Simpson-Golabi-Behmel syndrome (SGBS) is a rare X-linked recessive inherited condition. It causes general overgrowth in height and weight. Individuals with SGBS also have characteristic facial features in childhood which tend to become less obvious in adulthood. SGBS is also known as Simpson dysmorphia syndrome (SDYS), bulldog syndrome, Golabi-Rosen syndrome, and dysplasia gigantism syndrome X-linked (DGSX). SGBS is a rare X-linked recessive inherited condition. Individuals with this condition have increased height and weight for their age; a broad, stocky appearance; a large protruding jaw; a short, broad nose; incomplete closure of the roof of the mouth (cleft palate); and broad, short hands and fingers. Individuals with SGBS are usually taller than average. The characteristic features usually become less apparent in adulthood. There are at least two genes for SGBS. Both genes are located on the X chromosome.
The spectrum of clinical features in SGBS is broad, ranging from very mild forms in carrier females to forms that are lethal in the newborn male. SGBS affects the face, hands, chest, abdomen, genitals, internal organs and overall growth. Individuals with SGBS are larger than average at birth in height, weight, and head size. This overgrowth continues into adulthood with affected males being taller than average. Final height in males ranges from 74 in to 83 in (188 cm to 210 cm). There are typical facial characteristics in affected males including widely spaced eyes, short nose, large mouth, large tongue, a groove in the lower lip, and teeth that do not align properly. Incomplete closure of the lip (cleft lip) and/or the roof of the mouth (cleft palate) can also occur. The large tongue and improperly aligned teeth can be a cause of speech difficulties. The hands and feet of males with SGBS tend to be short and broad. Other hand abnormalities such as small nails, webbing of the skin between the fingers, and extra fingers/toes, is also common. Males with SGBS have extra nipples and some may have undescended testicles. The internal organs are larger than average, particularly the liver, spleen, and kidneys. The kidneys may also have many cysts on them. A few individuals have been known to have lung and diaphragm abnormalities. Heart abnormalities can also occur in SGBS1 and have been a cause of death in several individuals under two years of age. These include conduction defects causing arrythmias. The stomach and intestines can also be affected, which may cause digestive problems. The bones may also be affected. Some individuals have an abnormal curving and twisting of the spine (scoliosis), extra ribs, and/or problems with the structure of the bones of the spine. The bony changes can be seen on x ray but may not cause any symptoms. Despite their large size, newborns with SGBS tend to be floppy babies with decreased muscle tone. Due to this low muscle tone, there are several features that can result such as mouth breathing, a deformity of the chest wall (pectus excavatum), shoulders that droop, hernias, and undescended testicles. There is an increased risk to develop tumors of the kidney (Wilms tumor) in SGBS in early childhood. This risk appears to be greatest in individuals under two years of age. Most individuals with SGBS are of average intelligence, although some degree of mental impairment has been observed in males who are more severely affected. Individuals with SGBS may have psychological difficulties dealing with their distinctive facial appearance and speech difficulties, which often give the false impression that they are mentally impaired.
Mutations in the GPC3 gene are responsible for some cases of Simpson-Golabi-Behmel syndrome. This gene provides instructions for making a protein called glypican 3, which is involved in the regulation of cell growth and division (cell proliferation). Researchers believe that the GPC3 protein can also cause certain cells to self-destruct (undergo apoptosis) when they are no longer needed, which can help establish the body's shape.
GPC3 mutations can delete part or all of the gene, or alter the structure of glypican 3. These mutations prevent the protein from performing its usual functions, which may contribute to an increased rate of cell growth and cell division starting before birth. It is unclear, however, how a shortage of functional glypican 3 causes overgrowth of the entire body and the other abnormalities characteristic of Simpson-Golabi-Behmel syndrome.
Some individuals with Simpson-Golabi-Behmel syndrome do not have identified mutations in the GPC3gene. In these cases, the cause of the condition is unknown.
The diagnosis of SGBS is based on the presence of certain clinical features and in some cases may be confirmed through genetic testing. Not all affected individuals will have all of the features associated with SGBS. SGBS should be considered in an individual who is large in height, weight, and head circumference both before and after birth. Features of the condition that are almost always present include overgrowth; extra nipples; chest deformity; low muscle tone; and characteristic facial features including widely spaced eyes, short nose, large tongue and mouth, central groove of the lower lip, and improperly aligned teeth. It may be possible to confirm the diagnosis of SGBS through genetic testing. Genetic testing for mutations in the GPC3 gene causing SGB1 is available. Genetic testing involves obtaining a blood sample from the affected individual in order to look for the specific disease-causing mutation in the GPC3 gene. Since not all individuals with SGBS have mutations in the GPC3 gene, it may not be possible to confirm the diagnosis through genetic testing in all individuals suspected of having this condition. Genetic testing for the SGBS can be done on the developing baby before birth through amniocentesis or chorionic villus sampling if a mutation in the gene for GPC3 is first identified in an affected family member. Prenatal testing for parents of an affected individual should only be undertaken after the SGBS carrier status of the parents has been confirmed and the couple has been counseled regarding the risks of recurrence.
The spectrum of clinical manifestations in SGBS is broad, varying from very mild forms in carrier females to infantile lethal forms in affected males. As many as 50% of males affected with SGBS die in the newborn period. The cause of this high mortality is not known but may be related to heart defects. In one reported family with a severe form of SGBS causing death in the newborn period, the responsible gene was not glypican-3 but the second candidate gene on the X chromosome.