Genotype-phenotype correlations in fetuses and neonates with autosomal recessive polycystic kidney disease.

The prognosis of autosomal recessive polycystic kidney disease is known to correlate with genotype. The presence of two truncating mutations in the PKHD1 gene encoding the fibrocystin protein is associated with neonatal death while patients who survive have at least one missense mutation. To determine relationships between genotype and renal and hepatic abnormalities we correlated the severity of renal and hepatic histological lesions to the type of PKHD1 mutations in 54 fetuses (medical pregnancy termination) and 20 neonates who died shortly after birth. Within this cohort, 55.5% of the mutations truncated fibrocystin. The severity of cortical collecting duct dilatations, cortical tubule and glomerular lesions, and renal cortical and hepatic portal fibrosis increased with gestational age. Severe genotypes, defined by two truncating mutations, were more frequent in patients of less than 30 weeks gestation compared to older fetuses and neonates. When adjusted to gestational age, the extension of collecting duct dilatation into the cortex and cortical tubule lesions, but not portal fibrosis, was more prevalent in patients with severe than in those with a non-severe genotype. Our results show the presence of two truncating mutations of the PKHD1 gene is associated with the most severe renal forms of prenatally detected autosomal recessive polycystic kidney disease. Their absence, however, does not guarantee survival to the neonatal period.

Contribution of diffusion-weighted imaging in the evaluation of diffuse white matter ischemic lesions in fetuses: correlations with fetopathologic findings.

BACKGROUND AND PURPOSE: The sensitivity of fetal MR imaging is poor with regard to the evaluation of diffuse ischemic white matter (WM) abnormalities. Our purpose was to evaluate the contribution of diffusion-weighted imaging (DWI) in the analysis of microstructural changes in WM and to correlate neuroimaging with neurofetopathologic findings. MATERIALS AND METHODS: We included fetuses with MR imaging, DWI, and a fetopathologic examination. In a region of interest defined by MR imaging, where T1 and T2 intensities were abnormal, the apparent diffusion coefficient (ADC) was measured and immunohistochemical analysis was performed. In fetuses with no WM abnormality in signal intensity, region of interest was defined at random. Histologic reading was performed with a complete blinding of the MR imaging results and ADC values. Three degrees of histologic appearance were defined with regard to vasogenic edema, astrogliosis, microgliosis, neuronal and oligodendrocytic abnormalities, and proliferation or congestion of vessels and were compared with a chi(2) test in groups A (normal ADC) and B (increased ADC) fetuses. RESULTS: We included 12 fetuses in group A and 9 in group B, ranging from 29 to 38 weeks of gestation. All group B fetuses and 1 group A fetus demonstrated WM abnormalities in signal intensity. WM edema and astrogliosis were more common in group B than in group A (7/9 vs 2/12 and 8/9 vs 4/12, respectively). No significant difference was observed between both groups with regard to the other parameters. CONCLUSION: This study showed a strong correlation between increased ADCs and 1) WM abnormalities in signal intensity on MR imaging, and 2) vasogenic edema with astrogliosis of the cerebral parenchyma.

Molecular heterogeneity in fetal forms of type II lissencephaly.

Type II lissencephaly (type II LIS) is a group of autosomal recessive congenital muscular dystrophies (CMD) associated with defects in alpha-DG O-glycosylation, which comprises Walker-Warburg syndrome, Fukuyama cerebral and muscular dystrophy, or muscle-eye-brain disease. The most severe forms of these diseases often have a fetal presentation and lead to a pregnancy termination. We report here the first molecular study on fetal type II LIS in a series of 47 fetuses from 41 unrelated families. Sequencing of the different genes known to be involved in alpha-DG O-glycosylation allowed the molecular diagnosis in 22 families: involvement of POMT1 was demonstrated in 32% of cases, whereas POMGNT1 and POMT2 were incriminated in 15% and in 7% of cases, respectively. We found 30 different mutations in these three genes, 25 were described herein for the first time, 15 in POMT1, and five in POMT2 and POMGNT1. Despite sequencing of FKRP, FCMD, and LARGE, no definitive molecular diagnosis could be made for the other half of our cases. Preliminary results concerning genotype-phenotype correlations show that the choice of the first gene sequenced should depend on the clinical severity of the type II LIS; POMT1 and POMT2 for severest clinical picture and POMGNT1 for milder disease. The other genes, FKRP, FCMD, and LARGE, seem not to be implicated in the fetal form of CMD.

Fetal type IV glycogen storage disease: clinical, enzymatic, and genetic data of a pure muscular form with variable and early antenatal manifestations in the same family.

We report on a family of three consecutive fetuses affected by type IV glycogen storage disease (GSD IV). In all cases, cervical cystic hygroma was observed on the 12-week-ultrasound examination. During the second trimester, fetal hydrops developed in the first pregnancy whereas fetal akinesia appeared in the second pregnancy. The diagnosis was suggested by microscopic examination of fetal tissues showing characteristic inclusions exclusively in striated fibers, then confirmed by enzymatic studies on frozen muscle. Antenatal diagnosis was performed on the third and fourth pregnancies: cervical cystic hygroma and low glycogen branching enzyme (GBE) activity on chorionic villi sample (CVS) were detected in the third pregnancy whereas ultrasound findings were normal and GBE activity within normal range on CVS in the fourth pregnancy. Molecular analysis showed that the mother was heterozygous for a c.1471G > C mutation in exon 12, leading to the replacement of an alanine by a tyrosine at codon 491 (p.A491T); the father was heterozygous for a c.895G > T mutation in exon 7, leading to the creation of a stop codon at position 299 (p.G299X). GSD IV has to be considered in a context of cervical cystic hygroma with normal karyotype, particularly when second trimester hydrops or akinesia develop. Enzymatic analysis of GBE must be performed on CVS or amniotic cells to confirm the diagnosis. Characteristic intracellular inclusions are specific to the disease and should be recognized, even in macerated tissues after fetal death. Genetic analysis of the GBE gene may help to shed some light on the puzzling diversity of GSD IV phenotypes.

[Ductus venosus agenesis]. / Agénésie du canal d'Arantius.

OBJECTIVE: Congenital absence of the ductus venosus is a rare anomaly in the fetus. The aim of our study was to evaluate the clinical and ultrasonographic features and outcome of the fetuses with ductus venosus agenesis. STUDY DESIGN: We describe 12 cases in the period between 1992 and 2004. The umbilical vein drained either into the right atrium directly (2 cases) or by the coronary sinus (1 case), or in the inferior vena cava (5 cases), or in the azygos vein (1 case), or in the portal vein (3 cases). Our data where analyzed with the cases published in the literature. Two groups of anastomoses where defined on the basis of the hemodynamic consequences: the group of extrahepatic anastomoses (53 cases) and the group of intrahepatic anastomoses (22 cases). RESULTS: In the group of extra hepatic anastomoses, cardiomegaly was the most common antenatal finding (39%), while in the intra hepatic group hydrops fetalis occurred most frequently (23%). Malformation rate was high in both groups (56% and 45%) and chromosomal anomalies where present in 9% of cases. CONCLUSION: Careful assessment of the umbilical venous return and the ductus venosus should be a part of examination of every fetus with cardiomegaly, polyhydramnios, ascites or hydrops. In case of absence of the ductus venosus a referral scan, a fetal echocardiography and a karyotype should be performed.

Prenatal diagnosis of a cystic type IV sacrococcygeal teratoma mimicking a cloacal anomaly: contribution of MR.

OBJECTIVE: To report a case of pelvic midline cystic mass in a female fetus without visibility of the rectum and which is not a cloacal anomaly. METHODS: Ultrasound (US) and magnetic resonance imaging (MRI) were performed respectively at 27 and 27.5 weeks' gestation and the findings of these examinations were compared with post-mortem examination after termination of pregnancy (TOP). RESULTS: US showed a pelvic midline cystic mass in a female fetus with mild enlargement of the left ureter and renal pelvis. MRI did not show the T1 hypersignal of meconium in the rectum. The analysis of MR findings were suggestive of the diagnosis of a sacrococcygeal teratoma. Pregnancy was terminated because of the possibility of severe sphincterial disorders and the fetopathological examination confirmed this diagnosis. CONCLUSION: This observation illustrates the diagnostic problems generated by the detection of a pelvic midline cystic mass in a female fetus. The absence of visibility of the T1 hypersignal of the meconium in the rectum is traditionally supposed to be highly suggestive of a cloaca, but may also be explained by the emptiness of the rectum, compressed by the mass.

Prenatal rupture of a left ventricular diverticulum: a case report and review of the literature.

Congenital left ventricular diverticulum is a rare malformation. We report a case of a ruptured congenital left ventricular diverticulum in a 24-week-old fetus. The fetus was referred for a large and circumferential pericardial effusion confirmed by cross-sectional echocardiography in our tertiary fetal cardiology unit. Pericardiocentesis removed 25 mL of old hematic fluid. The fetus died 5 days later. The pathological examination showed a ruptured submitral fibrous diverticulum of the posterior wall of the left ventricle. There is no previous report in the literature of prenatal rupture of a cardiac diverticulum. The submitral location and the fibrous wall of the diverticulum is uncommon. As regards this case, we reviewed the diagnostic criteria and the outcome of 11 cases of prenatal cardiac diverticulum reported in the literature.

Perinatal-lethal Gaucher disease.

Gaucher disease is a lysosomal storage disease caused by glucocerebrosidase deficiency. Although purely visceral in most cases, some Gaucher disease patients have neurological signs. Signs of Gaucher disease appear after a symptom-free period, except in rare cases with fetal onset. The description of such cases was based mainly on single reports and siblings. We report here a series of perinatal-lethal Gaucher disease cases highlighting the specificity of this phenotype. We retrospectively studied eight original cases of proven Gaucher disease with fetal onset. Non-immune hydrops fetalis was present in all cases but one, and associated with hepatosplenomegaly, ichthyosis, arthrogryposis, and facial dysmorphy. The similarities between our cases and 33 previously described cases allow us to better delineate the perinatal-lethal Gaucher disease phenotype. Hydrops fetalis, in utero fetal death and neonatal distress are prominent features. When hydrops is absent, neurological involvement begins in the first week and leads to death within three months. Hepatosplenomegaly is a major sign, and associated with ichthyosis, arthrogryposis, and facial dysmorphy in some 35-43% of cases. Perinatal-lethal Gaucher disease is a specific entity defined by its particular course and signs that are absent in classical type 2 Gaucher disease. Our study provides clues to the diagnosis of this likely underdiagnosed condition, which must be biochemically confirmed in order to propose appropriate genetic counselling.

Standards for dysmorphological diagnosis in human fetuses.

This study provides new standards for some fetal dimensions frequently concerned with dysmorphological syndromes. Seven dimensions were included: the outer and inner canthal distances (OCD and ICD), the anteroposterior and transversal ocular diameters, the biparietal diameter and head circumference, and the inter-nipple distance. Subjects came from a large data set including more than 4000 fetuses autopsied in fetopathology units of pediatric hospitals in Paris between 1986 and 2001. From this data set, 673 subjects were carefully selected by exclusion of multiple pregnancies, macerated and malformed fetuses, and subjects with abnormal karyotypes and severe infections. Fetal ages ranged from 11 to 42 gestational wk, with a very large sample of fetuses in the first half of gestation. The standards of each dimension were computed in relation to age, as well as the ratio ICD/OCD. The mathematical models used to fit the percentile growth curves were carefully selected for each variable. This study supplies a set of accurate standards of specific dimensions useful for dysmorphological diagnosis in fetuses.

[Acardiac twins]. / Les jumeaux acardiaques.

An acardiac twin in a multiple pregnancy initially develops normally and is a specific complication of monozygous multiple pregnancies. Development results from arterio-arterial and veno-venous anastomoses leading to predominance of one of the twins. The haemodynamic abnormalities in the dominated twin lead to the disappearance of the heart and major morphologic malformations. Outcome is generally unfavourable in 50% of the pregnancies with an acardiac twin. Complications in the healthy twin include heart failure, then hydramnios, and finally premature delivery which is the cause of most of the deaths. Proposed treatment currently relies on treating the heart failure in the healthy twin or interrupting vascularization between the two twins leading to in utero death of the acardiac twin. Antenatal diagnosis is made by echography and is useful for evaluating the prognosis for the pregnancy according to the growth of the acardiac twin.

[Malformed tumoral hemangioma of the mediastinum. Apropos of 10 cases]. / Les hémangiomes tumoraux malformatifs du médiastin. A propos de dix observations

The malformed tumoral hemangioma of the mediastinum is highly specific tumoral entity, which must be distinguished from other varieties of hemangioma -- tumors arising in young subjects above all, and frequently large tumors of the mediastinum, whose radiological discovery leads to the most disturbing suppositions. It is however a benign tumor, most frequently surgically curable. Il is not so rare as it is said to be, at least in the child: it can be evoked in certain cases and even characterized sometimes. It is always better to avoid operative surprises in this connection, in this surgery of the mediastinum.