Dent disease

Dent disease (DD) is an X-linked recessive condition and consequently affects males. It is characterised by a proximal tubulopathy, with features including low molecular weight proteinuria, hypercalciuria and hypophosphataemia.  This is associated with nephrocalcinosis, rickets and chronic kidney disease (CKD). While DD typically presents with asymptomatic proteinuria and hypercalciuria in childhood, 30%–80% of affected males progress to end-stage kidney disease between 30 and 50 years of age.

Polyps and cancer risk

If an individual has both low molecular weight proteinuria and hypercalciuria, DD should be suspected.

Other features may include:

• nephrocalcinosis;
• calcium based kidney stones;
• haematuria;
• hypophosphatemia;
• reduced glomerular filtration rate (GFR); and
• positive family history.

Note that these additional features may not be present, particularly in children.

Children with DD often present first with an incidental finding of proteinuria, including albuminuria. The proteinuria may be in the nephrotic range, but there is no oedema and blood albumin levels are typically normal. Detailed investigation will reveal increased excretion of low-molecular weight proteins.

Intra-familial phenotypic variability is common.

• DD is caused by pathogenic variants in one of two genes that follow an X-linked recessive inheritance pattern. DD1 and DD2 are caused by heterozygous pathogenic variants in the CLCN5 (60%) and OCRL (15%) genes respectively.
• 25% of cases do not have an identifiable pathogenic variant, suggested by some to represent DD3.
• OCRL gene variants are also associated with oculocerebrorenal (Lowe) syndrome. In addition to the DD phenotype, individuals with Lowe syndrome develop additional features including early-onset intellectual disability, cataracts, glaucoma, hypotonia and developmental delay.

• DD should be suspected in males presenting with proteinuria and hypercalciuria, especially in the absence of other known causes of proximal tubulopathy.
• Urine retinol binding protein testing helps confirm the presence of low molecular weight proteinuria, while a spot urine calcium:creatinine ratio test or 24-hour urine collection to assess calcium concentration is required to screen for hypercalciuria.
• An ultrasound scan of the renal tract may detect the presence of nephrocalcinosis and/or kidney stones.
• If DD is suspected, genomic testing should be arranged via the National Genomic Test Directory. The correct indication is R256 Nephrocalcinosis or nephrolithiasis.

The true prevalence of DD is unknown due to variable expressivity and incomplete penetrance. Many cases remain undiagnosed. Families should be referred for genomic counselling to discuss inheritance and reproductive options such as prenatal diagnosis and preimplantation genetic testing.

DD is inherited in an X-linked recessive manner:

• Symptoms are usually only present in males.
• Males cannot pass the pathogenic genomic variant on to their sons, but they always pass their affected X chromosome on to their daughters, who will therefore be carriers for the condition.
• Female carriers have a second, normal copy of the gene and are therefore usually unaffected, or affected only mildly. For instance they may develop proteinuria, hypercalciuria or stones, but CKD is uncommon.
• In rare instances, presumably due to skewed X-inactivation, female carriers can become symptomatic.
• Sons of female carriers of X-linked recessive conditions have a 50% (1-in-2) chance of being affected by the condition, and their daughters have a 50% (1-in-2) chance of being carriers.

There is no curative therapy for DD and management is therefore supportive, including:

• screening for and managing kidney stones and nephrocalcinosis;
• reducing urine calcium excretion via recommended dietary changes and thiazide diuretics;
• oral supplementation for hypophosphataemia and metabolic acidosis;
• vitamin D supplementation to prevent rickets; and
• managing CKD and the associated complications.

For clinicians

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

For patients

• Kidney Care UK: Dent Disease