Добавил:
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз: Предмет: Файл:

Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 2 - M-Z - I

.pdf
Скачиваний:
78
Добавлен:
17.08.2013
Размер:
6.14 Mб
Скачать

Genetic profile

Researchers have identified the gene responsible for about seven out of ten PJS cases. The gene is named STK11, and it is located at the 19p13 site on chromosome 19. In some older studies, the same gene is referred to as LKB1. As of 2001, researchers have connected more than 50 different STK11 mutations to cases of PJS.

However, some cases do not appear to be connected to STK11. As a result, PJS qualifies as a genetically heterogeneous condition; this means that it has more than one known genetic cause. Research continues in order to locate the genes involved in the three out of ten cases not related to STK11.

When linked to STK11, PJS is an autosomal dominant disorder. This means that the condition occurs even when an individual inherits only one abnormal copy of STK11 from either parent. In some people with PJS, the condition is limited to freckles on the lining of the cheeks inside the mouth. Many of these people also have gastrointestinal polyps. One abnormal copy of STK11 also increases a person’s risk of developing the kinds of cancer associated with PJS.

However, since only one abnormal copy of STK11 is needed to cause PJS, most people with the condition still have one normal copy of the gene. One normal copy is usually enough to protect against the kinds of cancer associated with PJS. This is because STK11 is a tumor suppressor gene. A properly working tumor suppressor gene makes a product that controls cell growth. Since cancer is the result of uncontrolled cell growth, tumor suppressors prevent cancer. Even one working copy of STK11 protects against cancer.

The reason people with PJS have an increased risk of developing cancer is that one STK11 gene is already abnormal at birth. If damage to the normal STK11 gene occurs later, the ability to control cell growth is lost, leading to the kinds of cancers associated with PJS.

Damage to normal genes can occur in anyone. However, it generally takes less time to damage one gene than two genes. Therefore, people with PJS are likely to develop cancer at earlier ages than are people born with two normal STK11 genes.

About half of all PJS cases occur because a child inherits a changed gene from a parent with PJS. The other half are due to a mutation in the cell from which the child develops. A person born with one abnormal gene can pass that gene on to the next generation. One out of two of this person’s children will inherit the gene. In addition, if PJS is inherited, each parent or sibling of the affected person has a one out of two chance of carrying the gene.

K E Y T E R M S

Biopsy—The surgical removal and microscopic examination of living tissue for diagnostic purposes.

Colon—The large intestine.

Colonoscopy—Procedure for viewing the large intestine (colon) by inserting an illuminated tube into the rectum and guiding it up the large intestine.

Endoscopy—A slender, tubular optical instrument used as a viewing system for examining an inner part of the body and, with an attached instrument, for biopsy or surgery.

Enteroscopy—A procedure used to examine the small intestine.

Esophagus—The part of the digestive tract which connects the mouth and stomach; the foodpipe.

Gastrointestinal—Concerning the stomach and intestine.

Hamartoma.—An overgrowth of normal tissue.

Hyperpigmentation.—An abnormal condition characterized by an excess of melanin in localized areas of the skin, which produces areas that are much darker than the surrounding unaffected skin.

Laparoscopy—A diagnostic procedure in which a small incision is made in the abdomen and a slender, hollow, lighted instrument is passed through it. The doctor can view the ovaries more closely through the laparoscope, and if necessary, obtain tissue samples for biopsy.

Macule—A flat, discolored spot or patch on the skin.

Mammogram—A procedure in which both breasts are compressed/flattened and exposed to low doses of x rays, in an attempt to visualize the inner breast tissue.

Polyp—A mass of tissue bulging out from the normal surface of a mucous membrane.

Polypectomy—Surgical removal of polyps.

Tumor suppressor gene—Genes involved in controlling normal cell growth and preventing cancer.

Demographics

PJS occurs in about one out of 25,000 people. It affects males and females of all races and ethnic groups. The particular genetic mutation may differ among groups and even among families within a group.

syndrome Jeghers-Peutz

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

911

Peutz-Jeghers syndrome

Signs and symptoms

The first sign of PJS, freckling inside the mouth or in unusual places, generally appears in infants. Polyps usually begin causing symptoms by age 10. Polyps make themselves known in a variety of ways. They can cause abdominal pain or intestinal bleeding. Sometimes the blood loss leads to anemia (a condition where there is a reduction in circulating red blood cells, the amount of hemoglobin, or the volume of packed red cells). Polyps sometimes protrude outside the rectum or obstruct the gastrointestinal tract. Untreated obstructions can be fatal.

Tumors may appear in childhood. Children as young as six may develop a particular kind of ovarian or testicular tumor that causes early puberty. Affected boys sometimes begin to develop breasts. These tumors can be non-cancerous, but they have the potential to become malignant.

A few patients develop malignant tumors in the first decade of life. Other patients have stomach, breast, or cervical cancer before age 30. The specific form of cervical cancer is extremely rare in the general population.

Diagnosis

Because the peculiar freckling seen in PJS is present so early, doctors familiar with the condition may suspect PJS even before other symptoms occur. This is ideal, since early diagnosis greatly improves the prognosis.

Many children or young adults come to medical attention due to the pain, bleeding, or anemia caused by polyps. Doctors can confirm the presence of multiple polyps using a variety of methods. Noninvasive methods include ultrasound and x ray techniques. Invasive methods use a tube and an optical system to conduct an internal inspection of the gastrointestinal tract. These methods include endoscopy, enteroscopy, and colonoscopy, all of which involve entry to the gastrointestinal tract through an existing body orifice. Laparoscopy is another invasive method; it involves entering the gastrointestinal tract through an incision in the abdomen. All invasive methods allow for removal of polyps found during the exam. Once the polyps are removed and examined, their unique structure and large number lead to diagnosis of PJS. The average age at PJS diagnosis is 17.

Freckles and polyps occur in more than 95% of people with PJS. Sometimes, though, the freckles fade before symptoms of polyps appear. It is important to take a medical history in order to determine if freckles were present on the skin earlier in life. The doctor should also examine the lining of the cheeks inside the mouth, where freckles are likely to remain throughout life.

The number and intensity of the freckles do not predict the severity of gastrointestinal symptoms or the risk

of developing cancer. Any patient diagnosed with PJS needs regular cancer screening.

The presence of the rare cervical cancer, ovarian tumor, or testicular tumor associated with PJS leads to diagnosis in some patients.

A family history of PJS is suspicious but not required for diagnosis, since PJS can occur as a new mutation. Once PJS has occurred in a family, parents, siblings, and children of the affected person should seek medical attention.

Genetic testing is available to confirm clinical diagnosis or to determine if a person carries an abnormal STK11 gene. Using a swab, cells are removed from the lining of the cheeks inside the mouth. DNA is extracted and analyzed. The test confirms PJS if analysis reveals an STK11 mutation. However, the test cannot rule out PJS if an STK11 mutation is not found, since some cases are due to other genetic causes.

Prenatal diagnosis of PJS is possible only if the family’s specific STK11 mutation has previously been identified. Prenatal testing is done by amniocentesis or chorionic villus sampling. Amniocentesis involves removal of a small amount of amniotic fluid from the uterus. Chorionic villus sampling involves removal of a small sample of placental tissue. In either case, DNA is extracted from sample cells and analyzed.

Even without genetic testing, diagnosis of PJS is fairly straightforward. Although several other conditions cause multiple intestinal polyps or hyperpigmentation, the distinctive structure of PJS polyps and the unusual location of PJS freckles eliminate other conditions from consideration.

Treatment and management

For people with a family history of PJS, treatment and management of the condition may begin even before diagnosis. If PJS freckles do not appear at birth and if there are no symptoms of polyps, affected families may desire genetic testing for their children.

For most genetic conditions, testing is delayed until children are old enough to understand the disease, its consequences, and the advantages and disadvantages of genetic screening. However, since PJS can affect children under the age of 10, any delay could be risky. Therefore, it is appropriate for families with PJS to consider genetic testing for their children. Children who do carry an STK11 mutation can begin a preventive care program immediately, and children who do not carry an STK11 mutation can avoid unnecessary intervention.

The decision to seek genetic testing requires careful consideration. A positive test for PJS cannot predict the

912

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

precise age of onset, symptoms, severity, or progress of the condition. A genetic counselor can assist interested family members as they confront the medical, social, personal, and economic issues involved in genetic testing.

Parents, siblings, and children of people with STK11 mutations may not wish to undergo genetic testing. In this case, they should have a thorough clinical exam to confirm or rule out PJS. The exam includes a careful inspection for freckles. In addition, people age 10 or older require gastrointestinal screening, abdominal ultrasound, and a blood test for anemia. Males over age 10 should have a testicular exam. Females should have a pelvic exam and ultrasound, pap smear, and breast exam annually, by age 20. Women age 35 or older should have a mammogram.

For people with no family history of PJS, treatment and management usually begin when PJS is diagnosed.

In past generations, polyp complications such as intestinal obstruction or hemorrhage were a frequent cause of death in PJS patients. However, treatment of polyps is now widely available. The doctor performs a polypectomy to remove the polyps. Polypectomy may be done at the same time as endoscopy, enteroscopy, colonoscopy, or laparoscopy. Anesthesia is used to make the patient more comfortable.

To manage polyps and screen for early signs of cancer, all people who have PJS and are age 10 or older need preventive screening on a regular basis. Gastrointestinal screening is the first test, and polypectomy is performed at the same time. Also at age 10, the person begins an annual screening program that includes a blood test for anemia and a testicular exam for boys.

After age 10, gastrointestinal screening with polypectomy is performed every two years.

By age 20, annual screening is expanded to include an abdominal ultrasound for both males and females, as well as a pelvic exam and ultrasound, pap smear, and breast exam for females.

By age 35, a woman with PJS should have her first mammogram; mammograms should be repeated every two years until the woman is 50. At that time, a mammogram should be added to the annual screening program.

Polyps found during preventive screening are immediately treated by polypectomy. Preventive screening may also reveal suspicious growths in the gastrointestinal tract or outside of it. These growths require urgent medical attention, since they may be precancerous or cancerous. Diagnosis may require additional tests or biopsy. Treatment is determined on an individual basis, depending on the patient’s medical condition and the nature of the growth.

Some people with PJS do not care for the appearance of their freckles. Removal of freckles using laser therapy is an available treatment option.

Many people with PJS find the preventive screening program psychologically exhausting, and young children can find it frightening. These individuals often need the ongoing support and understanding of friends, family, and community. Several organizations composed of people with PJS, their family members, and medical professionals offer additional support and information. There is also an on-line support group dedicated to PJS.

People with PJS may find it helpful to consult a genetic counselor. Genetic counselors can provide up-to- date information about PJS research, therapy, and management.

Prognosis

Early detection of PJS is the key to its prognosis. Polyps cause less pain and fewer complications when found and removed early. In addition, the patient can begin a preventive screening program at an early age. This increases the likelihood of finding suspicious growths before they become malignant.

Unless they undergo regular screening, people with PJS have a one in two chance of dying from cancer before the age of 60. Moreover, the average age of cancer death in unscreened people with PJS is 39.

Researchers are actively investigating cancer screening, prevention, and treatment methods. In the meantime, regular preventive screening may reduce the illness and premature death associated with PJS.

Resources

BOOKS

Rimoin, David L., et al., eds. Emery and Rimoin’s Principles and Practice of Medical Genetics. Third Edition. New York: Churchill Livingstone, 1996.

Sybert, Virginia P. Genetic Skin Disorders. New York: Oxford University Press, 1997.

PERIODICALS

Boardman, Lisa A., et al. “Genetic Heterogeneity in PeutzJeghers syndrome.” Human Mutation 16, no. 1 (2000):2330.

Hemminki, Akseli. “The molecular basis and clinical aspects of Peutz-Jeghers syndrome.” Cellular and Molecular Life Sciences 55 (2000):735-750.

Westerman, Anne Marie, et al. “Peutz-Jeghers syndrome: 78year follow-up of the original family.” The Lancet 353 (April 1999):1211-1215.

ORGANIZATIONS

Genetic Alliance. 4301 Connecticut Ave. NW, #404,

Washington, DC 20008-2304. (800) 336-GENE (Help-

syndrome Jeghers-Peutz

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

913

Pfeiffer syndrome

line) or (202) 966-5557. Fax: (888) 394-3937 info @geneticalliance. http://www.geneticalliance.org .

Hereditary Colon Cancer Association (HCCA). 3601 N 4th Ave., Suite 201, Sioux Falls, SD 57104. (800) 264-6783.http://hereditarycc.org .

IMPACC (Intestinal Multiple Polyposis and Colorectal Cancer). PO Box 11, Conyngham, PA 18219. (570) 7881818.

International Peutz-Jeghers Support Group. Johns Hopkins Hospital, Blalock 1008, 600 North Wolfe St., Baltimore, MD 21287-4922.

WEBSITES

Association of Cancer Online Resources: Peutz-Jeghers Syndrome Online Support Group. 2001. http://www

.acor.org .

CancerNet. 2001. http://www.cancernet.nci.nih.gov . GeneClinics. 2001. http://www.geneclinics.org . GeneTests. 2001. http://www.genetests.org .

Network for Peutz-Jeghers and Juvenile Polyposis Syndrome. 2001. http://www.epigenetic.org .

OMIM: Online Mendelian Inheritance in Man. http://www3

.ncbi.nlm.nih.gov/omim .

Avis L. Gibons

I Pfeiffer syndrome

Definition

Pfeiffer syndrome is one of a group of disorders defined by premature closure of the sutures of the skull, resulting in an abnormal skull shape. People affected with these conditions, known as craniosynostosis syndromes, may also have differences in facial structure and hand and foot abnormalities. The defining features of Pfeiffer syndrome are abnormalities of the hands, feet, and shape of the skull.

Description

Pfeiffer syndrome is a complex disorder. Three subtypes of Pfeiffer have been defined based on symptoms. The syndrome is caused by a mutation (alteration) in either of two different genes. As the genes that cause craniosynostosis syndromes were discovered throughout the 1990s, scientists realized that these syndromes have overlapping underlying causes. Crouzon, Apert, Jackson-Weiss, and other syndromes are related to Pfeiffer syndrome by genetic causation as well as associated symptoms. Noack syndrome, once thought to be a separate condition, is now known to be the same as Pfeiffer syndrome. Acrocephalosyndactyly, Type V

(ACS5) and Noack syndrome both refer to Pfeiffer syndrome.

Genetic profile

Pfeiffer syndrome is an autosomal dominant condition. Every person has two copies of every gene, one maternally inherited and one paternally inherited. Autosomal dominant conditions occur if a person has a change in one member of a gene pair. The chance for an affected individual to have an affected child is 50% with each pregnancy.

A person who has an autosomal dominant condition may have it because he or she inherited the altered gene from an affected parent or because of a new mutation. A new mutation occurs when the gene is altered for the first time in that individual. A person with an autosomal dominant condition due to a new mutation is the first person in his or her family to be affected.

Nearly all of the individuals with Pfeiffer syndrome types 2 and 3 described in the medical literature have new mutations. When a person has a new mutation, his or her parents are usually not at risk to have another child with the condition. The milder form, Pfeiffer syndrome type 1, is more likely to be inherited. When the mutation is inherited, the child’s symptoms are often similar to those of the affected parent. Pfeiffer syndrome is fully penetrant. This means that all of the individuals who have the mutated gene associated with the condition are expected to have symptoms. In other words, the mutant gene is always expressed.

The two genes that cause Pfeiffer syndrome are called FGFR1 and FGFR2. FGFR1 is on chromosome 8. FGFR2 is on chromosome 11. These genes are members of a group of genes called the “fibroblast growth factor receptors.”

Fibroblasts play an important role in the development of connective tissue (e.g. skin and bone). Fibroblast growth factors (FGFs) stimulate certain cells to divide, differentiate (specialize to perform a specific function different than the function of the original cell), and migrate. FGFs are important in limb development, wound healing and repair, and other biological processes. FGFs communicate with targeted cells through the action of the fibroblast growth factor receptors. Fibroblast growth factor receptors (FGFRs) on the targeted cells bind the FGFs and relay their message within the cell.

In 1999, 11 conditions were known to be caused by mutations in three of the four FGFR genes. However, only one condition is present in each affected family. Mutations in FGFR2 may cause Pfeiffer syndrome as well as Apert, Jackson-Weiss, and Crouzon syndromes. Nonetheless, a parent with Pfeiffer syndrome is at risk to

914

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

have a child with Pfeiffer but is not at risk to have a child with Crouzon, Apert, or Jackson-Weiss syndromes. Because family members in multiple generations all have the same condition, the condition is said to “breed true” within families. A few exceptions—families with more than one FGFR-associated condition—are reported in the medical literature.

A given genetic condition may be associated with mutations in one particular gene, and mutations in a given gene may cause only one genetic condition. Alternatively, mutations in a gene may be associated with more than one genetic condition, and a particular genetic condition may be caused by any mutation in a number of multiple genes. FGFR2 causing both Pfeiffer and Apert syndromes is an example of the former; FGFR1 and FGFR2 causing Pfeiffer syndrome is an example of the latter. Various mutations of a particular gene are called alleles. Sometimes a gene causes different genetic conditions because each allele leads to a specific set of symptoms.

The exact same mutation in the FGFR2 gene may cause Pfeiffer syndrome in one family and cause a different craniosynostosis syndrome in another family. However, each family continues to have the same symptoms (the conditions breed true in each family). Differing effects of genes are sometimes explained by differing environmental influences and by differing interactions with other genes. However, the diverse effects of the FGFR2 gene probably have a more specific explanation/mechanism. The underlying reasons for these phenomena may be explained when fibroblast growth factors and their receptors are better understood. At that time, criteria defining various craniosynostosis syndromes (e.g. Pfeiffer, Crouzon, and Jackson-Weiss) may be reexamined and revised.

Demographics

The incidence of Pfeiffer syndrome is approximately one in 100,000. The incidence of craniosynostosis is one in 2,000 to one in 2,500, which includes syndromic and nonsyndromic cases. In non-syndromic cases, the craniosynostosis is an isolated finding; no other abnormalities are present. Non-syndromic craniosynostosis is much more common than syndromic craniosynostosis. Usually isolated craniosynostosis is sporadic (not familial).

Signs and symptoms

Individuals with Pfeiffer syndrome have a high forehead, a “tower shaped” skull, and broad, deviated thumbs and great toes. The symptoms of type 1 are milder than those of types 2 and 3. Undergrowth of the midface leads to down-slanting, low-placed, widely spaced eyes; a

K E Y T E R M S

Craniosynostosis—Premature, delayed, or otherwise abnormal closure of the sutures of the skull.

Gene—A building block of inheritance, which contains the instructions for the production of a particular protein, and is made up of a molecular sequence found on a section of DNA. Each gene is found on a precise location on a chromosome.

Suture—“Seam” that joins two surfaces together.

small upper jaw bone; and a low nasal bridge. The larynx (voice organ below the base of the tongue) and the pharynx (tube that connects the larynx to the lungs) may be abnormal. Additional symptoms include a projecting chin, divergent visual axes, abnormalities of the passage between the nose and the pharynx, and hearing loss. Fingers and toes may be short and/or partially grown together. The palate may be especially high, and teeth may be crowded. In type 2, the elbow joint is frozen in place.

The skull is composed of many bones that fuse when the brain has finished growing. If the bones of the skull fuse prematurely (craniosynostosis), the skull continues to grow in an abnormal pattern. The places where the bones of the skull fuse are called sutures.

The suture that fuses prematurely in Pfeiffer syndrome is the coronal suture. This suture separates the frontal bone of the skull from the two middle bones (called the parietal bones). When the coronal suture closes prematurely, upward growth of the skull is increased and growth toward the front and back is decreased. Sometimes the sagittal suture will also be fused prematurely in individuals with Pfeiffer syndrome. This suture separates the right and left sides of the middle of the skull. If both the coronal and sagittal sutures fuse prematurely, the skull develops a somewhat cloverleaf shape. Individuals with Pfeiffer type 2 have cloverleaf skulls more often than individuals with types 1 and 3.

The coronal suture is also fused prematurely in Crouzon, Jackson-Weiss, Apert, and Beare-Stevenson syndromes. The thumbs and big toes are normal in Beare-Stevenson and Crouzon syndromes. Additional associated abnormalities distinguish Apert and JacksonWeiss syndromes.

Serious complications of Pfeiffer syndrome include respiratory problems and hydrocephalus. Hydrocephalus is excessive fluid in the brain, which leads to mental impairment if untreated. Breathing problems may be caused by trachea abnormalities or be related to under-

syndrome Pfeiffer

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

915

Pfeiffer syndrome

growth of the midface. Some individuals may require an incision in the trachea (tracheostomy). Serious complications are more common in Pfeiffer types 2 and 3. Individuals with types 2 and 3 are severely affected, and often do not survive past infancy. Death may result from severe brain abnormalities, breathing problems, prematurity, and surgical complications. Even without accompanying hydrocephalus, developmental delays and mental retardation are common (in types 2 and 3). Lower displacement of the eyes may be so severe that the infant is unable to close his or her eyelids. Individuals with types 2 and 3 may also have seizures. Intellect is usually normal in Pfeiffer type 1.

Diagnosis

The diagnosis of Pfeiffer syndrome is based primarily on clinical findings (symptoms). Although genetic testing is available, the diagnosis is usually made based on physical examination and radiological testing.

Often the doctor can determine which cranial suture closed prematurely by physical examination. For confirmation, an x ray or computerized tomography (CT) scan of the head may be performed. Determining which suture is involved is crucial in making the correct craniosynostosis diagnosis.

Craniosynostosis may be caused by an underlying genetic abnormality, or it may be due to other, nongenetic factors. In Pfeiffer syndrome, the tissue itself is abnormal and causes the suture to fuse prematurely. The doctor will consider nongenetic causes of craniosynostosis. These secondary causes include external forces such as abnormal head positioning (in the uterus or in infancy) and a small brain.

Genetic testing may be useful for prenatal diagnosis, confirmation of the diagnosis, and to provide information to other family members. Mutations are not detected in all individuals with Pfeiffer syndrome. Approximately one-third of affected individuals with Pfeiffer syndrome do not have an identifiable mutation in the FGFR1 or FGFR2 gene. People with Pfeiffer syndrome due to a mutation in the FGFR1 gene may have less severe abnormalities than people who have Pfeiffer due to mutations in the FGFR2 gene.

Prenatal diagnosis is available by chorionic villus sampling (CVS) or amniocentesis if a mutation has been identified in the affected parent. Amniocentesis is performed after the fifteenth week of pregnancy and CVS is usually performed in the tenth and twelfth weeks of pregnancy.

Craniosynostosis may be visible by fetal ultrasound. Conditions caused by mutations in the FGFR genes account for only a small portion of craniosynostosis.

Therefore, assuming that the fetus does not have a family history of one of these conditions, genetic testing for the FGFR genes is unlikely to provide useful additional information.

Treatment and management

Children with Pfeiffer syndrome usually see a team of medical specialists at regular intervals. This team typically includes plastic surgeons, neurosurgeons, orthopedists, ear, nose, and throat doctors (otolaryngologists), dentists, and other specialists. The affected person may see the specialists all at once in a craniofacial clinic at a hospital. Many physical problems must be addressed. Developmental, psychosocial, and financial issues are additional concerns. Unfortunately, treatment is aimed at the symptoms, not the underlying cause. Even if craniosynostosis is discovered prenatally, only the symptoms can be treated.

Multiple surgeries are usually performed to progressively correct the craniosynostosis and to normalize facial appearance. A team of surgeons is often involved, including a neurosurgeon and a specialized plastic surgeon. The timing and order of surgeries vary. Patients with syndromic craniosynostosis often require surgery earlier than patients with nonsyndromic craniosynostosis. The first surgery is usually performed early in the first year of life, even in the first few months.

Additional surgeries may be performed for other physical problems. Limb abnormalities often are not correctable. If the limb malformations do not lead to a loss of function, surgery is usually not required. Fixation of the elbow joints may be partially corrected, or at least altered to enable better functioning.

Hydrocephalus, airway obstruction, hearing loss, incomplete eyelid closure, and spine abnormalities require immediate medical attention.

Prognosis

The prognosis for an individual is based on the symptoms he or she has. Individuals with Pfeiffer syndrome type 1 have a better prognosis than individuals with types 2 or 3. But the designation of type is based on that person’s symptoms.

Although people with Pfeiffer syndrome may not obtain a completely normal appearance, significant improvement is possible. Timing the surgeries correctly is an important factor in whether they are successful and whether repeat surgeries are required.

Although Pfeiffer syndrome is rare, craniosynostosis is relatively common. Multiple agencies and organizations exist to help families face the challenges of having

916

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

a child with craniosynostosis and facial differences. The identification of the FGFR genes that cause Pfeiffer (and other) craniosynostosis syndromes has promoted research into the underlying process that causes Pfeiffer syndrome. It will be another enormous challenge to go from understanding the process to treating the process. But better understanding is a big first step. Also, when the process that causes Pfeiffer and related conditions is better understood, a much clearer knowledge of human development in general will be established.

Resources

BOOKS

Lansdown, Richard. Children in the Hospital, A Guide for

Family and Care Givers. New York: Oxford University Press, Inc., 1996.

PERIODICALS

Marino, Dan. “A New Face for Nicole.” Parents (July 2000): 77–80.

McIntyre, Floyd L. “Craniosynostosis.” American Family Physician (March 1997): 1173–77.

ORGANIZATIONS

AboutFace International. 123 Edwards St., Suite 1003, Toronto, ONT M5G 1E2. Canada (800) 665-FACE. info@aboutfaceinternational.org. http://www.aboutfaceinternational

.org .

American Cleft Palate-Craniofacial Association. 104 South Estes Dr., Suite 204, Chapel Hill, NC 27514. (919) 9939044. Fax: (919) 933-9604. http://www.cleftline.org .

Children’s Craniofacial Association. PO Box 280297, Dallas, TX 75243-4522. (972) 994-9902 or (800) 535-3643. contactcca@ccakids.com. http://www.ccakids.com .

Craniosynostosis and Parents Support, Inc. (CAPS). 1136 Iris Lane, Beaufont, SC 29906. (877) 686-CAPS.http://www.CAPS2000.org .

FACES: The National Craniofacial Association. PO Box 11082, Chattanooga, TN 37401. (423) 266-1632 or (800) 3322373. faces@faces-cranio.org. http://www.faces-cranio

.org/ .

Headlines: the Craniofacial Support Group.http://www.headlines.org.uk .

Let’s Face It. PO Box 29972, Bellingham, WA 98228-1972. (360) 676-7325. letsfaceit@faceit.org. http://www.faceit

.org/letsfaceit .

World Craniofacial Foundation. PO Box 515838, 7777 Forest Lane, Ste C-621, Dallas, TX 75251-5838. (972) 566-6669 or (800) 533-3315. worldcf@worldnet.att.net. http://www

.worldcf.org .

WEBSITES

Craniofacial Anomalies. Fact Sheet. Pediatric Surgery, Columbia University. http://cpmcnet.columbia.edu/dept/ nsg/PNS/Craniofacial.html .

Pfeiffer Syndrome Fact Sheet. FACES.

http://www.faces-cranio.org/ .

OTHER

Our child was just diagnosed with Craniosynostosis—What do we do now? Fact sheet. Craniosynostosis and Parents Support, Inc. http://www.caps2000.org .

My child looks different: a guide for parents. Booklet. Changing Faces. http://www.cfaces.demon.co.uk/ resources.html .

Exploring faces through fiction. Booklet. Changing Faces.

http://www.cfaces.demon.co.uk/resources.html .

Michelle Queneau Bosworth, MS, CGC

I Pharmacogenetics

Definition

Pharmacogenetics is one of the newest subspecialties of genetics that deals with the relationship between inherited genes and the ability of the body to metabolize drugs.

Description

Medicine today relies on the use of therapeutic drugs to treat disease, but one of the longstanding problems has been the documented variation in patient response to drug therapy. The “recommended” dosage is usually established at a level shown to be effective in 50% of a test population, and based on the patient’s initial response, the dosage may be increased, decreased, or discontinued. In rare situations, the patient may experience an adverse reaction to the drug and be shown to have a pharmacogenetic disorder. The unique feature of this group of diseases is that the problem does not occur until after the drug is given, so a person may have a pharmacogenetic defect and never know it if the specific drug required to trigger the reaction is never administered.

Adverse reactions

Consider the case of a 35-year-old male who is scheduled for surgical repair of a hernia. The patient is otherwise in excellent health and has no family history of any serious medical problems. After entering the operating theater, an inhalation anesthetic and/or muscle relaxant is administered to render the patient unconscious. Unexpectedly, there is a significant increase in body temperature, and the patient experiences sustained muscle contraction. If this condition is not reversed promptly, it can lead to death. Anesthesiologists are now very familiar with this type of reaction. It occurs only rarely, but it uniquely identifies the patient as having malignant

Pharmacogenetics

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

917

Pharmacogenetics

hyperthermia, a rare autosomal dominant disorder that affects the body’s ability to respond normally to anesthetics. Once diagnosed with malignant hyperthermia, it is quite easy to avoid future episodes by simply using a different type of anesthetic when surgery is necessary, but it often takes one negative, and potentially life-threat- ening, experience to know the condition exists.

An incident that occurred in the 1950s further shows the diversity of pharmacogenetic disorders. During the Korean War, service personnel were deployed in a region of the world where they were at increased risk for malaria. To reduce the likelihood of acquiring that disease, the antimalarial drug primaquine was administered prophylactically. Shortly thereafter, approximately 10% of the African-American servicemen were diagnosed with acute anemia and a smaller percentage of soldiers of Mediterranean ancestry showed a more severe hemolytic anemia. Investigation revealed that the affected individuals had a mutation in the glucose 6-phosphate dehydrogenase (G6PD) gene. Functional G6PD is important in the maintenance of a balance between oxidized and reduced molecules in the cells, and, under normal circumstances, a mutation that eliminates the normal enzyme function can be compensated for by other cellular processes. However, mutation carriers are compromised when their cells are stressed, such as when the primaquine is administered. The system becomes overloaded, and the result is oxidative damage of the red blood cells and anemia. Clearly, both the medics who administered the primaquine and the men who took the drug were unaware of the potential consequences. Fortunately, once the drug treatment was discontinued, the individuals recovered.

Research efforts

Drugs are essential to modern medical practice, but, as in the cases of malignant hyperthermia and G6PD deficiency, it has become clear that not all individuals respond equally to each drug. Reactions can vary from positive improvement in the quality of life to life threatening episodes. Annually, in the United States, there are over two million reported cases of adverse drug reactions and a further 100,000 deaths per year as a result of drug treatments. The Human Genome Project and other research endeavors are now providing information that is allowing a better understanding of the underlying causes of pharmacogenetic anomalies with the hope that eventually the number of negative episodes can be reduced.

In particular, research on one enzyme family is beginning to revolutionize the concepts of drug therapy. The cytochrome P450 system is a group of related enzymes that are key components in the metabolic conversion of over 50% of all currently used drugs. Studies

involving one member of this family, CYP2D6, have revealed the presence of several polymorphic genetic variations (poor, intermediate, extensive, and ultra) that result in different clinical phenotypes with respect to drug metabolism. For example, a poor metabolizer has difficulty converting the therapeutic drug into a useable form, so the unmodified chemical will accumulate in the body and may cause a toxic overdose. To prevent this from happening, the prescribed dosage of the drug must be reduced.

An ultra metabolizer, on the other hand, shows exceedingly rapid breakdown of the drug to the point that the substance may be destroyed so quickly that therapeutic levels may not be reached, and the patient may therefore never show any benefit from treatment. In these cases, switching to another type of drug that is not associated with CYP2D6 metabolism may prove more beneficial.

The third phenotypic class, the extensive metabolizers, is less extreme than the ultra metabolism category, but nevertheless presents a relatively rapid turnover of drug that may require a higher than normal dosage to maintain a proper level within the cells. And, finally, the intermediate phenotype falls between the poor and extensive categories and gives reasonable metabolism and turnover of the drug. This is the group for whom most “recommended” drug dosages appear to be appropriate.

However, the elucidation of the four different metabolic classes has clearly shown that the usual “one size fits all” recommended drug dose is not appropriate for all individuals. In the future, it will become increasingly necessary to know the patient’s metabolic phenotype with respect to the drug being given to determine the most appropriate regimen of therapy for that individual.

Future applications

At the present time, pharmacogenetics is still in its infancy with its full potential yet to be realized. Based on current studies, it is possible to envision many different applications in the future. In addition to providing patient-specific drug therapies, pharmacogenetics will aid in the clinician’s ability to predict adverse reactions before they occur and identify the potential for drug addiction or overdose. New tests will be developed to monitor the effects of drugs, and new medications will be found that will specifically target a particular genetic abnormality. Increased knowledge in this field should provide a better understanding of the metabolic effects of food additives, work related chemicals, and industrial byproducts. In time, these advances will improve the practice of medicine and become the standard of care.

Constance K. Stein, PhD

918

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

Phenotype see Genotypes and phenotypes

I Phenylketonuria

Definition

Phenylketonuria (PKU) can be defined as a rare metabolic disorder caused by a deficiency in the production of the hepatic (liver) enzyme phenylalanine hydroxylase (PAH). PKU is the most serious form of a class of diseases referred to as “hyperphenylalaninemia,” all of which involve above normal (elevated) levels of phenylalanine in the blood. The primary symptom of untreated PKU, mental retardation, is the result of consuming foods that contain the amino acid phenylalanine, which is toxic to brain tissue.

PKU is an inherited, autosomal recessive disorder. It is the most common genetic disease involving amino acid metabolism. PKU is incurable, but early, effective treatment can prevent the development of serious mental incapacity.

Description

PKU is a disease caused by the liver’s inability to produce a particular type of PAH enzyme. This enzyme converts (metabolizes) the amino acid called phenylalanine into another amino acid, tyrosine. This is the only role of PAH in the body. A lack of PAH results in the build-up of abnormally high phenylalanine concentrations (or levels) in the blood and brain. Above normal levels of phenylalanine are toxic to the cells that make up the nervous system and causes irreversible abnormalities in brain structure and function in PKU patients. Phenylalanine is a type of teratogen. Teratogens are any substance or organism that can cause birth disorders in a developing fetus.

The liver is the body’s chief protein processing center. Proteins are one of the major food nutrients. They are generally very large molecules composed of strings of smaller building blocks or molecules called amino acids. About twenty amino acids exist in nature. The body breaks down proteins from food into individual amino acids and then reassembles them into “human” proteins. Proteins are needed for growth and repair of cells and tissues, and are the key components of enzymes, antibodies, and other essential substances.

PKU and the human nervous system

The extensive network of nerves in the brain and the rest of the nervous system are made up of nerve cells.

Nerve cells have specialized extensions called dendrites and axons. Stimulating a nerve cell triggers nerve impulses, or signals, that speed down the axon. These nerve impulses then stimulate the end of an axon to release chemicals called neurotransmitters that spread out and communicate with the dendrites of neighboring nerve cells.

Many nerve cells have long, wire-like axons that are covered by an insulating layer called the myelin sheath. This covering helps speed nerve impulses along the axon. In untreated PKU patients, abnormally high phenylalanine levels in the blood and brain can produce nerve cells with abnormal axons and dendrites, and cause imperfections in the myelin sheath referred to as hypomyelination and demylenation. This loss of myelin can “short circuit” nerve impulses (messages) and interrupt cell communication. A number of brain scan studies also indicate a degeneration of the white matter in the brains of older patients who have not maintained adequate dietary control.

PKU can also affect the production of one of the major neurotransmitters in the brain, called dopamine. The brain makes dopamine from the amino acid tyrosine. PKU patients who do not consume enough tyrosine in their diet cannot produce sufficient amounts of dopamine. Low dopamine levels in the brain disrupt normal communication between nerve cells, which results in impaired cognitive (mental) function.

Some preliminary research suggests that nerve cells of PKU patients also have difficulty absorbing tyrosine. This abnormality may explain why many PKU patients who receive sufficient dietary tyrosine still experience some form of learning disability.

Behavior and academic performance

IQ (intelligence quotient) tests provide a measure of cognitive function. The IQ of PKU patients is generally lower than the IQ of their healthy peers. Students with PKU often find academic tasks difficult and must struggle harder to succeed than their non-PKU peers. They may require special tutoring and need to repeat some of their courses. Even patients undergoing treatment programs may experience problems with typical academic tasks such as math, reading, and spelling. Visual perception, visual-motor skills, and critical thinking skills can also be affected. Ten years of age seems to be an important milestone for PKU patients. After age 10, variations in a patient’s diet seems to have less influence on their IQ development.

People with PKU tend to avoid contact with others, appear anxious, and show signs of depression. However, some patients may be much more expressive and tend to

Phenylketonuria

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

919

Phenylketonuria

K E Y T E R M S

Amino acid—Organic compounds that form the building blocks of protein. There are 20 types of amino acids (eight are “essential amino acids” which the body cannot make and must therefore be obtained from food).

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

Enzyme—A protein that catalyzes a biochemical reaction or change without changing its own structure or function.

Gene—A building block of inheritance, which contains the instructions for the production of a particular protein, and is made up of a molecular sequence found on a section of DNA. Each gene is found on a precise location on a chromosome.

Genetic disease—A disease that is (partly or completely) the result of the abnormal function or expression of a gene; a disease caused by the inheritance and expression of a genetic mutation.

IQ—Abbreviation for Intelligence Quotient. Compares an individual’s mental age to his/her true or chronological age and multiplies that ratio by 100.

Metabolism—The total combination of all of the chemical processes that occur within cells and tissues of a living body.

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.

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

Nervous system—The complete network of nerves, sense organs, and brain in the body.

Phenylalanine—An essential amino acid that must be obtained from food since the human body cannot manufacture it.

Protein—Important building blocks of the body, composed of amino acids, involved in the formation of body structures and controlling the basic functions of the human body.

Recessive—Genetic trait expressed only when present on both members of a pair of chromosomes, one inherited from each parent.

have hyperactive, talkative, and impulsive personalities. It is also interesting to note that people with PKU are less likely to display such habits as lying, teasing, and active disobedience. It should be emphasized that current research findings are still quite preliminary and more extensive research is needed to clearly show how abnormal phenylalanine levels in the blood and brain might affect behavior and academic performance.

Genetic profile

PKU symptoms are caused by alterations or mutations in the genetic code for the PAH enzyme. Mutations in the PAH gene prevent the liver from producing adequate levels of the PAH enzyme needed to break down phenylalanine. The PAH gene and its PKU mutations are found on chromosome 12 in the human genome. In more detail, PKU mutations can involve many different types of changes, such as deletions and insertions, in the DNA of the gene that codes for the PAH enzyme.

PKU is described as an inherited, autosomal recessive disorder. The term autosomal means that the gene for PKU is not located on either the X or Y sex chromosome. The normal PAH gene is dominant to recessive PKU mutations. A recessive genetic trait, such as PKU, is one that is expressed—or shows up—only when two copies are inherited (one from each parent).

A person with one normal and one PKU gene is called a carrier. A carrier does not display any symptoms of the disease because their liver produces normal quantities of the PAH enzyme. However, PKU carriers can pass the PKU genetic mutation onto their children. Two carrier parents have a 25% chance of producing a baby with PKU symptoms, and a 50% chance having a baby that is a carrier for the disease. Although PKU conforms to these basic genetic patterns of inheritance, the actual expression, or phenotype, of the disease is not strictly an “either/or” situation. This is because there are at least 400 different types of PKU mutations. Although some PKU mutations cause rather mild forms of the disease, others can initiate much more severe symptoms in untreated individuals. The more severe the PKU mutation, the greater the effect on cognitive development and performance (mental ability).

Also, it must be remembered that human cells contain two copies of each type of gene. Different combinations of any two PKU mutations tend to produce a wide spectrum of physiological and psychological symptoms. For example, patients who receive two “severe” PKU mutations from their parents can potentially develop more serious symptoms than people who possess a combination of one severe type and one milder form of mutation. To further complicate the genetic picture of PKU,

920

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