HNF1B is a transcription factor with a role in regulating gene expression in a number of tissues including the pancreas, kidneys, liver, genital tract, and gut. Heterozygous deletions or variants in HNF1B can cause developmental abnormalities in all these organs, although the commonest phenotypes are renal abnormalities and diabetes. Renal cysts and diabetes (RCAD) syndrome is used to describe the combination of diabetes and renal cysts related to HNF1B variants. HNF1B abnormalities may show autosomal dominant inheritance, although up to 50 % of cases arise spontaneously and there is a wide variation in phenotype even with identical variants.
Clinical features
The clinical features are summarized in Table 1 and Figure 1. Developmental renal disease is the most consistent feature, with renal cysts being the commonest manifestation. Other possible renal abnormalities include glomerulocystic kidney disease, cystic renal dysplasia, and morphological abnormalities such as horseshoe or single kidney. Renal function can range from nor mal to dialysis dependent. The mean age of diagnosis of diabetes is 24 years, but the age of diagnosis can vary from infancy to over 60 years old. Diabetes is usually associated with pancreatic hypoplasia and may be associated with exocrine dysfunction, although this can result in mild or moderate symptoms of malabsorption. Low birth weight is common and very rarely transient neonatal diabetes has been described. Other clinical manifestations include non- progressive abnormal liver function tests, genital tract malformations, hypomagnesaemia, hyperuricaemia, and familial hyperuricaemia nephropathy. Neurodevelopmental disorders including autism spectrum disorder are identified in ~40 % of individuals with an HNF1B whole- gene deletion occur ring as part of a chromosome 17q12 microdeletion, but are not associated with HNF1B intragenic variants. Mild facial dysmorphic features are also suggestive of a 17q12 deletion and include high forehead, high arched eyebrows, long philtrum, long face, and anteverted nares. An association with chromophobe renal cell carcinoma has been reported, reflecting a probable role for HNF1B as a tumour suppressor gene.
Table1. Features of people with HNF1B variants causing RCAD (renal cysts and diabetes) in a UK cohort.
Fig1. Phenotypes of (a) renal cysts and diabetes syndrome due to HNF1B variant or deletion; and (b) maternally inherited diabetes and deafness caused by mitochondrial m.3243A>G variant. LFTs, liver function tests. Source: Adapted from Murphy et al. and Clissold et al.
Differentiating from type 1 diabetes and type 2 diabetes
Approximately 50% of HNF1B variants and deletions are spontaneous and so there may be no family history. Testing for HNF1B abnormalities should be considered where there is unexplained cystic renal disease, glomerulocystic disease, or other renal developmental abnormalities with or without a past medical or family history of diabetes. It should also be considered in individuals with genital tract abnormalities associated with renal abnormalities. Both simple renal cysts and diabetes are common in the general population and should not lead to automatic testing for HNF1B abnormalities; testing would be considered when the diabetes is young onset and atypical for type 1 diabetes and type 2 diabetes. Testing for HNF1B should always include dosage analysis to detect gene deletions, as these are common and will be missed if the laboratory performs sequencing only.
Management
Although the majority of individuals with HNF1B variants will require insulin treatment, some individuals, soon after diagnosis, may be briefly managed with sulfonylurea therapy [167]. Renal management is similar to management of other chronic progressive renal diseases. Our recommendation is that adults with nor mal renal function should have their serum creatinine and estimated glomerular filtration rate (eGFR) repeated annually. Children with normal renal function should have their serum creatinine and eGFR checked every 2–3 years. All individuals should undergo a renal ultrasound scan to assess for structural anomalies. If initial imaging is abnormal, repeat renal ultrasound imaging every 3–5 years is recommended. If the initial ultrasound scan is unremarkable, we suggest repeating imaging every 3–5 years throughout childhood. In adults, monitoring renal function using serum creatinine and eGFR would be sufficient. Annual assessment of HbA1c in adults without a diagnosis of diabetes is recommended. In children without a diagnosis of diabetes, annual urinalysis to test for glycosuria and monitoring HbA1c when routine blood samples are being collected may be helpful. Faecal elastase should be tested to check for pancreatic insufficiency when there are gastrointestinal symptoms, as treatment with Creon® (AbbVie, North Chicago, IL, USA) may be required. Other tests that may be useful in diagnosis of HNF1B include liver function tests, serum magnesium, and serum urate.
