Renal Cysts And Diabetes Syndrome Research Articles

A Boy with End-stage Kidney Disease and Hypertriglyceridemia

Abstract Mutations in the HNF-1β gene have been found to be associated with renal cysts and diabetes syndrome (RCAD), also known as MODY5. The mutation is inherited in an autosomal dominant fashion, although sporadic mutations can be seen. Pediatric cases of HNF - 1β mutations are more likely to present with renal involvement like renal failure or renal hypoplasia. In young individuals, the detection of renal abnormalities usually pre-date the diagnosis of diabetes with a mean age of 24 years. We report a 5 year old, end stage kidney disease patient with renal cysts and hypertriglyceridemia (in the absence of overt diabetes) with a known pathogenic mutation in the Hepatocyte Nuclear Factor-1β (HNF-1β) gene on chromosome 17q12. This case expands the clinical spectrum of HNF-1β mutation disorders with a take home message, that end stage renal disease patients with unexplained hypertriglyceridemia (even in absence of diabetes mellitus) should alert a clinician for HNF-1β mutational analysis.

Review of neurodevelopmental disorders in patients with HNF1B gene variations.

This review investigates the association between neurodevelopmental disorders (NDD) and variations of the gene HNF1B. Heterozygous intragenetic mutations or heterozygous gene deletions (17q12 microdeletion syndrome) of HNF1B are the cause of a multi-system developmental disorder, termed renal cysts and diabetes syndrome (RCAD). Several studies suggest that in general, patients with genetic variation of HNF1B have an elevated risk for additional neurodevelopmental disorders, especially autism spectrum disorder (ASD) but a comprehensive assessment is yet missing. This review provides an overview including all available studies of patients with HNF1B mutation or deletion with comorbid NDD with respect to the prevalence of NDDs and in how they differ between patients with an intragenic mutation or 17q12 microdeletion. A total of 31 studies was identified, comprising 695 patients with variations in HNF1B, (17q12 microdeletion N = 416, mutation N = 279). Main results include that NDDs are present in both groups (17q12 microdeletion 25.2% vs. mutation 6.8%, respectively) but that patients with 17q12 microdeletions presented more frequently with any NDDs and especially with learning difficulties compared to patients with a mutation of HNF1B. The observed prevalence of NDDs in patients with HNF1B variations seems to be higher than in the general population, but the validity of the estimated prevalence must be deemed insufficient. This review shows that systematical research of NDDs in patients with HNF1B mutations or deletions is lacking. Further studies regarding neuropsychological characteristics of both groups are needed. NDDs might be a concomitant of HFN1B-related disease and should be considered in clinical routine and scientific reports.

17q12 deletion syndrome mouse model shows defects in craniofacial, brain and kidney development, and glucose homeostasis.

17q12 deletion (17q12Del) syndrome is a copy number variant (CNV) disorder associated with neurodevelopmental disorders and renal cysts and diabetes syndrome (RCAD). Using CRISPR/Cas9 genome editing, we generated a mouse model of 17q12Del syndrome on both inbred (C57BL/6N) and outbred (CD-1) genetic backgrounds. On C57BL/6N, the 17q12Del mice had severe head development defects, potentially mediated by haploinsufficiency of Lhx1, a gene within the interval that controls head development. Phenotypes included brain malformations, particularly disruption of the telencephalon and craniofacial defects. On the CD-1 background, the 17q12Del mice survived to adulthood and showed milder craniofacial and brain abnormalities. We report postnatal brain defects using automated magnetic resonance imaging-based morphometry. In addition, we demonstrate renal and blood glucose abnormalities relevant to RCAD. On both genetic backgrounds, we found sex-specific presentations, with male 17q12Del mice exhibiting higher penetrance and more severe phenotypes. Results from these experiments pinpoint specific developmental defects and pathways that guide clinical studies and a mechanistic understanding of the human 17q12Del syndrome. This mouse mutant represents the first and only experimental model to date for the 17q12 CNV disorder. This article has an associated First Person interview with the first author of the paper.

Establishment of PLAFMCi005-A induced pluripotent stem cells derived from PBMC from a patient with renal cysts and diabetes syndrome

Renal cysts and diabetes syndrome (RCAD) is caused by gene mutations in hepatocyte nuclear factor 1-β (HNF1B), but the underlying molecular mechanism is still unclear. This study established PLAFMCi005-A human induced pluripotent stem cells (iPSCs) by reprogramming peripheral blood mononuclear cells (PBMCs) from an RCAD patient. PLAFMCi005-A has differentiation potential and can be used to investigate the pathogenesis of RCAD caused by HNF1B gene mutations, thus promoting the development of related drugs.

Blood pressure in children with renal cysts and diabetes syndrome.

Cystic kidney diseases such as autosomal recessive or dominant polycystic kidney disease (ARPKD and ADPKD) are associated with high prevalence of arterial hypertension. On the contrary, studies on hypertension in children with renal cysts and diabetes (RCAD) syndrome caused by abnormalities in the HNF1B gene are rare. Therefore, the primary aim of our study was to investigate the prevalence of high blood pressure in children with RCAD syndrome due to HNF1B gene abnormalities and secondary to search for possible risk factors for development of high blood pressure. Data on all children with genetically proven RCAD syndrome from three pediatric nephrology tertiary centers were retrospectively reviewed (office blood pressure (BP), ambulatory blood pressure monitoring (ABPM), creatinine clearance, renal ultrasound, echocardiography, albuminuria/proteinuria). High blood pressure was defined as BP ≥ 95th percentile of the current ESH 2016 guidelines and/or by the use of antihypertensive drugs. Thirty-two children with RCAD syndrome were investigated. Three children received ACE inhibitors for hypertension and/or proteinuria. High blood pressure was diagnosed using office BP in 22% of the children (n = 7). In the 7 performed ABPM, 1 child (14%) was diagnosed with hypertension and one child with white-coat hypertension. Creatinine clearance, proteinuria, albuminuria, body mass index, enlargement, or hypodysplasia of the kidneys and prevalence of HNF1B-gene deletion or mutation were not significantly different between hypertensive and normotensive children.Conclusion:High blood pressure is present in 22% of children with RCAD syndrome. What is Known: • Arterial hypertension is a common complication in children with polycystic kidney diseases. What is New: • High office blood pressure is present in 22% and ambulatory hypertension in 14% of children with renal cyst and diabetes (RCAD) syndrome.

Variable Expressivity of HNF1B Nephropathy, From Renal Cysts and Diabetes to Medullary Sponge Kidney Through Tubulo-interstitial Kidney Disease

IntroductionIn humans, heterozygous mutations of hepatocyte nuclear factor 1beta (HNF1B) are responsible for a dominant inherited disease with both renal and extrarenal phenotypes. HNF1B nephropathy is the umbrella term that includes the various kidney phenotypes of the disease, ranging from congenital anomalies of the kidney and urinary tract (CAKUT), to tubular transport abnormalities, to chronic tubulointerstitial and cystic renal disease.MethodsWe describe 7 families containing 13 patients with ascertained HNF1B nephropathy. All patients underwent genetic testing and clinical, laboratory, and instrumental assessment, including renal imaging and evaluation of extrarenal HNF1B manifestations.ResultsSignificant inter- and intrafamilial variability of HNF1B nephropathy has been observed. In our cohort, HNF1B pathogenic variants presented with renal cysts and diabetes syndrome (RCAD); renal cystic phenotype mimicking autosomal dominant polycystic kidney disease (ADPKD); autosomal dominant tubulointerstitial kidney disease (ADTKD) with or without hyperuricemia and gout; CAKUT; and nephrogenic diabetes insipidus (NDI). Of note, for the first time, we describe the occurrence of medullary sponge kidney (MSK) in a family harboring the HNF1B whole-gene deletion at chromosome 17q12. Genotype characterization led to the identification of an additional 6 novel HNF1B pathogenic variants, 3 frameshift, 2 missense, and 1 nonsense.ConclusionHNF1B nephropathy may present with a highly variable renal phenotype in adult patients. We expand the HNF1B renal clinical picture to include MSK as a potential new finding. Finally, we expand the allelic repertoire of the disease by adding novel HNF1B pathogenic variants.

Clinical characteristics of HNF1B-related disorders in a Japanese population.

Hepatocyte nuclear factor 1β (HNF1B), located on chromosome 17q12, causes renal cysts and diabetes syndrome (RCAD). Moreover, various phenotypes related to congenital anomalies of the kidney and urinary tract (CAKUT) or Bartter-like electrolyte abnormalities can be caused by HNF1B variants. In addition, 17q12 deletion syndrome presents with multi-system disorders, as well as RCAD. As HNF1B mutations are associated with different phenotypes and genotype-phenotype relationships remain unclear, here, we extensively studied these mutations in Japan. We performed genetic screening of RCAD, CAKUT, and Bartter-like syndrome cases. Heterozygous variants or whole-gene deletions in HNF1B were detected in 33 cases (19 and 14, respectively). All deletion cases were diagnosed as 17q12 deletion syndrome, confirmed by multiplex ligation probe amplification and/or array comparative genomic hybridization. A retrospective review of clinical data was also conducted. Most cases had morphological abnormalities in the renal-urinary tract system. Diabetes developed in 12 cases (38.7%). Hyperuricemia and hypomagnesemia were associated with six (19.3%) and 13 cases (41.9%), respectively. Pancreatic malformations were detected in seven cases (22.6%). Ten patients (32.3%) had liver abnormalities. Estimated glomerular filtration rates were significantly lower in the patients with heterozygous variants compared to those in patients harboring the deletion (median 37.6 vs 58.8ml/min/1.73 m2; p = 0.0091). We present the clinical characteristics of HNF1B-related disorders. To predict renal prognosis and complications, accurate genetic diagnosis is important. Genetic testing for HNF1B mutations should be considered for patients with renal malformations, especially when associated with other organ involvement.

Not only Alagille syndrome. Syndromic paucity of interlobular bile ducts secondary to HNF1\u03b2 deficiency: a case report and literature review

Backgroundpaucity of interlobular bile ducts is an important observation at liver biopsy in the diagnostic work-up of neonatal cholestasis. To date, other than in the Alagille syndrome, syndromic paucity of interlobular bile ducts has been documented in four cholestatic neonates with HFN1β mutations. A syndromic phenotype, known as renal cysts and diabetes syndrome (RCAD), has been identified. This is usually characterized by a wide clinical spectrum, including renal cysts, maturity-onset diabetes of the young, exocrine pancreatic insufficiency, urogenital abnormalities and a not well established liver involvement. Herein we report a novel case of paucity of interlobular bile ducts due to an HFN1β defect.Case presentationA 5-week-old boy was admitted to our department for cholestatic jaundice with increased gamma-glutamyl transpeptidase and an unremarkable clinical examination. He had been delivered by Caesarian section at 38 weeks’ gestation from unrelated parents, with a birth weight of 2600 g (3rd percentile). Screening for cholestatic diseases, including Alagille syndrome, was negative except for a minor pulmonary artery stenosis at echocardiography and a doubt of a thoracic butterfly hemivertebra. The finding of hyperechogenic kidneys with multiple bilateral cortical cysts at ultrasound examination, associated with moderately impaired renal function with proteinuria, polyuria and metabolic acidosis, was suggestive of ciliopathy. A liver biopsy was performed revealing paucity of interlobular bile ducts, thus the diagnosis of Alagille syndrome was reconsidered. Although genetic tests for liver cholestatic diseases were performed with negative results for Alagille syndrome (JAG1 and NOTCH2), a de-novo missense mutation of HNF1β gene was detected. At 18 months of age our patient has persistent cholestasis and his itching is not under satisfactory control.ConclusionsAlagille syndrome may not be the only syndrome determining paucity of interlobular bile ducts in neonates presenting with cholestasis and renal impairment, especially in small for gestational age newborns. We suggest that HNF1β deficiency should also be ruled out, taking into consideration HNF1β mutations, together with Alagille syndrome, in next generation sequencing strategies in neonates with cholestasis, renal impairment and/or paucity of interlobular bile ducts at liver biopsy.

Urinary proteome signature of Renal Cysts and Diabetes syndrome in children

Renal Cysts and Diabetes Syndrome (RCAD) is an autosomal dominant disorder caused by mutations in the HNF1B gene encoding for the transcriptional factor hepatocyte nuclear factor-1B. RCAD is characterized as a multi-organ disease, with a broad spectrum of symptoms including kidney abnormalities (renal cysts, renal hypodysplasia, single kidney, horseshoe kidneys, hydronephrosis), early-onset diabetes mellitus, abnormal liver function, pancreatic hypoplasia and genital tract malformations. In the present study, using capillary electrophoresis coupled to mass spectrometry (CE-MS), we investigated the urinary proteome of a pediatric cohort of RCAD patients and different controls to identify peptide biomarkers and obtain further insights into the pathophysiology of this disorder. As a result, 146 peptides were found to be associated with RCAD in 22 pediatric patients when compared to 22 healthy age-matched controls. A classifier based on these peptides was generated and further tested on an independent cohort, clearly discriminating RCAD patients from different groups of controls. This study demonstrates that the urinary proteome of pediatric RCAD patients differs from autosomal dominant polycystic kidney disease (PKD1, PKD2), congenital nephrotic syndrome (NPHS1, NPHS2, NPHS4, NPHS9) as well as from chronic kidney disease conditions, suggesting differences between the pathophysiology behind these disorders.

Hypomagnesaemia is absent in children with autosomal dominant polycystic kidney disease

Hypomagnesaemia is present in 40-50% of children with autosomal dominant renal cysts and diabetes syndrome (RCAD). On the contrary, the prevalence of hypomagnesaemia in children with autosomal dominant polycystic kidney disease (ADPKD) has never been examined. We aimed to investigate whether hypomagnesaemia is present in children with polycystic kidney diseases. Children with cystic kidney diseases were investigated in a cross-sectional study. Serum concentrations of magnesium (S-Mg) and fractional excretion of magnesium (FE-Mg) were tested. Fifty-four children with ADPKD ( n = 26), autosomal recessive polycystic kidney disease (ARPKD) ( n = 16) and RCAD ( n = 12) with median age of 11.2 (0.6-18.6) years were investigated. Hypomagnesaemia (S-Mg < 0.7 mmol/L) was detected in none of the children with ADPKD/ARPKD and in eight children (67%) with RCAD. Median S-Mg in children with ADPKD/ARPKD was significantly higher than in children with RCAD (0.89 vs. 0.65 mmol/L, P < 0.01). The FE-Mg was increased in 23% of patients with ADPKD/ARPKD (all had chronic kidney disease stages 2-4) and in 63% of patients with RCAD, where it significantly correlated with estimated glomerular filtration rate (r = -0.87, P < 0.01). Hypomagnesaemia is absent in children with ADPKD or ARPKD and could serve as a marker for differential diagnostics between ADPKD, ARPKD and RCAD in children with cystic kidney diseases of unknown origin where molecular genetic testing is lacking. However, while hypomagnesaemia, in the absence of diuretics, appears to rule out ADPKD and ARPKD, normomagnesaemia does not rule out RCAD at least in those aged <3 years.

An interesting unfolding of the diagnosis of hepatocyte nuclear factor‐1 beta (HNF1β) monogenic diabetes

AbstractThe HNF1B gene plays an important role in endodermal development, and mutations of HNF1B are associated with the renal cysts and diabetes (RCAD) syndrome. Other than renal cystic malformations and monogenic diabetes, various other abnormalities have been described depending on HNF1β expression. Molecular diagnosis has huge implications for the treatment of the patient and their family members.We present a case of RCAD syndrome with a previously unreported mutation. A 49‐year‐old man with diabetes mellitus was admitted with worsening chronic kidney disease requiring haemodialysis. He developed recurrent, unexplained hypoglycaemia despite discontinuing insulin, making the diagnosis of type 1 diabetes mellitus questionable. He had detectable serum C‐peptide (742 pmol/L), and anti‐GAD and anti‐pancreatic islet cell antibodies were negative. Abdominal imaging revealed renal cortical cysts and atrophic pancreas. A significant family history of diabetes mellitus with renal disease was also established which prompted us to suspect mutation of the HNF1B gene.Genetic testing confirmed the diagnosis: he was found to have a novel HNF1B missense mutation p.R165C previously not reported. This case study identified a mutation previously unreported thereby expanding the spectrum of HNF1B gene mutations. Copyright © 2017 John Wiley &amp; Sons.

Prenatal diagnosis of renal cysts and diabetes syndrome (RCAD) managed by continuation of pregnancy and adapted perinatal comfort care

Purpose: Urogenital dysplasia is the third most common of all congenital malformations and can be detected by ultrasound at an early stage. If no renal function is present the termination of pregnancy would be recommended. This can lead to versatile mental, social, and also healthy problems. Continuation of pregnancy and vaginal delivery with specialized perinatal palliation may be an appropriate option. For this reason we present a case of prenatally diagnosed complex renal dysplasia with fatal prognosis.

Prenatal diagnosis of fetal multicystic dysplastic kidney via high-resolution whole-genome array.

Women with fetal multicystic dysplastic kidneys (MCDK) are commonly referred for genetic counseling, for which identification of the correct etiology is a prerequisite. A total of 72 women with fetal MCDK at Guangzhou Women and Children's Medical Center were examined via invasive prenatal diagnosis from May 2010 to June 2015. Standard karyotyping analysis was provided to all fetuses, and chromosomal microarray with Affymetrix CytoSan HD arrays was offered to cases whose DNA samples were available. Abnormal karyotypes were detected in 3 of 72 (4.17%) fetuses. Of the 69 (95.8%, 69/72) fetuses with normal karyotypes, 30 (42%, 30/69) underwent chromosome microarray analysis (CMA) testing. The CMA identified pathogenic copy number variations in five fetuses, leading to a pathogenic detection rate of 16.7% (5/30). Well-known microdeletion or microduplication syndromes including renal cysts and diabetes (RCAD) syndrome and Williams-Beuren syndrome (WBS) were identified in three cases. Moreover, four chromosomal imbalanced regions were also identified in our MCDK fetuses: 22q11.1 duplication, 4q35.2 deletion, 22q13.33 duplication and 1p33 duplication. Genes PEX26, ELN, HNF1B, ALG12, FRG1, FRG2 and CYP4A11 were possible candidates for fetal MCDK. The proportions of variants of unknown significance before and after parental analysis were 13.3% (4/30) and 3.3% (1/30), respectively. In the present study, the frequency of chromosomal abnormalities in MCDK fetuses was 4.17% and all rearrangements were imbalanced aberrations. CMA was able to increase the pathogenic detection rate to 16.7% in MCDK fetuses with normal karyotype. Critical regions for RCAD syndrome, WBS and copy number variants of 22q11.1 duplication, 4q35.2 deletion, 22q13.33 duplication and 1p33 duplication were associated with fetal MCDK. Genes PEX26, ELN, HNF1B, ALG12, FRG1, FRG2 and CYP4A11 were possible candidates for fetal MCDK.

Novel mutation in the hepatocyte nuclear factor 1B/maturity – onset diabetes of the young type 5 gene – unreported Vietnamese case

Maturity-onset diabetes of the young type 5 (MODY5), a type of dominantly inherited diabetes mellitus and nephropathy, has been associated with mutations of the hepatocyte nuclear factor-1 (HNF-1β) gene, mostly generating truncated protein. Various phenotypes are related to HNF-1β mutations. Our aim to describe clinical and genetic findings in the unreported Vietnamese case identified with HNF-1β mutations. The proband with kidney failure from 7.5 years of age and diabetes diagnosed at 13.5 years of age who were described. Case report included information: characteristics of diabetes, renal function and structure, pancreas structure. Genomic DNA were extracted from WBC of whole blood and HNF-1β mutation was performed using PCR and direct sequencing. The proband is heterozygous for a novel HNF1B missense mutation (c.505T>C; p.Y169H). This mutation results in the substitution of the amino acid histidine (charged polar) for tyrosine (uncharged polar) at codon 169. The tyrosine residue is conserved across species and it is therefore likely that the p.Y169H mutation is pathogenic. This result is consistent with a diagnosis of renal cysts and diabetes syndrome (RCAD). Testing was done for proband's parents and no mutation was found in HNF1B. It is therefore likely that the p.Y169H mutation has arisen de novo. Kidney MRI showed right kidney atrophy and pancreas MRI showed only tissue of head of pancreas. Investigations at 14.5 years of age – diagnosed diabetes showed: plasma urea 10.1 mmol/l; creatinine 250 micrommol/l; HbA1C 13.6%. He was given insulin of 0.8 UI/Kg/day and HbA1C was 6.8% after one year of treatment with insulin injection. Maturity-onset diabetes of the young type 5 encompasses a wide clinical spectrum. Analysis for mutations of HNF-1β is warranted, even without a family history of diabetes, in non obese patients with diabetes and slowly progressive non diabetic nephropathy, particularly when pancreatic atrophy. 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 Editor-in-Chief of this journal.

Systematic review of TCF2 anomalies in renal cysts and diabetes syndrome/maturity onset diabetes of the young type 5.

There is a paucity of published works that systematically evaluate gene anomalies or clinical features of patients with renal cysts and diabetes syndrome (RCAD)/maturity onset diabetes of the young type 5 (MODY5). The purpose of this review was to systematically assess the detection rate, genetic and phenotypic implications of heterozygous autosomal dominant TCF2 anomalies. MEDLINE database was searched to select articles recorded in English from 1997 to 2008. The focus was monoallelic germline TCF2 gene mutations/deletions. Biallelic inactivation, polymorphisms, DNA modification (hypomethylation and hypermethylation), loci associated with cancer risk, and somatic TCF2 anomalies were all excluded. After searching the literature, 50 articles were selected. The detection rate of TCF2 anomalies was 9.7% and varied considerably among MODY (1.4%), renal structure anomalies (RSA) (21.4%) and RSA with MODY (41.2%) subgroups. Mutations were strikingly located within the DNA binding domain and varied among exons of the DNA binding domain: exons 2 and 4 were the hottest spots, while mutations were sporadically distributed in exon 3. The consistent phenotypes were RSA (89.6%) and diabetes mellitus (DM) (45.0%). However, the concurrence of RSA and DM was relatively low (27.5%), which hinders the optimal performance of genetic testing and obtainment of timely diagnosis. Other organ involvements were complementary and necessary for the early identification of patients with TCF2 anomalies. Analysis of phenotypes of TCF2 point mutations showed significant differences in the detection rates of RSA, impaired renal function (IRF) and DM according to mutation type but not mutation location. These valuable features of TCF2 anomalies that previously did not receive sufficient attention should not be neglected.

Deletion 17q12 Is a Recurrent Copy Number Variant that Confers High Risk of Autism and Schizophrenia

Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10⁻⁵). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only.

The Renal Cysts and Diabetes (RCAD) Syndrome in a Child with Deletion of the Hepatocyte Nuclear Factor-1β Gene

The authors describe a 14-yr-old boy who presented with non-ketotic hyperglycemia, elevated serum creatinine levels and deranged liver function. There was no microalbuminuria or proteinuria. He also had mild mental retardation with learning difficulties. Ultrasonography of the abdomen revealed multiple renal cysts of varying sizes in both the kidneys. Dosage analysis of the hepatocyte nuclear factor (HNF)-1β gene by multiplex ligation-dependent probe amplification (MLPA) detected a heterozygous whole gene deletion (p.Met1_Trp557del). This finding is consistent with the diagnosis of renal cysts and diabetes (RCAD) syndrome. This is the first case of the RCAD syndrome reported in an Indian patient. Pediatricians need to be aware of this entity whenever renal disease is seen in a diabetic child in the absence of microalbuminuria or proteinuria.

Severe hyperglycemia after renal transplantation in a pediatric patient with a mutation of the Hepatocyte Nuclear Factor-1β gene

After renal transplantation for congenital cystic kidney disease of unknown origin, a 14-year-old boy, who was previously normoglycemic, had “steroid-induced” diabetes mellitus, which was treated with insulin. Transplant failure from chronic rejection and subsequent transplant nephrectomy allowed discontinuation of corticosteroids, the gradual withdrawal of insulin and normoglycemia. The recent description of renal cysts and diabetes (RCAD) syndrome and a strong paternal family history of early-onset diabetes mellitus prompted genetic screening of the hepatocyte nuclear factor-1β gene. A novel heterozygous frameshift mutation in exon 1 was identified, adding to the 12 kindreds thus far described. This case highlights the unmasking of the hyperglycemic component of the RCAD syndrome in the immediate postoperative period after renal transplantation and emphasizes the pleiotropic manifestations of this important genetic kidney disease. Am J Kidney Dis 40:1325-1330. © 2002 by the National Kidney Foundation, Inc.