Renal Cysts And Diabetes Syndrome

A number sign (#) is used with this entry because of evidence that renal cysts and diabetes syndrome (RCAD), also referred to as MODY5, is caused by heterozygous mutation in the TCF2 gene (HNF1B; 189907) on chromosome 17q12.

For a phenotypic description and a discussion of genetic heterogeneity of MODY, see 606391.

Description

The 'renal cysts and diabetes syndrome' is an autosomal dominant disorder comprising (1) nondiabetic renal disease resulting from abnormal renal development, and (2) diabetes, which in some cases occurs earlier than age 25 years and is thus consistent with a diagnosis of maturity-onset diabetes of the young (MODY). The renal disease is highly variable and includes renal cysts, glomerular tufts, aberrant nephrogenesis, primitive tubules, irregular collecting systems, oligomeganephronia, enlarged renal pelvises, abnormal calyces, small kidney, single kidney, horseshoe kidney, and hyperuricemic nephropathy. Affected individuals may also have abnormalities of the genital tract, including vaginal aplasia, rudimentary uterus, bicornuate uterus, epididymal cysts, and atresia of the vas deferens (Bingham et al., 2001; Fajans et al., 2001; Bellanne-Chantelot et al., 2004; Edghill et al., 2006).

The renal abnormalities seen in the RCAD syndrome are part of a spectrum of malformations known as congenital anomalies of the kidney and urinary tract (CAKUT; see 610805) (summary by Nakayama et al., 2010).

Clinical Features

Horikawa et al. (1997) reported a Japanese family in which 3 sibs developed MODY at ages 14, 10, and 15 years, respectively. Their mother and maternal uncle developed diabetes at ages 40 and 60, respectively; their father developed diabetes at age 50. A nonspecific nephropathy was described.

Lindner et al. (1999) reported a Norwegian family with autosomal dominant inheritance of a syndrome comprising mild diabetes and progressive nondiabetic renal disease; 2 of the 4 affected females also had severe genital malformations, consisting of vaginal aplasia and rudimentary uterus (see 277000), but no virilization or hirsutism.

Sovik et al. (2002) reported follow-up on the family with MODY5 originally reported by Lindner et al. (1999). One of the female patients in that family had dental anomalies with enamel defects, vaginal aplasia, and rudimentary uterus. She developed renal failure necessitating renal transplantation at age 21 years. Postoperative immunosuppressive treatment with cyclosporin A was stopped after 1 year owing to possible neurotoxicity. On continued treatment with steroids, she developed manifest diabetes. Following renal transplantation she developed progressive neurologic symptoms, spastic paraparesis, visual disturbances, ataxia, hearing loss, and 1 epileptic seizure. Neurologic examination indicated multiple lesions in the central nervous system, and cerebrospinal fluid analysis showed elevated IgG and oligoclonal bands, but normal cell count. MRI was normal, but visual, auditory, and somatosensory evoked responses showed pathologic signals. No evidence of viral infection was detected. Overall, the neurologic evaluation showed a progressive multifocal disease compatible with primary progressive multiple sclerosis, although with normal brain MRI. She died at age 27 years.

Rizzoni et al. (1982) reported 2 Italian sisters with what they termed 'familial hypoplastic glomerulocystic kidney disease.' The kidneys were small, with absence of the renal papillae, and chronic renal failure was observed from the first months of life. The mother had chronic renal failure with similar urographic abnormalities. Kaplan et al. (1989) reported a mother and son with hypoplastic glomerulocystic kidney disease similar to that described by Rizzoni et al. (1982). The kidneys were small, with cysts and abnormal calyces. Both mother and son had proportionate short stature; the mother also had pyloric stenosis and marked prognathism, the latter of which had been described in one of the patients of Rizzoni et al. (1982). Five of the mother's 7 sibs had evidence of cysts on renal ultrasonography. Bingham et al. (2001) reported follow-up on the families described by Rizzoni et al. (1982) and Kaplan et al. (1989). All affected members had small kidneys and renal impairment. Intravenous pyelogram showed absent calyces and irregular, enlarged collecting systems. Renal histology showed cortical cysts with cystic glomeruli and glomerular tufts. All patients developed early-onset diabetes mellitus with onset ranging from 17 to 39 years of age.

Bingham et al. (2003) reported a family in which 7 individuals had juvenile-onset hyperuricemic nephropathy inherited in an autosomal dominant pattern. Three patients developed early-onset gout at ages 21, 23, and 27 years. Four of the patients developed diabetes at ages 40, 43, 38, and 12 years, 3 had renal cysts or other disorders of renal development, and 2 had small kidneys. All patients showed improved renal function on allopurinol treatment. The family had originally been reported by Calabrese et al. (1990) as part of a large series of patients with hyperuricemia or gout due to subnormal renal tubular clearance of uric acid.

Bingham et al. (2003) found that 9 unrelated patients with TCF2 mutations had significantly increased mean serum urate levels compared to 18 normal controls and 24 patients with type II diabetes (125853). Moreover, Bingham et al. (2003) found evidence of gout in young females in 3 of 9 other reported families with TCF2 mutations. The findings suggested that hyperuricemia and gout are additional independent features of the renal cysts and diabetes syndrome.

Bellanne-Chantelot et al. (2004) reported 13 patients from 8 families with renal cysts and diabetes syndrome caused by heterozygous mutations in the TCF2 gene. The patients had various renal abnormalities, including agenesis, dysplasia, and cystic disease. Pancreas atrophy was observed in 5 of 6 probands. Some patients had genital tract abnormalities, including bicornuate uterus, epididymal cysts, and atresia of the vas deferens. Eleven patients had abnormal liver enzyme levels without impaired liver function. Bellanne-Chantelot et al. (2004) concluded that the phenotype caused by mutations in the TCF2 gene encompasses a wide clinical spectrum, and that TCF2 gene mutation analysis is warranted even without a family history of diabetes.

From a cohort of 160 patients with renal disease of unknown etiology, Edghill et al. (2006) described 23 patients (14%) with heterozygous mutations in the HNF1B (TCF2) gene, 10 of whom had previously been reported. Renal cysts were the most common manifestation, present in 19 (83%) of 23 individuals. Four of these patients had a specific diagnosis of glomerulocystic kidney disease. Although 11 (48%) of 23 patients had diabetes, only 6 (26%) met the minimal MODY diagnostic criteria of families with at least 2 generations of diabetes with at least 1 patient diagnosed under the age of 25 years. Nine probands (39%) had both renal cysts and diabetes. In addition to renal cysts and diabetes, 2 probands (9%) had genital tract malformations; uterus didelphys with single ovary and hemi-uterus, respectively, whereas another female mutation carrier had unexplained primary infertility. Edghill et al. (2006) emphasized the clinical variability of renal disease associated with mutation in the TCF2 gene and noted that MODY is not an essential finding in patients carrying mutations.

Clinical Variability

Nakayama et al. (2010) identified heterozygous pathogenic HNF1B mutations in 5 (10%) of 50 Japanese children with congenital anomalies of the kidney and urinary tract, including 2 with hypodysplastic kidneys and 3 with unilateral multicystic dysplastic kidneys. No mutations were found in 4 patients with a single kidney. There were 3 whole-gene deletions, 1 truncating mutation, and 1 missense mutation. The clinical spectrum of renal disease was variable, ranging in severity from unilateral disease and normal renal function to bilateral disease necessitating transplant. However, none of the patients had evidence of diabetes.

Thomas et al. (2011) identified heterozygous pathogenic HNF1B mutations in 4 of 73 children with chronic kidney disease due to renal hypodysplasia. It was not known if the patients with HNF1B mutations had features of diabetes, and Thomas et al. (2011) concluded that they should be followed for extrarenal manifestations. The findings also had implications for genetic counseling.

Molecular Genetics

In 2 Japanese sibs with a phenotype consistent with renal cysts and diabetes syndrome, Horikawa et al. (1997) identified a heterozygous mutation in the TCF2 gene (189907.0001). The sibs developed diabetes mellitus at ages 10 and 15 years, respectively, consistent with a diagnosis of MODY5. Although both parents also had late-onset diabetes, only the mother carried the TCF2 mutation. Horikawa et al. (1997) postulated that the early onset in the children reflected bilineal inheritance of 2 different diabetes susceptibility genes.

In affected members of a Norwegian family with diabetes and progressive nondiabetic renal disease, Lindner et al. (1999) identified a heterozygous 75-bp deletion in the TCF2 gene (189907.0002). The presence of vaginal aplasia and rudimentary uterus (see 277000) in 2 of 4 female mutation carriers suggested that additional clinical features are associated with TCF2 mutations.

In affected members of the families reported by Rizzoni et al. (1982) and Kaplan et al. (1989), Bingham et al. (2001) identified 2 different heterozygous mutations in the TCF2 gene (189907.0004 and 189907.0005, respectively). Bingham et al. (2001) concluded that hypoplastic glomerulocystic kidney disease is part of the clinical spectrum of the renal cysts and diabetes syndrome.

In 7 affected members of a family with renal cysts and diabetes syndrome and hyperuricemic nephropathy, Bingham et al. (2003) identified a heterozygous mutation in the TCF2 gene (189907.0010).

Bellanne-Chantelot et al. (2005) found molecular alterations of the TCF2 gene in 28 (70%) of 40 unrelated patients with a clinical phenotype consistent with MODY5. Point mutations were identified in 18 of the 28 patients and 10 had gross genomic rearrangements, which in 9 patients involved a deletion of at least 1.2 Mb, delimited by the TCF2 and TRIP3 (604500) genes and encompassing 7 other genes and 2 predicted proteins; 1 patient had a single-exon deletion of exon 5. Patients with mutations and patients with large deletions had a similar phenotype, whereas a different clinical profile was seen in patients with no detected abnormality of TCF2 despite a suggestive phenotype: the latter patients were older and had a higher BMI at diagnosis, less often required insulin therapy or had liver test abnormalities, were more likely to report a family history of diabetes, and in all but 1 patient the renal morphologic abnormalities were restricted to the presence of cysts. In patients with TCF2 alterations, various genital tract abnormalities were found in 80% of the patients tested. Bellanne-Chantelot et al. (2005) concluded that large genomic rearrangements of TCF2 can cause MODY5 and that whole-gene deletion is the most frequent molecular alteration in MODY5 patients.

Edghill et al. (2006) stated that a total of 40 mutations in the TCF2 gene had been reported, with the majority occurring in the first 4 exons, particularly in exon 2. They found no clear genotype/phenotype correlations.

Cytogenetics

In 155 autopsy samples from fetuses with well-defined developmental pathologies, Mefford et al. (2007) studied chromosomal regions predisposed to recurrent rearrangements and identified a fetus with multicystic dysplastic kidneys and a 1.8-Mb deletion encompassing the TCF2 gene on chromosome 17q12 (see 614517). Oligonucleotide array analysis of deletion breakpoints in 8 patients known to have deletions encompassing the TCF2 gene, including 5 patients with pediatric renal disease without diabetes and 3 patients with MODY5, revealed that 4 of the 5 pediatric patients and all 3 of the MODY5 patients had deletions 'nearly identical' to that of the fetal case, with breakpoints in all cases mapping to flanking segmental-duplication blocks. The deletion was not found in a control group of 960 unrelated Caucasian individuals. Mefford et al. (2007) concluded that 17q12 deletion is a recurrent genomic disorder with breakpoints in flanking segmental duplications that results in renal disease and diabetes. The authors also identified the reciprocal duplication (see 614516).

Nagamani et al. (2010) studied 9 patients with genomic rearrangements in chromosome 17q12, including 4 patients with a deletion, of whom 2 had cystic renal disease with preserved renal function, 1 had multicystic renal dysplasia and a nonfunctioning right kidney, and 1 had renal agenesis and end-stage renal disease treated with a renal transplant. All 4 patients had short stature; 3 had features suggestive of central nervous system involvement, ranging from speech delay to moderately severe mental retardation, and 2 of those patients had complex partial seizures. The 4 patients were all in the first 2 decades of life, and only 1 had been diagnosed with diabetes, which was post-renal transplant drug-induced diabetes. The deletions in all 4 patients encompassed a minimum of 1.06 Mb, extending from the LHX1 gene (601999) to LOC28400, and a maximum of 2.46 Mb, extending from the CCL3L3 gene (609468) to the SNIP gene (610786).

Genotype/Phenotype Correlations

Lindner et al. (1999) noted that heterozygous mutations in the TCF1 (142410) and TCF2 genes can cause MODY3 (600496) and MODY5, respectively. In addition to effects on beta-cell function, deficiency of either TCF1 or TCF2 affects renal function. Patients with TCF1 mutations appeared to have lower renal thresholds for glucose (Menzel et al., 1998) and those with TCF2 mutations seemed especially susceptible to severe renal disease (Horikawa et al., 1997; Nishigori et al., 1998).