Renal cysts and diabetes syndrome

HNF1B-associated disease is due to a heterozygous gene variant in, or deletion of, the HNF1B gene, which encodes a transcription factor that is found in many organs and tissues. As a result, there are a number of different clinical features. The most commonly-occurring features are renal anomalies and a form of diabetes mellitus known as maturity-onset diabetes of the young (MODY).  The combination of renal cysts and diabetes due to variants in HNF1B is known as renal cysts and diabetes syndrome (RCAD).

The clinical features of RCAD include:

• Renal features:
  • unexplained cystic renal disease (note: renal cysts may be detected in utero, appearing as echogenic or bright kidneys.);
  • a single kidney;
  • horseshoe or duplex kidneys; and
  • collecting system anomalies, such as bilateral hydronephrosis.

The severity of the renal phenotype is variable, ranging from enlarged cystic kidneys incompatible with life to normal renal development and function.

• Other features include:
  • early-onset non-insulin-dependent diabetes mellitus;
  • genital tract malformations;
  • hyperuricaemia and early-onset gout;
  • hypomagnesaemia;
  • atypical liver function tests;
  • pancreatic hypoplasia and pancreatic exocrine deficiency; and
  • neurodevelopmental disorders, including autism spectrum disorder, which is observed at increased frequency in individuals with an HNF1B whole gene deletion.

RCAD is caused by heterozygous variants and whole gene deletions in the HNF1B gene. Whole gene deletions account for up to 50% of variants, occurring as part of a chromosome 17q12 microdeletion.

• If there is a clinical suspicion of RCAD, or the presence of echogenic kidneys, consider genomic testing for monogenic diabetes. See ‘Child with cystic renal disease’.
• All patients should undergo a renal ultrasound scan to look for evidence of a renal structural anomaly. Imaging may also detect genital tract malformations.
• Recommended blood tests include: serum creatinine and glomerular filtration rate (GFR); glycated haemoglobin; serum magnesium; urate; liver function.
• Faecal elastase measurement is helpful if there is a history of unexplained weight loss or abdominal pain.

HNF1B-associated disease has an autosomal dominant pattern of inheritance. 40% of HNF1B variants are de novo. An absence of a family history of renal disease or diabetes should therefore not be used to rule out genomic testing.

• Individuals affected by an autosomal dominant condition have one working copy of the gene and one with a pathogenic variant.
• The chance of a child inheriting the gene with the variant from an affected parent is 50% (1-in-2).

Incomplete penetrance is possible, meaning that not everyone who has the variant develops the disease.

The management of HNF1B-associated disease is largely supportive:

• If a patient has evidence of chronic kidney disease, they should be monitored in accordance with the clinical guidelines set out by the National Institute for Health and Care Excellence (NICE).
• Adults with normal renal function should have their serum creatinine and GFR checked annually. For children with normal renal function, the frequency of monitoring will depend on their clinical situation.
• Patients with diabetes will need their HbA1c level monitored regularly. Adults without a diagnosis of diabetes should have their HbA1c checked annually. In children without a diagnosis of diabetes, annual urinalysis to test for glycosuria may be helpful. The majority of patients with diabetes will rapidly progress to requiring treatment with insulin.

Other treatments that may be necessary include standard management of gout and pancreatic enzyme replacement therapy if there is evidence of clinically significant malabsorption.

Specialist HNF1B clinic

A national clinical service offers patients, both adults and children, with HNF1B-associated disease the opportunity to see a series of specialist healthcare professionals in one visit. These specialists provide clinical assessments and advice for each of the different aspects of the patient’s condition.

How to refer to the service

Referrals are accepted from GPs and hospital consultants. Alternatively, patients can access the service directly (self-funded). See the Diabetes Genes website for more details.

National Registry of Rare Kidney Diseases (RaDaR)

Patients affected by HNF1B-related renal disease should be registered on the National Registry of Rare Kidney Diseases (RaDaR).  RaDaR facilitates translational and epidemiological research into rare diseases through a comprehensive clinical database.  It is managed by the UK Renal Registry on behalf of the UK Kidney Association (formerly the Renal Association). Recruitment is open to all UK hospitals.

For clinicians

• • Genomics England: NHS Genomic Medicine Service (GMS) signed off panels resource
  • NHS England: National Genomic Test Directory

For patients

• DiabetesGenes (information about research and clinical care in genetic types of diabetes)