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Pediatric Nephrology

Erschienen in:

22.04.2017 | Original Article

Renal findings in patients with Mulibrey nanism

verfasst von: Johanna Sivunen, Susann Karlberg, Jouko Lohi, Niklas Karlberg, Marita Lipsanen-Nyman, Hannu Jalanko

Erschienen in: Pediatric Nephrology | Ausgabe 9/2017

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Abstract

Background

Mulibrey nanism (MUL) is a rare inherited disease caused by genetic defects affecting peroxisomal TRIM37 protein. MUL affects multiple organs, leading to growth retardation and early onset type 2 diabetes. We aimed to characterize the structure and function of kidneys and the urinary tract in a large cohort of Finnish MUL patients.

Methods

Ultrasound, magnetic resonance imaging (MRI), and autopsy findings of the kidneys and urinary tract from 101 MUL patients were retrospectively analyzed. Renal function was examined using blood and urine biochemistry. Kidney pathology was assessed by histology and immunohistochemistry from biopsy and autopsy samples.

Results

Structural anomalies of the kidneys and urinary tract were found in 13 % of MUL patients and renal tumors and macroscopic cystic lesions in 14 % and 43 % respectively. Overall, kidney histology was well preserved, but glomerular cysts with a wide Bowman’s space were observed in most samples (87 %). Also, prominent and abundant blood vessels with thick walls were typically seen. Expression of endothelial cell markers and angiogenic growth factors PDGF-B and FGF1 (but not VEGF-A) was significantly increased in MUL kidneys. Markers of fibrosis and epithelial–mesenchymal transformation, α-SMA, and vimentin were moderately up-regulated. Despite radiological and histological changes, most MUL patients (age 0.2–51 years) had normal kidney function. However, 9 out of 36 patients (25 %) had hypertension and 6 out of 26 (23 %) had mildly decreased glomerular filtration.

Conclusions

Genetic defects in the TRIM37 gene lead to an increased risk for kidney anomalies, renal tumors, and solitary cysts in addition to glomerular cystic lesions, but not to progressive deterioration of renal function.

Kallijarvi J, Avela K, Lipsanen-Nyman M, Ulmanen I, Lehesjoki AE (2002) The TRIM37 gene encodes a peroxisomal RING-B-box-coiled-coil protein: classification of mulibrey nanism as a new peroxisomal disorder. Am J Hum Genet 70:1215–1228CrossRefPubMedPubMedCentral

Putoux A, Attie-Bitach T, Martinovic J, Gubler MC (2012) Phenotypic variability of Bardet-Biedl syndrome: focusing on the kidney. Pediatr Nephrol 27:7–15CrossRefPubMed

Karlberg N, Jalanko H, Perheentupa J, Lipsanen-Nyman M (2004) Mulibrey nanism: clinical features and diagnostic criteria. J Med Genet 41:92–98CrossRefPubMedPubMedCentral

Karlberg N, Jalanko H, Lipsanen-Nyman M (2007) Growth and growth hormone therapy in subjects with Mulibrey nanism. Pediatrics 120:e102–e111CrossRefPubMed

Karlberg S, Tiitinen A, Lipsanen-Nyman M (2004) Failure of sexual maturation in Mulibrey nanism. N Engl J Med 351:2559–2560CrossRefPubMed

Karlberg S, Toppari J, Karlberg N, Nurmio M, Karikoski R, Jalanko H, Lipsanen-Nyman M (2011) Testicular failure and male infertility in the monogenic Mulibrey nanism disorder. J Clin Endocrinol Metab 96:3399–3407CrossRefPubMed

Lipsanen-Nyman M, Perheentupa J, Rapola J, Sovijarvi A, Kupari M (2003) Mulibrey heart disease: clinical manifestations, long-term course, and results of pericardiectomy in a series of 49 patients born before 1985. Circulation 107:2810–2815CrossRefPubMed

Karlberg N, Jalanko H, Kallijarvi J, Lehesjoki AE, Lipsanen-Nyman M (2005) Insulin resistance syndrome in subjects with mutated RING finger protein TRIM37. Diabetes 54:3577–3581CrossRefPubMed

Karlberg N, Karlberg S, Karikoski R, Mikkola S, Lipsanen-Nyman M, Jalanko H (2009) High frequency of tumours in mulibrey nanism. J Pathol 218:163–171CrossRefPubMed

10.

National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents (2004) The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 114:555–576CrossRef

11.

Birth defects monitoring program (BDMP)/commission on professional and hospital activities (CPHA) surveillance data, 1988–1991 (1993) Teratology 48:658–675

12.

Bissler JJ, Siroky BJ, Yin H (2010) Glomerulocystic kidney disease. Pediatr Nephrol 25:2049–2056 quiz 2056–2059CrossRefPubMedPubMedCentral

13.

Bingham C, Hattersley AT (2004) Renal cysts and diabetes syndrome resulting from mutations in hepatocyte nuclear factor-1beta. Nephrol Dial Transplant 19:2703–2708CrossRefPubMed

14.

Raaijmakers A, Corveleyn A, Devriendt K, van Tienoven TP, Allegaert K, Van Dyck M, van den Heuvel L, Kuypers D, Claes K, Mekahli D, Levtchenko E (2015) Criteria for HNF1B analysis in patients with congenital abnormalities of kidney and urinary tract. Nephrol Dial Transplant 30:835–842CrossRefPubMed

15.

Pusztaszeri MP, Seelentag W, Bosman FT (2006) Immunohistochemical expression of endothelial markers CD31, CD34, von Willebrand factor, and Fli-1 in normal human tissues. J Histochem Cytochem 54:385–395CrossRefPubMed

16.

Reinders ME, Rabelink TJ, Briscoe DM (2006) Angiogenesis and endothelial cell repair in renal disease and allograft rejection. J Am Soc Nephrol 17:932–942CrossRefPubMed

17.

Boor P, Ostendorf T, Floege J (2014) PDGF and the progression of renal disease. Nephrol Dial Transplant 29 [Suppl 1]:i45–i54CrossRefPubMed

18.

Rossini M, Cheunsuchon B, Donnert E, Ma LJ, Thomas JW, Neilson EG, Fogo AB (2005) Immunolocalization of fibroblast growth factor-1 (FGF-1), its receptor (FGFR-1), and fibroblast-specific protein-1 (FSP-1) in inflammatory renal disease. Kidney Int 68:2621–2628CrossRefPubMed

19.

Nies VJ, Sancar G, Liu W, van Zutphen T, Struik D, Yu RT, Atkins AR, Evans RM, Jonker JW, Downes MR (2016) Fibroblast growth factor signaling in metabolic regulation. Front Endocrinol (Lausanne) 6:193

20.

Stokes MB, Hudkins KL, Zaharia V, Taneda S, Alpers CE (2001) Up-regulation of extracellular matrix proteoglycans and collagen type I in human crescentic glomerulonephritis. Kidney Int 59:532–542CrossRefPubMed

21.

Phanish MK, Winn SK, Dockrell ME (2010) Connective tissue growth factor-(CTGF, CCN2)—a marker, mediator and therapeutic target for renal fibrosis. Nephron Exp Nephrol 114:e83–e92CrossRefPubMed

22.

Liu Y (2011) Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol 7:684–696CrossRefPubMedPubMedCentral

23.

Rastaldi MP, Ferrario F, Giardino L, Dell’Antonio G, Grillo C, Grillo P, Strutz F, Muller GA, Colasanti G, D’Amico G (2002) Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies. Kidney Int 62:137–146CrossRefPubMed

24.

Kallijarvi J, Lahtinen U, Hamalainen R, Lipsanen-Nyman M, Palvimo JJ, Lehesjoki AE (2005) TRIM37 defective in mulibrey nanism is a novel RING finger ubiquitin E3 ligase. Exp Cell Res 308:146–155CrossRefPubMed

25.

Balestra FR, Strnad P, Flückiger I, Gönczy P (2013) Discovering regulators of centriole biogenesis through siRNA-based functional genomics in human cells. Dev Cell 25:555–571CrossRefPubMed

Titel: Renal findings in patients with Mulibrey nanism
verfasst von: Johanna Sivunen
Susann Karlberg
Jouko Lohi
Niklas Karlberg
Marita Lipsanen-Nyman
Hannu Jalanko
Publikationsdatum: 22.04.2017
Verlag: Springer Berlin Heidelberg
Erschienen in: Pediatric Nephrology / Ausgabe 9/2017
Print ISSN: 0931-041X
Elektronische ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-017-3669-5

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Renal findings in patients with Mulibrey nanism