Hepatocyte Nuclear Factor 1B–Associated Kidney Disease: More Than Renal Cysts and Diabetes

BRIEF REVIEW www.jasn.org Hepatocyte Nuclear Factor 1b–Associated Kidney Disease: More than Renal Cysts and Diabetes Jacobien C. Verhave, Anneke P. Bech, Jack F.M. Wetzels, and Tom Nijenhuis Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands ABSTRACT Hepatocyte nuclear factor 1b (HNF1b)–associated disease is a recently recognized of this disease for the clinician. We illus- clinical entity with a variable multisystem phenotype. Early reports described an trate the heterogenic presentation of association between HNF1B mutations and maturity-onset diabetes of the young. HNF1b-associated disease on the basis These patients often presented with renal cysts and renal function decline that pre- of five selected patients, and we then ceded the diabetes, hence it was initially referred to as renal cysts and diabetes provide a concise review of the associated syndrome. However, it is now evident that many more symptoms occur, and diabe- signs and symptoms and their molecular tes and renal cysts are not always present. The multisystem phenotype is probably pathogenesis. attributable to functional promiscuity of the HNF1b transcription factor, involved in the development of the kidney, urogenital tract, pancreas, liver, brain, and para- HETEROGENIC PRESENTATION thyroid gland. Nephrologists might diagnose HNF1b-associated kidney disease in OF THE MULTISYSTEM patients referred with a suspected diagnosis of autosomal dominant polycystic kid- PHENOTYPE OF HNF1b- ney disease, medullary cystic kidney disease, diabetic nephropathy, or CKD of un- ASSOCIATED DISEASE known cause. Associated renal or extrarenal symptoms should alert the nephrologist to HNF1b-associated kidney disease. A considerable proportion of fi these patients display hypomagnesemia, which sometimes mimics Gitelman syn- The rst patient, a woman aged 39 years, drome. Other signs include early onset diabetes, gout and hyperparathyroidism, was referred to the nephrologist with elevated liver enzymes, and congenital anomalies of the urogenital tract. Because suspected polycystic kidney disease be- many cases of this disease are probably undiagnosed, this review emphasizes the cause of reduced eGFR (45 ml/min per 2 clinical manifestations of HNF1b-associated disease for the nephrologist. 1.73 m ) and renal cysts, without a family history of polycystic kidney disease. J Am Soc Nephrol 27: 345–353, 2016. doi: 10.1681/ASN.2015050544 Her medical history revealed recurrent urinary tract infections, enuresis noc- turna until age 25 years, and type 2 di- Hepatocyte nuclear factor 1 homeobox b with renal cystic disease shortly after their abetes mellitus and gout at age 32 years. (HNF1b)–associated disease is a re- recognition as a cause of MODY.2 This At the time of referral, her serum creat- cently recognized clinical entity with a disease was therefore renamed renal cysts inine was 94 mmol/L, uric acid was 0.46 variable, multisystemic phenotype. and diabetes syndrome in 2001.3 How- mmol/L, magnesium was 0.79 mmol/L, hemoglobin A1c was 39 mmol/mol HNF1B mutations were first described ever, it now seems to be a clinical entity while receiving subcutaneous insulin in 1997 as a rare genetic cause of maturity- with a more broad and variable pheno- therapy, and endogenous creatinine onset diabetes of the young (MODY).1 type. Moreover, not all patients with an clearance was approximately 80 ml/min MODY comprises a group of disorders HNF1B mutation actually have renal cysts without proteinuria. A renal ultrasound that are typically characterized by early and/or diabetes. age of onset of diabetes mellitus, usually Knowledge about the possible clinical before age 25 years, and pancreatic b cell manifestations of HNF1b-associated Published online ahead of print. Publication date dysfunction. MODY is classified accord- disease is important for the nephrologist available at www.jasn.org. ing to the underlying genetic defect and 13 in order to recognize these patients in the Correspondence: Dr. Tom Nijenhuis, Department fi of Nephrology, Radboud University Medical Center, different genes have been identi ed to clinical setting, because many of these PO Box 9101, 6500 HB, Nijmegen, The Netherlands. date. Most MODY subtypes rarely present clinical manifestations could warrant Email: [email protected] with extrapancreatic disease, except for nephrologic consultation. In this brief Copyright © 2016 by the American Society of HNF1B mutations, which were associated review,weemphasizethesignificance Nephrology J Am Soc Nephrol 27: 345–353, 2016 ISSN : 1046-6673/2702-345 345 BRIEF REVIEW www.jasn.org demonstrated multiple cortical as well demonstrated a large 1.43-Mb deletion hypocalciuria, the presence of additional as parapelvine cysts in both kidneys. at chromosomal location 17q12 (31,89– mutations in SLC12A3 or CLCNKB was The combination of diabetes at a young 33,32 Mb deletion including approxi- excluded. age and renal cysts was suggestive of mately 17 genes), including the HNF1B These clinical cases, summarized in HNF1b-associated disease. Genetic gene, which had occurred de novo in this Table1,illustratethehighlyvariable analysis indeed revealed a previously de- patient but had been previously described spectrum of renal and extrarenal pheno- scribed c.883C.T p.Arg295Cys HNF1B in patients with HNF1b-associated phe- types associated with HNF1b mutations, point mutation in an evolutionary con- notypes. The presence of additional mu- which is depicted in Figure 1. HNF1b- served amino acid in the homeobox do- tations in SLC12A3 or CLCNKB,causing associated disease occurs as a result of main of the HNF1b protein.4 Gitelman syndrome, was excluded. heterozygous mutations or deletions in The second patient is a man who was We were asked to evaluate patient 4, a the HNF1B gene (also known as tran- diagnosed with renal insufficiency (eGFR 50-year-old inpatient at the oncology scription factor 2 or TCF2) on chromo- 38 ml/min per 1.73 m2)atage27years.He clinic. She had refractory hypomagnese- somal region 17q12.5 It can occur as an was not obese (body mass index 23 kg/m2) mia during treatment for disseminated autosomal dominant inherited gene and no proteinuria was present. A renal ovarian malignancy. The hypomagnese- defect or as a spontaneous (de novo)mu- ultrasound revealed a congenital solitary mia had been attributed to cisplatin- tation, which is seen in 50%–60% of pa- kidney, and multiple small cortical cysts based chemotherapy and necessitated tients.6 HNF1b is a transcription factor were also reported on repeated ultraso- weekly intravenous supplementation. that is important in the regulation of the nography. His medical history revealed Her medical history included congenital transcription and expression of several unexplained elevated liver enzymes and anomalies of both ureters, leading to different target genes. The multisystem normal serum magnesium levels. His fa- urinary reflux that was surgically correc- phenotype is probably related to the fact ther also had a congenital solitary kidney, ted at age 10 years but led to chronic renal that HNF1b is a rather promiscuous chronic renal insufficiency, diabetes at age insufficiency (eGFR approximately transcription factor, which plays a role 37 years, and unexplained elevation of 40 ml/min per 1.73 m2) without protein- in the development of different organs liver enzymes despite multiple liver biop- uria. She was diagnosed with diabetes at such as the kidney, urinary and genital sies. Our patient later developed gout at age 24 years and had recurrent arthralgias, tract, pancreas, brain, parathyroid gland, age 32 years as well as diabetes mellitus, which were classified as diabetic arthrop- and liver. Figure 2 demonstrates that the and he now has mildly progressive CKD athy; however, the patient had been using HNF1b transcription factor regulates at age 40 years. Only recently, the combi- allopurinol because of increased serum many genes, some of them being tran- nation of symptoms and family history uric acid levels for some years. Interest- scription factors as well, which may be pointed us toward the presence of an ingly, her father suffered from frequent responsible for the diverse clinical phe- HNF1B mutation, which turned out to attacks of gout as well as persistent hypo- notype. Why loss of function of only one be a heterozygous missense mutation magnesemia after chemotherapeutic allele encoding this transcription factor [c.826C.T; p.(Arg276*)]. treatment for renal cell carcinoma is sufficient to lead to clinical disease is Patient 3 was referred to the nephrol- (RCC). No renal anomalies or cysts were largely unexplained, as is the cause of ogist because of chronic electrolyte dis- apparent on abdominal computed to- the clinical variability per se.7 In addi- turbances, in particular hypomagnesemia mography scanning. Genetic analysis tion, although the phenotype within (0.43 mmol/L) and a tendency for hypo- showed heterozygous deletion of all exons the family appears largely conserved kalemia (3.5 mmol/L), together with a of the HNF1B gene. in patients 3 and 5, the literature sug- mild metabolic alkalosis. Additional lab- Patient 5 is a man who was diagnosed gests that in general there is only a lim- oratory investigations showed a reduced with renal hypomagnesemia at age 24 ited genotype-phenotype correlation.8 eGFR of 44 ml/min per 1.73 m2,inap- years. One year earlier, he underwent Environmental factors or epigenetic propriately high fractional excretion of parathyroidectomy because of refrac- regulation

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