Shprintzen-Goldberg syndrome is a disorder that affects many parts of the body. Affected individuals have a combination of distinctive facial features and skeletal and neurological abnormalities.

A common feature in people with Shprintzen-Goldberg syndrome is craniosynostosis, which is the premature fusion of certain skull bones. This early fusion prevents the skull from growing normally. Affected individuals can also have distinctive facial features, including a long, narrow head; widely spaced eyes (hypertelorism); protruding eyes (exophthalmos); outside corners of the eyes that point downward (downslanting palpebral fissures); a high, narrow palate; a small lower jaw (micrognathia); and low-set ears that are rotated backward.

People with Shprintzen-Goldberg syndrome are often said to have a marfanoid habitus, because their bodies resemble those of people with a genetic condition called Marfan syndrome. For example, they may have long, slender fingers (arachnodactyly), unusually long limbs, a sunken chest (pectus excavatum) or protruding chest (pectus carinatum), and an abnormal side-to-side curvature of the spine (scoliosis). People with Shprintzen-Goldberg syndrome can have other skeletal abnormalities, such as one or more fingers that are permanently bent (camptodactyly) and an unusually large range of joint movement (hypermobility).

People with Shprintzen-Goldberg syndrome often have delayed development and mild to moderate intellectual disability.

Other common features of Shprintzen-Goldberg syndrome include heart or brain abnormalities, weak muscle tone (hypotonia) in infancy, and a soft out-pouching around the belly-button (umbilical hernia) or lower abdomen (inguinal hernia).

Shprintzen-Goldberg syndrome has signs and symptoms similar to those of Marfan syndrome and another genetic condition called Loeys-Dietz syndrome. However, intellectual disability is more likely to occur in Shprintzen-Goldberg syndrome than in the other two conditions. In addition, heart abnormalities are more common and usually more severe in Marfan syndrome and Loeys-Dietz syndrome.

Shprintzen-Goldberg syndrome is often caused by mutations in the SKI gene. This gene provides instructions for making a protein that regulates the transforming growth factor beta (TGF-β) signaling pathway. The TGF-β pathway regulates many processes, including cell growth and division (proliferation), the process by which cells mature to carry out special functions (differentiation), cell movement (motility), and the self-destruction of cells (apoptosis). By attaching to certain proteins in the pathway, the SKI protein blocks TGF-β signaling. The SKI protein is found in many cell types throughout the body and appears to play a role in the development of many tissues, including the skull, other bones, skin, and brain.

SKI gene mutations involved in Shprintzen-Goldberg syndrome alter the SKI protein. The altered protein is no longer able to attach to proteins in the TGF-β pathway and block signaling. As a result, the pathway is abnormally active. Excess TGF-β signaling changes the regulation of gene activity and likely disrupts development of many body systems, including the bones and brain, resulting in the wide range of signs and symptoms of Shprintzen-Goldberg syndrome.

Not all cases of Shprintzen-Goldberg syndrome are caused by mutations in the SKI gene. Other genes may be involved in this condition, and in some cases, the genetic cause is unknown.

Normal Function

The SKI gene provides instructions for making a protein involved in a signaling pathway that transmits chemical signals from the cell surface to the nucleus. This pathway, called the transforming growth factor beta (TGF-β) pathway, allows the environment outside the cell to affect how the cell produces other proteins. It helps regulate cell growth and division (proliferation), the process by which cells mature to carry out special functions (differentiation), cell movement (motility), and the self-destruction of cells (apoptosis). Through this pathway, a group of proteins called the SMAD complex is turned on (activated). The activated SMAD protein complex moves to the cell nucleus and attaches (binds) to specific areas of DNA to control the activity of particular genes, which help regulate various cellular processes.

The SKI protein controls the activity of the TGF-β pathway by binding to certain SMAD proteins, which interrupts signaling through the pathway. SKI protein binding within the cell can keep the SMAD protein complex from entering the nucleus, so it is unable to activate genes. Binding of the SKI protein can also occur in the nucleus. Although the SMAD complex binds to DNA, the SKI protein attracts other proteins (corepressors) that block its ability to turn genes on.

The SKI protein is found in many cell types throughout the body and appears to play a role in the development of many tissues, including the skull, other bones, skin, and brain.

Health Conditions Related to Genetic Changes

Shprintzen-Goldberg syndrome

At least 10 mutations in the SKI gene have been found in people with Shprintzen-Goldberg syndrome, a condition characterized by distinctive facial features, skeletal abnormalities, and intellectual disability. Most of these mutations change single protein building blocks (amino acids) in the SKI protein. Many of the mutations alter the region of the SKI protein that binds to SMAD proteins. It is thought that altered SKI proteins are unable to attach to SMAD proteins, which allows TGF-β signaling to continue uncontrolled. Excess TGF-β signaling changes the regulation of gene activity and likely disrupts development of many body systems, including the bones and brain, resulting in the wide range of signs and symptoms of Shprintzen-Goldberg syndrome.

Other Names for This Gene

• proto-oncogene c-Ski
• ski oncogene
• ski oncoprotein
• SKI_HUMAN
• v-ski avian sarcoma viral oncogene homolog
• v-ski sarcoma viral oncogene homolog (avian)

Genomic Location

Shprintzen-Goldberg syndrome is described as autosomal dominant, which means one copy of the altered gene in each cell is sufficient to cause the disorder. The condition almost always results from new (de novo) gene mutations and occurs in people with no history of the disorder in their family. Very rarely, people with Shprintzen-Goldberg syndrome have inherited the altered gene from an unaffected parent who has a gene mutation only in their sperm or egg cells. When a mutation is present only in reproductive cells, it is known as germline mosaicism.

Shprintzen-Goldberg syndrome is a rare condition, although its prevalence is unknown. It is difficult to identify the number of affected individuals, because some cases diagnosed as Shprintzen-Goldberg syndrome may instead be Marfan syndrome or Loeys-Dietz syndrome, which have overlapping signs and symptoms.