Simpson-Golabi-Behmel syndrome

Definition

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.

Description

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.

Genetic profile

SGBS is caused by an alteration (mutation) in one of two genes on the X chromosome. Chromosomes are units of hereditary material passed from a parent to a child through the egg and sperm. The information on the chromosomes is organized into units called genes. Genes contain information necessary for normal human growth and development. Each cell in the body usually contains 46 chromosomes, arranged as 23 pairs. Twenty-two pairs of chromosomes are the same in males and females. The twenty-third pair is the sex chromosomes: females have two X chromosomes and males have an X and a Y chromosome. There are two genes on the X chromosome that can cause SGBS. The first gene is responsible for making a protein called glypican-3 (GPC3). The exact role of GPC3 is not known but it is thought to play a role in growth and development. When the gene for GPC3 is altered, the signs and symptoms of SGBS result. A second candidate gene, which causes a more severe form of SGBS, is also located on the X chromosome. The function of this second gene is not known. Generally, individuals who have SGBS due to a gene alteration in the GPC3 gene are said to have SGBS type 1 (SGBS1) and individuals who have SGBS due to an alteration in the second gene on the X chromosome are said to have SGBS type 2 (SGBS2).

SGBS is inherited as an X-linked recessive condition. With X-linked recessive conditions, males are usually more severely affected than females. Females have two copies of the SGBS gene (because they have two X chromosomes) while males have one copy of SGBS gene (because they have one X chromosome). Females who have an alteration in one copy of the SGBS gene are said to be carriers of SGBS. Generally, carriers show minimal or no effects of the altered gene because they have a second normal copy of the gene that is able to compensate for the altered copy. Since males have only one working copy of the SGBS gene to start, if that gene is altered, they will develop SGBS. When carrier females have children, they are at risk to have a child with SGBS. In each pregnancy, carrier females have a 25% chance of having a child (always a son) with SGBS and a 25% chance of having a child (always a daughter) whom is a carrier of SGBS. Males who are affected with SGBS cannot pass this condition to their sons (because their sons inherit the Y chromosome); however, all daughters of a male affected with SGBS will be carriers for the condition.

Demographics

SGBS is a rare inherited condition that primarily affects males from all ethnic groups. Female carriers for SGBS may show subtle features of the condition. It is not known precisely how many individuals are affected with SGBS.

Signs and symptoms

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.

Diagnosis

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.

Treatment and management

The heart function of individuals with SGBS should be carefully monitored because it can be a cause of early death. Individuals with SGBS should be regularly followed by a heart specialist (cardiologist).

Individuals with SGBS are at increased risk to develop kidney tumors. They should be screened for possible kidney tumor development or other tumors of infancy for at least the first five years of life. Screening usually involves an ultrasound (sound wave picture) of the abdomen, including the kidneys.

The large tongue and improperly aligned teeth may lead to speech difficulties. Some individuals may require surgery to reduce the size of the tongue to aid with speech development or for cosmetic reasons. Individuals with speech difficulties may benefit from speech therapy.

Individuals with SGBS may benefit from psychological support and social support to help them reach an adequate level of self-esteem. They may also benefit from genetic counseling , which may provide them with further information on the condition itself and recurrence risks for future pregnancies.

Prognosis

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.

Resources

PERIODICALS

Hughes-Benzie, R.M., et al. "Simpson-Golabi-Behmel Syndrome: Genotype/Phenotype Analysis of 18 Affected Males From 7 Unrelated Families." American Journal of Medical Genetics 66 (1996): 227-234.

Neri, Giovanni, et al. "Clinical and Molecular Aspects of the Simpson-Golabi-Behmel Syndrome." American Journal of Medical Genetics 79 (1998): 279-283.

ORGANIZATIONS

Beckwith-Wiedemann Support Network. 2711 Colony Rd., Ann Arbor, MI 48104. (734) 973-0263 or (800) 837-2976. <http://www.beckwith-wiedemann.org>.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.

WEBSITES

"Simpson-Golabi-Behmel Syndrome, type 1." Online Mendelian Inheritance in Man.<http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=312870>. (March 9, 2001)

Nada Quercia, MS, CGC, CCGC