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Simpson-Golabi-Behmel syndrome

ORPHA373
Synonym(s) DGSX
Golabi-Rosen syndrome
SDYS
SGBS
SGBS1
Simpson dysmorphia syndrome
Simpson-Golabi-Behmel syndrome type 1
X-linked dysplasia gigantism syndrome
Prevalence Unknown
Inheritance X-linked recessive
Age of onset Antenatal
Neonatal
ICD-10
  • Q87.3
OMIM
UMLS -
MeSH
  • C537340
MedDRA -

Summary

Simpson-Golabi-Behmel syndrome (SGBS) is characterized by pre- and postnatal overgrowth, facial dysmorphism, and a variety of inconstant visceral and skeletal malformations. Prevalence is unknown. More than 100 patients with SGBS have been reported to date. Characteristic dysmorphic features include macrocephaly with coarse, distinctive facies (becoming less obvious in adulthood) with a large protruding jaw, broad nasal bridge and cleft palate. Hands and feet are broad and short. Supernumerary nipples, rib abnormalities, pectus excavatum, hepatosplenomegaly, umbilical or inguinal hernia, and cryptorchidism may be present. Cardiac abnormalities are frequent, occurring in about one third of the cases. Intellectual deficiency is rare and usually mild, but language difficulties are frequent and psychosocial problems have been observed. There is an increased risk of embryonic neoplasia, including Wilms tumour, neuroblastoma and hepatoblastoma, with an overall tumour frequency of about 10%. Simpson-Golabi-Behmel syndrome follows an X-linked recessive pattern of transmission. A major causative gene has been identified at Xq26. It codes for an extracellular proteoglycan called glypican 3 (GPC3), mainly expressed in tissues derived from the mesoderm, such as the kidneys, liver, and lungs. GPC3 is a heparan sulfate proteoglycan and interacts with insulin-like growth factor 2 (IGF2), influencing its signalling activities. Not all individuals with SGBS present mutations in the GPC3 gene, which suggests that other loci could be involved in some cases. A more severe variant of the syndrome (Simpson-Golabi-Behmel syndrome, type 2; see this term) described in a single family, and characterized by multiple craniofacial, skeletal and visceral abnormalities (but no heart defect), hydrops fetalis and early lethality, has been mapped to Xp22. No biological test is available. Diagnosis is suspected on medical history and clinical features, and family history in some cases. GPC3 mutation screening confirms the diagnosis when a mutation is identified, but the diagnosis cannot be ruled out when no mutation is found. Differential diagnoses include Beckwith-Wiedemann syndrome (BWS), Weaver syndrome, Perlman syndrome and Sotos syndrome. In the offspring of an affected male, all the daughters are heterozygous and all the sons are unaffected. A heterozygous female has a 50% chance of transmitting the mutated gene: she has a 25% chance of having an affected son and a 25% chance of having a carrier daughter. Heterozygous detection may be based on the recognition of mild physical signs. Identification of the mutation in a male index case allows carrier detection by molecular testing in the females at risk in the family. Early prenatal diagnosis is feasible by molecular analysis when a mutation has previously been identified in an index case. In the absence of a family history, the diagnosis may only be suggested during the pregnancy through ultrasound abnormalities. Congenital malformations may require surgery. Early perinatal and infant mortality is high and probably related to cardiac abnormalities; special attention should therefore be paid to heart problems. Tumour screening in SGBS should include abdominal ultrasound, urinalysis, and biochemical markers for embryonic tumours. Language problems and intellectual impairment require special education.

Expert reviewer(s)

  • Pr Annick TOUTAIN

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Detailed information

Review article
  • EN (2014)
Clinical genetics review
  • EN (2011)
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