Orofaciodigital syndrome type IV (Mohr-Majewski syndrome): report of a family with two affected siblings.

We report on sibling fetuses with orofaciodigital syndrome (OFDS) type IV (Mohr-Majewski syndrome). The 1st was a 13-week-old fetus with hypertelorism; a median cleft defect of the upper lip, soft palate, and uvula; a polypoid lower lip and multiple frenula of the tongue adherent to the mandible; a congenital heart defect; pre- and postaxial polydactyly of the upper and preaxial polydactyly of the lower limbs; and an intersex genitalia. However, the shortening of both arms and forearms was particularly striking, with shortening of the ulna and ulnar deviation of both hands. The 2nd fetus was of the same parents, was 11 weeks old, and presented with a similar spectrum of malformations. The features of both fetuses showed a transitional phenotype between the OFDS type II (Mohr syndrome) and the short rib-polydactyly syndrome type II (Majewski syndrome), thus extending the known spectrum of the OFDS type IV.

Percutaneous fetoscopic patch coverage of spina bifida aperta in the human--early clinical experience and potential.

OBJECTIVE: The current operative approach for fetal repair of spina bifida aperta requires maternal laparotomy and hysterotomy. Following technical feasibility studies in sheep, we performed percutaneous fetoscopic patch coverage of this lesion in 3 human fetuses between 23 + 4 and 25 + 3 weeks of gestation. METHODS AND RESULTS: Whereas the patch detached in the first case 3 weeks after the procedure, it covered the exposed neural tissue in the 2 other fetuses beyond their delivery. Two of the three children survived, but 1 unexpectedly died from a ventilation problem in its 3rd week of life. In 1 of the 2 survivors, ventriculoperitoneal shunt insertion was delayed. CONCLUSIONS: Percutaneous fetoscopic patch coverage of spina bifida aperta is feasible in human fetuses and offers a substantial reduction of maternal trauma compared to open fetal repair. Further clinical experience is now required before the efficacy of the new approach to protect the exposed neural tissue from mechanical and chemical damage and to improve hindbrain herniation can be evaluated.

Stomatin is mis-trafficked in the erythrocytes of overhydrated hereditary stomatocytosis, and is absent from normal primitive yolk sac-derived erythrocytes.

The 32 kD lipid-raft-associated membrane protein 'stomatin' is deficient from the erythrocyte membrane in the Na+-K+ leaky haemolytic anaemia, overhydrated hereditary stomatocytosis (OHSt). To date, no mutation in the gene coding for this protein has so far been found in OHSt. In this study, we have analysed the distribution of stomatin in both cultured erythroid cells from OHSt patients and in normal embryological and fetal erythroid development. In erythroid cell cultures from OHSt patients, stomatin-immunoreactivity (stomatin-IR) was present in progenitor cells but remained restricted to the area of the multivesicular complexes and the nucleus in the developing cells and was not seen in the plasma membrane. This could be consistent with the idea that stomatin is an innocent passenger in a more fundamental trafficking abnormality. In normal embryonic development, we found that, in extraembryonic (yolk sac) erythropoiesis, neither the nucleated red cells nor their enucleated mature derivatives displayed any stomatin-IR. In contrast, all haemangiopoietic progenitor cells of intraembryonic haematopoiesis, starting with the mesodermal precursors in the aorta-gonad-mesonephros region, exhibited strong stomatin-IR. The significance of this observation on these poorly understood cells is currently unclear.

Human metapneumovirus RNA in encephalitis patient.

We describe a fatal case of encephalitis that might be correlated with primary human metapneumovirus (HMPV) encephalitis. Postmortem HMPV RNA was detected in brain and lung tissue samples from the patient. Furthermore, HMPV RNA was found in culture fluids from cells coincubated with lung tissue.

Hepatic erythropoietin gene regulation by GATA-4.

Erythropoietin production switches from fetal liver to adult kidney during development. GATA transcription factors 2 and 3 could be involved in modulating this switch, because they were shown to negatively regulate erythropoietin gene transcription through a promoter proximal GATA site. Herein, we analyzed the role of several GATA factors in the regulation of the erythropoietin gene in human liver and in hepatoma cells. Although GATA-3 expression in hepatocytes increases during human development, erythropoietin mRNA accumulation is unaltered in mutant mice lacking GATA-3. We found that GATA-2, -3, -4, and -6 are all expressed in human hepatocytes and that GATA-4 exhibits the most prominent Epo promoter binding activity in vitro and in vivo. Inhibition of GATA-4 expression by RNA interference leads to a dramatic reduction in Epo gene transcription in Hep3B cells. Moreover, GATA-4 expression is high and limited to hepatocytes in the fetal liver, whereas GATA-4 expression in the adult liver is low and restricted to epithelial cells surrounding the biliary ducts. Thus, GATA-4 is critical for transcription of the Epo gene in hepatocytes and may contribute to the switch in the site of Epo gene expression from the fetal liver to the adult kidney.

Stomatin immunoreactivity in ciliated cells of the human airway epithelium.

Stomatin is a widely distributed 32kD membrane protein of unknown function. In biochemical studies it is associated with cholesterol+sphingomyelin-rich 'rafts' in the cytomembrane. Genetic studies in C. elegans, supported by microscopic studies in mammalian tissue and co-expression studies in oocytes, suggest a functional link with the DEG/ENaC (degenerin/epithelial Na+ channel) superfamily of monovalent ion channels. Since ENaC channels play a prominent role in the physiology of the respiratory epithelium, we have studied the immunolocalization of stomatin in mature and developing human airway epithelium by means of Western blot analysis, immunocytochemistry, and immunoelectron microscopy. Stomatin immunoreactivity (stomatin-IR) was found in the ciliated cells of the conductive airway epithelium in a distinct distribution pattern with the strongest signal along the cilia. Immunogold labelling revealed immunogold particles at the basal bodies, along the cilia, and at the membrane of the microvilli. The presence of stomatin-IR paralleled the stages of ciliogenesis in airway development, and its appearance preceded the elongation of the axoneme and the cilial outgrowth. Due to its presence in the different cellular locations in the ciliated cell, we suggest that stomatin is involved in various cellular functions. From its ultrastructural position, stomatin could be a candidate for a membrane-associated mechanotransducer with a role in the control of ciliary motility. Stomatin as a raft protein might be a microtubule associated protein moving along the outer surface of the microtubules to its terminal site of action in the cilia. Stomatin-IR in microvilli supports the hypothesis of a co-localization with beta- and gamma- ENaC and, in conclusion, their potential functional interaction to control the composition of periciliary mucus electrolytes.

Developmental changes in the expression of transcription factors GATA-1, -2 and -3 during the onset of human medullary haematopoiesis.

Regulation of gene expression during the ontogeny of haematopoiesis in the human fetal bone marrow is poorly understood. Studies in mice demonstrated that GATA-1, -2 and -3 play pivotal roles in haematopoiesis. In this study, we identified GATA-1-, GATA-2- and GATA-3-expressing cells in bone marrow sections and analysed the expression of GATA-transcription factors during the development of human fetal bone marrow haematopoiesis using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). We showed that GATA-1, -2 and -3 were expressed only in haematopoietic cells in the bone marrow. RT-PCR analysis demonstrated that (1) GATA-1 expression significantly increased during gestation; (2) GATA-2 expression peaked at the onset of medullary haematopoiesis, declined thereafter, and remained at a constant level after 30 weeks post conception; and (3) GATA-3 expression revealed no changes during development. The results indicated that the onset of medullary haematopoiesis in humans is accompanied by high expression of GATA-2, reflecting high proliferation rates of early haematopoietic progenitor cells, whereas expression of GATA-1 mirrors haematopoietic activity.

Clinical, cytogenetic, and molecular findings in 45,X/47,XX,+18 mosaicism: clinical report and review of the literature.

We report cytogenetic and molecular findings performed in a patient with double mosaic aneuploidy. Chromosome analysis of amniotic fluid cells from a 17-week-old fetus was performed because of advanced maternal age. Two karyotypes were detected: 45,X and 47,XX,+18 (50:50%). The same cell lines were determined in uncultured and cultured amniocytes of a second amniotic fluid sample, in fetal lymphocytes, and in uncultured and cultured cells of achilles tendon by conventional cytogenetics and fluorescence in situ hybridization (FISH). In the different investigated tissues, the percentage of cells with 45,X karyotype ranged from 20-99% and the percentage of cells with 47,XX,+18 ranged from 1-80%. The pregnancy was terminated at 22 + 0 weeks because of a severe cardiac malformation. Pathologic examination showed a fetus with aspects typical for manifestation of trisomy 18 and monosomy X, especially in the internal organs. The parent and cell stage of origin was determined by short tandem repeat typing and revealed a maternal meiotic division error that led to trisomy 18, as well as a somatic loss of a paternal sex chromosome. Only two other patients with the same mosaicism have been reported so far. Genetic counseling and prognosis remains challenging.