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 will progressively worsen causing severe 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 (end-stage 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 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 doctor 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 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 advanced chronic kidney disease include loss of appetite, unintended weight loss, fatigue, and anemia. In some cases, usually between the ages of 30-50, affected individuals can develop end-stage renal 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 as occurs in osteomalacia. In adults, the growth plate is not present so that osteomalacia is the evident bone problem. 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, affected individuals 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 characteristic 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 symptoms 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. In the medical literature, only 10 females with a Dent disease gene mutation have been reported to have developed kidney stones and only one affected female has been reported whose disease progressed to end-stage renal 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.
Investigators have determined that the CLCN5 gene is located on the short arm arm (p) of chromosome X (Xp11.23-11p22). The OCRL1 gene is located on the long arm (q) of chromosome X (Xq25-q26). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xp11.23-p11.22” refers to bands 11.23-11.22 on the short arm of chromosome X. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
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 cases 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). 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 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).
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 thiazides 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 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.
Vitamin D to treat rickets, if used, may be done so 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 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 end-stage renal disease, 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 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:
International Registry for Hereditary Calcium Stone Diseases
Mayo Clinic
200 First Street SW
Eisenberg SL-33
Rochester, MN 55905
Email: hyperoxaluriacenter@mayo.edu
Email rarekidneystones@mayo.edu
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
Information on current clinical trials in Dent disease by Rare Kidney Stone Consortium is available on the Internet at http://rarediseasesnetwork.epi.usf.edu/RKSC/studies/index.htm.
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: prpl@cc.nih.gov
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
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 J, Milliner DS, Beara-Lasic L, Rossetti S. Dent Disease. 2012 Aug 9. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Internet. Seattle, WA: University of Washington, Seattle; 1993-. Available at: http://www.ncbi.nlm.nih.gov/books/NBK99494/ Accessed on: October 27, 2013
Devuyst O, Thakker RV. Dent Disease. Orphanet Encyclopedia, January 2011. Available at: http://www.orpha.net/ Accessed on: October 27, 2013.
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