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

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I Paine syndrome

Definition

Paine syndrome is a rare genetic condition that is present at birth. Characterized by an undersized head and related abnormalities in the brain, the disease results in severe mental and physical retardation, movement disorders, and vision problems. Most infants with Paine syndrome do not survive their first year of life.

Description

The cerebellum, which is Latin for “little brain,” is the part of the brain that controls involuntary movements, such as maintaining balance and coordinating muscles during physical activity. When shaking hands, for example, the cerebellum plays a primary role in coordinating the dozens of muscles involved in this seemingly simple task. Paine syndrome, which is named after the American pediatrician who first described the condition in 1960, interferes with the proper growth of the cerebellum and other parts of the brain while the fetus is still in the womb. Though this syndrome is considered a single entity, it actually includes several disorders that emerge together. The result is a variety of debilitating effects.

Children born with Paine syndrome have microcephaly. This neurological disease, which is also associated with conditions other than Paine syndrome, is characterized by an abnormally small head. The head of an infant with microcephaly is smaller than average when compared to other babies of the same age and gender. This decreased skull size is an indication that the brain did not grow properly during fetal development. The form of microcephaly associated with Paine syndrome causes physical and mental retardation. Aside from a small head, infants with Paine syndrome may have undersized bodies. Motor skills, language abilities, and other aspects of normal development are impaired. Babies with Paine syndrome, for example, may require a

feeding tube due to difficulties or trouble swallowing. Unlike most infants, they may seem disinterested in the world around them.

Paine syndrome also produces specific problems related to movement. Infants affected by the disease develop spasticity. This nervous system disorder, in which muscles do not relax properly after being stretched, can cause muscle stiffness, pain, or physical deformity. It can also lead to repetitive spasms by a particular muscle or group of muscles (these spasms are known as myoclonic jerks). Aside from spasticity, an infant with Paine syndrome may experience generalized seizures.

Vision can also be affected, resulting in optic atrophy. This eye disorder causes a degeneration of the nerves carrying information from the eyes to the brain. Optic atrophy can lead to blurry vision or other visual disturbances.

The underlying cause of Paine syndrome, which is sometimes referred to as microcephaly-spastic diplegia syndrome, is unknown. The effects of the disease are thought to stem from the limited growth of the cerebellum and other areas of the brain. Autopsies of affected children have revealed underdevelopment of this region, as well as abnormalities in the cerebrum and other brain structures.

Paine syndrome is considered very similar to another genetic, congenital disease known as Seemanova syndrome. Both diseases have a number of symptoms in common, though Seemanova syndrome lacks certain characteristics of the former (such as an underdeveloped cerebellum). Some doctors view both conditions as variations of a more broadly defined disorder called PaineSeemanova syndrome.

Genetic profile

The gene responsible for Paine syndrome has not been identified, but is believed to lie on the X chromosome. For this reason, the disease is referred to as an X-

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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).

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

Gavage—Feeding tube.

Neurological—Relating to the brain and central nervous system.

linked genetic condition. Only males are affected. Females do not usually develop the symptoms of Paine syndrome but they may be carriers of the gene associated with the disease. This is because women have two X chromosomes, while men only possess one. Even if a woman possesses the gene for Paine syndrome on one of her X chromosomes, she still has a second X chromosome that is free of the faulty gene. This second X chromosome is what protects her from developing symptoms of Paine syndrome, though she may be able to transmit the disease to her children.

Demographics

Paine syndrome is a rare, congenital disease that only affects males. Most children born with it do not survive infancy.

Signs and symptoms

The most visible symptom of Paine syndrome is often the size of the head, which is smaller than normal. Affected infants may experience feeding difficulties or swallowing problems. They may not appear to be growing properly or may seem disinterested in their environment. The development of motor skills and speech is delayed.

In simple terms, Paine syndrome causes structural abnormalities in the cerebellum, cerebrum, and other parts of the brain. The skull itself is abnormally small, due to the fact that its size is dictated by brain growth. Damage to the optic nerve may also occur. In addition, Paine syndrome produces elevated amino acid levels in the urine and cerebrospinal fluid.

Diagnosis

The disease is often diagnosed at birth when the size of the head is measured, though a small head cir-

cumference may be identified later during a routine exam if it is not detected shortly after delivery. Imaging procedures (such as an x ray, CT scan, or MRI) are used to identify the structural abnormalities of the brain and skull. Analyses of blood and urine are also performed. An electroencephalogram (EEG), a noninvasive test that measures the electrical activity of the brain, may be recommended to help assess developmental problems or detect relevant brain or nervous system abnormalities.

Treatment and management

There is no cure for Paine syndrome. The changes in brain structure associated with the disease cannot be reversed. When possible, treatment focuses on alleviating symptoms. Anticonvulsants, for example, can be used to help control seizures; dextroamphetamine may also be prescribed to ease symptoms. In addition to drugs, orthopedic surgery is sometimes necessary. Family education and genetic counseling for parents is also recommended.

Prognosis

Due to its debilitating effects on the brain and nervous system, Paine syndrome is usually fatal within one year after birth.

Resources

BOOKS

Victor, Maurice, et al. Principles of Neurology. 7th ed. New York: McGraw-Hill, 2001.

PERIODICALS

Lubs, H.A., P. Chiurazzi, J.F. Arena, et al. “XLMR genes: Update 1996.” American Journal of Medical Genetics 64 (1996): 147–57.

Opitz, J.M., et al. “International workshop on the fragile X and X-linked mental retardation.” American Journal of

Medical Genetics 17 (1984): 5–94.

Paine, R.S. “Evaluation of familial biochemically determined mental retardation in children, with special reference to aminoaciduria.” New England Journal of Medicine 262 (1960): 658–65.

ORGANIZATIONS

U.S. National Library of Medicine. 8600 Rockville Pike,

Bethesda, MD 20894.

WEBSITES

U.S. National Library of Medicine.http://www.nlm.nih.gov .

Greg Annussek

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I Pallister-Hall syndrome

Definition

Pallister-Hall syndrome is an extremely rare developmental disorder marked by a spectrum of features ranging from mild (extra fingers or toes or a noncancerous malformation in the hypothalamus region of the brain) to severe (laryngotracheal cleft, an opening between the windpipe and voicebox that can be fatal in newborns).

Description

First reported in 1980 by American geneticist Judith G. Hall and American medical doctor Philip D. Pallister, Pallister-Hall syndrome is often diagnosed at birth. Some symptoms are immediately noticeable, including short limbs, extra digits, unusual facial features, or blockage of the anal opening. Some signs, such as mental retardation and abnormalities of the heart, lung, or kidneys, must be diagnosed by a physician.

Newborn infants with Pallister-Hall syndrome must be carefully watched for signs of hypopituitarism (insufficient production of growth hormones by the pituitary gland), which can cause fatal complications if not promptly treated. Similarly, inadequate activity of the adrenal gland can be lethal in newborns. If not immediately recognized, an imperfectly formed anus can also develop serious complications in a newborn. Because of its sometimes-serious consequences, Pallister-Hall syndrome is considered part of the CAVE (cerebro-acro-vis- ceral early lethality) group of disorders.

This syndrome is also known by a variety of alternative names, including congenital hypothalamic hamartoblastoma, hamartopolydactyly syndrome, hypothalamic hamartoblastoma syndrome, Hall syndrome 2, hypothalamic hamartoblastoma-hyperphalangeal hypoendocrinehypoplastic anus (4H) syndrome, hypothalamic hamartoblastoma-hypopituitarism-imperforate anuspostaxial polydactyly syndrome, microphallus-imperfo- rate anus-syndactyly-hamartoblastoma-abnormal lung lobulation-polydactyly (MISHAP) syndrome, and renal- anal-lung-polydactyly-hamartoblastoma (RALPH) syndrome.

Genetic profile

Pallister-Hall syndrome is believed to have autosomal dominant inheritance, meaning that it can occur in either sex, and is passed from generation to generation when an abnormal gene is received from one parent and a normal gene is received from the other. Affected

patients have a 50% chance of passing the disorder to each offspring. In most such cases, signs and symptoms in affected offspring are similar to those of the parents. However, Pallister-Hall syndrome is more commonly found in isolated cases involving individuals with no family history of the disorder. These cases are thought to result from new, random, genetic mutations with no known cause. The gene responsible is GL13 (chromosonal locus 7p13). Because of the rarity of this disorder and the subtlety of its identifying characteristics, the ratio of these random mutation cases to inherited cases is not known.

Demographics

As of early 2001, only about 100 cases of this very rare genetic disorder were known. Males are believed affected by Pallister-Hall syndrome about twice as often as females. The disorder is not limited to particular ethnic groups. Some researchers have proposed that many patients with Pallister-Hall signs and symptoms have been misdiagnosed as having a related genetic disorder, isolated post-axial polydactyly type A (PAP-A). It should be noted that Pallister-Hall has only been known since 1980, and that the syndrome’s full spectrum is still being investigated. As this spectrum expands, greater numbers of milder cases are being uncovered.

Signs and symptoms

This disorder is noted for a wide range of signs and symptoms, including the following:

Abnormalities of the head, neck, and facial areas including short neck, short midface, flat nasal bridge, small tongue, noticeable underdevelopment of one jaw compared to the other, asymmetric skull, cleft palate and other irregularities of the palate, cleft larynx or epiglottis, cysts on the gums, and ears that are small, low-set, and abnormally rotated toward the back of the head.

Hypothalamic hamartoblastoma, a non-cancerous tumor in the hypothalamus. It grows at the same rate as nearby brain tissue, up to 4 cm across, taking the place of the hypothalamus. Most hypothalamic hamartomas have no symptoms, but in some cases they can cause neurological problems including gelastic epilepsy, which causes chest and diaphragm movements similar to those that occur during laughter.

Inhibited flow of cerebrospinal fluid in the brain.

Limb abnormalities including short limbs, extra fingers or toes (central or postaxial polydactyly), webbing of fingers or toes (syndactyly), abnormally small fingernails or toenails, or absent nails.

syndrome Hall-Pallister

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K E Y T E R M S

Adrenal gland—A triangle-shaped endocrine gland, located above each kidney, that synthesizes aldosterone, cortisol, and testosterone from cholesterol. The adrenal glands are responsible for salt and water levels in the body, as well as for protein, fat, and carbohydrate metabolism.

Hypothalamus—A part of the forebrain that controls heartbeat, body temperature, thirst, hunger, body temperature and pressure, blood sugar levels, and other functions.

Pituitary gland—A small gland at the base of the brain responsible for releasing many hormones, including luteinizing hormone (LH) and folliclestimulating hormone (FSH).

Respiratory abnormalities including underdeveloped or abnormally developed lungs

Anus lacking the usual opening

Congenital heart defects

Kidneys with abnormal development or placement

Underdeveloped or abnormally developed adrenal, pituitary, or thyroid glands. This can lead to decreased activity of these glands. Some Pallister-Hall newborns cannot survive due to insufficient activity of the adrenal gland. An underdeveloped pituitary gland can also have lethal consequences. Symptoms of hypopituitarism may include hypoglycemia, jaundice, or unusual drowsiness.

In males, unusually small penis, underdeveloped testicles, or failure of one or both testes to descend normally

Retarded growth in most patients

Mild mental retardation

Spinal abnormalities

Dislocated hips

Signs of puberty may appear unusually early

Diagnosis

Both clinical examination and family history are used to diagnose Pallister-Hall syndrome.

The hallmark clinical findings are hypothalamic hamartoma (a non-cancerous tumor in the hypothalamus), as well as extra fingers or toes. Another sign useful for diagnostic purposes is bifid epiglottis, a cleft in the thin flap of cartilage behind the base of the tongue. This particular malformation is almost never seen except in cases of Pallister-Hall syndrome. It rarely causes problems.

Prenatal testing may be conducted by ultrasound, however its effectiveness in detecting Pallister-Hall syndrome is not conclusive.

A molecular genetic test exists to scan the coding regions of the GL13 gene for mutations, but as of early 2001 such testing was available only for scientific research purposes.

Treatment and management

Management will depend on the specific signs and symptoms present.

Unless there are unusual complications, hamartoblastomas are usually left in place. However, it is sometimes necessary to surgically remove a hamartoblastoma when it causes undue pressure on the brain (hydrocephalus). Hamartoblastomas are usually monitored throughout the life of the patient. Typically, magnetic resonance imaging (MRI) is used, because hypothalamic hamartomas are sometimes not visible on computerized tomography (CT) scans or cranial ultrasound examinations.

Because of the dangers posed by adrenal insufficiency, Pallister-Hall patients will often be assessed for cortisol deficiency. Cortisol (hydrocortisone) is an important steroid hormone released by the adrenal glands. Patients are also likely to see an endocrinologist to evaluate their growth hormone, luteinizing hormone, follicle-stimulating hormone, and thyroid hormone levels. X rays may be taken of limbs, and the kidneys may be examined by ultrasound. The epiglottis may be examined by laryngoscope, an instrument used to view the larynx through the mouth.

If patients show evidence of aspiration (when breathing forces foreign matter into the lungs) they should be seen immediately by an ear, nose, and throat specialist to determine whether laryngotracheal cleft is present.

Newborns with hypopituitarism should immediately be given hormonal replacement therapy and watched closely for life-threatening complications.

A surgical procedure known as a colostomy may be needed to correct an imperforate anus.

Similarly, extra toes or fingers can be surgically corrected on an elective basis.

Seizures, such as those caused by gelastic epilepsy, may also require symptomatic treatment.

Whenever a new case of Pallister-Hall syndrome is uncovered, it is advisable to also examine the parents and any offspring for the disorder. Evaluation for a parent is likely to include a cranial MRI, x rays of hands and feet, and laryngoscopy.

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At the time of writing in early 2001, the U.S. National Human Genome Research Institute was seeking to recruit between 50 and 100 Pallister-Hall patients for a comprehensive study of the severity, natural history, origins, and other aspects of the syndrome. Researchers there intend to investigate the relationship between Pallister-Hall and some disorders with similar characteristics, including Greig cephalopolysyndactyly syndrome (GCPS), McKusick-Kaufman syndrome

(MKS), Bardet-Biedl syndrome (BBS), and oro-facial digital syndromes (OFDs). No special drugs or other treatments were to be used in this study.

Prognosis

Because of the broad range and severity of PallisterHall signs and symptoms, the prognosis varies widely from case to case.

In families in which multiple cases of Pallister-Hall syndrome exist, the prognosis for any new case is likely to be similar to the existing cases. Mild forms of the syndrome have been identified in a number of large, healthy families believed to have a normal life expectancy.

In cases that occur in isolated individuals, the prognosis is based on the specific abnormalities present. Reviews of these abnormalities as reported in scientific literature have limited usefulness because published cases tend to be more severe than those normally encountered. Unless there are life-threatening malformations such as hypopituitarism, the prognosis for these random cases is considered excellent.

There is a 50% chance that any child of a PallisterHall patient will be affected.

Resources

ORGANIZATIONS

Pallister-Hall Foundation. RFD Box 3000, Fairground Rd., Bradford, VT 05033.

Patient Recruitment and Public Liaison Office Building 61, 10 Cloister Court, Bethesda, Maryland 20892-4754 1 (800) 411-1222.

WEBSITES

Biesecker, Leslie G., MD. “Pallister-Hall Syndrome.” [May 24, 2000]. GeneClinics. University of Washington, Seattle.http://www.geneclinics.org/profiles/phs/details.html .

“Pallister-Hall syndrome.” NORD—National Organization for

Rare Disorders. http://www.stepstn.com/cgi-win/nord

.exe?proc=Redirect&type=rdb_sum&id=1016.htm . “Pallister-Hall syndrome.” United States National Library of

Medicine. http://www.nlm.nih.gov/mesh/jablonski/ syndromes/syndrome521.html .

David L. Helwig

I Pancreatic beta cell agenesis

Definition

Pancreatic beta cell agenesis is a rare disorder in which a child is born with no beta cells—the cells in the pancreas that produce insulin—resulting in diabetes.

Description

Diabetes mellitus is a disease caused by elevated blood sugar and can result in numerous medical problems that can affect the kidney, eyes, cardiovascular system, skin, and joints. There are two common types. Type 1 results from destruction of the insulin-producing cells (beta cells) of the pancreas and usually occurs in children of at least one year of age or young adults. Injected insulin is required to allow glucose (sugar) to enter the body’s cells to be used for energy. Type 2 diabetes occurs mostly in older, often obese, adults and results from the body’s cells’ decreased ability to respond to the insulin the body produces. In contrast to these two types, neonatal diabetes is extremely rare. Neonatal diabetes is usually transient, meaning that it goes away after some time. It appears to be caused by immaturity of the beta cells; babies with this form of the disease usually recover and do not require insulin before about three months of age. Fewer than forty cases of permanent neonatal diabetes had been reported as of 2001. Reported causes of neonatal diabetes have included absence of the whole pancreas, absence of the clusters (called islets) that contain the beta cells, and absence of the beta cells themselves. This last form is known as pancreatic beta cell agenesis.

Only one confirmed case of pancreatic beta cell agenesis has been reported (1994). This was an infant girl who had a low birth weight and showed high glucose (sugar) in her blood during a routine test. She was also pale, with a low body temperature, rapid breathing and low muscle tone. Her health was further complicated by a diagnosis of an additional metabolic disorder, methylmalonic acidemia (MMA). She died at the age of 16 days. An autopsy showed that her pancreas had islets, which are the bundles of cells containing insulin-produc- ing cells as well as cells that produce other hormones. However, the islets did not contain insulin-producing cells.

Genetic profile

Pancreatic beta cell agenesis may be an autosomal recessive disorder. This means that a child would have to inherit two abnormal copies of a specific gene, one from each parent, in order to have the disorder. The infant

agenesis cell beta Pancreatic

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K E Y T E R M S

Agenesis—Failure of an organ, tissue, or cell to develop or grow.

Beta cells—Specialized cells of the pancreas that make insulin.

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

Insulin—A hormone produced by the pancreas that is secreted into the bloodstream and regulates blood sugar levels.

Metabolic disorder—A disorder that affects the metabolism of the body.

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

Pancreas—An organ located in the abdomen that secretes pancreatic juices for digestion and hormones for maintaining blood sugar levels.

described above had both pancreatic beta cell agenesis and MMA, also known to be an autosomal recessive disorder. A gene causing MMA is located on chromosome 6, and studies of this child’s genes and chromosomes showed that she inherited two identical copies of at least part of chromosome 6 from her father, a condition known as paternal uniparental isodisomy, instead of one copy of this region from each parent. The MMA was caused by the inheritance of two identical defective MMA genes from her father and the beta cell agenesis was then believed to have been caused by the inheritance of two abnormal copies of another gene. On other chromosomes, it has been shown that certain genes only work when they come from the mother and others only from the father. Several cases of transient neonatal diabetes have also had two identical copies of paternal chromosome 6 or other abnormalities of chromosome 6. This suggests that there may be a connection between pancreatic beta cell agenesis and transient neonatal diabetes. It is believed that the relevant region of chromosome 6 contains a gene that delays the production of insulin and only works when inherited from the father. As of 2001, there were no reports in the literature describing the status of the beta cells in infants with transient neonatal diabetes. Presumably, this is because a pancreatic biopsy would be required, and this procedure would be too strenuous for a fragile baby.

Demographics

The overall incidence of neonatal, or newborn, diabetes mellitus is approximately one in 400,000 to one in 600,000 live births, and many cases are transient, with the infants requiring insulin for an average of three months. These infants do appear to be at an increased risk of developing type 2 diabetes in young adulthood. As of 2001, fewer than 40 cases of well-documented permanent neonatal diabetes had been reported. Only two infants with neonatal diabetes had been demonstrated (by autopsy) to completely lack the insulin-producing cells in the pancreas at birth. One of these is described above and had both pancreatic beta cell agenesis and another disorder called methylmalonic acidemia. She also had low birth weight, typical of children with neonatal diabetes because of the inability to metabolize glucose. The second child was of normal birth weight, suggesting that she originally had beta cells that were subsequently destroyed, perhaps by an autoimmune process as in type 1 diabetes. Both of these infants died in the newborn period.

Signs and symptoms

Symptoms of neonatal diabetes include lethargy, dehydration, and breathing difficulties. In the laboratory, high levels of glucose (sugar) in the blood and urine are demonstrated. Children with neonatal diabetes, including the child with pancreatic beta cell agenesis, are generally of low birth weight.

Diagnosis

Neonatal diabetes, like other forms of diabetes, is diagnosed by high blood sugar levels. Permanent and transient forms of neonatal diabetes are indistinguishable at initial diagnosis. Determining if the cause of neonatal diabetes is pancreatic beta cell agenesis was done after death in the published cases by studying the pancreas from an autopsy; a pancreatic biopsy would be required to make this diagnosis in a living child.

Treatment and management

Pancreatic beta cell agenesis, like type 1 and some cases of type 2 diabetes mellitus, is treated by insulin injection.

Prognosis

Both children reported to have absence of beta cells were diagnosed on autopsy because they died at birth. The second child’s prognosis was complicated by the fact that she had the additional MMA disorder. It is not

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known as of 2001 if any living children have pancreatic beta cell agenesis.

Resources

PERIODICALS

Abramowics, Marc J., et al. “Isodisomy of Chromosome 6 in a Newborn with Methylmalonic Acidemia and Agenesis of Pancreatic Beta Cells Causing Diabetes Mellitus.” Journal of Clinical Investigation 94 (1994): 418–21.

Blum, D., et al. “Congenital absence of insulin cells in a neonate with diabetes mellitus and mutase-deficient methymalonic acidaemia.” Diabetologia 36 (1993): 352–7.

ORGANIZATIONS

American Diabetes Association. 1701 N. Beauregard St., Alexandria, VA 22311. (703) 549-1500 or (800) 342-2383.http://www.diabetes.org .

Juvenile Diabetes Foundation International (JDF). 120 Wall St., New York, NY 10005. (212) 785-9500 x708 or (800) 5332873. http://www.jdf.org .

Toni I. Pollin, MS, CGC

I Pancreatic cancer

Definition

The pancreas is a gland found in the abdomen behind the stomach. The pancreas secretes juice that breaks down fats and proteins and releases hormones, such as insulin, to control blood sugar levels. Pancreatic cancer is uncontrolled growth of cells of the pancreas. Spreading of cancer from the original site to other areas in the body is known as metastasis. A higher than average number of pancreatic cancer cases occurring in the same family is known as familial pancreatic cancer.

Description

Most pancreatic cancer grows from cells from the exocrine pancreas, the secreting portion of the pancreas. The most common appearance of pancreatic cancer cells is gland-like, which is termed “adenocarcinoma.”

In most cases, it is difficult to determine the cause of the pancreatic cancer. Both environmental as well as genetic risk factors have been suggested for pancreatic cancer. A high fat diet has been linked to increased pancreatic cancer risk whereas diets high in vegetables and fruits seem to lower the risk. Smoking is known to increase the risk of pancreatic cancer. It is estimated that as many as 30% of pancreatic cancer cases are linked to

smoking. Alcohol use and coffee consumption has been linked with increased pancreatic cancer risk, in some studies, but this connection has not been proven. Previous stomach surgery also may increase the risk of pancreatic cancer. Certain occupations such as farming or manufacturing may increase the risk of pancreatic cancer. The relationship of diabetes to pancreatic cancer has been closely studied. It is uncertain whether diabetes is the cause or the symptom of pancreatic cancer. Presence of diabetes; however, may alert health care providers to the presence of pancreatic cancer. Long-term inflammation of the pancreas, chronic pancreatitis, may increase the risk of pancreatic cancer, as well. Genetic risk factors have also been reported.

Genetic profile

Several studies have reported a higher rate of pancreatic cancer in relatives of individuals with the disease. Hereditary causes are estimated to account for about 10% of all pancreatic cancer. Some risk is thought to be due to known hereditary conditions whereas in other cases a known genetic syndrome has not been determined.

Known syndromes

There are several known genetic syndromes that increase the risk of pancreatic cancer. Alterations in the gene, BRCA2, have been clearly linked to increases in breast and ovarian cancer as well as a potential increased pancreatic cancer risk. Hereditary pancreatitis, which is due to alterations in the cationic trypsinogen gene on chromosome 7 at 7q35, causes long-term, recurrent inflammation of the pancreas. Individuals with hereditary pancreatitis are estimated to have a 40% risk of pancreatic cancer by age 70. Changes or “mutations” in the CDKN2A (p16) gene increase risks of melanoma, a type of skin cancer, and, possibly, pancreatic cancer. Hereditary Non-polyposis Colon Cancer (HNPCC) or Lynch syndrome, increases the risk of colon cancer and other cancers including pancreatic cancer, in some families. Peutz-Jeghers, Familial adenomatous polyposis (FAP), and Li-Fraumeni syndromes all cause relatively increased risks of pancreatic cancer in addition to the other symptoms of the disorders. All of these disorders are inherited in an autosomal dominant pattern. With autosomal dominant inheritance, men and women are equally likely to inherit the syndrome and children of affected individuals are at 50% risk of inheriting the gene alteration. Other syndromes, some with different inheritance patterns, may be linked to pancreatic cancer as well. Genetic testing is available for many of these known syndromes but, due to the complexity of the disorders, genetic counseling should be considered before testing.

cancer Pancreatic

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K E Y T E R M S

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

BRCA2—Gene, when altered, known to cause increased risks of breast, ovarian and, possibly, pancreatic cancer.

Cationic trypsinogen gene—Gene known to cause hereditary pancreatitis when significantly altered.

CDKN2A or p16—Gene, when altered, known to cause Familial atypical multiple mole melanoma (FAMMM) syndrome and possibly increased pancreatic cancer risk.

Chemotherapy—Treatment of cancer with synthetic drugs that destroy the tumor either by inhibiting the growth of the cancerous cells or by killing the cancer cells.

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

Duct—Tube-like structure that carries secretions from glands.

Duodenum—Portion of the small intestine nearest the stomach; the first of three parts of the small intestine.

Endoscopic retrograde cholangiopancreatography (ERCP)—A method of viewing the pancreas by inserting a thin tube down the throat into the pancreatic and bile ducts, injection of dye and performing x rays.

Exocrine pancreas—The secreting part of the pancreas.

Familial adenomatous polyposis (FAP)—Inherited syndrome causing large numbers of polyps and increased risk of colon cancer and other cancers.

Fine needle aspiration (FNA)—Insertion of a thin needle through the skin to an area of sample tissue.

Hereditary non-polyposis colon cancer (HNPCC)—A genetic syndrome causing increased cancer risks, most notably colon cancer. Also called Lynch syndrome.

Insulin—A hormone produced by the pancreas that is secreted into the bloodstream and regulates blood sugar levels.

Jaundice—Yellowing of the skin or eyes due to excess of bilirubin in the blood.

Li-Fraumeni syndrome—Inherited syndrome known to cause increased risk of different cancers, most notably sarcomas.

Melanoma—Tumor, usually of the skin.

Metastasis—The spreading of cancer from the original site to other locations in the 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.

Palliative—Treatment done for relief of symptoms rather than a cure.

Pancreas—An organ located in the abdomen that secretes pancreatic juices for digestion and hormones for maintaining blood sugar levels.

Pancreatitis—Inflammation of the pancreas.

Peutz-Jeghers syndrome—Inherited syndrome causing polyps of the digestive tract and spots on the mouth as well as increased risk of cancer.

Radiation—High energy rays used in cancer treatment to kill or shrink cancer cells.

Staging—A method of describing the degree and location of cancer.

Whipple procedure—Surgical removal of the pancreas and surrounding areas including a portion of the small intestine, the duodenum.

Familial pancreatic cancer

Some families with increased pancreatic cancer rates do not have a known genetic syndrome as the cause. It is possible that environmental factors or chance could explain some cases of pancreatic cancer in families; however, it is also possible that other as yet unknown genetic causes could explain some cases of familial pancreatic cancer. While genetic testing may not be available in some cases, some families do participate in collections or

“registries” of familial pancreatic cancer cases for research purposes.

Demographics

Pancreatic cancer is the fifth leading cause of cancerrelated death for both men and women in the United States. Pancreatic cancer is more common in industrialized countries, with African Americans in the United States having one of the highest rates. The rate of pan-

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creatic cancer increases with age, with most patients diagnosed between the ages of 60 and 80. Pancreatic cancer is more common in men than in women.

Signs and symptoms

Since the symptoms of pancreatic cancer are not specific to the disease, and typically do not develop until the cancer has progressed, it is difficult to diagnosis pancreatic cancer at an early stage. The symptoms of pancreatic cancer can include:

weight loss

loss of appetite

abdominal or back pain

jaundice (yellow color to skin and eyes)

digestive problems including greasy stool

sudden diabetes

Diagnosis

If pancreatic cancer is suspected, regardless of the cause, a physical exam often is done first and then certain body imaging tests may be recommended. One imaging test that may be done is a computed tomography (CT) scan. This exam creates pictures of the interior of the body from computer-analyzed differences in x rays passing through the body. Evidence of substantial tumors or any metastasis can be detected by CT scanning. Sometimes, CT is used to assist with sampling of tissue, a biopsy. There are different types of biopsies. One type of biopsy is performed by inserting a thin needle through the skin into a suspicious area (called fine needle aspiration or FNA) and a sample of tissue is removed. Once a biopsy is taken, the tissue is examined for evidence of cancer and this typically determines the diagnosis. Ultrasound is another method of viewing internal body structures. In ultrasound, sound waves are passed into the body. Since tissues bounce sound waves differently, a computer is able to develop an image based on the returned sound waves. Ultrasound is generally less expensive and more easily available than CT; however, there are limitations to the use of ultrasound in viewing the pancreas. So, ultrasound may be used in addition to CT. Endoscopic retrograde cholangiopancreatography (ERCP) is a method of viewing the pancreas by inserting a thin tube down the throat, injecting of dye into the pancreatic and bile ducts and then x rays are taken.

Once the tumor and any metastasis has been identified and the biopsy tissue evaluation has been done, the tumor can be “staged.” Staging is a ranking system that provides a method of describing the extent and characteristics of a cancer. There are different staging systems. One simple staging system ranks cancers from 0 to IV

Illustration of invading cancer of the human pancreas. The gallbladder and gallstones at top right of image are green, and the pink c-shaped tube at left and center are the duodenum. (Custom Medical Stock Photo, Inc.)

with IV being the most advanced cancer. Staging can be used to help determine the treatment and prognosis for a given cancer.

Treatment and management

Surgery

While surgery oftens provides the best chance of a cure, frequently, it is not possible due to the spread of cancer. Removal of all or part of the pancreas and other areas such as the duodenum (the first part of the small intestine) is known as the Whipple procedure. Complications of this surgery include infection and bleeding.

Chemotherapy

Cancer-killing medicine, chemotherapy, has been found to increase survival in some patients. This medi-

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cine can be given intravenously or by mouth. Once in the bloodstream, chemotherapy agents reach other parts of the body. There are different chemotherapy agents and the side effects may be different as well. Side effects may include nausea, hair loss, low blood counts, and other effects.

Radiation therapy

Recent improvements in radiation, high-energy rays directed at cancer cells, have made this therapy more effective. Although cures due to radiation therapy are uncommon, relief from pain and increased survival are possible. Side effects of radiation therapy may include skin changes, upset stomach, and other effects.

Palliative treatment

Sometimes, surgery, radiation, or other therapies are done to relieve symptoms rather than cure the cancer. This is known as palliative treatment.

Clinical trials

Involvement in research as part of clinical trials may be offered to certain patients. Although treatments through clinical trials may not be proven, it is an opportunity to potentially benefit from new therapies.

Screening

Screening before cancer development may be considered for patients with a higher risk of the disease either due to a known genetic syndrome or a family history of pancreatic cancer. ERCP and ultrasound has been used for screening purposes; however, the usefulness and costeffectiveness of these tests for screening needs evaluation. Surveillance may be considered for persons with two or more close relatives (first degree relatives) with pancreatic cancer or one close relative (first degree) with

pancreatic cancer at an early age (before age 50) or two or more distant relatives (second degree) with one affected before age 50. Prophylactic pancreatectomy, surgical removal of the pancreas before any cancer development, has been considered in cases with a hereditary risk. The concern with prophylactic pancreatectomy is that there is a risk of serious complications and so the decision must be weighed carefully.

Prognosis

It is difficult to diagnose pancreatic cancer early and so, frequently, the cancer has spread to other locations in the body such as the liver or lymph nodes (part of the immune system). Survival rates five years after pancreatic cancer, in general, have been reported to be between 3% and 25%. Most long-term survivors originally had smaller tumors and no spreading of the cancer. Of course, every case of pancreatic cancer is different and it is difficult to predict the course and survival for each individual patient. The prognosis of individuals with hereditary risk factors is dependent on the syndrome, if any, and the aggressiveness of the particular cancer.

Resources

BOOKS

Flanders, Tamar et al. “Cancers of the Digestive System.” In

Inherited Susceptibility to Cancer: Clinical, Predictive and Ethical Perspectives. Edited by William D. Foulkes and Shirley V. Hodgson, 170–74. Cambridge, UK: Cambridge University Press, 1998.

Redlich, Philip, et al. “Tumors of the Pancreas, Gallbladder and Bile Ducts.” InClinical Oncology. Edited by Raymond E. Lenhard, Jr., et al., 373–94. American Cancer Society, 2001.

ORGANIZATIONS

American Cancer Society. 1599 Clifton Rd. NE, Atlanta, GA 30329. (800) 227-2345. http://www.cancer.org .

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