Yves Dumez

Pleiotropic Effects of CEP290 (NPHP6) Mutations Extend to Meckel Syndrome

Meckel syndrome (MKS) is a rare autosomal recessive lethal condition characterized by central nervous system malformations, polydactyly, multicystic kidney dysplasia, and ductal changes of the liver. Three loci have been mapped (MKS1-MKS3), and two genes have been identified (MKS1/FLJ20345 and MKS3/TMEM67), whereas the gene at the MKS2 locus remains unknown. To identify new MKS loci, a genomewide linkage scan was performed using 10-cM-resolution microsatellite markers in eight families. The highest heterogeneity LOD score was obtained for chromosome 12, in an interval containing CEP290, a gene recently identified as causative of Joubert syndrome (JS) and isolated Leber congenital amaurosis. In view of our recent findings of allelism, at the MKS3 locus, between these two disorders, CEP290 was considered a candidate, and homozygous or compound heterozygous truncating mutations were identified in four families. Sequencing of additional cases identified CEP290 mutations in two fetuses with MKS and in four families presenting a cerebro-reno-digital syndrome, with a phenotype overlapping MKS and JS, further demonstrating that MKS and JS can be variable expressions of the same ciliopathy. These data identify a fourth locus for MKS (MKS4) and the CEP290 gene as responsible for MKS.

Phenotypic spectrum of CHARGE syndrome in fetuses with CHD7 truncating mutations correlates with expression during human development

Background: The acronym CHARGE refers to a non-random cluster of malformations including coloboma, heart malformation, choanal atresia, retardation of growth and/or development, genital anomalies, and ear anomalies. This set of multiple congenital anomalies is frequent, despite rare patients with normal intelligence, and prognosis remains poor. Recently, CHD7 gene mutations have been identified in CHARGE patients; however, the function of CHD7 during development remains unknown. Methods: We studied a series of 10 antenatal cases in whom the diagnosis of CHARGE syndrome was suspected, considering that a careful pathological description would shed light on the CHD7 function during development. CHD7 sequence analysis and in situ hybridisation were employed. Results: The diagnosis of CHARGE syndrome was confirmed in all 10 fetuses by the identification of a CHD7 heterozygous truncating mutation. Interestingly, arhinencephaly and semi-circular canal agenesis were two constant features which are not included in formal diagnostic criteria so far. In situ hybridisation analysis of the CHD7 gene during early human development emphasised the role of CHD7 in the development of the central nervous system, internal ear, and neural crest of pharyngeal arches, and more generally showed a good correlation between specific CHD7 expression pattern and the developmental anomalies observed in CHARGE syndrome. Conclusions: These results allowed us to further refine the phenotypic spectrum of developmental anomalies resulting from CHD7 dysfunction.

Twin-to-Twin Transfusion Syndrome : Role of the Fetal Renin-Angiotensin System

The twin-to-twin transfusion syndrome (TTS) results from an unbalanced blood supply through placental anastomoses in monochorionic twins. It induces growth restriction, renal tubular dysgenesis, and oliguria in the donor and visceromegaly and polyuria in the recipient. A better understanding of its pathophysiology could contribute to improving the management of TTS, which still carries a high perinatal mortality in both twins. As well as several other candidates, the renin-angiotensin system might be involved in TTS. To evaluate its role in the pathogenesis of the syndrome, we studied the kidneys of 21 twin pairs who died from TTS at 19 to 30 weeks, compared with 39 individuals in a control group, using light microscopy, immunohistochemistry, and in situ hybridization. The overexpression of the renin protein and transcript with frequent evidence of renin synthesis by mesangial cells was observed in the donor kidneys, presumably as a consequence of chronic renal hypoperfusion. This upregulation of renin synthesis might be beneficial to restore euvolemia. In severe cases of TTS, however, angiotensin-II-induced vasoconstriction acts as an additional deleterious factor by further reducing the renal blood flow in donors. In recipients, renin expression was virtually absent, possibly because it was down-regulated by hypervolemia. However, in addition to congestion and hemorrhagic infarction, there were severe glomerular and arterial lesions resembling those observed in polycythemia- or hypertension-induced microangiopathy. We speculate that fetal hypertension in the recipient might be partly mediated by the transfer of circulating renin produced by the donor, through the placental vascular shunts.

Fetal lung volume measurement by magnetic resonance imaging in congenital diaphragmatic hernia

Objective To study the potential for prenatal magnetic resonance imaging to predict pulmonary hypoplasia in congenital diaphragmatic hernia.

Efficacy of second-trimester selective termination for fetal abnormalities: International collaborative experience among the world's largest centers

OBJECTIVE Our goal was to develop the most comprehensive database possible to counsel patients about selective termination for fetal abnormalities, because no one center has sufficient data to assess much more than crude loss rates. STUDY DESIGN A total of 183 completed cases of selective termination from 9 centers in 4 countries were combined (169 twins, 11 triplets, 3 quadruplets). Variables included indications, methods, (potassium chloride, exsanguination, air embolus), gestational age at procedure, pregnancies lost (< or = 24 weeks), gestational age at delivery, and neonatal outcome. RESULTS Indications for selective termination were 96 chromosomal, 76 structural, and 11 mendelian. Selective termination was technically successful in 100% of cases. In 23 of 183 (12.6%) miscarriage occurred before 24 weeks; 2 of 37 (5.4%) occurred when the procedure done at < or = 16 weeks and 21 of 146 (14.4%) when it was done thereafter. Air embolization had a higher loss rate: 10 of 24 (41.7%) compared with 13 of 156 (8.3%) by potassium chloride (chi 2 = 117, p < 0.0001). Three cases of selective termination performed in monochorionic pregnancies all resulted in pregnancy loss. Among 183 potentially viable deliveries, 7 occurred before 28 weeks, 19 at 29 to 32 weeks, 41 at 33 to 36 weeks, and 93 at > or = 37 weeks. Gestational age at delivery was not influenced by the technique used or the indication but was negatively correlated with gestational age at the time of selective termination. No coagulopathy or ischemic damage was observed in survivors. There was no maternal morbidity. CONCLUSIONS (1) Selective termination in experienced hands for a dizygotic abnormal twin is safe and effective when done with potassium chloride. A total of 83.8% of viable deliveries occurred after 33 weeks and only 4.3% at 25 to 28 weeks. (2) Gestational age at the procedure correlated positively with loss rate and inversely with gestational age at delivery; this emphasizes the need for early diagnosis in multifetal pregnancies. (3) Coagulopathy tests are probably unnecessary.

Three‐dimensional ultrasonographic assessment of fetal lung volume as prognostic factor in isolated congenital diaphragmatic hernia

Objective  To evaluate the potential of three‐dimensional ultrasound to predict outcome in congenital diaphragmatic hernia.

Accuracy of fetal lung volume assessed by three-dimensional sonography

To determine the accuracy and precision of prenatal three‐dimensional (3D) ultrasound in estimating fetal lung volume using the rotational multiplanar technique (VOCAL™) by comparing it to postmortem volume measurements.

Pathogenesis of Twin-Twin Transfusion Syndrome: The Renin-Angiotensin System Hypothesis

In spite of active perinatal management, twin-twin transfusion syndrome (TTTS) remains a severe disease with a high risk of neonatal mortality and morbidity. TTTS initially results from an unbalanced blood flow from a donor to a recipient twin. However, its pathogenesis remains unclear, although cardiovascular disturbances and regulation of fetal volemia and diuresis seem central in this syndrome. Previously, we demonstrated that the renin-angiotensin system (RAS) was up-regulated in donor twins as a consequence of hypovolemia, and down-regulated in recipients. This was the first evidence of the implication of the RAS in TTTS. We hypothesize that the RAS plays a key role in the pathogenesis of TTTS. In the donor, RAS up-regulation aggravates oligohydramnios and may increase arterial resistance, which could contribute to placental dysfunction leading to intrauterine growth restriction. In the recipient, paradoxical RAS activation, due to transfer of effectors such as angiotensin II through placental shunts, could explain fetal vascular disturbances and cardiomyopathy. According to our hypothesis, TTTS would appear similar to the classical model of hypertension referred to as ‘2 kidneys-1 clip’ with a donor twin, comparable to the clipped kidney, intoxicating its cotwin, comparable to the normal kidney.

Transabdominal versus transcervical and transvaginal multifetal pregnancy reduction: International collaborative experience of more than one thousand cases * ** *

OBJECTIVES Two major approaches for multifetal pregnancy reduction have been developed over the past several years: transabdominal potassium chloride by injection and pelvic procedures by either transcervical aspiration or transvaginal potassium chloride injection or by an automated spring-loaded puncture device. The purpose of this study was to create the largest database from among the worlds largest centers to assess possible differences in efficacy and complication rates by transabdominal or transcervical or multifetal pregnancy reduction. STUDY DESIGN Data on over 1000 completed pregnancies that underwent multifetal pregnancy reduction by both methods from major centers with among the highest worldwide experience were combined. Transabdominal cases were divided temporally (1986 through 1991 and 1991 through 1993). RESULTS Transabdominal multifetal pregnancy reduction was successfully performed on 846 patients and transcervical or transvaginal on 238 patients. Transcervical or transvaginal reduction is performed earlier and starts and finishes with fewer embryos. In 12.6% of cases transcervical or transvaginal reduction left a singleton as opposed to 4.4% for transabdominal reduction. Pregnancy losses (up to 24 weeks) were observed in 13.1% of transcervical or transvaginal cases and in 16.2% of transabdominal cases early in the series and 8.8% of late transabdominal cases. Transcervical or transvaginal reduction may be safer very early in gestation and transabdominal safer later in the first trimester. Premature deliveries were comparable, with only about 5% delivered between 25 and 28 weeks. The smaller starting numbers for transcervical and transvaginal reduction may explain a slightly higher term delivery rate. The transabdominal route tends to reduce the fundal embryos and the transcervical and transvaginal the lower ones. The significance of this is not clear. CONCLUSIONS (1) Multifetal pregnancy reduction by either method is a relatively safe and efficient method for improving outcome in multifetal pregnancies. (2) More than 84% are delivered at > 33 weeks. (3) The experience and preference of the operator are probably the key determinants for an individual patient. (4) An inverse relationship of starting and finishing number to loss rates and gestational age at delivery suggests that there still is a cost of iatrogenic multifetal pregnancies, even if multifetal pregnancy reduction can be successfully performed.

Congenital adenomatoid malformation of the lung: When is active fetal therapy indicated?☆☆☆★

OBJECTIVE Although aggressive fetal therapies such as thoracoamniotic shunting can be applied to cystic adenomatoid malformations of the lung diagnosed in utero, there is no clear consensus regarding their indications. Our purpose was to evaluate a management policy in which aggressive fetal therapy was restricted to those cases complicated by major polyhydramnios or hydrops; all other cases were managed conservatively. STUDY DESIGN A prospective cohort study of 33 cases with a prenatal diagnosis of cystic adenomatoid malformations of the lung was performed. Thoracoamniotic shunting was offered only in nine macrocystic cases with acute polyhydramnios or hydrops. RESULTS Four cases were diagnosed postnatally as sequestrations. Of 12 cases complicated by acute polyhydramnios or hydrops, 5 survived (1 type III with spontaneous incomplete resolution in utero, 4 type I with substantial volume reduction after shunting). The 17 cases without acute polyhydramnios or hydrops were managed conservatively and survived. CONCLUSION Conservative management is indicated in cases of cystic adenomatoid malformations of the lung without acute polyhydramnios or hydrops.