Twin-twin transfusion syndrome recipient with arterial calcification and heterozygous variant in ABCC6: Evidence of a gene-environment interaction?

We report a case of a twin-twin transfusion syndrome (TTTS) recipient who, after successful fetoscopic surgery, developed a large pericardial effusion and calcifications of the aorta and main pulmonary artery. The donor fetus never had cardiac strain and never developed cardiac calcifications. A heterozygous likely pathogenic variant in ABCC6 (c.2018T > C, p.Leu673Pro) was identified in the recipient twin. While TTTS recipient twins are at risk of arterial calcifications and right heart failure secondary to the disease, calcifications of the great vessels are also observed in generalized arterial calcification of infancy, a Mendelian genetic disorder with associated biallelic pathogenic variations in ABCC6 or ENPP1, which can result in significant pediatric morbidity or mortality. The recipient twin in this case had some degree of cardiac strain prior to TTTS surgery; however, the progressive calcification of the aorta and pulmonary trunk occurred weeks after TTTS resolution. This case raises the possibility of a gene-environment interaction and emphasizes the need for genetic evaluation in the setting of TTTS and calcifications.     

Insights into the pathophysiology of twin–twin transfusion syndrome

Twin–twin transfusion syndrome (TTTS) is attributed to trans-anastomotic transfusion between twins. Anastomoses are ubiquitous in monochorionic (MC) placentae, yet TTTS develops in only 15%. Although ex vivo and in vivo studies fail to identify a unique anastomotic signature, TTTS placentae are typically associated with an imbalance in unidirectional arteriovenous anastomoses with absent bidirectional anastomoses. Doppler detection of an artery-artery anastomosis reduces the chance of TTTS, whereas, in those that develop the disease, it improves stage-independent survival. Selective laser is often curative, but an increasingly recognized risk of persistent or reverse TTTS may be attributable to atypical arteriovenous anastomoses not identifiable from the chorionic plate. Simple dysvolaemia fails to explain several phenotypic features, including haematological concordancy, recipient hypertension, and reversibly absent end diastolic flow in the donor. The renin-angiotensin system is upregulated in the donor and downregulated in the recipient's kidneys, while paradoxically raised renin levels in the recipient may contribute to raised afterload along with endothelin. Although research is limited in humans by therapy and the lack of a suitable experimental model, further studies of placental and vascular pathophysiology may not only refine current treatment modalities but may also, in addition, suggest further avenues for downstream management such as genetic predisposition testing or pharmacological intervention. Copyright © 2005 John Wiley & Sons, Ltd.     

Pulmonary stenosis and reactive right ventricular hypertrophy in the recipient fetus as a consequence of twin-to-twin transfusion

The present study describes an association between adverse outcome in the twin-to-twin transfusion syndrome (TTTS) and pulmonary stenosis or reactive right ventricular hypertrophy. Six discordant monozygotic twin pregnancies with TTTS are described. Ventricular hypertrophy and atrioventricular valvular regurgitation occurred in all the recipient twins with pulmonary valvular stenosis in three cases and infundibular stenosis in one case. The recipient twin in one pair and both twins in another pregnancy died as a consequence of immaturity but the remaining twins all survived. Surgical intervention was required in one baby for valvular pulmonary stenosis. Our observations suggest that elevated blood pressure in the transfusion recipient may play an important role in pathogenesis. We hypothesise that both pulmonary stenosis and right chamber hypertrophy are secondary to hemodynamic changes. Although we have found valvular pulmonary stenosis in three recipients and infundibular stenosis in only one, this (obstruction to outflow) could be due to right chamber hypertrophy. Copyright © 2001 John Wiley & Sons, Ltd.     

Long-term outcome after intrauterine laser treatment for twin–twin transfusion syndrome

Twin–twin transfusion syndrome (TTTS) is a severe complication occurring in about 10% of monochorionic twin pregnancies. The chronic unbalanced transfusion of blood across placental vascular communications from the donor to the recipient twin may lead to impairment of various organ systems in the affected twins. In Hamburg, Germany, since 1995 patients with TTTS were treated with fetoscopic laser coagulation as the first causal therapeutic strategy. All survivors after laser surgery were followed up in the University Children's Hospital in Bonn, Germany. In this article, we summarize long-term follow-up studies from our German study population and compare our results with data from the literature. Copyright © 2011 John Wiley & Sons, Ltd.     

Twin–twin transfusion syndrome: mathematical modelling

Twin–twin transfusion syndrome (TTTS) represents a pregnancy complication with a high risk for perinatal mortality and postnatal morbidity. Mathematical models have been utilized to examine the mechanisms of disease and potential treatment modalities. We developed four consecutive models based on pathophysiology mechanisms. Conceptually, these models remained simple, but with increased complexity in details. We present our models tutorially with the necessary equations expressed in words. The aetiology of TTTS was related to AV anastomoses from donor to recipient and their growth commensurate with placental growth. We assessed that natural growth of placenta and foetuses causes the diameter and length of the AV, as well as the AV's pressure gradient, to increase proportional to gestational age. The AV transfusion then increases faster than natural foetal growth. A progressively increasing discordance subsequently develops, not compensated for by foetal growth. A simulation is performed to show how this discordance in blood volumetric development causes successive discordances in other functions, particularly renal, circulatory, and cardio-vascular, resulting in disease progression to the various stages of TTTS. In conclusion, mathematical modelling of TTTS has provided an understanding of the sequence of events that leads to the various presentations of TTTS stages as well as the efficacy of therapies. Copyright © 2008 John Wiley & Sons, Ltd.     

Recurrent congenital toxoplasmosis in a woman with lupus erythematosus

We describe the case of a patient with systemic lupus erythematosus, treated by corticosteroids, who presented during two successive pregnancies with serological reactivation of toxoplasmosis associated with fetal lesions. The first infected fetus died in utero with signs of hydrops. The second fetus was treated in utero with a combination of sulfadoxine and pyrimethamine, administered to the mother, and is now well. The increasing number of immunocompromised pregnant patients with immunity to Toxoplasma gondii may lead to a higher risk of reactivation of maternal toxoplasmosis and congenital infection.     

Fetal bradycardia in the first trimester: an unusual presentation of atrial extrasystoles

We report a fetus with fetal bradycardia at 13 weeks of gestation secondary to atrial extrasystoles. The fetus subsequently developed paroxysmal supraventricular tachycardia and hydrops fetalis. The cardiac arrhythmia recovered spontaneously without any medical intervention. This case illustrates that atrial ectopic beats can present in the first trimester with fetal bradycardia. Rapidly evolving hydrops fetalis secondary to supraventricular tachycardia can develop, warranting close monitoring with weekly heart rate assessment. Fetal bradycardia secondary to atrial extrasystole should be differentiated from first trimester sinus bradycardia and those associated with major structural cardiac abnormality, which have a high fetal loss rate. Copyright © 2002 John Wiley & Sons, Ltd.     

Perioperative fetal hemodynamic changes in twin-twin transfusion syndrome and neurodevelopmental outcome at two years of age

Objective

To investigate whether perioperative fetal hemodynamic changes in twin-to-twin transfusion syndrome (TTTS) are associated with neurodevelopmental impairment (NDI) at two years.

Methods

Doppler parameters of three sonograms (day before, first day after and 1 week after laser surgery for TTTS) were assessed for correlation with neurodevelopmental outcome at two years (2008-2016). NDI was defined as: cerebral palsy, deafness, blindness, and/or a Bayley-III cognitive/motor developmental test-score > 2SD below the mean.

Results

Long-term outcome was assessed in 492 TTTS survivors. NDI was present in 5% (24/492). After adjustment for severe cerebral injury (present in 4%), associated with NDI were: middle cerebral artery peak systolic velocity (MCA-PSV) >1.5 multiples of the median (MoM) 1 day after surgery (odds ratio [OR] 4.96; 95% confidence interval [CI]: 1.17-21.05, P = .03), a change from normal umbilical artery pulsatility index (UA-PI) presurgery to UA-PI >p95 postsurgery (OR 4.19; 95% CI: 1.04-16.87, P = .04), a change from normal to MCA-PSV >1.5MoM (OR 4.75; 95% CI: 1.43-15.77, P = .01).

Conclusion

Perioperative fetal hemodynamic changes in TTTS pregnancies treated with laser are associated with poor neurodevelopmental outcome. Prospective research on the cerebrovascular response to altered hemodynamic conditions is necessary to further understand the cerebral autoregulatory capacity of the fetus in relation to neurodevelopmental outcome.     

Prenatally diagnosed non-immune hydrops caused by congenital transient leukaemia

Congenital transient leukaemia (CTL) is a haematological disorder characterized by proliferation of myeloblasts within the bone marrow and peripheral blood of affected newborns. Infants with Down syndrome are most frequently affected and although the disorder can result in fetal death due to hydrops, it typically resolves spontaneously after birth. We present a case of prenatally diagnosed fetal hydrops accompanied by splenomegaly and an enlarged, echogenic liver in a fetus identified with CTL after birth.     

Hydrops fetalis and neonatal death from human parvovirus B19: an unusual complication

A case of prenatally diagnosed human parvovirus B19 (HPVB19) infection is reported. The neonate died after intrauterine therapy and premature delivery. The fetus was diagnosed with oedema, cardiomegaly, poor myocardial contractility and a pericardial effusion at 24/40 weeks' gestation. Ultrasound using colour flow Doppler showed a midcerebral artery peak systolic velocity (MCA PSV) raised at 45 cm/s, suggesting fetal anaemia. This was confirmed on fetal blood sampling, but recovery was suggested with a reticulocyte count of 16.8%. The fetal karyotype was normal, 46,XY. Fetal IgM was positive for Parvovirus. A week later, severe fetal anaemia was suspected and intrauterine transfusion carried out. Altogether three transfusions were given. At 31/40 weeks, the mother presented to her local hospital with suspected preterm labour, a caesarean section was carried out because of fetal compromise on cardiotocography. The baby was in poor condition at birth and resuscitation was stopped at 45 min of age. The post-mortem examination confirmed the hydrops and proved persistent Parvovirus infection, cardiac involvement and severe liver fibrosis. HPVB19 generally follows a benign course with intrauterine therapy; however, in this case, the fetus died despite successful transfusions. The reasons for this are discussed. Copyright © 2005 John Wiley & Sons, Ltd.     

Fetal hydrops caused by a novel pathogenic MECOM variant

We report a fetus with hydrops, congenital heart disease and bilateral radioulnar synostosis caused by a novel pathogenic MECOM variant. The female fetus was referred for post-mortem examination after fetal hydrops and intrauterine death was diagnosed at 20 weeks gestation. Post-mortem examination confirmed fetal hydrops, pallor, truncus arteriosus and bilateral radioulnar synostosis. Trio whole genome sequencing analysis detected a novel de novo heterozygous pathogenic loss-of-function variant in MECOM (NM_004991), associated with a diagnosis of Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia 2 (RUSAT-2). RUSAT-2 is a variable condition associated postnatally with bone marrow failure, radioulnar synostosis and congenital anomalies. RUSAT-2 is not currently associated with a prenatal phenotype or fetal demise, and was not present on diagnostic NHS prenatal gene panels at time of diagnosis. This case highlights the diagnostic value of detailed phenotyping with post-mortem examination, and of using a broad sequencing approach.     

Likely pathogenic variant in the BICD2 gene in fetus presenting with non-immune hydrops

Trio exome sequencing was performed on a fetus presenting with severe hydrops fetalis at 21 + 0 weeks gestation. A novel de novo BICD2 missense variant was identified in the fetus. Pathogenic variants in the BICD2 gene are associated with lower extremity-predominant spinal muscular atrophy. The variant was initially classified as a variant of uncertain clinical significance (VUS) as at the time of analysis and initial report, pathogenic variants in the BICD2 gene specifically had not been associated with fetal hydrops and no other abnormalities had been detected. It was agreed in multidisciplinary team discussions to include the variant in the report as a VUS recommending phenotypic follow-up. The pregnancy was terminated and post-mortem findings were in keeping with a BICD2-pathogenic variant. In addition, a paper was published reporting another case with a pathogenic BICD2 variant presenting with fetal hydrops. The variant classification was then upgraded to class 4 likely pathogenic and reported as consistent with the diagnosis. This case demonstrates the importance of reporting these new gene/phenotypes in enabling others in the classification of variants, staying up-to-date with literature and following up phenotype for class 3 variants of interest.     

Non-immunological hydrops fetalis and intrapericardial teratoma: Case report and review

A large intrapericardial teratoma was found at necropsy in a 38−week stillborn fetus, in which prenatal diagnosis of hydrops fetalis and an ehogenic cardiac mass had been made. Clinical and pathological data are reported. In utero intrapericardial teratomata lead to different outcomes depending on whether fetal hydrops is associated. When generalized fetal hydrops is not present, the outcome is good, even in cases with large pericardial effusions. When generalized fetal hydrops occurs, it often results in a poor outcome. In our literature review, we have found eight perinatal deaths in nine similar cases reported.     

Prenatal Diagnosis of congenital disorder of glycosylation type Ia (CDG-Ia) by cordocentesis and transferrin isoelectric focussing of serum of a 27-week fetus with non-immune hydrops

Blood was obtained by cordocentesis from a fetus with non-immune hydrops demonstrated by ultrasound scanning at 27 weeks' gestation. Abnormalities of serum transferrin isoelectric focussing (IEF) were identified, characteristic of a congenital disorder of glycosylation type I (CDG-Ia). A diagnosis of CDG-Ia was confirmed by enzyme analysis of cultured amniocytes. This is the first report of CDG-Ia diagnosed by serum analysis in a fetus. Previous reports have warned that diagnostic abnormalities do not appear in serum until several weeks after birth. The sensitivity of cordocentesis transferrin IEF is unknown but is less than 100% effective because cases have been diagnosed postnatally after normal prenatal or neonatal studies. Enzyme analysis or mutation analysis is required for diagnosis of congenital disorder of glycosylation (CDGs) regardless of whether a diagnostic transferrin pattern is identified prenatally. The analysis of a small sample of serum, from cordocentesis, performed to check for fetal anemia, simplified the investigation, diagnosis, and genetic counselling of a case of non-immune hydrops detected at 27 weeks' gestation. This might be a useful test for other cases in these circumstances, as fetal blood is usually collected to check for anemia. Copyright © 2006 John Wiley & Sons, Ltd.     

Prenatal treatment of fetal hydrops associated with the hypertelorism-dysphagia syndrome (opitz-g syndrome)

Non-immunological fetal hydrops diagnosed prenatally presents a difficult diagnostic and therapeutic problem. In the case presented, fetal hydrops was recognized at 19 weeks gestation and no specific cause was found prenatally in spite of extensive investigations. The fetal hydrops was treated in utero by thoracocentesis and an intravenous infusion of albumin carried out at fetoscopy. After birth the infant was recognized to have the hypertelorismdysphagia syndrome (or Opitz-G syndrome, McK no. 30710). This autosomal dominant syndrome consists of hypertelorism, laryngeal abnormalities, swallowing difficulties, hyprospadias and an imperforate anus. Fetal hydrops has been reported on one previous occasion in this syndrome. The intrauterine treatment given in this case may have been successful in reducing the neonatal complications of the Opitz-G syndrome.     

The value of echocardiography and Doppler in the prediction of fetal demise after laser coagulation for TTTS: A systematic review and meta-analysis

This study aimed to investigate the value of echocardiography and Doppler before fetoscopic laser coagulation for twin-twin transfusion syndrome (TTTS) in the prediction of intrauterine fetal demise (IUFD). We performed a systematic review and meta-analysis to compare preoperative parameters between fetuses with and without demise after laser surgery. Eighteen studies were included. Recipient twins have an increased risk of demise in case of preoperative absent/reversed flow (A/REDF) in the umbilical artery (odds ratio [OR] 2.76, 95% confidence interval [CI], 1.78-4.28), absent or reversed a-wave in the ductus venosus (OR 2.32, 95% CI, 1.70-3.16), or a middle cerebral artery peak systolic velocity > 1.5 multiples of the median (MoM) (OR 7.59, 95% CI, 2.56-22.46). In donors, only A/REDF in the umbilical artery (OR 3.40, 95% CI, 2.68-4.32) and absent or reversed a-wave in the ductus venosus (OR 1.66, 95% CI, 1.12-2.47) were associated with IUFD. No association was found between donor-IUFD and preoperative myocardial performance index (MPI). Two studies found an association between abnormal MPI and recipient demise. With this study, we have identified a set of preoperative Doppler parameters predictive of fetal demise after laser surgery. More research is needed to assess the utility of preoperative echocardiographic parameters such as the MPI in predicting IUFD.     

Twin–twin transfusion syndrome—possible roles for doppler ultrasound and amniocentesis

A 29-year-old woman was referred for suspicion of twin-twin transfusion syndrome (TTTS). Several ultrasonographic and neonatal criteria of TTTS were encountered in this twin pregnancy. The peculiar observations in this case were, firstly, the demonstration of superficial anastomosis by Doppler ultrasound and, secondly, that one single therapeutic amniocentesis could have been sufficient to partially correct the progression of the syndrome, as after amniocentesis it was no longer possible to demonstrate the vascular communication. This observation suggests that superficial anastomoses could also have a role in the genesis of TTTS. Their effect could be monitored by Doppler ultrasound and could be more easily corrected by therapeutic amniocentesis.     

Ultrasound demonstration of masses in a 15 week fetus: Hydrops in a fetus with umbilical cord occlusion

A fetal abnormality detected at 15 weeks by ultrasound consisted of cystic appearing masses in the neck and back region. The differential diagnosis included gonadal dysgenesis (Turner's syndrome) with cystic hygroma, neural tube defect, e.g. encephalocele or meningomyelocele, and fetal hydrops. Intrauterine fetal demise occurred at 17 weeks. The fetus had marked edema possibly related to umbilical cord occlusion.     

Spontaneous cessation of umbilical blood flow in the acardiac fetus of a twin pregnancy

The acardiac fetus is a rare entity found only in monozygotic multiple pregnancy. Although the acardiac fetus is non-viable, the perinatal mortality rate for the normal fetus may be as high as 50 per cent, and is usually associated with fetal heart failure and hydrops fetalis, or as the result of prematurity. In this communication, we describe a case of spontaneous cessation of blood flow to an acardiac fetus and discuss the management of this condition with special reference to optimizing the outcome for the normal fetus.     

Prenatal diagnosis of the pterygium syndrome

We report two second trimester pregnancy terminations in the same woman following intrauterine ultrasonic findings of hydrops fetalis, polyhydramnios, lack of fetal movements, and short, fixed malformed limbs. One fetus also showed a cystic mass at the back of the head. Radiographic and anatomic studies of the fetuses demonstrated multiple pterygia, flexion contracture of multiple joints, abnormal facial appearance, cleft palate, pulmonary hypoplasia, and gracile bones. The cystic mass of the back of the head was found to be a cystic hygroma. These findings are consistent with the lethal variant of multiple pterygium syndrome. Early prenatal diagnosis of this condition is possible using ultrasonography.