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

CMT causing genes—one inherited from each parent. The parents of an affected person are called carriers. They have one normal copy of the gene and one copy with a mutation. Carriers do not have symptoms of CMT. Two carrier parents have a 25%, or one in four chance of passing CMT on to each of their children.

Demographics

CMT has been diagnosed in people from all over the world. It occurs in approximately one in 2,500 people, which is about the same incidence as multiple sclerosis. It is the most common type of inherited neurologic condition.

Signs and symptoms

The onset of symptoms is highly variable, even among members of the same family. Symptoms usually progress very slowly over a person’s lifetime. The main problems caused by CMT are weakness and loss of sensation mainly in the feet and hands. The first symptoms are usually problems with the feet such as high arches and problems with walking and running. Tripping while walking and sprained ankles are common. Muscle loss in the feet and calves leads to “foot drop” where the foot does not lift high enough off the ground when walking. Complaints of cold legs are common, as are cramps in the legs, especially after exercise.

In many people, the fingers and hands eventually become affected. Muscle loss in the hands can make fine movements such as working buttons and zippers difficult. Some patients develop tremor in the upper limbs. Loss of sensation can cause problems such as numbness and the inability to feel if something is hot or cold. Most people with CMT remain able to walk throughout their lives.

Diagnosis

Diagnosis of CMT begins with a careful neurological exam to determine the extent and distribution of weakness. A thorough family history should be taken at this time to determine if other people in the family are affected. Testing may be also performed to rule out other causes of neuropathy.

A nerve conduction velocity test should be performed to measure how fast impulses travel through the nerves. This test may show characteristic features of CMT, but it is not diagnostic of CMT. Nerve conduction testing may be combined with electromyography (EMG), an electrical test of the muscles.

A nerve biopsy (removal of a small piece of the nerve) may be performed to look for changes characteristic of CMT. However, this testing is not diagnostic of

K E Y T E R M S

Axon—Skinny, wire-like extension of nerve cells.

Myelin—A fatty sheath surrounding nerves in the peripheral nervous system, which help them conduct impulses more quickly.

Nerve conduction testing—Procedure that measures the speed at which impulses move through the nerves.

Neuropathy—A condition caused by nerve damage. Major symptoms include weakness, numbness, paralysis, or pain in the affected area.

Peripheral nerves—Nerves throughout the body that carry information to and from the spinal cord.

CMT and is usually not necessary for making a diagnosis.

Definitive diagnosis of CMT is made only by genetic testing, usually performed by drawing a small amount of blood. As of early 2001, testing is available to detect mutations in PMP22, MPZ, Cx32, and EGR2. However, research is progressing rapidly and new testing is often made available every few months. All affected members of a family have the same type of CMT. Therefore once a mutation is found in one affected member, it is possible to test other members who may have symptoms or are at risk of developing CMT.

Prenatal diagnosis

Testing during pregnancy to determine whether an unborn child is affected is possible if genetic testing in a family has identified a specific CMT-causing mutation. This can be done after 10-12 weeks of pregnancy using a procedure called chorionic villus sampling (CVS). CVS involves removing a tiny piece of the placenta and examining the cells. Testing can also be done by amniocentesis after 16 weeks gestation by removing a small amount of the amniotic fluid surrounding the baby and analyzing the cells in the fluid. Each of these procedures has a small risk of miscarriage associated with it, and those who are interested in learning more should check with their doctor or genetic counselor. Couples interested in these options should obtain genetic counseling to carefully explore all of the benefits and limitations of these procedures.

Treatment and management

There is no cure for CMT. However, physical and occupational therapy are an important part of CMT treat-

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ment. Physical therapy is used to preserve range of motion and minimize deformity caused by muscle shortening, or contracture. Braces are sometimes used to improve control of the lower extremities that can help tremendously with balance. After wearing braces, people often find that they have more energy because they are using less energy to focus on their walking. Occupational therapy is used to provide devices and techniques that can assist tasks such as dressing, feeding, writing, and other routine activities of daily life. Voice-activated software can also help people who have problems with fine motor control.

It is very important that people with CMT avoid injury that causes them to be immobile for long periods of time. It is often difficult for people with CMT to return to their original strength after injury.

There is a long list of medications that should be avoided if possible by people diagnosed with CMT such as hydralazine (Apresoline), megadoses of vitamin A, B6, and D, Taxol, and large intravenous doses of penicillin. Complete lists are available from the CMT support groups. People considering taking any of these medications should weigh the risks and benefits with their physician.

Prognosis

The symptoms of CMT usually progress slowly over many years, but do not usually shorten life expectancy. The majority of people with CMT do not need to use a wheelchair during their lifetime. Most people with CMT are able to lead full and productive lives despite their physical challenges.

Resources

BOOKS

Parry, G. J., ed. Charcot-Marie-Tooth Disorders: A Handbook for Primary Care Physicians. Available from the CMT Association, 1995.

PERIODICALS

Keller. M. P., and P. F. Chance. “Inherited peripheral neuropathies.” Seminars in Neurology 19, no. 4 (1999): 353–62.

Quest. A magazine for patients available from the Muscular Dystrophy Association.

Shy, M. E., J. Kamholz, and R. E. Lovelace, eds. “Charcot- Marie-Tooth Disorders.” Annals of the New York Academy of Sciences 883 (1999).

ORGANIZATIONS

Charcot Marie Tooth Association (CMTA). 2700 Chestnut Parkway, Chester, PA 19013. [phone] or (800) 606-CMTA. Fax: [phone]. [e-mail] .

CMT International. Attn: Linda Crabtree, 1 Springbank Dr. St. Catherine’s, ONT L2S2K1. Canada [phone].www.cmtint.org .

Muscular Dystrophy Association. 3300 East Sunrise Dr., Tucson, AZ 85718. [phone] or [phone].http://www.mdausa.org .

Neuropathy Association. 60 E. 42nd St. Suite 942, New York, NY 10165. [phone]. www.neuropathy.org .

WEBSITES

HNPP—Hereditary Neuropathy with liability to Pressure Palsies. Online Support Group, http://www.hnpp.org .

GeneClinics. University of Washington, Seattle.www.geneclinics.org .

OMIM—Online Mendelian Inheritance in Man.

www.ncbi.nlm.nih.gov/Omim .

Karen M. Krajewski, MS, CGC

I CHARGE syndrome

Definition

CHARGE syndrome, also known as CHARGE association, is a group of major and minor malformations that have been observed to occur together more frequently than expected by chance. The name of the syndrome is an acronym for some of its features, and each letter stands for the following conditions:

•C—Coloboma and/or cranial nerves

•H—Heart defects

•A—Atresia choanae,

•R—Retarded growth and development

•G—Genital anomalies

•E—Ear anomalies

While these features have classically been used for identification of affected individuals, many other malformations and medical problems have been observed to occur with this syndrome.

Description

CHARGE syndrome was first described in 1979 as an association of multiple congenital anomalies, all of which included choanal atresia, meaning the blocking of the choanae, the passages from the back of the nose to the throat which allow breathing through the nose. Soon after, several other papers were published describing similar patients who all had both choanal atresia and coloboma, that is a cleft or failure to close off the eyeball. It was in 1981 that the CHARGE acronym was proposed to describe the features of the condition. Due to the

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large number of patients described since 1979, many physicians now regard CHARGE association as a recognizable syndrome. However, the cause for the condition remains unclear. It is believed that perhaps a new dominant change in a gene is the cause for many cases. There have been a few familial cases but most cases are sporadic. Crucial development of the choanoa, heart, ear and other organs occurs 35-45 days after conception and any disruption in development during this time is believed to lead to many of the features of the syndrome.

Infants with CHARGE syndrome generally have difficulty with feeding and most of those affected have mental retardation. About half die during the first year of life from respiratory insufficiency, central nervous system (CNS) malformations, and bilateral choanal atresia.

Genetic profile

Most cases of CHARGE syndrome are sporadic, meaning that they occur in a random or isolated way. However, reports of parent-to-child transmission of the condition indicate an autosomal dominant type of inheritance. There have also been cases in which a parent with one or two features of CHARGE had a child with enough features to fit the diagnosis. These families may demonstrate variable expressivity of a dominant gene. In addition, there have been a few cases of siblings affected, suggesting the possible presence of a mixture of cell types (germ line mosaicism) in a parent for a dominant mutation. Therefore, the recurrence risk for healthy parents of an affected child would be low, but not negligible.

Twin studies are often used to determine if the occurrence of a condition has a strong genetic component. One such study compared a pair of monozygotic twins, meaning identical twins resulting from a single zygote (fertilized egg that leads to the birth of two individuals), who were both affected with CHARGE syndrome and a pair of dizygotic twins, meaning twins that result from fertilization of two different eggs, of whom only one had the syndrome. Since monozygotic twins are roughly 100% genetically identical, this supports the idea that there is a strong genetic factor involved in CHARGE syndrome. Other interesting observations include slightly increased paternal age in sporadic cases. The mean paternal age in one study was 34 years as opposed to 30 years in a control group. Increased paternal age has been known to be associated with the increased occurrence of new dominant mutations in offspring.

Several patients with various chromosome defects have been diagnosed with CHARGE syndrome, again pointing to genetic factors as a cause. These cases of chromosomal abnormalities point to particular genes that should be further studied. In addition, some patients

K E Y T E R M S

Cryptorchidism—A condition in which one or both testes fail to descend normally.

Germ line mosaicism—A rare event that occurs when one parent carries an altered gene mutation that affects his or her germ line cells (either the egg or sperm cells) but is not found in the somatic (body) cells.

Phenotype—The physical expression of an individuals genes.

Variable expressivity—Differences in the symptoms of a disorder between family members with the same genetic disease.

with CHARGE syndrome also have features of another condition called Di George sequence which involves an immune deficiency, characteristic heart abnormalities and distinct craniofacial features. Many patients with Di George sequence have a missing chromosome 22q11. Therefore, newly diagnosed cases of CHARGE syndrome should have chromosome studies as well as molecular testing.

Demographics

The incidence of CHARGE syndrome is approximately one in 10,000. However, this is probably an underestimate of the true number of people affected. The incidence is likely to increase as the diagnostic features of the condition are refined and milder cases are diagnosed. CHARGE syndrome affects males more seriously than females, resulting in a higher number of females who survive. The cause of this is unclear. The syndrome has not been reported more often in any particular race or geographic area.

Signs and symptoms

CHARGE syndrome is believed to be caused by a disruption of fetal growth during the first three months of pregnancy and affecting many different organ systems undergoing development at that time.

Choanal atresia

Choanal atresia, the narrowing passages from the back of the nose to the throat, may occur on one or both sides (bilateral) of the nose. This condition usually leads to breathing difficulties shortly after birth. Bilateral choanal atresia may result in early death and surgery is

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often required to open up the nasal passages. Choanal atresia is also often accompanied by hearing loss. Since bilateral choanal atresia is rare, CHARGE syndrome should be considered in all babies with this finding. Fifty to sixty percent of children diagnosed with CHARGE syndrome have choanal atresia.

Heart abnormalities

Seventy-five to eighty-five percent of children with CHARGE syndrome have heart abnormalities. Many are minor defects, but many require treatment or surgery. Some of the heart abnormalities seen in CHARGE syndrome are very serious (e.g. tetralogy of Fallot) and life threatening. Every child with a diagnosis of CHARGE syndrome should have an echocardiogram, a test that uses sound waves to produce pictures of the heart.

Coloboma and eye abnormalities

A coloboma is a cleft or failure to close off the eyeball properly. This can result in a keyhole shaped pupil or abnormalities in the retina of the eye or its optic nerve. The condition is visible during an eye exam. Colobomas may or may not cause visual changes. About 80% of children with CHARGE syndrome have colobomas and the effect on vision varies from mild to severe. Other eye abnormalities include microphthalmia (small eye slits) or anophthalmia (no eyes). Consistent eye examinations are recommended for children diagnosed with the syndrome.

Ear abnormalities and deafness

At least 90% of patients with CHARGE syndrome have either external ear anomalies or hearing loss. The most common external ear anomalies include low-set ears, asymmetric ears, or small or absent ear lobes. The degree of hearing loss varies from mild to severe. It is important for all patients to have regular hearing exams over time so that changes in sound perception can be detected. Hearing aids are used as soon as hearing loss is detected. Some patients require corrective surgery of the outer ear, so that a hearing aid can be worn. Children with CHARGE syndrome often develop ear infections and this can affect hearing over time as well.

Cranial nerve defects

Defects related to the formation of the cranial nerves during fetal development are common in patients with CHARGE syndrome. The defects include anosmia (inability to smell), facial palsy, hearing loss, and swallowing difficulty. Facial palsy is the inability to sense or control movement of part of the face. This usually occurs

on one side of the face, which, in affected individuals, results in a characteristic asymmetric and expressionless look. Swallowing problems can also occur along with several different defects in the formation of the throat.

Facial features

The facial features of CHARGE syndrome are considered minor diagnostic signs because they are not as obvious as the facial features of other genetic syndromes. However, many patients have facial asymmetry, a small and underdeveloped jaw, a broad forehead, square face, arched eyebrows, and external ear malformations.

Growth and developmental delays

Most babies with CHARGE syndrome have normal length and weight at birth. Difficulty with feeding and the presence of other malformations often leads to weight loss, so that these babies usually weigh less for their age. Teenagers are also often shorter than average due to a delay in the onset of puberty. In a small number of patients, growth delay is due to a lack of growth hormone.

There are serious delays in motor development of children with CHARGE syndrome as well. Many children have low muscle tone and difficulty with balance that leads to delays in walking. Physical therapy is often helpful. Most children with CHARGE syndrome are classified as mentally retarded. However, successful treatment of other features of the condition can improve learning potential. Therefore, assessments made before other medical problems are addressed are often more pessimistic than later exams.

Urogenital abnormalities

Most obvious in males, underdevelopment of the genitals occurs in at least half of the male patients diagnosed with CHARGE syndrome and in some females as well. Abnormalities of genitalia in males include an underdeveloped penis (micropenis or microphallus) and testicles that fail to descend to the scrotum (cryptorchidism). In females, there may be overgrowth or underdevelopment of the labia or clitoris. Information concerning the fertility of patients is not available. About 25% of children have renal abnormalities that may lead to repeated infections. A renal ultrasound is indicated in children with the syndrome.

Central nervous system anomalies

In one series of tested patients, CNS anomalies were noted in 83% of the patients who underwent imaging tests that produce pictures of the brain such as MRI, CT

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scan, and ultrasound, or after autopsy. The CNS anomalies included diminution of the size of the brain (cerebral atrophy), asymmetry, and midline defects such as partial development (e.g. agenesis of the corpus callosum). In addition, brain stem dysfunction has also been observed after birth, a disorder that can cause respiratory and swallowing problems. These findings were associated with a poor prognosis.

Associated anomalies

Many other features have been reported in patients with CHARGE syndrome. Some of these include a cleft lip and/or palate, dental anomalies, absence of the thymus and parathyroid glands that leads to immunodeficiency (the inability of the body to produce a normal immune response), seizures, abormally low levels of calcium (hypocalcaemia) or sugar (hypoglycemia) in the body, obstruction of the anal opening (imperforate anus), groin hernias, curvature of the spine (scoliosis), skeletal anomalies, body temperature regulation problems and umbilical hernias.

Diagnosis

Since there is currently no genetic test available for CHARGE syndrome, the diagnosis is based on clinical features. There is disagreement about the conditions required for diagnosis. Some suggest that one major malformation plus four of the other features suggested by the CHARGE acronym are sufficient. Others suggest that four major characteristics or three major characteristics plus three minor characteristics are sufficient for diagnosis.

The Charge Syndrome Foundation defines a specific set of birth defects and most common features to diagnose CHARGE syndrome. These major features include: choanal atresia, coloboma, cranial nerve abnormalities and conditions, such as swallowing problems (due to cranial nerve IX/X defects), facial palsy (due to cranial nerve VII defects), hearing loss (due to cranial nerve VIII defects), heart defects, and retardation of growth and development.

Other minor features have also been reported that are either less common or less specific to CHARGE syndrome. These include genital abnormalities, cleft lip and/or palate, tracheoesophageal fistula and facial distortions.

Diagnosis of CHARGE syndrome before birth has not yet been reported. The condition may be suspected when a prenatal ultrasound reveals fetal growth restriction, CNS malformations, heart defects, and urinary tract malformations. In one series, 37.5% of patients diag-

nosed with CHARGE were noted to have an abnormal feature noted on ultrasound.

There are several other conditions that include signs similar to CHARGE syndrome. These include VACTERL association (for vertebral, anal, cardiac, tracheoesophageal, renal and limb abnormalities, velocardiofacial (VCF) syndrome (deletion 22q11 syndrome), and prenatal retinoic acid exposure (Accutane embryopathy).

Treatment and management

Treatment for CHARGE syndrome is specific to the features present in each child. Choanal atresia can be treated with dilatations of the choanoa or nasal passages. Heart defects may require surgery. Children with CHARGE syndrome should get ophthalmology and hearing screens every six months. Plastic surgery is sometimes needed for corrections of ear malformations or facial asymmetry. Medications are needed when seizures are present and growth hormone is sometimes taken for growth delay or underdeveloped genitalia.

A developmental evaluation and a plan for special education are required. Patients with CHARGE syndrome who have both hearing and vision difficulty should receive care from childhood educators experienced in dual sensory impairment. Once these children establish a system of mobility and communication, the degree of developmental retardation may improve. Lengthy hospital stays for children with CHARGE syndrome may limit the ability of specialists to work with the child in the early months. Once major hospitalizations are completed, development may improve as the result of regular care by the appropriate child specialists. Other learning problems have been noted and should also be addressed if present. These include attention deficit disorder, autism, and obsessive-compulsive disorder. Parents are often in the position of coordinating the many components of special education for their children. The national and international support groups for CHARGE syndrome are able to provide information and assistance in this area.

Prognosis

It has been noted in several studies that about half of patients diagnosed with CHARGE syndrome die from complications of the condition. One study suggests that 40% of those die after birth. Factors that appear to influence survival include the presence of CNS malformations, bilateral choanal atresia, TE fistula, and male gender. Heart abnormalities and brain stem dysfunctions were not found to be related to poor prognosis. Significant hospitalizations are needed for most children with CHARGE syndrome.

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Resources

BOOKS

Jones, Kenneth Lyons. Smith’s Recognizable Patterns of

Human Malformation, 5th Edition. Philadelphia: W.B. Saunders Company, 1997.

McKusick, Victor. Mendelian Inheritance in Man: A Catalog of

Human Genes and Genetic Disorders, 12th Edition. Baltimore: The Johns Hopkins University Press, 1998.

PERIODICALS

Blake, K., et. al. “CHARGE Association: An Update and Review for the Primary Pediatrician.” Clinical Pediatrics (1998): 159-173.

Tellier, A. L., et al. “CHARGE Syndrome: Report of 47 Cases and Review.” American Journal of Medical Genetics

(1998): 402-409.

ORGANIZATIONS

CHARGE Family Support Group. 82 Gwendolen Ave., London, E13 ORD. UK 020-8552-6961. http://www

.widerworld.co.uk/charge .

CHARGE Syndrome Foundation. 2004 Parkade Blvd., Columbia, MO 65202-3121. [phone]. http://www

.chargesyndrome.org .

Sonja Rene Eubanks, MS, CGC

I Chediak-Higashi syndrome

Definition

Chediak-Higashi syndrome (CHS) is a very rare disease that affects almost every organ in the body. It is an autosomal recessive disease that results from an abnormality in lysosomes (a sac-like container of enzymes) that travel within cells. The problems that occur with this disease are quite varied and present in two stages.

Description

Chediak-Higashi syndrome was named for the two scientists who, in 1957, further detailed the disorder first described by a Cuban doctor in 1943. The disease progresses through two different stages: the “stable phase” and the “accelerated phase.” This rare disease has both classic external signs and distinct cellular problems that always result in a fatal outcome.

Affected individuals have many kinds of immune system problems, making them more likely to get infections and cell proliferation problems. People with CHS have a lowered ability to target infectious organisms, and once their immune cells do become involved, they have a harder time killing the infectious organisms.

Affected individuals also have problems with their melanocytes, the cells that produce melanin, the compound that gives skin, hair, and eyes their color. Often, this can result in signs of albinism (lack of color in the skin, hair, and eyes).

Genetic profile

Chediak-Higashi is an autosomal recessive disease, which requires both parents to be carriers of altered, or mutated, genes. CHS often occurs in families with a history of marrying close relatives. Based on genetic mapping that was first done in a mouse model of Chediak-Higashi syndrome, a mutated gene found on chromosome 1q is thought to be the cause of the disease. This gene is called LYST.

Genetic tests of many different affected people with the disease have revealed strong signs of allelic variability (different mutations in the same gene). Some evidence suggests that the allelic variability accounts for the many different presentations of the disease, such as differing age of presentation, differences in the severity of symptoms, and different progression into the second stage of the disease.

Demographics

About 200 cases of CHS have been described in the world’s literature. It is seen in the same number of males and females. Often there is a history of intermarriage.

Signs and symptoms

People with Chediak-Higashi syndrome will often have many different clinical problems such as recurrent bacterial infections without clear causes, fevers that cannot be explained, severe gingivitis (gum disease), peripheral and cranial neuropathies, vision problems, lack of coordination, weakness, easy bruising, and loss of coloring (hypopigmentation) of the hair, skin and eyes.

During the accelerated phase, affected people may show signs of enlargement of the liver and spleen (hepatosplenomegaly), low blood platelet counts (thrombocytopenia), low counts of a certain white blood cell group (neutropenia), and low red blood cell counts (anemia). Abnormal cells can cause bone marrow infiltration and suppression, and this may lower blood counts further, making affected individuals even more susceptible to infections. The transformation to the accelerated phase of this disease tends to occur in the first or second decade of life.

Diagnosis

Diagnosis of CHS is based on microscopic examination of an affected person’s blood, and possibly their

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bone marrow. Examiners look for giant lysosomal granules, which are abnormal groups of cellular sections inside certain white blood cells. At present, the carrier state of Chediak-Higashi syndrome cannot be diagnosed. Prenatal testing has been done using fetal blood samples and cells taken from the amniotic fluid around the fetus. Genetic testing is not yet available.

Since this disorder is passed on in an autosomal recessive fashion, parents who have one affected child should have genetic counseling before future pregnancies. With each pregnancy these parents have a 25% chance of having another affected child.

Treatment and management

The treatment of Chediak-Higashi syndrome differs based on the stage of the illness. During the stable phase, treatment is aimed at controlling infectious problems. Prophylactic antibiotics can be given to affected individuals to reduce the risk of contracting the more common infections. Some evidence suggests that treatment with high doses of ascorbic acid (vitamin C) can help improve people clinically as well as improve immune system cell functions in laboratory tests.

During the accelerated phase of this disease, treatment is very difficult. Some affected people have done well with chemotherapy that is aimed at the abnormally growing cells. Some literature has claimed benefits from bone marrow transplants. Also, some literature has indicated that the vaccination of affected individuals against specific viruses may help prevent transformation of the disease from the stable phase into the accelerated phase.

Prognosis

Most affected people described in the medical literature died of infections during the accelerated phase of CHS. This occurred during their youth or teenage years. There are some reports of affected people living into their 30s.

Resources

BOOKS

Nathan, David, et al. “Disorders of Degranulation: ChediakHigashi Syndrome,” Nathan and Oski’s Hematology of

Infancy and Childhood. Philadelphia, Pennsylvania: WB Saunders Company, 1998.

WEBSITES

Lo, Wilson, et al. “#214500 Chediak-Higashi Syndrome; CHS1.” OMIM—Online Mendelian Inheritance In Man. http://www3.ncbi.nlm.nih.gov/Omim/searchomim.html.

Benjamin M. Greenberg

K E Y T E R M S

Allelic variability—Different mutations in the same gene, producing like outcomes.

Lysosome—Membrane-enclosed compartment in cells, containing many hydrolytic enzymes; where large molecules and cellular components are broken down.

Melanin—Pigments normally produced by the body that give color to the skin and hair.

Melanocyte—A cell that can produce melanin.

Chiari malformation see Arnold-Chiari malformation

Chondroectodermal dysplasia see Ellis-Van

Creveld syndrome

I Chondrosarcoma

Definition

Chondrosarcoma is a malignant tumor that produces a special type of connective tissue called cartilage. Malignant tumors have cells that have the ability to invade and are characterized by uncontrolled growth.

Description

Cartilage is a type of connective tissue that acts as a resistant surface. Cells called chondrocytes produce cartilage. Chondrosarcoma is a malignant growth arising in chondrocytes. There are two types of chondrosarcomas, either primary or secondary. Primary chondrosarcomas arise in areas of previously normal bone that are derived from cartilage. Secondary chondrosarcomas are lesions produced from pre-existing cartilage lesions. The chondrosarcoma tumors either produce enlargement or erosion of the area involved. The lesion is classified further as to where the lesion occurs and the grade of the lesion. It is graded from 1 (low-grade) to 3 (high-grade). This classification states that the higher the grade of the tumor, the higher the increased atypia, or abnormal cell growth.

Two non-cancerous diseases, Maffuci disease and Ollier disease, are similar to chondrosarcoma. Ollier disease, also known as enchondromatosis or dyschondroplasia, is a disorder affecting the growth plates of bone where new bone is deposited. The cartilage laid down is

Chondrosarcoma

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K E Y T E R M S

Atypia—Lacking uniformity.

Cartilage—Supportive connective tissue which cushions bone at the joints or which connects muscle to bone.

Computed tomography (CT) scan—An imaging procedure that produces a three-dimensional picture of organs or structures inside the body, such as the brain.

Curettage—A surgical scraping or cleaning.

Enchondromas—Benign cartilaginous tumors arising in the cavity of bone. They have the possibility of causing lytic destruction within the bone.

Excision—Surgical removal.

Lysis—Area of destruction.

Maffucci disease—A manifestation of Ollier disease (multiple enchondromatosis) with hemangiomas, which present as soft tissue masses.

Myxoid—Resembling mucus.

Ollier disease—Also termed multiple enchondromatosis. Excessive cartilage growth within the bone extremities that result in benign cartilaginous tumors arising in the bone cavity.

Radiolucent—Transparent to x ray or radiation. The black area on x-ray film.

Urinary urgency—An exaggerated or increased sense of needing to urinate.

not reabsorbed and masses form near the ends of the long bones such as the thigh bone (femur) and upper arm bone (humerus). Maffucci disease has the same abnormalities as Ollier disease as well as soft tissue destruction including the skin. Patients with Maffucci or Ollier disease should have bone scans every three to five years to monitor potential malignant transformations.

Genetic profile

Anomalies of chromosomes 5, 7, 8, and 18 and structural alterations of chromosomes 1, 12, and 15 are commonly found in patients diagnosed with chondrosarcoma. Interestingly, the gene for the area of normal cartilage production, type II collagen, has been found in the same regions as chondrosarcoma. Studies on the tumor suppressor gene, EXT1, have shown that changes (mutations) of this gene may also be important in the growth of chondrosarcoma.

Demographics

In 2001, an estimated 2,900 new cases of bone and joint cancer will be diagnosed. Primary cancer of bones accounts for less than 0.2% of all cancers. Chondrosarcoma is the second most common primary malignant bone tumor, meaning it did not originate at another site in the body. Osteosarcoma is the first most common.

There are conflicting reports as to how much more frequently men are diagnosed with chondrosarcoma than females. Findings range from twice as many males to only slightly more males than females. Chondrosarcoma occurs in people from the age of 30-70 years old, but it most commonly affects people over the age of 40. No ethnic group is affected more frequently than another.

Signs and symptoms

The signs and symptoms vary due to the type of tumor, but pain is typically the first symptom. If it is a fast growing, high grade form of chondrosarcoma, then the individual may have very severe pain. A low grade, slow growing, tumor usually has pain and swelling in the area of the tumor. If the tumor is located in the pelvis or hip area, the individual may have difficulty with urination or urinary urgency. The patient may also have the sensation of a groin pull if the tumor is in the pelvic area.

Diagnosis

Usually, chondrosarcoma is diagnosed with x ray radiography. X rays can show soft tissue calcification, where the muscles appear to be forming bone. The appearance of a soft tissue mass that has not yet calcified may also be visible. If the chondrosarcoma is secondary to another type of tumor, the chondrosarcoma may start to erode the edges of the other tumor. This is common where an enchondroma, a type of tumor within the bone shaft, is present. In this case, the chondrosarcoma produces areas of lysis, or destruction of the surrounding tissue.

Biopsy is used to determine the grade of the tumor. Grade 1 chondrosarcomas, or low-grade slow growing lesions, have a mild increase of new cell growth. Grade 3 chondrosarcomas are the opposite: they are high-grade, fast growing, and have a dramatic increase in cellular growth. The more radiolucent, or transparent to x rays, the tumor appears, the greater the chance it is a higher grade.

Other imaging tests may also be used. Computed tomography scanning, CT, is an advanced form of x ray that can also produce bone pictures and help determine how much calcification the tumor is producing. Magnetic

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resonance imaging, MRI, will aid diagnosis since it can differentiate soft tissues such as muscle and fat. MRI will help determine the amount of malignant degeneration of the chondrosarcoma.

Treatment and management

The main course of therapy for chondrosarcoma is surgical removal of the tumor. The amount of surgery depends on the location and the stage of the tumor. Very low-grade tumors may be surgically removed. Highgrade chondrosarcomas necessitate more radical operations where normal tissue is also removed due to the possibility of spread. If the tumor is located in an extremity such as an arm or leg, then amputation, or surgical removal of the extremity, may be necessary in order to prevent metastasis, or spread of the cancer. Chemotherapy and radiotherapy may also be used depending on the type of tumor and the area of the body affected, but are usually not effective.

Prognosis

The higher the grade of a chondrosarcoma, the more likely the tumor will spread and thus worsen the prognosis. One study found the five year survival rate of patients with grades 1, 2, and 3 to be 90%, 83%, and 43% respectively. This means that five years after the diagnosis of the tumor, 90 out of 100 people with grade 1 were still alive. On the opposite spectrum, 43 out of 100 patients with grade 3 chondrosarcoma survived five years. Therefore the survival rate is very much dependent on the stage of the tumor and also on its location. Size of the tumor is also an important factor. Tumors greater than 4 in (10 cm) are more likely to become aggressive and spread. When they do spread, or metastasize, they often migrate to the lungs and skeleton.

Resources

BOOKS

Bridge, Julia A., et. al. “Sarcomas of Bone.” In Clinical Oncology, 2nd ed. Edited by Martin D. Abeloff et. al. Philadelphia: Churchill Livingstone, 2000.

Levesque, Jerome, et al. A Clinical Guide to Primary Bone Tumors. Baltimore: Williams & Wilkins, 1998.

Rosenberg, Andrew E. “Skeletal System and Soft Tissue Tumors.” In Robbins Pathologic Basis of Disease, 5th ed. Edited by Ramzi S. Cotran, Vinay Kumar, Stanley Robbins, and Frederick J. Schoen. Philadelphia: W. B. Saunders Company, 1994.

ORGANIZATIONS

Cancernet. National Cancer Institute, National Institutes of Health. NCI Public Inquiries Office, Building 31, Room 10A03, 31 Center Dr., MSC 2580, Bethesda, MD 208922580 USA.

American Cancer Society. Bone Cancer Resource Center. 1599 Clifton Road, NE, Atlanta, GA 30329. [phone] or [phone]. http://www.cancer.org/ .

WEBSITES

Bone Tumor Organization.

http://www.bonetumor.com/page39.html .

Jason S. Schliesser, DC

I Choroideremia

Definition

Choroideremia is a rare genetic disorder causing progressive eyesight loss due to the wasting away of retinal layers. It first affects the choroid and the retinal pigmented epithelium (RPE) layers and finally the photoreceptor cell layer. Atrophy (wasting) of the optic nerve is also observed in choroideremia.

Description

Formerly called tapetochoroidal dystrophy, choroideremia is a chronic form of retinal disease characterized by degeneration of the layers of the retina, which is the light-sensitive part of the eye. There are four main retinal layers: the outer neural retina, consisting of nerve cells and blood vessels; the retinal pigment epithelium (RPE); the choroid layer that contains connective eye tissue and a capillary layer (chorio capillaris); and the photoreceptor (light-sensitive) layer that contain the rods and cones, which function as detectors to process light, color and shape signals to the brain. Choroideremia is a progressive disease, meaning that the layers become affected one after the other over time.

The pigmentary changes in the RPE begin with fine spotting and continue with areas of depigmentation and increasing loss of the chorio capillaris. Chorio capillaris loss and degeneration of the larger choroidal blood vessels causes areas of bare sclera, the tough white fibrous tissue that covers the “white” of the eye. The disease begins in midperiphery of the choroid but then progresses to include the entire choroid.

Choroidal vessels provide oxygen and nutrients to both the RPE and the retina’s photoreceptor cells. The RPE, which lies directly beneath the retina, supports the function of photoreceptor cells. Photoreceptor cells (rods and cones) convert light into the electrical impulses that transfer messages to the brain where “seeing” actually occurs. In the early stages of choroideremia, the choroid and the RPE begin to deteriorate. Eventually, photore-

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ceptor cells also degenerate, resulting in a loss of central vision.

The age at which choroideremia first appears varies; initial symptoms (usually night blindness) may occur as early as three years of age and as late as 40 years. However, occurrence peaks between the ages of ten and 40. The visual field becomes progressively constricted, and patients usually reach legal blindness by 25 years of age. Loss of central vision usually occurs after the age of 35. However, in nearly all patients with choroideremia, visual acuity (acuteness or sharpness of vision) is well maintained until the late stages of the disease.

Genetic profile

Choroideremia is an X-linked, recessive disorder, or a condition that is transmitted on the X chromosome. Females have two X chromosomes; males have an X and a Y chromosome. Thus in females, the altered gene on one X chromosome can be masked by the normal gene on the other X chromosome. Female carriers—who may or may not be symptomatic—have a 50% chance of passing the X-linked abnormal gene to their daughters, who become carriers, and a 50% chance of passing the gene to their sons, who are then affected by the disease.

Choroideremia was the first of the retinal disorders to be mapped, the first to be cloned, and the first to have a simple protein test assigned to it. In 1991, Dr. Fran Cremers of the University of Nijmegen in the Netherlands isolated the gene believed to be responsible for choroiderermia. The gene for choroideremia was found on the Xq21 band of the X chromosome.

Although the choroideremia gene causes problems in the retina, choroid, and RPE, expression of this gene is not limited to the eyes. Choroideremia may also manifest as a generalized disorder. Choroideremia has been classified into two general types: isolated or associated.

Isolated choroideremia

In isolated choroideremia, which is the most common form of the disorder, affected individuals display only disease-related ocular symptoms.

Associated choroideremia

Although relatively rare, associated choroideremia with mental retardation occurs in patients with a deletion of part of the X chromosome, including the region called Xq21. Such a deletion may cause choroideremia with severe mental retardation or with mental retardation and congenital deafness. In these individuals, the mothers are the carriers, showing the same deletions but not the severe clinical manifestations.

Demographics

Choroideremia is believed to affect approximately one in 100,000 individuals—primarily men—although women who are carriers may exhibit mild symptoms as well. The disorder may be generally under-reported because there was no diagnostic test for choroideremia until the late 1990s.

In an area of northern Finland (the Sala region), for reasons that have yet to be determined, choroideremia has affected an unusually large number of people; about one in forty people have the disorder.

Signs and symptoms

A variety of other degenerations of the choroid may look like choroideremia. The decreased night and peripheral vision and diffuse pigmentary abnormalities seen in the early stages of the disorder are symptoms also seen in X-linked retinitis pigmentosa (one of a group of genetic vision disorders causing retinal degeneration). However, unlike retinitis pigmentosa, which starts in early childhood, the onset of choroideremia is variable and is rarely seen in childhood. The distinguishing feature of choroideremia is the diffuse choroidal atrophy that is uncommon in early retinitis pigmentosa.

Because the diffuse, progressive atrophy of the chorio capillaris and RPE layers begins peripherally and spreads centrally, central macular function is preserved until late in the course of the disease. Myopia occurs more frequently in men diagnosed with choroideremia. Although symptoms vary widely among affected individuals, men usually retain little or no useful vision beyond the age of 60.

Choroideremia is characterized by extensive abnormalities in the RPE layer. The initial symptoms include wasting of the retinal layers and choroid of the eye. The choroid (the vascular membrane located between the retina inside the eye and the sclera) contains large branched pigmented cells and prevents light rays from passing through areas of the eye outside of the pupils. Night blindness is usually the first noticeable symptom of choroideremia, usually occurring during childhood.

Degeneration of the vessels of the choroid and functional damage to the retina occur later in life and usually lead to progressive central vision field loss and eventual blindness. Small bony-like formations and scattered pigment clumps tend to accumulate in the middle portion and on the edges of the choroid. In addition, color vision is initially normal but may later evolve into tritanopia (color blindness in which there is an abnormality in the perception of blue).

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