About cryptophthalmos-syndactyly syndrome

What is cryptophthalmos-syndactyly syndrome?

Fraser syndrome is a rare genetic disorder characterized by partial webbing of the fingers and/or toes (partial syndactyly), kidney (renal) abnormalities, genital malformations, and/or, in some cases, complete fusion of the eyelids (cryptophthalmos) that may be associated with malformation of the eyes, causing blindness. In infants with Fraser syndrome, renal malformations may include improper development (dysplasia), underdevelopment (hypoplasia), or absence of one or both kidneys (unilateral or bilateral renal agenesis). In affected males, one or both testes may fail to descend into the scrotum (cryptorchidism), the urinary opening (meatus) may be abnormally placed on the underside of the penis (hypospadias), and/or the penis may be abnormally small (micropenis). Affected females may have malformed fallopian tubes, an abnormally enlarged clitoris (clitoromegaly), and/or an abnormally shaped uterus (bicornate uterus). In addition, the folds of skin on either side of the vaginal opening (labia) may be abnormally fused. Infants and children with Fraser syndrome may also have additional abnormalities including malformations of the middle and outer ear that may result in hearing impairment. Fraser syndrome is inherited as an autosomal recessive genetic trait.

What are the symptoms for cryptophthalmos-syndactyly syndrome?

Fraser syndrome is characterized by multiple physical abnormalities.

Failure of the eyelids to form properly (cryptophthalmos) is the most common abnormality, seen in 93% of affected individuals. Other less common forms of cryptophtalmos seen in these individuals are only one eye completely covered by skin, or one or both eyes partially covered. In addition, there are other possible malformations of the eyes such as small eyes (microphthalmia), missing eyes (anophthalmia), absent or malformed lacrimal tear ducts (nasolacriminal ducts) and increased distance between the eyes (hypertelorism). These eye abnormalities lead to vision loss or impairment.

Cutaneous syndactyly is another common abnormality in people with Fraser syndrome. Affected individuals typically have their three middle fingers joined and their three middle toes joined, but the other fingers/toes can also be joined.

Another common sign is kidney abnormalities such as the absence of one or both kidneys (unilateral or bilateral renal agenesis). Other kidney malformations may include improper development (dysplasia) and underdevelopment (hypoplasia).

Genital malformations are common in individuals with FS. In affected males, one or both testes may fail to descend into the scrotum (cryptorchidism), the urinary opening (meatus) may be abnormally placed on the underside of the penis (hypospadias), and/or the penis may be abnormally small (micropenis). Affected females may have malformed fallopian tubes, an abnormally enlarged clitoris (clitoromegaly), an abnormally shaped uterus with two horn-like extensions (bicornate uterus) and/or abnormally closed or absent vagina (vaginal atresia). Some affected individuals’ outer genitals may not have the typical appearance of either a male or female (ambiguous genitalia).

Respiratory tract abnormalities are another common sign in people with FS. There may be malformations of the voice box (larynx) (laryngeal stenosis or atresia), meaning it is more narrow than average or blocked. Malformations of the nose and lungs are also common. This can cause breathing difficulties leading to potentially fatal respiratory insufficiency.

Other possible signs and symptoms are:

  • Mouth: an opening or split in the roof of the mouth (cleft palate), difficulty in tongue movements, teeth overlapping because there is not enough space for all the teeth to properly fit within the mouth (dental crowding)
  • Nose: a wide nose, flattening of the top part of the nose (depressed nasal bridge), deep indentations on the side of each nostril, abnormal narrowing of the posterior nasal aperture (choanal stenosis)
  • Ears: malformations of ear structure, hearing impairment or loss
  • Eyes: absence of the eyeball (anophthalmia)
  • Face: hair growth that extends from the forehead to the eyebrows, missing eyebrows and/or eyelashes
  • Breast: widely spaced nipples (wide intermamillary distance)
  • Cardiovascular: abnormal structure of the heart (abnormal heart morphology)
  • Respiratory system: underdeveloped/small lung (pulmonary hypoplasia)
  • Digestive system: abnormality of the small intestine, liver, abnormality of the anus, abnormality of the structure of the belly button (abnormal umbilicus morphology)
  • Endocrine system: abnormality of the thymus
  • Immune system: severe T-cell immunodeficiency
  • Skeletal system: abnormality of the pubic bone (wide pubic symphysis) absent/underdeveloped sternum (aplasia/hypoplasia of the sternum)
  • Nervous system: intellectual disability, small head size (microcephaly), incomplete formation of the bones of the spine (myelomeningocele)

What are the causes for cryptophthalmos-syndactyly syndrome?

Fraser syndrome is caused by changes (mutations) in the FRAS1, FREM1, FREM2 or GRIP1 genes). More specifically, Fraser syndrome 1 (FRASRS1) is caused by mutations in the Fraser extracellular matrix complex subunit 1 (FRAS1) gene. Fraser syndrome 2 (FRASRS2) is caused by mutations in the FRAS1-related extracellular matrix protein 2 (FREM2) gene. Fraser syndrome 3 (FRASRS3) is caused by mutations in the glutamate receptor-interacting protein 1 (GRIP1) gene. FRAS1 gene mutations are the most common cause for Fraser syndrome, representing approximately half of the FS cases; whereas FREM2 gene and GRIP1 gene mutations account for a smaller percentage of cases.

Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.

The FRAS1 and FREM2 genes produce proteins (FRAS1 and FREM2 proteins, respectively) that work together as part of the FRAS/FREM complex. One of the FRAS/FREM complex’s functions is to connect the different layers of skin together, one on top of the other, to essentially form the skin. Its function is important during the embryonic period before birth. This group of proteins play a role in the proper development of the skin, internal organs including kidneys and other tissues. Therefore, a mutation in the FRAS1 or FREM2 gene causes its respective protein to be faulty, thus the FRAS/FREM complex cannot function properly and therefore leading to improper development of the skin, internal organs and other tissues. This improper development ultimately causes signs and symptoms such as cryptophthalmos, cutaneous syndactyly and renal agenesis. The GRIP1 gene produces the GRIP1 protein that ensures that FRAS1 and FREM2 proteins get to their correct location within the cell to carry out their function. Mutations in the GRIP1 gene prevent normal function of the FRAS1 and FREM2 proteins, causing an improper development of the skin, internal organs and other tissues.

Fraser syndrome is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits the same abnormal/mutated gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

What are the treatments for cryptophthalmos-syndactyly syndrome?

There is currently no cure for Fraser syndrome. Treatment of FS may include surgery to correct some of the malformations associated with this disorder depending on their severity. Other treatment is symptomatic and supportive. A team of specialists is required to evaluate each patient and determine ways to treat the symptoms. The prognosis without treatment depends on the severity of the specific anomalies in the patient, especially respiratory tract malformations and anal imperforations. Unfortunately, death in the first year of life is common in children with severe anomalies.

Genetic counseling is recommended for families of children with this disorder.

What are the risk factors for cryptophthalmos-syndactyly syndrome?

An uncommon genetic condition known as cryptophthalmos syndactyl syndrome is characterized by a number of birth defects.

  • A narrow, blocked, and malformed voice box and lower respiratory tract (nostrils, larynx, and lungs); limb anomalies; kidney (renal) abnormalities; external genital malformations; eyes that are completely covered by skin and usually malformed (cryptophthalmos) causing blindness; a fusion of the skin between the fingers and toes (cutaneous syndactyly); a blocked or missing anal opening (imperforate anus); and intellectual disability. It’s also known as Fraser Syndrome.
  • Fraser syndrome has an autosomal recessive inheritance pattern. When a person inherits the same abnormal/mutated gene for the same trait from both parents, recessive genetic diseases develop.
  • A person will be a carrier for the disease if they have one normal gene and one sick gene, although they often won't exhibit any symptoms.
  • With each pregnancy, there is a 25% chance that two carriers will carry the faulty gene to their offspring and cause them to be impaired.
  • Each pregnancy carries a 50% chance of passing the gene to the unborn child. A child has a 25% probability of inheriting normal genes from both parents and being genetically normal for that specific trait. The risk is the same for males and females.


Conditions
Eyes that are completely covered by skin and usually malformed (cryptophthalmos),Abnormalities of the genitalia and the urinary tract,Fusion of the skin between the fingers and toes (cutaneous syndactyly)
Drugs
NA
Symptoms
Difficulty in tongue movement,Hearing impairment

Is there a cure/medications for cryptophthalmos-syndactyly syndrome?

Fraser syndrome/cryptophthalmos syndactyl syndrome is currently incurable. Depending on the severity of the abnormalities, surgery may be used to treat some of the FS-related defects.

  • Other forms of treatment are supportive and symptomatic. Each patient must be assessed by a team of doctors who must also decide how to treat the symptoms.
  • The severity of the patient's unique defects, particularly deformities of the respiratory system and anal perforations, determines the prognosis in the absence of treatment. Unfortunately, infants with severe defects frequently pass away during the first year of life.
  • It is advised that families of children with this disease seek genetic counseling.
  • Unfortunately, the life expectancy of someone with the syndrome is less than a year, and there is nothing we can do about it.
  • According to estimates, 1 in 200,000 neonates has Fraser syndrome. About 1 in 10,000 fetuses that do not survive birth have the syndrome.


Conditions
Eyes that are completely covered by skin and usually malformed (cryptophthalmos),Abnormalities of the genitalia and the urinary tract,Fusion of the skin between the fingers and toes (cutaneous syndactyly)
Drugs
NA
Symptoms
Difficulty in tongue movement,Hearing impairment

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