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

• Shiga toxin-associated hemolytic uremic syndrome (Stx HUS)
• thrombotic thrombocytopenia purpura

Atypical hemolytic uremic syndrome presents with vague feelings of illness, fatigue, irritability, and lethargy that often lead to hospitalization. The early phases may be difficult to diagnose, and the condition tends to be progressive. Because complications and relapse are common, it is critical that aHUS be recognized at this stage.

Patients with aHUS do not present with the aggressive and bloody diarrhea that characterize the onset of Stx HUS. The absence of bloody diarrhea, negative stool cultures for Shiga toxin producing-E. coli (most frequently E. coli 0157:h7) associated with HUS, a progressive course, and prior manifestations of "nephritic syndrome", such as swelling from the accumulation of fluid (edema), presence of blood in the urine (hematuria), excessive protein in the urine (proteinuria), and reduced albumin in the serum (hypoalbuminemia), with marked elevation in blood pressure are features that alert pediatricians and kidney specialists (nephrologists) to the diagnosis of aHUS.

Evidence is emerging that 50%-60% of the aHUS is associated with genetically determined alterations of the complement system. Some cases of aHUS are associated with malfunctions in the gene responsible for the production of a blood protein known as Factor H. Factor H is one of the regulatory proteins of the complement system that protect blood vessels from injury. When Factor H is deficient or inactive, there is the potential for damage to the small vessels in the kidneys with secondary injury to red blood cells and platelets.

In some families, atypical hemolytic uremic syndrome (aHUS) is transmitted (inherited) as an autosomal dominant trait while in other families it appears to be transmitted as an autosomal recessive trait. The mainly responsible gene has been mapped to chromosome 1q32.

An episode of aHUS may occur without the stimulation of a precipitating event such as a bacterial or viral infection.

The recessive form of aHUS most often affects infants and children who may or may not experience relapses. The dominant form affects adults more often than children. Patients rarely recover completely. Unfortunately, many patients have recurrences after kidney transplants.

Because of the high likelihood of recurrences after renal transplants, and the possibility that this likelihood may be increased when kidneys are obtained from a family member, it is not advisable to use kidneys from family members.

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 1q32" refers to band 32 on the long arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are the result of mutations of genes for any particular trait that are on the chromosomes received from the father and the mother.

Dominant genetic disorders occur when inheritance of a single copy of an abnormal gene is sufficient to cause the disease. The abnormal gene can be inherited form either parent, or can be the result of a new mutation (gene change) in the ovum or sperm of the parent. The risk of passing the abnormal gene from an affected parent to an offspring is 50 percent for each pregnancy, regardless of the sex of the child or the number of previously affected children.

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 abnormal gene, that person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk of having a child who is an unaffected carrier is 50 percent with each pregnancy. The chances for a child to receive normal genes from each parent and not be affected by aHUS is 25 percent for each pregnancy. The risk is the same for males and females.

All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have an increased risk of carrying copies of the same abnormal recessive gene, as opposed to parents who are not related.

There are about 300 cases of aHUS in the United States. AHUS may represent fewer than 5 percent of all cases of HUS.

Shiga toxin-associated hemolytic-uremic syndrome (Stx HUS) is an uncommon disorder that primarily affects young children between the ages of one and 10 years, with a peak incidence around three years of age. The onset of Stx HUS is preceded by a gastroenteritis characterized by vomiting, abdominal pain, fever, and diarrhea that becomes bloody. Symptoms of Stx HUS usually become apparent three to 10 days after the development of gastroenteritis, and include sudden paleness (pallor), irritability, weakness, lack of energy (lethargy), and/or excretion of diminished amounts of urine (oliguria). The disease typically progresses to include inability of the kidneys to process waste products from the blood and excrete them into the urine (acute renal failure); a decrease in circulating red blood cells (microangiopathic hemolytic anemia); a decrease in circulating blood platelets, which assist in blood-clotting functions (thrombocytopenia); and the abnormal accumulation of platelets within certain blood vessels (microthrombi), reducing the blood flow to several organs (kidneys, pancreas, brain). This potentially leads to multiple organ dysfunction or failure. In some cases, neurological problems may be present at the onset of Stx HUS or may occur at any time during the illness. Neurological symptoms are uncommon and may include dizziness, seizures (partial or generalized), disorientation or confusion, and/or loss of consciousness (coma). The cause of Stx HUS most frequently is infection by a particular strain (0157:h7) of Escherichia coli (E. coli) bacterium. Occasionally, adults may be affected by hemolytic-uremic syndrome. (For more information on this disorder, choose Hemolytic Uremic Syndrome as your search term in the Rare Disease Database.)

Thrombotic thrombocytopenic purpura (TTP) is a rare blood disorder characterized by the development of blood clots in small blood vessels (thrombotic microangiopathy). There is considerable overlap between the physical findings of this disorder and those associated with HUS. Recent studies show that these are completely different conditions. HUS occurs more commonly in children. TTP occurs most often in females in the third or fourth decade of life. Findings may include low levels of platelets in the blood (thrombocytopenia), a diminished number of circulating red blood cells (microangiopathic hemolytic anemia), and/or neurological abnormalities.

Thrombocytopenia is associated with a variety of symptoms, including the development of purple bruises on the skin, hematuria, and/or small red or purple spots on the skin and/or mucous membranes (petechiae). Neurological abnormalities may include disorientation, headaches, visual abnormalities, seizures, paralysis (paresis), and/or, in severe cases, coma. In addition, affected individuals may also experience fever, fatigue, weakness, abdominal pain, and/or diarrhea. In some cases, individuals with TTP may have acute renal failure that may result in diminished excretion of urine; blood in the urine (hematuria); high blood pressure (hypertension); an abnormal accumulation of fluid between layers of tissue under the skin (oedema); and/or unusually low water content in the body (dehydration). In some cases, acute renal failure may lead to life-threatening complications. The causes of TTP are either an inherited deficiency of an enzyme (metalloproteinase) or acquired antibodies to this enzyme. (For more information on this disorder, choose Thrombotic Thrombocytopenic Purpura as your search term in the Rare Disease Database.)

Diagnosis

The diagnosis of aHUS is difficult and complicated by the fact that the diagnosis is difficult to make without a family history of the disorder. The diagnostic criteria associated with aHUS are hemolytic anemia (anemia in the presence of broken red blood cells), low platelet count (thrombocytopenia) and severe kidney lesions in a patient with minimal or no diarrhea without bloody stools. aHUS is considered genetic when two or more members of the same family are affected by the disease at least six months apart and exposure to a common triggering infectious agent has been excluded, or when a disease-causing mutation(s) is identified in one of the genes known to be associated with aHUS, irrespective of familial history.


Treatment

Proper nutrition and electrolyte and fluid balance are maintained by intravenous feeding (parenteral) when and if necessary. Blood transfusions are administered when the haemoglobin level is below 7 g/dl. Platelet transfusions are avoided if at all possible. Drugs that expand the blood vessels (vasodilators) are used to control blood pressure (hypertension). Plasma manipulation (plasma infusion or exchange) may be indicated. Bilateral nephrectomy has been performed in a small number of rare individuals with extensive microvascular thrombosis at renal biopsy, refractory hypertension, and signs of hypertensive encephalopathy, in whom conventional therapies including plasma manipulation are not adequate to control the disease.

Patients who do not recover kidney function are treated with peritoneal or haemodialysis.

Renal transplantation is not necessarily an option for aHUS in contrast to typical HUS. An estimated 50% of individuals with aHUS who underwent renal transplantation had a recurrence of the disease in the grafted organ. Molecular genetic tests could help to define graft prognosis; thus, all patients should undergo such testing prior to transplantation. Molecular genetic testing should be particularly recommended before live related donation to avoid the risk of triggering disease in the donors.

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.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). H Factor 1; (HF1). The Johns Hopkins University. Entry Number: 134370. Last edit date: 1/8/2003.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Hemolytic-uremic syndrome; (HUS). The Johns Hopkins University. Entry number: 235400. Last edit date: 3/4/2003.


Textbooks

Kaplan BS. Inherited hemolytic-uremic syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:690-91.

Beers MH, Berkow R, eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:924-2225.


Review Articles

Ruggenenti P, Noris M, Remuzzi G. Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombocytopenic purpura. Kidney Int. 2001;60:831-46.

Bosch T, Wendler T. Extracorporeal plasma treatment in thrombotic thrombocytopenic purpura and hemolytic uremic syndrome: a review. Ther Apher. 2001;5:182-85.

Taylor Cm. Hemolytic-uremic syndrome and complement factor H deficiency: clinical aspects. Semin Thromb Hemost. 2001;27:185-90.

Ault BH. Factor H and the pathogenesis of renal diseases. Pediatr nephrol. 2000;14:1045-53.

Ruggenenti P, Remuzzi G. Pathophysiology and management of thrombotic microangiopathies. J Nephrol. 1998;11:300-10.

Neuhaus TJ, Calonder S, Leumann EP. Heterogeneity of atypical hemolytic uraemic syndromes. Arch Dis Child. 1997;76:518-21.


Journal Articles

Veyradier A, Obert B, Haddad E, et al. Severe deficiency of the specific von Willebrand factor-cleaving protease (ADAMTS 13) activity in a subgroup of children with atypical hemolytic uremic syndrome. J pPediatr. 2003;142:310-17.

Quan A, Sullivan EK, Alexander SR. Recurrence of hemolytic uremic syndrome after renal transplantation in children: a report of the North American Pediatric Renal Transplant Cooperative Study. Transplantation. 2001;72:742-45.

Magen D, Oliven A, Shechter Y, et al. Plasmapheresis in a very young infant with atypical hemolytic uremic syndrome. Pediatr Nephrol. 2001;16:87-90.

Buddles MR, Donne RL, Richards A, et al. Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome. Am J Hum Genet. 2000;66:1721-22.

Richards A, Buddles MR, Donne RL, Kaplan BS, Kirk E, Venning MC, Tielemans CL, Goodship JA, Goodship TH. Factor H mutations in hemolytic uremic syndrome cluster in exons 18-20, a domain important for host cell recognition. Am J Hum Genet 2001; 68:485-90.

Kaplan BS, Meyers KE, Schulman SL. The pathogenesis and treatment of hemolytic uremic syndrome. J AM Soc Nephrol. 1998;9:1126-33.

Saland JM, Ruggenenti P, Remuzzi G; Consensus Study Group. Liver-Kidney Transplantation to Cure Atypical Hemolytic Uremic Syndrome.
J Am Soc Nephrol. 2008 Dec 17.


From The Internet:

Bernard S. Kaplan: Professional to Professional; Managing E. Coli Outbreaks. IKidney.com. Reprinted with permission from the December 1999 issue of Contemporary Dialysis & Nephrology Magazine.

The Atypical HUS Website: http://atypicalhus.50megs.com/

Elstrom R. Hemolytic-uremic syndrome (HUS). MEDLINEplus. Medical Encyclopedia. Last Update: 10 January 2003. 4pp.

NIDDK. National Kidney and Urologic Diseases Information Clearinghouse. Last Update: March 2000. 3pp. www.niddk.nih.gov/health/kidney/summary/hus/index.htm

Noris M, Bresin E, Mele C, Remuzzi G, Caprioli J (November 2007) Atypical Hemolytic-Uremic Syndrome in: GeneReviews at GeneTests: Medical Genetics Information Resource [database online]. Available at http://www.genetests.org.