Acrocephalopolysyndactyly disorders (Apert syndrome, Chotzen syndrome, Carpenter syndrome, Jackson-Weiss syndrome, Pfeiffer syndrome, Sakati syndrome)

Cause

• Apert syndrome is caused by a change (mutation) in the fibroblast growth factor receptor-2 (FGFR2) gene. This gene plays a critical role in skeletal development.
  • Genes provide instructions for creating proteins that play distinct roles in our body. When a mutation of a gene occurs, the protein product may not work as it should.
  • In Apert syndrome, mutations in FGFR2 result in these receptors not properly communicating with fibroblast growth factors. This affects the formation of normal sutures in the brain and can obstruct the development of many other structures in the body.
  • This improper formation is what causes the malformations seen in Apert syndrome.
  • In almost all reported patients, the disorder has been caused by one of two specific mutations of the FGFR2 gene. (These mutations are designated “Ser252Trp” and “Pro253Arg.”) These mutations may cause slightly different presentations, including the severity of syndactyly.
  • Different mutations in the FGFR2 gene may cause several other related disorders, including Pfeiffer syndrome, Crouzon syndrome, and Jackson-Weiss syndrome.
  • In up to 95% of patients, Apert syndrome results from a new mutation in the FGFR2 gene.
• These new mutations appear to occur randomly for unknown reasons (sporadically). It has been reported that sporadic cases may be associated with increased age of the father.
• Rarely, Apert syndrome is inherited in an autosomal dominant fashion.
  • Dominant genetic disorders occur when only a single copy of a mutation is necessary to cause a particular disease.
  • The risk of passing the mutation from an affected parent to an offspring is 50% for each pregnancy.
  • The risk is the same for males and females.

National Organization for Rare Disorders Apert syndrome

• Crouzon syndrome is caused by alterations (mutations) in one of the FGFR genes, most commonly FGFR2.
  • 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, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
  • The alterations in the FGFR gene that cause Crouzon syndrome are inherited in an autosomal dominant manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual.
  • The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy.
  • The risk is the same for males and females.
• In most individuals, the disorder occurs because of spontaneous (de novo) genetic mutations that occur in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
• The FGFR2 gene regulates the production of a protein known as a fibroblast growth factor receptor (FGFR). Genetic mutations that disrupt the functioning of such proteins may result in abnormalities of bone growth and development, ultimately leading to certain malformations of the craniofacial area. Evidence indicates that different mutations in the FGFR2 gene may cause a number of other related disorders, including Apert syndrome, isolated coronal synostosis, Beare-Stevenson syndrome, Pfeiffer syndrome, and Jackson-Weiss syndrome. In addition, according to some reports, certain FGFR2 mutations may result in Crouzon syndrome in some families (kindreds), whereas the same mutations cause Pfeiffer syndrome in other kindreds.
• The implications of such findings are not completely understood

National Organization for Rare Disorders Crouzon syndrome

• Saethre Chotzen syndrome- mutations in the TWIST1 gene.
• • The TWIST1 gene has been mapped to the short arm (p) of chromosome 7 (7p21)
  • Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. For example, “7p21” refers to band 21 on the short arm of chromosome 7.
• The majority of individuals with an identified mutation have a fault in the TWIST gene, however at least one individual has been identified with a mutation in the FGFR2 gene.
• SCS is an autosomal dominant condition. Dominant genetic disorders occur when only a single copy of an abnormal gene is sufficient to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% (1 in2) for each pregnancy. The risk is the same for males and females.
• In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.

National Organization for Rare Disorders Saethre Chotzen syndrome

• Carpenter syndrome was caused by mutations in the RAB23 gene (Carpenter syndrome type 1)  and MEGF8 gene (Carpenter syndrome type 2)
• Both types of Carpenter syndrome are inherited in an autosomal recessive manner.
  • Family history autosomal recessive disorder (Both parents who are carriers of  the recessive genes responsible and can cause a 25% chance of their sibling getting this condition)
  • If both parents are carriers, a child has a 25 percent chance of inheriting two recessive genes (and getting this condition), a 50 percent chance of getting one dominant and one recessive gene (and becoming a carrier), and a 25 percent chance of getting two dominant genes (and remaining unaffected).
• All individuals carry 4-5 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.

National Organization for Rare Disorders Carpenter syndrome

• Jackson-Weiss syndrome is caused by a mutation in the FGFR2 gene.
• The FGFR2 gene regulates the production of a protein known as a fibroblast growth factor receptor (FGFR).
• Genetic mutations that disrupt the functioning of such proteins may result in certain abnormalities during embryonic development, such as premature fusion of the craniofacial area and the limbs.
• A number of syndromes have been identified that are associated with mutations of the FGFR2 gene including Crouzon, Pfeiffer, and Apert syndromes.
• Most individuals with a FGFR2 gene mutation associated with JWS will have symptoms and findings associated with the disorder, but range and severity may vary greatly from person to person.
• Jackson-Weiss syndrome is an autosomal dominant genetic disorder.
• Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease.
• The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual.
• The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy.
• The risk is the same for males and females.

National Organization for Rare Disorders Jackson-Weiss syndrome

• Pfeiffer syndrome type I is associated with mutations in FGFR1 and FGFR2.
• Pfeiffer syndrome type II and type III are associated with mutations in FGFR2.
• Pfeiffer syndrome is an autosomal dominant genetic disorder.
  • Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. Essentially all cases of Pfeiffer syndrome type II and type III have resulted from new mutations. Advanced paternal age is associated with an increased risk for new mutations for Pfeiffer syndrome. The risk of passing the abnormal gene from an affected parent to offspring is 50% for each pregnancy.
  • The risk is the same for males and females.

National Organization for Rare Disorders Pfeiffer syndrome

Sakati syndrome

• Thought to be caused by a new genetic change (mutation) that occurs randomly for unknown reasons (sporadically).
• If a person with Sakati syndrome were to have children, the altered gene for the disorder may be transmitted as an autosomal dominant trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.
• Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

National Organization for Rare Disorders Sakati syndrome