Dent Disease

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Retrieved

2021-01-18

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Genes

CLCN5, OCRL, LRP2, CLCN4, CUBN, RBP4, SHROOM4, CLTRN, NBAS, CLDN16, TFE3, SYP, SCN7A, ALB, PHEX, AR, NAGLU, GH1, EXT2, DAB2, CTSD, CLC, PHETA1

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Summary

Clinical characteristics.

Dent disease, an X-linked disorder of proximal renal tubular dysfunction, is characterized by low molecular weight (LMW) proteinuria, hypercalciuria, and at least one additional finding including nephrocalcinosis, nephrolithiasis, hematuria, hypophosphatemia, chronic kidney disease (CKD), and evidence of X-linked inheritance. Males younger than age ten years may manifest only LMW proteinuria and/or hypercalciuria, which are usually asymptomatic. Thirty to 80% of affected males develop end-stage renal disease (ESRD) between ages 30 and 50 years; in some instances ESRD does not develop until the sixth decade of life or later. The disease may also be accompanied by rickets or osteomalacia, growth restriction, and short stature. Disease severity can vary within the same family. Males with Dent disease 2 (caused by pathogenic variants in OCRL) may also have mild intellectual disability, cataracts, and/or elevated muscle enzymes. Due to random X-chromosome inactivation, some female carriers may manifest hypercalciuria and, rarely, renal calculi and moderate LMW proteinuria. Females rarely develop CKD.

Diagnosis/testing.

The diagnosis is established in a male proband with the typical clinical findings and a family history consistent with X-linked inheritance who has a pathogenic variant in either CLCN5 (known as Dent disease 1) or in OCRL (known as Dent disease 2). Heterozygous females are usually asymptomatic, but some exhibit LMW proteinuria and hypercalciuria, and others with kidney stones have also been described. Heterozygous females are most likely to be identified by familial molecular genetic testing related to a male proband.

Management.

Treatment of manifestations: The primary goals of treatment are to decrease hypercalciuria, prevent kidney stones and nephrocalcinosis, and delay the progression of CKD. Interventions aimed at decreasing hypercalciuria and preventing kidney stones and nephrocalcinosis have not been tested in randomized controlled trials. Although thiazide diuretics can decrease urinary calcium excretion in boys with Dent disease, side effects limit their use. The effectiveness of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in preventing or delaying further loss of kidney function in children with proteinuria is unclear. Renal replacement therapy is necessary in those with ESRD.

Prevention of secondary complications: Bone disease, when present, responds to vitamin D supplementation and phosphorus repletion. Growth failure may be treated with human growth hormone without adversely affecting kidney function.

Surveillance: Monitor at least annually urinary calcium excretion, renal function (glomerular filtration rate), and the parameters used to stage CKD (i.e., blood pressure, hematocrit/hemoglobin, and serum calcium and phosphorous concentrations). Monitor more frequently when CKD is evident.

Agents/circumstances to avoid: Exposure to potential renal toxins (nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics, and intravenous contrast agents).

Evaluation of relatives at risk: Clarify the genetic status of at-risk male relatives either by molecular genetic testing (if the pathogenic variant in the family is known) or by measurement of urinary excretion of low molecular weight proteins (LMWPs).

Genetic counseling.

Dent disease is inherited in an X-linked manner. The father of an affected male will not have the disease nor will he be hemizygous for the pathogenic variant. If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be significantly affected. Affected males pass the pathogenic variant to all of their daughters (who become carriers) and none of their sons. Carrier testing for at-risk female relatives and prenatal and preimplantation genetic testing are possible if the pathogenic variant in the family has been identified.

Diagnosis

Suggestive Findings

Dent disease should be suspected in an individual with the three criteria below in the absence of other known causes of proximal tubule dysfunction [Hoopes et al 2004, Edvardsson et al 2013]. Note: A possible diagnosis of Dent disease is considered if LMW proteinuria and at least one other criterion are present.

1.

LMW proteinuria (the pathognomonic finding of Dent disease) at least five times (and often 10x) above the upper limit of normal. Commonly screened LMW proteins are retinol binding protein and α1 microglobulin.

Note: β2 microglobulin is also often measured to screen for LMW proteinuria. To the authors' knowledge, no known cases of Dent disease have been missed using this screening method; however, its use is cautioned since it is not stable in even minimally acidic urine [Davey & Gosling 1982] and thus could theoretically yield a false negative result.

2.

Hypercalciuria

Adults (age >18 years). >4.0 mg calcium (0.1 mmol) /kg in 24 hours or >0.25 calcium/creatinine mg/mg (0.57 mmol/mmol) in spot urine
Children. See Table 1 for 95th percentile calcium/creatinine mg/mg reference values in random urine collections.

3.

At least one of the following:

Nephrocalcinosis (diffuse renal calcification)
Nephrolithiasis (kidney stones; composed of calcium oxalate and/or calcium phosphate)
Hematuria (microscopic or macroscopic blood in the urine)
Hypophosphatemia (low blood phosphorous concentration)
Chronic kidney disease (CKD); measured or estimated glomerular filtration rate (GFR) that is below the normal limits for age
Family history consistent with X-linked inheritance

Table 1.

Calcium/Creatinine (mg/mg) Reference Values in Children (age <18 yrs)

Age (yrs)	95th percentile
0-1	<0.81
1-2	<0.56
2-3	<0.50
3-5	<0.41
5-7	<0.30
7-10	<0.25
10-14	<0.24
14-17	<0.24

: In random urine collections
: Matos et al [1997]

Establishing the Diagnosis

Male proband. The diagnosis of Dent disease is established in a male proband with the identification of a hemizygous pathogenic variant in either CLCN5 (Dent disease 1) or OCRL (Dent disease 2) by molecular genetic testing (see Table 2).

Female proband. Female carriers, who are heterozygous for a pathogenic variant in either CLCN5 (Dent disease 1) or OCRL (Dent disease 2), are usually asymptomatic. However, some exhibit LMW proteinuria and hypercalciuria, and others with kidney stones have also been described [Hoopes et al 1998]. Rare females with CKD have been reported. Although biallelic pathogenic variants could occur, it has been assumed that any manifestations are due to skewed X-chromosome inactivation, and many of these symptomatic carriers have other unaffected male children [Dinour et al 2009].

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Single-gene testing can be considered:

For males or females. Sequence analysis of CLCN5 is usually performed first; if a pathogenic variant is not identified, sequence analysis of OCRL is performed next.
Note: Sequence analysis of affected males provides putative identification of (multi)exon and whole-gene deletions due to lack of amplification; confirmation may require gene-targeted deletion/duplication analysis.
In a female. If a pathogenic variant is not detected in either gene by sequence analysis, consider gene-targeted deletion/duplication analysis of CLCN5, followed by OCRL.

A multigene panel that includes CLCN5, OCRL, and other genes of interest (see Differential Diagnosis) can also be considered as a first step. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 2.

Molecular Genetic Testing Used in Dent Disease

Gene ¹	Proportion of Dent Disease Attributed to Pathogenic Variants in Gene ²	Proportion of Pathogenic Variants ³ Detectable by Method
Gene ¹		Sequence analysis ^4, 5	Gene-targeted deletion/duplication analysis ⁶
CLCN5	60%	~92%	~8% ⁷
OCRL	15%	~95%	~5% ⁸
Unknown ⁹		NA

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: Claverie-Martín et al [2011]
3.: See Molecular Genetics for information on allelic variants detected in this gene.
4.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
5.: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
6.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
7.: Of the 245 different CLCN5 pathogenic variants known to cause Dent disease 1 identified to date, 7.8% are complex rearrangements (large deletions, insertions, or indels) (HGMD 2016).
8.: Of the 42 different OCRL pathogenic variants known to cause Dent disease 2 identified to date, 4.7% are multiexon deletions (HGMD 2016).
9.: In a cohort of affected individuals, approximately 18% (20/110) of males with a Dent disease phenotype did not have a pathogenic variant identified in CLCN5 and OCRL1 [Authors, unpublished observation].

Clinical Characteristics

Clinical Description

Presentation. In the early stages of Dent disease, children (typically <~10 years) may manifest only low molecular weight (LMW) proteinuria and/or hypercalciuria, both of which are usually asymptomatic [Claverie-Martín et al 2011]. In the asymptomatic individual, detection of proteinuria may occur on a urinalysis done for screening or other purposes.

LMW proteinuria and/or hypercalciuria can be accompanied by stone disease or nephrocalcinosis, and less frequently by other manifestations of proximal tubular dysfunction including aminoaciduria, phosphaturia, and glycosuria [Hodgin et al 2008].

Hypercalciuria is typically accompanied by elevated or high-normal levels of 1,25-dihydroxyvitamin D, and depressed or low-normal levels of intact parathyroid hormone (PTH) [Scheinman 1998].
Hypercalciuria largely or completely resolves with dietary calcium restriction, suggesting that the major component of hypercalciuria is intestinal hyperabsorption.

Renal biopsy. Since patients often present with CKD and proteinuria, a renal biopsy is often obtained. Findings consistent with Dent disease include nephrocalcinosis, interstitial fibrosis, and focal segmental glomerulosclerosis and/or focal global glomerulosclerosis [Copelovitch et al 2007, Frishberg et al 2009]. However, a kidney biopsy alone cannot definitively diagnose Dent disease, and is not required to make the diagnosis.

Other features. The disease may also be accompanied by rickets or osteomalacia, growth restriction, and short stature [Bökenkamp et al 2009].

Short stature is common, although not usually profound in Dent disease 1. In one series height was -0.58 SD of the age-appropriate mean value for Dent disease 1, but more significantly reduced at -2.10 SD for Dent disease 2 [Bökenkamp et al 2009].

Disease progression. An estimated 30%-80% of affected males develop end-stage renal disease (ESRD) between ages 30 and 50 years; in some instances ESRD does not develop until the sixth decade or later [Wrong et al 1994, Lloyd et al 1997]. Of note, deterioration of renal function can occur even in the absence of nephrocalcinosis. Disease severity can vary even within the same family.

Dent Disease 1 (caused by pathogenic variants in CLCN5)

The renal phenotypic findings in Dent 1 vary considerably.

Scheinman et al [2000] reported a family in which all affected individuals had the same CLCN5 missense variant (c.1517G>A; p.Gly506Glu) and the Dent disease phenotype ranged from severe in several members to isolated hypercalciuria without proteinuria, nephrocalcinosis, or chronic kidney disease (CKD) in one individual. It is not currently known how often an individual with a CLCN5 pathogenic variant manifests only asymptomatic hypercalciuria and/or proteinuria without developing CKD.

Some individuals with a pathogenic variant in CLCN5 and a family history of Dent disease developed ESRD with proteinuria, but without other typical features of Dent disease (i.e., kidney stones, nephrocalcinosis, and bone disease) [Copelovitch et al 2007, Frishberg et al 2009]. Renal biopsy revealed focal segmental glomerulosclerosis (FSGS) and focal global glomerulosclerosis. The findings in these individuals illustrate that the spectrum of Dent disease includes persons with proteinuria and a biopsy consistent with FSGS and that the diagnosis is only considered when evaluations for LMW proteinuria and/or hypercalciuria are performed.

It is currently unclear whether Dent disease will be diagnosed among a larger number of individuals with clinical FSGS, although it is now known that focal global sclerosis is very common in Dent disease [Wang et al 2016] and instances of Dent disease being misdiagnosed as FSGS continue to be reported [Fervenza 2013].

Dent Disease 2 (caused by pathogenic variants in OCRL)

To date, 42 pathogenic variants have been identified in males with a Dent disease 2 phenotype and have been reported in the literature.

In addition to the Dent disease-related renal findings, individuals with Dent disease 2 may also have:

Mild intellectual disability
Cataracts (rare)
Elevated muscle enzymes (LDH, CK)

Symptomatic Females

There have been occasional reports of renal calculi and moderate LMW proteinuria when carrier females have been studied in large kindreds. Rarely, heterozygous females manifest clinically significant kidney disease resulting from skewed X-chromosome inactivation. One female from a family with Dent disease developed renal insufficiency and nephrocalcinosis; however, she did not have molecular genetic testing [Wrong et al 1994]. Another carrier female with a known pathogenic variant, developed symptomatic nephrolithiasis and stage 3B CKD by age 65 [Hoopes et al 1998].

Although not reported in the literature, a symptomatic female could have an X-chromosome abnormality (e.g., absence of one X chromosome [45,X] and a CLCN5 or OCRL pathogenic variant on the remaining X chromosome).

Although not reported in the literature, a female with biallelic pathogenic variants in CLCN5 or OCRL (inherited from a carrier mother and an affected father) would be predicted to manifest clinically significant kidney disease.

Genotype-Phenotype Correlations

CLCN5. Genotype-phenotype correlations have yet to be established.

OCRL. It has been suggested that pathogenic variants in OCRL are associated with a phenotypic spectrum ranging from Lowe syndrome at the severe end (see Genetically Related Disorders) to Dent disease 2 at the mild end.

Note: Although the renal tubulopathy in Lowe syndrome (which is mainly characterized by altered protein reabsorption) and Dent disease is similar, it is generally milder in Dent disease. Of note, this milder Dent disease phenotype could not be attributed to lesser protein expression or enzyme activity.

Frameshift and nonsense OCRL variants associated with Dent disease 2 have been mapped to exons different from those causing Lowe syndrome [Hichri et al 2011]; however, OCRL missense and splicing variants and in-frame deletions that cause these two disorders do not map exclusively to specific gene regions.

Frameshift and nonsense variants associated with Dent disease 2 are in the first seven exons. Missense variants associated with Dent disease 2 are most often, but not exclusively, located in exons 9-15, which encode the catalytic phosphatase domain.
Frameshift and nonsense variants associated with Lowe syndrome are located in the middle and later regions of the gene, exons 8-23, which encode the catalytic phosphatase and the Rho-GAP-like domain [Tosetto et al 2009, Hichri et al 2011].

Prevalence

To date about 250 affected families have been reported [Devuyst & Thakker 2010]. However, the wide variability of clinical presentation in Dent disease and (in some cases) absence of family history make diagnosis difficult; thus, the disorder is likely underdiagnosed.

Differential Diagnosis

The differential diagnosis of Dent disease includes other causes of proximal tubular dysfunction.

Renal Fanconi syndrome. The presence of more generalized proximal tubular dysfunction (glucosuria, amino aciduria, renal tubular acidosis) would suggest the possibility of a renal Fanconi syndrome. Causes of renal Fanconi syndromes can be hereditary (e.g., Wilson disease, glycogen storage disease) or acquired (e.g., exposure to heavy metal, toluene, or cisplatin).

Glomerular disease. Some individuals with Dent disease 1 with more severe proteinuria were found to have focal segmental glomerulosclerosis (FSGS) or global sclerosis on kidney biopsy [Copelovitch et al 2007, Frishberg et al 2009]. Most cases of FSGS are idiopathic, but FSGS can be seen in association with obesity or progressive chronic kidney disease of any cause. FSGS associated with Dent disease can be identified by the prominent low molecular weight (LMW) proteinuria and confirmed by genetic testing.

Donnai-Barrow syndrome, caused by biallelic pathogenic variants in LRP2, which encodes a 600-kd megalin protein, bears some similarities to Dent disease [Kantarci et al 2007]. Clinical manifestations of this rare disorder include hypertelorism, large anterior fontanelle, agenesis of the corpus callosum, and congenital diaphragmatic hernia [Pober et al 2009]. LMW proteinuria and high myopia have been consistently observed in these patients [Pober et al 2009]. However, other typical findings of Dent disease, including nephrolithiasis, nephrocalcinosis, hypercalciuria, chronic kidney disease, or bone disease, have not been reported to date.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with Dent disease, the following evaluations are recommended if they have not already been completed:

Assessment of renal function (measured or estimated GFR; urine protein excretion)
Assessment for nephrocalcinosis and kidney stones by imaging studies, typically low-dose noncontrast CT scan or ultrasound
For those with evidence of renal stones or nephrocalcinosis, urine studies for kidney stone risk factors (including calcium and citrate excretion)
Assessment of risk for bone disease (serum calcium, phosphorus, and alkaline phosphatase)
Note: Elevated alkaline phosphatase has been reported in all individuals with clinical rickets [Wrong et al 1994].
For those with evidence of bone disease and/or growth delay, more complete assessment of bone health (i.e., serum vitamin D concentration and PTH level; x-ray of long bones for evidence of osteomalacia)
In children, evaluation of stature using standard growth charts. If short stature is present, evaluation by an endocrinologist for the possibility of growth hormone therapy can be considered.
Evaluation for intellectual disability
Careful eye exam for cataracts, especially if there is any concern for visual impairment
Consultation with a clinical geneticist and/or genetic counselor
Although it is not necessary to specifically screen for the possibility, elevated serum muscle enzyme levels are often seen in patients with Dent disease.

Treatment of Manifestations

No guidelines have been established for treatment of Dent disease. The primary goals of treatment are to decrease hypercalciuria, prevent kidney stones and nephrocalcinosis, and delay the progression of chronic kidney disease (CKD).

Interventions aimed at decreasing hypercalciuria and preventing kidney stones and nephrocalcinosis have not been tested in randomized controlled trials. Thiazide diuretics in doses greater than 0.4 mg/kg/day have decreased urinary calcium excretion by more than 40% in boys with Dent disease [Raja et al 2002, Blanchard et al 2008]. However, frequent side effects included hypokalemia, volume depletion, and cramping. Careful dosing and close monitoring for these side effects are necessary.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have been used in children with proteinuria to prevent or delay further loss of kidney function; however, their effectiveness has not been clear. Although treatment with ACE inhibitors or ARB may be somewhat beneficial for individuals with focal segmental glomerulosclerosis (FSGS), they are not known to be helpful for the focal global glomerulosclerosis that is associated with Dent disease, and angiotensin blockade is not thought to significantly affect LMW proteinuria or any potential ill effects of it. A kidney biopsy to exclude other causes of proteinuria and CKD is reasonable.

While a high-citrate diet has been shown to slow progression of CKD in Clcn5 knockout mice [Cebotaru et al 2005] and has been used in the treatment of Dent disease, no human trials have proven its effectiveness. Note: Citrate is commonly used in Lowe syndrome to treat the metabolic acidosis resulting from renal tubular acidosis.

If males with Dent disease progress to ESRD, renal replacement therapy becomes necessary. Hemodialysis, peritoneal dialysis, and renal transplantation are appropriate options. Because Dent disease manifestations are largely localized in the kidney, the disease will not recur.

School-aged individuals with mild intellectual disability will benefit from individual educational plans and special educational services.

Cataracts, if present, are treated in a standard manner.

Prevention of Secondary Complications

Bone disease has not been a prominent component of Dent disease in a recent case series based in France [Blanchard et al 2016] but was more prominent in a Chinese population [Li et al 2016]; whether this reflects environmental or genetic effects is not known. When present it has been reported to respond to vitamin D supplementation and phosphorus repletion in those with elevated serum alkaline phosphatase levels [Wrong et al 1994].

Limited reports suggest that growth failure can be successfully treated with human growth hormone without adversely affecting kidney function [Sheffer-Babila et al 2008].

Surveillance

Renal function measured as glomerular filtration rate (GFR) should be monitored at least annually together with the parameters used to stage chronic kidney disease (i.e., blood pressure, hematocrit/hemoglobin, urinary calcium excretion, and serum calcium and phosphorus concentrations).

More frequent visits and monitoring for complications of chronic kidney disease (i.e., hypertension, anemia, and secondary hyperparathyroidism) as well as consideration of intensified treatment of cardiovascular risk factors may be indicated if GFR falls below 45 mL/min/1.73 m² (CKD Stage 3B).

Agents/Circumstances to Avoid

Exposure to potential renal toxins (nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics, and intravenous contrast agents) should be avoided, especially if renal function is below 45 mL/min/1.73 m² (CKD stage 3B).

Evaluation of Relatives at Risk

It is appropriate to evaluate male relatives at risk for Dent disease 1 (caused by mutation of CLCN5) or Dent disease 2 (caused by mutation of OCRL) in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.

If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
If the pathogenic variant in the family is not known, measurement of urinary excretion of low molecular weight proteins (e.g., alpha 1 microglobulin, retinol binding protein) is a sensitive and specific test.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.