Simpson-Golabi-Behmel Syndrome Type 1
Summary
Clinical characteristics.
Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is characterized by pre- and postnatal macrosomia; distinctive craniofacial features (including macrocephaly, coarse facial features, macrostomia, macroglossia, and palatal abnormalities); and commonly, mild to severe intellectual disability with or without structural brain anomalies. Other variable findings include supernumerary nipples, diastasis recti / umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and gastrointestinal anomalies. Skeletal anomalies can include vertebral fusion, scoliosis, rib anomalies, and congenital hip dislocation. Hand anomalies can include large hands and postaxial polydactyly. Affected individuals are at increased risk for embryonal tumors, including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma, and medulloblastoma.
Diagnosis/testing.
The diagnosis of SGBS1 is established in a male proband with suggestive findings and/or a hemizygous pathogenic variant in GPC3, an intragenic or whole-gene deletion of GPC3 that may include part or all of GPC4, or a large multiexon duplication of GPC4 identified by molecular genetic testing. The diagnosis is usually established in a female proband who has suggestive findings and a heterozygous pathogenic variant in GPC3, an intragenic or whole-gene deletion of GPC3 that may include part or all of GPC4, or a large multiexon duplication of GPC4 identified by molecular genetic testing.
Management.
Treatment of manifestations: Prompt treatment of neonatal hypoglycemia and airway obstruction resulting from micrognathia and glossoptosis. Treatment of cleft lip and/or cleft palate or macroglossia and related feeding difficulties, obstructive sleep apnea, ophthalmologic issues, hearing loss, heart defects, urogenital abnormalities, skeletal abnormalities, and seizures in a standard fashion by appropriate pediatric specialists. Speech therapy as needed. Neurodevelopmental assessment to determine the need for special education, occupational therapy, and/or physical therapy.
Surveillance: Screening for Wilms tumor and hepatoblastoma with abdominal ultrasound and serum AFP level every three months from time of diagnosis until age four years; renal ultrasound every three months from age four to seven years; no specific tumor screening protocol has been established for neuroblastoma, gonadoblastoma, or medulloblastoma. Annual (or as indicated) ophthalmologic and audiologic evaluations in childhood; sleep study if there are concerns about sleep disturbance or sleep apnea; routine monitoring of renal function if renal anomalies are present; evaluation for scoliosis at least annually or during periods of rapid growth; monitoring of serum glucose level in the neonatal period; monitoring of developmental progress at each visit through adolescence.
Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the GPC3 or GCP4 pathogenic variant in the family in order to identify as early as possible those who would benefit from preventive measures, such as tumor surveillance in males.
Genetic counseling.
Simpson-Golabi-Behmel syndrome type 1 is inherited in an X-linked manner. If the mother of the proband has a pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be carriers, although due to X-chromosome inactivation, carrier females may have manifestations of SGBS1. Males with SGBS1 will pass the pathogenic variant to all of their daughters and none of their sons. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible for families in which the pathogenic variant has been identified.
Diagnosis
Consensus clinical diagnostic criteria for Simpson-Golabi-Behmel syndrome type 1 (SGBS1) have not been established.
Suggestive Findings
The diagnosis of SGBS1 should be suspected in males with the following findings:
- Macrosomia (weight or length ≥95th percentile)
- Characteristic facial features
- Widely spaced eyes, epicanthal folds, and downslanted palpebral fissures
- Redundant, furrowed skin over the glabella
- Wide nasal bridge and anteverted nares in infants; broad nose and coarsening of facial features in older individuals
- Macrocephaly with or without a prominent forehead
- Macrostomia (abnormally large mouth)
- Macroglossia (abnormally large tongue) with or without a midline 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
- Small mandible (micrognathia) in neonates; macrognathia in older individuals
- Multiple congenital anomalies (see Clinical Description)
- Congenital heart disease
- Conduction defects (transient QT interval prolongation)
- Supernumerary nipples
- Diastasis recti / umbilical hernia
- Diaphragmatic hernia
- Renal dysplasia / nephromegaly
- Cryptorchidism/hypospadias in males
- Hand and feet anomalies (brachydactyly, cutaneous syndactyly, polydactyly)
Establishing the Diagnosis
Male proband. The diagnosis of SGBS1 is established in a male proband with suggestive findings and/or a hemizygous pathogenic variant in GPC3, an intragenic or whole-gene deletion of GPC3 that may include part or all of GPC4, or a large multiexon duplication of GPC4 identified by molecular genetic testing (see Table 1).
Female proband. The diagnosis of SGBS1 is usually established in a female proband with suggestive findings and a heterozygous pathogenic variant in GPC3, an intragenic or whole-gene deletion of GPC3 that may include part or all of GPC4, or a large multiexon duplication of GPC4 identified by molecular genetic testing (see Table 1).
Note: (1) Intragenic pathogenic GPC4 variants have not been described in isolation and are usually an extension of a deletion that includes GPC3 [Vuillaume et al 2018]; however, 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 pathogenic variant had been identified [Waterson et al 2010]. (2) There are currently no reports of a female proband with biallelic pathogenic variants in either GPC3 or GPC4. (3) To date, GPC3 remains the principal monogenic contributor to SGBS [Vuillaume et al 2018].
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, concurrent or serial single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of SGBS1 is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of SGBS1 has not been considered are more likely to be diagnosed using genomic testing (see Option 2). Any molecular findings must be interpreted in the context of the affected individual's clinical presentation [Vuillaume et al 2018].
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of SGBS1, molecular genetic testing approaches can include serial single-gene testing, chromosomal microarray, or use of a multigene panel.
Serial single-gene testing. Sequence analysis of GPC3 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Note: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
- Sequence analysis of GPC3 is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
- If no pathogenic variant is found, chromosomal microarray analysis (CMA), which uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including GPC3 and GPC4) that cannot be detected by sequence analysis, may be considered next.Note: (1) CMA cannot determine the location or orientation of a duplication. (2) If a deletion or duplication is of sufficient size, fluorescence in situ hybridization (FISH) can be used to test parental samples for inheritance of the deletion or duplication.
A multigene panel that includes GPC3, GPC4, and other genes of interest (see Differential Diagnosis) may also be considered. A multigene panel may identify the genetic cause of the condition at a reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of SGBS1 is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Simpson-Golabi-Behmel Syndrome Type 1 (SGBS1)
| Gene 1 | Proportion of SGBS1 Attributed to Pathogenic Variants in Gene | Proportion of Pathogenic Variants 2 Detectable by Method | |||
|---|---|---|---|---|---|
| Sequence analysis 3, 4 | Gene-targeted deletion/duplication analysis 5 | CMA 6 | Karyotype | ||
| GPC3 | 70% 7 | ~55% 8 | ~43% 8, 9 | Rare 10 | 2 individuals 11 |
| GPC4 | Rare | Unknown 12 | Unknown 12 | Rare 10, 13 | None reported |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including GPC3 and GPC4) that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the Xq26.2 regions.
- 7.
Spencer et al [2016]
- 8.
Vuillaume et al [2018]
- 9.
Gene-targeted methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined. CMA testing is appropriate to define breakpoints of large deletions.
- 10.
A contiguous deletion of GPC3 and GPC4 has been identified in one family with SGBS1 [Veugelers et al 1998].
- 11.
Two females reported [Punnett 1994, Pilia et al 1996]
- 12.
Intragenic pathogenic GPC4 variants have not been described in isolation and are usually an extension of a deletion that includes GPC3 [Spencer et al 2016].
- 13.
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 pathogenic variant had been identified [Waterson et al 2010].
Clinical Characteristics
Clinical Description
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
- Diaphragmatic 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 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.
Genotype-Phenotype Correlations
In a study of genotype-phenotype correlations, Mariani et al [2003] determined that all deletions and single-nucleotide variants occurring in the eight GPC3 exons result in loss of function with no phenotypic distinctions based on size or position of a deletion or single-nucleotide variant.
Penetrance
Penetrance in heterozygous females is unknown, but mildly affected females have been reported. All males reported with a GPC3 pathogenic variant have had clinical findings of SGBS1.
Nomenclature
SGBS1 was initially described by Simpson et al [1975], with later accounts by Golabi & Rosen [1984] and Behmel et al [1984].
Terms no longer in use for SGBS:
- Gigantism-dysplasia syndrome
- Encephalo-tropho-schisis syndrome
- Golabi-Rosen syndrome
- Simpson dysmorphia syndrome
Prevalence
The prevalence of SGBS1 is unknown; however, it is believed to be underdiagnosed due to the wide spectrum of clinical severity.
Differential Diagnosis
Table 2.
Disorders to Consider in the Differential Diagnosis of SGBS1
| Disorder | Gene(s) | MOI | Clinical Features of the Differential Dignosis Disorder | |
|---|---|---|---|---|
| Overlapping w/SGBS1 | Distinguishing from SGBS1 | |||
| Simpson-Golabi-Behmel syndrome type 2 (infantile lethal variant) (OMIM 300209) | OFD1, PIGA 1 | XL |
| More lethal form usually associated w/hydrops fetalis 2 |
| Beckwith-Wiedemann syndrome (BWS) | See footnote 3 | See footnote 3 |
|
|
| Sotos syndrome | NSD1 | AD |
| Seizures are more common. 4 |
| Weaver syndrome (see EZH2-Related Overgrowth) | EZH2 | AD |
|
|
| Nevoid basal cell carcinoma syndrome (NBCCS, Gorlin syndrome) | PTCH | AD |
|
|
| Fryns syndrome | Unknown | AR |
|
|
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
- 1.
Fauth et al [2016]
- 2.
Tenorio et al [2014]
- 3.
BWS is associated with abnormal regulation of gene transcription through methylation at one or both imprinted domains on chromosome 11p15.5. Most alterations are postzygotic, but rare cases are due to deletions, duplications, or chromosome rearrangements affecting 11p15.5. Most individuals with BWS have no family history of BWS; approximately 5%-10% have a family history consistent with parent-of-origin autosomal dominant transmission.
- 4.
Baujat et al [2005]
Other syndromes that may share overlapping features:
- Perlman syndrome (OMIM 267000), a rare autosomal recessive condition caused by biallelic pathogenic variants in DIS3L2, includes 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 pathogenic variants in exon 9 of PLOD1 [Giunta et al 2005]. (See Ehlers-Danlos Syndrome, Kyphoscoliotic Form.)
- Marshall-Smith syndrome (OMIM 602535), which shares advanced bone age and intellectual disability with SGBS1; differences include facial features and predisposition to fractures. This condition is caused by a heterozygous pathogenic variant in NFIX and frequently occurs de novo.
- Elejalde syndrome (acrocephalopolydactylous dysplasia) (OMIM 256710). Infrequently described, Elejalde syndrome includes findings of macrosomia, abnormal facies, craniosynostosis with acrocephaly, 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, and flat nasal bridge; and developmental delay
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with Simpson-Golabi-Behmel syndrome type 1 (SGBS1), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with Simpson-Golabi-Behmel Syndrome Type 1
| System/Concern | Evaluation | Comment |
|---|---|---|
| Oropharynx | Assess for macroglossia & orofacial clefting. | Referral to craniofacial team, incl feeding specialists |
| Eyes | Ophthalmologic examination | |
| Ears/Hearing | Audiologic evaluation | |
| Cardiac | Consider chest radiograph, EKG, & echocardiogram. | To evaluate for structural heart defects & conduction abnormalities |
| Respiratory | Assess for upper-airway sufficiency & signs/symptoms of sleep apnea; formal sleep study should be considered. | Particularly in those w/hypotonia & macroglossia |
| Renal | Examination for hypospadias & undescended testes in males | Referral to urologist, as needed |
| Renal ultrasound to assess for renal anomalies | ||
| Abdomen/Pelvis | Abdominal/pelvic ultrasound to initiate tumor screening | Further studies (e.g., MRI) may be indicated if findings are suspicious for a tumor. |
| Measurement of serum alpha fetoprotein | As a baseline screen for hepatoblastoma | |
| Musculoskeletal | Clinical evaluation for scoliosis | Particularly during times of rapid growth |
| Neurologic | Neurologic evaluation, head MRI, &/or EEG | If concerns for seizures |
| Endocrinologic |