Fraser syndrome

Description

Fraser syndrome is a rare disorder that affects development before birth. Characteristic features of this condition include:

• Eyes that are covered by skin (cryptophthalmos)
• Fusion of the skin between the fingers and toes (cutaneous syndactyly)
• Abnormalities of the genitalia and the urinary tract (genitourinary anomalies)

Cryptophthalmos is the most common abnormality in people with Fraser syndrome. In most cases, both eyes are completely covered by skin. However, in some affected individuals, only one eye is covered, or one or both eyes are partially covered. Additional eye abnormalities may include:

• Eyes that do not develop fully and are abnormally small (microphthalmia)
• Eyes that are severely underdeveloped or absent (anophthalmia)

Because of these eye abnormalities, people with Fraser syndrome may have partial or complete vision loss.

Individuals with Fraser syndrome often have abnormalities in their reproductive and urinary tracts. These can include:

• Absence of one or both kidneys (renal agenesis)
• Abnormal development of the vagina
• Undescended testes (cryptorchidism)
• External genitalia that do not appear clearly male or female

Affected individuals may also have other kidney problems or abnormalities of other parts of the urinary tract, such as the bladder.

A variety of other signs and symptoms can be associated with Fraser syndrome:

• Heart abnormalities
• Abnormalities of the voicebox (larynx) or other parts of the upper airway
• Abnormalities of the ears or nose
• An opening in the upper lip (cleft lip) with or without an opening in the roof of the mouth (cleft palate)
• An absence (atresia) or narrowing (stenosis) of the anus

Intellectual disabilities sometimes occur, although many people with Fraser syndrome have normal intelligence. The specific features and the severity of Fraser syndrome can vary widely. In severe cases, abnormalities of the airway or kidneys can be fatal before or shortly after birth.

Frequency

Fraser syndrome is a rare condition. It is believed to affect up to 1 in 250,000 newborns. More than 250 cases have been reported in the scientific literature.

Causes

Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in the FRAS1, FREM2, or GRIP1 genes can cause Fraser syndrome. FRAS1 gene variants are the most common cause of Fraser syndrome. FREM2 and GRIP1 gene variants are each responsible for a small percentage of cases.

The proteins that are produced from the FRAS1 and FREM2 genes are part of a group of proteins called the FRAS/FREM complex. The protein that is produced from the GRIP1 gene ensures that the FRAS1 and FREM2 proteins get to the correct location 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 the cells in many tissues. One of the roles of the FRAS/FREM complex is to anchor the basement membrane of the top layer of skin to the layer of skin below. The FRAS/FREM complex is also involved in the proper organization and development of certain organs and tissues, including the kidneys.

The pathogenic variants in the FRAS1, FREM2, or GRIP1 genes that cause Fraser syndrome interfere with the proper formation of the FRAS/FREM complex. This disrupts the connection between tissue layers, including the connection between the top layer of skin and the layer of skin underneath. Disrupting the interactions between tissue layers impairs cellular movement and communication during early development, which can lead to the cryptophthalmos and cutaneous syndactyly seen in affected individuals.

Through a mechanism that is not well understood, the pathogenic variants that cause Fraser syndrome appear to interfere with the self-destruction of cells that are no longer needed (apoptosis), which may contribute to the additional abnormalities seen in people with Fraser syndrome.

In some people with Fraser syndrome, a pathogenic variant cannot be identified. In these cases, the cause of the disorder is unknown.

Inheritance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a pathogenic variant to cause the disorder. Usually, the parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

Autosomal recessive inheritance. Credit: U.S. National Library of Medicine.

Other Names for This Condition

• Cryptophthalmos syndactyly syndrome
• Cryptophthalmos syndrome
• Cryptophthalmos with other malformations
• Fraser-Francois syndrome
• Meyer-Schwickerath syndrome
• Ullrich-Feichtiger syndrome

Where this page came from

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