Fraser syndrome

Overview

Fraser syndrome (FS) was recognised as a clinical entity and named after George Fraser, who described two sibships with physical findings of CO, syndactyly, genital anomalies, laryngeal stenosis, ear malformations, and renal abnormalities.

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

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).

Causes

Mutations in the FRAS1, FREM2, or GRIP1 gene can cause Fraser syndrome. FRAS1 gene mutations are the most common cause, accounting for about half of cases of Fraser syndrome. FREM2 and GRIP1 gene mutations are each found in a small percentage of cases.

The FRAS1 and FREM2 proteins (produced from the FRAS1 and FREM2 genes, respectively) are part of a group of proteins called the FRAS/FREM complex. The GRIP1 protein (produced from the GRIP1 gene) ensures that FRAS1 and FREM2 get to the correct location of the cell to form the FRAS/FREM complex.

The FRAS/FREM complex is found in basement membranes, which are thin, sheet-like structures that separate and support cells in many tissues. This complex is particularly important during development before birth. One of the complex's roles is to anchor the top layer of skin by connecting its basement membrane to the layer of skin below. The FRAS/FREM complex is also involved in the proper development of other organs and tissues, including the kidneys, although the mechanism is unclear.

Mutations in any of these genes prevent formation of the FRAS/FREM complex. Lack of this complex in the basement membrane of the skin leads to detachment of the top layer of skin, causing blisters to form during development. These blisters likely impair the proper formation of certain structures before birth, leading to cryptophthalmos and cutaneous syndactyly. It is unknown how lack of the FRAS/FREM complex leads to kidney and genital abnormalities and other problems in Fraser syndrome.

Diagnosis

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).

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

Treatment

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 person