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

the auditory canal (Eustachian tube). In cases where the Eustachian tube is absent, connective tissue fills the space where the auditory canal should be and bone covers what would be the opening of the auditory canal to the outer ear. As a result of these abnormalities, some individuals may be deaf or suffer from hearing problems.

Approximately 85% of those affected with Fraser syndrome have abnormalities of the nose. The most common nasal abnormalities are blockage or narrowing of the nasal cavities that open into the mouth and throat (the internal nares or choanae) by either excess bone or by membranous tissue. Forking of the tongue and cleavage of the internal nasal passage are also seen.

Blockage and narrowing of the voice box (larynx) are also commonly associated with Fraser syndrome. Occasionally an abnormal web-like structure is seen in the vocal apparatus of the larynx (glottis) that causes an inability of speech if not corrected.

Abnormalities of the digestive system, otherwise known as the gastrointestinal, or GI, tract are also common. These abnormalities include an incomplete development of the membrane (mesentery) that connects the small intestine to the back wall of the abdominal cavity; malrotation of the small intestine; a protrusion of parts of the large intestine through an abnormal opening in the abdominal wall near the navel (umbilical hernia); and, defects of the muscle beneath the lungs (diaphragm) that is responsible for the flow of air into and out of the lungs.

Approximately 50-80% of all individuals with Fraser syndrome have abnormalities of the genitalia. Affected females may have partial or complete fusion of the folds of skin on either side of the vagina (labia), an abnormally large clitoris, a malformation of the paired tubes that connect the ovaries to the uterus (fallopian tubes), and/or an abnormally shaped uterus (bicornate uterus). Affected females beyond puberty also may not have a menstrual cycle. In affected males, one or both testicles may fail to descend into the scrotum, the urinary opening may occur on the underside of the penis rather than at the tip of the penis (hypospadias), the penis may be abnormally small, and/or the urinary opening of the penis may be fused shut (anterior urethral atresia).

Another complication of Fraser syndrome is malformations of one or both kidneys. These malformations may include improper development (renal dysplasia), underdevelopment (renal hypoplasia), or the complete absence of one or both kidneys (unilateral or bilateral renal agenesis).

Both the navel and the nipples may develop in irregular locations. The navel can be located lower than normal and the nipples are generally wider set. A hairline that extends forward over the temples is an additional cosmetic symptom of Fraser syndrome.

K E Y T E R M S

Apoptosis—The normally programmed cell death process in which cells die in order to be replaced with new cells.

Atresia—An abnormal condition in which a structure that should be hollow is fused shut.

Autosomal—Relating to any chromosome besides the X and Y sex chromosomes. Human cells contain 22 pairs of autosomes and one pair of sex chromosomes.

Consanguineous—Sharing a common bloodline or ancestor.

Cryptophthalmos—An abnormal formation of the eye in which the eyelid, or overlaying skin of the eye, is fused shut. Literally, “hidden eye.”

Hypertelorism—A wider-than-normal space between the eyes.

Microphthalmia—Small or underdeveloped eyes.

Postaxial polydactyly—A condition in which an extra finger or toe is present outside of the normal fifth digit.

Renal agenesis—Absence or failure of one or both kidneys to develop normally.

Stenosis—The constricting or narrowing of an opening or passageway.

Syndactyly—Webbing or fusion between the fingers or toes.

Many infants with Fraser syndrome suffer from water on the brain (hydrocephaly) and some cases have been found in which one of the normal cavities within the brain (the left ventricle) is not present. Dandy-Walker syndrome, a brain malformation of the fourth ventricle of the brain, has also been associated with Fraser syndrome. These brain abnormalities can all cause mental retardation.

Diagnosis

The symptoms of Fraser syndrome have been classified into four major and eight minor characteristics. A patient is diagnosed with Fraser syndrome rather than another genetic syndrome by the presence of at least two of the four major characteristics of the syndrome accompanied by at least one of the eight minor characteristics of the syndrome, or by the presence of one major characteristic and at least four minor characteristics.

syndrome Fraser

Fraser syndrome

The four major characteristics of Fraser syndrome are hidden eyes (cryptophthalmos), fused or partially fused fingers and/or toes (syndactyly), abnormalities of the genitals, and the existence of an affected sibling.

The eight minor characteristics of Fraser syndrome are malformations of the nose, malformations of the ears, malformations of the voice box, a protrusion of parts of the large intestine through an abnormal opening in the abdominal wall near the navel (umbilical hernia), the absence or the incomplete development of one or both kidneys (renal agenesis), abnormalities of the bones other than syndactyly, cleavage of the tongue or other oral clefts, and mental retardation.

Prenatal diagnosis of Fraser syndrome is possible as early as 18 weeks into the pregnancy and is accomplished by the observance via ultrasound of a combination of some or all of the following conditions: blockage of urine flow out of the bladder; small eyes; fused or partially fused fingers and/or toes; blockage of the lungs (pulmonary obstruction) resulting from an absence or closure of the voice box (laryngeal atresia); the accumulation of thin, watery fluid (serous fluid) in the abdominal cavity (ascites); a blood disorder (fetal hydrops) that prevents proper formation of the oxygen-carrying molecule of blood (hemoglobin); a presence of an abnormally high amount of fluid in the tissues comprising the nape of the neck (nuchal edema), and an absence of amniotic fluid due to an incomplete development of the kidney (oligohydramnios).

Treatment and management

Genetic counseling is particularly important in the prenatal treatment and management of Fraser syndrome. This is because the severity of symptoms and appearance of an infant with this syndrome is likely to be very similar in a sibling also born with the disease.

Surgery is almost always necessary to correct the improperly fused tissues of the eyelids, ears, nose, and genitals. Most affected individuals are blind at birth, however, if some visual function is observed to be present, such as a wincing reaction to strong light, partial vision is possible after surgery to repair the damaged eyelids. Recently, corneal transplant surgery has been used to achieve improvements in vision. In cases of a missing eye (anophthalmia) reshaping of the eye socket may be necessary and a glass eye will need to be fitted for cosmetic purposes. Many infants diagnosed with Fraser syndrome are also deaf or partially deaf at birth. Special programs for the hearing and vision impaired will be necessary for these affected persons.

The most serious and life-threatening abnormalities associated with Fraser syndrome are those of the kidneys and the larynx. In some cases, the laryngeal malforma-

tions cannot be repaired, which leads to either stillbirth or death shortly after birth. This is particularly true of blockage of the larynx (laryngeal atresia). Corrective surgery is often possible in cases of narrowing of the larynx (laryngeal stenosis).

If both kidneys are absent (bilateral renal agenesis), the affected individual is usually stillborn. If only one kidney is present (unilateral renal agenesis), the kidney or kidneys are improperly developed (renal dysplasia), or underdeveloped (renal hypoplasia) the affected individual may require kidney dialysis or a kidney transplant. The abnormalities of the small intestine that are associated with Fraser syndrome are generally correctable through surgery.

Prognosis

The type and severity of the kidney and voice box malformations that may result in Fraser syndrome usually determine the prognosis. Overall, 25% of all babies born with Fraser syndrome are stillborn. Another 20% die within the first year of infancy, usually in the first few weeks of life. The cause of death is usually lack of kidney function or blockage of the larynx. Kidney and larynx defects tend to be either very slight or absent in the surviving 55% of Fraser syndrome affected individuals, but developmental delay is observed in most patients.

Resources

PERIODICALS

“Craniofacial Clinic: Correction of Ptosis in Children.”

Pediatrics & Medical Genetics News of the Cedars-Sinai Medical Center (Summer 1997): 6-7.

Martinez-Frias, M., et al. “Fraser Syndrome: Frequency in our Environment and Clinical-Epidemiological Aspects of a Consecutive Series of Cases.” Anales Espanoles de Pediatria (June 1998): 634-8.

Thomas, I., et al. “Isolated and Syndromic Cryptophthalmos.”

American Journal of Medical Genetics (September 1996): 85-98.

ORGANIZATIONS

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

National Kidney Foundation. 30 East 33rd St., New York, NY 10016. (800) 622-9010. http://www.kidney.org .

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. http://www

.rarediseases.org .

WEBSITES

“Fraser Syndrome.” OMIM—Online Mendelian Inheritance in

Man. http://www.ncbi.nlm.nih.gov/htbin-post/Omim/ dispmim?219000 . (06 February 2001).

Jeanty, Philippe, MD, PhD, and Sandra R. Silva, MD. “Fraser Syndrome.” (May 13, 1999) TheFetus.Net. http://www

.thefetus.net/sections/articles/Syndromes/Fraser_ syndrome.html#_ednref10 . (February 6, 2001).

“Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes: Fraser Syndrome.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database. http://www.nlm.nih.gov/cgi/ jablonski/syndrome_cgi?index=302 . (February 6, 2001)

Paul A. Johnson

FRDA-1 see Friedreich ataxia

I Freeman-Sheldon syndrome

Definition

Freeman-Sheldon syndrome (FSS) is a very rare genetic disorder characterized by a small, puckered mouth, which gives the appearance of a person whistling. For this reason, Freeman-Sheldon syndrome is also known as whistling face syndrome. FSS may also be referred to as windmill vane hand syndrome or craniocarpotarsal dystrophy.

Description

Ernest Freeman and Joseph Sheldon, two British physicians, first described this distinct disorder in 1938. The syndrome is characterized by skeletal malformations in the hands and feet and facial abnormalities.

In addition to the small mouth, characteristics of FSS include a flat, mask-like face, underdeveloped nose cartilage, contracted muscles of the joints of fingers and hand, and clubbed feet. Most of the features of FSS are caused by muscle weakness. In addition to those characteristics noted above, individuals with FSS may also have crossed eyes, drooping upper eyelids, scoliosis, hearing loss, and walking difficulties. Intelligence is usually normal, health is generally good, and life expectancy is normal.

Genetic profile

Usually, FSS follows an autosomal dominant inheritance pattern. With this pattern of inheritance, the syndrome appears when a child inherits one defective gene from one parent. In some families, FSS follows an autosomal recessive inheritance pattern. In these cases, the condition only appears when a child receives the same defective gene from each parent. This syndrome can also occur sporadically, that is, neither parent passes on the gene responsible for FSS.

K E Y T E R M S

Autosomal—Relating to any chromosome besides the X and Y sex chromosomes. Human cells contain 22 pairs of autosomes and one pair of sex chromosomes.

Distal arthrogryposis—A disorder characterized by contractions of the muscles in the hands.

Ultrasound—An imaging technique that uses sound waves to help visualize internal structures in the body.

As of 2001, the gene responsible for FSS has not been located. Current genetic research is focusing on chromosome 11. Some experts consider FSS a form of distal arthrogryposis, which has been mapped to chromosome 11, specifically to location 11p15.5.

Demographics

Freeman-Sheldon syndrome is extremely rare. It affects males and females in equal numbers.

Signs and symptoms

Doctors can recognize Freeman-Sheldon syndrome at birth. Babies born with FSS usually have distinct abnormalities of the head, face, hands, and feet.

Facial abnormalities usually include an extremely small and puckered mouth, a full forehead, prominent cheeks, and thin, pursed lips. The middle part of the face may be flat, giving the baby a mask-like appearance. There may be a high palate, unusually small jaw, abnormally small tongue, and a raised mark or dimpling in the shape of an “H” or “V” on the chin. Other common facial abnormalities associated with FSS include widelyspaced, deep-set eyes, crossed eyes, and down-slanting eye openings.

Infants born with FSS may have malformations of the hands or feet, including clubbed feet. The muscles in the joints of the fingers and hands may be contracted.

Characteristics of FSS are often linked with other problems such as impaired speech, swallowing and eating difficulties, and vomiting. Children may fail to grow and gain weight at the expected rate, and there may be respiratory problems. Although most of the characteristics of FSS will be discovered fairly early in life, scoliosis (curvature of the spine) may be diagnosed later in childhood or adolescence as the child grows.

syndrome Sheldon-Freeman

Friedreich ataxia

Description

Ataxia is a condition marked by impaired coordination. Friedreich ataxia is the most common inherited ataxia, affecting between 3,000–5,000 people in the United States.

Genetic profile

FA is an autosomal recessive disease, which means that two defective gene copies must be inherited to develop symptoms, one from each parent. A person with only one defective gene copy is called a carrier and will not show signs of FA, but has a 50% chance of passing along the gene to offspring with each pregnancy. Couples in which both parents are carriers of FA have a 25% chance with each pregnancy of conceiving an affected child. The gene for FA is on chromosome 9 and codes for a protein called frataxin. Normal frataxin is found in the cellular energy structures known as mitochondria, where it is involved in regulating the transport of iron.

In approximately 96% of patients with FA, both copies of the frataxin gene are expanded with nonsense information known as a “triple repeat” of a particular sequence of DNA bases called “GAA”. Normally, the GAA sequence is repeated between six and 34 times, but those with FA have between 67 and 1,700 copies. About 4% of patients have been found to have the triple repeat in only one copy of the frataxin gene and a different gene change in the other. Longer GAA repeats are associated with more severe disease, but the severity of disease in a particular individual cannot be predicted from the repeat length. The extra DNA or other gene change interferes with normal production of frataxin, thereby impairing iron transport. FA is thought to develop at least in part because defects in iron transport prevent efficient use of cellular energy supplies. Extra iron builds up in the mitochondria, leading to the accumulation of damaging chemicals called free-radicals.

The nerve cells most affected by FA are those in the spinal cord involved in relaying information between muscles and the brain. Tight control of movement requires complex feedback between the muscles promoting a movement, those restraining it, and the brain. Without this control, movements become uncoordinated, jerky, and inappropriate for the desired action.

Demographics

The prevalence of FA in the Caucasian population is approximately one in 50,000 to one in 25,000. Prevalence appears to be highest in Italy. Approximately 1% of Caucasian individuals carry one defective copy of the gene for frataxin. Friedreich ataxia is very rare in people of Asian or African descent.

K E Y T E R M S

Ataxia—A deficiency of muscular coordination, especially when voluntary movements are attempted, such as grasping or walking.

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

Scoliosis—An abnormal, side-to-side curvature of the spine.

Signs and symptoms

Symptoms of FA usually first appear between the ages of eight and 15, although onset as early as 18 months or as late as age 25 is possible. The first symptom is usually gait incoordination. For instance, a child with FA may graze doorways when passing through or trip over low obstacles. Unsteadiness when standing still and deterioration of position sense is common. Foot deformities and walking up off the heels often results from uneven muscle weakness in the legs. Muscle spasms and cramps may occur, especially at night.

Ataxia in the arms usually follows within several years, leading to decreased hand-eye coordination. Arm weakness does not usually occur until much later. Speech and swallowing difficulties are common. The loss of reflexes in the lower legs is common. Diabetes mellitus, a condition characterized by elevated blood sugar, may also occur. One study suggested that carriers of one FAA gene with an “intermediate” sized GAA region (10 to 36 copies of GAA) are also at increased risk for diabetes, but as of 2001, other similar studies did not show this finding. Nystagmus, or eye tremor, is common in FA, along with some loss of visual acuity. Hearing loss may also occur. A side-to-side curvature of the spine (scoliosis) occurs in many cases and may become severe.

Heart muscle enlargement with or without heartbeat abnormality occurs in about two thirds of FA patients, leading to shortness of breath after exertion, swelling in the lower limbs, and frequent complaints of cold feet.

There are some atypical forms of FA. For example, the Acadian population that descended from Northern France and now live in Louisiana, have a very slow progressing disease and rarely have heart problems, leading them to live longer than most patients with FA. Other forms include late onset Friedreich ataxia (LOFA), in which symptoms begin after the age of 25 years, and Friedreich ataxia with retained reflexes (FARR). All three of these forms have been shown to result from changes in the same gene as the “classic” form. There have been a few patients with classic FA described in which the

ataxia Friedreich

Friedreich ataxia

frataxin gene on chromosome 9 has been shown not to be the cause. A form of ataxia caused by a gene change resulting in vitamin E deficiency, but having similar symptoms to FA, has been identified with changes in a different gene on chromosome 8.

In 1988, a Spanish family was reported in which several members had FA along with congenital glaucoma, a disease caused by increased pressure inside the eye. Glaucoma is not normally seen in patients with Friedreich ataxia or other types of inherited ataxia. Most of the affected family members had parents who were closely related to each other, which placed children at increased risk for autosomal recessive conditions in general. Therefore, the glaucoma and FA may have been caused by two distinct genes inherited in an autosomal recessive manner. As of 2001, there was no follow-up of this family reported, so it is not known if their unusual disease was caused by a gene other than the since-identi- fied frataxin gene or if the glaucoma and the FA were caused by two different genes.

Diagnosis

Diagnosis of FA involves a careful medical history and thorough neurological exam. Lab tests include electromyography, an electrical test of muscle, and a nerve conduction velocity test. An electrocardiogram may be performed to diagnose heart arrhythmia.

Direct DNA testing is available, allowing FA to be more easily distinguished from other types of ataxia. Testing is accomplished by counting the number of GAA repeats in the frataxin gene to see if there is an expansion (67 or more sets of the DNA bases GAA) and by looking for other gene changes in patients who only show a GAA expansion in one copy of the frataxin gene. As of 2001, no patient with FA has been reported to have non-GAA changes in both copies of the frataxin gene. Many of these non-GAA changes completely prevent the frataxin protein from being made, so having two copies may not be compatible with life. The same genetic test may be used to determine the presence of the genetic defect in the carrier state (i.e., one normal copy and one defective copy of the frataxin gene) in unaffected individuals, such as adult siblings, who would like to learn their chances of producing an affected child. During pregnancy, the DNA of a fetus can be tested using cells obtained from procedures called chorionic villi sampling (CVS), in which cells from the placenta are studied, and amniocentesis, in which skin cells from the amniotic fluid surrounding the baby are tested.

Treatment

As of 2001, there is no prevention or cure for FA, nor any proven treatment that can slow its progress. One

recent (1999) study in three patients has suggested that a drug called idebenone can reduce heart problems. Idebenone is an antioxidant—a drug that captures freeradicals, the toxic chemicals generated by increased iron. Amantadine may provide some limited improvement in ataxic symptoms, but is not recommended in patients with cardiac abnormalities. Physical and occupational therapy are used to maintain range of motion in weakened muscles, and to design adaptive techniques and devices to compensate for loss of coordination and strength. Some patients find that using weights on the arms can help dampen the worst of the uncoordinated arm movements.

Heart problems and diabetes are treated with drugs specific to those conditions.

Prognosis

The rate of progression of FA is highly variable. Most patients lose the ability to walk within 15 years of symptom onset, and 95% require a wheelchair for mobility by age 45. Reduction in lifespan from FA complications, usually cardiac, is also quite variable. Average age at death, usually from heart problems, is in the mid-30s, but may be as late as the mid-60s. As of 2001, the particular length of the triple repeat has not been correlated strongly enough with disease progression to allow prediction of the course of the disease on this basis.

Resources

BOOKS

Isselbacher, Kurt J., et al., eds. “Spinocerebellar Degeneration (Friedreich’s Ataxia).” In Harrison’s Principles of Internal Medicine. New York: McGraw-Hill, 1994, p. 2285.

PERIODICALS

Delatycki, Martin B., Robert Williamson, and Susan M. Forrest.

“Friedreich Ataxia: An Overview.” Journal of Medical

Genetics 37 (2000): 1-8.

ORGANIZATIONS

Friedreich’s Ataxia Research Alliance. 2001 Jefferson Davis Highway #209, Arlington, VA 22202. (703) 413-4468.http://www.frda.org .

Muscular Dystrophy Association. 3300 East Sunrise Dr., Tucson, AZ 85718. (520) 529-2000 or (800) 572-1717.http://www.mdausa.org .

National Ataxia Foundation. 2600 Fernbrook Lane, Suite 119, Minneapolis, MN 55447. (763) 553-0020. Fax: (763) 5530167. naf@ataxia.org. http://www.ataxia.org .

National Institute of Neurological Disorders and Stroke. 31 Center Drive, MSC 2540, Bldg. 31, Room 8806, Bethesda, MD 20814. (301) 496-5751 or (800) 352-9424.http://www.ninds.nih.gov .

Toni I. Pollin, MS, CGC

I Frontonasal dysplasia

Definition

Frontonasal dysplasia, also called median cleft syndrome, is a rare disorder affecting primarily the face and head. The causes of frontonasal dysplasia are unknown. Most cases appear to occur randomly (sporadically), but it is suspected that some cases are genetically inherited. The term frontonasal dysplasia was first used in 1970 to describe this disorder.

Description

Frontonasal dysplasia is characterized by malformations of the central portion of the face, especially of the forehead, the nose, and the philtrum (the area between the nose and upper lip). A cleft, or divided area, that traverses one or more of the upper lip, philtrum, nose, and forehead is a hallmark of the disease. Occasionally, affected individuals also experience abnormalities of the brain, heart, and certain bones. In the most severe cases, mild to moderate mental retardation has been observed.

Genetic profile

Most cases of frontonasal dysplasia do not seem to show any genetic linkage. However, a case of an affected male with a spontaneous chromosome rearrangement, in which the abnormality was not inherited from either parent (a de novo rearrangement), involving chromosomes 3, 7, and 11 has been reported in the medical literature. From this case report, it is suggested that the search for the genetic mutation, or mutations, responsible for the appearance of frontonasal dysplasia should focus on locations 3q23, 3q27, 7q22.1, and 11q21. Other researchers have suggested an X-linked dominant trait or a non-sex linked (autosomal) recessive trait is responsible for genetic cases of frontonasal dysplasia. As of early 2001, further research into the genetic origin of this disorder is still needed.

Demographics

Frontonasal dysplasia is rare and statistical data on its occurrence has not been reported. It has not been associated with any particular ethnic or social group. Some reports show frontonasal dysplasia occurs twice as often in males as in females, and that it is associated with increased parental age, which points to chromosome mutation being a possible cause.

Signs and symptoms

Individuals affected with frontonasal dysplasia most often have widely spaced eyes (hypertelorism), a broad-

K E Y T E R M S

Corpus callosum—A thick bundle of nerve fibers deep in the center of the forebrain that provides communications between the right and left cerebral hemispheres.

de novo mutation—Genetic mutations that are seen for the first time in the affected person, not inherited from the parents.

Hallucal polydactyly—The appearance of an extra great toe.

Hypertelorism—A wider-than-normal space between the eyes.

Philtrum—The center part of the face between the nose and lips that is usually depressed.

Tetralogy of Fallot—A congenital heart defect consisting of four (tetralogy) associated abnormalities: ventricular septal defect (VSD—hole in the wall separating the right and left ventricles); pulmonic stenosis (obstructed blood flow to the lungs); the aorta “overrides” the ventricular septal defect; and thickening (hypertrophy) of the right ventricle.

ening of the nose (nasal root), absence of the skin that forms the tip of the nose, and a hairline that extends farther than normal and comes to a point in the center of the forehead (widow’s peak). A cleft lip along the centerline (median cleft lip) of the skin between the nose and the upper lip (philtrum) is also generally seen in individuals affected with the condition.

In some cases, an individual diagnosed with frontonasal dysplasia may also have a vertical groove down the middle of the face; which, in the most extreme instances, may cause the nose to vertically separate into two parts (median cleft nose). Additionally, in some cases of frontonasal dysplasia, a skin-covered gap may be present in the bones of the forehead (anterior cranium bifidum occultum). In cases where the bone deformations of the nose and forehead are quite severe, there may be a malformation of the bony structures (orbits) that hold the eyeballs. Eye defects and even blindness may be present.

In a few cases of frontonasal dysplasia, the group of heart abnormalities known as the tetralogy of Fallot have been observed. This is a combination of four disorders of the heart: an abnormal narrowing of the valve that opens from the right ventricle of the heart into the pulmonary artery (pulmonary stenosis); a hole or perforation in the wall between the left and right ventricles of the heart that

dysplasia Frontonasal

Frontonasal dysplasia

allows blood to flow directly from the higher pressure left ventricle to the lower pressure right ventricle (ventricular septal defect); abnormal positioning of the aorta on the right, rather than the left, side of the heart (dextroposition of the aorta) which means that blood flows out of the right ventricle into the aorta so that deoxygenated blood rather than oxygenated blood is being delivered to the body; and finally, an abnormally large right ventricle (hypertrophy of the right ventricle), which is generally associated with the three other anomalies since each of these over-burdens the right ventricle. This set of conditions leads to an improper oxygenation of the blood, causing “blue baby” at birth. When these defects are observed, surgery is required.

Skeletal deformities have also been observed in some cases of frontonasal dysplasia. These include the presence of an extra toe arising from the great toe (hallucal polydactyly) and a severe under-development of the major bone of the shin (tibial aplasia).

Brain anomalies are also associated with frontonasal dysplasia. These include the absence of the connection between the left and right hemispheres of the brain (corpus callosum) and swelling or hernias of the brain (basal encephalocele). In extreme cases of frontonasal dysplasia, mental retardation may be seen. The extent of retardation appears linked with the degree of hypertelorism, which is an abnormal increase of the distance between the eye sockets. The greater the observed distance between the eyes, the greater the likelihood of mental retardation or developmental delays.

Diagnosis

Frontonasal dysplasia is generally diagnosed at birth based on the observed facial abnormalities. A presence of two or more of the following symptoms is considered a positive diagnosis for frontonasal dysplasia: a skin-cov- ered gap in the bones of the forehead (anterior cranium bifidum occultum); hypertelorism; median cleft lip; median cleft nose; and/or any abnormal development of the center (median cleft) of the face.

Because the genetic cause of frontonasal dysplasia remains unclear and because the majority of cases are sporadic, the only way to diagnose frontonasal dysplasia before birth (prenatally) is via ultrasound observation of craniofacial deformations (holoprosencephaly). This is a technique that produces pictures of the fetus.

Treatment and management

Cosmetic surgery to correct the facial defects associated with frontonasal dysplasia is recommended for all affected individuals. In severe cases, additional facial

surgeries may be required after the initial surgery. These include reformation of the eyelids (canthoplasty), reformation of the orbits (orbitoplasty), surgical positioning of the eyebrows, and plastic surgery of the nose (rhinoplasty).

In cases of congenital heart defects, surgery to correct the defects is required shortly after birth.

Surgery is available to remove the extra toe seen in some affected individuals. Surgeries to correct underdevelopment of the tibia, or shin bone, may also be required. The tibia supports five-sixths of the body weight when a person is standing, with the smaller fibula supporting the remaining one-sixth. If surgery is not performed to correct the shin bone defects seen in some cases of frontonasal dysplasia, the affected individual may never be able to stand or walk.

In the rare instance of mental retardation associated with frontonasal dysplasia, early and continuing intervention programs may be necessary to assist the affected individual.

Prognosis

Individuals diagnosed with frontonasal dysplasia usually are of average intelligence and can expect a normal lifespan. In the rare cases of associated heart abnormalities, the affected individual may die shortly after birth if corrective surgery is not performed as soon as possible.

Resources

PERIODICALS

Guion-Almeida, M., et al. “Frontonasal Dysplasia: Analysis of 21 Cases and Literature Review.” International Journal of Oral and Maxillofacial Surgery (April 1996): 91-7.

Stevens, C., and M. Qumsiyeh. “Syndromal Frontonasal Dysostosis in a Child with a Complex Translocation Involving Chromosomes 3, 7, and 11.” American Journal of Medical Genetics (February 1995): 494-7.

Trifiletti, R., et al. “Aicardi Syndrome with Multiple Tumors: A Case Report with Literature Review.” Brain Development (July-August 1995): 283-5.

ORGANIZATIONS

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

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

.org/ .

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. http://www

.rarediseases.org .

WEBSITES

OMIM—Online Mendelian Inheritance in Man. http://www

.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?136760

(14 February 2001).

Reader’s Digest Health—Frontonasal Dysplasia. http://rdhealth

.com/kbase/nord/nord809.htm (14 February 2001).

Paul A. Johnson

Frontonasal malformation see Frontonasal dysplasia

I Fryns syndrome

Definition

Fryns syndrome is a multiple congenital anomaly syndrome usually resulting in neonatal death.

Description

Fryns syndrome is a genetic condition involving abnormalities in many organ systems that usually results in neonatal death. The condition was first reported in 1979 by J. P. Fryns.

Typical anomalies include a characteristic facial appearance, including a broad nasal bridge (part of the nose between the eyes), small jaw, abnormal ears, cleft palate, abnormal fingers, underdevelopment of the lungs, and abnormalities of the urogenital system (kidneys and genitals). Diaphragmatic hernia (opening in the diaphragm muscle that can allow contents of the lower abdomen like the liver or intestine or stomach to move up into the chest cavity through the hole) can also be seen in some cases. Some researchers believe that there may be a distinct subset of patients without diaphragmatic hernia who are more mildly affected.

Genetic profile

Fryns syndrome is inherited in an autosomal recessive manner. This means that two defective gene copies must be inherited, one from each parent, for the disease to manifest itself. Persons with only one gene mutation are carriers for the disorder. A person who is a carrier for Fryns syndrome does not have any symptoms and does not know he/she is a carrier unless he/she has had a child with Fryns syndrome. Carrier testing is not available since the gene location is not known at this time. The likelihood that each member of a couple would be a carrier for a mutation in the same gene is higher in people who are related (called consanguineous). When both parents are carriers for Fryns syndrome, there is a one in four

chance (25%) in each pregnancy for a child to have the disease. There is a two in three chance that a healthy sibling of an affected child is a carrier.

There have been several different chromosome abnormalities reported with a Fryns syndrome-like appearance. Investigation for a candidate gene causing Fryns syndrome has not yet identified the causative gene.

Demographics

The number of affected individuals is reported as seven in 100,000. There does not appear to be any ethnic difference in prevalence. As of 2001, there were more than 50 documented cases of Fryns syndrome in the literature.

Signs and symptoms

The most frequent anomalies have been described as diaphragmatic defects, underdeveloped lungs, cleft lip and palate (usually on both sides, called bilateral), heart defects, cysts in the kidneys, urinary tract abnormalities, and limb underdevelopment.

Most patients also have underdeveloped external genitals, abnormal internal reproductive structures, abnormalities in the digestive tract, and abnormalities in the structure of the brain. Fewer patients have eye abnormalities.

Other reported anomalies include fetal hydops (fluid surrounding the fetus prenatally, usually fatal), prematurity, scoliosis (curvature of the spine), extra vertebrae or ribs, abnormal bone formation, and small chest cavity.

Diagnosis

Prenatal diagnosis has been possible in several fetuses by use of ultrasound to identify in one fetus fetal hydrops, diaphragmatic hernia, and dilation of the cerebral ventricles and in another with cystic hygroma and diaphragmatic hernia. These anomalies themselves can be isolated or as a part of another genetic syndrome; it is the specific combination of anomalies that would lead one to suspect Fryns syndrome. Definitive diagnosis is not possible until after birth or autopsy.

Treatment and management

Since Fryns syndrome is a genetic disease, caused by mutations in specific genes, there is no cure at this time. Some of the anomalies may be amenable to surgery, such as diaphragmatic hernia or cleft palate, but the entire prognosis for the baby must be considered.

Special education for mentally retarded individuals is indicated if the child survives.

syndrome Fryns

FSH muscular dystrophy

Prognosis

Unfortunately, the prognosis for babies with Fryns syndrome is poor, with usual neonatal death occurring due to the lung hyperplasia and respiratory distress or other anomalies. Approximately 14% of infants survive the neonatal period. Survivors typically do not have complex heart malformations and less frequently have diaphragmatic hernias, milder lung hypoplasia, and neurologic impairment (usually severe to profound mental retardation with serious brain malformations).

Resources

PERIODICALS

Ramsing, M., et al. “Variability in the Phenotypic Expression of Fryns Syndrome: A Report of Two Sibships.” American Journal of Medical Genetics 95 (2000): 415.

ORGANIZATIONS

Genetic Alliance. 4301 Connecticut Ave. NW, #404, Washington, DC 20008-2304. (800) 336-GENE (Helpline) or (202) 966-5557. Fax: (888) 394-3937 info@geneticalliance.http://www.geneticalliance.org .

SHARE-Pregnancy and Infant Loss Support, Inc. St Joseph Health Center, 300 First Capital Dr., St. Charles, MO 63301. (800) 821-6819.

WEBSITES

Online Mendelian inheritance in Man (OMIM).

http://www.ncbi.nlm.nig.gov .

Amy Vance, MS, CGC

I FSH muscular dystrophy

Definition

The term muscular dystrophy refers to a group of conditions characterized by progressive muscle weakness and atrophy (deterioration). Many different types of muscular dystrophy have been described, each of which have unique features and usually a unique underlying genetic cause. Facioscapulohumeral (FSH) muscular dystrophy affects the muscles of the face and shoulders first. Usually the first signs of weakness appear before the age of 20 years. The symptoms of FSH muscular dystrophy are variable and are not fatal. One in five people who are affected require a wheelchair after the age of 40 years.

Description

Facio refers to the face, scapulo to the shoulder blades, and humeral to the bone of the upper arm. The

symptoms of FSH muscular dystrophy are quite variable, even within the same family. Some individuals who have the altered DNA sequence never develop noticeable symptoms. Most people with the condition first notice weakness in their teenage years. Muscles of the shoulders and face are usually the first to be affected. These may remain the only parts of the body that are affected, or the weakness may progress to include the pelvic muscles, the lower limbs, and the hands. Intelligence and life expectancy are not affected.

Genetic profile

FSH muscular dystrophy has autosomal dominant inheritance. This means that an affected person has a 50% chance, with each pregnancy, to pass the altered gene on to the child. Every person has two copies of every DNA sequence, one inherited maternally and the other inherited paternally. The altered DNA sequence that causes FSH muscular dystrophy is on chromosome 4. If a person has one normal sequence and one altered sequence, he or she will probably develop FSH muscular dystrophy.

When an autosomal dominant condition is present in multiple generations of a family, usually someone from each generation is affected. If a person is the first in his or her family to have an autosomal dominant condition, doctors often assume that the gene mutated for the first time in the egg or sperm that came together to make that person. (This is called a new mutation.) However, when the physical symptoms associated with an altered gene are highly variable, the distinction between these two scenarios is less obvious.

The term non-penetrance refers to altered genes that do not always cause a person to have the typical associated symptoms. FSH muscular dystrophy is non-pene- trant in some individuals. Therefore, an individual who appears to be the first person affected in his or her family may have actually inherited the mutated DNA sequence from his or her mother or father. If so, his or her siblings would be at a 50% risk to also have inherited the altered sequence. Similarly, a mildly affected individual may have a child who is severely affected. Occasionally, two affected siblings are born to unaffected parents because of a genetic process called germline mosaicism.

Describing the genetics of FSH muscular dystrophy is slightly complicated by an interesting phenomenon. Genes are the DNA sequences that give the body instructions for growth, development, and functioning. Usually a mutation that causes a disease occurs in the gene associated with that disease. The above description refers to the mutation in FSH muscular dystrophy as an altered DNA sequence because it does not appear that this