Simpson-Golabi-Behmel syndrome is an X-linked condition characterized by pre- and postnatal overgrowth, coarse facies, congenital heart defects, and other congenital abnormalities (Xuan et al., 1999). It shows phenotypic similarities to Beckwith-Wiedemann syndrome (BWS; 130650), another overgrowth syndrome. ... Simpson-Golabi-Behmel syndrome is an X-linked condition characterized by pre- and postnatal overgrowth, coarse facies, congenital heart defects, and other congenital abnormalities (Xuan et al., 1999). It shows phenotypic similarities to Beckwith-Wiedemann syndrome (BWS; 130650), another overgrowth syndrome. See also Simpson-Golabi-Behmel syndrome type 2 (SGBS2; 300209), which has been associated with a mutation in the CXORF5 gene (300170) on chromosome Xp22.
Hughes-Benzie et al. (1992) drew attention to the superficial similarities in the appearance of pedigrees segregating in an X-linked recessive pattern and those exhibiting an autosomal dominant pattern with imprinting of specific genes. ... - Differential Diagnosis Hughes-Benzie et al. (1992) drew attention to the superficial similarities in the appearance of pedigrees segregating in an X-linked recessive pattern and those exhibiting an autosomal dominant pattern with imprinting of specific genes. As an illustration of the confusion, they referred to a family misdiagnosed as having Beckwith-Wiedemann syndrome, who was found to have SGBS based on clinical findings of postaxial polydactyly, midline groove in the lower lip, and more severely affected males (Niikawa et al., 1986; case 4). Shared clinical features of BWS and SGBS include macrosomia, macroglossia, cleft palate, visceromegaly, earlobe creases, hernias, neonatal hypoglycemia, and a risk of embryonal tumors. Xuan et al. (1994) pointed to the report by Punnett et al. (1974) of a female with a putative diagnosis of Beckwith-Wiedemann syndrome and a balanced reciprocal (X;1)(q26;q12) translocation. Xuan et al. (1994) suggested that the description of the young woman was entirely compatible with SGBS and that the translocation may have disrupted the SGBS gene. Punnett (1994) reexamined this 23-year-old patient who, in addition to typical manifestations, had diaphragmatic hernia and pulmonic valve stenosis, and concluded that she actually had SGBS. Verloes et al. (1995) commented on the difficulties in the differential diagnosis of overgrowth syndromes in the neonatal period and the phenotypic overlap of BWS, SGB syndrome, and Perlman syndrome (267000). They suggested that it may be necessary to add genital ambiguity, hydramnios, and nephroblastomatosis to the clinical spectrum of Simpson-Golabi-Behmel syndrome and to keep in mind a possible risk for embryonal tumors in patients with this syndrome. Gertsch et al. (2010) reported a male infant initially diagnosed with Timothy syndrome (601005) after birth on the basis of QT interval prolongation in the neonatal period and syndactyly. At day 7 of life, the patient received an implantable cardioverter-defibrillator (ICD). However, genetic testing did not identify a mutation in the CACNA1C gene (114205), thus excluding a diagnosis of Timothy syndrome. Reevaluation of the patient showed that the syndactyly was postaxial and with bony fusion, not consistent with that observed in Timothy syndrome. Repeat genetic testing identified a truncating mutation in the GPC3 gene, confirming the diagnosis of SGBS. Other features in this infant included prenatal nuchal translucency on fetal imaging, high alpha-fetoprotein levels in the mother during pregnancy, macrosomia, hypoplastic index fingers, submucosal cleft palate, bifid uvula, and coarse facial features. The mother, who also carried the mutation, had tall stature, dolichocephaly, high-arched palate, pectus excavatum, joint laxity, and nonspecific T-wave abnormalities on EKG. The patient was found to have a normal QT interval at age 9 months, and the ICD was removed. Gertsch et al. (2010) emphasized the importance of distinguishing between Timothy syndrome and SGBS, since the former has a high incidence of neonatal mortality. They also noted that transient QT prolongation had not been reported in SGBS.
Simpson et al. (1975) reported 2 male first cousins, sons of sisters, who had a distinctive facial appearance, including a large protruding jaw, widened nasal bridge, upturned nasal tip, and enlarged tongue. Other features included broad stocky appearance ... Simpson et al. (1975) reported 2 male first cousins, sons of sisters, who had a distinctive facial appearance, including a large protruding jaw, widened nasal bridge, upturned nasal tip, and enlarged tongue. Other features included broad stocky appearance and broad, short hands and fingers. One of the patients had clefting of the lower lip. Intelligence was normal. The family referred to the appearance as 'bulldog'-like. Laboratory tests excluded hypothyroidism. Close linkage with the Xg blood group locus was excluded. Kaariainen (1981) observed a tall (192 cm) 40-year-old man with operated pectus excavatum, ventricular septal defect, central cleft of the lower lip, peculiar cup-shaped ears with knobbiness and nodularity, short clubbed terminal phalanges, low-pitched voice, and cataracts developing at age 35. The parents, who came from different parts of Finland, were 170 and 160 cm tall. A brother, height 180 cm, died at age 18 years of ventricular septal defect and pulmonary hypertension. He looked like the surviving brother and quite different from other members of the family. Kaariainen (1982) concluded that the disorder was the same as that described by Simpson et al. (1975). Golabi and Rosen (1984) reported a family in which 4 males in 4 sibships spanning 3 generations connected through females had prenatal and postnatal overgrowth; short, broad, upturned nose; large mouth, midline groove of tongue, inferior alveolar ridge and lower lip; submucous cleft palate; 13 ribs; Meckel diverticulum; intestinal malrotation; coccygeal skin tag and bony appendage; hypoplastic index fingernails; unilateral postaxial polydactyly; and bilateral syndactyly of fingers 2 and 3. Mental retardation was also a feature. The carrier mother of the propositus had a large mouth, coccygeal skin tag and bony appendage, and hypoplastic index fingernails. Behmel et al. (1988) suggested that the mental retardation in the family reported by Golabi and Rosen (1984) may have had a basis unrelated to the rest of the syndrome. Intelligence in the dysplasia gigantism syndrome is usually normal or only mildly retarded. Chen et al. (1993) reported the birth of a fifth affected male in the family reported by Golabi and Rosen (1984) and provided a follow-up of a patient who was 8 years old at the time of the initial report. He was 190 cm tall, had coarse facial features, micrognathia, short fingers, and dental abnormalities. Problems with speech and psychosocial development were also described. The newborn member of the family and a second unrelated male with this syndrome were found to have congenital diaphragmatic hernia. On the basis of these cases, Chen et al. (1993) noted that radiologic findings include flaring of the iliac wings, narrow sacroiliac notches, and the presence of 2 carpal ossification centers as a newborn ('advanced bone age'). In a pedigree pattern consistent with X-linked recessive inheritance, Behmel et al. (1984) observed 11 male newborns with a syndrome similar to that described by Simpson et al. (1975): elevated birth weight and length; disproportionately large head with coarse, distinctive facies; short neck; slight obesity; and broad, short hands and feet. The affected males who reached adulthood attained heights of about 2 m; their unusual facial and general appearance and clumsiness, remarkable during infancy and childhood, became somewhat less conspicuous. In all but 1, intelligence was normal, as it was in the 2 cases of Simpson et al. (1975). Behmel et al. (1988) provided follow-up on the family reported by Behmel et al. (1984) and added a second Austrian family. They concluded on the basis of these studies that the syndrome was identical to that reported by Simpson et al. (1975) and Golabi and Rosen (1984). Opitz (1984) reported a family in which 3 boys born to half sisters were affected. The nose in affected males was particularly similar to that in the patients of Golabi and Rosen (1984). Opitz et al. (1988) provided follow-up of 1 of the patients reported by Opitz (1984). He died at age 25 months without attaining any psychomotor development and with a neurologic picture of irritability, hypotonia, seizures, deafness, and possible cortical blindness. Autopsy showed spongiform degeneration of brainstem and cerebrum; this patient may have had a different disorder. Kajii and Tsukahara (1984) reported a possible case, which was originally described by Tsukahara et al. (1984) as 'a Weaver-like syndrome.' Garganta et al. (1988) and Garganta and Bodurtha (1992) concluded on the basis of 2 affected brothers with overgrowth, macrocephaly, polydactyly, supernumerary nipples, and a characteristic facial appearance that mental retardation is not a consistent feature. One of the boys had pulmonic stenosis and cleft palate. One of the boys also had creases of the posterior helix, suggesting the Beckwith-Wiedemann syndrome. Garganta et al. (1988) suggested that the Simpson dysmorphia syndrome and Golabi-Rosen syndrome are the same disorder. Neri et al. (1988) reported an affected kindred. They commented on the high frequency of infant death, a finding noted by others, and stated that postaxial hexadactyly of the hands is an occasional feature. They suggested the designation 'Simpson-Golabi-Behmel syndrome.' An affected patient reported by Gurrieri et al. (1992) also had postaxial polydactyly and extra nipples. Hughes-Benzie et al. (1992) reported a family with 6 affected males in 5 sibships in 3 generations. All had pre- and postnatal overgrowth, with 2 adult males attaining heights over 195 cm. Other features included coarse facies with hypertelorism, broad nasal root, cleft palate, full lips with a midline groove in the lower lip, grooved tongue with tongue tie, prominent mandible, congenital heart defects, arrhythmias, supernumerary nipples, splenomegaly, large dysplastic kidneys, cryptorchidism, hypospadias, and postaxial hexadactyly. All affected individuals were of normal intelligence. One affected male died at age 19 months of a neuroblastoma. Eight carriers who showed varying manifestations of the syndrome were identified. Ireland et al. (1993) presented a 5-generation family. Overgrowth was present in 4 affected males and 3 out of 4 carrier females. The facial features in affected males included facial asymmetry with hypertelorism and upward slanting palpebral fissures. In addition, they had a broad nose, thin lips, and a prominent mandible. The palate was high-arched, the tongue was grooved and tethered with an anterior notch, and there was a groove in the lower lip. None of the affected males was mentally retarded. One of the affected males had bilateral hydronephrosis and a nonfunctioning kidney; another had bilateral cataracts diagnosed at age 2 years and retinal detachment at age 5 years. Facial features in carrier females included short, narrow palpebral fissures, upturned nasal tip with a prominent columella, and a prominent chin. Both affected males and carrier females showed extra lumbar and thoracic vertebrae and accessory nipples. From a review of reported cases, Garganta and Bodurtha (1992) concluded that early perinatal and infant mortality is high in patients with SGBS. Terespolsky et al. (1995) commented on the wide clinical range in reported cases of SGBS, ranging from a mild form associated with long-term survival to an early lethal form with multiple congenital anomalies and severe mental retardation. They found 8 reported families in which affected individuals died in infancy. Konig et al. (1991) suggested that cardiac arrhythmias may be a major component of the SGB syndrome and can be responsible for death in early infancy and perhaps for cardiac arrest in the adult. Lin et al. (1999) concluded that cardiac abnormalities of any type are common in SGBS, occurring perhaps in almost one-half of cases, with cardiovascular malformations seen in one-third of cases. Neri et al. (1998) reviewed the clinical and molecular aspects of SGBS. They emphasized that an increased risk of neoplasia in SGBS must be kept in mind, especially in young patients. They stated that Wilms tumor of the kidney had been found in several members of affected families in Canada (Hughes-Benzie et al., 1992; Xuan et al., 1994). Kim et al. (1999) reported choledochal cysts in SGB syndrome. The patient was a new member of a family with this disorder previously reported by Chen et al. (1993) and Golabi and Rosen (1984). The diagnosis of SGBS had been suspected prenatally because of the family history and prenatal ultrasound findings of polyhydramnios, macrosomia, double-bubble sign suggestive of duodenal atresia, bilateral clubfoot, and visualization of a penis indicating male gender. At birth the length was 55 cm (97%). He had a coarse facial appearance, vertical furrows between the eyebrows, increased interpupillary distance, bifid uvula but no cleft lip or palate, and macrostomia. He had low-set, large floppy ears. The choledochal cyst was discovered at operation for other intraabdominal anomalies. Kim et al. (1999) provided an updated pedigree of the family with 7 affected individuals in 3 generations. Griffith et al. (2009) reported 3 brothers with SGBS, aged 20 months, 4 years, and 6 years, all of whom had cryptorchidism. The eldest brother also had chordee of the penis, penoscrotal hypospadias, and penoscrotal transposition requiring multiple surgeries. The authors stated that this was the first SGBS patient with such anomalies to survive beyond the neonatal period, and suggested that a range of genital anomalies should be considered a nonrandom feature of SGBS.
Pilia et al. (1996) identified microdeletions in the GPC3 gene that cosegregated with SGBS in 3 affected families.
In affected members of a family described by Xuan et al. (1994), Xuan ... - GPC3 Gene Pilia et al. (1996) identified microdeletions in the GPC3 gene that cosegregated with SGBS in 3 affected families. In affected members of a family described by Xuan et al. (1994), Xuan et al. (1999) identified a 13-bp deletion in the GPC3 gene (300037.0001). Xuan et al. (1999) confirmed their previous suggestion that a female in the family who had multiple thoracic hemivertebrae, Sprengel deformity of her right shoulder, and Wilms tumor did not carry the SGBS exon 2 deletion of the GPC3 gene. Xuan et al. (1999) suggested that the presence of skeletal abnormalities and Wilms tumor in this patient may be due to a trans effect from the maternal carrier in this SGBS kindred. Li et al. (2001) performed GPC3 deletion screening on 80 male patients with somatic overgrowth in the following categories: 19 with Simpson-Golabi-Behmel syndrome, 26 with possible SGBS, and 35 with Beckwith-Wiedemann syndrome. Using exon-specific PCR and Southern blot analysis, 7 GPC3 deletions were identified, 6 from the SGBS category and 1 from the possible SGBS category. None of the patients with Beckwith-Wiedemann syndrome had GPC3 deletions. GPC3 deletions were identified in 2 patients from families published previously as having other overgrowth syndromes: one with a diagnosis of Sotos syndrome (117550) and the other with Perlman syndrome with nephroblastomatosis. One patient developed hepatoblastoma, which had not previously been described in SGBS. Direct sequencing of all GPC3 exons of the 13 SGBS patients without deletions failed to identify any further mutations, suggesting that alternative silencing mechanisms and/or other genes may be involved in the pathogenesis of SGBS. Rodriguez-Criado et al. (2005) described 2 molecularly confirmed families with SGBS. All patients had typical manifestations of SGBS, including some female relatives who had minor manifestations. Some patients had novel findings such as a deep V-shaped sella turcica and 6 lumbar vertebrae. Molecular studies in affected patients showed a deletion of exon 6 of the GPC3 gene in family 1 (300037.0008) and an intronic mutation in the GPC3 gene in family 2 (300037.0009). Romanelli et al. (2007) reported 2 brothers with SGBS caused by a truncating mutation in the GPC3 gene (300037.0010). The mutation was not present in the mother, indicating germinal mosaicism. Sakazume et al. (2007) identified mutations in the GPC3 gene in 7 Japanese boys with SGBS. One of the boys had an affected younger brother. All the mutations were predicted to resulted in complete loss of function. Only 1 patient had a large deletion, and there were 5 nonsense and 1 frameshift mutation. There were no apparent genotype/phenotype correlations. - GPC4 Gene Veugelers et al. (1998) found that 1 of the SGBS patients reported by Pilia et al. (1996) had a deletion of the entire GPC4 gene (300168) as well as deletion of the last 2 exons of GPC3. In 2 males with SGBS who were part of the original family reported by Golabi and Rosen (1984), Waterson et al. (2010) found no mutations in exons or intron/exon boundaries of the GPC3 gene. However, multiple ligation-dependent probe amplification (MLPA) analysis identified a duplication of exons 1 through 9 of the GPC4 gene. Dosage studies in 1 of the patients confirmed the duplication, whereas dosage of the GPC3 gene was normal. The 2 genes are closely linked and encode similar proteoglycans. Waterson et al. (2010) suggested that the duplication may affect, and possibly decrease, expression of the GPC3 gene, thus leading to the phenotype. The phenotype of the 2 boys was consistent with SGBS, with features of an overgrowth syndrome, genitourinary anomalies, vertebral anomalies, clefting, and coarse facial features. Waterson et al. (2010) concluded that GPC4 testing should be considered in patients who have no identifiable GPC3 mutations.
The diagnosis of Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is based on clinical findings, family history consistent with X-linked inheritance, and molecular genetic testing....
DiagnosisClinical DiagnosisThe diagnosis of Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is based on clinical findings, family history consistent with X-linked inheritance, and molecular genetic testing.No clinical diagnostic criteria have been established. The diagnosis is suspected in males with the following:Macrosomia (weight or length ≥95th percentile when adjusted for sex and age) Characteristic facial features Macrocephaly (occipitofrontal circumference [OFC] ≥95th percentile when adjusted for sex and age) Ocular hypertelorism, epicanthal folds, and downslanting palpebral fissures Redundant, furrowed skin over the glabella Wide nasal bridge and anteverted nares in infants; broad nose and "coarse" facial appearance in older individuals Macrostomia (abnormally large mouth) Macroglossia (abnormally large tongue) Dental malocclusionMidline groove in the lower lip and/or deep furrow in the middle of the tongue Cleft lip and/or submucous cleft palate (with a bifid uvula); high and narrow palate [Hughes-Benzie et al 1996] Small mandible (micrognathia) in neonates; macrognathia in older individuals Multiple congenital anomalies (see Natural History) Congenital heart disease Conduction defects (transient QT interval prolongation) Supernumerary nipples Diastasis recti/umbilical hernia Diaphragmatic hernia Renal dysplasia/nephromegaly Cryptorchidism/hypospadias Hand anomalies (brachydactyly, cutaneous syndactyly, polydactyly) Molecular Genetic TestingGenesGPC3, encoding glypican-3, was the first gene known to be associated with Simpson-Golabi-Behmel syndrome type 1 (SGBS1). GPC4, encoding glypican-4, flanks the centromeric end of GPC3 on Xq26 [Waterson et al 2010]. Clinical testing Table 1. Summary of Molecular Genetic Testing Used in Simpson-Golabi-Behmel Syndrome Type 1View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityMalesHeterozygous FemalesGPC3Sequence analysisSequence variants 237%-70% 3, 4, 5Unknown 6ClinicalDeletion / duplication analysis 7Deletion of one or more exons or the whole gene 8Unknown 9UnknownGPC4Deletion / duplication analysis 7Duplication of one or more exons or the whole geneUnknownResearch only1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. 26/37 individuals with SGBS1 [Lin et al 1999]; 7/10 [Veugelers et al 2000]; 7/19 [Li et al 2001]. Note: (1) Lin et al [1999] hypothesized that the high detection rate may reflect sampling bias. (2) In the study by Li et al [2001], two individuals clinically diagnosed with Perlman syndrome and Sotos syndrome prior to the availability of molecular genetic testing were found to have a GPC3 mutation.4. Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis. 5. Includes the mutation detection frequency using deletion/duplication analysis6. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or of the entire X-linked gene in a heterozygous female. 7. Testing that identifies deletions not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. 8. A contiguous deletion of GPC3 and GPC4 has been identified in one family with SGBS1 [Veugelers et al 1998].9. Duplication of exons 1-9 in GPC4 without deletion or mutation of GPC3 was found in the original family described by Golabi & Rosen [1984] in which no GPC3 mutation had been identified [Waterson et al 2010].Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis in an individual with findings consistent with SGBS1: 1.Sequence analysis of GPC32.If no mutation is identified, deletion/duplication analysis of GPC33.If no mutation in GPC3 is detected, deletion/duplication analysis of GPC4. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.Note: (1) Carriers are heterozygotes for this X-linked disorder and may have clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in GPC3 and GPC4.
Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is characterized by pre- and postnatal macrosomia, distinctive facies, and variable visceral, skeletal, and neurodevelopmental abnormalities....
Natural History MalesSimpson-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 Clinical Diagnosis. Characteristic facies. See Clinical Diagnosis. 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]. 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 been reported [Gertsch et al 2010].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), winged scapula, 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, including 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 has 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 description. 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.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; however, in a review of more than 100 persons with SGBS1, Li et al [2001] found a tumor frequency of about 10%. At least five tumor types have been described [Lapunzina et al 1998, Li et al 2001, Lapunzina 2005]Wilms tumor (4 cases)Hepatoblastoma (2)Adrenal neuroblastoma (1)Gonadoblastoma (1)Hepatocellular carcinoma (1) See Wilms Tumor Overview. OtherDiaphragmatic hernia and associated lung hypoplasia [Chen et al 1993]. See Congenital Diaphragmatic Hernia Overview. Thymic hypoplasia and generalized lymphoid atrophy [Chen et al 1993] Heterozygous FemalesDue to skewed X-chromosome inactivation, carrier females can have manifestations of SBGS including macrosomia, macrocephaly, hypertelorism, 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, course facial features, and developmental delay have also been reported [Gertsch et al 2010].Two female carriers with a GPC3 mutation 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]. Due to insufficient information other possible genetic causes for breast/ovarian cancer in the family could not be excluded.
In a study of genotype-phenotype correlations, Mariani et al [2003] determined that all deletions and point mutations occurring in the eight GPC3 exons result in loss of function with no phenotypic distinctions based on size or position of a deletion or point mutation....
Genotype-Phenotype CorrelationsIn a study of genotype-phenotype correlations, Mariani et al [2003] determined that all deletions and point mutations occurring in the eight GPC3 exons result in loss of function with no phenotypic distinctions based on size or position of a deletion or point mutation.
Simpson-Golabi-Behmel syndrome type 2, also known as the infantile lethal variant, maps to Xp22 and is postulated to be a distinct disorder with overlapping phenotypic features. Clinical features described in four individuals include hydrops fetalis, jaundice, brisk deep tendon reflexes, seizures, and trilobate left lung [Terespolsky et al 1995, Brzustowicz et al 1999]. Budny et al [2006] identified a CXORF5 mutation in one family. ...
Differential DiagnosisSimpson-Golabi-Behmel syndrome type 2, also known as the infantile lethal variant, maps to Xp22 and is postulated to be a distinct disorder with overlapping phenotypic features. Clinical features described in four individuals include hydrops fetalis, jaundice, brisk deep tendon reflexes, seizures, and trilobate left lung [Terespolsky et al 1995, Brzustowicz et al 1999]. Budny et al [2006] identified a CXORF5 mutation in one family. Beckwith-Wiedemann syndrome (BWS) is characterized by macrosomia, macroglossia, visceromegaly, embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma), omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, and renal abnormalities (e.g., medullary dysplasia, nephrocalcinosis, medullary sponge kidney, and nephromegaly). BWS is associated with abnormal regulation of gene transcription by any one of a number of mechanisms in an imprinted domain on chromosome 11p15.5. BWS demonstrates the greatest number of clinical similarities with SGBS1 including macrosomia, macroglossia, ear anomalies, genitourinary malformations, and an increased incidence of tumors. However, the facies in these two syndromes are appreciably different, the skeletal abnormalities seen in SGBS1 are not present in BWS, and omphalocele seen in BWS is rare in SGBS1. Additionally, the X-linked inheritance of SGBS1 may help to differentiate these two overgrowth syndromes [Pilia et al 1996].Sotos syndrome is characterized by a typical facial appearance, intellectual impairment, and overgrowth involving both height and head circumference. It is associated with neonatal jaundice, scoliosis, seizures, strabismus, conductive hearing loss, congenital cardiac anomalies, renal anomalies, and behavioral problems. The risk of sacrococcygeal teratoma and neuroblastoma is slightly increased. About 80%-90% of individuals with Sotos syndrome have a demonstrable mutation or deletion of NSD1. Inheritance is autosomal dominant.Weaver syndrome shares clinical features of overgrowth, umbilical hernia, ear anomalies, hypotonia, advanced bone age, vertebral defects, and hypertelorism, but has different facies and more prominent psychomotor delay. The diagnosis of Weaver syndrome is made on clinical grounds [Weaver et al 1974].Nevoid basal cell carcinoma syndrome (NBCCS, Gorlin syndrome) is characterized by multiple jaw keratocysts frequently beginning in the second decade of life and/or basal cell carcinomas usually from the third decade onwards. About 60% of individuals have a recognizable appearance with macrocephaly, bossing of the forehead, coarse facial features, and facial milia. Most individuals with NBCCS have skeletal anomalies such as bifid ribs or wedge-shaped vertebrae. Other less common findings include ectopic calcification, particularly in the falx; cardiac and ovarian fibromas; and medulloblastoma (primitive neuroectodermal tumor [PNET]) in early childhood. In about 60%-85% of individuals fulfilling diagnostic criteria, it is possible to identify a germline mutation of PTCH. Inheritance is autosomal dominant.Fryns syndrome, an autosomal recessive multiple congenital anomaly syndrome, is characterized by coarse facies, diaphragmatic hernia with lung hypoplasia, distal limb hypoplasia and malformations of the cardiovascular system, gastrointestinal system, genitourinary system (renal cystic dysplasia), and central nervous system (arrhinencephaly, Dandy-Walker anomaly, agenesis of the corpus callosum).Other syndromes that may share overlapping features:Perlman syndrome, a rare autosomal recessive condition, with macrosomia and a high incidence of Wilms tumor; facial features are distinctive and neonatal mortality is high. Nevo syndrome, an autosomal recessive condition that shares vertebral anomalies, ear malformations, cryptorchidism, overgrowth, and intellectual disability with SGBS1. Nevo syndrome manifestations further include accelerated osseous maturation, large extremities, and hypotonia. This condition is caused by mutations in exon 9 of PLOD1 [Giunta et al 2005]. (See Ehlers-Danlos Syndrome, Kyphoscoliotic Form.)Marshall-Smith syndrome, which shares advanced bone age and intellectual disability with SGBS1; differences include facial features and predisposition to fractures. Elejalde syndrome (acrocephalopolydactylous dysplasia). Infrequently described, Elejalde syndrome includes findings of macrosomia, abnormal facies, craniosynostosis with acrocepaly, omphalocele, organomegaly, cystic renal dysplasia, and polydactyly. Infant of a diabetic mother syndrome. Infants born to diabetic mothers (IDM) have a higher rate of congenital malformations. Sacral agenesis or hypogenesis and/or caudal dysgenesis are classic findings [Williamson 1970], but other frequently observed anomalies include congenital heart defects, renal anomalies, vertebral anomalies, limb defects, and structural brain abnormalities. Mosaic trisomy 8. Phenotype is variable, with characteristic findings of advanced growth, long slender trunk with multiple skeletal abnormalities (spinal deformities, contractures of fingers and toes), absence of the corpus callosum, and moderate intellectual disability. Typical facial features include high, prominent forehead, hypertelorism, full lips, and micrognathia. Mosaic tetrasomy 12p (or Pallister-Killian syndrome), characterized by variegated skin pigmentation, facial anomalies including prominent forehead with sparse anterior scalp hair, ocular hypertelorism, short nose with anteverted nares, flat nasal bridge, as well as developmental delay Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs of an individual diagnosed with Simpson-Golabi-Behmel syndrome type 1 (SGBS1), the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with Simpson-Golabi-Behmel syndrome type 1 (SGBS1), the following evaluations are recommended:Assessment of neonates for hypoglycemia Assessment for upper airway sufficiency if macroglossia is present Evaluation of young children with hypotonia and macroglossia for sleep apnea Evaluation by a craniofacial team, including a feeding specialist if orofacial clefting is present Hearing evaluationEye examinationCardiac evaluation for structural defects and conduction abnormalities including chest radiograph, electrocardiogram, and echocardiogram Renal ultrasound examination to evaluate for genitourinary malformations Abdominal/pelvic ultrasound examination to evaluate for intra-abdominal tumors Abdominal ultrasound examination to evaluate for visceral anomalies; further studies (e.g., MRI) if findings are suspiciousExamination for evidence of skeletal anomalies requiring intervention (e.g., scoliosis during period of rapid growth rate)Development assessment including speech and language assessmentNeurology evaluation/ MRI of the brain if seizures are presentTreatment of ManifestationsThe following are appropriate:Prompt treatment of hypoglycemia if present Prompt treatment of upper airway obstruction resulting from macroglossia, micrognathia, and/or glossoptosisReferral of children to the following pediatric specialists as needed: Craniofacial team for management of cleft lip and/or palate, or macroglossia and related feeding difficulties Audiologist, otolaryngologist, and speech therapy for management of hearing lossOphthalmologist for management of vision problems Cardiologist for management of congenital heart defects and/or cardiac conduction defects Orthopedist for the treatment of vertebral malformations and scoliosis if present Urologist for surgical correction of anomalies such as hypospadias and cryptorchidismNeurologist if seizures are presentOncologist if a tumor is identifiedNeurodevelopmental follow up for individual treatment plan that may include special education, occupational therapy, and physical therapy Prevention of Secondary ComplicationsRoutine pre- and post-surgical preparation and monitoring for individuals with congenital heart disease and/or conduction defects SurveillanceFor males with SGBS1:Monitoring for hypoglycemia in the newborn period Physical examination to monitor for scoliosis during period of rapid growth rate; radiographs as needed If development appears to be normal on initial assessment, routine monitoring of social and intellectual development Monitoring of renal function if renal anomalies are present Physical examinations to monitor for tumor risk [Lapunzina 2005]: Every three months until age four years Every four months from age four to seven years Biannually after age seven years The following screening recommendations require further study to determine benefit. The clinician and family should discuss the methods to be used:Wilms tumor. Abdominal ultrasound examination every three or four months from birth until at least age seven or eight years, and yearly thereafter [Choyke et al 1999, Lapunzina 2005]. Abdominal ultrasound examination should assess for both Wilms tumor and hepatic tumors. Note: When associated with an overgrowth syndrome, the risk of Wilms tumor decreases after age eight years [Beckwith 1998].Gonadoblastoma or hepatocellular carcinoma. Serial measurement of serum alpha fetoprotein and beta human chorionic gonadotropin concentrations with the following suggested frequency [Lapunzina 2005]: Every four months until age four years Every six months between ages four and seven years Annually after age seven years Neuroblastoma. Measurements of urinary catecholamine metabolites including vanillylmandelic acid and homovanillic acid as well as urinary free fractionated catecholamines with the following suggested frequency [Lapunzina 2005]: Every four months until age four years Every six months from age four to seven years Annually after age seven years Annual lifelong chest radiograms have also been suggested [Lapunzina 2005].Evaluation of Relatives at RiskEarly diagnosis of affected males in a family helps identify those who will benefit from early diagnosis and intervention to reduce morbidity and mortality.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Simpson-Golabi-Behmel Syndrome Type 1: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDGPC3Xq26.2Glypican-3GPC3 homepage - Mendelian genesGPC3GPC4Xq26.2Glypican-4GPC4 @ LOVDGPC4Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Simpson-Golabi-Behmel Syndrome Type 1 (View All in OMIM) View in own window 300037GLYPICAN 3; GPC3 300168GLYPICAN 4; GPC4 312870SIMPSON-GOLABI-BEHMEL SYNDROME, TYPE 1; SGBS1GPC3Normal allelic variants. GPC3 comprises eight exons that span more than 500 kb.Pathologic allelic variants. All eight exons of GPC3 have been found to harbor either deletions or point mutations that lead to the Simpson-Golabi-Behmel syndrome type 1 (SGBS1) phenotype. Approximately 50% of GPC3 deletions involve exon 8 [Veugelers et al 2000]. Point mutations include splice site, frameshift, missense, and nonsense mutations [Veugelers et al 2000]. Point mutations have been described in all exons. As expected, most point mutations occur in exon 3, the largest exon.Normal gene product. Glypican-3 is a glycosylphosphatidylinositol-linked cell surface heparan sulfate proteoglycan [Pilia et al 1996]. Heparan sulfate proteoglycans bind and regulate the activities of a variety of extracellular ligands essential to cellular functions. Glypicans have a role in cell growth and cell division. Abnormal gene product. The mechanism by which a loss-of-function GPC3 mutation leads to the SGBS1 phenotype is unknown. At least 43% loss of functional GPC3 protein is required to develop the SGBS1 phenotype in heterozygous females (total number of detection rate is unknown) [Yano et al 2010]. GPC4Normal allelic variants. GPC4 is adjacent to the 3' end of GPC3 and comprises nine exons.Pathologic allelic variants. Duplication of exons 1-9 of GPC4withoutGPC3 mutation leads to the SGBS1 phenotype [Waterson et al 2010]. Note: Loss-of-function mutations in GPC4 are not associated with SGBS1 [Veugelers et al 2000].Normal gene product. Glypican-4 is also a glycosylphosphatidylinositol-linked cell surface heparan sulfate proteoglycan [Veugelers et al 1998].Abnormal gene product. The mechanism by which a loss-of-function GPC4 mutation leads to the SGBS1 phenotype is unknown.