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Simpson-Golabi-Behmel Syndrome

Last updated Dec. 25, 2018

Approved by: Krish Tangella MD, MBA, FCAP

Simpson-Golabi-Behmel Syndrome (SGBS) is a rare inherited disorder that occurs predominantly in males. It is caused by mutation in the GPC3 gene. The condition is inherited in an X-linked manner.

What are the other Names for this Condition? (Also known as/Symptoms)

  • Bulldog Syndrome
  • SDYS (Simpson Dysmorphia Syndrome)
  • X-Linked Dysplasia Gigantism Syndrome (DGSX)

What is Simpson-Golabi-Behmel Syndrome? (Definition/Background Information)

  • Simpson-Golabi-Behmel Syndrome (SGBS) is a rare inherited disorder that occurs predominantly in males. It is caused by mutation in the GPC3 gene. The condition is inherited in an X-linked manner
  • This gene codes for the protein glypican 3, which is involved in the regulation of cell growth and multiplication. When mutated, there occurs a dysregulation of cell growth, resulting in excess growth in the fetal stages as well as after birth
  • Simpson-Golabi-Behmel Syndrome is classified into the following 2 types:
    • Type 1 or the classical type - it is the most frequent type encountered
    • Type 2 or the lethal type - this form is very rare, with about 10 cases being reported in scientific literature. This type of SGBS is the lethal variant of type 1, and is characterized by accumulation of fluids in different fetal parts (hydrops fetalis)
  • The symptoms of Simpson-Golabi-Behmel Syndrome may include a distinctive facial appearance (such as widely-spaced eyes, a wide and upturend nose, abnormally large mouth), an abnormal rate of growth and weight gain, formation of tumors in the abdomen, enlarged organs (liver, spleen, kidneys), cardiac problems, low muscle tone, speech impediment, intellectual impairment, and attention deficit hyperactivity disorder (ADHD)
  • Some females with a single copy of mutated gene can also show symptoms, which may include a broad and upturned nose, wide mouth, extra bones in the vertebral column, malformed nails, and extra nipples
  • Simpson-Golabi-Behmel Syndrome may be suspected and diagnosed prenatally during routine examination of the pregnant woman. Molecular genetic testing of the fetus can confirm the diagnosis. After birth, a physical examination, assessment of symptoms, evaluation of family medical history, imaging studies, and molecular genetic testing aid in the diagnostic process
  • Many complications can arise in individuals with Simpson-Golabi-Behmel Syndrome, which include enlarged organs, formation of tumors in organs (such as Wilms tumor in the kidneys and neuroblastoma in developing nerve cells), intellectual deficiency, and the often fatal fluid retention in several fetal compartments
  • There is no cure for Simpson-Golabi-Behmel Syndrome, and the treatment is geared towards symptom management. Speech therapy and occupational therapy may be required for an affected individual to lead as normal a life as possible
  • The prognosis of Simpson-Golabi-Behmel Syndrome is dependent on the severity of symptoms. The severe form of the disease is often fatal; the child may die in utero or after birth

Who gets Simpson-Golabi-Behmel Syndrome? (Age and Sex Distribution)

  • Simpson-Golabi-Behmel Syndrome is rare, and its exact prevalence is not known. About 250 cases worldwide have been reported in the medical literature
    • So far, the type 1 disease has been reported in individuals belonging to around 10-20 families
    • Type 2 SGBS has been recorded only in a single family
  • Predominantly, SGBS affects males. However, some women with a single mutated gene copy have also been reported to show symptoms of the disorder
  • No specific racial or ethnic group bias has been observed

What are the Risk Factors for Simpson-Golabi-Behmel Syndrome? (Predisposing Factors)

The risk factors for Simpson-Golabi-Behmel Syndrome may include:

  • Being male
  • Having a family history of SGBS; having a mother with a mutated copy of the GPC3 gene
  • Being a female with a mutation in the GPC3 gene (since even a single copy of the defective gene can lead to symptoms)

Note: There are some reports of this syndrome in individuals with no identifiable mutation in the GPC3 gene. In such cases, the risk factors are not known.

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Simpson-Golabi-Behmel Syndrome? (Etiology)

Simpson-Golabi-Behmel Syndrome is caused by mutations in the GPC3 gene. The condition is inherited in an X-linked recessive fashion.

  • Under normal circumstances, the gene codes for glypican protein 3 (GPC3 protein). This protein is present on the cell surface, and negatively regulates cell growth and proliferation via suppression of Hedgehog (Hh) signalling pathway
  • This pathway is involved in signalling for differentiation of cells during embryonic development. Increasingly, the Hh pathway is shown to play a role in tumor malignancies in adults. The GPC3 protein is also believed to play a role in a cellular process known as apoptosis, which, in other words is “programmed cell death.” Apoptosis allows cells to destroy themselves in a controlled manner, which is required for an organism to grow, develop and gain a form
  • When the GPC3 gene is mutated, the result can either be an abnormal or absent glypican protein. Both types of mutation lead to an icreased proliferation of cells, which can begin in the fetus. The exact mechanism of cellular overgrowth is not known.

X-linked inheritance: X-linked conditions are traits or disorders that occur when two copies of an abnormal gene are inherited on a sex chromosome (X or Y chromosome). All X-linked recessive traits are fully evident in males, because they have only one copy of the X chromosome. This means that there is no normal gene present to mask the effects of the mutant copy. All males who are affected will pass the mutated gene onto their female offspring, because they must inherit one copy of the X chromosome from each parent. This means that they will be unaffected carriers. Females are rarely affected by X-linked recessive disorders because they have two copies of the X chromosome. In the rare case that females inherit two mutated copies of the gene, they will inherit the condition.

  • However, in some X-linked conditions, the presence of a single mutated gene may be sufficient to cause some symptoms. The symptoms tend to be less severe in women who are carriers of the syndrome
  • A single case of Simpson-Golabi-Behmel Syndrome due to combined GPC3 and GPC4 gene mutations has been reported
  • There are some reported cases of the syndrome with no mutations in the GPC3 gene. The cause of the syndrome in such cases is not known

What are the Signs and Symptoms of Simpson-Golabi-Behmel Syndrome?

The signs and symptoms of Simpson-Golabi-Behmel Syndrome include:

  • Presentations in the male fetus may include:
    • Larger than normal size for gestational age
    • Abnormal facial and head features
    • Enlarged organs in the abdomen
    • Extra digits in hands and feet
    • Increased/excess amniotic fluid
    • Presence of a single umbilical artery in place of two
    • Presence of embryonic tumors
  • Males, after birth, through childhood and adulthood may show the following:
    • Hypoglycemia, or low blood sugar, during the neonatal phase
    • Big head (macrocephaly); large forehead, and widely-spaced eyes
    • Upturned nose, broad nose
    • Cleft lip, thick lips, cleft palate and improper teeth development
    • Presence of extra fingers and toes (polydactyly)
    • Webbed fingers and toes; improperly formed nails
    • Problems with the vertebral column, such as scoliosis
    • Blood vessel malformations
    • Problems with heart structure and functions; arrhythmia or irregular heartbeat
    • Presence of extra nipples
    • Diaphragmatic hernia; a hole in the diaphragm, through which abdominal organs push into the chest
    • Umbilical hernia (protrusion of intestines through abdominal muscles, such that a pouching effect is seen near the belly button)
    • Enlarged kidney, liver, and spleen
    • Cirrhosis of the liver
    • Muscle separation and bulging in the abdomen (diastasis recti)
    • Cryptorchidism (testes not descending into the scrotal sac) and hypospadias (the opening of the penis on its underside)
    • Fluids accumulation in the brain (hydrocephalus)
    • Epilepsy
    • Weak muscle tone
    • Intellectual deficiency; speech problems
    • Sleep apnea
    • Attention deficiency hyperactivity disorder

The following tumors are known to develop:

  • Nephroblastoma or Wilms tumor (kidneys)
  • Hepatoblastoma (liver)
  • Hepatocarcinoma (liver)
  • Neuroblastoma (typically in adrenal glands)
  • Gonadolastoma (genitals)

In females with one defective copy of the causative gene (occurs rarely, with milder symptoms compared to males), the following may be observed:

  • Wide mouth, protruding chin, and upturned nose
  • Bone deformities; extra vertebral bones
  • Extra nipples

How is Simpson-Golabi-Behmel Syndrome Diagnosed?

The diagnosis of Simpson-Golabi-Behmel Syndrome is made through the following tests and exams:

During gestation via the following prenatal tests:

  • Measurement of fundal height during pregnancy
  • Prenatal ultrasound: In which a mismatch between gestational age and size of fetus may be observed, as well as enlarged abdominal organs, facial abnormalities, and a single umbilical artery
  • Further analysis may be undertaken to rule out the following conditions:
    • Diabetes in the pregnant mother
    • Confusion regarding date of baby’s conception
  • Molecular genetic testing of fetal cells to identify causative gene mutation 

After birth, by the following post-natal tests:

  • Complete physical examination and an assessment of symptoms
  • An evaluation of family medical history
  • Imaging studies to check for skeletal malformations; chest X-ray
  • Computed tomography (CT) scanning or magnetic resonance imaging of brain
  • Abdominal ultrasound; ultrasound of the kidney
  • Echocardiogram and electrocardiogram
  • Urine analysis
  • Tests to check for kidney function
  • Analysis of biochemical marker for tumor development
  • Check for blood glucose levels
  • Tests to rule out other medical conditions with similar symptoms
  • Molecular genetic testing to confirm diagnosis

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Simpson-Golabi-Behmel Syndrome?

The complications of Simpson-Golabi-Behmel Syndrome may include:

  • Hydrops fetalis, a condition where fluid accumulation occurs in the brain. This condition is often fatal
  • Formation of tumors, particularly in the kidney and liver
  • Arrhythmia
  • Enlarged organs (such as the liver and kidney)
  • Severe intellectual deficit

How is Simpson-Golabi-Behmel Syndrome Treated?

The treatment of Simpson-Golabi-Behmel Syndrome is dependent on the type and severity of symptoms in the affected individual. A coordinated effort by a team of medical professionals from various specialties, with continuous monitoring, is often needed to manage the condition.

The following are some of the treatment options:

  • Maintaining the glycemic index by ingestion of glucose
  • Surgery to repair cleft palate
  • Surgery to repair bone deformities
  • Correction of dental problems
  • Speech therapy
  • Occupational therapy
  • Monitoring for tumor development based on the following schedule:
    • Every 3 months till a child turns 4
    • Every 4 months from 4-7 years of age
    • Every 6 months after 7 years of age
  • Treatment for tumors as recommended by the healthcare professional(s)

How can Simpson-Golabi-Behmel Syndrome be Prevented?

  • Currently, there are no specific methods or guidelines to prevent Simpson-Golabi-Behmel Syndrome, since it is a genetic condition
  • Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
  • If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
  • Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as Simpson-Golabi-Behmel Syndrome

Regular medical screening at periodic intervals with tests and physical examinations are mandatory.

What is the Prognosis of Simpson-Golabi-Behmel Syndrome? (Outcomes/Resolutions)

The prognosis of Simpson-Golabi-Behmel Syndrome can be only determined based on the severity of the symptoms.

  • SGBS can be fatal before or immediately after birth, if the symptoms are severe
  • When the disease manifestation is mild, the prognosis gets better, with affected individuals living into adulthood
  • The quality of life can be affected owing to speech impediments and intellectual deficiency

Additional and Relevant Useful Information for Simpson-Golabi-Behmel Syndrome:

Simpson-Golabi-Behmel Syndrome is also known as ‘Bulldog Syndrome’ and ‘X-Linked Dysplasia Gigantism Syndrome (DGSX)’.

What are some Useful Resources for Additional Information?

References and Information Sources used for the Article:

Helpful Peer-Reviewed Medical Articles:

Reviewed and Approved by a member of the DoveMed Editorial Board
First uploaded: Jan. 15, 2017
Last updated: Dec. 25, 2018