Dent disease

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Dent disease is a chronic kidney disorder that occurs almost exclusively in males. The kidney problems seen in affected individuals are a result of damage to structures called proximal tubules. These structures help reabsorb water, protein, and other nutrients into the bloodstream or release them into the urine.

The signs and symptoms of Dent disease tend to appear in childhood and worsen over time. However, the features and the severity of Dent disease vary greatly among affected individuals.

The most frequent sign of Dent disease is the loss of small proteins in the urine (also called low-molecular-weight or LMW proteinuria). Too much calcium in the urine (hypercalciuria) is another common sign of Dent disease. LMW proteinuria and hypercalciuria may be the only signs of Dent disease in affected children.

Additional signs and symptoms of Dent disease can include calcium deposits in the kidneys (nephrocalcinosis) and kidney stones (nephrolithiasis). Kidney stones can cause abdominal pain and blood in the urine (hematuria). Thirty to 80 percent of people with Dent disease develop kidney failure in early to mid-adulthood. Kidney failure can be life-threatening and occurs when the kidneys are no longer able to effectively filter fluids and waste products from the body.

In some people with Dent disease, low levels of vitamin D and other factors can cause bones to soften and weaken. This can result in a condition called rickets or a similar condition called osteomalacia. These conditions can cause bone pain and make bones more likely to break. Rickets can also be associated with bowed legs, difficulty walking, and short stature.

Researchers have described two forms of Dent disease that are caused by changes in different genes: Dent disease 1 and Dent disease 2. Both forms are characterized by the features described above, but Dent disease 2 can also be associated with mild intellectual disabilities and developmental delays. People with Dent disease 2 may also have a clouding of the lens of the eye (cataract) that does not typically cause severe visual impairment. Studies have also suggested that people with Dent disease 2 may be more likely to develop a painful skin condition called hidradenitis suppurativa.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Changes in the CLCN5 gene cause Dent disease 1, while changes in the OCRL gene cause Dent disease 2. Genetic changes that cause disease are called pathogenic variants. Approximately 60 percent of people with Dent disease have type 1. Another 15 to 20 percent of people with Dent disease have type 2.

The proteins produced from the CLCN5 and OCRL genes play important roles in normal kidney function, particularly within the proximal tubules. Studies suggest that certain pathogenic variants in the CLCN5 or OCRL genes lead to abnormal protein reabsorption within the proximal tubules. As a result, proteins that should be reabsorbed into the bloodstream are released in the urine. This leads to the kidney problems seen in people with Dent disease.

Approximately 20 to 25 percent of people with Dent disease do not have an identified variant in the CLCN5 or OCRL genes. The cause of the condition in these cases is not known.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Dent disease is inherited in an X-linked pattern. The CLCN5 and OCRL genes are located on the X chromosome, which is one of the two sex chromosomes in each cell. In males (who have only one X chromosome), a pathogenic variant in the only copy of the gene in each cell is typically sufficient to cause the condition. This is not always the case for X-linked disorders in females (who have two X chromosomes in each cell). However, some females with a pathogenic variant in the CLCN5 or OCRL gene have mild features of Dent disease, including LMW proteinuria, hypercalciuria, and nephrolithiasis. Kidney failure in females is extremely rare. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Some cases of Dent disease likely result from a new (de novo) variant in the gene that occurs during the formation of reproductive cells (eggs or sperm) in an affected individual's parent or during early embryonic development. These affected individuals typically have no history of the disorder in their family.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Approximately 850 families with Dent disease have been reported in the scientific literature. However, because the features of Dent disease can vary and may overlap with those seen in other disorders, this number may not accurately represent the number of people with this condition.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Aminoaciduria · Very frequent (99-80%)

An increased concentration of an amino acid in the urine.

Chronic kidney disease · Very frequent (99-80%)

Functional anomaly of the kidney persisting for at least three months.

Focal segmental glomerulosclerosis · Very frequent (99-80%)

Segmental accumulation of scar tissue in individual (but not all) glomeruli.

Glycosuria · Very frequent (99-80%)

An increased concentration of glucose in the urine.

Hematuria · Very frequent (99-80%)

The presence of blood in the urine. Hematuria may be gross hematuria (visible to the naked eye) or microscopic hematuria (detected by dipstick or microscopic examination of the urine).

High serum calcitriol · Very frequent (99-80%)

The concentration of calcitriol in the blood circulation is above the upper limit of normal.

Hyperphosphaturia · Very frequent (99-80%)

An increased excretion of phosphates in the urine.

Hyperuricosuria · Very frequent (99-80%)

An abnormally high level of uric acid in the urine.

Other findings in the same source

From: Orphanet

Additional reported features include Low-molecular-weight proteinuria (Very frequent (99-80%)); Nephrolithiasis (Very frequent (99-80%)); Non-acidotic proximal tubulopathy (Very frequent (99-80%)); Proteinuria (Very frequent (99-80%)); Proximal tubulopathy (Very frequent (99-80%)); Recurrent fractures (Very frequent (99-80%)); Renal hypophosphatemia (Very frequent (99-80%)); Renal insufficiency (Very frequent (99-80%)); Renal phosphate wasting (Very frequent (99-80%)); Renal tubular atrophy (Very frequent (99-80%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Dent disease is Nephrology, with a nephrologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• How is kidney function being assessed over time?
• Are any current medicines or supplements relevant to kidney safety?
• Is there an individual recommendation about fluids, diet or blood pressure?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Dent disease. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.