• Disease Overview
  • Synonyms
  • Subdivisions
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
  • Programs & Resources
  • Complete Report

Simpson-Golabi-Behmel Syndrome

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Last updated: August 07, 2020
Years published: 1994, 1996, 2005, 2020


Acknowledgment

NORD gratefully acknowledges NORD gratefully acknowledges Laura M. Davids, MMSc, NORD Editorial Intern from the Emory University Genetic Counseling Training Program and Cecelia A. Bellcross, PhD, MS, CGC, Associate Professor, Director, Genetic Counseling Training Program, Emory University School of Medicine, for assistance in the preparation of this report.


Disease Overview

Summary

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.

Introduction

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.

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Synonyms

  • Simpson dysmorphia syndrome
  • SGB syndrome
  • SGBS
  • SGBS1
  • bulldog syndrome
  • dysplasia gigantism syndrome, X-Linked
  • SDYS
  • DGSX Golabi-Rosen syndrome
  • Golabi-Rosen syndrome
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Subdivisions

  • Simpson-Golabi-Behmel syndrome type 1
  • Simpson-Golabi-Behmel syndrome type 2
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Signs & 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.

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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.

The 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.

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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.

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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.

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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

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
http://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS
Enns GM. Simpson Dysmorphia Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:251-52.

Firth, Helen V., and Jane A. Hurst, editors. Oxford Desk Reference: Cinical Genetics and Genomics. Second ed., 2017.

Gorlin RJ, Cohen MMJr, Levin LS, eds. Syndromes of the Head and Neck. 3rd ed. Oxford University Press, London, UK; 1990:343-45.

Jones KL, ed. Smith’s Recognizable Patterns of Human Malformation. 5th ed. W. B. Saunders Co., Philadelphia, PA; 1997:168.

JOURNAL ARTICLES
Schirwani S, Novelli A, Digilio MC, et al. Duplications of GPC3 and GPC4 genes in symptomatic female carriers of Simpson-Golabi-Behmel syndrome type 1. European Journal of Medical Genetics. 2019;62(4):243-247. doi:10.1016/j.ejmg.2018.07.022

Monique E  De Paepe, Lawrence Young, Julie R  Jones, Umadevi Tantravahi. Ovotesticular Disorder of Sex Development (Ovotestis) in Simpson-Golabi-Behmel Syndrome: Expansion of the Clinical Spectrum. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society. 2018; 22(1):70–74. doi:10.1177/1093526618770327

Vuillaume M-L, Moizard M-P, Rossignol S, et al. Mutation update for the GPC3 gene involved in Simpson–Golabi–Behmel syndrome and review of the literature. Human Mutation. 2018;39(12):2110-2112. doi:10.1002/humu.23612

Fauth C, Steindl K, Toutain A, Farrell S, Witsch-Baumgartner M, Karall D, Joset P, Bo€hm S, Baumer A, Maier O, Zschocke J, Weksberg R, Marshall CR, Rauch A. A recurrent germline mutation in the PIGA gene causes Simpson-Golabi-Behmel syndrome type 2. Am J Med Genet Part A 2016; 170A:392–402.

Knopp C, Rudnik-Scho ̈neborn S, Zerres K, Gencik M, Spengler S, Eggermann T. Twenty-one years to the right diagnosis – clinical overlap of Simpson–Golabi–Behmel and Beckwith–Wiedemann Syndrome. Am J Med Genet Part A 2015; 167A:151–155.

Tenorio J, Arias P, Martínez-Glez V, et al. Simpson-Golabi-Behmel syndrome types I and II. Orphanet J Rare Dis. 2014;9. doi:10.1186/s13023-014-0138-0

Cottereau E, Mortemousque I, Moizard M‐P, et al. Phenotypic spectrum of Simpson–Golabi–Behmel syndrome in a series of 42 cases with a mutation in GPC3 and review of the literature. Am J Med Genet Part C Semin Med Genet. 2013;163C:92–105.

Chen C-P. Prenatal findings and the genetic diagnosis of fetal overgrowth disorders: Simpson-Golabi-Behmel syndrome, Sotos syndrome, and Beckwith-Wiedemann syndrome. Taiwanese Journal of Obstetrics & Gynecology. 2012 Jun;51(2):186-91. doi: 10.1016/j.tjog.2012.04.004

Young EL, Wishnow R, Nigro MA. Expanding the clinical picture of Simpson-Golabi-Behmel syndrome. Pediatric Neurology. 2006 Feb;34(2):139-42. doi: 10.1016/j.pediatrneurol.2005.07.008

Behmel A, Plöchl E, Rosenkranz W. A new X-linked dysplasia gigantism syndrome: Identical with the Simpson dysplasia syndrome? Human Genetics 1984; 67: 409-413.

Golabi M Rosen L. A new X-linked mental retardation-overgrowth syndrome. American Journal of Medical Genetics 1984; 17: 345-358.

INTERNET
McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Simpson-Golabi-Behmel Syndrome, Type 2. Entry Number; 300209: Last Edit Date; 4/2/2020. https://www.omim.org/entry/300209 Accessed July 8, 2020.

Sajorda BJ, Gonzalez-Gandolfi CX, Hathaway ER, et al. Simpson-Golabi-Behmel Syndrome Type 1. 2006 Dec 19 [Updated 2018 Nov 29]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1219/ Accessed July 8, 2020.

Simpson-Golabi-Behmel Syndrome. Orphanet. April 2015. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=373#:~:text=Simpson%2DGolabi%2DBehmel%20syndrome%20(,and%20an%20increased%20tumor%20risk. Accessed July 8, 2020.

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