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• W2012943123 abstract "A 49-year-old woman was admitted with chronic renal failure. Her previous history included poor vision, with photophobia at 3 years; retinitis pigmentosa resulting in legal blindness by age 40; sensorineural hearing loss by age 20 progressing to deafness. By the age of 27, she developed congestive heart failure; echocardiography showed dilated cardiomyopathy. Myocardial biopsy showed interstitial fibrosis and myocellular hypertrophy (Figure 1). Chronic renal failure (serum creatinine 1.5 mg/dl) was found with negative urinalysis. At the age of 42, insulin resistance was first documented. At admission, her weight was 63 kg, height 145 cm, body mass index 30 kg/m2. She had normal intelligence. Serum creatinine was 1.6 mg/dl; creatinine clearance 38 ml/min; urinalysis negative; urinary osmolality 360 mosmol/kg. Ultrasonography revealed small kidneys with a few bilateral cysts. Renal biopsy showed interstitial fibrosis, tubular atrophy (Figure 2). Family characterization (Figure 3) revealed unaffected parents, a phenotypically normal sister, and a brother who died at 1 year from congenital heart disease. A 43-year-old brother had retinitis pigmentosa, sensorineural deafness, hepatic fibrosis, adult-onset dilated cardiomyopathy, chronic renal failure (serum creatinine 1.4 mg/dl; creatinine clearance 55 ml/min) with negative urinalysis, small kidneys and hepato-splenic enlargement by ultrasound. Liver rigidity, measured by transient elastography (Fibroscan, Echosens, Paris, France), was significantly increased. What is your diagnosis? The complex spectrum of phenotypes of our patients is consistent with those described for ciliopathies, which are genetic disorders resulting from dysfunction of cilia usually involving the kidneys.1.Fliegauf M. Benzing T. Omran H. When cilia go bad: cilia defects and ciliopathies.Nat Rev Mol Cell Biol. 2007; 8: 880-893Crossref PubMed Scopus (811) Google Scholar The combination of tubulointerstitial nephritis, retinitis pigmentosa, and liver fibrosis can be observed in nephronophthisis, a ciliopathy causing the most frequent hereditary tubulointerstitial nephritis.2.Hildebrandt F. Zhou W. Nephronophthisis-associated ciliopathies.J Am Soc Nephrol. 2007; 18: 1855-1871Crossref PubMed Scopus (257) Google Scholar However, metabolic abnormalities are not typical features of nephronophthisis, whereas they are part of the clinical spectrum of two pleiotropic ciliopathies, Bardet–Biedl (BBS) and Alström syndrome (ALMS).1.Fliegauf M. Benzing T. Omran H. When cilia go bad: cilia defects and ciliopathies.Nat Rev Mol Cell Biol. 2007; 8: 880-893Crossref PubMed Scopus (811) Google Scholar Mutational analysis of the known variants in BBS 1-12 genes (microarray analysis; Asper Biotech, Tartu, Estonia) did not reveal mutations. Sequencing analysis of all exons of the ALMS1 gene revealed, in both affected individuals, a heterozygous frameshift mutation (S524fsX535) inherited from the mother. Haplotype analysis found identical haplotypes in the 2p13 ALMS1 region in the two sibs (Figure 3). ALMS is a rare recessive ciliopathy caused by mutations in ALMS1, a novel gene of unknown function. The major phenotypes are observed in young children; other phenotypes emerge as the child develops. The diagnosis of ALMS relies primarily on clinical findings and can be proven by molecular testing when two mutations are identified. However, two disease-causing mutations are not easily identified, suggesting that some patients can harbor mutations in the promoter/intronic regions.3.Marshall J.D. Bronson R. Collin G. et al.New Alström syndrome phenotypes based on the evaluation of 182 cases.Arch Intern Med. 2005; 165: 675-683Crossref PubMed Scopus (202) Google Scholar, 4.Minton J.A. Owen K.R. Ricketts C.J. et al.Syndromic obesity and diabetes: changes in body composition with age and mutation analysis of ALMS1 in 12 United Kingdom kindreds with Alström syndrome.J Clin Endocrinol Metab. 2006; 91: 3110-3116Crossref PubMed Scopus (56) Google Scholar, 5.Marshall J.D. Beck S. Maffei P. Naggert J.K. Alström Syndrome.Eur J Hum Genet. 2007; 15: 1193-1202Crossref PubMed Scopus (145) Google Scholar To help clinicians in making the diagnosis, a set of age-related diagnostic criteria have been proposed.5.Marshall J.D. Beck S. Maffei P. Naggert J.K. Alström Syndrome.Eur J Hum Genet. 2007; 15: 1193-1202Crossref PubMed Scopus (145) Google Scholar Our patients fulfilled the diagnostic criteria for adult ALMS, showing a combination of two major criteria (retinitis pigmentosa and ALMS1 mutation in a single allele) and at least four minor criteria (sensorineural hearing loss, hepatic fibrosis, dilated cardiomyopathy, and renal disease). Renal disease develops with age in all individuals with ALMS. Onset occurs in early adolescence/adulthood, with polyuria and polydipsia. Renal insufficiency leading to end-stage renal disease occurs in 50% of patients. Histopathological changes include interstitial fibrosis and tubular atrophy. Similar fibrotic infiltrations underlie many of the other clinical phenotypes, particularly cardiac, pulmonary, and hepatic disease, suggesting common pathogenic mechanisms.3.Marshall J.D. Bronson R. Collin G. et al.New Alström syndrome phenotypes based on the evaluation of 182 cases.Arch Intern Med. 2005; 165: 675-683Crossref PubMed Scopus (202) Google Scholar, 4.Minton J.A. Owen K.R. Ricketts C.J. et al.Syndromic obesity and diabetes: changes in body composition with age and mutation analysis of ALMS1 in 12 United Kingdom kindreds with Alström syndrome.J Clin Endocrinol Metab. 2006; 91: 3110-3116Crossref PubMed Scopus (56) Google Scholar, 5.Marshall J.D. Beck S. Maffei P. Naggert J.K. Alström Syndrome.Eur J Hum Genet. 2007; 15: 1193-1202Crossref PubMed Scopus (145) Google Scholar The mechanisms of the induction of fibrosis are unknown. Further insights into the function of the ALMS1 protein will contribute to elucidate this process, increasing the knowledge of molecular mechanisms involved in fibrogenesis. Tubulointerstitial nephritis due to ALMS is a challenging diagnosis. A high index of suspicion should be maintained in patients presenting with familial recessive tubulointerstitial renal disease, retinal degeneration, and sensorineural hearing loss. The presence of hepatic, cardiac involvement, and metabolic abnormalities should raise the level of suspicion." @default.
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• W2012943123 title "The Case ∣ Familial occurrence of retinitis pigmentosa, deafness, and nephropathy" @default.
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