Males
Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is characterized by pre- and postnatal macrosomia, distinctive facies, and variable visceral, skeletal, and neurodevelopmental abnormalities.
Macrosomia. Virtually all persons with SGBS1 have pre- and postnatal overgrowth. As with other macrosomic syndromes, hypoglycemia may be present in the neonatal period.
Macrocephaly. See Suggestive Findings.
Characteristic facies. See Suggestive Findings.
Eyes. Esotropia, cataracts, and coloboma of the optic disc [Golabi & Rosen 1984] have been noted. Ocular nerve palsies and strabismus can occur.
Ears. Minor ear abnormalities are frequent, most often preauricular tags, fistulas, ear lobule creases, and helical dimples. Conductive hearing loss has been described [Golabi & Rosen 1984].
Oropharynx. Macroglossia is a characteristic feature. Other anomalies include various degrees of palatal clefting (including submucous cleft and bifid uvula), laryngeal cleft, and laryngeal web. Obstructive sleep apnea may be present. Silent aspiration leading to chronic respiratory infections and bronchiectasis has also been described [Glamuzina et al 2009, Tenorio et al 2014].
Neck. Cystic hygroma has been described [Chen et al 1993].
Thoracoabdominal wall. Supernumerary nipples are common, either one or multiple, unilateral or bilateral. Diastasis recti and umbilical hernias are observed frequently; however, true omphalocele is rare.
Cardiothoracic. Congenital heart defects are variable; septal defects are common. Pulmonic stenosis, aortic coarctation, transposition of the great vessels, and patent ductus arteriosus or patent foramen ovale have been reported.
Conduction defects and arrhythmias have frequently been described [Lin et al 1999]. Transient QT interval prolongation has also been reported [Gertsch et al 2010].
Lungs. Abnormal branching of the bronchi and an abnormal lower airway pit have been described in one affected individual [Glamuzina et al 2009].
Genitourinary. Nephromegaly, multicystic kidneys, hydronephrosis, hydroureter, and duplicated ureters are described. Other genitourinary anomalies include hypospadias, bifid scrotum, cryptorchidism, hydrocele, and inguinal hernia [Hughes-Benzie et al 1996].
Gastrointestinal. GI anomalies include pyloric ring, Meckel's diverticulum, intestinal malrotation [Golabi & Rosen 1984], hepatosplenomegaly, pancreatic hyperplasia of islets of Langerhans, choledochal cysts [Kim et al 1999], duplication of the pancreatic duct, and polysplenia.
Skeletal. Skeletal anomalies can include vertebral fusion, scoliosis, pectus excavatum, rib anomalies (including cervical ribs), congenital hip dislocation [Terespolsky et al 1995], small sciatic notches, and flared iliac wings [Chen et al 1993]. Extra lumbar vertebrae, spina bifida occulta, coccygeal skin tag, and bony appendage have also been documented [Golabi & Rosen 1984].
Hand anomalies such as large hands, broad thumbs, and brachydactyly are common. Other findings include syndactyly, clinodactyly, and postaxial polydactyly. Striking index finger hypoplasia with congenital abnormalities of the proximal phalanx have been reported [Day & Fryer 2005]. Nail dysplasia, hypoplasia (particularly of the index finger), and hypoconvexity are common.
Advanced bone age, including presence of ossified carpal bones in a newborn, has been described [Chen et al 1993].
Central nervous system (CNS). Normal intelligence has been described, but mild-to-severe intellectual disability is common, with language delay being the most characteristic finding.
Neurologic manifestations are perhaps the most varied findings. Hypotonia and absent primitive reflexes, a high-pitched cry in neonates, seizures, and abnormal EEG have all been described. Hydrocephalus, epilepsy, and attention-deficit/hyperactivity disorder may also be present [Tenorio et al 2014].
CNS malformations include agenesis of the corpus callosum, Chiari malformation and hydrocephalus [Young et al 2006], and aplasia of the cerebellar vermis.
Neoplasia. An absolute incidence and relative risk for tumors has not been established; the embryonic tumor frequency in persons with SGBS1 is likely between 5% and 10%; however, these numbers are based on case reports [Lapunzina et al 1998, Lin et al 1999]. At least six tumor types have been described [Lapunzina et al 1998, Li et al 2001, Lapunzina 2005, Thomas et al 2012].
Wilms tumor (in 4 individuals)
Hepatoblastoma (2)
Adrenal neuroblastoma (1)
Gonadoblastoma (1)
Hepatocellular carcinoma (1)
Medulloblastoma (1)
See Wilms Tumor Overview.
Other
Heterozygous Females
Due to skewed X-chromosome inactivation, carrier females can have manifestations of SBGS including macrosomia, macrocephaly, widely spaced eyes, broad and upturned nasal tip with prominent columella, macrostomia, prominent chin, hypoplastic fingernails, coccygeal skin tag and bony appendage, extra lumbar and thoracic vertebrae, and accessory nipples [Golabi & Rosen 1984]. Tall stature, coarse facial features, and developmental delay have also been reported [Gertsch et al 2010].
To date, eight heterozygous females with clinical expression of SGBS1 have been reported [Schirwani et al 2019]. The molecular genetic causes in these eight females are as follows: heterozygous GPC3 and GPC4 duplication (3), GPC3 deletion (2), balanced X-chromosome translocations (2), and a heterozygous GPC3 duplication (1) [Punnett 1994, Pilia et al 1996, Yano et al 2011, Mujezinović et al 2016, Shimojima et al 2016, Vaisfeld et al 2017, Schirwani et al 2019]. Although the genotype-phenotype correlation remains unknown, postnatal overgrowth, coarse facial features, congenital heart defects, intellectual disability, and hernias appear to be common features [Schirwani et al 2019].
Two females with a heterozygous GPC3 pathogenic variant were reported to have two different types of cancer: one had a sero-papilliferous cystoadenoma, a low-grade ovarian carcinoma; the other had breast cancer [Gurrieri et al 2011]. Information was not sufficient to exclude other possible genetic causes for breast/ovarian cancer in the family.