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 12. 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.

A now 38-year-old female patient was born as the third of four daughters of healthy parents. Her oldest sister remains healthy, while her second oldest sister suffers from idiopathic focal epilepsy and her youngest sister from Prader-Willi-Syndrome caused by a maternal parental disomy on chromosome 15. Following a regular pregnancy our patient first presented with a pyelonephritis at the age of four months. Right kidney aplasia and a significantly impaired renal function (serum creatinine 1.9 mg/dl, urea 83 mg/dl) were then noted, already indicating dysplasia of the left kidney. Her female external genitalia showed no anomalies and cystoscopy documented the presence of bilateral ureters. Over the following years chronic renal failure progressed as recurrent urinary tract infections occurred. Finally, she was referred to a pediatric nephrology unit at the age of 10 years and started hemodialysis six years later with a serum creatinine of 6 mg/dl. Aged 19 she received her first kidney transplant without any complications. As primary amenorrhea had persisted while pubertal development was commensurate with age, a diagnostic laparoscopy was undertaken and revealed a rudimentary uterus and regular ovaries. On the basis of a normal 46/XX karyotype the diagnosis of atypical Mayer-Rokitansky-Kuester-Hauser-Syndrome (i.e. MRKH Type II) was made. Aged 28 her first kidney transplant was lost due to consuming nephrotic syndrome caused by biopsy-proven de novo MN. At the age of 36 a second kidney transplantation was performed. Despite thymoglobulin induction and an intensified triple immunosuppressive therapy (tacrolimus, mycophenolate mofetil, prednisolone), under which she developed

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In addition to her urogenital anomalies our patient is affected by a hyperelasticity syndrome with congenital joint laxity, kyphoscoliosis, and bilateral hip dysplasia. She shows persistent hypermobility of both elbows and knees and is easily able to place her feet behind her head, all of which are very unusual findings in a longstanding dialysis patient (Figure 2a-c). Her Beighton score is currently 8/9. As a result of dilating hyperelastic vascular walls arterio-venous fistulas on both arms rapidly developed hyperdynamic flows. Repeated surgical banding of the fistulas accomplished only a temporary improvement, so that vascular access was ligated shortly after transplantation to control right heart failure with tricuspid valve insufficiency (Figure 2d).

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.

We therefore performed an array-based comparative genomic hybridisation (CGH) and detected a heterozygous 1.43 Mb deletion on chromosome 17q12 (Figure 3). This deletion contained sixteen RefSeq genes and was absent in both the father and the mother of our patient, consistent with a de novo copy number variant (CNV).

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 456. Microdeletions of chromosome 17q12 including HNF1β, such as the one detected in this case have recently been identified as a rare cause of MRKH 456. 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 78910. 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 3. The identification of further glomerular components as targets for autoantibodies in MN has been suggested 3. 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 LHX111. 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 1213. 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.

CNV, Copy number variants; COL3A1, Collagen type III, alpha 1; EDS, Ehlers-danlos-syndrome; FBN1, Fibrillin 1 gene; GBM, Glomerular basement membrane; HNF1β, Hepatocyte nuclear factor-1β gene; LHX1, Homeobox transcription factor 1 gene; MN, Membranous nephropathy; MRKH, Mayer-rokitansky-kuester-hauser-syndrome; NODAT, New onset diabetes mellitus after transplantation; NT-pro BNP, N-terminal pro brain natriuretic peptide; PLA2R, Phospholipase A2 receptor.

The author(s) declare that they have no competing interest.

BH wrote and revised the manuscript, coordinated the studies for this manuscript. JJ was the treating physician and substantially supported the writting of this manuscript. KA carried out the nephropathologic studies. HB, SN, CB carried out the molecular genetic studies. KH, MGS, WR, KUE supported this work by providing critique of succesive drafts of the manuscript. All authors read and approved the final manuscript.