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 cryptophthalmos with other malformations because over 90% of the people born with this syndrome have hidden (crypto-) eyes (ophthalmos). It is alternately called cryptophthalmos-syndactyly 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. 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 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.

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.

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 malformations 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, often 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. [email protected]. <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