NDT Advance Access originally published online on November 24, 2006
Nephrology Dialysis Transplantation 2007 22(4):1271-1272; doi:10.1093/ndt/gfl695
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Renal cysts and diabetes due to a heterozygous HNF-1ß gene deletion
Email: josef.patsch{at}uki.atSir,
Diabetic nephropathy has become the major cause of end-stage renal failure in Western countries. However, in the renal cysts and diabetes (RCAD) syndrome, nephropathy is an independent feature rather than a direct consequence of the diabetes. This RCAD syndrome is caused by mutations of the hepatocyte nuclear factor-1ß (HNF-1ß) [1]. It is a non-diabetic renal disease resulting from abnormal renal development, and a non-ketonic diabetes mellitus characterized by an early onset, due to a primary defect in the function of the ß-cells of the pancreas [2].
We present a 28-year-old proband, diagnosed with diabetes mellitus in his adolescence. He had received low-dose once-daily insulin therapy since the age of 18 years, and presented himself to our University Hospital at the age of 28. On clinical examination, the patient was lean (BMI of 19.4 kg/m2), the daily insulin requirement was low (0.19 IU/kg), the basal C-peptide concentration was reduced to 0.29 pmol/ml and liver enzyme levels were in the normal range. The patient displayed no antibodies to glutamate decarboxylase or IA-2, but a chronic renal insufficiency with a glomerular filtration rate of 25.5 ml/min. Unlike most patients with diabetic nephropathy, our patient had no relevant proteinuria (0.15 g/day). He was hyperuricaemic, and had a low fractional excretion rate of uric acid (2.2%). We performed a magnetic resonance imaging of the abdomen, which revealed multiple renal cysts and an atrophic pancreatic body and tail (Figure 1). Furthermore, the right kidney and the right ureter were duplicated. His birth had been pre-term at the 35th gestational week with a birth weight of 1870 g (5th centile). Neither his parents, nor his two sisters showed any clinical signs of diabetes or nephropathy.
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The association of diabetes mellitus, renal cysts and urogenital anomalies prompted us to suspect that our patient has an HNF-1ß mutation. The molecular genetic analysis of the HNF-1ß gene by sequencing failed to detect a mutation [2]. Therefore, a multiplex ligation-dependent probe amplification assay was performed, which revealed a heterozygous deletion of the entire HNF-1ß gene, thus confirming the diagnosis of RCAD syndrome [3].
Patients with an HNF-1ß gene mutation present with renal abnormalities before the manifestation of diabetes mellitus; in most cases, renal abnormalities are present in utero [4]. Pancreatic atrophy and low birth weight are also features of HNF-1ß mutations. Most importantly, patients with an HNF-1ß mutation may also be at risk of developing renal cell carcinomas, since recent evidence suggests that HNF-1ß is a tumour suppressor gene [5].
In conclusion, patients with unexplained nephropathy and/or renal cysts should be routinely screened for an HNF-1ß mutation in order to differentiate the RCAD syndrome from diabetic nephropathy. Ultimately, these patients are good candidates for combined kidney and pancreas transplantation.
Conflict of interest statement. None declared.
1Department of Internal Medicine
Division of General Internal Medicine
2Department of Internal Medicine
Division of Nephrology
Innsbruck Medical University
Austria
3Institute of Biomedical and
Clinical Science
Penisula Medical School
Exeter, UK
References
- Horikawa Y, Iwasaki N, Hara M, et al. (1997) Mutation in hepatocyte nuclear factor-1 beta gene (TCF2) associated with MODY. Nat Genet 17:384–385.[CrossRef][ISI][Medline]
- Edghill EL, Bingham C, Ellard S, Hattersley AT. (2006) Mutations in hepatocyte nuclear factor-1beta and their related phenotypes. J Med Genet 43:84–90.
[Abstract/Free Full Text] - Edghill EL, Owens M, Harries LH, et al. (2006) Hepatocyte nuclear factor-1beta gene deletions are common in subjects with unexplained renal disease and diabetes. Diabet Med Suppl 23:41.
- Haumaitre C, Fabre M, Cormier S, Baumann C, Delezoide AL, Cereghini S. (2006) Severe pancreas hypoplasia and multicystic renal dysplasia in two human fetuses carrying novel HNF1beta/MODY5 mutations. Hum Mol Genet 15:2363–2375.
[Abstract/Free Full Text] - Rebouissou S, Vasiliu V, Thomas C, et al. (2005) Germline hepatocyte nuclear factor 1alpha and 1beta mutations in renal cell carcinomas. Hum Mol Genet 14:603–614.
[Abstract/Free Full Text]
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  E. L. Edghill, R. A. Oram, M. Owens, K. L. Stals, L. W. Harries, A. T. Hattersley, S. Ellard, and C. Bingham Hepatocyte nuclear factor-1{beta} gene deletions--a common cause of renal disease Nephrol. Dial. Transplant., February 1, 2008; 23(2): 627 - 635. [Abstract] [Full Text] [PDF]
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