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At a glance

It is a very rare X-linked inherited disorder with an onset in childhood or adulthood and characterized by the presence of tubular proteinuria, hypercalciuria, calcium nephrolithiasis, nephrocalcinosis, and chronic renal failure. It affects only males. Kidney disease can progressively worsen until end-stage renal failure is reached when the patient is 30 to 50 years of age or later. Some affected individuals may never reach the end-stage kidney failure.

Synonyms

Renal Fanconi Syndrome with Nephrocalcinosis and Renal Stones Syndrome; Nephrolithiasis, X-Linked Recessive Type II Syndrome; Nephrolithiasis II; Idiopathic Hypercalciuria Syndrome.

History

This is a genetic disorder that was first described by Charles Enrique Dent and M. Friedman in 1964. They reported two unrelated British boys affected with rickets and associated with renal tubular damage causing hypercalciuria, hyperphosphaturia, proteinuria, and aminoaciduria. This clinical presentation was named after Dent only 30 years later when Oliver Wrong fully described the disease and decided to honor his mentor.

Classification

Two types of Dent Disease have been described on the basis of the genetic phenotype.

  • Dent Disease Type 1: X-linked recessive disorder. The males are prone to manifesting symptoms in early adulthood with symptoms of calculi, rickets or even with kidney failure in more severe cases.

  • Dent Disease Type 2: Characterized by the same symptoms as type I but also characterized by mild intellectual disability, severe nystagmus, cataracts, and hypotonia. Also, it is often reported as a nephrolithiasis Type 2. This consists of a proximal tubular acidosis in comparison to the distal one.

Incidence

The exact incidence remains unknown. Dent Disease Type 1 has been reported in approximately 250 families whereas Dent Disease Type 2 in approximately 25 individuals. It is often diagnosed as idiopathic hypercalciuria due to its rather rare occurrence.

Genetic inheritance

It is inherited as an X-linked recessive trait. About 60% of patients have mutations in the CLCN5 gene (Dent 1), which encodes a kidney-specific chloride/proton antiporter. The CLCN5 gene is located on chromosome Xp11.22. This gene belongs to the family of voltage-gated chloride channel genes (CLCN1-CLCN7, CLCKa, and CLCKb). These chloride channels have an important role in the control of membrane excitability, transepithelial transport, and possibly cell volume. Fifteen percent of affected individuals present mutations in the OCRL1 gene (Dent 2).

Pathophysiology

Generalized transport dysfunction of the proximal renal tubule caused by mutation in the CLCN5 chloride channel gene (gene map locus at Xp11.22), leading to impaired reabsorption of amino acids, glucose, calcium, phosphate, bicarbonate, magnesium, sodium, potassium, water, uric acid, and low-molecular-weight proteins. Urinary losses can lead to polyuria, polydipsia, dehydration, hypokalemia, metabolic acidosis, and hypophosphatemia. The second component of the syndrome is a vitamin D-resistant metabolic bone disease that is responsible for rickets in children ...

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