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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, also referred to as SGBS type 1) is a rare X-linked multiple congenital anomalies syndrome, characterized by pre- and postnatal overgrowth, distinctive craniofacial features, variable congenital malformations, organomegaly and an increased tumor risk.

The birth prevalence is unknown. Approximately 250 cases have been reported to date.

SGBS manifests a broad clinical picture with varying degrees of severity. It is characterized by pre- and postnatal overgrowth with macrosomia, distinctive craniofacial features (macrocephaly with coarse face, macroglossia, hypertelorism, dental malocclusion, palatal abnormalities), supernumerary nipples, congenital heart defects and arrhythmias, vertebral segmental defects, abdominal visceromegaly (renal dysplasia/nephromegaly, spleenomegaly and hepatomegaly), diaphragmatic hernia, diastasis recti/umbilical hernia, limb anomalies (polydactyly/brachydactyly of the hands, cutaneous syndactyly, nail hypoplasia), and genital involvement (cryptorchidism, hypospadias). Involvement of central nervous system presents with variable degrees of intellectual disability, motor delay and speech delay. Patients with SGBS are at increased risk for embryonal tumors, (Wilms tumor (see this term), hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma). A lethal form of SGBS, known as SGBS type 2 (see this term) and characterized by hydrops fetalis, has also been described.

SGBS is due to loss-of-function mutations in the GPC3 gene (Xq26), encoding Glypican-3 (GPC3), a cell surface heparin sulfate proteoglycan which acts as a negative regulator of Hedgehog (Hh) signaling during development. Mutations in GPC3 result in the hyperactivation of Hh signaling, that ultimately leads to overgrowth and cancer. GPC4 gene involvement (duplication) has also been reported in one case.

Diagnosis is based on clinical findings, family history, genetic testing for GPC3, GPC4 and CXORF5 mutations, and array comparative genomic hybridization (aCGH) analysis of genomic imbalance in Xp22 or Xq26. Imaging techniques help to detect skeletal anomalies and central nervous system involvement. Screening of embryonic tumors is performed by imaging (serial abdominal ultrasonogram and chest X rays), serial measurement of tumor markers and catecholamine metabolites in urine. Renal function is monitored in cases of renal involvement.

Differential diagnosis include overgrowth syndromes such as Beckwith-Wiedemann syndrome and Sotos syndrome, and additional disorders such as fragile X syndrome, Bannayan-Zonana syndrome, PTEN hamartoma tumor syndrome, Marshall syndrome, Nevo syndrome, mosaic trisomy 8 and Pallister-Killian syndrome (see these terms).

Prenatal diagnosis and/or pre-implantational genetic testing are possible for at-risk pregnancies when a mutation has previously been identified in the family. Prenatal ultrasound examination can detect disproportionate fetal overgrowth, while elevated maternal serum alpha-fetoprotein (AFP) levels may also be useful to suspect SGBS.

SGBS follows an X-linked semi-dominant pattern of transmission. In the offspring of an affected male, daughters are heterozygous and sons are unaffected. A heterozygous female has a 25% chance of having an affected son and a 25% chance of having a carrier daughter (usually not affected or showing minimal clinical findings due to lyonization). SGBS may also result from de novo mutations (20-30% of cases).

Management requires a multidisciplinary approach with pediatric cardiologists, neurologists, orthopedics, and speech therapists. Congenital malformations may require surgery. Special attention should be paid to cardiac abnormalities that are responsible for the increased perinatal and infant mortality. Tumor management and follow-up should be performed.

Prognosis depends on the severity of the disease; in the most severe cases, SGBS is life-threatening before birth or in infancy, whereas in milder cases patients often live into adulthood.

Expert reviewer(s)

  • Dr Sixto GARCÍA-MIÑAÚR
  • Dr Pablo LAPUNZINA BADIA
  • Dr Víctor MARTÍNEZ-GLEZ
  • Dr Julián NEVADO BLANCO
  • Dr Fernando SANTOS SIMARRO
  • Dr Jair Antonio TENORIO CASTAÑO

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Detailed information

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