Simpson-Golabi-Behmel syndrome is a condition that affects many parts of the body and occurs primarily in males. This condition is classified as an overgrowth syndrome, which means that affected infants are considerably larger than normal at birth (macrosomia) and continue to grow and gain weight at an unusual rate. The other signs and symptoms of Simpson-Golabi-Behmel syndrome vary widely. People with mild cases often live into adulthood.

People with Simpson-Golabi-Behmel syndrome have distinctive facial features including widely spaced eyes (ocular hypertelorism), an unusually large mouth (macrostomia), a large tongue (macroglossia) that may have a deep groove or furrow down the middle, a broad nose with an upturned tip, and abnormalities affecting the roof of the mouth (the palate). The facial features are often described as "coarse" in older children and adults with this condition.

Other features of Simpson-Golabi-Behmel syndrome involve the chest and abdomen. Affected infants may be born with one or more extra nipples, an abnormal opening in the muscle covering the abdomen (diastasis recti), a soft out-pouching around the belly-button (an umbilical hernia), or a hole in the diaphragm (a diaphragmatic hernia) that allows the stomach and intestines to move into the chest and crowd the developing heart and lungs.

Simpson-Golabi-Behmel syndrome can also cause heart defects, malformed or abnormally large kidneys, an enlarged liver and spleen (hepatosplenomegaly), and skeletal abnormalities. Additionally, the syndrome can affect the development of the gastrointestinal system, urinary system, and genitalia. Some people with this condition have mild to severe intellectual disability, while others have normal intelligence.

About 10 percent of people with Simpson-Golabi-Behmel syndrome develop cancerous or noncancerous tumors in early childhood. The most common tumors are a rare form of kidney cancer called Wilms tumor and a cancerous tumor called a neuroblastoma that arises from developing nerve cells.

Mutations in the GPC3 gene are the most common cause of Simpson-Golabi-Behmel syndrome. This gene provides instructions for making a protein called glypican 3, which blocks (inhibits) a developmental pathway called the hedgehog signaling pathway. This pathway is critical for cell growth and division (proliferation), cell specialization, and the normal shaping (patterning) of many parts of the body during embryonic development. Researchers believe that glypican 3 also helps establish the body's shape by causing certain cells to self-destruct (undergo apoptosis) when they are no longer needed.

GPC3 gene mutations prevent glypican 3 from inhibiting the hedgehog signaling pathway. The resulting overactivity of this pathway leads to an increased rate of cell growth and division starting before birth. This increased cell proliferation accounts, at least in part, for the overgrowth that occurs in Simpson-Golabi-Behmel syndrome. It is unclear how changes in hedgehog signaling contribute to the other abnormalities that can occur with this disorder.

Some individuals with Simpson-Golabi-Behmel syndrome do not have an identified mutation in the GPC3 gene. Mutations in other genes have been studied as possible causes of this condition, but most of these genetic changes have been described only in single families or have not been confirmed in subsequent studies. In some cases, the cause of the condition is unknown.

Researchers have described a disorder with features overlapping those of Simpson-Golabi-Behmel syndrome, which they designated as Simpson-Golabi-Behmel syndrome type 2 (SGBS2). The signs and symptoms of this disorder are more severe than those that typically occur with Simpson-Golabi-Behmel syndrome, and affected individuals live only into infancy. This more severe disorder likely has a different genetic cause. Because of these differences, many researchers now consider SGBS2 to be a separate condition, distinct from Simpson-Golabi-Behmel syndrome.

Normal Function

The GPC3 gene provides instructions for making a protein called glypican 3. This protein is one of several glypicans in humans, each of which consists of a core protein attached to long sugar molecules called heparan sulfate chains. Glypicans are anchored to the outer cell membrane, where they interact with a variety of other proteins outside the cell. Glypicans appear to play important roles in development before birth. These proteins are involved in numerous cell functions, including regulating cell growth and division (cell proliferation) and cell survival.

Several studies have found that glypican 3 interacts with other proteins at the surface of cells to restrain cell proliferation. Specifically, glypican 3 blocks (inhibits) a developmental pathway called the hedgehog signaling pathway. This pathway is critical for cell proliferation, cell specialization, and the normal shaping (patterning) of many parts of the body during embryonic development.

Researchers believe that in some cell types, glypican 3 may act as a tumor suppressor, which is a protein that prevents cells from growing and dividing in an uncontrolled way to form a cancerous tumor. Glypican 3 may also cause some types of cells to self-destruct (undergo apoptosis) when they are no longer needed, which can help keep growth in check.

Although glypican 3 is known primarily as an inhibitor of cell growth and cell division, in some tissues it appears to have the opposite effect. Research suggests that in certain types of cells, such as cells in the liver, glypican 3 may interact with proteins called growth factors to promote cell growth and cell division.

Health Conditions Related to Genetic Changes

Simpson-Golabi-Behmel syndrome

More than 50 mutations in the GPC3 gene have been identified in people with Simpson-Golabi-Behmel syndrome. This condition is classified as an overgrowth syndrome, which means that affected infants are considerably larger than normal at birth (macrosomia) and continue to grow and gain weight at an unusual rate. The condition can also be associated with a variety of other birth defects and health problems.

Most of the mutations that cause Simpson-Golabi-Behmel syndrome delete part or all of the GPC3 gene, which prevents cells from producing functional glypican 3. Other mutations insert or delete a small amount of genetic material in the gene, or change one or a few protein building blocks (amino acids) in glypican 3. These mutations change the structure of the protein.

Mutations in the GPC3 gene prevent glypican 3 from inhibiting the hedgehog signaling pathway. The resulting overactivity of this pathway leads to an increased rate of cell growth and division starting before birth. This increased cell proliferation accounts, at least in part, for the overgrowth that occurs in Simpson-Golabi-Behmel syndrome. It is unclear how changes in hedgehog signaling contribute to the other abnormalities that can occur with this disorder.

Other Names for This Gene

• DGSX
• glypican proteoglycan 3
• glypican-3
• GPC3_HUMAN
• GTR2-2
• Intestinal protein OCI-5
• MXR7
• OCI-5
• SGBS1

Genomic Location

This condition is inherited in an X-linked pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. Because females have two copies of the X chromosome, one altered copy of the gene in each cell usually leads to less severe health problems in females than in males, or it may cause no signs or symptoms at all.

Some females who have one altered copy of the GPC3 gene have distinctive facial features including an upturned nose, a wide mouth, and a prominent chin. Their fingernails may be malformed and they can have extra nipples. Skeletal abnormalities, including extra spinal bones (vertebrae), are also possible in affected females. Other females who carry one altered copy of the GPC3 gene do not have any health problems associated with Simpson-Golabi-Behmel syndrome.

The incidence of Simpson-Golabi-Behmel syndrome is unknown. At least 250 people worldwide have been diagnosed with this disorder.