Childhood-onset systemic lupus erythematosus with trisomy X and the increased risk for bone complications: a case report.

BACKGROUND: Systemic lupus erythematosus is a multi-organ inflammatory autoimmune disease; immune complexes are part of the pathogenesis, but not entirely responsible. Trisomy X is the most common female chromosomal abnormality and the role of an additional X chromosome in the development of systemic lupus erythematosus is well recognized. However, the potential complications and optimal management of childhood lupus with trisomy X remain unclear. Herein, we describe a case of childhood-onset systemic lupus erythematosus associated with severe bone complications presumably secondary to trisomy X. CASE PRESENTATION: A 16-year-old Japanese girl was diagnosed with childhood-onset systemic lupus erythematosus and trisomy X. A chromosomal abnormality (47, XXX) was incidentally identified on bone marrow examination initially done to determine the cause of pancytopenia. She had a persistent headache, fever　for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Furthermore, thrombocytopenia, anemia, and erythrocyte fragmentation were detected, suggesting secondary thrombotic microangiopathy. She was initially treated with intravenous methylprednisolone pulse therapy and prescribed monthly cyclophosphamide for severe disease activity, prednisolone, mycophenolate mofetil, and hydroxychloroquine as remission maintenance drugs. She developed generalized extremity pain that had been worsening throughout the disease. Extremity magnetic resonance imaging performed 12 months after the treatment onset revealed multifocal avascular necrosis, and dual-energy X-ray absorptiometry revealed further decreased bone mineral density. High plasma levels of factor VIII were detected by additional tests for coagulation functions, and we suspected the possibility that factor VIII might cause avascular necrosis due to thrombosis. Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively even under the administration of non-steroidal anti-inflammatory drugs and pregabalin. CONCLUSIONS: An additional X chromosome has been reported to be associated with factor VIII and osteoporosis. Additionally, elevated plasma levels of FVIII is the risk factors for thrombosis, which leads to the risk of avascular necrosis. Patients with systemic lupus erythematosus complicated by trisomy X might be at a higher risk of avascular necrosis and osteoporosis that can also manifest in childhood systemic lupus erythematosus.

Reproductive outcomes of intracytoplasmic sperm injection using testicular sperm and ejaculated sperm in patients with AZFc microdeletions: a systematic review and meta-analysis.

Studies have explored the assisted reproductive technology (ART) outcomes of Y-chromosome azoospermia factor c (AZFc) microdeletions, but the effect of sperm source on intracytoplasmic sperm injection (ICSI) remains unknown. To determine the ART results of ICSI using testicular sperm and ejaculated sperm from males with AZFc microdeletions, we searched Embase, Web of Science, and PubMed to conduct a systematic review and meta-analysis. The first meta-analysis results for 106 cycles in five studies showed no significant differences in the live birth rate between the testicular sperm group and the ejaculated sperm group (risk ratio: 0.97, 95% confidence interval [CI]: 0.73-1.28, P = 0.82). The second meta-analysis of 106 cycles in five studies showed no difference in the abortion rate between the testicular sperm group and ejaculated sperm group (risk ratio: 1.06, 95% CI: 0.54-2.06, P = 0.87). The third meta-analysis of 386 cycles in seven studies showed no significant difference in clinical pregnancy rates between the testicular sperm group and the ejaculated sperm group (risk ratio: 1.24, 95% CI: 0.66-2.34, P = 0.50). Inevitable heterogeneity weakened our results. However, our results indicated that testicular sperm and ejaculated sperm yield similar ART outcomes, representing a meaningful result for clinical treatment. More properly designed studies are needed to further confirm our conclusions.

Effect of Y Chromosome Microdeletions on the Pregnancy Outcome of Assisted Reproduction Technology: a Meta-analysis.

This systematic analysis aimed to summarize the effects of Y chromosome microdeletions (YCMs) on pregnancy outcomes of assisted reproductive technology (ART). This retrospective controlled meta-analysis evaluated the effect of YCMs on pregnancy outcomes of ART. Full-text retrieval was conducted in the PubMed, CBM, Web of Science, CNKI, VIP, and WANFANG databases. The pregnancy outcomes included fertilization rate, good embryo rate, clinical pregnancy rate, early miscarriage rate, miscarriage rate, live birth rate, and baby boy rate. The quality of these studies was evaluated using the Newcastle-Ottawa scale. Statistical software Review Manager 5.3 and STATA 14.0 were used. Twelve high-quality studies were included in the analysis. Compared with that in the normal group, the fertilization rate in the YCMs group decreased significantly (odds ratio [OR] = 0.75, 95% confidence interval [CI] [0.63, 0.88], P = 0.0006). However, there was no significant difference (P > 0.05) between groups in the good embryo rate (OR = 0.88, 95% CI [0.72, 1.07]), clinical pregnancy rate (OR = 0.94, 95% CI [0.78, 1.11]), early miscarriage rate (OR = 1.70, 95% CI [0.93, 3.10]), miscarriage rate (OR = 1.3, 95% CI [0.93, 1.91]), live birth rate (OR = 0.90, 95% CI [0.74, 1.08]), and baby boy rate (OR = 1.15, 95% CI [0.85, 1.56]). YCMs are associated with a reduced fertilization rate of ART, but they do not decrease the good embryo rate, clinical pregnancy rate, early miscarriage rate, miscarriage rate, live birth rate, or baby boy rate.

Obstetric and perinatal outcomes of intracytoplasmic sperm injection for infertile men with Y chromosome microdeletions.

BACKGROUND: To evaluate the safety of intracytoplasmic sperm injection (ICSI) for men with Y chromosome azoospermia factor (AZF) microdeletions. METHODS: Twenty-five men with Y chromosome microdeletions and their partners underwent ICSI treatment. These subjects were matched against 50 ICSI cycles in which the patients had normal Y chromosomes. RESULTS: Among the 25 couples, 17 achieved a clinical pregnancy of which 14 continued to a live birth. Sixteen men had deletions of AZFc markers (sY152, sY254, and sY255), 1 had a deletion of sY152, 3 had a deletion of sY254, sY255, 1 had a deletion of sY152, sY239, Sy242, sY254, and sY255, and 3 had deletions of sY152, sY254, sY255, and sY157. AZFb microdeletions (sY127, sY134, and sY143) were found in 1 patient. AZF microdeletions had no adverse effects on the clinical pregnancy, implantation or delivery rates, birth weight, gestational age, or sex ratio when compared with the control group. Overall, the multiple gestation and preterm delivery rates of the AZF microdeletion group were similar to those in the control group. CONCLUSION: Men with AZF microdeletions can achieve the delivery of healthy children using ICSI. In this series, it produced good implantation rate and obstetric and perinatal outcomes.

Controlled ovarian stimulation and IVF pregnancy in a trisomy X carrier with associated hypogonadotropic hypogonadism.

We describe successful controlled ovarian stimulation (COS) and the first known IVF pregnancy in a trisomy X carrier with associated hypogonadotropic hypogonadism (HH) linked to a chromosome 4 double mutation in the allele of the Gonadotropins Releasing Hormone receptor (GnRHr) gene. Previous administration of low dose of gonadotropins, as recommended in patients with HH, led to poor follicular recruitment. Since trisomy X is a risk factor for diminished ovarian reserve (DOR) and premature ovarian insufficiency (POI), higher doses of gonadotropins led to better ovarian response. The report readknowledges the importance of a correct genetic evaluation in a competent laboratory as a reliable base for treatment planning in this kind of patients.

Outcomes of intracytoplasmic sperm injection in oligozoospermic men with Y chromosome AZFb or AZFc microdeletions.

We investigated whether the presence of Y chromosome azoospermia factor (AZF) microdeletions impacts upon the outcomes of intracytoplasmic sperm injection (ICSI) using fresh ejaculated spermatozoa. Sixteen oligozoospermia patients with Y chromosome AZFb or AZFc microdeletions and undergoing ICSI cycles between March 2013 and November 2014 were studied. Twenty-six infertile men with normal Y chromosomes and also undergoing IVF/ICSI in the same time period were used as controls. A retrospective case-control study approach was used. Among the 16 cases, 12 (75%, 12/16) had deletions of AZFc markers (sY152, sY254 and sY255), one (6.25%, 1/16) had a deletion of sY152, and two (12.5%, 2/16) had deletions of sY152, sY254, sY255 and sY157. AZFb microdeletions were found in one patient (6.25%, 1/16). There were no significant differences between groups for cleaved embryo rate, high-grade embryo rate, blastocyst formation rate, embryo implantation rate, clinical pregnancy rate and delivery rate. The clinical outcomes of ICSI for oligozoospermic patients with Y chromosome AZF microdeletion are comparable to those of infertile patients with normal Y chromosomes. Our findings indicate that ICSI should be offered to patients with an AZFc deletion and that oligozoospermia patients with AZFb microdeletions are likely to father children.

Expanding the phenotype of Triple X syndrome: A comparison of prenatal versus postnatal diagnosis.

Triple X syndrome (47, XXX) occurs in approximately 1:1,000 female births and has a variable phenotype of physical and psychological features. Prenatal diagnosis rates of 47, XXX are increasing due to non-invasive prenatal genetic testing. Previous studies suggest that prenatal diagnosed females have better neurodevelopmental outcomes. This cross-sectional study describes diagnosis, physical features, medical problems, and neurodevelopmental features in a large cohort of females with 47, XXX. Evaluation included review of medical and developmental history, physical exam, cognitive, and adaptive testing. Medical and developmental features were compared between the prenatal and postnatal diagnosis groups using rate calculations and Fisher's exact test. Cognitive and adaptive tests scores were compared using t-tests. Seventy-four females age 6 months-24 years (mean 8.3 years) participated. Forty-four (59.5%) females were in the prenatal diagnosis group. Mean age of postnatal diagnosis was 5.9 years; developmental delay was the most common indication for postnatal genetic testing. Common physical features included hypertelorism, epicanthal folds, clinodactyly, and hypotonia. Medical problems included dental disorders (44.4%), seizure disorders (16.2%), genitourinary malformations (12.2%). The prenatal diagnosis group had higher verbal (P < 0.001), general ability index (P = 0.004), and adaptive functioning scores (P < 0.001). Rates of ADHD (52.2% vs. 45.5%, P = 0.77) and learning disabilities (39.1% vs. 36.3%, P = 1.00) were similar between the two groups. These findings expand on the phenotypic features in females with Triple X syndrome and support that prenatally ascertained females have better cognitive and functional outcomes. However, prenatally diagnosed females are still at risk for neurodevelopmental disorders. Genetic counseling and treatment recommendations are summarized. © 2016 Wiley Periodicals, Inc.

Y chromosome microdeletions and alterations of spermatogenesis, patient approach and genetic counseling.

Infertility affects 15% of couples at reproductive age and human male infertility appears frequently idiopathic. The main genetic causes of spermatogenesis defect responsible for non-obstructive azoospermia and severe oligozoospermia are constitutional chromosomal abnormalities and microdeletions in the azoospermia factor region of the Y chromosome. The improvement of the Yq microdeletion screening method gave new insights in the mechanism responsible for the genesis of Yq microdeletions and for the consequences of the management of male infertility and genetic counselling in case of assisted reproductive technology.

Clinical characteristics and treatment of azoospermia and severe oligospermia patients with Y-chromosome microdeletions.

Clinical characteristics, testicular pathology, serum levels of reproductive hormones, and genetic analysis were compared among 100 azoospermic, 20 oligozoospermic cases with azoospermia factor (AZF) microdeletion, and 50 fertile males to evaluate the relationship between the AZF microdeletion regions and the azoospermia phenotype. AZF microdeletion region, testicular volume, and serum reproductive hormone levels of patients were compared against histological examination of testicular biopsies. The number of cases of AZFa, AZFb, AZFc, AZFb + c, and AZFa + b + c microdeletion was respectively 2 (1.7%), 15 (12.5%), 77 (64.2%), 24 (20.0%), and 2 (1.7%). The testicular volume of patient with AZF microdeletion was smaller (P < 0.01), while luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were significantly higher than that of fertile individuals (P < 0.01 and P < 0.05, respectively). Among the patients, testicular volume with AZFb-microdeletion cases was larger compared to patients with AZFc or AZFb + c microdeletions (P < 0.05 and P < 0.01, respectively), whereas FSH levels were significantly lower than that of AZFc or AZFb + c microdeletions (P < 0.05). The Johnsen score of patients with an AZFb + c microdeletion was lower than that of patients with AZFb and AZFc microdeletions, but no significant difference was observed. Pathological findings of testicular biopsies poorly correlated with the pattern of AZF deletion, with the AZFc microdeletion exhibiting the most varied phenotypes. In subsequent assisted reproductive treatments, sperm from patients with an AZFc microdeletion that was obtained by testicular sperm aspiration (TESA) or microdissection testicular sperm extraction (m-TESE) were more likely to result in pregnancy. Combined with testis pathology pattern, the specific region of AZF microdeletion and hormonal assessments provide reliable prognostic information on the chance of successful sperm retrieval for assisted reproductive technologies.

AZFb microdeletions and oligozoospermia--which mechanisms?

OBJECTIVE: To characterize the deletion patterns and its breakpoints in oligozoospermic patients presenting AZFb and AZFc microdeletions and to understand the recombination mechanisms underlying these microdeletions. DESIGN: Case report. SETTING: Genetics Department of Faculty of Medicine of Porto, Porto, Portugal. PATIENT(S): Two men with severe oligozoospermia and two men with nonobstructive azoospermia identified as having different AZFb+c deletion patterns via Y chromosome microdeletion analysis. INTERVENTION(S): Definition of microdeletions and the fine characterization of the respective breakpoints by sequence-tagged sites (STS) polymerase chain reaction (PCR) and single-nucleotide variant (SNV) PCR. MAIN OUTCOME MEASURE(S): Study of the fine structure of the Y-chromosome and discussion of the putative mechanisms involved in each microdeletion pattern. RESULT(S): From the four patients studied, three deletion patterns were identified: IR4/distal-P2 (25%; 1 of 4), P5/proximal-P1 (50%; 2 of 4), and P5/distal-P1 (25%; 1 of 4). Although severe oligozoospermia is normally associated with AZFc, a complete AZFb deletion was found in one case. CONCLUSION(S): Analysis of these patients has revealed a new putative region that may be involved in spermatogenesis conservation.

[Y-chromosome microdeletions do not affect the outcomes of ICSI for infertile males].

OBJECTIVE: To compare the outcomes of intracytoplasmic sperm injection (ICSI) for infertile males with Y-chromosome microdeletions and for those with azoospermia or severe oligospermia but without Y-chromosome microdeletions. METHODS: We retrospectively analyzed 56 cycles of ICSI for 48 infertile cases with Y microdeletions (Group A) and 94 cycles for 90 cases with azoospermia or severe oligospermia but without Y-chromosome microdeletions (Group B) during the same period. We compared the two groups in the females' age, duration of infertility, males' age, number of oocytes retrieved, number of ICSI oocytes, fertilization rate, good embryo rate, number of embryos transferred, implantation rate, clinical pregnancy rate, abortion rate, live birth rate and babies' sexes. RESULTS: There were no significant differences between Groups A and B in the females' age, duration of infertility, males' age, number of oocytes retrieved, number of ICSI oocytes and number of embryos transferred (P > 0.05), nor in the rates of fertilization (69.0% vs 73.2%), good embryos (53.3% vs 48.7%), implantation (24.0% vs 30.3%), biochemical pregnancy (41.1% vs 44.7%), clinical pregnancy (37.5% vs 35.1%), early abortion (4.8% vs 6.1%) and live birth (35.7% vs 29.2%) (P > 0.05). CONCLUSION: Y-chromosome microdeletions do not affect the outcomes of ICSI. The affected couples should be informed of the necessity of prenatal genetic diagnosis before embryo implantation and the inevitability of vertical transmission to male offspring.

In vitro fertilization surrogacy in rare coexisting Mayer-Rokitansky-Kuster-Hauser syndrome and triple X karyotype.

OBJECTIVE: To report the responses to IVF surrogacy attempts in a female with a heretofore never described combination of Mayer-Rokitansky-Kuster-Hauser (MRHK) syndrome and triple X karyotype. DESIGN: Case report. SETTING: Reproductive unit of a university-affiliated medical center. PATIENT(S): A 29-year-old female diagnosed as having both MRHK syndrome and a triple X (47XXX) karyotype. INTERVENTION(S): Five cycles of IVF surrogacy. MAIN OUTCOME MEASURE(S): Recovery of oocytes after controlled ovarian stimulation. RESULT(S): A maximum of five oocytes were retrieved by percutaneous abdominal aspiration of a single subcostal left ovary. After five unsuccessful IVF trials due to low ovarian response attributed to her coexisting MRHK syndrome and triple X karyotype, the patient's choice was oocyte donation. CONCLUSION(S): An abnormal karyotype can coexist with MRKH syndrome, albeit very rarely, and probably accounts for a low ovarian response to attempts to achieve IVF surrogacy.

Association between venous leg ulcers and sex chromosome anomalies in men.

We report here two cases of men, aged 46 and 23 years, with refractory chronic venous leg ulcers in association with sex chromosome aberrations: one with a 47,XXY/48,XXXY karyotype (Klinefelter syndrome) and the other with a 47,XYY karyotype (Jacob syndrome). In both patients, the occurrence of leg ulcers was the reason for seeking medical care; their medical history was other-wise unremarkable. Chromosomal analyses were performed due to the unusually young age for development of venous leg ulcers. The pathophysiology behind the occurrence of venous leg ulcers in patients with numerical aberrations of the sex chromosomes is incompletely understood. Involvement of elevated plasminogen activator inhibitor-1 levels in the pathogenesis of venous leg ulcers has been reported in patients with Klinefelter syndrome. Notably, our patient with 47,XXY/48,XXXY presented with androgen deficiency but normal plasminogen activator inhibitor-1 activity.