Information on the following diseases can be found in the Related Disorders section of this report:

• Gout
• Medullary Cystic Disease
• Adult Polycystic Kidney Disease

The symptoms and signs of familial juvenile hyperuricemic nephropathy are:

(1) Gout. Gout is a type of arthritis that causes severe pain in one or more joints (frequently the big toe). After a long time, bumps (tophi) form on these joints. In the general population, gout occurs most frequently in middle-aged men. In this disorder, gout occurs in the teenage years and it also occurs in women. Gout occurs in many, but not all, patients with FJHN.

(2) Kidney failure. Signs of kidney failure (an increased blood creatinine level) may occur as early as the second decade of life. Patients usually end up with kidney failure requiring dialysis or a transplant at some time from the age of 30 to the early 70s.

(3) Inheritance. There is a 50/50 chance that children of an affected parent will suffer from the disease. For this reason, the disease runs in families, and a number of family members usually have it.

(4) An elevated blood uric acid level occurs in almost all patients with this disease, and is present from childhood. The elevated blood uric acid level is the cause of gout. The cause of the elevated blood uric acid level is a decreased removal (excretion) of uric acid in the urine.

(5) Some patients with this condition have cysts in their kidneys, and some suffer from bed-wetting.

FJHN may be caused by changes (mutations) in several different genes. Recently, one cause for FJHN has been found. One group of patients with FJHN have been found to have a mutation in one copy of the uromodulin gene. This gene makes the protein uromodulin (also called Tamm-Horsfall protein). This is the most common protein found in the normal urine. Somehow, a mistake in the protein leads tot gout and kidney failure. How this happens is currently being studied.

Discovering the gene means that, in many cases now, families and individuals can be tested to see if they have the disease.

The gene that codes for uromodulin is on chromosome 16 (16p11-p13).

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 "16p11-p13" refers to a space on the short arm of chromosome 16 between band 11 and band 13. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait which are on the chromosomes received from the father and the mother.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

This disease is likely to occur in all populations regardless of ethnicity, race, or sex. A strong family history of gout and kidney failure is often found, but new changes appearing for no apparent reason (sporadic mutations) in a person’s genes can make him the first family member to suffer from the disease.

Symptoms of the following disorders may be similar to those of FJHN. Comparisons may be useful for a differential diagnosis:

Gout is a common disorder characterized by periods of elevated levels of uric acid in the blood (hyperuricemia). Gout usually occurs in the big toe, ankles, knees, or elbows. Gout is a symptom of FJHN, but many patients have gout from other causes and do not have FJHN. In FJHN, gout typically runs in the family and is associated with kidney failure. It occurs at a younger age (often in the teens) and in women, whereas in typical gout, the first attach of gouty arthritis occurs between the ages of 40 and 60 years.

Medullary cystic disease, also known as medullary cystic kidney disease, is a rare inherited chronic kidney disorder (nephropathy) that usually becomes apparent during childhood or adolescence. Affected individuals typically pass abnormally large volumes of urine (polyuria), lose large quantities of salt through excessive urination (sodium wasting), and have difficulty with urinary control, resulting in the involuntary discharge of urine (enuresis), particularly during sleep (nocturnal enuresis). Impaired kidney function is progressive and, without treatment, leads to kidney failure. In most cases, medullary cystic disease is thought to be inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose "Medullary Cystic" as your search term in the Rare Disease Database.)

Adult polycystic kidney disease (APKD), also known as autosomal dominant polycystic kidney disease, is an inherited kidney disorder characterized by the presence of multiple cysts throughout both kidneys. Affected individuals experience progressive renal failure, characterized by blood in the urine (hematuria), excessive urination at night (nocturia), pain in the area between the ribs and the hips (flank pain), and repeated urinary infections. In most cases, symptoms and findings associated with APKD become apparent during the second or third decade of life. (For more information on this disorder, choose "Polycystic Kidney" as your search term in the Rare Disease Database.)

Diagnosis
Gout is the most common symptom that occurs in families that suffer from FJHN, but not every affected individual in the family will have gout. Some family members will have a history of bed-wetting as children, though individuals who bed-wet do not necessarily have the disease. Some patients may have no symptoms of the disease but be found to have an elevated blood creatinine level (market of kidney damage) or an elevated blood uric acid level in the setting of a family history that is consistent with FJHN.

Kidney failure occurs in family members. Affected family members will have elevated blood creatinine levels and will usually need dialysis at some time in their lives, typically between the ages of 30 and 70.

The first laboratory evidence of FJHN is an elevated blood uric acid level, and a reduced uric acid level in the urine. Thereafter, an increased blood creatinine level develops.

In some individuals with FJHN, surgical removal (renal biopsy) and microscopic examination of a small sample of kidney tissue may reveal abnormal thickening and scarring (interstitial fibrosis) of connective tissue within the kidneys, with degeneration (atrophy) of the tiny tubes (renal tubules) that play a role in filtering the blood as it enters the kidneys. Kidney biopsy results, however, are frequently not specific enough to make the diagnosis, and many patients who have had a kidney biopsy will still not know that FJHN is the cause of their kidney disease.

With the identification of the gene causing this condition, FJHN can now be diagnosed by genetic sequencing.

Treatment
Treatment may require the coordinated efforts of a team of specialists. Pediatricians or internists, specialists who diagnose and treat kidney disorders (nephrologists), dietitians, and/or other healthcare professionals may need to systematically and comprehensively plan an affected individual’s treatment.

In individuals with FJHN, treatment typically consists of therapy with medications such as allopurinol that decrease the formation of uric acid. Allopurinol may slow the development of kidney failure in affected individuals, though this is uncertain.

Affected individuals should be closely monitored by physicians for the potential development of kidney failure.

In individuals with FJHN who experience end-stage kidney failure, dialysis or kidney transplant are possible therapies. In a kidney transplant, the new kidney will not be affected by the disease.

Genetic counseling will be of benefit for affected individuals and their families.

Recent reports have indicated that allopurinol therapy may not only prevent gout attacks but may also slow disease progression when therapy is initiated before renal function is severely diminished. Many researchers stress the importance of screening all family members of those with the disease to ensure early diagnosis and suggest initiating allopurinol therapy for presymptomatic individuals to help decrease blood uric acid levels and prevent the progression of renal disease. Further investigation is needed to determine the effectiveness of aggressive, early control of hyperuricemia in halting disease progression in individuals with FJHN.

A database is currently being established of individuals affected by this disorder in order to study the rates of kidney disease progression and to see what medications may be helpful in treatment. Interested individuals should contact:

Anthony Bleyer, MD, MS
Section on Nephrology
Department of Internal Medicine
Bowman Gray School of Medicine of Wake Forest University
Medical Center Boulevard
Winston-Salem, NC 2711157
Tel: (910) 716-4513
e-mail: ableyer@wfubmc.edu

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Hyperuricemic Neuropathy, Familial Juvenile. Entry Number: 162000: Last Edit Date: 7/15/2003.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Uromodulin; UMOD. Entry Number: 191845: Last Edit Date: 7/15/2003.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Medullary Cystic Kidney Disease 2; MCKD2. Entry Number: 603860: Last Edit Date: 7/29/2003.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Medullary Cystic Kidney Disease 1; MCKD1. Entry Number: 174000: Last Edit Date: 7/29/2003.

TEXTBOOKS
Bleyer AJ. Familial Juvenile Hyperuricemia Nephropathy. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:696.

Fauci AS, Braunwald E, Isselbacher KJ, et al. Eds. Harrison’s Principles of Internal Medicine. 14th ed.McGraw-Hill Companies. New York, NY; 1998:1556.

Becker MA. Hyperuricemia and Gout. In: Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:2513-30.


REVIEW ARTICLE
Scolaris F, Viola BF, Ghiggeri GM, et al. Toward the identification of (a) gene(s) for autosomal medullary cystic kidney disease. J Nephrol. 2003;16:321-28.

JOURNAL ARTICLES
Bleyer AJ, Trachtman H, Sandhu J, et al. Renal manifestations of a mutation in the uromodulin (Tamm Horsfall protein) gene. Am J Kidney Dis. 2003;42:E20-26.

Stiburkova B, Majewski J, Hodanova K, et al. Familial juvenile hyperuricaemic nephropathy (FJHN): linkage analysis in 15 families, physical and transcriptional characterization of FJHN critical region on chromosome 16p11.2 and the analysis of seven candidate genes. Eur J Hum Genet. 2003;11:145-54.

Turner JJ, Stacey JM, Harding B, et al. Uromodulin Mutations cause familial juvenile hyperuricaemic nephropathy. J Clin Endocrinol Metab. 2003;88:1398-401.

Stacey JM, Turner JJ, Harding B, et al. Genetic mapping studies of familial juvenile hyperuricaemic nephropathy on chromosome 16p11-p13. J Clin Endocrinol Metab. 2003;88:464-70.

Dohan K, Fuchshuber A, Adamis S, et al. Familial juvenile hyperuricaemic nephropathy and autosomal medullary cystic disease type 2. J AM Soc Nephrol. 2001;12:2348-57.

Stiburkova B, Majewski J, Sebesta I, et al. Familial juvenile hyperuricemic nephropathy: localization of the gene chromosome 16p11.2- and evidence for genetic heterogeneity. Am J Hum Genet. 2000;66:1989-94.

FROM THE INTERNET
Ghiggeri GM. Familial Nephropathy with Gout. Orphanet encyclopedia, June 2001.
http://orphanet.infobiogen.fr/data/patho/GB/uk-gouty.htm

Wake Forest, Pittsburgh doctors find gene behind two kidney diseases. 12/5. 2pp.
http://www.scienceblog.com/community/article509.html