Identification of the genes underlying complex phenotypes and the definition of the evolutionary forces that have shaped eukaryotic genomes are among the current challenges in molecular genetics. Variation in gene copy number is increasingly recognized as a source of inter-individual differences in genome sequence and has been proposed as a driving force for genome evolution and phenotypic variation. Here we show that copy number variation of the orthologous rat and human Fcgr3 genes is a determinant of susceptibility to immunologically mediated glomerulonephritis. Positional cloning identified loss of the newly described, rat-specific Fcgr3 paralogue, Fcgr3-related sequence (Fcgr3-rs), as a determinant of macrophage overactivity and glomerulonephritis in Wistar Kyoto rats. In humans, low copy number of FCGR3B, an orthologue of rat Fcgr3, was associated with glomerulonephritis in the autoimmune disease systemic lupus erythematosus. The finding that gene copy number polymorphism predisposes to immunologically mediated renal disease in two mammalian species provides direct evidence for the importance of genome plasticity in the evolution of genetically complex phenotypes, including susceptibility to common human disease.

One hundred eighty-two patients were evaluated after functional endoscopic sinus surgery. The goal was to establish whether any anatomical finding correlated with symptoms and to find any historical predictors of symptomatic failure. Of all physical findings reviewed, only scarring of middle meatal antrostomy and scarring of the ethmoids approached significance in predicting poor outcome. Surprisingly, of the historical factors reviewed, only gastroesophageal reflux disease was statistically significant as a predictor of poor symptomatic outcome.

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Our review shows a definite association of MetS with kidney stone disease. Although multifactorial in etiology, lifestyle and dietary factors seem to be increasingly important in prevention of stone disease.

BackgroundMutation specific effects in monogenic disorders are rare. We describe atypical Fanconi syndrome caused by a specific heterozygous mutation in HNF4A. Heterozygous HNF4A mutations cause a beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes. Autosomal dominant idiopathic Fanconi syndrome (a renal proximal tubulopathy) is described but no genetic cause has been defined.Methods and ResultsWe report six patients heterozygous for the p.R76W HNF4A mutation who have Fanconi syndrome and nephrocalcinosis in addition to neonatal hyperinsulinism and macrosomia. All six displayed a novel phenotype of proximal tubulopathy, characterised by generalised aminoaciduria, low molecular weight proteinuria, glycosuria, hyperphosphaturia and hypouricaemia, and additional features not seen in Fanconi syndrome: nephrocalcinosis, renal impairment, hypercalciuria with relative hypocalcaemia, and hypermagnesaemia. This was mutation specific, with the renal phenotype not being seen in patients with other HNF4A mutations. In silico modelling shows the R76 residue is directly involved in DNA binding and the R76W mutation reduces DNA binding affinity. The target(s) selectively affected by altered DNA binding of R76W that results in Fanconi syndrome is not known.ConclusionsThe HNF4A R76W mutation is an unusual example of a mutation specific phenotype, with autosomal dominant atypical Fanconi syndrome in addition to the established beta cell phenotype.

We report on a series of 33 consecutive cases of antrochoanal polyp (ACP) treated by endoscopic sinus surgery over a five-year period. All but one patient was treated by endoscopic sinus surgery alone. This method of treatment was quite effective for ACPs. These 33 patients represent 22.3% of all nasal polyp patients on whom we operated during the same period. This incidence of ACP is greater than that generally reported in the literature. Some authors have attempted to distinguish ACPs from common nasal polyps primarily on the basis of morphology, histology, and the clinical behavior of the ACPs. In our series, a multivariate analysis, including histopathologic correlation, did not support the notion that ACPs are clearly distinct from common nasal polyps. Some interesting differences between the polyp groups did, however, become evident in our data analysis. Generally, ACPs are not thought to be associated with allergic disease; however, in our series we found the association of allergic disease with ACPs to be statistically significant (Chi-square=4.575, p<.05).

Seventy paranasal sinus computed tomography scans of patients with cystic fibrosis were compared with those of age-matched control groups of randomly selected chronic sinusitis patients without cystic fibrosis to determine whether differences in disease patterns existed. In patients older than 10 years, frontal sinus agenesis and maxilloethmoid sinus opacification were significantly more prevalent in patients with cystic fibrosis than in chronic sinusitis patients without cystic fibrosis. Medial bulging of the lateral nasal wall was significantly greater in patients with cystic fibrosis than in chronic sinusitis patients without cystic fibrosis in patients older than 5 years. On the basis of these findings, a diagnostic triad of radiologic findings for cystic fibrosis detection is presented, as well as its clinical implications.

Neonates with congenital cardiac disease face significant barriers to successfully achieving oral feeding on hospital discharge. Enteral feeding guidelines focus on physiological stabilisation and do not always address the developmental milestones necessary to support oral feeding. Future prospective studies are necessary to identify multimodal strategies to optimise early feeding.