#137920
ICD+
| ||||||||||||||||||||||||||||||||||||||||||
| RENAL CYSTS AND DIABETES SYNDROME | ||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||
| RCAD MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 5; MODY5 HYPERURICEMIC NEPHROPATHY, FAMILIAL JUVENILE, ATYPICAL FJHN, ATYPICAL GLOMERULOCYSTIC KIDNEY DISEASE, HYPOPLASTIC TYPE GLOMERULOCYSTIC KIDNEY, FAMILIAL HYPOPLASTIC | ||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||
| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||
| TEXT | ||||||||||||||||||||||||||||||||||||||||||
| A number sign (#) is used with this entry because the renal cysts and diabetes syndrome (RCAD), also referred to as MODY5, is caused by mutation in the gene encoding hepatocyte nuclear factor-1-beta (TCF2, or HNF1B; 189907). For general information on MODY and on genetic heterogeneity in this disorder, 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 pelves, 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). | ||||||||||||||||||||||||||||||||||||||||||
| 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. Edghill et al. (2006) described 23 (14%) of 160 individuals with renal disease who were found to have a heterozygous mutation in the HNF1B gene; 10 patients 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. | ||||||||||||||||||||||||||||||||||||||||||
| 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). 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 | ||||||||||||||||||||||||||||||||||||||||||
| Using array-based comparative genomic hybridization, Mefford et al. (2007) assessed chromosomal regions predisposed to recurrent rearrangements in 155 autopsy samples from fetuses with well-defined developmental pathologies. They found that 6% of fetal material showed evidence of microdeletion or microduplication, including 3 independent events that likely resulted from unequal crossing-over between segmental duplications. One of the microdeletions, identified in a fetus with multicystic dysplastic kidneys, encompassed the TCF2 gene on 17q12, previously shown to be mutated in maturity-onset diabetes, as well as in a subset of pediatric renal abnormalities. In 5 pediatric patients with such microdeletions, all had multicystic dysplastic kidneys. Fine-scale mapping of the breakpoints in different patient cohorts revealed a recurrent 1.5-Mb de novo deletion in individuals with phenotypes that ranged from congenital renal abnormalities to MODY5. Mefford et al. (2007) also identified the reciprocal duplication, which appeared to be enriched in samples from patients with epilepsy. They asserted that this was the first example of a recurrent genomic disorder associated with diabetes. | ||||||||||||||||||||||||||||||||||||||||||
| 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). | ||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | ||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||