Limits of the surgically induced model of myelomeningocele in the fetal sheep.

PURPOSE: The prevention of Chiari type II malformation (CM) is commonly used as a primary outcome for the evaluation of techniques of fetal myelomeningocele (MMC) surgery in the fetal lamb. The aim of our study was to investigate the frequency of the associated CM in the MMC fetal sheep model and to investigate the contribution of prenatal ultrasound evaluation of CM at the time of prenatal repair. METHODS: A MMC-like lesion was surgically created at 75 days of gestation in 21 fetuses performing a L1-L5 laminectomy followed by an excision of the exposed dura and a midline myelotomy. At a 90-day gestation, among the 19 alived fetuses, a conventional repair of the MMC-like lesion was performed in seven, four of whom underwent cerebral ultrasound (US) examination before the repair. Twelve fetuses remained untreated (control group). All fetuses underwent post-mortem examination (PM) at 138 days. RESULTS: At a 90-day gestation, CM was demonstrated by US examination in all four evaluated fetuses. At birth, CM was found in 3/6 control whether CM was absent in all alived fetuses in the prenatal repair group (n = 4). CONCLUSIONS: Creation of a MMC-like lesion with an additional myelotomy does not always lead to hindbrain herniation. Our study suggests that CM should be assessed by ultrasound examination at the time of the prenatal repair to demonstrate the effectiveness of new techniques for the prenatal repair of MMC.

Prenatal abnormal features of the fourth ventricle in Joubert syndrome and related disorders.

Joubert syndrome and related disorders (JSRD) are characterized by absence or underdevelopment of the cerebellar vermis and a malformed brainstem. This family of disorders is a member of an emerging class of diseases called ciliopathies. We describe the abnormal features of the brain, particularly the fourth ventricle, in seven fetuses affected by JSRD. In three cases abnormality of the fourth ventricle was isolated and in four cases there were associated malformations. The molar tooth sign (MTS) was always present and visible on two-dimensional ultrasound and, when performed, on three-dimensional ultrasound and magnetic resonance imaging. The fourth ventricle was always abnormal, in both axial and sagittal views, presenting pathognomonic deformities. It is important to identify JSRD, preferably prenatally or at least postnatally, due to its high risk of recurrence of about 25%. A detailed prenatal assessment of the fourth ventricle in several views may help to achieve this goal.

[Prenatal repair of myelomeningocele: State of the art]. / Thérapie in utero des myéloméningocèles : où en sommes-nous ?

Myelomeningocele is characterized by the extrusion of the spinal cord into a sac filled with cerebrospinal fluid. One part of the postnatal disabilities could be related to the spinal damage and to the cerebral repercussion of the leak of cerebrospinal fluid from the defect. Several experimental studies in animals have demonstrated that a surgical repair of the lesion at middle gestation reduced the postnatal disabilities. These results were confirmed in humans by the Management of Myelomeningocele (MOM) Trial. However, the prenatal surgical repair is associated with maternal and fetal morbidity.

Fetal tumors of the choroid plexus: is differential diagnosis between papilloma and carcinoma possible?

Fetal choroid plexus tumors are uncommon. The prognosis is widely variable and depends on the histological findings: papilloma or carcinoma. We report a case of prenatal diagnosis of choroid plexus mass detected by ultrasound at 33 weeks of gestation. Prenatal (T1, T2, T2* and diffusion weighted sequences) magnetic resonance imaging (MRI) was used to rule out a hematoma. Follow-up examination by ultrasound and MRI revealed a significant increase in the volume of the mass, suggesting a diagnosis of malignant tumor. A healthy neonate was delivered by Cesarean section at 38 weeks of gestation. Full surgical excision of the tumor was performed at 20 days after delivery and histological analysis revealed a papilloma.

[Venous infarction of the neonate]. / L'infarctus veineux hémorragique du nouveau-né

PURPOSE: To determine the imaging features of hemorrhagic infarction in neonates. PATIENTS AND METHODS: Retrospective study (1998-2008) of 19 children (17 premature and 2 term deliveries) with early lobar hyperechogenicity on transfontanel US (TFUS). Group I: 11 born infants with clinical as well as TFUS and MRI follow-up. Group II: 8 premature infants deceased within a week from multisystem pathology, with neuropathological study available in 3 cases. RESULTS: Group I (n=11): periventricular hyperechogenicity in a frontal (7), frontoparietal (2), parietooccipital (1) and temporoparietal (1) distribution with developing cavitary change (n=6). MRI showed a cortex sparing intraparenchymal hematoma. Group II (n=8): periventricular hyperechogenicity in a frontal (4), frontoparietal or parietal (3) and occipital (1) with developing cavitary change (3). Neuropathological examination showed characteristic lesions of venous hemorrhagic infarction. Clinical outcome was generally favorable for the surviving infants with contralateral motor deficit (n=5) non-correlated to the extent of the initial lesions. CONCLUSION: Venous hemorrhagic infarction mainly affetcs premature infants and typically involves the periventricular frontal white matter. Prognosis is generally favorable. It is thus important to differentiate this entity from asymmetrical cystic periventricular leukomalacia with much different prognosis.

Mycobacterium chelonae infection under adalimumab therapy for spondylarthritis.

Tumour necrosis factor (TNF)-alpha antagonists have been prescribed increasingly over the past few years to manage various inflammatory diseases. This widespread use was quickly followed by the heightened frequency of opportunistic mycobacterial infections including environmental non-tuberculous mycobacterial infections (ENTM). We describe a 66-year-old man taking adalimumab for spondyloarthropathy who developed an inflammatory infiltration in his right index finger. A non-necrotising granuloma with epitheloid and giant cells in the dermis and eosinophilic acid-fast bacilli, identified by using Ziehl-Neelsen staining suggested a mycobacterial infection. Cultures for mycobacteria grew positive on Loewenstein-Jensen medium and molecular identification confirmed M. chelonae infection. The outcome was favourable after five months of clarythromycin. In this context of more frequent ENTM infections, chronic non-specific cutaneous lesions of the extremities should evoke systematically cutaneous ENTM infections. Skin biopsy with histological examination and oriented microbiological cultures and molecular identification are mandatory to confirm the diagnosis.

Refining the clinicopathological pattern of cerebral proliferative glomeruloid vasculopathy (Fowler syndrome): report of 16 fetal cases.

Cerebral proliferative glomeruloid vasculopathy (PGV) is a severe disorder of brain angiogenesis, resulting in abnormally thickened and aberrant perforating vessels, forming glomeruloids with inclusion-bearing endothelial cells. This peculiar vascular malformation was delineated by Fowler in 1972 as a stereotyped lethal fetal phenotype associating hydranencephaly-hydrocephaly with limb deformities, called Fowler syndrome (FS) or "proliferative vasculopathy and hydranencephaly-hydrocephaly" or "encephaloclastic proliferative vasculopathy" (OMIM#225790). In PGV, the disruptive impact of vascular malformation on the developing central nervous system (CNS) is now well admitted. However, molecular mechanisms of abnormal angiogenesis involving the CNS vasculature exclusively remain unknown, as no genes have been localized nor identified to date. We observed the pathognomonic FS vascular malformation in 16 fetuses, born to eight families, four consanguineous and four non-consanguineous. A diffuse form of PGV affecting the entire CNS and resulting in classical FS in 14 cases, can be contrasted to two cases with focal forms, confined to restricted territories of the CNS. Interestingly in PGV, immunohistological response to a marker of pericytes (SMA, Smooth in PGV Muscle Actin), was drastically reduced as compared to a match control. Our studies has expanded the description of FS to additional phenotypes, that could be called Fowler-like syndromes and suggest that the pathogenesis of PGV may be related to abnormal pericyte-dependent remodelling of the CNS vasculature, during CNS angiogenesis. Gene identification will determine the molecular basis of PGV and will help to know whether the Fowler-like phenotypes are due to the same underlying molecular mechanisms.

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 aqueductal glioneuronal hamartoma: a clinicopathological and physiopathological study of three cases.

UNLABELLED: Fetal hydrocephalus due to aqueductal stenosis is classified into two main groups: congenital (X-linked, atresia, septa and forking) and acquired (post-infectious or post-hemorrhagic, gliosis and tumors). MATERIAL AND METHODS: We report three fetal cases presenting with severe hydrocephalus, two of which being apparently sporadic, and the third possibly inherited. On macroscopic examination, no associated malformations were identified, either craniofacial dysmorphy, or visceral abnormalities. Neuropathological study revealed massive hydrocephalus caused by narrowing of the Aqueduct of Sylvius. Histological examination evidenced a nodular, well-demarcated mass producing into the aqueductal lumen, and containing numerous immature proliferating glioneuronal cells. Immunohistochemical analyses did not suggest a developmental abnormality of the subcommissural organ but rather a hamartomatous malformative process. RESULTS: Hamartoma of the posterior fossa has been rarely reported. Post-natal cases have been described in the cerebello-pontine angle or in the quadrigeminal plate, and have always been diagnosed as pilocytic or low-grade astrocytomas. In our cases, the lesions could be related to so-called pencil glioma, sometimes associated with type 1 neurofibromatosis and, to our knowledge, have never been described prior to birth. The occurrence during fetal life and the progressive maturation of the nodules are more likely in favor of a hamartomatous process. CONCLUSION: Even though they could sporadically occur, an accurate genetic counseling should be required in order to ensure that there is no familial history of Recklinghausen disease, and to provide a more precise evaluation of recurrence risk.

Prenatal detection of a de novo terminal inverted duplication 4p in a fetus with the Wolf-Hirschhorn syndrome phenotype.

OBJECTIVES: To present the prenatal diagnosis of a de novo terminal inversion duplication of the short arm of chromosome 4 and a review of the literature. CASE: An amniocentesis for chromosome analysis was performed at 33 weeks' gestation because ultrasound examination showed a female fetus with multiple abnormalities consisting of severe intrauterine growth retardation, microcephaly, a cleft lip and renal hypoplasia. RESULTS: Cytogenetic analysis and FISH studies of the cultured amniocytes revealed a de novo terminal inversion duplication of the short arm of chromosome 4 characterized by a duplication of 4p14-p16.1 chromosome region concomitant with a terminal deletion 4p16.1-pter. The karyotype was thus: 46,XX, inv dup del (4)(:p14-->p16.1::p16.1-->qter). The parents opted to terminate the pregnancy. Fetopathological examination showed dysmorphic features and abnormalities consistent with a Wolf-Hirschhorn syndrome (WHS) diagnosis, clinical manifestations of partial 4p trisomy being mild. CONCLUSION: Although relatively rare, inverted duplications have been reported repeatedly in an increasing number of chromosomes. Only two previous cases with de novo inv dup del (4p) and one with tandem dup 4p have been reported, all of them associated with a 4pter deletion. We report the first case diagnosed prenatally. Breakpoints are variable, resulting in different abnormal phenotype. In our case, clinical manifestations resulted in a WHS phenotype.

Fetal hemangiopericytoma with an associated cerebral anomaly.

We report the first case of infantile hemangiopericytoma explored prenatally by fetal ultrasonography and magnetic resonance imaging (MRI). It was associated with a developmental cerebral anomaly identified on MRI. The largest lesions of the multifocal hemangiopericytoma were located in the soft tissue adjacent to the left temporal bone, and smaller lesions were found in the lumbar area and in the retroperitoneum. MRI showed no connection between the tumor and the fetal brain but there was anomalous cerebral gyration in the region and the Sylvian fissure beneath the tumor was enlarged. The pregnancy was terminated because of the severe brain anomalies and postmortem examination confirmed the prenatal findings. Microscopic analysis of the tumor tissue showed branching vessels which are typical of hemangiopericytoma. The lesions in our case occurred in association with macrosomia with visceromegaly detected at autopsy, suggesting a possible role of tumor suppressor genes.

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.

Prenatal diagnosis of a small supernumerary, XIST-negative, mosaic ring X chromosome identified by fluorescence in situ hybridization in an abnormal male fetus.

Marker or ring X [r(X)] chromosomes of varying size are often found in patients with Turner syndrome. Patients with very small r(X) chromosomes that did not include the X-inactivation locus (XIST) have been described with a more severe phenotype. Small r(X) chromosomes are rare in males and there are only five previous reports of such cases. We report the identification of a small supernumerary X chromosome in an abnormal male fetus. Cytogenetic analysis from chorionic villus sampling was performed because of fetal nuchal translucency thickness and it showed mosaicism 46,XY/47,XY,+r(X)/48,XY,+r(X),+r(X). Fluorescence in situ hybridizations (FISH) showed the marker to be of X-chromosome origin and not to contain the XIST locus. Additional specific probes showed that the r(X) included a euchromatic region in proximal Xq. At 20 weeks gestation, a second ultrasound examination revealed cerebral abnormalities. After genetic counselling, the pregnancy was terminated. The fetus we describe is the first male with a mosaic XIST-negative r(X) chromosome identified at prenatal diagnosis. The phenotype we observed was probably the result of functional disomy of the genes in the r(X) chromosome, secondary to loss of the XIST locus.

Congenital erythropoietic porphyria (Günther's disease): two cases with very early prenatal manifestation and cystic hygroma.

Congenital erythropoietic porphyria (CEP) or Günther's disease is the rarest form of the porphyrias. The disease is usually diagnosed at birth or during early infancy, but rarely in utero. We describe here the first two cases of very early prenatal expression of CEP with cystic hygroma diagnosed at 14 weeks in the first fetus and at 19 weeks in the second. Both fetuses presented with severe nonimmune hydrops fetalis as early as 19 and 22 weeks, associated with intrauterine growth retardation, hyperechogenic kidneys and bones. Amniotic fluid was dark brown and uro- and coproporphyrin I was dramatically increased. Molecular screening of the CEP gene detected heterozygous C73R mutation in both fetuses, the other parental mutation being as yet unknown.

The human lumbar anterior epidural space: morphological comparison in adult and fetal specimens.

To increase our understanding of the clinical anatomy of the epidural space, the human lumbar anterior epidural space was studied morphologically and developmentally. Histological transverse sections of human lumbar spines were taken at the level of the intervertebral disc and the vertebral body in adult specimens and in fetuses aged 13, 15, 21, 32 and 39 weeks (menstrual age). At 13 weeks, connective tissue filled the epidural space. The dura mater was attached anteriorly to the posterior longitudinal ligament (PLL). The PLL was attached to the vertebral body beside the midline, whereas it adhered to the posterior edge of intervertebral disc. The anterior internal vertebral venous plexus was located anterolaterally and anteromedially. The vertebral canal was lined with connective tissue that differentiated in a periosteum in contact with the ossification centers. At 15 weeks, the PLL was composed of deep and superficial layers. At 21 weeks, the attachment between the dura mater and PLL was ligament-like at the level of the vertebral body. At 32 weeks, the dura mater was adherent to the superficial layer of PLL. At 39 weeks, groups of adipocytes were identified, and the dura mater was attached to the PLL by some ligaments. There were many more similarities between the adult and the 39-week fetus. In conclusion, some differences in the anatomy of the epidural space exist at each fetal stage studied. The structures of the epidural space are already formed in the fetus of 13 weeks, but they differentiate progressively within the connective tissue.

[Prenatal diagnosis of isolated posterior fossa anomalies: attempt at a simplified approach]. / Diagnostic anténatal des anomalies isolées de la fosse postérieure: tentative d'approche simplifiée.

The authors suggest, after some embryological, anatomical and nosological reviews, a simplified approach mainly based on the appearance of the pons, cerebellar hemispheres and vermis, independently from an associated cystic dilatation of the posterior fossa. Pontocerebellar hypoplasias and partial or total vermian agenesis are detailed because they can be diagnosed with a prenatal MRI. This classification based on our experience and on the literature data should be of value to evaluate the neurological prognosis.

Prenatal diagnosis of fetal tail and postabortum anatomical description.

Fetal ultrasound examination at 13 weeks of gestation demonstrated a homogeneously echogenic protrusion, or tail, 7 mm in length, in the sacral region. At 15 weeks, the ultrasound appearance was consistent with a regression of the tail and by 21 weeks it had completely disappeared. Severe intrauterine growth restriction with reduced uterine blood flow was diagnosed at 21 weeks and intrauterine death occurred at 24 weeks of gestation. Postmortem examination revealed a 4-mm caudal appendage which contained no vertebrae on radiography. The appendage was located under and behind the last sacral vertebra suggesting a true vestigial tail with a delayed process of regression.