title: Autosomal-dominant familial hematuria with retinal arteriolar tortuosity and contractures: a novel syndrome.
abstract: BACKGROUND
  Autosomal-dominant forms of hematuria have been mostly related to mutations in the COL4A3/COL4A4 genes. Patients with thin basement membrane (BM) disease do not have extrarenal manifestations, while those with Alport syndrome often present with hearing loss, anterior lenticonus, and dot-and-fleck retinopathy.
  
  
  METHODS
  We performed a phenotypic study and a candidate gene approach in a four-generation family presenting with autosomal-dominant hematuria associated with extrarenal manifestations. Renal biopsy was analyzed for determination of BM thickness and expression of chains of type IV collagen. Linkage to 18 candidate genes/loci was investigated using polymorphic microsatellite markers.
  
  
  RESULTS
  In all affected patients, hematuria without proteinuria was associated with muscular contractures and retinal arterial tortuosities responsible for retinal hemorrhages. Cardiac arrhythmia, Raynaud phenomena, and brain MRI abnormalities were also observed. Despite the presence of red cells in tubule sections, no glomerular abnormalities were found by electron microscopy. Expression of type IV collagen chains and glomerular BM thickness was normal. We searched for a molecular defect affecting either BM or angiogenesis. Linkage analyses of genes encoding BM components (COL4A3/COL4A4, COL6A1, COL6A2, COL6A3, FBLN1), and angiogenic factors or their receptors (VHL, ANPT1, ANPT2, TIE, TEK, NOTCH2, NOTCH3, NOTCH4, DLL4, JAG1, JAG2) and of the facio-sapulo-humeral dystrophy and 3q21 loci failed to show segregation of the disease with those gene loci.
  
  
  CONCLUSIONS
  We have identified a new inherited hematuria syndrome associated with retinal vessel tortuosities and contractures. We recommend performing a fundus examination in patients with familial hematuria and episodes of visual impairment, as well as a urinary analysis in patients with retinal arterial tortuosity or congenital muscular contractures.
authors.affiliation: INSERM Unit 489; Departments of Neurology, and Nephrology, Tenon Hospital (AP-HP), Paris, France. emmanuelle.plaisier@tnn.ap-hop-paris.fr
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Plaisier
authors.forename: Sonia
authors.initials: S
authors.lastname: Alamowitch
authors.forename: Olivier
authors.initials: O
authors.lastname: Gribouval
authors.forename: Béatrice
authors.initials: B
authors.lastname: Mougenot
authors.forename: Alain
authors.initials: A
authors.lastname: Gaudric
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
authors.forename: Etienne
authors.initials: E
authors.lastname: Roullet
authors.forename: Pierre
authors.initials: P
authors.lastname: Ronco
mesh_terms: D024141:Collagen Type IV / Q000235:genetics*; D003286:Contracture / Q000235:genetics*; D005260:Female; D006417:Hematuria / Q000235:genetics*; D006801:Humans; D008297:Male; D010375:Pedigree; D012164:Retinal Diseases / Q000235:genetics*; D013577:Syndrome
chemical_list: D024141:Collagen Type IV