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 1 - A-L - I

.pdf
Скачиваний:
96
Добавлен:
17.08.2013
Размер:
7.12 Mб
Скачать

the life-long complications of FAS, and intervention. Streissguth has described a model in which an individual affected by FAS has one or more advocates to help provide guidance, structure, and support as the individual seeks to become independent, successful in school or employment, and develop satisfying social relationships.

Prognosis

The prognosis for FAS depends on the severity of birth defects and the brain damage present at birth. Miscarriage, stillbirth, or death in the first few weeks of life may occur in very severe cases. Major birth defects associated with FAS are usually treatable with surgery. Some of the factors that have been found to reduce the risk of secondary disabilities in FAS individuals include diagnosis before the age of six years, stable and nurturing home environments, never having experienced personal violence, and referral and eligibility for disability services. The long-term data helps in understanding the difficulties that individuals with FAS encounter throughout their lifetime and can help families, caregivers, and professionals provide the care, supervision, education, and treatment geared toward their special needs.

Prevention of FAS is the key. Prevention efforts must include public education efforts aimed at the entire population, not just women of child-bearing age, appropriate treatment for women with high-risk drinking habits, and increased recognition and knowledge about FAS by professionals, parents, and caregivers.

Resources

BOOKS

Jones, Kenneth Lyons. Smith’s Recognizable Patterns of

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

Streissguth, Ann. Fetal Alcohol Syndrome: A Guide for Families and Communities. Baltimore, MD: Paul H. Brookes Publishing Company, 1997.

PERIODICALS

Committee of Substance Abuse and Committee on Children with Disabilities. “Fetal Alcohol Syndrome and AlcoholRelated Neurodevelopmental Disorders.” Pediatrics 106 (August 2000): 358-361.

Cramer, C., and F. Davidhizar. “FAS/FAE: Impact on Children.” Journal of Child Health Care 3 (Autumn 1999): 31-34.

Gladstone, J., et al. “Reproductive Risks of Binge Drinking during Pregnancy.” Reproductive Toxicology 10 (JanuaryFebruary 1996): 3-13.

Hannigan, J.H., and D.R. Armant. “Alcohol in Pregnancy and Neonatal Outcome.” Seminars in Neonatology 5 (August 2000): 243-54.

Olson, Heather Carmichael, et al. “Association of Prenatal Alcohol Exposure with Behavioral and Learning Problems in Early Adolescence.” Journal of the American Academy of Child and Adolescent Psychiatry 36 (September 1997): 1187-1194.

“Prenatal Exposure to Alcohol.” Alcohol Research and Health 24 (2000): 32-41.

Sampson, Paul D., et al. “Incidence of Fetal Alcohol Syndrome and Prevalence of Alcohol-Related Neurodevelopmental Disorder.” Teratology 56 (November 1997): 317-326.

Streissguth, Ann Pytkowicz, et al. “Fetal Alcohol Syndrome in Adolescents and Adults.” JAMA 265 (April 1991): 19611967.

ORGANIZATIONS

Arc’s Fetal Alcohol Syndrome Resource Guide. The Arc’s Publication Desk, 3300 Pleasant Valley Lane, Suite C, Arlington, TX 76015. (888) 368-8009. http://www

.thearc.org/misc/faslist.html .

Fetal Alcohol Syndrome Family Resource Institute. PO Box 2525, Lynnwood, WA 98036. (253) 531-2878 or (800) 999-3429. http://www.fetalalcoholsyndrome.org .

Institute of Medicine. National Academy Press, Washington, DC http://www.come-over.to/FAS/IOMsummary.htm .

March of Dimes Birth Defects Foundation. 1275 Mamaroneck Ave., White Plains, NY 10605. (888) 663-4637. resourcecenter@modimes.org. http://www.modimes

.org .

Nofas. 216 G St. NE, Washington, DC 20002. (202) 785-4585.http://www.nofas.org .

Laurie Heron Seaver, MD

Fetal facies syndrome see Robinow syndrome

I FG syndrome

Definition

FG syndrome (FGS) is a genetic disorder characterized by mental retardation, low muscle tone (hypotonia), large head, constipation, and anal abnormalities.

Description

FGS refers to a rare genetic condition that has a variety of physical and mental symptoms. Most individuals affected by FGS have symptoms including mental retardation, low muscle tone, brain abnormalities (partial agenesis of the corpus callosum), seizures, large head, characteristic facial features, large intestinal and anal abnormalities, constipation, short stature, joints that tend to stay in one place (fixed), broad big toes, and light and

syndrome FG

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

425

FG syndrome

K E Y T E R M S

Heterogeneous—A set of symptoms or a disorder caused by several different gene mutations.

Imperforate anus—Also known as anal atresia. A birth defect in which the opening of the anus is absent or obstructed.

Variable penetrance—A term describing the way in which the same mutated gene can cause symptoms of different severity and type within the same family.

dark skin streaking. The syndrome was first described by Opitz and Kaveggia in 1974 based on physical findings and family history. All of these features appear to be caused by mutated or changed genes on the X chromosome. Although the full effect of the mutation or change in the gene is not fully understood, the mutations are believed to interrupt the genes’ normal functions in the brain, digestive tract, and muscle tissue.

Other names for FG syndrome include OpitzKaveggia Syndrome and Keller syndrome.

Genetic profile

FGS is caused by mutations on the long arm of the X-chromosome. Studies in 1998 and 2000 found that individuals affected by FGS can have a mutation on the X-chromosome in two different locations on the long arm

(q) of the X-chromosome: Xq12-Xq21 [called FGS1] and Xq28 [called FGS2]. When a set of symptoms are caused by gene mutations at different locations, the disorder is called heterogeneous. Although a gene mutation causing FGS can appear in an individual for the first time and is not found in the affected individual’s parents, most cases of FGS are inherited.

Since both possible gene mutations are found on the X chromosome, FGS is inherited in an X-linked recessive pattern. Every individual has approximately 30,000–35,000 genes that tell their bodies how to form and function. Each gene is present in pairs, since one is inherited from their mother and one is inherited from their father. Females have two X chromosomes, while males have a single X chromosome and Y chromosome. In other words, females receive two copies of the genetic information stored on the X chromosome. When a female inherits the gene for an X-linked recessive condition, she is known as a “carrier.” She usually has no problems related to that condition, because the gene on her other X chromosome continues to function properly

and “masks” the abnormal gene. However, males only inherit one copy of the information stored on the X chromosome. When a male inherits the gene for an X-linked recessive condition, he will experience the symptoms associated with that condition. The mutated or changed genes which cause FGS are located on the X chromosome and thus the full-blown disorder primarily affects males carrying the mutated or changed gene on their one X chromosome. When a condition is X-linked, the gene for the condition travels through the family on the X chromosome. In X-linked genetic conditions, the risk for a carrier female to have an affected son is 50%, while the risk to have a carrier daughter is also 50%. An affected male has a 100% chance of having carrier daughters and no chance to have an affected son.

Individuals inheriting the same mutated gene in the same family can have very different symptoms. For example, approximately 38% of individuals affected by FGS have anal anomalies, like a missing anal opening (imperforate anus), while mental retardation is present in 97% of individuals affected by FGS. The difference in physical findings within the same family is known as variable penetrance or intrafamilial variability.

Demographics

FG syndrome can appear in any ethnic population. FGS has been described in individuals of Japanese, American, European, African, and other ethnic background. FGS is not believed to be more common in one specific population.

Signs and symptoms

Individuals affected by FG syndrome (can be affected by a variety of symptoms. Most affected individuals have signs of FGS such as mental retardation, low muscle tone and physical development, seizures, large heads, big foreheads, a front cowlick of hair, widespaced eyes, extra eye folds (short, palpebral fissures), constipation, and an outgoing, talkative personality. Other fairly common signs of FGS include anal abnormalities (imperforate anus), brain abnormalities (partial agenesis of the corpus callosum, hearing impairments, broad thumbs and big toes, small ears, fine/thinning hair, fused fingers, minor back bone abnormalities, cleft lip and palate, heart defects, and fetal fingertip pads.

Diagnosis

Diagnosis of FGS is usually made from physical examination by a medical geneticist. The physical examination looks for the combined characteristic features, low muscle tone, mental retardation, etc., of FGS.

426

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

Although mutations in specific genes that cause FGS have been found, molecular genetic testing (prenatal or diagnostic) is not available in 2001.

Treatment and management

FG syndrome does not have a specific therapy that removes, cures, or fixes all signs of the disorder.

Management and treatment for FGS mainly focuses on the treatment of specific symptoms. More specifically, individuals with incompletely formed anal openings and serious heart defects would need surgery to try to correct the problems. Individuals affected by FGS who have mental retardation benefit from special school and early intervention programs.

Prognosis

The prognosis of an individual affected by FGS depends on the severity of the symptoms by which they are affected. For example, approximately one-third of individuals affected by FGS will die before two years of age due to the severity of heart defects and anal abnormalities.

Most individuals affected by FGS who do not have severe physical problems, such as serious heart defects and anal abnormalities, are still affected by mental retardation. Individuals affected by FGS who have mental retardation benefit from special schools and early intervention programs.

Resources

BOOKS

Smith, Raomayne, and Eunice Kennedy Shriver, eds. Children with Mental Retardation, A Parents’ Guide. Bethesda, MD: Woodbine House, 1993.

Trainer, Marilyn, and Helen Featherstone. Differences in Common: Straight Talk on Mental Retardation, Down

Syndrome, and Your Life. Bethesda, MD: Woodbine House, 1991.

PERIODICALS

FG Syndrome Family Alliance Print Newsletter FG Syndrome

Family Alliance, subscribe by sending email to:

FGSNewsl@aol.com

ORGANIZATIONS

Arc (a National Organization on Mental Retardation). 1010 Wayne Ave., Suite 650, Silver Spring, MD 20910. (800) 433-5255. http://www.thearclink.org .

WEBSITES

The Family Village. http://www.familyvillage.wisc.edu .

FG Syndrome Family Alliance. FG Syndrome Homepage.

http://www.geocities.com/HotSprings/Spa/3687/ .

On-line Mendelian Inheritance of Man.

http://www3.ncbi.nlm.nih.gov/Omim// .

Dawn A. Jacob, MS

I Fibroblast growth factor receptor mutations

Definition

Fibroblast growth factor receptors (FGFRs) are a family of proteins specialized in growth inhibition. Mutations in these molecules lead to various genetic disorders involving short stature and/or premature fusion of the bones of the skull. There are at least four known FGFRs (FGFR1, FGFR2, FGFR3, FGFR4).

Description

As a group, FGFRs are very similar to each other in their structure and function. All are transmembrane proteins composed of three distinct parts. A binding site on the exterior of the cell membrane, an active site on the interior of the cell membrane, and a connecting section spanning the cell membrane and joining the inner and outer components.

Fibroblast growth factors (FGFs) attach to the binding site of extracellular portion of the FGFR protein. There are at least 17 known FGFs that bind and interact with FGFRs. Two FGFs must first bind with each other and, as a pair, are able to fit into the FGFR binding site forming an FGF/FGFR complex. FGF pairing and FGF/FGFR binding is non-specific, with any two FGFs coupling and binding any FGFR.

When the binding site is empty and no FGF is bound, the FGFR is inactive and cellular growth continues unchecked. When an FGF pair binds, the FGF/FGFR complex sends a signal that travels the length of the FGFR protein, resulting in the stimulation of the active site on the inside of the cell membrane.

The active site of the FGFR stimulates molecules within the cell through the biochemical process of phosphorylation. Each activated molecule goes on to affect another molecule, thereby propagating the original signal and, much like the domino effect, a cascade of events is triggered. The process continues, molecule by molecule, until the signal reaches the nucleus of the cell, ultimately resulting in the inhibition of cell growth.

Although highly recognized in the process of growth restriction, FGFRs are also thought to be involved in a

mutations receptor factor growth Fibroblast

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

427

Fibroblast growth factor receptor mutations

K E Y T E R M S

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.

Chorionic villus sampling (CVS)—A procedure used for prenatal diagnosis at 10-12 weeks gestation. 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.

Deoxyribonucleic acid (DNA)—The genetic material in cells that holds the inherited instructions for growth, development, and cellular functioning.

Genome—A term used to describe a complete representation of all of the genes in a species.

Phosphorylation—The addition of phosphoric acid to another compound.

Transmembrane—Anything that spans the width of a membrane.

wide variety of biological processes including migration of cells during embryo development, blood vessel growth, wound healing, cell death, and cancer.

Genes

A different gene codes for each of the four types of FGFR proteins (Table 1). Genes are the genetic material passed down from generation to generation that tell a person’s body how to work and how to grow. Genes are packaged into chromosomes, with hundreds of genes on each chromosome. Individual cells contain 46 chromosomes, which may be matched into 23 pairs. One of each pair is inherited from the egg of the mother and one of each pair is inherited from the sperm of the father.

A mutation, meaning a change in an FGFR gene, also changes the structure of the FGFR protein, which then affects the protein’s function. Most FGFR gene mutations are thought to cause the protein receptors to become overly active. These defective receptors continuously start the activation cascade independent of FGF

TABLE 1

FGFR Genes

Gene

Chromosome

Protein product

FGFR1

8p11

FGFR1

FGFR2

10q26

FGFR2

FGFR3

4p16

FGFR3

FGFR4

5q35

FGFR4

binding. This causes a strong slowing-down effect on growth, which is readily observed in the symptoms of affected individuals. Common features of the disease include abnormalities of the limbs, skin, head, and face.

Inheritance

Approximately ten genetic disorders have been linked to abnormal FGFRs. All FGFR-related syndromes are autosomal dominant. That is, although individuals inherit two copies of each gene FGFR gene, only one copy must be mutated for a person to be affected with a disorder. Some individuals with an FGFR-related disorder have a parent affected by the same disease, in which case the disease is said to be familial. Other individuals are the first person in their family to be affected. These cases are considered sporadic, meaning they arose from a new mutation in the affected person’s DNA.

Whether familial or sporadic, all affected individuals have a 50% chance of passing on the disease to a child in any future pregnancy. The overall risk for a pregnancy can change if an affected person has a child with an individual affected by the same disease.

Prenatal testing

Prenatal testing is available for all of the FGFR-asso- ciated syndromes. Some cases are diagnosed based on clinical presentation, while others are diagnosed by DNA mutation analysis. Chorionic villus sampling (CVS) or amniocentesis may be used when there is a known familial mutation. If there is no family history of FGFRrelated disease, but prenatal examination by ultrasound gives rise to concern, prognosis and diagnosis are traditionally based on clinical findings after birth.

Disease causing mutations

Syndromes involving FGFR gene mutations fall into two categories. The first category includes four disorders of short stature, all caused by mutations in the FGFR3 gene. The second category includes six syndromes involving skull malformations (craniosynostosis), all caused by mutations in the FGFR1, FGFR2, or FGFR3

428

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

TABLE 2

 

FGFR-related dwarfism syndromes

 

 

 

 

 

Syndrome*

Incidence

Gene

Common mutations1

 

 

Achondroplasia (ACH)

1/15,00–1/40,000

FGFR3

Gly380Arg

 

Hypochondroplaisa (HCH)

Unknown

FGFR3

Asn540Lys

 

Thanatophoric dysplasia Type I (TD1)

1/60,000 (TD1 and TD2)

FGFR3

Arg248Cys

 

Thanatophoric dysplasia type II (TD2)

See above

FGFR3

Lys650Glu

 

Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN)

3 reported cases

FGFR3

Lys650Met

 

*Please see the entry of the specific disease for further information and an exact description of the disorder.

 

 

 

 

1This represents common mutations and is not a complete list of mutations.

 

 

 

 

 

 

 

 

 

 

genes. As of 2001, there have been no disease-causing

phoric dysplasiaa Types I and II have their own distinct

mutations reported in the FGFR4 gene.

FGFR3 gene mutations.

Dwarfism

Craniosynostosis

FGFR-related dwarfism disorders are all due to abnormal FGFR3 function (Table 2). Mutations in the FGFR3 gene are among the most common mutations in the human genome.

Achondroplasia was the first disease associated with FGFRs. It is the most common form of inherited disproportionate short stature with an incidence of one in 15,000 to one in 40,000 live births. Over 80% of cases of achondroplasia are sporadic, with a strong link to advanced paternal age.

Achondroplasia is characterized by abnormal bone growth that results in short stature with disproportionately short arms and legs, a large head, and characteristic facial features. Intelligence and life span are usually normal, although there is an increased risk of death in infancy from compression of the spinal cord and/or upper airway obstruction.

Hypochondroplasia is a form of short-limbed dwarfism also caused by a mutation in the FGFR3 gene. Although it appears clinically as a mild form of dwarfism, hypochondroplasia is caused by unique mutations in the FGFR3 gene, different than those that cause achondroplasia.

Thanatophoric dysplasia Types I and II and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) dysplasia are the most severe forms of FGFR-related dwarfism. Both types of thanatophoric dysplasia are fatal with death occurring before birth or during early infancy. As of 2001 there have been only three reported cases of SADDAN dysplasia. Although it is much like thanatophoric dysplasia in its presentation, affected individuals survive past infancy. Affected individuals are severely affected both mentally and physically. Both SADDAN dysplasia and thanato-

Craniosynostosis is the hallmark feature of the second subset of disorders caused by FGFR gene mutations (Table 3). Craniosynostosis is the premature fusion of some or all of the bones of the skull. During normal development the bones of the skull do not completely fuse until the first to second year of life. This allows for passage through the narrow birth canal at delivery and for maximum brain growth during early developmental years.

There are over 150 genetic disorders that involve craniosynostosis that are not related to FGFR mutations. The collective incidence of all forms of craniosynostosis is 1/2000–1/2500 live births.

As of 2001, there are six craniosynotosis syndromes thought to be FGFR-related. All six display some form of craniosynostosis, distinctive facial features, and hand and foot deformations. Syndromes range from severe (neonatal death) to mild (no clinical manifestations). The characteristic facial features observed include underdevelopment of the midface, protruding eyes, down-slanting eyes, small beaked nose, protruding jaw (prognathism), and eyes that are unusually far apart (hypertelorism). Hand and foot anomalies are distinct for each syndrome and are sometimes used to distinguish between the disorders.

Future

Although the FGFR-related syndromes have been well-characterized, scientists continue to face some puzzling questions. It has been observed that identical FGFR gene mutations may result in two or more clinically distinct disorders, meaning with different symptoms. For example, a single mutation in the FGFR1 gene has been shown to result in Pfeiffer syndrome. The same mutation in the FGFR2 gene leads to Apert syndrome, while

mutations receptor factor growth Fibroblast

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

429

Fragile X syndrome

TABLE 3

FGFR-related craniosynostosis syndromes

Syndrome*

Incidence

Gene

Common Mutations&

Muenke syndrome

Unknown

FGFR3

Pro250Arg

Crouzon syndrome

1.6/100,000

FGFR2

25 mutations

Crouzon with Acanthosis Nigricans

Unknown

FGFR3

Ala391Glu

Jackson-Wiess syndrome

Unknown

FGFR2

Cys342Arg, Ala344Gly

Apert syndrome

1/100,000

FGFR2

Pro250Arg, Ser252Trp

Pfeiffer types 1–3

1/100,000 (collective)

FGFR1, FGFR2

Pro250Arg

Beare-Stevenson cutis gyrata

10 cases reported

FGFR2

Ser372Cys, Tyr375Cys

*Please see the entry of the specific disease for further information and an exact description of the disorder. This represents common mutations and is not a complete list of mutations.

the equivalent mutation in the FGFR3 gene produces Muenke craniosynostosis. Likewise, a single mutation in the FGFR2 gene may lead to any of the Crouzon, Pfeiffer, or Jackson-Weiss syndromes. The mechanism by which a particular mutation may lead to multiple different genetic disorders is not clearly understood.

Resources

BOOKS

Jorde, Lynne B., et al. Medical Genetics. St. Louis: Mosby, 1999.

PERIODICALS

Burke, David, et al. “Fibroblast Grown Factor Receptors: Lessons From the Genes.” Trends in Biochemical Science

(February 1998): 59-62.

Vajo, Z., et al. “The Molecular and Genetic Basis of Fibroblast Growth Factor Receptor 3 Disorders: The Achondroplasia Family of Skeletal Dysplasias, Muenke Craniosynostosis, and Crouzon Syndrome with Acanthosis Nigricans.” Endocrine Reviews (February 2000): 23-39.

Webster, M. K., and D. J. Donoghue. “FGFR Activation in Skeletal Disorders: Too Much of a Good Thing.” Trends in Genetics (May 1997): 178-182.

WEBSITES

GeneClinics. http://www.geneclinics.org .

Little People Online. http://www.lpaonline.org .

Online Inheritance of Man.

http://www3.ncbi.nlm.nih.gov/Omim .

Java Olympia Solis, MS

Fifth digit syndrome see Coffin-Siris syndrome

Focal dermal hypoplasia (DHOF) see Goltz syndrome

Fragile site (FRAXE) see Fragile X syndrome

Fragile site mental retardation 1 (FMR1) see

Fragile X syndrome

I Fragile X syndrome

Definition

Fragile X syndrome is the most common form of inherited mental retardation. Individuals with this condition have developmental delay, variable levels of mental retardation, and behavioral and emotional difficulties. They may also have characteristic physical traits. Generally, males are affected with moderate mental retardation and females with mild mental retardation.

Description

Fragile X syndrome is also known as Martin-Bell syndrome, Marker X syndrome, and FRAXA syndrome. It is the most common form of inherited mental retardation. Fragile X syndrome is caused by a mutation in the FMR-1 gene, located on the X chromosome. The role of the gene is unclear, but it is probably important in early development.

Genetic profile

In order to understand fragile X syndrome it is important to understand how human genes and chromosomes influence this condition. Normally, each cell in the body contains 46 (23 pairs of) chromosomes. These chromosomes consist of genetic material (DNA) needed for the production of proteins, which lead to growth, development, and physical/intellectual characteristics. The first 22 pairs of chromosomes are the same in males and females. The remaining two chromosomes are called

430

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

the sex chromosomes (X and Y). The sex chromosomes determine whether a person is male or female. Males have only one X chromosome, which is inherited from the mother at conception, and they receive a Y chromosome from the father. Females inherit two X chromosomes, one from each parent. Fragile X syndrome is caused by a mutation in a gene called FMR-1. This gene is located on the X chromosome. The FMR-1 gene is thought to play an important role in the development of the brain, but the exact way that the gene acts in the body is not fully understood.

The mutation involves a short sequence of DNA in the FMR-1 gene. This sequence is designated CGG. Normally, the CGG sequence is repeated between six and 54 times. People who have repeats in this range do not have fragile X syndrome and are not at increased risk to have children with fragile X syndrome. Those affected by fragile X syndrome have expanded CGG repeats (over 200) in the first exon of the FMR1 gene (the full mutation).

For reasons not fully understood, the CGG sequence in the FMR-1 gene can expand to contain between 54 and 230 repeats. This stage of expansion is called a premutation. People who carry a premutation do not usually have symptoms of fragile X syndrome; although there have been reports of individuals with a premutation and subtle intellectual or behavioral symptoms. Individuals who carry a fragile X premutation are at risk to have children or grandchildren with the condition. Female premutation carriers may also be at increased risk for earlier onset of menopause; however, premutation carriers may exist through several generations of a family and no symptoms of fragile X syndrome will appear.

The size of the premutation can expand over succeeding generations. Once the size of the premutation exceeds 230 repeats, it becomes a full mutation and the FMR-1 gene is disabled. Individuals who carry the full mutation may have fragile X syndrome. Since the FMR- 1 gene is located on the X chromosome, males are more likely to develop symptoms than females. This is because males have only one copy of the X chromosome. Males who inherit the full mutation are expected to have mental impairment. A female’s normal X chromosome may compensate for her chromosome with the fragile X gene mutation. Females who inherit the full mutation have an approximately 50% risk of mental impairment. The phenomenon of an expanding trinucleotide repeat in successive generations is called anticipation. Another unique aspect fragile X syndrome is that mosaicism is present in 15-20% those affected by the condition. Mosaicism is when there is the presence of cells of two different genetic materials in the same individual.

K E Y T E R M S

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.

CGG or CGG sequence—Shorthand for the DNA sequence: cytosine-guanine-guanine. Cytosine and guanine are two of the four molecules, otherwise called nucleic acids, that make up DNA.

Chorionic villus sampling (CVS)—A procedure used for prenatal diagnosis at 10-12 weeks gestation. 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.

Chromosome—A microscopic thread-like structure found within each cell of the body and consists of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Changes in either the total number of chromosomes or their shape and size (structure) may lead to physical or mental abnormalities.

FMR-1 gene—A gene found on the X chromosome. Its exact purpose is unknown, but it is suspected that the gene plays a role in brain development.

Mitral valve prolapse—A heart defect in which one of the valves of the heart (which normally controls blood flow) becomes floppy. Mitral valve prolapse may be detected as a heart murmur but there are usually no symptoms.

Premutation—A change in a gene that precedes a mutation; this change does not alter the function of the gene.

X chromosome—One of the two sex chromosomes (the other is Y) containing genetic material that, among other things, determine a person’s gender.

syndrome X Fragile

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

431

Fragile X syndrome

A fragile X chromosome is identifed as purple. (Custom Medical Stock Photo, Inc.)

Fragile X syndrome is inherited in an X-linked dominant manner (characters are transmitted by genes on the X chromosome). When a man carries a premutation on his X chromosome, it tends to be stable and usually will not expand if he passes it on to his daughters (he passes his Y chromosome to his sons). Thus, all of his daughters will be premutation carriers like he is. When a woman carries a premutation, it is unstable and can expand as she passes it on to her children; therefore, her grandchildren are at greater risk of developing the syndrome. There is a 50% risk for a premutation carrier female to transmit an abnormal mutation with each pregnancy. The likelihood for the premutation to expand is related to the number of repeats present; the higher the number of repeats, the greater the chance that the premutation will expand to a full mutation in the next generation. All mothers of a child with a full mutation are carriers of an FMR-1 gene expansion. Ninety-nine percent of patients with fragile X syndrome have a CGG expansion, and less than one percent have a point mutation or deletion on the FMR-1 gene.

Demographics

Fragile X syndrome affects males and females of all ethnic groups. It is estimated that there are about one in

4,000 to one in 6,250 males affected with fragile X syndrome. There are approximately half as many females with fragile X syndrome as there are males. The carrier frequency in unaffected females is one in 100 to one in 600, with one study finding a carrier frequency of one in 250.

Signs and symptoms

Individuals with fragile X syndrome appear normal at birth but their development is delayed. Most boys with fragile X syndrome have mental impairment. The severity of mental impairment ranges from learning disabilities to severe mental retardation. Behavioral problems include attention deficit and hyperactivity at a young age. Some may show aggressive behavior in adulthood. Short attention span, poor eye contact, delayed and disordered speech and language, emotional instability, and unusual hand mannerisms (hand flapping or hand biting) are also seen frequently. Characteristic physical traits appear later in childhood. These traits include a long and narrow face, prominent jaw, large ears, and enlarged testes. In females who carry a full mutation, the physical and behavioral features and mental retardation tend to be less severe. About 50% of females who have a full mutation are men-

432

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

tally retarded. Other behavioral characteristics include whirling, spinning, and occasionally autism.

Children with fragile X syndrome often have frequent ear and sinus infections. Nearsightedness and lazy eye are also common. Many babies with fragile X syndrome may have trouble with sucking and some experience digestive disorders that cause frequent gagging and vomiting. A small percentage of children with fragile X syndrome may experience seizures. Children with fragile X syndrome also tend to have loose joints which may result in joint dislocations. Some children develop a curvature in the spine, flat feet, and a heart condition known as mitral valve prolapse.

Diagnosis

Any child with signs of developmental delay of speech, language, or motor development with no known cause should be considered for fragile X testing, especially if there is a family history of the condition. Behavioral and developmental problems may indicate fragile X syndrome, particularly if there is a family history of mental retardation. Definitive identification of the fragile X syndrome is made by means of a genetic test to assess the number of CGG sequence repeats in the FMR- 1 gene. Individuals with the premutation or full mutation may be identified through genetic testing. Genetic testing for the fragile X mutation can be done on the developing baby before birth through amniocentesis or chorionic villus sampling (CVS), and is 99% effective in detecting the condition due to trinucleotide repeat expansion. Prenatal testing should only be undertaken after the fragile X carrier status of the parents has been confirmed and the couple has been counseled regarding the risks of recurrence. While prenatal testing is possible to do with CVS, the results can be difficult to interpret and additional testing may be required.

Treatment and management

Presently there is no cure for fragile X syndrome. Management includes such approaches as speech therapy, occupational therapy, and physical therapy. The expertise of psychologists, special education teachers, and genetic counselors may also be beneficial. Drugs may be used to treat hyperactivity, seizures, and other problems. Establishing a regular routine, avoiding over stimulation, and using calming techniques may also help in the management of behavioral problems. Children with a troubled heart valve may need to see a heart specialist and take medications before surgery or dental procedures. Children with frequent ear and sinus infections

may need to take medications or have special tubes placed in their ears to drain excess fluid. Mainstreaming of children with fragile X syndrome into regular classrooms is encouraged because they do well imitating behavior. Peer tutoring and positive reinforcement are also encouraged.

Prognosis

Early diagnosis and intensive intervention offer the best prognosis for individuals with fragile X syndrome. Adults with fragile X syndrome may benefit from vocational training and may need to live in a supervised setting. Life span is typically normal.

Resources

BOOK

Sutherland, Grant R., and John C. Mulley. “Fragile X Syndrome.” In Emery and Rimoin’s Principles and Practice of Medical Genetics. Edited by David L. Rimoin, J. Michael Connor, and Reed E. Pyeritz. New York: Churchill Livingstone, 1997, pp. 1745-66

PERIODICALS

de Vries, B.B.A., et al. “The Fragile X Syndrome.” Journal of Medical Genetics 35 (1998): 579–89.

Kaufmann, Walter E., and Allan L. Reiss. “Molecular and Cellular Genetics of Fragile X Syndrome.” American Journal of Medical Genetics 88 (1999): 11–24.

ORGANIZATIONS

Arc of the United States (formerly Association for Retarded Citizens of the US). 500 East Border St., Suite 300, Arlington, TX 76010. (817) 261-6003. http://thearc

.org .

National Fragile X Foundation. PO Box 190488, San Francisco, CA 94119-0988. (800) 688-8765 or (510) 763-6030. Fax: (510) 763-6223. natlfx@sprintmail.com. http://nfxf

.org .

National Fragile X Syndrome Support Group. 206 Sherman Rd., Glenview, IL 60025. (708) 724-8626.

WEBSITES

“Fragile X Site Mental Retardation 1;FMR1.” Online Mendelian Inheritance in Man http://www3.ncbi.nlm

.nih.gov/Omim/ . (March 6, 2001).

Tarleton, Jack, and Robert A. Saul. “Fragile X Syndrome.” GeneClinics http://www.geneclinics.org . (March 6, 2001).

Nada Quercia, MS, CCGC, CGC

Francois dyscemphalic syndrome see

Hallermann-Streiff syndrome

syndrome X Fragile

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

433

Fraser syndrome

I Fraser syndrome

Definition

Fraser syndrome, also called cryptophthalmos with other malformations, is a rare non-sex linked (autosomal) recessive genetic disorder that primarily affects the eyes.

Description

Fraser syndrome is named for Canadian geneticist C. R. Fraser, who first described the syndrome in 1962. The syndrome is also referred to as crytophthalmos with other malformations because over 90% of the people born with this syndrome have hidden (crypto-) eyes (ophthalmos). It is alternately called cryptophthalmos-syn- dactyly syndrome since most affected individuals also have partial fusion or webbing of their fingers or toes (syndactyly).

Individuals affected with Fraser syndrome appear to have hidden eyes (cryptophthalmos) because the skin of their eyelids is partially or fully sealed shut. Cryptophthalmos is classified into three types: complete, in which the eyelid is completely fused over an existing eye; incomplete, in which the eyelid is only partially fused over the underlying eye; and abortive, in which the eyelid is completely fused and the underlying eye does not form.

Approximately half of all individuals affected with Fraser syndrome have abnormalities of the genitals, while 37% have kidney (renal) problems, including the lack of one or both kidneys. Some individuals also have abnormalities of the voice box (larynx) and of the middle and outer ear.

Genetic profile

The gene responsible for Fraser syndrome has not yet been identified, but it is known to be transmitted as a non-sex linked (autosomal) recessive trait. It seems likely that the gene responsible for Fraser syndrome alters the normally programmed cell death process (apoptosis) in affected individuals. This is suggested by the fact that several of the symptoms of Fraser syndrome result from a failure of apoptosis.

Cells are normally programmed to die when certain conditions have been met. These cells are then replaced by new cells in an ongoing process. Cancer cells do not have the ability to undergo this natural cell death process. It is for this reason that many cancers are associated with tumor growth. Tumors are made up of cells that do not undergo apoptosis. The cells in individuals with Fraser syndrome that do not seem to undergo apoptosis are

those cells that cause the overgrowth of certain tissues, such as the eyelids in the case of cryptophthalmos or the tissues of the fingers and toes in the case of syndactyly.

Demographics

Fraser syndrome is very rare, occurring in fewer than one of every 100,000 births. It has been reported that the frequency of the syndrome is over 100 times higher in the Roma (gypsy) population as in the non-Roma population. As in all recessive genetic disorders, both parents must carry the gene mutation in order for their child to have the disorder. Approximately 15% of individuals diagnosed with Fraser syndrome have been observed in cases where the parents are related by blood (consanguineous). Parents with one child affected by Fraser syndrome have a 25% likelihood that their next child will also be affected with the disease. As of 2000, the specific gene mutations responsible for Fraser syndrome have not been identified.

Signs and symptoms

Fraser syndrome is characterized by hidden eyes (cryptophthalmos) resulting from either partial or complete fusion of the eyelids. This condition may be observed on only one side (unilaterally), but it is generally observed in both eyes of affected individuals (bilateral cryptophthalmos). In most cases the underlying eyes are not fully formed which causes small eyes (microphthalmia). In some cases of Fraser syndrome the underlying eyes are completely absent (abortive cryptophthalmos).

Individuals with Fraser syndrome have abnormal or absent tear ducts and widely spaced eyes (hypertelorism). Blindness from birth is quite common in affected individuals. However, in cases where there is a functioning visual pathway to the inner, light-sensitive layer of the eye (retina), partial vision has been observed.

Approximately half of those individuals affected with Fraser syndrome have partial or complete fusion of the fingers or toes (syndactyly). In cases of Fraser syndrome, the observed syndactyly is most often of the third and fourth digits of the hands or feet. An extra finger or toe situated outside the normal fifth digit (postaxial polydactyly) and webbing of the fingers or toes (cutaneous syndactyly) are also symptoms seen in individuals with Fraser syndrome. The only other bone abnormality seen with any high frequency is a greater than normal width of the cartilaginous joint between the pubic bones in the front of the pelvis (symphysis pubis).

Abnormalities of the middle and/or outer ear occur in approximately 50% of affected individuals. These symptoms range from malformations and closures of the outer ear (called the pinna or the auricle) to an absence of

434

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