Twin-to-twin transfusion syndrome (TTTS) is caused by uneven shunting of blood between monochorionic twins, resulting in polycythemia in the recipient twin and growth restriction, anemia, and oliguria in the donor twin. Recent reports have described loss of proximal convoluted tubules in the kidneys of TTTS donor twins. In order to elucidate the pathogenesis of tubular deficiency in TTTS, we have reviewed the renal pathology in 25 twin pairs with autopsy-proven TTTS. Loss of differentiated proximal tubules, associated with atrophy of medullary tubules, was identified in 12/25 donor twins. In seven of these cases (all > 23-wk gestational age), the kidneys showed diffuse or partial tubular atrophy without evidence of cell death, similar to previously reported patterns. In five cases (all between 18- and 22-wk gestation), proximal and medullary tubules showed active injury characterized by markedly increased apoptosis, cell detachment, and intraluminal cell debris associated with calcifications. Tubular apoptosis tended to be more prevalent in donor fetuses with greater inter-twin body weight discordance, consistent with a more severe degree of TTTS. These results extend the spectrum of tubular alterations in TTTS to include an early stage of active apoptotic injury. The temporal distribution of injury patterns suggests that apoptotic injury of proximal and medullary tubules may be a precursor to partial or diffuse tubular atrophy. We speculate that the risk for development of tubular apoptosis in TTTS depends on the severity and timing of the hemodynamic imbalance, whereby early mid-trimester fetuses may be more vulnerable.

The Von Hippel-Lindau (VHL) gene product has a wide spectrum of tissue-specific functions, and specific germline mutations are associated with clinical phenotypes in VHL disease. In particular, missense mutations are correlated with the susceptibility to pheochromocytomas. An association between VHL aberrations and prognosis has been suggested in renal clear cell carcinoma but has not been studied in pheochromocytomas. We studied the frequency and spectrum of VHL alterations in apparently sporadic pheochromocytomas in relation to the clinical behavior in 72 patients, including 48 patients with clinically benign and 24 patients with malignant pheochromocytomas. Single-strand conformation polymorphism (SSCP) analysis followed by DNA sequencing, loss of heterozygosity analysis of the VHL locus and immunohistochemistry for VHL protein expression were used to investigate somatic VHL gene alterations. In 2 patients, 1 with a malignant tumor, germline mutations were identified in the stop codon. Tumor-specific intragenic VHL mutations and accompanying loss of heterozygosity were identified in 2 (4.3%) of 47 sporadic benign pheochromocyto- Key words: Von Hippel-Lindau; pheochromocytoma; mutation; loss of heterozygosityVon Hippel-Lindau (VHL) disease is characterized by the development of multiple highly vascularized tumors in mesenchymal and neural crest-derived tissues of several organ systems. These concern mostly the central nervous system (hemangioblastoma), eye (retinal angioma), kidney (renal clear cell carcinoma), adrenal medulla (pheochromocytoma), inner ear (endolymphatic sac tumor) and endocrine pancreas (islet cell tumors). 1 In nearly all VHL patients, germline mutations or deletions in the VHL gene can be identified. 2,3 The VHL gene codes for a 213-amino acid protein (pVHL), which is involved in regulation of angiogenesis, extracellular matrix formation and plays a role in the cell cycle. 4 -9 As a recessive tumor suppressor gene, VHL demonstrates some important additional features, such as allelic heterogeneity resulting in genotypephenotype correlations and epigenetic effects. 10 -12 A correlation has been found between the nature and localization of inactivating mutations and the clinical consequences in patients afflicted by VHL disease. In particular, the development of pheochromocytoma (PCC) in VHL disease (type II VHL disease) is strongly correlated with missense mutations. These are found in 96% of these families, frequently in the exon 3-encoded ␣-domain of pVHL. 10 -13 PCC may even be the only tumor arising in some individuals with VHL type II disease. It is hypothesized that some retention of pVHL function is necessary in the development of PCC, arising from a dominant-negative effect of mutated pVHL and based on its involvement in the VHL-Elongin C-Elongin B complex. 14 The majority of PCCs occur sporadically, and the genetic mechanisms underlying their tumorigenesis and progression towards malignancy are poorly understood. At present, one cannot predict which patient will experience progres...

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Glutamic acid decarboxylase (GAD) is a major inhibitory neurotransmitter in the brain, which catalyses the reaction of L-glutamate to γ-aminobutyric acid. There are two isoforms of GAD, a 65-kDa form and a 67-kDa form, which are encoded by two different genes. As previous studies suggested a role for GAD67 splice variants during fetal pancreas development, we have investigated the mRNA expression of GAD67 and GAD67 splice variants in a series of 14 human fetal pancreases between 14 weeks gestation and term and in adult control pancreases by RT-PCR. In this study, we demonstrate mRNA expression of GAD67 and four GAD67 splice variants, including GAD25, in human fetal and adult specimens. Some of the splice variants, including various proportions of exon 7 or a new exon between exons 6 and 7, have not been described before in the human pancreas. We speculate that the expression of these GAD67 splice variants might be related to human fetal pancreas development.