Dent disease type 2 (ORPHA:93623)
A rare genetic renal tubular disease, characterized by manifestations of proximal tubule dysfunction with low-molecular-weight (LMW) proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure. Extra-renal involvement is frequent, but may be mild and not recognized.
Epidemiology
The exact prevalence is unknown. Compared to Dent disease type 1, Dent disease type 2 is approximately 4 times less frequent.
Clinical description
The disease is generally found in males only, who may have manifestations of the disease from early childhood. It is characterized by proximal tubule (PT) dysfunction and low-molecular-weight (LMW) proteinuria (100% of cases), associated with hypercalciuria (>95%), nephrolithiasis (20-30%), nephrocalcinosis (10-20%), and progressive renal failure. PT dysfunction may be severe, resulting in complete Fanconi syndrome, i.e. aminoaciduria, phosphaturia, uricosuria, kaliuresis, and impaired urinary acidification, and can be complicated by rickets or osteomalacia. Unlike Dent disease type 1, glycosuria is rarely observed. Patients may present symptoms related to renal stones (abdominal pain, hematuria), Fanconi syndrome (polyuria, poor growth, rickets), or chronic kidney failure. Patients are also frequently referred after fortuitous discovery of nephrocalcinosis, renal stones, proteinuria or other biological signs of PT dysfunction. Extra-renal symptoms include variable degrees of intellectual impairment in approximately one-quarter of patients, partial cataract in approximately 10% of patients, and growth retardation (mean height Z-score: -2.1). Nearly all patients have creatine phosphokinase (CPK) and/or lactate dehydrogenase (LDH) levels above the normal range.
Etiology
The disease is due to variants on the OCRL1 gene (Xq26.1) and is allelic with oculocerebrorenal syndrome of Lowe (Lowe syndrome). Unlike Lowe syndrome, severe pathogenic variants causing Dent disease type 2 (nonsense, frameshift, and splice site mutations) are clustered in exons 4-7; variants that are located in other regions of the OCRL1 gene are nearly always missense mutations.
Diagnostic methods
The diagnosis is based on the presence of LMW proteinuria, which is associated in the majority of cases with hypercalciuria and other biological, radiological and clinical symptoms of the disease. Elevated CPK and LDH help distinguishing Dent disease type 1 from type 2. When present, lens abnormalities and intellectual impairment also favor the diagnosis of Dent disease type 2. Molecular genetics confirms the diagnosis.
Differential diagnosis
The differential diagnosis includes other causes of low molecular weight proteinuria and Fanconi syndrome. There is a continuum in the clinical manifestations of Dent disease type 2 and Lowe syndrome, which are both caused by OCRL1 pathogenic variants. In some patients, the distinction between these two phenotypes can be difficult.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is X-linked. Genetic counseling should be offered to at-risk couples informing them that there is a 50% risk of having an affected boy or a carrier girl at each pregnancy, if the mother carries the mutation.
Management and treatment
Care is supportive. From the renal perspective, the focus is on the prevention of nephrolithiasis, maintaining appropriate hydration and treatment of chronic kidney disease, if present. Experimental data in Dent 1 disease suggest that long-term treatment with a high citrate diet or supplementation with citrate might delay progression of renal disease, but data are not available for Dent 2 disease. Treatment of rickets with vitamin D must be cautious in patients with hypercalciuria and/or nephrocalcinosis. Patients with intellectual impairment require neuropsychological and educational support.
Prognosis
Progression to end-stage renal failure occurs between the second and fifth decades of life in the majority of affected males. The disease does not recur in the transplanted kidney.

                            Last update: 
                            August 2021


                            - Expert reviewer(s): 
                            Pr Gema ARICETA | ERKNet* - Pr Francesco EMMA | ERKNet*


                                * European Reference Network