A complex microdeletion 17q12 phenotype in a patient with recurrent de novo membranous nephropathy
© Hinkes et al.; licensee BioMed Central Ltd. 2012
Received: 9 November 2011
Accepted: 14 May 2012
Published: 14 May 2012
Microdeletions on chromosome 17q12 cause of diverse spectrum of disorders and have only recently been identified as a rare cause of Mayer-Rokitansky-Kuester-Hauser-Syndrome (MRKH), which is characterized by uterus aplasia ± partial/complete vaginal aplasia in females with a regular karyotype. For the first time we report about a patient with a 17q12 microdeletion who is affected by MRKH in combination with a vascular and soft tissue disorder. Repeatedly she suffered from kidney transplant failure caused by consuming membranous nephropathy.
A 38-year-old female patient had been diagnosed with right kidney aplasia, left kidney dysplasia and significantly impaired renal function during infancy. Aged 16 she had to start hemodialysis. Three years later she received her first kidney transplant. Only then she was diagnosed with MRKH. The kidney transplant was lost due to consuming nephrotic syndrome caused by de novo membranous nephropathy, as was a second kidney transplant years later. In addition, a hyperelasticity syndrome affects the patient with congenital joint laxity, kyphoscoliosis, bilateral hip dysplasia, persistent hypermobility of both elbows, knees and hips. Her clinical picture resembles a combination of traits of a hypermobile and a vascular form of Ehlers-Danlos-Syndrome, but no mutations in the COL3A1 gene was underlying. Instead, array-based comparative genomic hybridisation (CGH) detected a heterozygous 1.43 Mb deletion on chromosome 17q12 encompassing the two renal developmental genes HNF1β and LHX1.
Deletions of HNF1β have recently drawn significant attention in pediatric nephrology as an important cause of prenatally hyperechogenic kidneys, renal aplasia and renal hypodysplasia. In contrast, membranous nephropathy represents an often-unaccounted cause of nephrotic syndrome in the adult population. A causative connection between theses two conditions has never been postulated, but is suggestive enough in this case to hypothesize it.
KeywordsMicrodeletion 17q12 syndrome Mayer-Rokitansky-Kuester-Hauser-Syndrome membranous nephropathy Nephrotic syndrome HNF1β LHX1
Microdeletions on chromosome 17q12 encompassing the hepatocyte nuclear factor 1β (HNF1β) have recently been characterized as an important cause of prenatally hyperechogenic kidneys, renal aplasia and renal hypodysplasia, which represent an important cause of chronic renal failure among children [1, 2]. The following case expands the diverse spectrum of disorders associated with 17q12 microdeletions and reveals a hypothetical link with membranous nephropathy (MN), a common and often unaccounted cause of nephrotic syndrome in the adult population.
In summary, this clinical picture resembles a mixture between a hypermobile (EDS3) and a vascular (EDS4) form of Ehlers-Danlos-Syndrome (EDS). Mutation analysis of the collagen type 3 alpha 1 gene (COL3A1), which is mutated in EDS4 and rarely in EDS3, was negative. We did not analyze tenascin-X (TNXB), another rare cause of EDS3, because characteristic hyperelastic skin changes were missing in our case. Mutations in the FBN1 gene, which is mutated in Marfan syndrome, had been excluded previously. As a next step a skin biopsy was taken for electron microscopy. It revealed a soft tissue disorder with loosely packed collagen fibres. The picture resembled findings in EDS4, without meeting the obligatory criteria of this disease, and was not suggestive of any other form of EDS.
Mayer-Rokitansky-Kuester-Hauser (MRKH) is a quite common inherited condition (1:4.000-5.000) characterized by uterus aplasia ± partial/complete vaginal aplasia in females with a regular karyotype XX/46 and physiological ovarial function [4–6]. Microdeletions of chromosome 17q12 including HNF1β, such as the one detected in this case have recently been identified as a rare cause of MRKH [4–6]. In a series of only five published cases, three women presented without (MRKH type I/typical) and two with kidney affection (MRKH type II/atypical). This finding reflects the highly variable clinical picture of even identical 17q12 microdeletions, reaching from diabetes (MODY5 or NODAT, as observed in our patient), to pancreas and liver anomalies, epilepsy, sensorineural hearing loss, cognitive impairment, autism and even schizophrenia [7–10]. Our patient has no neurological impairments and works as a teacher. Nevertheless, in addition to previously reported cases, she is affected by a soft tissue disorder with joint hypermobility and vascular hyperelasticity resembling a picture with features of both the hypermobile (EDS3) and the vascular (EDS4) form Ehlers-Danlos-Syndrome. We observed structural collagen changes of the skin in electron and light microscopy and excluded mutations in COL3A1. A causative genetic defect in another unknown locus is thereby not excluded. However, joint laxity has been described in selected individuals with deletions on 17q12 (DECIPHER patients 248627, 249204) and could result from the microdeletion itself.
Following kidney transplantation our patient repeatedly developed MN, a major cause of nephrotic syndrome in adults. We excluded secondary causes of MN and detected no PLA2R autoantibodies, which are found in approximately 75% of all cases of “idiopathic” MN in the adult population . The identification of further glomerular components as targets for autoantibodies in MN has been suggested . Our patient developed MN and consuming nephrotic syndrome years after her first, but only weeks after her second kidney transplantation. This clinical course may reflect a boostered alloimmune response against the kidney transplants, or alternatively a boostered response against a physiological glomerular epitope, which had not been expressed in the patient’s native kidney. Consistent with the second assumption, incubation of renal tissue specimens from healthy human controls with the patients’ serum resulted in granular deposits of immunoglobulin G (IgG) along the surface of the glomerular basement membrane (Figure 1d). Staining of respective mouse and rat kidney samples was negative. No candidate gene encoding a structural component of the glomerular filtration barrier as a hypothetical antibody target is located within the microdeletion on 17q12. Still, it is remarkable that the deletion includes two transcription factors, which are important in kidney development. HNF1β and LHX1 are physically adjacent genes on 17q12. Their gene products are involved in one signaling pathway in which HNF1β directly activates the promotor of LHX1. LHX1 is a major and dose-dependent regulator of various steps of renal and urogenital development. In the kidney LHX1 is required for epithelial tubular genesis and for podocyte development, including the crucial morphogenic step of the glomerulus from a comma to an S-shape stage and consecutively for the development of the glomerular filtration barrier [12, 13]. The significance of LHX1 in human disease remains an open question and it will be interesting to observe if eventually a connection between alterations of LHX1 and cases of membranous nephropathy such as ours can be demonstrated.
Above all, our case illustrates how recent molecular findings in inborn orphan disease may permit the diagnosis for complex phenotypes in adult patients - a circumstance which was truly appreciated by our patient 38 years after her first clinical presentation.
Written informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Series Editor of this journal.
Copy number variants
Collagen type III, alpha 1
Fibrillin 1 gene
Glomerular basement membrane
Hepatocyte nuclear factor-1β gene
Homeobox transcription factor 1 gene
New onset diabetes mellitus after transplantation
- NT-pro BNP:
N-terminal pro brain natriuretic peptide
Phospholipase A2 receptor.
We would like to thank our patient and her family for participating in this study. Also, we would like to thank the following colleagues: Gérard Lambeau, Institut de Pharmacologie Moléculaire et Cellulaire, Université de Nice Sophia Antipolis et Centre National de la Recherche Scientifique Valbonne, France for PLA2R antibody screening. Michaela Arend, Department of Nephrology and Hypertension, University of Erlangen-Nuremberg for technical assistance. Maike Büttner and Christoph Daniel, Department of Nephropathology, Thomas Winkler and Ute Wellmann, Department of Genetics, University of Erlangen-Nuremberg for tissue sample preparation. Sybille Thoma-Uszynski, Department of Dermatology, University of Erlangen-Nuremberg for clinical assessment of the vascular and soft tissue disorder. Ingrid Hauser, Electron Microscopy Unit, Department of Dermatology, University of Heidelberg, for reference assessment of the skin biopsy.
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