Molar ultrasonographic appearances associated with increased maternal serum alpha-fetoprotein but normal, or slightly elevated, levels of ss human Chorionic Gonadotrophin should raise the clinical suspicion of PMD. The diagnosis of this condition should not be disregarded when an abnormal fetus and/or an abnormal karyotype are demonstrated.
Neutrophils are key mediators of the innate immune response and are required to function at sites of low oxygenation. We have shown that in hypoxia neutro-phils are protected from apoptosis via a mechanism dependent on prolyl hydroxy-lase domain/hypoxia-inducible factor 1 (PHD/HIF-1). This response would be predicted to involve the von Hippel Lindau protein (pVHL)-dependent ubiquitination and degradation of HIF-1. Patients with VHL disease inherit a mutation in one VHL allele, which allows us to study the effects of heterozygous VHL expression in human neutrophils. Neutrophils exhibited a striking "partial hypoxic" phenotype , with delayed rates of apoptosis and enhanced bacterial phagocytosis under normoxic conditions and preserved responses to low levels of oxygen. This provides direct evidence that the HIF-1/ VHL pathway regulates the innate immune response in humans. It also establishes that heterozygous VHL defects are sufficient to perturb normal responses and illustrates the potential to use this to address the role of HIF and VHL in human biology. (Blood. 2006;108:3176-3178) Introduction The regulation of neutrophil activation and longevity is critical to the resolution of acute inflammation. Apoptosis results in the functional "shut down" of the neutrophil 1 and initiates its recognition , engulfment, and removal from an inflamed site. 2 In contrast to its effects in many other cell types, hypoxia causes a profound inhibition of neutrophil apoptosis. 3 This effect appears to be directly dependent on hypoxia-inducible factor 1 (HIF-1) because neutrophils from mice lacking this transcription factor display a marked reduction in survival under hypoxic conditions. 4 HIF is a heterodimer composed of a constitutively expressed subunit and a hydroxylase-regulated oxygen sensitive subunit. 5,6 In the presence of dioxygen the N-terminal domain of the subunit is hydroxylated by prolyl hydroxylase domain (PHD)-containing enzymes, enabling its high-affinity binding to the von Hippel Lindau (VHL) E3 ubiquitin ligase complex and allowing subsequent ubiquitination and rapid proteasomal degradation. 7,8 The VHL tumor syndrome affects 1:36 000 of the population with its manifestations (retinal angioma, cerebellar hemangioblastoma, renal-cell carcinoma, and pheochromocytoma) arising only after a second, somatic mutation. 9 Approximately 70% of germline mutations of VHL are inactivating (frameshift, nonsense, deletions) with the remainder being missense mutations; a close correlation between genotype and tumor predisposition has also been described in families with VHL disease. To establish the importance of the PHD/HIF/VHL oxygen-sensing pathway in regulating both neutrophil longevity and function we have used neutrophils derived from patients with heterozygous germline mutations in the VHL gene. Here we show that such neutrophils exhibit delayed apopto-sis, increased sensitivity to hydroxylase inhibition, and enhanced rates of bacterial phagocytosis. This is the first demonstration of an effect of hypoxia on neutrophil ...
Familial visceral neuropathy (FVN) is a heterogeneous group of disorders due to abnormalities of the myenteric plexus. FVN with neuronal intranuclear inclusions is one particular form of FVN with a variable phenotype that includes achalasia, gastro‐esophageal reflux, intestinal dysmotility and pseudo‐obstruction, dysarthria, peripheral neuropathy and pupillary defects, and the presence of intranuclear inclusions within the neurons of the enteric nervous system. We present a four‐generation family in which 10 individuals (7 of whom have been examined) are affected with FVN. The family was previously reported as familial esophageal achalasia, an autosomal recessive condition (MIM200400). At that time, several individuals in a single sibship were affected and there were no manifestations in either parent. Since that report, two individuals have had affected children and the mother has developed symptoms and has abnormalities on electromyography, thus enabling us to reclassify the family. This family provides further evidence of autosomal dominant inheritance, with marked variation in expression. © 2005 Wiley‐Liss, Inc.
Brachydactyly is a relatively common congenital anomaly and can be associated with many other malformations. However, brachydactyly in association with biliary atresia is rare. We present a male child with strikingly symmetrical brachydactyly and nail hypoplasia, extrahepatic biliary atresia, patent ductus arteriosus, seizures, developmental delay and cataracts. This combination of features has not previously been described and we suggest that this case represents a new syndrome.
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