Simpson-Golabi-Behmel syndrome (ORPHA:373)
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.
Epidemiology
The birth prevalence is unknown. Approximately 250 cases have been reported to date.
Clinical description
Simpson-Golabi-Behmel syndrome (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, splenomegaly 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), hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma.
Etiology
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.
Diagnostic methods
Diagnosis is based on clinical findings, family history, genetic testing for GPC3 mutations, and array comparative genomic hybridization (aCGH) analysis of genomic imbalance in Xq26. Imaging techniques help to detect skeletal anomalies and central nervous system involvement. Screening for embryonic tumors is performed by imaging (serial abdominal ultrasonogram and chest X rays), serial measurement of tumor markers and catecholamine metabolites in urine. Kidney function is monitored in cases of kidney involvement.
Differential diagnosis
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.
Antenatal diagnosis
Prenatal diagnosis and/or pre-implantation 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.
Genetic counseling
SGBS follows an X-linked recessive pattern of transmission. In the offspring of an affected male, daughters are heterozygous and sons are unaffected. For each pregnancy, a heterozygous female has a 25% risk of having an affected son and a 25% risk 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 and treatment
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
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.

                            Last update: 
                            November 2020


                            - Expert reviewer(s): 
                            Pr Pablo LAPUNZINA | ITHACA* - Dr Jair Antonio TENORIO CASTAÑO 


                                * European Reference Network