DIABETES WITH EXTRA-PANCREATIC FEATURES
Renal cysts and diabetes (RCAD) syndrome: HNF1B-MODY
Molecular genetics of RCAD
HNF1B is a transcription factor with a role in regulating gene expression in a number of tissues. HNF1B forms homo and heterodimers with HNF1A, is present in similar tissues although at different levels, and binds to the same DNA consensus sequence. Despite these similarities HNF1B mutations cause diabetes by a different mechanism and have a distinct phenotype. There is autosomal dominant inheritance, although up to 50% of cases arise from de novo mutations or deletions.
Phenotype of RCAD
The predominant phenotype in HNF1B mutations is that of nondiabetic developmental renal disease, most frequently resulting in renal cysts, and diabetes is a less consistent finding. The association of renal cysts with diabetes in HNF1B mutations has led to the designation “Renal Cysts and Diabetes” (RCAD) syndrome .
Developmental abnormalities can also be seen in the genital tract, liver, and gut. Uterine and genital tract abnormalities have been described in about 30% of patients . The reason for this is that HNF1B is expressed earlier in embryogenesis and it has a role in regulating gene expression in a number of tissues, including the pancreas, kidneys, liver, genital tract, and gut . Birth weight is reduced by around 800 g as a result of reduced insulin secretion in utero . Atrophy of the pancreatic tail can be seen on radiologic scan; associated with loss of pancreatic exocrine function  (see Table 28.4).
Most cases of HNF1B mutations present to the renal physicians as the varied renal phenotype usually precedes the onset of diabetes. The most common renal phenotype is developmental renal disease, most commonly renal cysts. Renal cysts are present in >75% of patients with HNF1B mutations and are frequently seen on antenatal scanning [51,83]. Three discreet renal histologies have been described: cystic dysplasia, oligomeganephronia, and familial hypoplastic glomerulocystic kidney disease . There are varying degrees of renal dysfunction with approximately 50% of patients ultimately requiring dialysis or transplantation for end-stage renal failure. There is also an association with chromophobe renal cell carcinoma. The severity of the renal disease does not correlate with the genotype . Hypomagnesemia, hyperuricemia, and familial hyperuricemic nephropathy [85–87] have also been described and may reflect a specific defect in renal tubular transport.
In marked contrast to HNF1A-MODY, the diabetic people with RCAD have insulin resistance with hypertriglyceridemia. Approximately 50% of cases of RCAD are due to 17q12 gene deletions, and there can be associated learning disability and autism .
Diagnosis of RCAD
Testing for RCAD should be considered where there is unexplained renal cystic disease (or other renal developmental disease) with or without genito-urinary tract abnormalities or diabetes. As about half the cases of RCAD are spontaneous, lack of a family history should not be a barrier to testing. Testing should not be done in the presence of simple renal cysts and typical type 1 or type 2 diabetes as both conditions are common in the general population. As heterozygous deletions or mutations can cause HNF1B-MODY it is important that copy number analysis, as well as sequencing, is performed when seeking a diagnosis.
Treatment of RCAD
Renal disease needs to be managed as any other chronic renal condition, with periodic monitoring of renal function and treatment as appropriate. In addition biennial ultrasounds are recommended to screen for chromophobe renal carcinoma. Patients with diabetes are not sensitive to sulfonylurea therapy and are best treated with insulin.
Mitochondria play an essential role in generating chemical energy for cells. Individual cells often contain a variable mixture of mutated and normal mtDNA—termed heteroplasmy. The degree of heteroplasmy varies between tissues and within families and this explains the varied phenotypes seen with the same mitochondrial mutation. Mitochondrial mutations are inherited maternally, as during fertilization the mitochondria in the tail of the sperm do not enter the oocyte.
Maternally inherited diabetes and deafness (MIDD) is the most common mitochondrial diabetes syndrome and will be discussed in the following section. A number of other mitochondrial mutations have been described in families with maternally inherited diabetes (with or without deafness); these are rare (reviewed in ).