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

• Polycystic kidney disease
• Tuberous sclerosis

The symptoms of nephronophthisis (the juvenile familial form of medullary cystic disease) typically begin during childhood or adolescence. Symptoms are related to a slow increase in the level of urea (uremia), a waste product of normal metabolism, and other substances in the blood. In some cases, the first symptoms include the production of large amounts of urine (polyuria) and excessive thirst (polydipsia). Other symptoms may include general weakness, paleness, and bed-wetting. Sometimes the affected children will have no symptoms but be diagnosed based on abnormal laboratory tests.

Children with nephronophthisis may have growth delays as a result of the kidney failure. Some young people with this disorder may not have any recognizable symptoms and may be undiagnosed until severe kidney failure develops. An abnormally low level of hemoglobin in the blood (anemia) may also be an early clue to nephronophthisis.

Approximately 15 percent of people with nephronophthisis also have progressive degenerative changes in the retinas of their eyes (retinal dysplasia). People with this form of the disease are said to have renal-retinal dysplasia with nephronophthisis. Unusual amounts of pigment may also accumulate in the retina, causing inflammation. Further visual impairment may occur. Affected individuals with failing eyesight may be particularly difficult to fit with corrective lenses. (For more information on this disorder, choose "Retinitis Pigmentosa" as your search term in the Rare Disease Database.)

In the adult form, medullary cystic disease, patients frequently have few symptoms. They may be found to have poor kidney function on routine laboratory tests performed by their doctor. Bedwetting may have been present in childhood. Gout is also present in this form of the disease, and unlike common gout, occurs in the teenage years and frequently in women. For more information, see the report on familial juvenile hyperuricemic nephropathy, which is the same disease as medullary cystic kidney disease type 2.

All forms of this disease are caused by mutations (mistakes) in genes that are inherited from one or both parents. Scientists are actively involved in finding the genes that cause this disease. For several types of this disease, the genes causing the condition have been found.

Each of the four types of nephronophthisis is transmitted as an autosomal recessive trait.

Nephronophthisis Type 1 (NPH1): The mutation occurs on chromosome 2 (2q13).
Nephronophthisis Type 2 (NPH2): The mutation occurs on chromosome 9 (9q22-q21).
Nephronophthisis Type 3 (NPH3): The mutation occurs on chromosome 3 (3q22).
Nephronophthisis Type 4 (NPH4): The mutation occurs chromosome 1 (1p36).

Each of the two types of medullary cystic kidney disease is transmitted as an autosomal dominant trait.

Medullary cystic kidney disease Type 1 (MCKD1): This type is caused by a mutation of a gene on chromosome 1 (1q21).
Medullary cystic kidney disease Type 2 (MCKD2): This type is caused by a defect in a protein known as Tamm Horsfall (also called uromodulin). This protein lines the small tubules in the kidney. For more information on this disease, see the NORD report on "familial juvenile hyperuricemic nephropathy", which is the same as medullary cystic kidney disease Type 2.

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 11p13" refers to band 13 on the short arm of chromosome 11. 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 that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

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.

Both the nephronophthisis and medullary cystic disease groups are rare disorders that affect males and females equally. Most cases of these disorders are diagnosed during childhood or adolescence (familial juvenile nephronophthisis). It is thought that this form of the disease occurs in 1 in 50,000 children in the United States. However, the symptoms of the disease may not develop until adulthood and have appeared as late as the 7th decade of life

Symptoms of the following disorders can be similar to those of medullary cystic disease.

Polycystic kidney disease is an inherited disorder characterized by the presence of cysts in both kidneys. Progressive enlargement of these cysts causes the loss of normal kidney function and an abnormal increase in the vascular blood pressure around the kidneys (renal hypertension). There are infantile and adult forms of polycystic kidney disease. Symptoms may include abdominal enlargement, back pain, blood in the urine (hematuria), high blood pressure (hypertension), weight loss, and/or unusually low levels of fluid in the body (dehydration). Some people with this disorder may also have liver problems and abnormal enlargement of the spleen (splenomegaly). (For more information on this disorder, choose "Polycystic Kidney" as your search term in the Rare Disease Database.)

Tuberous sclerosis is a rare genetic multisystem disorder that usually presents shortly after birth. The disorder may be characterized by episodes of uncontrolled electrical activity in the brain (seizures); mental retardation; distinctive skin abnormalities (lesions); and benign (noncancerous), tumor-like nodules (hamartomas) in the brain, certain regions of the eyes (e.g., retinas), the heart, the kidneys, the lungs, or other tissues or organs. Characteristic skin lesions include sharply defined areas of decreased skin coloration (hypopigmentation) during infancy and relatively small reddish nodules that may appear on the cheeks and nose beginning at approximately age four. These reddish lesions eventually enlarge, blend together (coalesce), and develop a wart-like appearance (sebaceous adenomas). Additional skin lesions may also develop, including flat, "coffee-colored" areas of increased skin pigmentation (café-au-lait spots); benign, fibrous nodules (fibromas) arising around or beneath the nails; or rough, elevated, "knobby" lesions (shagreen patches) on the lower back.

Tuberous sclerosis results from changes (mutations) in a gene or genes that may occur spontaneously (sporadically) for unknown reasons or be inherited as an autosomal dominant trait. Most cases represent new (sporadic) gene mutations, with no family history of the disease. Mutations of at least two different genes are known to cause Tuberous sclerosis.

Diagnosis
The diagnosis of medullary cystic disease is based on a thorough clinical evaluation and special laboratory tests. Urine and blood tests usually reveal abnormalities that are similar to those found in individuals with chronic kidney disease. In most cases, excessive amounts of urinary protein (proteinuria) are not present, and blood is usually not found in the urine.

Ultrasound or CAT scans may show small kidneys or cysts deep within the kidneys. The medulla is the middle of the kidneys where the cysts occur. However, many patients with medullary cystic kidney disease do not have medullary cysts on x-ray testing.

For some types of these diseases, the gene has been found, and the diagnosis can be made by checking for the gene. Genetic testing can now be performed for nephronophthisis types 1 and 4, and medullary cystic kidney disease type 2. For types for which the gene has not yet been identified, it may be possible to tell which family members are suffering from the condition by studying the family history (linkage).

Treatment
Treatment of these disorders consists of the careful management of kidney failure, when it occurs. It is important to note that excessive urination (polyuria) associated with this disease is not responsive to treatment with drugs such as vasopressin.

As kidney failure worsens, patients may require medicines to help treat anemia and other symptoms of kidney disease. Dialysis or kidney transplant may be needed if the kidneys fail totally.

Gout develops in some families with this disorder, and specific treatments for gout may be helpful (see familial juvenile hyperuricemic nephropathy).

Research on this group of diseases is progressing rapidly. Many different investigators are trying to find the genes that cause these diseases. Identifying families that suffer from these diseases and collecting blood samples from these families may help to identify the genes responsible for the disease.

Affected individuals or families who would like additional information about participating in studies to help find the genes and enhance understanding of this group of disorders may contact:

Anthony Bleyer, MD, MS
Section on Nephrology
Department of Internal Medicine
Wake Forest University Health Sciences
Medical Center Boulevard
Winston-Salem, NC 27157
Tel: (910) 716-4513
e-mail: ableyer@wfubmc.edu

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Nephronophthisis 1; NPHP1. Entry Number; 256100: Last Edit Date; 6/10/2002.
Nephronophthisis 2; NPHP2. Entry Number; 602088: Last Edit Date; 7/31/2003
Nephronophthisis 3; NPHP3. Entry Number; 604387: Last Edit Date; 7/31/2003
Nephronophthisis 4; NPHP4. Entry Number; 606966: Last Edit Date; 5/28/2003

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University.
Medullary Cystic Kidney Disease 1; MCKD1. Entry No: 174000; Last Entry: 7/29/2003
Medullary Cystic Kidney Disease 2; MCKD2. Entry No: 603860; Last Entry: 7/29/2003

TEXTBOOKS
Simkes AM. Medullary Cystic Kidney Disease. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:693-94.

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

Beers MH, Berkow R, eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:1905.

Berkow R., ed. The Merck Manual-Home Edition.2nd ed. Whitehouse Station, NJ: Merck Research Laboratories; 2003:855.

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

Caridi G, Dagnino M, Miglietti N, et al. Juvenile nephronophthisis and related variants: clinical features and molecular approach. Contrib Nephrol. 2001;(136):57-67.

Hildebrandt F, Otto E. Molecular genetics of nephronophthisis and medullary cystic kidney disease. J Am Soc Nephrol. 2000;11:1753-61.

Gusmano R, Ghiggeri GM, Caridi G. Nephronophthisis-medullary cystic kidney disease: clinical and genetic aspects. J Nephrol. 1998;11:224-28.

JOURNAL ARTICLES
Otto EA, Schermer B, Obara T, et al. Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. Nat Genet. 2003 Jul 20 [Epub ahead of print]

Olbrich H, Fliegauf M, Hoefele J, et al. Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis tapeto-retinal degeneration and hepatic fibrosis. Nat Genet. 2003 Jul 20 [Epub ahead of print]

Otto E, Hoefele J, Ruf R, et al. A gene mutated in nephronophthisis and retinitis pigmentosa encodes a novel protein, nephroretinin, conserved in evolution. Am J Hum Genet. 2002;71:1161-67.

Schuermann MJ, Otto E, Becker A, et al. Mapping of gene loci for nephronophthisis type 4, and Senior-Loken syndrome, to chromosome 1p36. Am J Hum Genet. 2002;70:1240-46.

Hateboer N, Gumbs C, Teare MD, et al. Confirmation of a gene locus for medullary cystic kidney disease (MCKD2) on chromosome 16p12. Kidney Int. 2001;60:1233-39.

Omran H, Haffner K, Burth S, et al. Evidence for further genetic heterogeneity in nephronophthisis. Nephrol Dial Transplant. 2001;16:755-58.

FROM THE INTERNET
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www.merck.com/pubs/mmanual_home2/sec11/ch146/ch1461.htm

Del Rio M, Devarajan P. Medullary Cystic Disease. EMedicine. Last Updated: September 9, 2002. 12pp.
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Nephronophthisis. GPnotebook. Ó2003. 4pp.
www.gpnotebook.co.uk/simplepage.cfm?ID=1154482211

medullary cystic disease. HealthCentral. Nd. 5pp.
www.healthcentral.com/mhc/top/000465.cfm