. Cytogenetic analysis, rather than chromosomal microarray analysis is recommended for diagnosis of this syndrome, as the mosaic cases do not have copy number alterations and are therefore not identified by array-based analysis.

Molecular analysis of ring chromosome 20 syndrome reveals two distinct groups of patients

BackgroundThe ring chromosome 20 syndrome (R20) is a rare genetic disorder associated with a refractory electroclinical epilepsy syndrome and variably expressed comorbidities of intellectual disability and dysmorphism.MethodsTo understand the structure...

Outcomes of TESE (Testicular Sperm Extraction) -ICSI (Intra-Cytoplasmic Sperm Injection) in 17 Patients of Klinefelter’s Syndrome

We examined the outcomes of TESE-ICSI in non-mosaic and mosaic Klinefelter’s syndrome. Retrospective study in Kyono Ladies Clinic. We preformed TESE in 192 azoospermic patients from 1997 to 2004. Sixteen of the 192 had non-mosaic Klinefelter’s syndrome and one had mosaic Klinefelter’s syndrome. Testicular spermatozoa were obtained by open testicular biopsy. After disintegration with a sterile microscope slide, the presence of spermatozoa in the wet preparations was assessed under the inverted microscope at X200 or X400 magnification. We got spermatozoa from the testis of 59.4% (114/192) of azoospermic patients, and 31.3% (5/16) of non-mosaic Klinefelter’s syndrome patients. ICSI was then performed using the spermatozoa taken from their own testis in 8 cycles of 5 patients (A-E, non-mosaic) and the ejaculated spermatozoa in one cycle of one patient (F, mosaic). Three non-mosaic patients (A, B, and C) and one mosaic patient (F) became pregnant. Both patient A and B became pregnant twice: once each by fresh sperm and by frozen- thawed spermatozoa. Patient A delivered a single healthy girl weighing 3542g from fresh sperm the first time, and a healthy boy and girl weighing 2664g and 2602g respectively from frozen-thawed spermatozoa the second time. Patient B delivered a single healthy girl weighing 3290g from fresh spermatozoa the first time and is currently at 35 gestational weeks in an on-going pregnancy using frozen-thawed spermatozoa. Patient C is currently at 36 gestational weeks in an on-going pregnancy using fresh spermatozoa. Patient F became pregnant from fresh ejaculated spermatozoa and delivered a healthy girl weighing 3194g. Patient D and E got a few spermatozoa and ICSI using fresh sperm was performed one time, but they failed. Patient D is going to redo the treatment using frozen-thawed spermatozoa but patient E has chosen to use donor insemination because there were not any frozen spermatozoa remaining. TESE-ICSI is useful in non-mosaic Klinefelter’s syndrome. To elevate the spermatozoa recovery, the microscopical extraction method may be needed to get larger and whitish seminiferous tubules.

Birth of healthy male twins after intracytoplasmic sperm injection of frozen-thawed testicular spermatozoa from a patient with nonmosaic Klinefelter syndrome

Birth of healthy male twins after intracytoplasmic sperm injection of frozen-thawed testicular spermatozoa from a patient with nonmosaic Klinefelter syndrome

Birth of twin males with normal karyotype after intracytoplasmic sperm injection with use of testicular spermatozoa from a nonmosaic patient with Klinefelter’s syndrome

Objective: To report the birth of healthy twin males after the use of testicular spermatozoa from a nonmosaic patient with Klinefelter’s syndrome. Design: Case report. Setting: Private reproduction center with university affiliation. Patient(s): A couple undergoing intracytoplasmic sperm injection (ICSI) combined with testicular sperm extraction because of the husband’s secretory azoospermia and a nonmosaic 47,XXY peripheral blood karyotype. The wife, a healthy female, presented with a history of oligomenorrhea. Intervention(s): ICSI was performed using testicular spermatozoa; 3 mM pentoxifylline solution was used to induce sperm motility because the spermatozoa recovered were all immotile. Main Outcome Measure(s): Normal fertilization, embryo cleavage, pregnancy outcome, and peripheral blood karyotype of the newborns. Result(s): Thirteen metaphase II oocytes were injected. Seven of them fertilized normally and six did not fertilize. Three good-quality embryos (4-cell stage class III) were transferred, and four were cryopreserved at the two-cell and four-cell stages using a slow freezing protocol. Twelve days after ET, a β-hCG determination was positive. Ultrasonographic examination revealed three intrauterine fetal sacs, but one of them showed a fetal pole without cardiac activity and vanished in subsequent ultrasonographic examinations. The patient delivered twins with normal male peripheral blood karyotypes. Conclusion(s): Normal outcome after the use of testicular sperm extraction and ICSI in a nonmosaic patient with Klinefelter’s syndrome reaffirms the notion of low transmission risk of this gonosomal aneuploidy.

Acute blood flow changes and efficacy of vagus nerve stimulation in partial epilepsy.

To determine possible sites of therapeutic action of vagus nerve stimulation (VNS), by correlating acute VNS-induced regional cerebral blood flow (rCBF) alterations and chronic therapeutic responses. We previously found that VNS acutely induces rCBF alterations at sites that receive vagal afferents and higher-order projections, including dorsal medulla, somatosensory cortex (contralateral to stimulation), thalamus and cerebellum bilaterally, and several limbic structures (including hippocampus and amygdala bilaterally). VNS-induced rCBF changes were measured by subtracting resting rCBF from rCBF during VNS, using [O-15]water and PET, immediately before ongoing VNS began, in 11 partial epilepsy patients. T-statistical mapping established relative rCBF increases and decreases for each patient. Percent changes in frequency of complex partial seizures (with or without secondary generalization) during three months of VNS compared with pre-VNS baseline, and T-thresholded rCBF changes (for each of the 25 regions of previously observed significant CBF change), were rank ordered across patients. Spearman rank correlation coefficients assessed associations of seizure-frequency change and t-thresholded rCBF change. Seizure-frequency changes ranged from 71% decrease to 12% increase during VNS. Only the right and left thalami showed significant associations of rCBF change with seizure-frequency change. Increased right and left thalamic CBF correlated with decreased seizures (p < 0.001). Increased thalamic synaptic activities probably mediate some antiseizure effects of VNS. Future studies should examine neurotransmitter-receptor alterations in reticular and specific thalamic nuclei during VNS.

Chromosomal localisation of a gene(s) for Turner stigmata on Yp.

Although recent cytogenetic and molecular studies in patients with Turner stigmata are consistent with a gene(s) for Turner stigmata being present on both Xp and Yp, the precise location has not been determined. In this report, we describe a phenotypically female infant with Turner stigmata and a partial Yp deletion and review genotype-phenotype correlations of the putative Turner gene(s) in non-mosaic patients with Y chromosome rearrangements resulting from chromosomal breakage at Yp or Yc (pericentromeric region). The results indicate that the putative Turner gene(s) on Yp is located in the Y specific region from interval 1A1A to interval 2B. In addition, assessment of ZFX/ZFY and RPS4X/RPS4Y in the context of the Turner gene(s) suggests that ZFX/ZFY rather than RPS4X/RPS4Y could be a candidate gene for the Turner stigmata.