Simpson-Golabi-Behmel Syndrome

 Simpson-Golabi-Behmel Syndrome

Overview

Simpson-Golabi-Behmel syndrome (SGBS) is a rare genetic condition that mostly affects males. In SGBS type 1, one of the main features is overgrowth, which is when an individual is larger than expected. This can be seen in overgrowth before birth, where the unborn baby is unusually large, and in overgrowth after birth, where a baby is unusually large. Other physical features that are commonly seen in individuals with SGBS are specific facial features like large forehead, nose, lips, and tongue. Some people with SGBS have an opening in the roof of their mouth (cleft palate). They can also have an opening in the upper lip (cleft lip). People with SGBS can have differences in other parts of their bodies too. Some of the differences that are more commonly seen include having an extra nipple, problems with their bones, and a bulge near the belly button called an umbilical hernia. Having SGBS can also mean that a person has a higher chance of having a heart problem. People with SGBS normally have some of these features, but not all of them. People with SGBS have differences and similarities, and some people have a more serious version of the condition than others. Some people with SBGS have intellectual disability, with a wide range of severity. About 10% of people with SGBS develop specific types of tumors as children. SGBS type 2 is the more serious form of the condition, and it can be life threatening in babies who are affected. Although there is no specific treatment or cure, there are ways to manage the symptoms, or specific features a person has. A team of doctors and other health care providers is often needed to determine the treatment options based on each person’s symptoms

There are many different names for Simpson-Golabi-Behmel syndrome. Some of these names have words that relate to symptoms of the condition and some contain names of doctors who have worked with patients with this condition. The name that is currently the most commonly used is Simpson-Golabi-Behmel syndrome, which combines the names of three doctors. Dr. Simpson published a paper on the condition in 1975, and Dr. Golabi and Dr. Behmel published papers on the condition in 1984.

Symptoms

Simpson-Golabi-Behmel Syndrome Type 1

Many different parts of the body can be affected when a person has SGBS. Not every person with SGBS has the same symptoms, and none have all of these symptoms.

Overall

General muscle weakness and low muscle tone (hypotonia) in 61% of people

Large size (macrosomia)

Head

Abnormal shape of the skull due to early bone fusion (craniosynostosis)

Large jaw (macrognathia) in more than half of affected people

Large sized head (macrocephaly) in the majority of affected people

Specific facial feature that don’t look like other family members

Large forehead

Large and thick nose and lips

Large tongue with a groove in the middle going from the front to the back in the majority of people

Opening in the roof of the mouth (cleft palate) in 1 out of 4 people

Split opening in the lip (cleft lip) in 1 out of 4 people

Central Nervous System

Attention deficit hyperactivity disorder

Build-up of fluid in the brain (hydrocephalus)

Disorder that causes breathing to pause or slow down during sleep (obstructive sleep apnea)

Intellectual disability in about half of people

Seizure disorder (epilepsy)

Speech and Language

Speech disorder in the majority of people

Heart

Any type of abnormality of the heart in about 1 out of 3 of people

Abdomen

A weak area or defect in the belly that allows organs to push through (abdominal wall defect) in 1 out of 3 people

Abnormal opening in the muscle between the chest and abdomen that helps with breathing and is present at birth (congenital diaphragmatic hernia) occurs rarely

Extra nipples (supernumerary nipples) in half of people

Kidney abnormalities in 33% of people

Large kidney (nephromegaly) in half of people

Large liver (hepatomegaly) in half of people

Large spleen (splenomegaly)

Organs that are larger than they should be (organomegaly) in most people

Genitals

Opening of where the urine comes out (urethra) on the underside of the penis instead of at the tip (hypospadias)

Testes that do not descend properly and are still inside the body (cryptorchidism)

Skeletal

Abnormalities of the hands and feet

Broad thumbs

Extra fingers or toes (polydactyly)

Large hands

Short fingers and toes (brachydactyly) in half of people

Underdevelopment of the pointer finger (index finger hypoplasia)

Webbed or conjoined 2nd and 3rd fingers (syndactyly of the 2nd-3rd fingers)

Chest deformity in less than half of people

Rib malformations

Scoliosis in one out of ten people

Tumors

A 10% risk for certain tumors including:

Adrenal neuroblastoma (a cancer found in the adrenal glands on top of the kidneys)

Gonadoblastoma (a tumor with cells from the early testes or ovaries)

Hepatoblastoma (cancerous liver tumor)

Hepatocellular carcinoma (most common form of liver cancer)

Medulloblastoma (a brain cancer that starts in the brain at the base of the skull)

Wilms tumor (a kidney cancer seen in children)

Pregnancy

Birth before 37 weeks (prematurity) in half of people

Low blood sugar as a newborn (neonatal hypoglycemia) in 1 in 4 people

More amniotic fluid than there should be (polyhydramnios) in the majority of people

Simpson-Golabi-Behmel Syndrome Type 2

SGBS type 2 is more serious and rarer than type 1. Boys with SGBS type 2 usually die a few months after birth. Most affected boys are born with extra fluid in multiple parts of the body (hydrops fetalis) and they also can have problems with their bones, distinct facial features, issues with organs and other medical problems.

Causes

SGBS type 1 is caused by harmful changes (mutations) in the genes GPC3 and GPC4, located on the X chromosome. SGBS type 2 is caused by mutations in the genes OFD1 and PIGA, also located on the X chromosome. They are genetic disorders that are inherited in a recessive X-linked pattern.

TSimpson-Golabi-Behmel Syndrome Type 1

Many different parts of the body can be affected when a person has SGBS. Not every person with SGBS has the same symptoms, and none have all of these symptoms.

Overall

General muscle weakness and low muscle tone (hypotonia) in 61% of people

Large size (macrosomia)

Head

Abnormal shape of the skull due to early bone fusion (craniosynostosis)

Large jaw (macrognathia) in more than half of affected people

Large sized head (macrocephaly) in the majority of affected people

Specific facial feature that don’t look like other family members

Large forehead

Large and thick nose and lips

Large tongue with a groove in the middle going from the front to the back in the majority of people

Opening in the roof of the mouth (cleft palate) in 1 out of 4 people

Split opening in the lip (cleft lip) in 1 out of 4 people

Central Nervous System

Attention deficit hyperactivity disorder

Build-up of fluid in the brain (hydrocephalus)

Disorder that causes breathing to pause or slow down during sleep (obstructive sleep apnea)

Intellectual disability in about half of people

Seizure disorder (epilepsy)

Speech and Language

Speech disorder in the majority of people

Heart

Any type of abnormality of the heart in about 1 out of 3 of people

Abdomen

A weak area or defect in the belly that allows organs to push through (abdominal wall defect) in 1 out of 3 people

Abnormal opening in the muscle between the chest and abdomen that helps with breathing and is present at birth (congenital diaphragmatic hernia) occurs rarely

Extra nipples (supernumerary nipples) in half of people

Kidney abnormalities in 33% of people

Large kidney (nephromegaly) in half of people

Large liver (hepatomegaly) in half of people

Large spleen (splenomegaly)

Organs that are larger than they should be (organomegaly) in most people

Genitals

Opening of where the urine comes out (urethra) on the underside of the penis instead of at the tip (hypospadias)

Testes that do not descend properly and are still inside the body (cryptorchidism)

Skeletal

Abnormalities of the hands and feet

Broad thumbs

Extra fingers or toes (polydactyly)

Large hands

Short fingers and toes (brachydactyly) in half of people

Underdevelopment of the pointer finger (index finger hypoplasia)

Webbed or conjoined 2nd and 3rd fingers (syndactyly of the 2nd-3rd fingers)

Chest deformity in less than half of people

Rib malformations

Scoliosis in one out of ten people

Tumors

A 10% risk for certain tumors including:

Adrenal neuroblastoma (a cancer found in the adrenal glands on top of the kidneys)

Gonadoblastoma (a tumor with cells from the early testes or ovaries)

Hepatoblastoma (cancerous liver tumor)

Hepatocellular carcinoma (most common form of liver cancer)

Medulloblastoma (a brain cancer that starts in the brain at the base of the skull)

Wilms tumor (a kidney cancer seen in children)

Pregnancy

Birth before 37 weeks (prematurity) in half of people

Low blood sugar as a newborn (neonatal hypoglycemia) in 1 in 4 people

More amniotic fluid than there should be (polyhydramnios) in the majority of people

Simpson-Golabi-Behmel Syndrome Type 2

SGBS type 2 is more serious and rarer than type 1. Boys with SGBS type 2 usually die a few months after birth. Most affected boys are born with extra fluid in multiple parts of the body (hydrops fetalis) and they also can have problems with their bones, distinct facial features, issues with organs and other medical problems.

Affected populations

SGBS is present from birth (congenital) and can be diagnosed in a baby, even though some of the features might not appear until a child is older. All males who have a mutation in one of the genes for SGBS will have the condition. It is not known what percentage of carrier females have symptoms. As of 2014, there were 250 known cases of SGBS type 1. As of 2019, there have been 8 symptomatic female carriers reported.

Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of SGBS. Comparisons may be useful for a differential diagnosis:

Beckwith-Wiedemann syndrome (BWS) is a rare genetic disorder. There are a broad range of symptoms that can vary in location and severity. Features may include above average weight and length at birth and/or increased growth after birth (postnatally); an unusually large tongue (macroglossia); enlargement of certain abdominal organs (visceromegaly); and/or abdominal wall defects. People with BWS may also have low blood sugar levels at birth (neonatal hypoglycemia); advanced bone age, particularly up to age four, and/or an increased risk of developing certain childhood cancers. (For more information on this disorder, choose “BWS” as your search term in the Rare Disease Database.)

Sotos syndrome is a rare genetic disorder characterized by excessive growth that occurs prior to and after birth (prenatally and postnatally). Newborns typically show advanced bone growth, abnormally large hands and/or feet, and unique facial features. These facial features may include an unusually large head (macrocephaly) that may appear elongated (dolichocephalic) with a large forehead (frontal bossing); widely-spaced eyes (ocular hypertelorism); downwardly slanting eyelid folds (palpebral fissures), a highly-arched roof of the mouth (palate), jutting of the lower jaw (prognathism); and/or a pointed chin. Most people with Sotos syndrome have mutations of the NSD1 gene. The mutation usually occurs by chance for no apparent reason (sporadically). When the mutation is already present, it is inherited as an autosomal dominant trait. Affected infants and children may also have delays in reaching developmental milestones (e.g., sitting, crawling, walking), delays in the coordination of muscular and mental activity and delayed language skills. (For more information on this disorder, choose “Sotos” as your search term in the Rare Disease Database.)

Weaver syndrome, also known as Weaver-Smith syndrome, is an extremely rare disorder characterized by accelerated growth. Affected individuals have a particular facial appearance that is similar to Sotos syndrome in that a high broad forehead is often present, but the face is usually round in shape with widely spaced eyes (ocular hypertelorism) and an abnormally small jaw. Children with Weaver syndrome often have increased muscle tone (hypertonia) and joint problems. Weaver syndrome is due to mutations in the EZH2 gene. (For more information on this disorder, choose “Weaver” as your search term in the Rare Disease Database.)

Craniometaphyseal dysplasia is a rare genetic disorder characterized by unique facial features that include a wide nasal bridge, widely spaced eyes (hypertelorism), overgrowth of the bone over the eyes, a small jawbone, and incomplete development of the sinuses. Multiple abnormalities of the teeth and bones may also be present. Intelligence is usually normal. (For more information on this disorder, choose “craniometaphyseal dysplasia” as your search term in the Rare Disease Database.)

Oral-facial-digital syndrome is a rare genetic disorder in which there have been four types identified. Symptoms common to all types include periods of muscle abnormalities, split (cleft) tongue, splits in the jaw, midline cleft lip, overgrowth of the membrane that supports the tongue (frenulum), a broad based nose, vertical folds of the skin covering the inner angle of the eyelids (epicanthic folds), more than the normal number of fingers and/or toes, shorter than normal fingers and/or toes, and more than the normal number of divisions between skull sections. (For more information on this disorder, choose “oral-facial-digital” as your search term in the Rare Disease Database.)

Otopalatodigital syndrome (OPD) types I and II are rare genetic disorders which are usually found in males. Females may be mildly affected with some of the symptoms. Some of the characteristics of both types I and II may be cleft palate, a downward slant of the opening between the upper and lower eyelids, hearing loss, and/or short fingers and toes. Symptoms of OPD I can include dislocation of the head of one of the bones of the forearm (radius), mild dwarfism, and/or underdeveloped bones of the face. Symptoms of OPD II can include a small head, fingers that are bent and overlap, or curved long bones of the forearm and legs. (For more information on this disorder, choose “otopalatodigital syndrome” as your search term in the Rare Disease Database.)

Larsen syndrome is a multi-system genetic disorder that is present at birth. It is characterized by multiple bone dislocations and differences, an extremely high arch of the foot, non-tapering cylindrically shaped fingers, and an unusual facial appearance. (For more information on this disorder, choose “Larsen” as your search term in the Rare Disease Database.)

Diagnosis

Diagnosis of SGBS type 1 is made based on physical features of the patient, family history and genetic testing. There are no official criteria that are used to diagnose the condition. The main physical features are the different types of overgrowth (large body, large head, large fetus, large baby), the specific facial features, abnormalities that happen in the middle of the body (midline defects), and risk for tumors. The other physical features that are considered are organs larger than expected (organomegaly), issues with the skeleton, and problems with the heart, central nervous system, kidney, and gastrointestinal tract that are present from birth. A family history showing an X-linked pattern of inheritance can help with diagnosis. Genetic testing can involve sequencing and deletion/duplication analysis of the GPC3 gene, a chromosomal microarray, or a multigene panel that includes GPC3, GPC4, and other genes related to differential diagnoses.

Screening

Patients with SGBS type 1 need to be screened regularly for tumors. Screening should be done every three months until they are four years old. From ages four to seven years old, screening should be done every four months. After age seven, screening should be done every 6 months. Screening should include abdominal ultrasounds, blood tests, urine tests, and chest x-rays.

Standard Therapies

Treatment

The treatment for SGBS is based on the type of symptoms that each individual patient has. In the newborn period, right after birth, the baby’s blood sugar levels should be monitored to make sure they are not too low (hypoglycemia). The baby should also be checked to see if they are having problems breathing (airway obstruction). If the baby has any problems with their kidneys (renal anomalies) then their kidney function should also be monitored. Physical examinations should be done to check for a sideways curvature of the spine (scoliosis) during periods of time when the child is growing quickly. Social and intellectual development should also be monitored routinely.

Individuals with cleft palate require the coordinated efforts of a team of specialists. Pediatricians, dental specialists, surgeons, speech therapist, and psychologists must systematically and comprehensively plan treatment and rehabilitation. The palate may be repaired surgically or covered by an artificial device that closes or blocks the opening. Speech and language development need to be assisted by a speech therapist during the preschool years.

For a complete list of different specialists to see based on the specific concern, reference the GeneReviews (listed under Internet sources) for Simpson-Golabi-Behmel Syndrome Type I.

Genetic counseling is recommended for patients and their familieshe gene glypican 3 (GPC3) contributes to the control of growth and changes in this gene may lead to overgrowth. It is thought that organs of the body such as the heart and liver reach normal size when the GPC3 protein is available in large enough quantities. Concentration is sufficient when GPC3, the growth inhibiting factor, balances the growth promoting factors, such as insulin-like growth factor 2, IGF2.

\/SGBS is inherited in an X-linked pattern. X-linked genetic disorders are conditions caused by a mutation in a gene on the X chromosome. Mutations are changes in the way that genes, the body’s instructions, are written that cause the genes to not work in the way they should. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. Some female carriers of SGBS have symptoms, but if they do their symptoms are normally mild. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.

Affected populations

SGBS is present from birth (congenital) and can be diagnosed in a baby, even though some of the features might not appear until a child is older. All males who have a mutation in one of the genes for SGBS will have the condition. It is not known what percentage of carrier females have symptoms. As of 2014, there were 250 known cases of SGBS type 1. As of 2019, there have been 8 symptomatic female carriers reported.

Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of SGBS. Comparisons may be useful for a differential diagnosis:

Beckwith-Wiedemann syndrome (BWS) is a rare genetic disorder. There are a broad range of symptoms that can vary in location and severity. Features may include above average weight and length at birth and/or increased growth after birth (postnatally); an unusually large tongue (macroglossia); enlargement of certain abdominal organs (visceromegaly); and/or abdominal wall defects. People with BWS may also have low blood sugar levels at birth (neonatal hypoglycemia); advanced bone age, particularly up to age four, and/or an increased risk of developing certain childhood cancers. (For more information on this disorder, choose “BWS” as your search term in the Rare Disease Database.)

Sotos syndrome is a rare genetic disorder characterized by excessive growth that occurs prior to and after birth (prenatally and postnatally). Newborns typically show advanced bone growth, abnormally large hands and/or feet, and unique facial features. These facial features may include an unusually large head (macrocephaly) that may appear elongated (dolichocephalic) with a large forehead (frontal bossing); widely-spaced eyes (ocular hypertelorism); downwardly slanting eyelid folds (palpebral fissures), a highly-arched roof of the mouth (palate), jutting of the lower jaw (prognathism); and/or a pointed chin. Most people with Sotos syndrome have mutations of the NSD1 gene. The mutation usually occurs by chance for no apparent reason (sporadically). When the mutation is already present, it is inherited as an autosomal dominant trait. Affected infants and children may also have delays in reaching developmental milestones (e.g., sitting, crawling, walking), delays in the coordination of muscular and mental activity and delayed language skills. (For more information on this disorder, choose “Sotos” as your search term in the Rare Disease Database.)

Weaver syndrome, also known as Weaver-Smith syndrome, is an extremely rare disorder characterized by accelerated growth. Affected individuals have a particular facial appearance that is similar to Sotos syndrome in that a high broad forehead is often present, but the face is usually round in shape with widely spaced eyes (ocular hypertelorism) and an abnormally small jaw. Children with Weaver syndrome often have increased muscle tone (hypertonia) and joint problems. Weaver syndrome is due to mutations in the EZH2 gene. (For more information on this disorder, choose “Weaver” as your search term in the Rare Disease Database.)

Craniometaphyseal dysplasia is a rare genetic disorder characterized by unique facial features that include a wide nasal bridge, widely spaced eyes (hypertelorism), overgrowth of the bone over the eyes, a small jawbone, and incomplete development of the sinuses. Multiple abnormalities of the teeth and bones may also be present. Intelligence is usually normal. (For more information on this disorder, choose “craniometaphyseal dysplasia” as your search term in the Rare Disease Database.)

Oral-facial-digital syndrome is a rare genetic disorder in which there have been four types identified. Symptoms common to all types include periods of muscle abnormalities, split (cleft) tongue, splits in the jaw, midline cleft lip, overgrowth of the membrane that supports the tongue (frenulum), a broad based nose, vertical folds of the skin covering the inner angle of the eyelids (epicanthic folds), more than the normal number of fingers and/or toes, shorter than normal fingers and/or toes, and more than the normal number of divisions between skull sections. (For more information on this disorder, choose “oral-facial-digital” as your search term in the Rare Disease Database.)

Otopalatodigital syndrome (OPD) types I and II are rare genetic disorders which are usually found in males. Females may be mildly affected with some of the symptoms. Some of the characteristics of both types I and II may be cleft palate, a downward slant of the opening between the upper and lower eyelids, hearing loss, and/or short fingers and toes. Symptoms of OPD I can include dislocation of the head of one of the bones of the forearm (radius), mild dwarfism, and/or underdeveloped bones of the face. Symptoms of OPD II can include a small head, fingers that are bent and overlap, or curved long bones of the forearm and legs. (For more information on this disorder, choose “otopalatodigital syndrome” as your search term in the Rare Disease Database.)

Larsen syndrome is a multi-system genetic disorder that is present at birth. It is characterized by multiple bone dislocations and differences, an extremely high arch of the foot, non-tapering cylindrically shaped fingers, and an unusual facial appearance. (For more information on this disorder, choose “Larsen” as your search term in the Rare Disease Database.)

Standard Therapies

Treatment

The treatment for SGBS is based on the type of symptoms that each individual patient has. In the newborn period, right after birth, the baby’s blood sugar levels should be monitored to make sure they are not too low (hypoglycemia). The baby should also be checked to see if they are having problems breathing (airway obstruction). If the baby has any problems with their kidneys (renal anomalies) then their kidney function should also be monitored. Physical examinations should be done to check for a sideways curvature of the spine (scoliosis) during periods of time when the child is growing quickly. Social and intellectual development should also be monitored routinely.

Individuals with cleft palate require the coordinated efforts of a team of specialists. Pediatricians, dental specialists, surgeons, speech therapist, and psychologists must systematically and comprehensively plan treatment and rehabilitation. The palate may be repaired surgically or covered by an artificial device that closes or blocks the opening. Speech and language development need to be assisted by a speech therapist during the preschool years.

For a complete list of different specialists to see based on the specific concern, reference the GeneReviews (listed under Internet sources) for Simpson-Golabi-Behmel Syndrome Type I.

Genetic counseling is recommended for patients and their families.

Type of Doctor Department : A Clinical Geneticist