The Gale Genetic Disorders of encyclopedia vol 1 - part 9 ppt

HSP is “complicated” if other complex problems are present such as seizures, dementia, loss of muscle mass, mental delays, dry and thick skin (ichthyosis), vision problems or loss, and ataxia. Problems with gait may progress over years or decades in uncomplicated HSP. This finding may begin at any age, from early childhood through late adulthood. The problems are usually limited to the lower extremities (legs and feet). Occasionally, urinary bladder distur- bances may develop over time. People with complicated HSP have other associated health problems including mental delays and dementia. Alternate names for HSP include hereditary spastic paraparesis, familial spastic paraplegia, familial spastic paralysis, and Stumpell-Lorrain syndrome. Genetic profile HSP is a genetically diverse group of disorders. It can be inherited in autosomal dominant or autosomal recessive manners; these are further divided into uncom- plicated and complicated groups. An X-linked recessive form also exists for complicated HSP. The genes for HSP are designated “spastic gait” (SPG) genes, and are num- bered 1–13 in order of their discovery. Determination of the exact type of HSP in a family is usually done by a detailed family history, rather than genetic testing. In autosomal recessive HSP, individuals may be car- riers, meaning that they carry a copy of an altered gene. However, carriers often do not usually have symptoms of HSP. Those affected with autosomal recessive HSP have two copies of an altered gene, having inherited one copy from their mother, and the other from their father. Thus, only two carrier parents can have an affected child. For each pregnancy that two carriers have together, there is a 25% chance for them to have an affected child, regardless of the child’s gender. In families with autosomal reces- sive HSP, one would not expect to find other affected family members in past generations. Autosomal recessive uncomplicated HSP is thought to represent about 25% of inherited spastic paraplegia. The SPG5 gene (found on chromosome 8 at 8p11–8q13) and SPG11 gene (on the long arm of chromosome 15 at 15q13–q15) appear to be responsible for this group of HSP. Autosomal recessive complicated HSP has been associated with alterations in the SPG7 gene (on the long arm of chromosome 16 at 16q24.3). Additionally, a gene named the paraplegin gene has been identified at the SPG7 locus. Although its function is not well understood, alterations in this gene appear to be responsible for auto- somal recessive complicated HSP. GALE ENCYCLOPEDIA OF GENETIC DISORDERS 547 Hereditary spastic paraplegia In autosomal dominant HSP, an affected individual has one copy of a genetic alteration that causes HSP. The individual has a 50% chance to pass the alteration on to each of his or her children, regardless of that child’s gen- der. There are often other affected family members in prior generations, and often a parent is affected. As of 2000, seven genes have been attributed to autosomal dominant uncomplicated HSP. The uncompli- cated form comprises about 80% of families with autoso- mal dominant HSP. They are: SPG3 (found on the long arm of chromosome 14 at 14q11–q21), SPG4 or spastin (short arm of chromosome 2 at 2p22), SPG6 (long arm of chromosome 15 at 15q11.1), SPG8 (long arm of chro- mosome 8 at 8q23–q24), SPG10 (long arm of chromo- some 12 at 12q13), SPG12 (long arm of chromosome 12 at 19q13), and SPG13 (long arm of chromosome 2 at 2q24–q34). Of this group, about 45% of families have SPG4 or spastin alterations. Autosomal dominant complicated HSP has been attributed to alterations in the SPG9 gene (on the long arm of chromosome 10 at 10q23.3–q24.2). In X-linked recessive HSP, only males are affected with the condition, because the genetic alterations are found on the X-chromosome. Males have only one X- chromosome, and females have two. Males with an X- linked condition have the genetic alteration on their single X-chromosome, and they develop symptoms of the condition. Females are carriers, and typically do not have symptoms. However, when carrier females have sons, they have a 50% chance of having an affected son. In families with X-linked HSP, males are affected and it is passed through women in the family. X-linked forms of HSP are complicated HSP. The SPG1 gene on the long arm of chromosome X at Xq28 (also known as the L1 cell adhesion molecule) and SPG2 gene on Xq28 (also known as the proteolipid protein) have been associated with this form of HSP. Specifically, proteolipid protein alterations cause a condition known as Pelizaeus-Merzbacher disease. Demographics HSP is relatively rare; through 1996 more than eighty unrelated families had been studied throughout the world. Hereditary spastic paraplegia appears to affect individuals and various age groups around the world. With the exception of X-linked recessive HSP, it affects men and women equally. Signs and symptoms The symptoms of uncomplicated HSP may appear at any age. It may progress very slowly, without any obvi- ous changes to bring symptoms to medical attention, pos- sibly appearing as general “clumsiness.” Individuals with uncomplicated HSP often have no problems with strength in their upper extremities and no problems with speech, chewing, or swallowing. They may notice their leg muscles becoming very stiff, and may stumble when climbing stairs or crossing curbs. These symptoms can progress and worsen with time. Each family with HSP is unique, with varying symp- toms. Additionally, affected individuals within the same family may have varying presentations of the disease. In 1999, a family was reported in which individuals in suc- cessive generations had increasingly severe symptoms of pure HSP, a phenomenon known as “genetic anticipa- tion.” People with pure HSP may experience difficulty walking and often eventually require canes, walkers, or wheelchairs. As a later symptom, people may experience an urgency to urinate, or may have problems with urinary control. Generally, the lower extremities experience increased reflexes, and may become stiff. Individuals with complicated HSP still have spastic paraplegia of the lower extremities as a common finding, but may also experience other associated health prob- lems. These may include seizures, mental delays, vision loss, and loss of muscle mass. Cataracts, gastric reflux, abnormal eye movements, severe general muscle weak- ness, and ataxia can also be present. For some forms of complicated HSP, specific syn- dromes have been identified. Silver syndrome is an auto- somal dominant condition involving progressive spastic paraplegia and loss of muscle mass, particularly in the hands. Pelizaeus-Merzbacher disease is an X-linked recessive form of complicated HSP. It usually develops in infancy or early childhood with abnormal eye move- ments, severe muscle weakness, feeding problems, and developmental delays. These findings can progress to include severe muscle spasticity and ataxia. Diagnosis HSP has classically been diagnosed by a careful physical examination, as well as obtaining a detailed per- sonal and family medical history. Other similar disorders often need to be ruled out before considering HSP. Uncomplicated HSP is diagnosed by four clinical criteria: • Clinical symptoms: Progressive spastic muscle weak- ness of both lower extremities, often with urinary urgency or lower extremity paresthesia. • Neurologic examination: Increased muscle tone/ reflexes at the hamstrings, quadriceps, and ankles; mus- cle weakness at hamstrings and lower limbs; decreased ability to sense vibrations in the lower limbs; abnormal gait with an uneven drop of the foot. (Mental delays or dementia are not expected in pure HSP.) • Family history: Similar to an autosomal dominant pat- tern (several affected family members in different gen- erations), autosomal recessive pattern (siblings may be affected but little or no history of affected family mem- bers in prior generations), or X-linked recessive pattern (primarily affected males who are related to each other through their mothers). • Exclusion of other conditions. 548 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Hereditary spastic paraplegia KEY TERMS Amniocentesis—A procedure performed at 16-18 weeks of pregnancy in which a needle is inserted through a woman’s abdomen into her uterus to draw out a small sample of the amniotic fluid from around the baby. Either the fluid itself or cells from the fluid can be used for a variety of tests to obtain information about genetic disorders and other medical conditions in the fetus. Ataxia—A deficiency of muscular coordination, especially when voluntary movements are attempted, such as grasping or walking. Chorionic villus sampling (CVS)—A procedure used for prenatal diagnosis at 10-12 weeks gesta- tion. Under ultrasound guidance a needle is inserted either through the mother’s vagina or abdominal wall and a sample of cells is collected from around the fetus. These cells are then tested for chromosome abnormalities or other genetic diseases. Dementia—A condition of deteriorated mental ability characterized by a marked decline of intel- lect and often by emotional apathy. Gait—A manner of walking. Magnetic resonance imaging (MRI)—A technique that employs magnetic fields and radio waves to create detailed images of internal body structures and organs, including the brain. Paraplegia—Loss of voluntary movement and sen- sation of both lower extremities. Paresthesia—An abnormal sensation resembling burning, pricking, tickling, or tingling. Spasticity—Increased mucle tone, or stiffness, which leads to uncontrolled, awkward move- ments. Magnetic resonance imaging (MRI) of the brain and spinal cord are usually normal in people with uncompli- cated HSP. It is a difficult task to eliminate other neuro- logic disorders with symptoms similar to HSP, such as structural abnormalities of the brain or spinal cord. Multiple sclerosis often includes gait incoordination, but it does not always progress or worsen with time. Some other genetic conditions involving muscle weakness include various forms of leukodystrophy; however, these neurological problems may progress rapidly, and may even result in death. Some infectious diseases may in some ways mimic HSP, such as AIDS or syphilis. Genetic testing for some forms of both pure and complicated HSP is available on a research basis. In these cases, testing is usually performed on a blood sample, and the genes are analyzed. Because the testing is con- sidered experimental research, testing may be cost-free but results may not always be available to the family. For Pelizaeus-Merzbacher disease, genetic testing is available on a clinical basis at a limited number of labo- ratories, and families receive their results. In this case, results would be considered abnormal if alterations in the proteolipid gene were identified. Because Pelizaeus- Merzbacher disease is an X-linked recessive disorder, any male with the alteration would always have carrier daughters and unaffected sons. The affected person’s mother would then be a carrier, and risks to her family members could be predicted by the same form of testing. An exception to this would be in the case of some moth- ers of boys with PLP mutations who are not carriers because their sons have new mutations. Prenatal testing for Pelizaeus-Merzbacher disease can be performed on DNA extracted from fetal cells obtained through amniocentesis or chorionic villus sam- pling (CVS). Treatment and management There is no specific treatment to prevent, slow, or reverse the progressive symptoms in HSP. Some treat- ment approaches for other patients with paraplegia have been useful. This includes oral and muscle injections of a medication known as Baclofen, which can be used in early stages of muscle weakness. A medication known as Oxybutynin has been helpful for the urinary distur- bances. Physical therapy and exercise are considered important elements in maintaining muscle strength and range of motion. However, it is still unclear whether physical therapy promotes muscle improvement or reduces the rate of muscle weakness and decline. Prognosis Complicated HSP may be associated with a short- ened lifespan, because involvement of other health prob- lems can worsen an individual’s prognosis. For example, in Pelizaeus-Merzbacher disease, lifespan is shortened because the associated severe muscle weakness and feed- ing problems for a young child may lead to early death. Though it is usually very physically disabling, uncompli- cated or pure HSP does not typically shorten lifespan. Resources PERIODICALS Fink, J.K., et al. “Hereditary Spastic Paraplegia: Advances in Genetic Research.” Neurology 46 (1996): 1507–14. ORGANIZATIONS HSPinfo.org. 2107 Worchester Drive, Salt Lake City, UT 84121. Phone: (801) 944-6295. Fax: (801) 328-7348. info@hspinfo.org. Ͻhttp://www.hspinfo.orgϾ. National Ataxia Foundation. 2600 Fernbrook Lane, Suite 119, Minneapolis, MN 55447. Phone: (763) 553-0020. Fax: (763) 553-0167. naf@mr.net. Ͻhttp://www.ataxia.orgϾ. National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (800) 999-6673 or (203) 746-6518. Fax: (203) 746-6481. Ͻhttp://www .rarediseases.orgϾ. WEBSITES The Familial Spastic Paraplegia Support Group (England). Ͻhttp://www.fspgroup.org/Ͼ. Fink, John K. “Hereditary Spastic Paraplegia Overview.” GeneClinics. Ͻhttp://www.geneclinics.org/profiles/hsp/ details.htmlϾ. (August 11, 2000). HealthLINK. Ͻhttp://www.healthlink.mcw.edu/article/921730935.htmlϾ. Hereditary Spastic Paraplegia Home Page. Ͻhttp://www.med.umich.edu/hsp/Ͼ. NINDS Hereditary Spastic Paraplegia Information Page. Ͻhttp://www.ninds.nih.gov/health_and_medical/disorders/ hereditarysp.htmϾ. Deepti Babu, MS I Hermansky-Pudlak syndrome Definition Hermansky-Pudlak syndrome (HPS) is a rare inher- ited disorder of melanin production. Melanin is the pig- ment that gives color to the skin, hair, and eyes. A lack or decrease of pigment in the skin and eyes is called oculo- cutaneous albinism. HPS is a specific type of oculocuta- neous albinism that also includes a bleeding tendency GALE ENCYCLOPEDIA OF GENETIC DISORDERS 549 Hermansky-Pudlak syndrome and have typical skin pigmentation. However, each time they have a child, the chance for the child to have HPS is 25%, or 1 in 4. Unless someone in the family has HPS, most couples are unaware of their risk. Researchers mapped the HPS1 gene to the long arm of chromosome 10 in 1995, and later identified its exact location in 1996. The protein produced by the HPS gene helps organelles (specialized parts) of the cell’s cyto- plasm (portion of the cell between the membrane and nucleus) to develop and function normally. In 1999, another group of researchers identified a mutation, or gene change, in the AP3B1 gene located on chromosome 5 as another cause of HPS. This gene makes AP3, a molecule that helps to sort proteins within the body’s cells. Demographics In northwest Puerto Rico, HPS is a common inher- ited disorder. More than 300 persons are affected. The carrier rate is about one in 21. Intermarriage accounts for the high frequency. Researchers have traced the origin of HPS to southern Spain. Cases have also been reported in the Dutch, Swiss, and Japanese. Both sexes are equally affected. However, females will have more lung symp- toms than males. Signs and symptoms People with HPS have a broad range of skin color from tan to white, reflecting the partial absence of pig- mentation. Hair color ranges from brown to white, also reflecting how much pigmentation is present. Poor vision and eye abnormalities are common in people with HPS. Visual acuity can approach 20/200. Nystagmus, an irregular rapid back and forth movement of the eyes, is also common. The eyes can have an improper muscle balance called strabismus. Sensitivity to bright light and glare, known as photophobia, is a fre- quent complaint of people with HPS. These visual prob- lems all result from abnormal development of the eye due to the lack of pigment. Just as skin and hair color vary, so will eye color. Red, brown, hazel, and violet eyes have been reported. A bleeding tendency distinguishes HPS from other types of albinism. People with HPS will bruise easily and bleed for an extended time after dental extractions and surgical procedures. Platelets are the disc-shaped struc- tures in the blood that cause clotting. In people with HPS, the platelets are missing certain internal components that cause them to clump together during the clotting process. The third finding of HPS is the accumulation of ceroid in certain cells of the body such as bone marrow 550 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Hermansky-Pudlak syndrome KEY TERMS Bioptics—Glasses that have small telescopes fitted in the lens. Ceroid—The byproduct of cell membrane break- down. Colitis—Inflammation of the colon. Cytoplasm—The substance within a cell including the organelles and the fluid surrounding the nucleus. Diarrhea—Loose, watery stool. Melanin—Pigments normally produced by the body that give color to the skin and hair. 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. Nystagmus—Involuntary, rhythmic movement of the eye. Oculocutaneous albinism—Inherited loss of pig- ment in the skin, eyes, and hair. Organelle—Small, sub-cellular structures that carry out different functions necessary for cellular survival and proper cellular functioning. Photophobia—An extreme sensitivity to light. Sputum—A mixture of saliva and mucus from the lungs. Strabismus—An improper muscle balance of the ocular muscles resulting in crossed or divergent eyes. and the storage of ceroid, the byproduct of cell mem- brane breakdown, in the body’s cells. Description In 1959, Drs. F. Hermansky and P. Pudlak reported two unrelated people with oculocutaneous albinism who had lifelong bleeding problems. The female died at age 33, and at that time large amounts of pigment were dis- covered in the walls of her small blood vessels. Genetic profile HPS is an autosomal recessive disorder. This means that the disease manifests itself when a person has inher- ited one nonworking copy of the HPS gene from each parent. Parents who carry the gene for HPS are healthy and the lung. As ceroid collects in the lungs, it makes the affected individual prone to respiratory infections and progressive lung disease that restricts breathing. Some people also complain of colitis (an inflammation of the colon) and diarrhea (loose, watery stools). Diagnosis Diagnosis of HPS can be made by specialized platelet testing and molecular testing for the known gene mutations. Very few laboratories are equipped to perform these tests. A person who is suspected to have HPS should consult with a geneticist or genetic counselor to arrange for the appropriate tests. Molecular testing is available for Puerto Rican families who usually have a specific detectable gene alteration, which is a duplication of a small segment of the gene. Analysis of the person’s platelets will determine if they are lacking the critical internal parts, called dense bodies, that help to clot blood. If dense bodies are not present, then HPS is the diagnosis. For affected people of Puerto Rican ancestry, one unique gene mutation is present. Several other muta- tions can also be detected, but the lack of a gene mutation does not mean a person does not have HPS, since all mutations have not been identified. For some families with an affected child, prenatal diagnosis may be possible for future pregnancies. Parents should consult with a genetics specialist when planning a pregnancy. Treatment and management For the individual with HPS, vision problems are always present. Many people will meet the legal defini- tion of blindness, but still have enough vision for reading and other activities. Other affected people may be far- sighted or near-sighted. An ophthalmologist, a specialist for the eyes, will help those individuals who have strabismus, a muscle imbalance in the eyes. They can have corrective surgery that will not only improve their physical appearance but also expand their visual field. Surgery, however, cannot restore pigment to the eyes nor correct the optic nerve pathways leading from the brain to the eyes. Many optical aids can help a person with HPS func- tion better in daily life. Aids like hand-held magnifiers, strong reading glasses, and glasses that have small tele- scopes fitted in the lens called bioptics can make hobbies, jobs, and other activities easier. Protection from excessive sunlight is crucial for peo- ple with HPS. Sunscreens of the highest rating should be used to decrease the chance for fatal skin cancers. By wearing clothing that blocks as much sunlight as possi- ble, people with HPS can enjoy outdoor activities. A der- matologist, a specialist in skin disorders, can examine the affected person if any changes in skin color or appear- ance occur. Annual skin check-ups are important. As people with HPS reach their 30s, they begin to have lung disease. The first sign is difficulty in breathing, followed by a cough that does not bring up sputum, a mixture of saliva and mucus, from the lungs. Gradually, the lungs develop a tough, fibrous tissue that further lim- its breathing. The inability to breathe is the most com- mon cause of death for people with HPS. Prolonged bleeding after tooth extraction, nosebleed, or surgery occurs regularly in people with HPS. Before any surgery, treatment with desmopressin, a drug that stimulates clotting activity, can be effective. Also, indi- viduals with HPS should avoid aspirin, because it makes blood less likely to clot. Prognosis Many people with HPS may have concerns about their physical appearance and decreased vision. Education about the disorder is important to prevent iso- lation and stigmatization. Once the visual difficulties are addressed, people with albinism can participate in most activities. Although many preventive efforts can improve the quality of life for a person with HPS, the progressive lung disease cannot be halted. The inability to breathe gener- ally becomes fatal when the affected person is 40–50 years old. Resources BOOKS Kanski, Jack J. Clinical Ophthalmology: A Systematic Approach. Woburn, MA: Butterworth-Heinemann Medical, 1999. Landau, Elaine. Living with Albinism (First Book). New York, NY: Franklin Watts, 1998. PERIODICALS Dell’Angelica, E.C., et al. “Altered Trafficking of Lysosomal Proteins in Hermansky-Pudlak Syndrome Due to Mutations in the Beta-3A Subunit of the AP-3 Adaptor.” Molec. Cell 3 (1999): 11-21. Depinho, R.A., and K.L. Kaplan. “The Hermansky-Pudlak Syndrome, Report of Three Cases and Review of Pathophysiology and Management Considerations.” Medicine 64 (1985): 192-202. Gahl, W.A., et al. “Genetic Defects and Clinical Characteristics of Patients with a Form of Oculocutaneous Albinism (Hermansky-Pudlak Syndrome).” New England Journal of Medicine 338 (1998): 1258-1264. GALE ENCYCLOPEDIA OF GENETIC DISORDERS 551 Hermansky-Pudlak syndrome Sandberg-Gertzen, H., R. Eid, and G. Jarnerot. “Hermansky- Pudlak Syndrome with Colitis and Pulmonary Fibrosis.” Scandinavian Journal of Gastroentology 34 (1999): 1055- 1056. Wijermans, P. W., and D. B. van Dorp. “Hermansky-Pudlak Syndrome, Correction of Bleeding Time by 1-Desamino- 8D-Arginine Vasopressin.” American Journal of Hematology 30 (1989): 154-157. Wildenberg, S. C., W. S. Oetting, and C. Almodovar. “Gene Causing Hermansky-Pudlak Syndrome in a Puerto Rican Population Maps to Chromosome 10q2.” Human Genetics 57 (1995): 755-765. ORGANIZATIONS Hermansky-Pudlak Syndrome Network. 39 Riveria Court, Malverne, NY 11565-1602. (800) 789-9477 or (516) 599- 2077. Ͻhttp://www.medhelp.org/web/hpsn.htmϾ. National Organization for Albinism and Hypopigmentation. 1530 Locust St. #29, Philadelphia, PA 19102-4415. (215) 545-2322 or (800) 473-2310. Ͻhttp://www.albinism.org/ infobulletins/hermansky-pudlak-syndrome.htmlϾ. WEBSITES FriendshipCenter.com. Ͻhttp://www.friendshipcenter.comϾ. NORD—National Organization for Rare Disorders. Ͻhttp://www.rarediseases.orgϾ. Suzanne M. Carter, MS, CGC I Hermaphroditism Definition Hermaphroditism is a rare condition in which ovar- ian and testicular tissue exist in the same person. The tes- ticular tissue contains seminiferous tubules or spermatozoa. The ovarian tissue contains follicles or cor- pora albicantia. The condition is the result of a chromo- some anomaly. Description Among human beings, hermaphroditism is an extremely rare anomaly in which gonads for both sexes are present. External genitalia may show traits of both sexes, and in which the chromosomes show male- female mosaicism (where one individual possesses both the male XY and female XX chromosome pairs). There are two different variants of hermaphroditism: true her- maphroditism and pseudohermaphroditism. There are female and male pseudohermaphrodites. True hermaph- roditism refers to the presence of both testicular and ovarian tissue in the same individual. The external geni- talia in these individuals may range from normal male to normal female. However, most phenotypic males have hypospadias. Pseudohermaphroditism refers to gonadal dysgenesis. Genetic profile The most common karyotype for a true hermaphro- dite is 46XX. DNA from the Y chromosome is translo- cated to one of the X-chromosomes. The karyotype for male pseudohermaphrodites is 46XY. Female pseudoher- maphroditism is more complicated. The condition is caused by deficiencies in the activity of enzymes. The genetic basis for three enzyme deficiencies have been identified. Deficiency of 3B hydroxysteroid dehydroge- nase—Type 2 is due to an abnormality on chromosome 1p13.1. Deficiency of 21-Hydroxylase is due to an abnor- mality on chromosome 6p21.3. Deficiency of 11B- Hydroxylase—Type 1 is due to an abnormality on chromosome 8q21. Demographics True hermaphrodites are extremely rare. Approximately 500 individuals have been identified in the world to date. Because of the ambiguity of genitalia and difficulties in making an accurate diagnosis, the inci- dence of pseudohermaphroditism is not well established. The incidence of male pseudohermaphroditism has been estimated at between 3 and 15 per 100,000 people. The incidence of female pseudohermaphroditism has been estimated at between 1 and 8 per 100,000 people. 552 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Hermaphroditism KEY TERMS Corpora albicantia—Plural of corpus albicans. A corpus albicans is the scar tissue that remains on an ovarian follicle after ovulation. Dysgenesis—Defective or abnormal formation of an organ or part usually occuring during embry- onic development. Follicle—A pouch-like depression. Mosaicism—A genetic condition resulting from a mutation, crossing over, or nondisjunction of chro- mosomes during cell division, causing a variation in the number of chromosomes in the cells. Semineferous tubules—Long, threadlike tubes that are packed in areolar tissue in the lobes of the testes. Spermatozoa—Mature male germ cells that develop in the seminiferous tubules of the testes. Signs and symptoms True hermaphroditism is characterized by ambigu- ous internal and external genitalia. On internal examina- tion (most often using laparoscopy), there is microscopic evidence of both ovaries and testes. Male pseudoher- maphroditism is also characterized by ambiguous inter- nal and external genitalia. However, gonads are often (but not always) recognizable as testes. These are frequently softer than normal. An affected person is often incom- pletely masculinized. Female pseudohermaphroditism is characterized by female internal genitals. External geni- tals tend to appear as masculine. This is most commonly characterized by clitoral hypertrophy. Most hermaphro- dites are infertile although a small number of pregnancies have been reported. Diagnosis True hermaphroditism is often diagnosed after laparoscopic investigation. An initial suspicion of male pseudohermaphroditism is often made by inspection of external genitals. This is confirmed by chromosomal analysis and assays of hormones such as testosterone. Initial suspicion of female pseudohermaphroditism is also made by inspection of external genitals. This is con- firmed by analysis of chromosomes and hormonal assay. Laparoscopic examination usually reveals nearly normal female internal genitals. Treatment and management Early assignment of gender is important for the emo- tional well being of any person with ambiguous genitalia. A decision to select a gender of rearing is based on the corrective potential of the ambiguous genitalia, rather than using chromosome analysis. Once the decision is made regarding gender, there should be no question in the family’s mind regarding the gender of the child from that point on. Corrective surgery is used to reconstruct the external genitalia. In general, it is easier to reconstruct female genitalia than male genitalia, and the ease of reconstruc- tion will play a role in selecting the gender of rearing. Treating professionals must be alert for stress in persons with any form of hermaphroditism and their families. Prognosis With appropriate corrective surgery, the appearance of external genitalia may appear normal. However, other problems such as virilization may appear later in life. As of 2001, there is some interest among persons with ambiguous genitalia at birth to reverse their gender of rearing. Resources BOOKS Rappaport, Robert. “Female Pseudohermaphroditism.” In Nelson Textbook of Pediatrics. Edited by Richard E. Behrman et al. 16th ed. Philadelphia, W.B. Saunders, 2000, p. 1760. Rappaport, Robert. “Male Pseudohermaphroditism.” In Nelson Textbook of Pediatrics, edited by Richard E. Behrman et al. 16th ed. Philadelphia, W.B. Saunders, 2000, pp. 1761- 1764. Rappaport, Robert. “True Hermaphroditism.” In Nelson Textbook of Pediatrics, edited by Richard E. Behrman et al. 16th ed. Philadelphia, PA: W.B. Saunders, 2000, pp. 1765-1766. Wilson, Jean D., and James E. Griffin. “Disorders of Sexual Differentiation.” In Harrison’s Principles of Internal Medicine. Edited by Anthony S. Fauci, et al. 14th ed. New York: McGraw-Hill, 1998, pp. 2119-2131. PERIODICALS Denes F. T., B.B. Mendonca, and S. Arap. “Laparoscopic Management of Intersexual States.” Urology Clinics of North America 28, no. 1 (2001): 31-42. Krstic Z. D., et al. “True Hermaphroditism: 10 Years’ Experience.” Pediatric Surgery International 16, no. 8 (2000): 580-583. Wiersma, R. “Management of the African Child With True Hermaphroditism.” Journal of Pediatric Surgery 36, no. 2 (2001): 397-399. Zuker, K. J. “Intersexuality and Gender Identity Differenti- ation.” Annual Review of Sexual Research 10 (1999): 1-69. ORGANIZATIONS Genetic Alliance. 4301 Connecticut Ave. NW, #404, Washing- ton, DC 20008-2304. (800) 336-GENE (Helpline) or (202) 966-5557. Fax: (888) 394-3937. info@geneticalliance. Ͻhttp://www.geneticalliance.orgϾ. Hermaphrodite Education and Listening Post. PO Box 26292, Jacksonville, NY 32226. help@jaxnet.com. Ͻhttp://users .southeast.net/~help/Ͼ. Intersex Society of North America. PO Box 301, Petaluma, CA 94953-0301. Ͻhttp://www.isna.orgϾ. March of Dimes Birth Defects Foundation. 1275 Mamaro- neck Ave., White Plains, NY 10605. (888) 663-4637. resourcecenter@modimes.org. Ͻhttp://www.modimes.orgϾ. WEBSITES Born True Hermaphrodite Ͻhttp://www.angelfire.com/ca2/BornHermaphrodite/Ͼ. Columbia Electronic Encyclopedia. Ͻhttp://www.infoplease.com/ce6/sci/A0823491.htmlϾ. Hermaphrodite Education and Listening Post. Ͻhttp://www.jax-inter.net/~help/Ͼ. Loyola University Stritch School of Medicine. Ͻhttp://matweb.hcuge.ch/matweb/Selected_images/ Developmental_genetic_diseases/hermaphroditism.htmϾ. National Library of Medicine. Ͻhttp://medlineplus.adam.com/ency/article/001669.htmϾ. UK Intersex Association. Ͻhttp://www.ukia.co.uk/Ͼ. L. Fleming Fallon, Jr., MD, DrPH GALE ENCYCLOPEDIA OF GENETIC DISORDERS 553 Hermaphroditism High density hypoprotein deficiency see Tangier disease I Hirschsprung’s disease Definition Hirschsprung’s disease, also known as congenital megacolon or aganglionic megacolon, is an abnormality in which certain nerve fibers are absent in segments of the bowel, resulting in severe bowel obstruction. Description Hirschsprung’s disease is caused when certain nerve cells (called parasympathetic ganglion cells) in the wall of the large intestine (colon) do not develop before birth. Without these nerves, the affected segment of the colon lacks the ability to relax and move bowel contents along. This causes a constriction and as a result, the bowel above the constricted area dilates due to stool becoming trapped, producing megacolon (dilation of the colon). The disease can affect varying lengths of bowel segment, most often involving the region around the rectum. In up to 10% of children, however, the entire colon and part of the small intestine are involved. Genetic profile Hirschsprung’s disease occurs early in fetal develop- ment when, for unknown reasons, there is either failure of nerve cell development, failure of nerve cell migration, or arrest in nerve cell development in a segment of bowel. The absence of these nerve fibers, which help control the movement of bowel contents, is what results in intestinal obstruction accompanied by other symptoms. There is a genetic basis to Hirschsprung’s disease, and it is believed that it may be caused by different genetic factors in different subsets of families. Proof that genetic factors contribute to Hirschsprung’s disease is that it is known to run in families, and it has been seen in association with some chromosome abnormalities. For example, about 10% of children with the disease have Down syndrome (the most common chromosome abnormality). Molecular diagnostic techniques have identified many genes that cause susceptibility to Hirschsprung’s disease. As of 200l, there are a total of six genes: the RET gene, the glial cell line-derived neu- rotrophic factor gene, the endothelin-B receptor gene, endothelin converting enzyme, the endothelin-3 gene, and the Sry-related transcription factor SOX10. Mutations that inactivate the RET gene are the most fre- quent, occurring in 50% of familial cases (cases which run in families) and 15-20% of sporadic (non-familial) cases. Mutations in these genes do not cause the disease, but they make the chance of developing it more likely. Mutations in other genes or environmental factors are required to develop the disease, and these other factors are not understood. For persons with a ganglion growth beyond the sig- moid segment of the colon, the inheritance pattern is autosomal dominant with reduced penetrance (risk closer to 50%). For persons with smaller segments involved, the inheritance pattern is multifactorial (caused by an inter- action of more than one gene and environmental factors, risk lower than 50%) or autosomal recessive (one disease gene inherited from each parent, risk closer to 25%) with low penetrance. Demographics Hirschsprung’s disease occurs once in every 5,000 live births, and it is about four times more common in males than females. Between 4% and 50% of siblings are also afflicted. The wide range for recurrence is due to the fact that the recurrence risk depends on the gender of the affected individual in the family (i.e., if a female is affected, the recurrence risk is higher) and the length of the aganglionic segment of the colon (i.e., the longer the segment that is affected, the higher the recurrence risk). Signs and symptoms The initial symptom is usually severe, continuous constipation. A newborn may fail to pass meconium (the first stool) within 24 hours of birth, may repeatedly vomit yellow or green colored bile and may have a distended (swollen, uncomfortable) abdomen. Occasionally, infants may have only mild or intermittent constipation, often with diarrhea. While two-thirds of cases are diagnosed in the first three months of life, Hirschsprung’s disease may also be diagnosed later in infancy or childhood. Occasionally, even adults are diagnosed with a variation of the disease. In older infants, symptoms and signs may include anorexia (lack of appetite or inability to eat), lack of the urge to move the bowels or empty the rectum on physical examination, distended abdomen, and a mass in the colon that can be felt by the physician during examination. It should be suspected in older children with abnormal bowel habits, especially a history of constipation dating back to infancy and ribbon-like stools. Occasionally, the presenting symptom may be a severe intestinal infection called enterocolitis, which is life threatening. The symptoms are usually explosive, 554 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Hirschsprung’s disease watery stools and fever in a very ill-appearing infant. It is important to diagnose the condition before the intestinal obstruction causes an overgrowth of bacteria that evolves into a medical emergency. Enterocolitis can lead to severe diarrhea and massive fluid loss, which can cause death from dehydration unless surgery is done immedi- ately to relieve the obstruction. Diagnosis Hirschsprung’s disease in the newborn must be dis- tinguished from other causes of intestinal obstruction. The diagnosis is suspected by the child’s medical history and physical examination, especially the rectal exam. The diagnosis is confirmed by a barium enema x ray, which shows a picture of the bowel. The x ray will indi- cate if a segment of bowel is constricted, causing dilation and obstruction. A biopsy of rectal tissue will reveal the absence of the nerve fibers. Adults may also undergo manometry, a balloon study (device used to enlarge the anus for the procedure) of internal anal sphincter pressure and relaxation. Treatment and management Hirschsprung’s disease is treated surgically. The goal is to remove the diseased, nonfunctioning segment of the bowel and restore bowel function. This is often done in two stages. The first stage relieves the intestinal obstruc- tion by performing a colostomy. This is the creation of an opening in the abdomen (stoma) through which bowel contents can be discharged into a waste bag. When the child’s weight, age, or condition is deemed appropriate, surgeons close the stoma, remove the diseased portion of bowel, and perform a “pull-through” procedure, which repairs the colon by connecting functional bowel to the anus. This usually establishes fairly normal bowel function. Prognosis Overall, prognosis is very good. Most infants with Hirschsprung’s disease achieve good bowel control after surgery, but a small percentage of children may have lin- gering problems with soilage or constipation. These infants are also at higher risk for an overgrowth of bacte- ria in the intestines, including subsequent episodes of enterocolitis, and should be closely followed by a physi- cian. Mortality from enterocolitis or surgical complica- tions in infancy is 20%. Prevention Hirschsprung’s disease is a congenital abnormality that has no known means of prevention. It is important to diagnose the condition early in order to prevent the GALE ENCYCLOPEDIA OF GENETIC DISORDERS 555 Hirschsprung’s disease KEY TERMS Anus—The opening at the end of the intestine that carries waste out of the body. Barium enema x ray—A procedure that involves the administration of barium into the intestines by a tube inserted into the rectum. Barium is a chalky substance that enhances the visualization of the gastrointestinal tract on x-ray. Colostomy—The creation of an artificial opening into the colon through the skin for the purpose of removing bodily waste. Colostomies are usually required because key portions of the intestine have been removed. Enterocolitis—Severe inflammation of the intes- tines that affects the intestinal lining, muscle, nerves and blood vessels. Manometry—A balloon study of internal anal sphincter pressure and relaxation. Meconium—The first waste products to be dis- charged from the body in a newborn infant, usu- ally greenish in color and consisting of mucus, bile and so forth. Megacolon—Dilation of the colon. Parasympathetic ganglion cell—Type of nerve cell normally found in the wall of the colon. development of enterocolitis. Genetic counseling can be offered to a couple with a previous child with the dis- ease or to an affected individual considering pregnancy to discuss recurrence risks and treatment options. Prenatal diagnosis is not available. Resources BOOKS Buyse, Mary Louise, MD., ed. “Colon, Aganglionosis.” In Birth Defects Encyclopedia. Oxford: Blackwell Scientific Publications, 1990. Phillips, Sidney F., and John H. Pemberton. “Megacolon: Congenital and Acquired.” In Sleisenger & Fordtran’s Gastrointestinal and Liver Disease. Edited by Mark Feldman, et al. Philadelphia: W.B. Saunders Co., 1998. PERIODICALS Kusafuka, T., and P. Puri. “Genetic Aspects of Hirschsprung’s Disease.” Seminars in Pediatric Surgery 7 (1998): 148-55. Martucciello, G., et al. “Pathogenesis of Hirschsprung’s Disease.” Journal of Pediatric Surgery 35 (2000): 1017- 25. Munnes, M., et al. “Familial Form of Hirschsprung Disease: Nucleotide Sequence Studies Reveal Point Mutations in the RET Proto-oncogene in Two of Six Families But Not in Other Candidate Genes.” American Journal of Medical Genetics 94 (2000): 19-27. Puri, P., K. Ohshiro, and T. Wester. “Hirschsprung’s Disease: A Search for Etiology.” Seminars in Pediatric Surgery 7 (1998): 140-7. Salomon, R., et al. “From Monogenic to Polygenic: Model of Hirschsprung Disease.” Pathol Biol (Paris) 46 (1998): 705-7. ORGANIZATIONS American Pseudo-Obstruction & Hirschsprung’s Society. 158 Pleasant St., North Andover, MA 01845. (978) 685-4477. Pull-thru Network. 316 Thomas St., Bessemer, AL 35020. (205) 428-5953. Amy Vance MS, CGC HLA region see Major histocompatibility complex I Holoprosencephaly Definition Holoprosencephaly is a disorder in which there is a failure of the front part of the brain to properly separate into what is commonly know as the right and left halves of the brain. This lack of separation is often accompanied by abnormalities of the face and skull. Holoprosen- cephaly may occur individually or as a component of a larger disorder. Description Types of holoprosencephaly Holoprosencephaly comes in three different types: alobar, semilobar, and lobar. Each of these classifications is based on the amount of separation between what is commonly known as the left and right halves of the brain. Alobar holoprosencephaly is considered to be the most severe form of the disease, in which the separation between the two halves, or hemispheres, completely fails to develop. Semilobar holoprosencephaly represents holoprosencephaly of the moderate type, where some separation between the hemispheres has occurred. Lobar holoprosencephaly represents the least severe type of holoprosencephaly in which the hemispheres are almost, but not completely, divided. The severity of the effect of the disease on the brain is often reflected in craniofacial abnormalities (abnormal- ities of the face and skull). This has led to many health care professionals utilizing the phrase “the face predicts the brain.” This phrase is generally but not always accu- rate. Children may have severe craniofacial abnormalities with mild (lobar) holoprosencephaly, or children may have severe (alobar) holoprosencephaly with mild facial changes. Since the development of the face, skull, and the front of the brain are interconnected, the changes in the face often, but do not always, correspond with changes in the brain. Finally, the designation of these disorders from least severe to most severe can be mildly misleading, since the best predictor of the severity of the disease, according to Barr and Cohen, is how well the brain func- tions, not its appearance. However, the alobar, semilobar, and lobar categories are universally utilized and give an indication of the severity of the disease, so knowledge of these categories and what they represent is useful. Other brain abnormalities in holoprosencephaly All patients with holoprosencephaly lack a sense of smell through the first cranial nerve (the olfactory nerve). Interestingly enough, one has a partial sense of smell through the sense of taste, which is governed by the sev- enth cranial nerve. The term “smell” and what it means in a conventional and strictly neurological sense differ, so it may be useful to think of persons with holoprosen- cephaly as lacking a portion of what is in common usage referred to as smell. This deficiency in smell can be detected by testing. One other important structural abnor- mality should be mentioned. The corpus callosum, which is the part of the brain that connects the right and left hemispheres with each other, is absent or deficient in per- sons with holoprosencephaly. Synonyms for holoprosencephaly Arrhinencephaly and familial alobar holoprosen- cephaly are synonyms for this disorder. Genetic profile Genetic causes of holoprosencephaly Holoprosencephaly is a feature frequently found in many different syndromes including, but not limited to: trisomy 13, trisomy 18, tripoloidy, pseudotrisomy 13, Smith-Lemli-Opitz syndrome, Pallister-Hall syn- drome, Fryns syndrome, CHARGE association, Goldenhar syndrome, frontonasal dysplasia, Meckel- Gruber syndrome, velocardiofacial syndrome, Genoa syndrome, Lambotte syndrome, Martin syndrome, and Steinfeld syndrome, as well as several teratogenic syn- dromes such as diabetic embryopathy, accutane embry- opathy, and fetal alcohol syndrome. Holoprosencephaly has been linked to at least 12 different loci on 11 different chromosomes. Some candidate genes are Sonic hedge- 556 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Holoprosencephaly [...]... American Journal of Medical Genetics 89 ( 19 99 ): 11 6 -1 2 0 ORGANIZATIONS National Organization for Rare Disorders (NORD) PO Box 892 3, New Fairfield, CT 06 812 -8 92 3 (203) 74 6-6 518 or (800) 99 9- 6 673 Fax: (203) 74 6-6 4 81 Ͻhttp://www rarediseases.orgϾ Michael V Zuck, PhD I Holt-Oram syndrome Definition Holt-Oram syndrome (HOS) is one of several hereditary conditions characterized by abnormalities of the heart and... Transplantation in FiftyFour Children.” Blood 91 , no 7 (April 19 98 ): 26 0 1- 2608 ORGANIZATIONS Genetic Alliance 43 01 Connecticut Ave NW, #404, Washington, DC 2000 8-2 304 (800) 336-GENE (Helpline) or (202) 96 6-5 557 Fax: (888) 39 4-3 93 7 info@geneticalliance Ͻhttp://www.geneticalliance.orgϾ National MPS Society 10 2 Aspen Dr., Downingtown, PA 19 335 ( 610 ) 94 2- 010 0 Fax: ( 610 ) 94 2- 718 8 info @mpssociety.org Ͻhttp://www.mpssociety.orgϾ... entering one of the ventricles Polydactyly The presence of extra fingers or toes Radius—One of the two bones of the forearm, the one adjacent to the base of the thumb Septal defect—A hole in the heart Syndactyly—Abnormal webbing of the skin between the fingers or toes Ulna—One of the two bones of the forearm, the one opposite the thumb Ventricles—One of the chambers (small cavities) of the heart through... non-responding patients are treated with combinations of folic acid, hydroxycobalamin, and betaine, which stimulate the conversion of homocysteine back to methionine The reason that the addition of folic acid can help is because within the methylene H4-folate GALE ENCYCLOPEDIA OF GENETIC DISORDERS GALE ENCYCLOPEDIA OF GENETIC DISORDERS have been related to the mother’s condition Potentially, the mother’s... 64 714 , Unionville, ONT L3R-OM9 Canada (90 5) 47 9- 8 7 01 or (800) 667 -1 8 46 Ͻhttp://www mpssociety.caϾ Children Living with Inherited Metabolic Diseases The Quadrangle, Crewe Hall, Weston Rd., Crewe, Cheshire, CW 1-6 UR UK 12 7 025 02 21 Fax: 087 0-7 70 0-3 27 Ͻhttp://www.climb.org.ukϾ National MPS Society 10 2 Aspen Dr., Downingtown, PA 19 335 (6 01) 94 2- 010 0 Fax: ( 610 ) 94 2- 718 8 info @mpssociety.org Ͻhttp://www.mpssociety.orgϾ... used set of criteria for the diagnosis of HOS require that there be 1) defect(s) of the radial side of the hand/arm, as well as 2) septal defect(s) or conduction abnormality of the heart, within one individual or family X rays may be necessary to determine involvement of the bones of the upper limb Diagnosis of structural GALE ENCYCLOPEDIA OF GENETIC DISORDERS Testing to identify changes in the TBX5... 10 032 ( 212 ) 30 5-0 378 Fax: ( 212 ) 30 5-3 6 29 Ͻhttp://cpmcnet.columbia edu/dept/nsg/PNS/Hydrocephalus.htmlϾ Hydrocephalus Association 870 Market St., Suite 705, San Francisco, CA 9 410 2 ( 415 ) 73 2-7 040 or (888) 59 8-3 7 89 ( 415 ) 73 2-7 044 hydroassoc@aol.com Ͻhttp://neurosurgery mgh.harvard.edu/haϾ Hydrocephalus Foundation, Inc (HyFI), 91 0 Rear Broadway, Saugus, MA 0 19 06 (7 81) 94 2 -1 1 61 HyFI1@netscape net Ͻhttp://www.hydrocephalus.orgϾ... 42 0-4 23 PERIODICALS Hunter, C “A rare disease in two brothers.” Proceedings of the Royal Society of Medicine 19 17: 10 :10 4 ORGANIZATIONS Alliance of Genetic Support Groups 43 01 Connecticut Ave NW, Suite 404, Washington, DC 20008 (202) 96 6-5 557 Fax: (202) 96 6-8 553 Ͻhttp://www.geneticalliance.orgϾ Canadian Society for Mucopolysaccharide and Related Diseases PO Box 64 714 , Unionville, ONT L3R-OM9 Canada (90 5)... fragments of sequence that overlapped with each other to generate the sequence of the genomic clone The sequence of each genomic clone could then be fitted together using the assembly (contig) of genomic clones on the genetic and physical map Although the ultimate aim was high-quality sequence of the human genome, it was recognized that the genetic and physical maps generated by the first stage of the HGP... and often, stillbirth microscope Each band corresponds to specific genes Based on studies of genetic material from affected and non-affected families, studies in 19 99 assigned the gene location for hydrolethalus syndrome to 11 q2 3-2 5, or somewhere between the 23rd and 25th band of the q arm of chromosome 11 Demographics The majority of cases of hydrolethalus syndrome have been reported in people of Finnish . Maps to Chromosome 10 q2.” Human Genetics 57 ( 19 95): 75 5-7 65. ORGANIZATIONS Hermansky-Pudlak Syndrome Network. 39 Riveria Court, Malverne, NY 11 565 -1 6 02. (800) 78 9- 9 477 or ( 516 ) 59 9- 2077. Ͻhttp://www.medhelp.org/web/hpsn.htmϾ. National. per- formance.” American Journal of Medical Genetics 89 ( 19 99) : 11 6 -1 2 0. ORGANIZATIONS National Organization for Rare Disorders (NORD). PO Box 892 3, New Fairfield, CT 06 812 -8 92 3. (203) 74 6-6 518 . They are: SPG3 (found on the long arm of chromosome 14 at 14 q 11 q 21) , SPG4 or spastin (short arm of chromosome 2 at 2p22), SPG6 (long arm of chromosome 15 at 15 q 11. 1), SPG8 (long arm of chro- mosome