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Hepatocyte Nuclear Factor 1b–Associated 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 , involved in the development of the kidney, urogenital tract, pancreas, liver, brain, and para- HETEROGENIC PRESENTATION thyroid gland. Nephrologists might diagnose HNF1b-associated 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 fam- ily 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 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 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 , 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 , 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 of HNF1b expression by magnesium (12%), and a urine calcium tory hyperparathyroidism. In addition, microRNA could contribute to the concentration ,0.5 mmol/L. There was there was aplasia of the right kidney with above findings. no evidence of diabetes mellitus (hemo- some small cortical cysts in the left globin A1c of 41 mmol/mol). The pa- solitary kidney. His endogenous creati- tient’smedicalhistoryrevealedprimary nine clearance was stable at approxi- HNF1b-ASSOCIATED KIDNEY amenorrhea with congenital anomalies mately 74 ml/min but he suffered from DISEASE compatible with the diagnosis of Mayer– gout. Twelve years after presentation, our Rokitansky–Küster syndrome. She had experience with patients with HNF1b- Cystic and Noncystic Kidney suffered from recurrent, although self- associated disease eventually led us to Disease limiting, arthritis in the past. A renal ul- confirm the heterozygous full deletion of Nishigori et al. were the first to describe a trasound showed two small kidneys with the HNF1B gene. Because of the concom- family with renal cysts, proteinuria, and multiple cysts. HNF1b genetic analysis itant presence of hypomagnesemia and renal dysfunction that preceded the

346 Journal of the American Society of Nephrology J Am Soc Nephrol 27: 345–353, 2016 www.jasn.org BRIEF REVIEW

Table 1. Five patients exemplifying the heterogenic presentation of the multisystem phenotype of HNF1b-associated disease Characteristic Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Referral reason Suspected Renal insufficiency Hypomagnesemia Cisplatin-induced Hypomagnesemia ADPKD and solitary hypomagnesemia and solitary kidney kidney Signs and symptoms at presentation Renal cysts Yes Yes Yes No Yes Diabetes Yes No No Yes No Reduced renal function No Yes Yes Yes No CAKUT No Yes No Yes Yes Hypomagnesemia No No Yes Yes Yes Hyperuricemia/gout Yes/no No/no No/no Yes/no Yes/yes Elevated liver enzymes No Yes No No No Exocrine pancreatic disease No No No No No Genital malformations No No Yes No No Mental retardation/autism No No No No No Hyperparathyroidism Yes No No Yes Yes Sex Woman Man Woman Woman Man Family history None Multipleb None Multipled None HNF1B mutation or deletiona c.883C.T c.826C.T Deletion Deletion Deletion Age at presentation (at nephrologist), yr 39 27 42 50 24 Diagnostic delay (from first 3 mo 13 yr 1 mo None 12 yr nephrologic referral) HNF1b score at presentation 12 7, 13c 10 8 9 ADPKD, autosomal dominant polycystic kidney disease. aSequencing was performed by ion semiconductor and/or Sanger sequencing, and all reported mutations were confirmed by Sanger sequencing. bThe patient’s family history included CAKUT, reduced renal function, diabetes, and elevated liver enzymes in the patient’sfather. cAt the first presentation to the nephrologist, the patient’sHNF1b score would have been 7; on reevaluation 13 years later, the HNF1b score had progressed to 13. dThe patient’s family history included gout and hypomagnesemia in the patient’s father.

clinical presentation of diabetes.9 Al- developmental and cystogenic pathways, second and fifth cases are examples of though the exact role of HNF1b in there is a wide spectrum of developmen- such renal developmental abnormalities, kidney development awaits further ex- tal renal abnormalities in patients with instead of classical cystic disease. amination, it is clear that HNF1B muta- HNF1B mutations. Renal abnormalities may be detected tions can lead to abnormal nephron Faguer et al. reported the clinical pre- by ultrasonography when analyzed for development.10 The latter process in- sentation in 27 adults from 20 families renal function decline at a later age or volves structures arising from the ure- with HNF1B mutations or deletions.12 antenatally by prenatal ultrasonography teric bud, giving rise to collecting ducts, Renal phenotype appeared to be ex- in pregnancy. HNF1b is therefore also the renal pelvis and , and the meta- tremely heterogenic, with 62% of pa- recognized as a cause of congenital nephric mesenchyme responsible for the tients having one or more renal cysts. anomalies of the kidney and urinary formationofthebiggestpartofthe These cysts may be apparent on a renal tract (CAKUT). Among anomalies nephron. Both embryonic structures ex- ultrasound, mostly in the cortex, but found at prenatal screening, CAKUT is press HNF1b,andHNF1b inactivation they sometimes require magnetic reso- present in 20%–30% of the cases.13,14 in mice leads to defective S-shaped body nance imaging to be detected. Our first Renal function ranges from normal to formation resulting in an enlarged patient showed the classical phenotype ESRD, but most patients have some de- Bowman’s capsule and renal tubular dys- of renal cysts and diabetes mellitus, but gree of impaired kidney function. Urine genesis.10 In addition to regulating genes not all patients display typical cortical analysis in general shows no cells and a involved in nephrogenesis per se,HNF1b renal cystic disease. Therefore, the term proteinuria of ,1 g/24 h. Occasionally, affects several genes that are known to be HNF1b nephropathy has been intro- renal biopsies are performed in patients involved in the pathogenesis of renal cys- duced to encompass all described renal that do not present with CAKUT, with tic disease. Examples are the PKD2 and abnormalities, including multicystic the histologic diagnosis often being vari- PKHD1 genes that are mutated in poly- renal dysplasia, renal hypoplasia, unilat- able and nonspecific. However, glomer- cystic kidney disease. HNF1b mutation eral , microcystic dyspla- ulomegaly, glomerulocystic disease, and in mice inhibited PKHD1 gene expres- sia, , atypical familial small tubular cysts may be encoun- sion and induced formation.11 juvenile hyperuricemic nephropathy, tered.15 Faguer et al. reported a renal Because HNF1b regulates several and urinary tract malformations. Our function decline of 22.45 ml/min per

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tubulopathy should also be considered in patients with a phenotype resembling Gitelman syndrome, especially when a genetic confirmation of the latter diag- nosis is absent, whether other clinical features of HNF1b-associated disease are present.

Hyperuricemia and Early Onset Gout Most patients with HNF1B mutations display hyperuricemia, and some pres- entwithearlyonsetgoutlikeour patients 2, 4, 5, and possibly 3.20 Impor- tantly, for this reason, some patients with HNF1B mutations would meet the diagnostic criteria for familial juve- nile hyperuricemic nephropathy. The latter condition is caused by mutations in the UMOD gene, which encodes uromodulin and is suggested to play a role in renal urate transport.21 HNF1B knockout mice also showed reduced UMOD expression, suggesting that HNF1b regulates transcription of Figure 1. Renal and extrarenal features of HNF1b-associated disease. The clinical signs UMOD.22 Thus, abnormal urate trans- and symptoms that are currently associated with HNF1B mutations and deletions are port could be the reason why patients depicted. with HNF1B mutations present with early onset gout and abnormal elevated urate levels discrepant to their level of 1.73 m2 per year over a median follow- HNF1b-associated disease is uncertain, renal function decline. up of 5.5 years in their cohort of HNF1b but it appears to be high. Adalat et al. sug- patients.12 About 13%–15% of patients gested that HNF1b is necessary for the eventually develop ESRD.16 In a retro- transcription of the FXYD2 gene, encoding HNF1b-ASSOCIATED spective study of 377 patients with the g-subunit of the sodium-potassium EXTRARENAL DISEASE HNF1b mutations, no correlation was ATPase expressed in the distal convoluted found between the type and location of tubule, which is thought to play a role in Diabetes and Exocrine Pancreas the genetic mutation and severity of transcellular magnesium reabsorption.17 Dysfunction .8 Indeed, FXYD2 mutations are associ- As described above, HNF1B mutations ated with hypomagnesemia and hypo- were first described as a cause of MODY. Hypomagnesemia and calciuria as well.18 Ferrè et al. confirmed HNF1b has structural similarity to Hypocalciuria that HNF1b specifically acts as an acti- HNF1a, the affected gene in the most Ina2009retrospectivestudy in66children vator of the g-subunit and that HNF1B common type of MODY (MODY3). with CKD who were tested for HNF1B mutations identified in patients with hy- Horikawa et al. sequenced the HNF1b mutations, Adalat et al. found that hypo- pomagnesemia prevented g-subunit tran- transcription factor in 57 patients with magnesemia was more prevalent in pa- scriptional activation, with a dominant MODY and found 1 patient with an tients with a HNF1B mutation (48%) negative effect on wild-type HNF1b.19 HNF1B loss-of-function mutation.1 versus patients without the mutation The combination of hypomagnese- HNF1b is thought to play an important (2%).17 In the patients with an HNF1B mia and hypocalciuria is also encoun- role in early development and differen- mutation and hypomagnesemia, there tered in Gitelman syndrome, in which a tiation of the pancreas.23 It regulates the was a renal magnesium leak (median frac- defect of distal convoluted tubule sodium expression of key pancreatic proteins, tional excretion of magnesium of 6.5%) as chloride cotransport is involved. Of note, including the HNF4A and SLC2A2 well as a concomitant hypocalciuria. Be- in two of the above-described patients, genes, the latter encoding the glucose cause this cohort was highly selected, the the diagnosis of Gitelman syndrome was transporter GLUT2.24 HNF1B mutations true prevalence of hypomagnesemia in initially considered. Therefore, HNF1b can therefore result not only in pancreatic

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Figure 2. HNF1b as a promiscuous transcription factor. Target genes known to be regulated by the HNF1b transcription factor in several organ systems, responsible for the diverse multisystem clinical signs and symptoms, are depicted. b cell dysfunction, leading to diabetes or aplasia, as was present in our third pa- sporadically in neonates and children, mellitus, but also pancreatic atrophy and tient. This indicates HNF1B as a candidate adult patients with HNF1B mutations exocrine pancreatic dysfunction. Pan- gene for Mayer–Rokitansky–Küster syn- mostly show asymptomatic liver enzyme creatic atrophy affecting either the drome, as was suggested in publications elevations.33 head or body of the pancreas is frequently preceding the description of genital abnor- observed on computed tomography in malities in renal cysts and diabetes syn- RCC and Other Malignancies patients with HNF1B mutations in com- drome.30 Hypospadia and other genital Case studies suggest that lack of HNF1b bination with exocrine pancreatic dys- abnormalities are sporadically described expression is related to chromophobe function, which is often subclinical.25 in male individuals. These may be coinci- RCC.34,35 Chromophobe RCC is a rare Patients mostly present with diabetes in dent findings, or they may be part of the renal cancer that has relatively pale cyto- their early adulthood but with a large CAKUT spectrum described above, in plasm under the microscope, as opposed variation from the neonatal period to which HNF1B mutations are the most to the clear cytoplasm in clear cell RCC. late middle age.7,26 Endogenous insulin commonly identified genetic cause.31,32 This raises the question of whether we production is present and patients with should screen patients with HNF1B mu- diabetes are not obligatorily insulin de- Elevated Liver Enzymes tations for renal tumors. Several reports pendent.27 However, the majority of pa- In contrast with what its name would have also suggested a role for HNF1b as a tients eventually require insulin therapy suggest, not much is currently known tumor marker in different tumors such for an adequate glycemic control, which regarding the molecular (patho)physiol- as hepatocellular carcinoma,36,37 gyne- is not the case for HNF1a-associated ogy of HNF1b in either hepatocytes or cologic tumors,38,39 and prostate carci- MODY. Overall, HNF1B mutations are the liver and biliary tract in general. Liver noma.40 The clinical significance of an infrequent cause of MODY, occurring enzymes, particularly alanine amino- these findings for patients with HNF1B in ,1% of cases.28 transferase and g-glutamyl transpepti- mutations is currently unknown but dase, are frequently elevated without deserves further attention. Genital Tract Malformations signs of liver disease or hepatic insuffi- Congenital abnormalities of the genital ciency, like in our second patient.15 Liver Mental Retardation and Autism tract are found rather frequently in pa- biopsy in HNF1b patients with abnor- In a cohort of 53 children with HNF1B tients with HNF1B mutations.29 These are mal liver enzyme levels generally reveals mutations, 3 children were found to often malformations resulting from normal liver tissue.25 Interestingly, he- have mental retardation and autism, a aplasia and failure of the fusion of the patic cyst formation does not appear to higher number than expected based on Müllerian ducts, resulting in congenital occur. In contrast with the potential se- the prevalence in the general pediatric uterine and upper vaginal abnormalities vere neonatal cholestasis that occurs population.41 Among patients referred

J Am Soc Nephrol 27: 345–353, 2016 HNF1b: Beyond Cysts and Diabetes 349 BRIEF REVIEW www.jasn.org for genetic testing for neurodevelop- were, however, all selected based on renal recognition of individual cases difficult. mental or psychiatric disorders, HNF1B abnormalities such as cysts and dysplasia, Differential diagnosis may vary based on mutations were also more frequently and HNF1B gene anomalies were detected the presenting features in the individual present compared with ethnically in 19% of these patients.48 patient. In children, the most prominent matched controls.42 Most of the epidemiologic data con- presentation of HNF1b-associated dis- cerns pediatric (CAKUT) populations, ease is with CAKUT. At adult age, how- Early Onset Hyperparathyroidism whereas diagnosis can be especially diffi- ever, especially when the presentation Ferrè et al. observed early hyperparathy- cult if the patient presents at adult age. We deviates from the classical cysts and di- roidism and parathyroid hormone reviewed the existing literature to evaluate abetes phenotype, the disease can be (PTH) levels that were judged inappro- differences in the phenotype between difficult to recognize. The clinical priately high relative to kidney function pediatric and adult populations. These nephrologist can encounter HNF1b- in several patients with known HNF1B studies are unable to provide sound quan- associated disease in the form of suspected mutations or deletions.43 HNF1b was titative data that can be generalized on a polycystic kidney disease, particularly demonstrated to be expressed by PTH- population level. Most studies consisted of when kidneys are not enlarged, or pre- producing parathyroid gland cells.43 selected patient groups, often with specific sumed diabetic nephropathy. CKD in Wild-type HNF1b inhibited transcrip- inclusion criteria. Moreover, there are combination with renal cysts is easily tion of the PTH gene, thus functioning limited studies in which both children incorrectly diagnosed as autosomal dom- as a transcriptional repressor of PTH and adults were described. The prevalence inant polycystic kidney disease or medul- production. HNF1b mutations found of hypomagnesemia ranges from 0 to lary cystic kidney disease. In such cases, in patients lost their repressive effects on 100% in the different studies, but the the localization of the cysts, the size of PTH transcription, which could explain prevalence in adults is consistently higher the kidneys, the absence of a clear family early onset hyperparathyroidism in pa- in those studies that included children and history, and the presence of extrarenal tients with HNF1B mutations. However, adults.43,44,49 The same appears to be true symptoms could help in being alert for whether this HNF1b-mediated PTH reg- with regard to the extrarenal phenotypes an alternative diagnosis. CKD in com- ulation indeed leads to increased and of elevated liver enzymes, pancreatic hy- bination with diabetes is frequently discrepant hyperparathyroidism needs poplasia, and diabetes mellitus. These dif- misdiagnosed as diabetic nephropathy, confirmationinothercohortsofpa- ferences might be related to a delayed although the renal impairment mostly tients with HNF1B mutations. onset of the phenotypical changes. Alter- precedes the diagnosis of diabetes mellitus natively, asymptomatic phenotypical in HNF1b-associated disease. Part of the changes may be detected during routine difficulty in recognizing these patients of EPIDEMIOLOGY investigations during follow-up. With re- course lies in the fact that many associated gard to the CAKUT phenotype, there is extrarenal signs and symptoms occur Because of the variable presentation, com- only one study including both children commonly in the (nephrologic) popula- binedwithalikelyconsiderablepercentage and adults that clearly reports frequencies tion. Gout and/or hyperparathyroidism in of patients with HNF1B mutations not of signs and symptoms; unfortunately, the presence of CKD are easily interpreted being recognized, interpretation of epide- CAKUT itself was an inclusion criterion, as complications secondary to the CKD miologic data is difficult. The currently at least when it came to the pediatric pa- itself but could be a diagnostic clue if available epidemiologic data mostly con- tients.44 With the emergence of whole- they are judged discrepant to the degree cern selected cohorts and are probably not exome sequencing in genetic diagnosis, a of renal insufficiency. HNF1b mutations readily applicable to the general popula- better estimate of overall prevalence(s) should also be part of the differential di- tion. For instance, a recent Belgian study can possibly be attained in the future. agnosis of renal hypomagnesemia and can found a 10% prevalence of HNF1B muta- However, whole gene deletions could be even mimic Gitelman syndrome because tions in 205 patients with CAKUT,44 and missed with this technique when no spe- of the concomitant hypocalciuria. Other similar cohorts yielded prevalence rates of cific post hoc copy number variation anal- clinical signs or symptoms of HNF1b- 5%–31%.6,8,45 In a large cohort of 419 ysis or similar is performed. associated disease should be actively children with CKD, 3 patients showed a sought for in these patients. HNF1b- mutation in the HNF1B gene.46 Other related disease can also be categorized as studies noted a prevalence of 9% in kidney WHICH INDIVIDUALS SHOULD BE part of the group of conditions called au- transplant recipients with unknown pri- SCREENED FOR HNF1b tosomal dominant tubulointerstitial mary disease (mostly CAKUT) and up to MUTATIONS? kidney disease. These are diseases charac- 40% in patients with the combination of terized by bland urinary sediment, tubular renal malformations and diabetes.16,47 The heterogenic presentation of HNF1B and interstitial fibrosis, and slowly pro- Clissold et al. summarized the prevalence mutations in combination with the fre- gressive kidney disease.50 Indeed, the of HNF1B mutations in nine studies in quent lack of a positive family history phenotypes associated with HNF1B mu- cohorts with $50 patients. These patients owing to de novo mutations makes tations partly overlap with mutations in

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REN, UMOD,andMUC1,whicharealso who would have scored below the cutoff DISCLOSURES part of the spectrum of autosomal domi- value for the HNF1b scoring system at None. nant tubulointerstitial kidney disease. presentation. Performance of such a score There are currently no clear directives of course also depends on the amount of REFERENCES on which patients should be genetically clinical screening that was done before the tested toconfirm the diagnosis. Ina cohort moment that the score is applied. Thus, of 205 CAKUT patients (147 pediatric, 58 deciding whether a patient should be 1. Horikawa Y, Iwasaki N, Hara M, Furuta H, HNF1B Hinokio Y, Cockburn BN, Lindner T, Yamagata K, adult) with renal anomalies in combina- screened for mutations currently Ogata M, Tomonaga O, Kuroki H, Kasahara T, tion with extrarenal symptoms associated still comes down to the presence of clinical Iwamoto Y, Bell GI: Mutation in hepatocyte with HNF1b,Raaijmakerset al. recently suspicion, possibly aided by a clinical risk nuclear factor-1 beta gene (TCF2) associated showed that bilateral renal anomalies, re- score, and the attention of the caring phy- with MODY. Nat Genet 17: 384–385, 1997 nal cysts from unknown origin, a combi- sician. In addition, one always needs to 2. Fajans SS, Bell GI: MODY: History, genetics, pathophysiology, and clinical decision mak- nation of two major renal anomalies, and keep in mind that proving causality in ing. Diabetes Care 34: 1878–1884, 2011 hypomagnesemia were all predictive for terms of interpretation of genetic diagno- 3. 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Fischer E, Pontoglio M: HNF1beta and de- 49 fi fi 91%, positive predictive value 19.8%). lation, with speci csigni cance to the fective nephrogenesis: A role for interacting This risk score may facilitate identification nephrologist.Itislikelythatanun- partners? Kidney Int 74: 145–147, 2008 of undetected patients with HNF1B known but potentially large percentage 6. Ulinski T, Lescure S, Beaufils S, Guigonis V, mutation-related disease. However, the of HNF1b-associated kidney disease is Decramer S, Morin D, Clauin S, Deschênes G, Bouissou F, Bensman A, Bellanné-Chantelot risk tool has only been validated in the currently not being recognized or is mis- ’ C: Renal phenotypes related to hepatocyte authors own cohort, which was a very diagnosed. In addition, there can be a nuclear factor-1beta (TCF2) mutations in a selected population of mostly pediatric considerable diagnostic delay before the pediatric cohort. JAmSocNephrol17: 497– patients with CAKUT who were previ- disease is eventually recognized, as ex- 503, 2006 ously selected for HNF1B mutational emplified in some of the presented cases. 7. Edghill EL, Bingham C, Ellard S, Hattersley AT: Mutations in hepatocyte nuclear factor- screening. The score excludes patients be- Although no causal therapy is currently 1beta and their related phenotypes. JMed low the cutoff from diagnostic evaluation, available, diagnosing the syndrome is Genet 43: 84–90, 2006 although sensitivity might be consider- important. Early recognition makes 8. Heidet L, Decramer S, Pawtowski A, Morinière V, ably lower when the score is eventually (family) screening for diabetes, renal Bandin F, Knebelmann B, Lebre AS, Faguer S, validated in other cohorts. Although all function decline, hypomagnesemia, Guigonis V, Antignac C, Salomon R: Spectrum of HNF1B mutations in a large cohort of pa- patients presented above eventually andassociatedhypokalemiapossible, ’ tients who harbor renal diseases. Clin J Am Soc scored above the cutoff on Faguer s and it may prevent unnecessary exami- Nephrol 5: 1079–1090, 2010 HNF1b score, patient 2 did not at the nations and biopsies. In addition, ge- 9. Nishigori H, Yamada S, Kohama T, Tomura H, time of initial presentation, indicating netic counseling should be offered to ShoK,HorikawaY,BellGI,TakeuchiT,TakedaJ: that an unknown percentage of patients patients and their family members. Frameshift mutation, A263fsinsGG, in the he- , patocyte nuclear factor-1beta gene associated with an initial risk score 8 could go un- with diabetes and renal dysfunction. Diabetes detected. Indeed, even in the rather se- 47: 1354–1355, 1998 lected CAKUT cohort of Raaijmakers ACKNOWLEDGMENTS 10. Massa F, Garbay S, Bouvier R, Sugitani Y, Noda T, et al., the HNF1b score would have missed Gubler MC, Heidet L, Pontoglio M, Fischer E: 3of20identified patients.44 Consequent Financial support was received from the Hepatocyte nuclear factor 1b controls nephron tubular development. Development 140: 886– use of this scoring system thus might lead Innovatiefonds Zorgverzekeraars (Inno- HNF1B 896, 2013 us to falsely exclude mutations vation Fund of the Dutch Health Insurace 11. Hiesberger T, Shao X, Gourley E, Reimann A, in a considerable percentage of patients, companies). Pontoglio M, Igarashi P: Role of the hepatocyte

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