NORD gratefully acknowledges Lada Beara Lasic, MD, MS, Assistant Professor of Medicine, Division of Nephrology, NYU Medical School, and John Lieske, MD, Professor of Medicine, Mayo Clinic, for assistance in the preparation of this report.
Summary
Dent disease is a rare genetic kidney disorder characterized by spillage of small proteins in the urine, increased levels of calcium in the urine, kidney calcifications (nephrocalcinosis), recurrent episodes of kidney stones (nephrolithiasis) and chronic kidney disease. Dent disease affects males almost exclusively. Symptoms usually appear during childhood, but some individuals may be undiagnosed well into adulthood. In some cases, the disorder may progressively worsen causing chronic kidney disease; in other cases affected individuals only experience mild or moderate disease into old age. Kidney disease can progressively worsen until the kidneys stop functioning (renal failure), although this usually does not occur until 30 to 50 years of age or later and will not occur at all in some individuals. Dent disease can be broken down into two subtypes. Dent disease type 1 is characterized by the previously-mentioned kidney symptoms. Dent disease type 2 is characterized by the same kidney symptoms, but individuals may have additional symptoms including mild intellectual disability, eye involvement or diminished muscle tone (hypotonia). Dent disease type 1 is caused by changes (mutations) in the CLCN5 gene. Dent disease type 2 is caused by mutations in the OCRL1 gene. Both of these genes are located on the X chromosome. These mutations may be inherited or occur randomly with no previous family history of the disorder (spontaneously). Dent disease is fully expressed only in males, although some females who carry the gene may develop mild manifestations such as spillage of small proteins in the urine, increased levels of calcium in the urine, or rarely kidney stones.
Introduction
Dent disease was first reported in the medical literature in 1964 by Drs. Dent and Friedman who described two unrelated boys with rickets. The disorder was eventually fully described by Dr. Oliver Wrong in 1990 who named the disease after his colleague and mentor Dr. Dent. Over the years Dent disease was referred to by other names including X-linked recessive nephrolithiasis with renal failure, X-linked recessive hypercalciuric hypophosphatemic rickets, and idiopathic low-molecular-weight proteinuria with hypercalciuria and nephrocalcinosis. Generally, Dent disease is now broken into type 1 and type 2 based upon the specific genetic mutation present. There are other individuals with Dent disease who lack known mutations of these two genes (non 1/ non 2).
The specific symptoms and severity of Dent disease can vary dramatically, even among individuals within the same family. Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about these disorders is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorders prevent physicians from developing a complete picture of associated symptoms and prognosis.
Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.
Common symptoms associated with Dent disease include elevated levels of proteins and calcium in the urine (proteinuria and hypercalciuria). The type of proteinuria seen in Dent disease is known as low-molecular-weight proteinuria, which is a characteristic finding of the disorder and not always detected in routine medical testing. Hypercalciuria and low molecular weight proteinuria may be the only symptoms that develop in some people.
Affected individuals may also develop calcium deposits or calcifications in the kidney tissue (nephrocalcinosis) and/or experience recurrent episodes of kidney stone formation. Kidney stones can cause various symptoms including blood in the urine (hematuria), painful urination (dysuria), the urge to urinate often, abdominal pain (renal colic), blockage of the urinary tract, and repeated urinary tract infections. Eventually, the disorder can progress to cause chronic kidney disease with a progressive decline in kidney function. Symptoms associated with very advanced chronic kidney disease include loss of appetite, unintended weight loss, fatigue, and anemia. In some cases, sometimes as early as 30-50 years old, affected individuals can develop kidney failure and require dialysis or kidney transplantation.
Some individuals with Dent disease may also develop bone disease such as softening of the bones (osteomalacia) and hypophosphatemic rickets, a condition caused by impaired transport of phosphate and altered vitamin D metabolism in the kidneys. In children, rickets is characterized by bowing deformity of the legs, as well as, growth plate abnormalities and progressive softening of the bones (called osteomalacia). . In children, growth rates may be slower than normal, frequently resulting in mild short stature. Children may also experience bone pain and difficulty walking. Because of bone abnormalities, both children and adults may have an increased risk of fractures.
Some individuals with Dent disease have developed vitamin A deficiency, which can lead to impaired night vision and dry eyes (xerophthalmia). This can be corrected by vitamin A supplementation.
DENT DISEASE TYPE 2
Dent disease type 2 is characterized by the same symptoms associated with Dent disease type 1. However, some affected individuals have developed additional symptoms including mild intellectual disability, hypotonia, and clouding of the lenses of the eyes (cataracts). Cataracts in Dent disease type 2 are classified as subclinical because they do not impair vision.
Dent disease type 2 is caused by mutations in the same gene that causes Lowe syndrome, a rare multisystem disorder. Lowe syndrome is characterized by the kidney abnormalities that occur in Dent disease, but also additional findings affecting the eyes, brain and other organ systems. Some researchers believe that Dent disease type 2 represents the mild end of a disease spectrum that includes Lowe syndrome at the severe end. (For more information on Lowe syndrome, see the Related Disorders section of this report).
FEMALE CARRIERS
Some females who inherited one of the mutations that cause Dent disease may develop mild manifestations of the disorder such as low-molecular-weight proteinuria and/or hypercalciuria. Kidney stones may be more common in female carriers, reported in 6 out of 14 Dent 1 mothers in one recent series. However, only one affected female has been reported in the literature to date whose disease progressed to kidney failure, however she did not have genetic testing to confirm the disease.
Dent disease type 1 is caused by a mutation in the CLCN5 gene; Dent disease type 2 is caused by mutations in the OCRL1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
In most cases, male children inherit the disorder from a carrier mother who has no symptoms or extremely mild symptoms of the disorder. When a mother is a known carrier of the CLCN5 or the OCRL1 mutation, there is a 50% chance of passing that mutation on to her children. Males who inherited a mutation will have the disorder; females who inherited the mutation will be carriers. In extremely rare cases, the mutation that causes the disorder occurs randomly for no apparent reason (de novo mutation). Affected males will not pass the disorder onto sons (who inherit the Y chromosome from fathers), but will pass the mutation on to all their daughters (who will become carriers).
Random X-chromosome inactivation is a normal process in females. Females have two X chromosomes, whereas males have one X chromosome and one Y chromosome. In females, certain disease traits on the X chromosome such as a mutated gene may be “masked” by the normal gene on the other X chromosome (random X-chromosome inactivation). Basically, in each cell of the body one X chromosome is active and one is turned off or “silenced.” This occurs randomly and generally happens as a 50-50 split. However, in some cases, females may have favorable X-inactivation, in which the affected X chromosome is silenced in most of the cells. In such cases, they may not develop any symptoms or only have mild symptoms of the disorder. In other cases, females may have unfavorable X-inactivation, in which the unaffected X chromosome is silenced in most of the cells. In such cases, affected females may develop various symptoms associated with Dent disease, but this has only occurred in extremely rare cases.
The CLCN5 and OCRL1 genes create (encode) specific enzymes that are necessary for the proper function of the kidneys. Mutations in these genes result in reduced activity of these enzymes. The enzyme product produced by the CLCN5 gene is believed to be expressed heavily in the kidneys, including within the proximal tubules, the tiny tubes that serve as the primary site of protein reabsorption in the nephron, in the cortical collecting tubules and the loop of Henle. Nephrons are hair-sized structures that are the basic units of the kidneys and remove waste from the blood. The proximal tubules are essential for the proper reabsorption of several important filtered substances such as proteins. Dysfunction of the proximal tubules is believed to play an important role in the development of Dent disease. The exact functions of the enzyme product produced by the OCRL1 gene are not fully understood; however it is known that it is also involved in reabsorption of proteins and recycling of receptors in proximal tubules. More research is necessary to determine the specific functions of these enzymes and how their deficiency contributes to the development of Dent disease.
Some individuals with Dent disease do not have mutations in either the CLCN5 or OCRL1 genes, suggesting that additional subtypes of Dent disease caused by mutations in as yet unidentified genes most likely exist.
The exact incidence and prevalence of Dent disease is unknown. Dent disease type 1 has been reported in approximately 250 families. Dent disease type 2 has been reported in approximately 25 individuals. Because some affected individuals go undiagnosed or misdiagnosed, determining these disorders’ true frequency in the general population is difficult. Dent disease is fully expressed in males only. Dent disease may be recognized during childhood, while other cases can remain undiagnosed well into adulthood.
A diagnosis of Dent disease is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis may be suspected in individuals with high levels of low-molecular-weight proteins in the urine, excess levels of calcium in the urine and one of the following: nephrocalcinosis, nephrolithiasis, hematuria, hypophosphatemia, chronic kidney disease, or evidence of X-linked recessive inheritance.
Clinical Testing and Workup
Chemical analysis of urine samples may reveal elevated levels of low-molecular-weight proteins and calcium. A biopsy of affected kidney tissue may also reveal changes indicative of Dent disease, although findings may not be specific and are sometimes reported out as focal segmental glomerulosclerosis (FSGS) or focal global glomerulosclerosis. A biopsy involves the surgical removal and microscopic examination of a piece of affected tissue. A kidney biopsy is not necessary for the diagnosis of Dent disease since laboratory findings and genetic testing can be sufficient to make the diagnosis. However kidney biopsies are often performed in patients who have unexplained kidney disease and significant proteinuria, so that many patients with Dent disease are biopsied before the final diagnosis is made.
A diagnosis of Dent disease can be confirmed through molecular genetic testing. Molecular genetic testing can detect mutations in the two specific genes known to cause Dent disease, but is not always necessary to make a clinical diagnosis of Dent disease if typical findings are present (for example low molecular weight proteinuria and hypercalciuria in male patient). However, genetic testing is generally recommended today since it is becoming increasingly recognized that other genetic causes of nephrocalcinosis and chronic kidney disease share clinical features with Dent disease.
Treatment
The treatment of Dent disease is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, specialists who assess and treat problems of the kidneys (nephrologists), specialists who assess and treat problems of the urinary tract (urologists), dieticians, and other healthcare professionals may need to systematically and comprehensively plan an affect individual’s treatment. Genetic counseling may be of benefit for affected individuals and their families.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of these diseases, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with Dent disease.
Medications known as thiazide diuretics may be used to treat individuals with Dent disease to prevent the recurrence of kidney stones and to lower levels of calcium in the urine. However, these medications can potentially cause significant adverse side effects.
Additional medications known as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have been used in children with other causes of chronic kidney disease associated with elevated levels of proteins in their urine to prevent or delay a further decline in kidney function. The effectiveness of these medications in children with Dent disease is unclear.
If vitamin D is used to treat rickets in a patient with Dent disease, it must be done cautiously because excess amounts of vitamin D can increase calcium levels in the urine. Growth failure in children may be treated with growth hormone supplementation. A high citrate diet or citrate supplements in pill or liquid form have also been used to treat some individuals with Dent disease, based on the observation that a high citrate diet slows progression of kidney disease in a mouse model of Dent disease, although the efficacy of citrate is unproven in humans.
If kidney function continues to decline, or in cases where an individual is first diagnosed with Dent disease after the development of kidney failure, additional more aggressive treatment may be required including hemodialysis, peritoneal dialysis, and a kidney transplant.
A registry for hereditary calcium stone disorders has been set up by the Rare Kidney Stone Consortium at the Mayo Clinic. A registry is a special database that contains information about individuals with a specific disorder or group of conditions. The collection of data about rare disorders may enable researchers to increase the understanding of such disorders, expand the search for treatments, and accelerate clinical trials into specific treatment options. For more information, contact:
Rare Kidney Stone Consortium
Mayo Clinic
200 First Street SW
Eisenberg SL-33
Rochester, MN 55905
Email: [email protected]
Email [email protected]
Phone: 1-800-270-4637
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
http://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Blanchard A, Curis E, Guyon-Roger T, Kahila D, Treard C, Baudouin V, Bérard
E, Champion G, Cochat P, Dubourg J, de la Faille R, Devuyst O, Deschenes G,
Fischbach M, Harambat J, Houillier P, et al. Observations of a large Dent disease cohort. Kidney Int. 2016;Aug;90(2):430-439. doi: 10.1016/j.kint.2016.04.022. Epub 2016 Jun 22. PMID: 27342959.
Li F, Yue Z, Xu T, et al. Dent disease in Chinese children and findings from heterozygous mothers: phenotypic heterogeneity, fetal growth, and 10 novel mutations. J Pediatr. 2016; Jul;174:204-210.e1. doi: 10.1016/j.jpeds.2016.04.007. Epub 2016 May 9. PMID: 27174143.
Edvardsson VO, Goldfarb DS, Lieske JC, et al. Hereditary causes of kidney stones and chronic kidney disease. Pediatr Nephrol. 2013;28:1923-1942. http://www.ncbi.nlm.nih.gov/pubmed/23334384
Becker-Cohen R, Rinat C, Ben-Shalom E, et al. Vitamin A deficiency associated with urinary retinol binding protein wasting in Dent’s disease. Pediatr Nephrol. 2012;27:1097-1102. http://www.ncbi.nlm.nih.gov/pubmed/22350370
Grand T, L’Hoste S, Mordasini D, et al. Heterogeneity in the processing of CLCN5 mutants related to Dent disease. Hum Mutat. 2011;32:476-483. http://www.ncbi.nlm.nih.gov/pubmed/21305656
Clayerie-Maratin F, Ramos-Trujillo E, Garcia-Nieto V. Dent’s disease: clinical features and molecular basis. Pediatr Nephrol. 2011;26:693-704. http://www.ncbi.nlm.nih.gov/pubmed/20936522
Devuyst O, Thakker RV. Dent’s disease. Orphanet J Rare Dis. 2010;5:28. http://www.ncbi.nlm.nih.gov/pubmed/20946626
Bokenkamp A, Bockenhauer D, Cheong HI, et al. Dent 2 disease: a mild variant of Lowe syndrome. J Pediatr. 2009;155:94-99. http://www.ncbi.nlm.nih.gov/pubmed/19559295
Blanchard A, Vargas-Poussou R, Peyrard S, et al. Effect of hydrochlorothiazide on urinary calcium excretion in Dent disease: an uncontrolled trial. Am J Kidney Dis. 2008;52:1084-1095. http://www.ncbi.nlm.nih.gov/pubmed/18976849
Hoopes RR Jr., Shrimpton AE, Knohl SJ, et al. Dent disease with mutations in OCRL1. Am J Hum Genet. 2005;76:260-267. http://www.ncbi.nlm.nih.gov/pubmed/15627218
Thakker RV. Pathogenesis of Dent’s disease and related syndromes of X-linked nephrolithiasis. Kidny Int. 2000;57:787-793. http://www.ncbi.nlm.nih.gov/pubmed/10720930
INTERNET
Lieske JC, Milliner DS, Beara-Lasic L, et al. Dent Disease. 2012 Aug 9 [Updated 2017 Dec 14]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK99494/ Accessed March 18, 2021.
Devuyst O, Thakker RV. Dent Disease. Orphanet. Last Update January 2011. Available at: http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=3719&Disease_Disease_Search_diseaseGroup=Dent-disease&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Dent-disease&title=Dent-disease&search=Disease_Search_Simple Accessed March 18, 2021.
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