Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 1 - A-L - I

•The infant should be placed in a humidified incubator immediately after delivery. Antibiotics should be administered via an intravenous (IV) line as a safeguard against infection. An IV should also be used to provide water and nutrients until the infant can suck sufficiently.

•Medication for pain management should be provided, as needed.

•Sponge baths or tub soaking and the application of skin moisturizers with antibiotics should be performed twice a day to soften the skin and reduce scaliness.

•Creams or ointments containing the drug etretinate should be used to decrease the amount of scale. Etretinate has been a successful mode of treatment for some infants with HF, although treated infants still died at relatively young ages due to complications from their disorder. Careful monitoring for etretinate-related side effects in children, such as bone toxicity, is recommended.

•Artifical tear treatments for infants with severe ectropion.

Prognosis

Most infants with harlequin fetus ichthyosis die within the first few days to weeks of life. Common causes of death include respiratory complications because of prematurity or constriction by the thick scale, dehydration, malnutrition, or severe skin infection. Longer-term survivors have been reported but these children have required intensive, on-going medical care. Etretinate has been an effective form of treatment for some infants but its use has only been for short periods of time since the affected infants have still died. Even with treatment, the ichthyosis does not completely go away. However, over time, the eversion of eyelids and lips gradually resolves. Large, thin scales with reddish edges gradually replace the cracked, thick skin. Variable neurological impairment has been reported among survivors, and, even with attentive medical care, sudden death may still occur.

Resources

BOOKS

Baden, Howard P. “Ichthyosiform Dermatoses.” In Emery and Rimoin’s Principles and Practice of Medical Genetics.

Edited by David L. Rimoin, J. Micheal Connor, and Reed E. Pyeritz. 3rd ed. St. Louis, MO: Churchill Livingstone, 1997, pp. 1205-1214.

“Disorders of Keratinization.” In Nelson’s Textbook of Pediatrics. Edited by Richard E. Behrman, Robert M. Kliegman, and Hal B. Jenson. 16th ed. Philadelphia: W.B. Saunders, 2000, p. 2007.

PERIODICALS

Akiyama, Masashi. “Severe Congenital Ichthyosis of the Neonate.” International Journal of Dermatology 37 (1998): 722-728.

Akiyama, Masashi, Kaoru Suzumori, and Hiroshi Shimizu. “Prenatal Diagnosis of Harlequin Ichthyosis by the Examination of Keratinized Hair Canals and Amniotic Fluid Cells at 19 Weeks Estimated Gestational Age.” Prenatal Diagnosis 19 (February 1999): 167-171.

Pejaver, Ranjan K., et al. “Etretinate in the Management of Harlequin Siblings.” Indian Journal of Pediatrics 65 (March-April 1998): 320-323.

ORGANIZATIONS

Foundation for Ichthyosis and Related Skin Types. 650 N. Cannon Ave., Suite 17, Landsdale, PA 19446. (215) 6311411 or [phone]. Fax: [phone].http://www.scalyskin.org .

National Registry for Ichthyosis and Related Disorders. University of Washington Dermatology Department, Box 356524, 1959 N.E. Pacific, Rm. BB1353, Seattle, WA 98195-6524. [phone] or [phone].http://www.skinregistry.org .

WEBSITES

“Ichthyosis Congenita, Harlequin Fetus Type.” Online

Mendelian Inheritance in Man. http://www.ncbi.nlm

.nih.gov/entrez/dispomim.cgi?id=242500 . Ichthyosis Information. http://www.ichthyosis.com .

Terri A. Knutel, MS, CGC

Harlequin ichthyosis see Harlequin fetus

Haw River syndrome see Dentatorubralpallidoluysian atrophy

Heart-hands syndrome see Holt-Oram syndrome

Hemifacial microsomia with radial defects see Goldenhar syndrome

I Hemihypertrophy

(Hemihyperplasia)

Definition

Hemihypertrophy, more correctly termed hemihyperplasia, is defined as the enlargement of one side of the body or part of the body.

(Hemihyperplasia) Hemihypertrophy

G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S

515

Hemihypertrophy (Hemihyperplasia)

K E Y T E R M S

Congenital—Refers to a disorder which is present at birth.

Hemihyperplasia—A condition in which overdevelopment or excessive growth of one half of a specific organ or body part on only one side of the body occurs.

Hemihypertrophy—Asymmetric overgrowth in which there is an increase in size of existing cells. Mental retardation—Significant impairment in intellectual function and adaptation in society. Usually associated an intelligence quotient (IQ) below 70.

Prenatal diagnosis—The determination of whether a fetus possesses a disease or disorder while it is still in the womb.

Ultrasound—An imaging technique that uses sound waves to help visualize internal structures in the body.

Description

Hemihypertrophy is characterized by unequal (asymmetric) growth of the cranium, face, trunk, limbs, and/or digits. Hemihypertrophy can be an isolated finding, or it can be associated with certain malformation syndromes. Isolated hemihypertrophy refers to hemihypertrophy for which no cause can be found. The degree of asymmetry is variable and very mild cases can go undiagnosed. There are three categories of hemihypertrophy, depending on the body parts involved. The size difference can involve only a specific part of the body such as a finger (called simple hemihypertrophy) or an entire half of the body (called total or complex hemihypertrophy). It usually involves only one side of the body, but can involve both sides (called crossed). There is also hemifacial hyperplasia, which involves one side of the face. Usually multiple organ systems are involved, i.e. the skin, vascular system, internal organs, or bones. In complex hemihypertrophy, the right side is more often involved than the left.

Hemihypertrophy may involve not only the part of the body that is visible, but also the underlying internal organs. Enlargement of one kidney, adrenal gland, testis, and ovary has been reported. The enlarged area usually also has thickened skin, more sebaceous (sweat) glands, more hair, may have pigmentary abnormalities, and the bones may be larger or may be deformed. In persons with

facial involvement, the asymmetry can include cheek, lip, nose, ear, eye, tongue, jaw, roof of the mouth, or teeth.

The nervous system may also be affected, causing unilateral nerve enlargement or sciatic nerve inflammation. Occasionally a part of the brain is affected causing mental retardation (15% to 20% of cases). Many cases of hemihypertrophy have hamartomatous lesions (birth marks which involve blood vessels) or abnormalities of the genito-urinary system.

As with other overgrowth syndromes, there is an increased risk for childhood cancers in people with isolated hemihypertrophy (about 6%), particularly cancers of the kidney (Wilms tumor, 3% of individuals), adrenals, and liver.

Genetic profile

The cause and exact mechanism of isolated hemihypertrophy is not known. The asymmetry occurs most likely as a result of an increase in the rate of cell growth, or unregulated cell growth. Most cases of hemihypertrophy are not inherited, but there have been seven familial cases reported as of 2000 in which two or more persons were affected. These cases are not well documented and it is possible that the families actually had another genetic syndrome. Males and females are equally affected with this condition.

It is clear that there is not a single gene responsible for hemihypertrophy, but the exact number of genes and their locations and functions are not known. It has been suggested that isolated hemihypertrophy may be related to another condition, called Beckwith-Wiedemann syndrome, a genetic overgrowth syndrome that can include both hemihypertrophy and Wilms tumor. BeckwithWiedemann syndrome has been associated with abnormalities on chromosome 11, which contains genes involved with growth, development, and cancer.

Good data does not exist for recurrence risk for siblings of patients or for children of affected persons. Case reports suggest a slightly increased risk for siblings and for offspring of affected mothers.

Demographics

Hemihypertrophy occurs in about one in 15,000 live births. Isolated hemihypertrophy occurs in about one in 86,000 live births. There are approximately 200 cases reported. Females and males are affected equally.

Signs and symptoms

Hemihypertrophy is usually recognized at birth by physical examination, but can become more serious over

516	G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S

Hemihypertrophy

A.

B.

Right ear

Left ear

C.

(Hemihyperplasia) Hemihypertrophy

The enlarged growth of only one side of the body is characteristic of hemihypertrophy. The asymetric development may be isolated to one organ or limb, or may occur to the entire body. (Gale Group)

time, especially during puberty. Very mild forms of this condition often go unnoticed and are very common.

Diagnosis

The diagnosis is made by clinical examination of body asymmetry. There are no laboratory tests available for this condition. X ray may show advanced bone age or larger bones in the hypertrophied limbs, supporting a diagnosis of hemihypertrophy, or characteristic bone changes supporting another diagnosis. Other genetic syndromes associated with asymmetry must be excluded, as must other causes of asymmetry, such as atrophy of one side of the body due to neurological disorder or skeletal abnormalities that cause asymmetric hand or limb enlargement.

Prenatal diagnosis is theoretically possible by ultrasound, provided that the difference in size is large enough

to be detected or if an embryonic tumor is present, although a confirmed diagnosis is not possible until after birth.

Treatment and management

The treatment for hemihypertrophy is different for each individual and depends on the specific symptoms. If leg-length differences are present, corrective shoes can increase the sole for the unaffected leg to prevent scoliosis and walking difficulties. Orthopedic devices such as braces or, more rarely, surgery to lengthen the normal leg may be indicated. Surgery to retard growth of the overgrown leg is controversial and not recommended. Surgery for congenital defects or laser surgery for birth marks may be indicated. Plastic surgery may be considered to correct very discrepant facial features.

G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S

517

Hemochromatosis

A protocol to screen for childhood cancers has been proposed, which includes abdominal ultrasound every three months until age six, every six months until puberty, and careful medical follow-up of patients into adulthood. Surgical intervention is appropriate if cancers are detected. Monitoring of serum alpha fetoprotein levels may also be useful as a marker of hepatic tumors.

Appropriate special education services are necessary for those with mental retardation. Counseling related to social stigmatism may be necessary if severe disfigurement is an issue.

Prognosis

Hemihypertrophy does not alter lifespan, although complications from associated abnormalities such as childhood cancer and mental retardation can cause problems. Asymmetry of the limbs can interfere with their proper function and cause pain. Insecurities due to disfigurement are possible and can be addressed through support groups or therapy.

Resources

BOOKS

Buyse, M.L., ed. “Hemihypertrophy.” In Birth Defects Encyclopedia. Boston: Blackwell Scientific Publications, 1990.

Goodman, R.M., and R.J. Gorlin. “Hemihypertrophy.” In The Malformed Infant and Child. New York: Oxford University Press, 1983.

PERIODICALS

Biesecker, L.G., et al. “Clinical Differentiation Between Proteus Syndrome and Hemihyperplasia: Description of a Distinct Form of Hemihyperplasia.” American Journal of Medical Genetics 79 (1998): 311-318.

Hoyme, H.E., et al. “Isolated Hemihyperplasia (Hemihypertrophy): Report of a Prospective Multicenter of the Incidence of Neoplasia and Review.” American Journal of Medical Genetics 79 (1998): 274-278.

ORGANIZATIONS

Klippel-Trenaunay Support Group. 5404 Dundee Rd., Edina, MN 55436. [phone].

Proteus Syndrome Foundation. 6235 Whetstone Dr., Colorado Springs, CO 80918. [phone]. [e-mail]://www.kumc.edu/gec/support/proteus.html .

WEBSITES

“Hemihypertrophy.” Online Mendelian Inheritance in Man.

http://www.ncbi.nlm.nig.gov/entrez/dispomim.cgi?id= 235000 .

National Organization of Rare Disorders.http://www.rarediseases.org .

Amy Vance, MS, CGC

I Hemochromatosis

Definition

Hemochromatosis is an inherited blood disorder that causes the body to retain excessive amounts of iron. This iron overload can lead to serious health consequences, most notably cirrhosis of the liver.

Description

Hemochromatosis is also known as iron overload, bronze diabetes, hereditary hemochromatosis, and familial hemochromatosis. The inherited disorder causes increased absorption of intestinal iron, well beyond that needed to replace the body’s loss of iron. Iron overload diseases afflict as many as 1.5 million persons in the United States. The most common of these, as well as one of the most common genetic disorders in the United States, is hereditary hemochromatosis. Men and women are equally affected by hemochromatosis, but women are diagnosed later in life because of blood loss from menstruation and childbirth. It most commonly appears in patients between the ages of 40 to 60 years, since it takes many years for the body to accumulate excessive iron. Symptoms appear later in females than in males—usu- ally after menopause.

Hemochromatosis causes excess iron storage in several organs of the body including the liver, pancreas, endocrine glands, heart, skin, joints, and intestinal lining. The buildup of iron in these organs can lead to serious complications, including heart failure, liver cancer, and cirrhosis of the liver. It is estimated that about 5% of cirrhosis cases are caused by hereditary hemochromatosis.

Idiopathic pulmonary hemosiderosis, a disorder afflicting children and young adults, is a similar overload disorder characterized by abnormal accumulation of hemosiderin. Hemosiderin is a protein found in most tissues, especially the liver. It is produced by digestion of hematin, an iron-related substance.

Genetic profile

Hereditary hemochromatosis is an autosomal recessive condition. This means that individuals with hemochromatosis have inherited an altered (mutated) gene from both of their parents. Affected individuals have two abnormal hemochromatosis genes and no normal hemochromatosis gene.

The gene that causes hemochromatosis has been identified, and the most common abnormalities of the gene have been described. The gene is on chromosome 6; it is called HFE. Scientists have not confirmed the function of the normal gene product; they do know that it

518	G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S

interacts with the cell receptor for transferrin. Transferrin binds and transports iron in the blood.

Because it is an autosomal recessive condition, siblings of individuals who have hemochromatosis are at a 25% risk to also be affected. However, the likelihood that an individual will develop symptoms depends on which gene mutation he or she has as well as environmental factors. The two most common changes in the HFE gene are C282Y and H63D. The age at which symptoms begin is variable, even within the same family.

Demographics

Hemochromatosis is one of the most common genetic disorders in the United States. Approximately one in nine individuals have one abnormal hemochromatosis gene (11% of the population). Since everyone has two copies of each gene, these individuals have an abnormal HFE gene and a normal gene. They are called carriers. Between 1/200 and 1/400 individuals have two abnormal genes for hemochromatosis and no normal gene.

With most autosomal recessive conditions, an affected person’s parents are carriers. If more than one family member has the condition, they are siblings. Hemochromatosis is so common, however, that families are seen in which both parents are affected, or one parent is affected and the other parent is a carrier. More than one generation may be affected, which is not usually seen in rare autosomal recessive conditions.

Signs and symptoms

The symptoms of hemochromatosis include fatigue, weight loss, weakness, shortness of breath, heart palpitations, chronic abdominal pain, and impaired sexual performance. The patient may also show symptoms commonly connected with heart failure, diabetes or cirrhosis of the liver. Changes in the pigment of the skin may appear, such as grayness in certain areas, or a tanned or yellow (jaundice) appearance. The age of onset and initial symptoms vary.

Idiopathic pulmonary hemosiderosis may first, and only, appear as paleness of the skin. Sometimes, the patient will experience spitting of blood from the lungs or bronchial tubes.

Diagnosis

The most common diagnostic methods for hemochromatosis are blood studies of iron, genetic blood studies, magnetic resonance imaging (MRI), and liver biopsy. Blood studies of transferrin–iron saturation and ferritin concentration are often used to screen for iron overload.

K E Y T E R M S

Autosomal—Relating to any chromosome besides the X and Y sex chromosomes. Human cells contain 22 pairs of autosomes and one pair of sex chromosomes.

Cirrhosis—A chronic degenerative disease of the liver, in which normal cells are replaced by fibrous tissue. Cirrhosis is a major risk factor for the later development of liver cancer.

Diabetes mellitus—The clinical name for common diabetes. It is a chronic disease characterized by inadequate production or use of insulin.

Phlebotomy—The taking of blood from the body through an incision in the vein, usually in the treatment of disease.

Ferritin is a protein that transports iron and liver enzymes. Additional studies are performed to confirm the diagnosis.

Blood studies used to confirm the diagnosis include additional iron studies and/or genetic blood studies. Genetic blood studies became available in the late 1990s. Genetic testing is a reliable method of diagnosis. However, in 2001 scientists and physicians studied how accurately having a hemochromatosis mutation predicts whether a person will develop symptoms. Most individuals affected with hemochromatosis (87%) have two identifiable gene mutations, so genetic testing will confirm the diagnosis. Genetic studies are also used to determine whether the affected person’s family members are at risk for hemochromatosis. The results of genetic testing are the same whether or not a person has developed symptoms.

MRI scans and/or liver biopsy may be necessary to confirm the diagnosis. MRI studies of the liver (or other iron-absorbing organs), with quantitative assessment of iron concentration, may reveal abnormal iron deposits. For the liver biopsy, a thin needle is inserted into the liver while the patient is under local anesthesia. The needle will extract a small amount of liver tissue, which can be analyzed microscopically to measure its iron content and other signs of hemochromatosis. Diagnosis of idiopathic pulmonary hemosiderosis begins with blood tests and x- ray studies of the chest.

Treatment and management

Patients who show signs of iron overload will often be treated with phlebotomy. Phlebotomy is a procedure

Hemochromatosis

G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S

519

Hemochromatosis

that involves drawing blood from the patient, just like blood donation. Its purpose as a treatment is to rid the body of excess iron storage. Patients may need these procedures one or two times a week for a year or more. Less frequent phlebotomy may be continued in subsequent years to keep excess iron from accumulating. Patients who cannot tolerate phlebotomy due to other medical problems can be treated with Desferal (desferrioxamine). Diet restrictions may also be prescribed to limit the amount of iron ingested. Complications from hemochromatosis, such as cirrhosis or diabetes, may also require treatment. Treatment for idiopathic pulmonary hemosiderosis is based on symptoms.

Diet restrictions may help lower the amount of iron in the body, but do not prevent or treat hemochromatosis. Individuals who are affected or who know they have two C282Y and/or H63D genes may reduce iron intake by avoiding iron and mineral supplements, excess vitamin C, and uncooked seafood. If a patient is symptomatic, he/she may be advised to abstain from drinking alcohol.

Prognosis

With early detection and treatment, the prognosis is usually good. All potential symptoms are prevented if iron levels are kept within the normal range, which is possible if the diagnosis is made before an individual is symptomatic. If a patient is symptomatic but treated successfully before he/she develops liver cirrhosis, the patient’s life expectancy is near normal. However, if left untreated, complications may arise which can be fatal. These include liver cancer, liver cirrhosis, diabetes mellitus, congestive heart failure, and difficulty depleting iron overload through phlebotomy. Liver biopsy can be helpful in determining prognosis of more severely affected individuals. Genetic testing may also be helpful, as variable severity has been noted in patients who have two C282Y genes compared to patients with two H63D genes or one of each. Men are two times more likely than women to develop severe complications. The prognosis for patients with idiopathic pulmonary hemosiderosis is fair, depending on detection and complications.

Prevention

Screening for hemochromatosis is cost effective, particularly for certain groups of people. Relatives of patients with hemochromatosis—including children, siblings, and parents—should be tested by the most appropriate method. The best screening method may be iron and ferritin studies or genetic testing. If the affected person’s diagnosis has been confirmed by genetic testing, relatives may have genetic testing to determine whether or not they have the genetic changes present in the

affected individual. Many medical groups oppose genetic testing of children. Relatives who are affected but do not have symptoms can reduce iron intake and/or begin phlebotomy prior to the onset of symptoms, possibly preventing ever becoming symptomatic.

Population screening for hereditary hemochromatosis is being widely debated. Many doctors and scientists want population screening because hemochromatosis is easily and cheaply treated, and quite common. Arguments against treatment include the range of symptoms seen (and not seen) with certain gene mutations, and the risk of discrimination in health and life insurance. Whether or not population screening becomes favored by a majority, the publicity is beneficial. Hemochromatosis is a common, easily and effectively treated condition. However, diagnosis may be difficult because the presenting symptoms are the same as those seen with many other medical problems. The screening debate has the positive effect of increasing awareness and suspicion of hemochromatosis. Increased knowledge leads to earlier diagnosis and treatment of symptomatic individuals, and increased testing of their asymptomatic at–risk relatives.

Resources

BOOKS

Barton, James C., and Corwin Q. Edwards, eds. Hemochromatosis: Genetics, Pathophysiology, Diagnosis and Treatment. Cambridge: Cambridge University Press, 2000.

Crawford, Roberta. The Iron Elephant. Glyndon, MD: Vida Publishing, 1995.

PERIODICALS

“Iron Overload, Public Health and Genetics.” Annals of Internal Medicine Supplement 129 (December 1998). http:// www.acponline.org/journals/annals/01dec98/supptoc. htm .

Motulsky, A.G., and E. Beutler. “Population Screening for Hemochromatosis.” Annual Review of Public Health 21 (2000): 65-79.

Wolfe, Yun Lee. “Case of the Ceaseless Fatigue.” Prevention Magazine (July 1997): 88.

ORGANIZATIONS

American Hemochromatosis Society, Inc. 777 E. Atlantic Ave., PMB Z-363, Delray Beach, FL 33483-5352. [phone] or (888) 655-IRON (4766). [e-mail]://www.americanhs.org .

American Liver Foundation. 75 Maiden Lane, Suite 603, New York, NY 10038. [phone] or [phone].http://www.liverfoundation.org .

Hemochromatosis Foundation, Inc. PO Box 8569, Albany, NY 12208-0569. [phone]. [e-mail]

.edu. http://www.hemochromatosis.org .

Iron Disorders Institute, Inc. PO Box 3021, Greenville, SC 29602. [phone]. [e-mail]. http://www

.irondisorders.org .

520	G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S

Iron Overload Diseases Association, Inc. 433 Westwind Dr., North Palm Beach, FL 33408. [phone]. [e-mail].

WEBSITES

“Hemochromatosis.” GeneClinics.http://www.geneclinics.org/profiles/hemochromatosis/ .

Hemochromatosis Information Sheet. National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)http://www.niddk.nih.gov/health/digest/pubs/hemochrom/ hemochromatosis.htm .

Hereditary Hemochromatosis. Lecture by Richard Fass, MD, hematologist, Advanced Oncology Associates, given April 25, 1999. http://www.advancedoncology.org/listen

.htm in Real Audio.

Michelle Q. Bosworth, MS, CGC

Hemoglobin-beta locus see

Beta thalassemia

I Hemolytic-uremic syndrome

Definition

Hemolytic-uremic syndrome (HUS) is a syndrome defined by the presence of acute hemolytic anemia (low red blood cell count caused by the break up of red cells within the blood stream by a person’s own immune system), thrombocytopenia (a low number of platelets), and kidney failure. Having these three symptoms all at once can be caused by a number of problems—some by infections, others by genes, and some are still unknown.

Description

About 90% of HUS cases occur in children less than five years of age. In most cases, there is an early phase of diarrhea, followed by the lowered blood counts and the renal failure. Most patients get better after HUS, a few die during the worst stage of the illness, others go on to have life-long kidney disease, and some will progress to having a form of HUS that comes and goes over the rest of their lives. Which patients will have which outcome is not known during the illness.

Many infectious organisms have been thought to play a role as things that may cause HUS outbreaks, such as one E. coli serotype and one Shigella dysenteriae serotype. About 40% of patients who ingest E. coli 0157:H7 (the implicated serotype) will go on to get some form of diarrhea. Of those that develop diarrhea, about 5% will progress to some form of HUS (ranging in strength from mild to fatal). The bacteria linked to HUS

have been shown to produce a toxin that gets released into the bloodstream after the organisms invade the colon’s mucosal lining. The toxin, once inside of cells, disrupts protein synthesis. The spreading of organisms that make toxins tends to occur through food products.

Many outbreaks of HUS in the United States have occurred over the last several decades. These outbreaks have been linked to various food sources such as hamburger meat that is not cooked enough, apple juice and apple cider that has not been pasteurized, water, fruits, vegetables, and unpasteurized milk. Hamburger meat is the most common way that E. coli spreads. This bacteria is part of the normal flora of cow intestines and it is thought that it gets into the meat during the process of killing and cutting up the cow. When this beef is then not cooked enough to kill the organism, it is able to travel into the human GI (gastro-intestinal) system with ease. The spreading of this disease can also occur with person- to-person contact through a fecal-oral route. Support for this theory includes data from daycare centers that had outbreaks of HUS.

About 10% of cases in children and 50% of cases in adults will be a type of HUS that occurs without diarrhea. Of these cases, some can be linked with other infections, but other cases have no clear cause. Out of these unclear cases, some will be a form of HUS that runs in families. There have been many research studies into families that have many members who have a form of HUS that keeps coming back over the patient’s lifetime. Genetic tests of these families have found what may be a gene that can cause some cases of HUS.

Patients with HUS all show signs of making thrombi (blood clots) in small vessels. These thrombi form in kidney blood vessels as well as small arteries all over the body. Thus, clots can cause infarcts (starvation and death) of kidney tissue, brain tissue, the bowel, and other organs.

Genetic profile

While most families that have a form of HUS that passes on the disease in an autosomal recessive pathway, there have been some families with signs of autosomal dominant transmission. Genetic tests have found that a region on chromosome 1q can play a role in the forms of HUS that run in families. The gene for factor H (a protein regulator of the alternate complement pathway) is the leading gene candidate. Molecular proof linking factor H to cases of HUS that occur without diarrhea was first produced in 1998. Since then, screening of patients and families of patients with HUS not linked to a preceding episode of diarrhea have found a subset of patients who have mutated copies of the factor H gene.

syndrome uremic-Hemolytic

G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S

521

Hemolytic-uremic syndrome

K E Y T E R M S

Alternate complement pathway—A cascade of enzymatic reactions that produce antibacterial proteins. This pathway helps to ward off infections.

Idiopathic—Of unknown origin.

Serotype—One form of a bacteria that has unique surface proteins. Each serotype causes a unique antibody response from a person’s immune system.

Tests that look at different families with an inherited form of HUS have shown that there are many different point mutations within the factor H gene. All of these mutations led to some reduced level of factor H. With this lower level, many researchers have noticed that patients also have reduced levels of a protein called C3. This protein is part of the complement cascade that is supposed to attack bacteria within the body. Patients with low levels of C3 may be at more risk of having very bad problems arise from infections than patients with normal immune systems. Also, the familial form of HUS is most likely a multifactorial disease (i.e. no one gene mutation causes it by itself) that occurs in certain patients who are predisposed to the disorder.

Demographics

The largest number of cases occur in children between the ages of six months and five years of age. The mean age of children who get HUS is four. Within the United States, this disease most often occurs in epidemics, versus an endemic form that is found in other parts of the world. For example, Argentina has a much higher incidence of HUS than America. Interestingly, the rate of E. coli that make the oxins that cause infections is higher in Argentina.

Signs and symptoms

The clinical history most often seen in patients with HUS is of a diarrheal illness that comes before the anemia and renal disease by five to seven days. Some children have symptoms other than diarrhea. These include belly pain, nausea, and throwing up.

When HUS occurs, patients can have many different types of symptoms. Patients tend to have pallor (pale skin), decreased urine output, and fatigue. Even though they tend to have low platelet (the cells that cause blood to clot) counts, they seldom have too much bleeding. About one quarter of patients will have neurologic signs

and symptoms that present as seizures, drowsiness, coma, and personality changes. Most of the patients that have HUS with diarrhea will also have hypertension (high blood pressure) that occurs with it. Almost one fifth of patients with HUS will also have some form of pancreatic problems that can lead to the body not making enough insulin and causing diabetes. In some cases, the diabetes may last for the rest of the patient’s life.

Kidney problems vary from patient to patient in how severe they may be. Some patients only have lower urine output, but others progress to full kidney failure. In some patients who develop HUS without diarrhea, the onset of renal failure will be more subtle such that they will present with symptoms of volume overload (too much retained fluid).

Diagnosis

The diagnosis of HUS should be considered in patients who present with symptoms of anemia or renal failure who either give a history of diarrhea before it or have certain problems that show up in their lab tests. Patients will always have low red blood cell counts (anemia) with signs of the ongoing break down of red blood cells. On peripheral smear (blood looked at through a microscope), Burr cells can be seen. These are red blood cells with bumps sticking out of the surface of the cell. Also schistocytes (pieces of red blood cells that have been destroyed) can be seen under the microscope which provide clues of the ongoing break down of red blood cells (hemolysis).

Diagnosis of familial HUS will depend on the presence of many cases within one family that are not linked to an outside epidemic. Often, the cases will occur over a stretch of many years. As of yet, there is no genetic or lab test that can tell which people will get familial HUS. Prenatal testing is not yet available either.

Treatment and management

There is no certain treatment for patients with HUS other than supportive care. Many types of treatments have been tried in attempts to reduce the amount of clotting that occurs in small vessels, but with little or no success. Antibiotic treatment for children with diarrhea caused by E. coli tended to raise, instead of lower, the rate of transformation into HUS. Thus, antibiotics tend to not be used for children with diarrhea. They are of little benefit and may be harmful. Treatment of diarrhea in children should consist of supportive care with ample fluids in order to prevent dehydration.

Careful notice must be paid to fluid intake. It is very easy for kidney failure patients to build up too much volume and have problems with their electrolyte levels.

522	G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S

Patients with really low red blood cell counts can be given blood transfusions. Those who get severe renal failure may need dialysis treatment to rid their blood of toxins that would have been cleared by the kidneys. These treatments apply to all forms of HUS including HUS with diarrhea, HUS without diarrhea, and familial HUS. In some patients with recurring familial disease, kidney transplants have been tried, but the disease did recur in many patients.

Prognosis

About 10% of children will die during the acute phase of the illness or will be left with chronic renal or brain damage. Most of the deaths during the acute phase occur in children where organs other than the kidneys are also involved (i.e. brain thrombi formation). Long term effects also include diabetes, rectal stricture (narrowing of the rectum caused by fibrous tissue formation), and neurologic deficits (related to strokes). Of children who have HUS with diarrhea (most of the cases), about 1% will have the illness return.

In adults, the death rate is much higher, at 15 to 30%. Also, 30% of those who do not die from HUS will have chronic kidney damage and 25% may go on to have the disease recur. This difference in age-related recurrence rates and outcomes may be due to the fact that a higher number of adults get the form of HUS that begins without diarrhea.

Resources

BOOKS

Nathan, David, et al. “Schistocytic Hemolytic Anemia with Severe Thrombocytopenia.” In Nathan and Oski’s Hematology of Infancy and Childhood. Philadelphia: W.B. Saunders, 1998.

Siegler, Richard. “Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura.” In Primer on Kidney Diseases. San Diego, CA: Academic Press, 1998.

PERIODICALS

Landau, Daniel, et al. “Familial Hemolytic Uremic Syndrome Associated with Complement Factor H Deficiency.” Journal of Pediatrics 138 (March 2001): 412-417.

Wong, Craig, et al. “The Risk of Hemolytic-Uremic Syndrome After Antibiotic Treatment of Escherichia coli 0157:H7 Infections.” New England Journal of Medicine 342, no. 26 (June 2000): 1930-1936.

WEBSITES

“H Factor 1; HF1.” Online Mendelian Inheritance in Man.

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id= 134370 .

“Hemolytic-Uremic Syndrome; HUS.” Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov/ entrez/dispomim.cgi?id=235400 .

Benjamin Morris Greenberg

I Hemophilia

Definition

Hemophilia is a genetic disorder—usually inher- ited—of the mechanism of blood clotting. Depending on the degree of the disorder present in an individual, excess bleeding may occur only after specific, predictable events (such as surgery, dental procedures, or injury), or occur spontaneously, with no known initiating event.

Description

The normal mechanism for blood clotting is a complex series of events involving the interaction of the injured blood vessel, blood cells (called platelets), and over 20 different proteins which also circulate in the blood.

When a blood vessel is injured in a way that causes bleeding, platelets collect over the injured area, and form a temporary plug to prevent further bleeding. This temporary plug, however, is too disorganized to serve as a long-term solution, so a series of chemical events occur, resulting in the formation of a more reliable plug. The final plug involves tightly woven fibers of a material called fibrin. The production of fibrin requires the interaction of several chemicals, in particular a series of proteins called clotting factors. At least thirteen different clotting factors have been identified.

The clotting cascade, as it is usually called, is the series of events required to form the final fibrin clot. The cascade uses a technique called amplification to rapidly produce the proper sized fibrin clot from the small number of molecules initially activated by the injury.

In hemophilia, certain clotting factors are either decreased in quantity, absent, or improperly formed. Because the clotting cascade uses amplification to rapidly plug up a bleeding area, absence or inactivity of just one clotting factor can greatly increase bleeding time.

Hemophilia A is the most common type of bleeding disorder and involves decreased activity of factor VIII. There are three levels of factor VIII deficiency: severe, moderate, and mild. This classification is based on the percentage of normal factor VIII activity present:

•Individuals with less than 1% of normal factor VIII activity level have severe hemophilia. Half of all people with hemophilia A fall into this category. Such individuals frequently experience spontaneous bleeding, most frequently into their joints, skin, and muscles. Surgery or trauma can result in life-threatening hemorrhage, and must be carefully managed.

Hemophilia

G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S

523

Hemophilia

K E Y T E R M S

Amplification—A process by which something is made larger. In clotting, only a very few chemicals are released by the initial injury; they result in a cascade of chemical reactions which produces increasingly larger quantities of different chemicals, resulting in an appropriately-sized, strong fibrin clot.

Factors—Coagulation factors are substances in the blood, such as proteins and minerals, that are necessary for clotting. Each clotting substance is designated with roman numerals I through XIII.

Fibrin—The final substance created through the clotting cascade, which provides a strong, reliable plug to prevent further bleeding from the initial injury.

Hemorrhage—Very severe, massive bleeding that is difficult to control. Hemorrhage can occur in hemophiliacs after what would be a relatively minor injury to a person with normal clotting factors.

Mutation—A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease, and can be transmitted to offspring.

Platelets—Small disc-shaped structures that circulate in the blood stream and participate in blood clotting.

Trauma—Injury.

•Individuals with 1–5% of normal factor VIII activity level have moderate hemophilia, and are at risk for heavy bleeding after seemingly minor traumatic injury.

•Individuals with 5–40% of normal factor VIII activity level have mild hemophilia, and must prepare carefully for any surgery or dental procedures.

Individuals with hemophilia B have symptoms very similar to those of hemophilia A, but the deficient factor is factor IX. This type of hemophilia is also known as Christmas disease.

Hemophilia C is very rare, and much more mild than hemophilia A or B; it involves factor XI.

Genetic profile

Hemophilia A and B are both caused by a genetic defect present on the X chromosome. (Hemophilia C is inherited in a different fashion.) About 70% of all people

Elbow x ray showing changes to bone structure as a result of hemophilia. (Custom Medical Stock Photo, Inc.)

with hemophilia A or B inherited the disease. The other 30% develop from a spontaneous genetic mutation.

The following concepts are important to understanding the inheritance of these diseases. All humans have two chromosomes determining their gender: females have XX, males have XY. Because the trait is carried only on the X chromosome, it is called “sex-linked.” The chromosome’s flawed unit is referred to as the gene.

Both factors VIII and IX are produced by a genetic defect of the X chromosome, so hemophilia A and B are both sex-linked diseases. Because a female child always receives two X chromosomes, she nearly always will receive at least one normal X chromosome. Therefore, even if she receives one flawed X chromosome, she will still be capable of producing a sufficient quantity of factors VIII and IX to avoid the symptoms of hemophilia. Such a person who has one flawed chromosome, but does not actually suffer from the disease, is called a carrier. She carries the flaw that causes hemophilia and can pass it on to her offspring. If, however, she has a son who receives her flawed X chromosome, he will be unable to produce the right quantity of factors VIII or IX, and he will suffer some degree of hemophilia. (Males inherit one X and one Y chromosome, and therefore have only one X chromosome.)

In rare cases, a hemophiliac father and a carrier mother can pass on the right combination of parental chromosomes to result in a hemophiliac female child. This situation, however, is rare. The vast majority of people with either hemophilia A or B are male.

About 30% of all people with hemophilia A or B are the first member of their family to ever have the disease. These individuals have had the unfortunate occurrence of a spontaneous mutation; meaning that in their early development, some random genetic accident befell their X chromosome, resulting in the defect causing hemo-

524	G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S