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Dent disease is a rare genetic renal tubular disease characterized by manifestations of proximal tubule dysfunction.
ORPHA:1652Classification level: Disorder
- Dent syndrome
- Low-molecular-weight proteinuria with hypercalciuria and nephrocalcinosis
- Renal Fanconi syndrome with nephrocalcinosis and renal stones
- X-linked recessive hypercalciuric hypophosphatemic rickets
- X-linked recessive nephrolithiasis
- Prevalence: Unknown
- Inheritance: X-linked recessive
- Age of onset: Childhood
- ICD-10: N25.8
- OMIM: 300009 300554 300555 308990 310468
- UMLS: C0878681 C1839874
- MeSH: C545036 D057973
- GARD: -
- MedDRA: 10069199
Prevalence is unknown. The disorder has been reported in around 250 families to date. The disease is generally found only in males and may be present in childhood, whereas female carriers present with a milder form.
Dent disease is characterized by proximal tubule (PT) dysfunction with low-molecular-weight (LMW) proteinuria and hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure. The PT dysfunction may be more severe, causing Fanconi syndrome, where these features are associated with aminoaciduria, phosphaturia, glycosuria, uricosuria, kaliuresis, and impaired urinary acidification. Dent disease is often complicated by rickets or osteomalacia. The occurrence of these predominantly renal manifestations is referred to as Dent disease type 1 (see this term) while occurrence of associated extra-renal manifestations such as mild intellectual impairment, hypotonia and sub-clinical cataract (i.e. symptoms milder than in the oculocerebrorenal syndrome of Lowe) is referred to as Dent disease type 2 (see this term).
The disease is caused by mutations in either the CLCN5 (Dent disease type 1) or OCRL1 (Dent disease type 2) genes that are located on chromosome Xp11.22 and Xq25, respectively. CLCN5 encodes the electrogenic Cl-/H+ exchanger ClC-5, which belongs to the CLC family of chloride (Cl-) channels/transporters. OCRL1 encodes a phosphatidylinositol bisphosphate (PIP2) 5-phosphatase and mutations are also associated with Lowe Syndrome. A few patients with Dent disease do not harbor mutations in CLCN5 and OCRL1, pointing to the involvement of other genes.
Diagnosis is based on the presence of LMW proteinuria, hypercalciuria and at least one of the following: nephrocalcinosis, kidney stones, hematuria, hypophosphatemia, or renal insufficiency. Molecular genetics confirms the diagnosis.
Differential diagnosis includes the other causes of generalized proximal tubule dysfunction (renal Fanconi syndrome; see this term), hereditary, acquired, or caused by exogenous substances.
Although technically feasible, antenatal diagnosis and pre-implantation genetic testing is not advised because there is no evidence of a genotype-phenotype correlation and because of the generally good vital prognosis.
Management and treatment
Care is supportive, focusing on the treatment of hypercalciuria and the prevention of nephrolithiasis. Thiazide diuretics can be used to treat hypercalciuria although significant adverse effects, including hypovolemia and hypokalemia related to the primary tubulopathy, have been reported. Similarly, treatment of rickets with vitamin D must be cautious since it may increase hypercalciuria. Long-term control of hypercalciuria by a high citrate diet might delay progression of renal disease even in the absence of stone formation.
The vital prognosis is good in the majority of patients. Progression to end-stage renal failure occurs between the 3rd and 5th decades of life in 30-80% of affected males.