Chimerism involving a RB1 pathogenic variant in monochorionic dizygotic twins with twin–twin transfusion syndrome

We report the first case of blood chimerism involving a pathogenic RB1 variant in naturally conceived monochorionic‐dizygotic twins (MC/DZ) with the twin–twin‐transfusion syndrome (TTTS), presumably caused by the exchange of stem‐cells. Twin A developed bilateral retinoblastoma at 7 months of age. Initial genetic testing identified a de novo RB1 pathogenic variant, with a 20% allelic ratio in both twins' blood. Subsequent genotyping of blood and skin confirmed dizygosity, with the affected twin harboring the RB1 pathogenic variant in skin and blood, and the unaffected twin carrying the variant only in blood.     

双胎输血综合征宫内治疗的探讨

目的探讨双胎输血综合征（TTTS）的诊断、分期，评价宫内治疗的可行性及临床效果。方法对双胎输血综合征病例进行诊断分期，并且行系列羊水减量等宫内治疗。结果邢严重程度的分期是决定TTTs治疗效果和围产儿预后的重要因素。诊断时分期越高，围产儿死亡率越高。Ⅰ-Ⅱ期TTTs患者，经羊水减量术治疗后，孕龄延长，胎儿预后好。结论尽可能早地确立诊断和临床分期有助于评估预后和临床处理。羊水减量术治疗TTTs，可操作性强，有较好的治疗效果。     

Early demise of twins in a cohort of stillbirths and second trimester miscarriages

Twins, particularly monochorionic (MC) pairs, are at increased risk for fetal death. Whereas previous work has sought to understand the mechanisms for this increased mortality, most studies analyze viable twin pregnancies or liveborn twin cohorts. In the Wisconsin Stillbirth Service Program cohort of 3,137 stillbirths and second trimester miscarriages, we identified 175 twin pregnancies for a twinning rate of 56/1,000, which is approximately double the general population. The excess of twins among miscarriages and stillbirths was attributable to MC pairs as the incidence of dizygotic (DZ) twinning was not increased compared to livebirth data. The leading causes of fetal demise among twins were twin–twin transfusion, acardia, and twin–twin disruption. Maternal causes of death, primarily premature rupture of membranes, were moderately increased in both MC and DZ twins relative to singletons. Although deceased twins were smaller than expected for viable twins at comparable gestational ages, placenta weights of deceased MC pairs were large compared to combined fetal weight, which indicates placental inefficiency likely due to vascular shunting. Co‐twin survival was much lower for MC than for DZ pairs. Therefore, earlier diagnosis and treatment of MC twinning complications may decrease prenatal mortality.     

Iron metabolism in monochorionic twin pregnancies in relation to twin--twin transfusion syndrome

Fetal iron metabolism was investigated in monochorionic (MC) twin pregnancies in relation to twin-twin transfusion syndrome (TTTS). Matched maternal and fetal blood samples were obtained both in utero and at birth from MC twins with TTTS (n = 23) and without TTTS (n = 18). In a second group of 30 twin pairs (15 with and 15 without TTTS), liver iron content was assessed by using archived paraffin wax-embedded blocks. Serum ferritin was determined by radioimmunoassay and values are given as gestation independent Z-scores and expressed as mean with 95% confidence intervals. Ferritin concentrations in the recipients were higher than in the donors both in utero (P < 0.01) and at birth (P < 0.01). Fetal serum ferritin in non-TTTS twins were similar to the recipient twins but higher than the donor twins (P < 0.05). A significant association was found between ferritin concentrations, the total red blood cell count and haemoglobin in the TTTS twin pairs (P < 0.01) and the non-TTTS twins as a group (P < 0.01). The total stainable liver iron was comparable between twin pairs in the TTTS and non-TTTS groups. This study fails to provide evidence of iron overload in the recipient and depletion in the donor twins and, thereby, questions the validity of the conventional theory of inter-twin transfusion as the cause of TTTS.     

Maternal vascular endothelial growth factor receptor and interleukin levels in pregnant women with twin-twin transfusion syndrome

Twin-twin transfusion syndrome (TTTS) is an unusual and serious condition that occurs in twin pregnancies when identical twins share a placenta but develop discordant amniotic fluid volumes. TTTS is associated with an increased risk of fetal death and birth defects if untreated. This study investigated the soluble levels of biomarkers including growth factors and interleukins in pregnant women with and without TTTS during pregnancy. We quantified plasma levels of VEGF-R1, VEGF-R2, IL-1β, IL-6 and IL-8 in twin pregnant women with (n=53) and without TTTS (n=72) and in women with single pregnancy (n=30) by ELISA and analyzed the association of maternal circulating biomarker levels with TTTS. Our results showed that maternal VEGF-R1 levels were significantly higher in twins compared to single pregnancy (P<0.05) and were decreased in the second trimester compared to the first trimester (P = 0.065, 0.019 and 0.072 for twins with and without TTTS and single pregnancy, respectively). VEGF-R2 levels had a trend to be lower in twins compared to single pregnancy. In addition, soluble VEGF-R1 and VEGF-R2 levels were significantly decreased while IL-6 levels were increased after surgical treatment with laser in twin pregnant women with TTTS (P = 0.016, 0.041 and 0.04, respectively). These results suggest that IL-6, VEGF-R1 and VEGF-R2 are involved in vascular regulation and stabilization in twin pregnancies and may contribute to the pathogenesis of TTTS and thus play a prognostic role in the surgical treatment of TTTS.     

Congenital focal glomerular lesions in only one monozygotic twin related to a probable twin transfusion syndrome

A case of congenital focal glomerular lesions involving crescent formation in only one monozygotic twin is reported. The possible effect of chronic hypotension in the pathogenesis of the lesion is discussed, considering the fact that the affected twin was probably the donor in a feto-fetal transfusion syndrome.     

Smith-Lemli-Opitz syndrome in female, monozygotic twins

A pair of monozygotic female twins with SLO syndrome is presented. We have found only one paper in the literature that referred to twins with this rare syndrome. The multiple congenital defects in these cases, consist of limb and genital abnormalities, retardation of growth, mental deficiency, craniofacial defects and abnormal neurological status.     

Outcome of pregnancies complicated by severe ovarian hyperstimulation syndrome (OHSS): a follow-up beyond the second trimester

The main aim of this study was to assess the obstetric complications for those pregnancies that are complicated by ovarian hyperstimulation syndrome (OHSS) and continue beyond the first trimester. We checked also for other related serious events that occurred during the first trimester. METHODS: We included only patients whose pregnancies continued beyond the first trimester and compared them with IVF-treated patients displaying moderate ovarian response. RESULTS: We studied 165 patients with OHSS (101 singletons and 64 twins) and 156 IVF control patients (85 singletons and 71 twins). Two serious complications, gestational diabetes mellitus (GDM) and pregnancy-induced hypertension (PIH), were noted in both groups. However, the incidence of these two complications did not differ significantly between the groups. In the OHSS group, GDM presented with an incidence of 9.9% for singletons and 9.4% for twins, and 12.9% and 7.0%, respectively, for the control group. PIH presented as 6.9% for singletons and 10.9% for twins in the OHSS group, and 8.2% and 7.0%, respectively, for the control groups. During the first trimester laparoscopies for suspected ovarian torsion were performed in 13 patients, and in 10 patients the diagnosis were confirmed. CONCLUSIONS: Although patients with OHSS-complicated pregnancies previously reported a relatively high risk of GDM and PIH, the occurrence rates do not differ from a matched control group of normally responding patients who conceived after IVF.     

Use of artificial dermis and recombinant basic fibroblast growth factor for creating a neovagina in a patient with Mayer-Rokitansky-Kuster-Hauser syndrome

Vaginal agenesis is an uncommon, but not rare, condition. Although there are many methods for creating a neovagina, the optimal treatment is unknown. An 18-year-old woman with Mayer-Rokitansky-Küster-Hauser syndrome received vaginoplasty with a modified Wharton procedure using an artificial dermis (atelocollagen sponge). From 10 days after the operation, the patient was administered human recombinant basic fibroblast growth factor (bFGF) spray to accelerate epithelialization on the neovagina. At 50 days after the operation, we confirmed histological squamous epithelialization of the vaginal epithelium. At 12 months after the operation, the neovagina was at least 3.5 cm in width and approximately 8 cm in length. In this case, use of artificial dermis and recombinant bFGF to create a neovagina was an easy, less invasive and useful method.     

Ovarian response to gonadotrophins, optimal method for oocyte retrieval and pregnancy outcome in patients with vaginal agenesis.

The aim of this study is to characterize the ovarian response to stimulation and the optimal method of oocyte retrieval in patients with vaginal agenesis (Mayer- Rokitansky-Küster-Hauser syndrome) in a gestational carrier programme. Twelve patients underwent gonadotrophin stimulation and hormonal monitoring. Forty-nine treatment cycles were initiated; seven cycles were cancelled secondary to poor stimulation. Five patients had undergone surgical neovagina construction; seven patients had utilized vaginal dilators. Oocyte retrieval was achieved in one cycle via transvesical ultrasound, in two cycles via transabdominal ultrasound, in nine cycles via laparoscopy and in 30 cycles via transvaginal ultrasound. Ten pregnancies were achieved which included two clinical pregnancies, two biochemical pregnancies, three singleton births and three sets of twin births. A live birth rate of 45.5% was achieved per patient. Hormonal response to gonadotrophin stimulation in this population was similar to that of patients with normal pelvic anatomy. Pregnancy outcome was comparable to other patients utilizing gestational carriers within the same program (i.e. surgically absent uterus, anatomically non-functioning uterus, etc.). The surgical creation of a neovagina makes transvaginal retrieval technically more difficult than when dealing with a dilator-created vagina, and may require laparoscopy or transabdominal ultrasound for oocyte retrieval.     

Relationships of serum pro-inflammatory cytokines and vascular endothelial growth factor with liver dysfunction in severe ovarian hyperstimulation syndrome

The aims of this study were to determine if differences in serum pro-inflammatory cytokines, vascular endothelial growth factor (VEGF) and clinical pregnancy rate, could be observed in women with severe ovarian hyperstimulation syndrome (OHSS) in those who did and did not have liver dysfunction. Twenty-nine in-vitro fertilization patients with severe OHSS were included. The patients were divided into the normal liver function tests (LFT) group (n = 14) and the abnormal LFT group (n = 15) according to the LFT on day of admission. Periodic measurements of serum interleukin (IL)-6, IL-8, tumour necrosis factor-alpha (TNF-alpha), VEGF, oestradiol, progesterone concentrations, and LFT were performed during hospitalization. Concentrations of IL-6 in the active phase of OHSS were significantly higher in the abnormal LFT group than in the normal LFT group (19.7 +/- 15.7 versus 8.1 +/- 7.0 pg/ml, respectively). The severity of liver dysfunction was not correlated with concentrations of oestradiol, progesterone, haematocrit, white blood cell counts, or any studied cytokine. The clinical pregnancy rate was significantly lower in the abnormal LFT group (46.7%) than in the normal LFT group (85.7%). These results suggest that IL-6 cytokine system may play a role in the pathogenesis of liver dysfunction in severe OHSS. Abnormal LFT were associated with lower clinical pregnancy rates.     

An investigation into FOXE1 polyalanine tract length in premature ovarian failure

Premature ovarian failure (POF) is a common condition affecting 1% of women worldwide. There is strong evidence for genetic involvement in POF as many cases are familial, and mutations in several genes have been associated with POF. We investigated variation in FOXE1 polyalanine tract length, following the observation that polyalanine tract deletions are seen in the closely related FOXL2 in patients with POF. In addition, polyalanine tract expansions in FOXL2 are often seen in patients with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), a rare eyelid disorder often associated with POF. The FOXE1 polyalanine tract shows marked variation in its length between POF patients and normal controls, existing as an allele of 12, 14, 16, 17 or 19 alanine residues. We found evidence to suggest that variation in FOXE1 polyalanine tract length predisposes to POF.     

Oocyte quality and treatment outcome in intracytoplasmic sperm injection cycles of polycystic ovarian syndrome patients

Patients with polycystic ovarian syndrome (PCOS) have higher miscarriage rates. It is postulated that this is caused by a lower rate of mature oocytes, and a lower quality of embryos. Retrospectively we analysed 51 intracytoplasmic sperm injection (ICSI) cycles of 31 PCOS patients. These data were compared to age-matched controls (105 cycles) during the same period. All patients of both groups received gonadotrophin-releasing hormone (GnRH) agonists prior to gonadotrophin treatment. The rate of metaphase II oocytes (MII) was not different. However, the mean absolute number of normally fertilized oocytes was significantly higher in PCOS patients (5.00 versus 3.56, P < 0.01), due to a higher number of oocytes retrieved. More embryos were transferred by cycle in the PCOS group (2.69 versus 2.17, P < 0.05), with a higher cumulative embryo score. The overall and multiple pregnancy rate showed no differences and the clinical abortion rate was lower (21 versus 41.67%, P < 0.05) in the controls. Our findings demonstrate that negative factors unconnected to oocyte morphology must be present in PCOS patients. It is possible that only cytoplasmic, not nuclear, maturity is influenced in these patients.     

Diagnosis and management of the phenotypic spectrum of twins with Beckwith‐Wiedemann syndrome

Beckwith‐Wiedemann syndrome (BWS) is an overgrowth disorder with a heterogeneous phenotypic spectrum. There is an increased prevalence of monozygotic twinning in BWS. Given the epigenetic nature and phenotypic spectrum that defines BWS, twins are often discordant for clinical features, and clinicians are faced with the challenge of diagnosing and managing these twins. We present a cohort of multiple pregnancies in which one or more child from each pregnancy was diagnosed with BWS. We conducted a chart review of monochorionic and dichorionic gestations. Clinical scores for monochorionic twins demonstrated phenotypic discordance between the proband and twin. Based on linear regression analysis, a higher clinical score in the proband correlated with larger phenotypic discordance between twin siblings. Despite phenotypic discordance, however, we observed a consistent additive clinical score for a pregnancy (proband's plus twin's scores from a pregnancy). This idea of a finite degree of affectedness for a pregnancy implies a finite number of epigenetically affected cells. This further corroborates the idea that timing of monozygotic monochorionic twinning correlates with the disruption of establishment and/or maintenance of imprinting. The difference in clinical score between a proband and their twin may be due to diffused mosaicism, whereby there is an asymmetric distribution of affected cells among the multiple fetuses in a monozygotic monochorionic pregnancy, leading to a spectrum of variably affected phenotypes. Based on these findings, we recommend an algorithm for a conservative approach to clinically evaluate all children in a monozygotic multiple gestation affected by BWS.     

Fluctuations in CA 125 and CA 15-3 serum concentrations during spontaneous ovulatory cycles

The aim of this study was to investigate cycle dependent changes of serum CA 125 and CA 15-3 concentrations during spontaneous ovulatory cycles. Twenty apparently healthy women with spontaneous menstrual cycles attending our infertility clinic were included. Of these women, 18 had occluded tubes as a result of sterilization. Ovulation was confirmed by luteinizing hormone test and ultrasonography and, to exclude endometriosis, a laparoscopy was performed. Serum samples for CA 125, CA 15-3, 17 beta-oestradiol and progesterone determinations were taken every second day starting on the 2nd day of the cycle until the 7th day of the next cycle. After correction for inter-individual variation in serum concentrations, highest CA 125 concentrations were found during the menstruation. During the follicular and peri-ovulatory phase CA 125 serum concentrations were lowest. For CA 15-3, serum concentrations were not statistically different throughout the cycle. CA 125 and oestradiol concentrations were negatively correlated, CA 15-3 and oestradiol concentrations were positively correlated. Absolute serum concentrations of both CA 125 and CA 15-3 vary among females. Within the female, fluctuations of CA 125 are phase related. In the population studied most of the patients had tubal obstruction and high CA 125 serum concentrations during menstruation, which revokes the theory that the menstrual rise of CA 125 is due only to retrograde menstruation.     

重症急性胰腺炎合并急性呼吸窘迫综合征的临床分析

目的探讨重症急性胰腺炎（SAP）合并急性呼吸窘迫综合征（ARDS）患者的临床特点和治疗经验。方法回顾分析2004年至2007年诊治的93例SAP及合并ARDS患者的临床特点和预后。结果 SAP合并ARDS患者在入院时的Ranson评分、APACHEⅡ评分、胰腺CT严重度指数、发病72 h时脏器功能障碍数目和未合并ARDS的患者有显著差异（P〈0.01）。SAP患者的死亡率为21.5%（20/93）,其中合并ARDS患者死亡率为35.0%（14/40）;而未合并ARDS患者的死亡率为11.3%（6/53）（P〈0.01）。SAP发病72 h以内发生ARDS的患者的死亡率为55.6%（10/18）,于SAP发病72 h后发生ARDS的患者的死亡率为18.2%（4/22）（P〈0.05）,两者从SAP发病至死亡的时间分别为（7.3±5.0）d和（15.3±8.4）d,有显著性差异（P〈0.05）。合并ARDS的SAP患者在死亡时平均累计有3.5个脏器功能障碍。结论 SAP合并的ARDS发生越早,死亡率越高。密切监测ARDS的高危患者,并在ARDS早期即给予保护性的呼吸机辅助通气,有助于ARDS的救治和降低SAP的死亡率。