Simpson-Golabi-Behmel Syndrome Type 1

Mendelian MONDO:0020602 Pathograph 19 Show in embeddings browser hereditary cancer-predisposing syndrome overgrowth syndrome

Simpson-Golabi-Behmel syndrome type 1 is an X-linked overgrowth disorder caused by loss of function variants and deletions in GPC3, which encodes the cell surface heparan sulfate proteoglycan glypican-3. Affected males show pre and postnatal macrosomia, macrocephaly with coarse facial features, visceromegaly, and a broad range of congenital anomalies, together with an increased risk of embryonal tumors in childhood, principally Wilms tumor and hepatoblastoma. The mechanism has been revised since the gene was identified, and the entry is curated to reflect that. Glypican-3 was originally proposed to act by binding and restraining IGF2, on the strength of a ligand blot interaction and the clinical resemblance to Beckwith-Wiedemann syndrome. The Gpc3 null mouse reproduced the overgrowth but showed unchanged IGF-II levels, which does not fit a simple ligand sequestration model. The mechanism now supported by direct experiment is that glypican-3 binds Hedgehog with high affinity, competes with Patched for that ligand, and drives Hedgehog endocytosis and degradation, so that losing GPC3 releases Hedgehog signaling and drives growth. The IGF2 model is retained here as an unsupported historical hypothesis rather than deleted, because it is what much of the older literature assumes.

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1
Inheritance
7
Pathophys.
18
Phenotypes
19
Pathograph
1
Genes
3
Medical Actions
1
Differentials
1
Models
3
References
1
Deep Research
👪

Inheritance

1
X-linked HP:0001417
Hemizygous males are affected. Heterozygous carrier females may show manifestations because of skewed X chromosome inactivation. Germline mosaicism has also been reported and affects recurrence risk counselling; see the notes on the GPC3 genetic entry for its attribution.
X-linked inheritance
Show evidence (3 references)
PMID:20301398 SUPPORT Human Clinical
"SGBS1 is inherited in an X-linked manner."
GeneReviews states the mode of inheritance.
PMID:20301398 SUPPORT Human Clinical
"Females who inherit the pathogenic variant will be carriers, although due to X-chromosome inactivation, carrier females may have manifestations of SGBS1."
Records manifesting carrier females, which matters for counselling and ascertainment.
PMID:20301398 SUPPORT Human Clinical
"If the mother of the proband has a pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%."
The per-pregnancy transmission risk given to a carrier mother.
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Pathophysiology

7
GPC3 Loss of Function
Hemizygous loss of function of GPC3 through point mutation, intragenic microdeletion, whole gene deletion, or translocation breakpoint disruption removes functional glypican-3 from the cell surface of embryonic mesodermal tissues, where it is selectively expressed.
Genetic context variant_origin: GERMLINE zygosity: HEMIZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Loss of function alleles of GPC3 spanning point mutations, intragenic and whole gene deletions, and X;autosome translocation breakpoints that disrupt the locus.
cell surface glypican-3 GO:0009986 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves cell surface glypican-3, annotated with cell surface (GO:0009986). GO:0009986 is a cellular component from the Gene Ontology.
Downstream
Loss of Glypican-3 Competition for Hedgehog Ligand
Show evidence (2 references)
PMID:8589713 SUPPORT Human Clinical
"The breakpoints occur near the 5' and 3' ends of a gene, GPC3, that spans more than 500 kilobases in Xq26; in three families, different microdeletions encompassing exons cosegregate with SGBS."
The gene-identification study, establishing GPC3 disruption as the cause through both translocation breakpoints and cosegregating microdeletions.
PMID:10814714 SUPPORT Human Clinical
"One frameshift, three nonsense, and one splice mutation predict a loss-of-function of the glypican-3 protein."
Enumerates the loss-of-function allele classes found in SGBS patients, establishing loss of function as the mechanism of the point-mutation alleles.
Loss of Glypican-3 Competition for Hedgehog Ligand
Glypican-3 binds Hedgehog with high affinity and competes with Patched, the Hedgehog receptor, for that ligand, then routes the bound Hedgehog to endocytosis and degradation. Without glypican-3 this sink is gone and more ligand reaches Patched.
glypican-3 restraint of Hedgehog signaling GO:0045879 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glypican-3 restraint of Hedgehog signaling, annotated with negative regulation of smoothened signaling pathway (GO:0045879). GO:0045879 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Hedgehog Pathway Hyperactivation
Show evidence (1 reference)
PMID:18477453 SUPPORT In Vitro
"we report that GPC3 interacts with high affinity with Hedgehog but not with its receptor, Patched, and that GPC3 competes with Patched for Hedgehog binding. Furthermore, GPC3 induces Hedgehog endocytosis and degradation."
Establishes the competition-and-clearance mechanism at the ligand level.
Hedgehog Pathway Hyperactivation
Released Hedgehog signaling raises the growth set point in embryonic tissues. Hedgehog positively regulates body size, so its de-repression is the proposed proximate driver of the overgrowth phenotype.
smoothened signaling pathway GO:0007224 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased smoothened signaling pathway (GO:0007224). GO:0007224 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Excess Embryonic Cell Proliferation
Show evidence (1 reference)
PMID:18477453 SUPPORT Model Organism
"We conclude that GPC3 acts as a negative regulator of Hedgehog signaling during mammalian development and that the overgrowth observed in SGBS patients is, at least in part, the consequence of hyperactivation of the Hedgehog signaling pathway."
The authors' own conclusion tying Hedgehog hyperactivation to the human overgrowth phenotype, with the hedged "at least in part" preserved rather than overstated.
Excess Embryonic Cell Proliferation
Increased proliferation in developing mesodermal tissues. In the kidney this was localized to the ureteric bud and collecting system in the null mouse, giving an early and persistent developmental abnormality rather than a purely postnatal growth excess.
cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Generalized Prenatal and Postnatal Overgrowth
Persistence of Embryonal Progenitor Tissue
Show evidence (1 reference)
PMID:10402475 SUPPORT Model Organism
"In the particular case of the kidney, we demonstrate that there is an early and persistent developmental abnormality of the ureteric bud/collecting system due to increased proliferation of cells in this tissue element."
Localizes the proliferative defect to a specific developing renal compartment.
Generalized Prenatal and Postnatal Overgrowth
The organism level consequence, expressed as macrosomia, macrocephaly, visceromegaly, and the characteristic coarse facies.
Animal models
Gpc3-null mouse Mouse recapitulates The null mouse reproduces the developmental overgrowth together with several other features of the human syndrome, including cystic and dysplastic kidneys and abnormal lung development.
Downstream
Overgrowth
Macrocephaly
Coarse Facial Features
Visceromegaly
Show evidence (1 reference)
PMID:10402475 SUPPORT Model Organism
"we report that GPC3-deficient mice exhibit several of the clinical features observed in SGBS patients, including developmental overgrowth, perinatal death, cystic and dyplastic kidneys, and abnormal lung development."
The null mouse recapitulates the human overgrowth phenotype, supporting GPC3 loss as sufficient for it.
Persistence of Embryonal Progenitor Tissue
Retained embryonal progenitor populations, notably nephrogenic rests in the kidney and hepatic progenitors in the liver, are the substrate on which the childhood embryonal tumors of this syndrome arise. This is why tumor surveillance is concentrated in the first years of life.
Downstream
Nephroblastoma
Hepatoblastoma
Show evidence (1 reference)
PMID:20301398 SUPPORT Human Clinical
"Affected individuals are at increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma, and medulloblastoma."
Establishes the embryonal tumor spectrum, which is the clinical expression of retained embryonal tissue.
IGF2 Sequestration by Glypican-3
The originally proposed mechanism, in which glypican-3 forms a complex with IGF2 and restrains its growth promoting action. It is recorded here because much of the older literature assumes it, but the ligand level data from the null mouse do not support a simple sequestration model. It is deliberately left unconnected to the downstream chain, since the evidence does not license an edge.
insulin-like growth factor receptor signaling pathway GO:0048009 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves insulin-like growth factor receptor signaling pathway (GO:0048009). GO:0048009 is a biological process from the Gene Ontology.
Animal models
Gpc3-null mouse Mouse fails to recapitulate The model does not reproduce what the IGF2 sequestration hypothesis predicts. If glypican-3 restrained IGF-II by binding it, removing glypican-3 should raise ligand levels; in the null mouse they are unchanged.
Show evidence (2 references)
PMID:8589713 SUPPORT In Vitro
"Initial western- and ligand-blotting experiments suggest that glypican 3 forms a complex with insulin-like growth factor 2 (IGF2), and might thereby modulate IGF2 action."
The original in vitro observation that motivated the IGF2 hypothesis, quoted with its own hedging intact.
PMID:10402475 REFUTE Model Organism
"Unlike the IGF2R-deficient mice, however, the levels of IGF-II in GPC3 knockouts are similar to those of the normal littermates."
Argues against simple IGF-II sequestration: if glypican-3 restrained IGF-II by binding it, removing glypican-3 should change ligand levels, and it does not.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Simpson-Golabi-Behmel Syndrome Type 1 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

18
Cardiovascular 1
Congenital Heart Defect OCCASIONAL Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301398 SUPPORT Human Clinical
"Other variable findings include supernumerary nipples, diastasis recti / umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and gastrointestinal issues."
GeneReviews lists congenital heart defects among the variable findings.
PMID:30683921 SUPPORT Human Clinical
"In addition to the detection of heart defects at the time of the diagnosis, a regular cardiac follow-up is necessary in order to detect and treat heart conduction and rhythm problems."
Establishes that cardiac involvement is not a one time finding but requires ongoing surveillance for conduction and rhythm disease.
Genitourinary 2
Nephroblastoma OCCASIONAL HP:0002667 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephroblastoma (HP:0002667). HP:0002667 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301398 SUPPORT Human Clinical
"Affected individuals are at increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma, and medulloblastoma."
GeneReviews names Wilms tumor first in the embryonal tumor spectrum.
Genitourinary Anomaly OCCASIONAL Abnormality of the genitourinary system HP:0000119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the genitourinary system (HP:0000119). HP:0000119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301398 SUPPORT Human Clinical
"Other variable findings include supernumerary nipples, diastasis recti / umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and gastrointestinal issues."
GeneReviews lists genitourinary defects among the variable findings.
Head and Neck 4
Coarse Facial Features FREQUENT HP:0000280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coarse facial features (HP:0000280). HP:0000280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301398 SUPPORT Human Clinical
"distinctive craniofacial features (including macrocephaly, coarse facial features, macrostomia, macroglossia, and palate abnormalities)"
GeneReviews lists the craniofacial phenotype.
Macrocephaly FREQUENT HP:0000256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocephaly (HP:0000256). HP:0000256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301398 SUPPORT Human Clinical
"distinctive craniofacial features (including macrocephaly, coarse facial features, macrostomia, macroglossia, and palate abnormalities)"
GeneReviews lists macrocephaly among the craniofacial features.
Macroglossia HP:0000158 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macroglossia (HP:0000158). HP:0000158 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301398 SUPPORT Human Clinical
"Prompt treatment of neonatal hypoglycemia and airway obstruction resulting from micrognathia and glossoptosis."
GeneReviews management text linking the oral and mandibular findings to neonatal airway obstruction.
Wide Mouth FREQUENT HP:0000154 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide mouth (HP:0000154). HP:0000154 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301398 SUPPORT Human Clinical
"distinctive craniofacial features (including macrocephaly, coarse facial features, macrostomia, macroglossia, and palate abnormalities)"
GeneReviews lists macrostomia among the distinctive craniofacial features.
Limbs 1
Postaxial Polydactyly OCCASIONAL HP:0100259 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postaxial polydactyly (HP:0100259). HP:0100259 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301398 SUPPORT Human Clinical
"Hand anomalies can include large hands and postaxial polydactyly."
GeneReviews records the hand phenotype.
Musculoskeletal 2
Scoliosis OCCASIONAL HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301398 SUPPORT Human Clinical
"Skeletal anomalies can include vertebral fusion, scoliosis, rib anomalies, and congenital hip dislocation."
GeneReviews lists scoliosis among the skeletal anomalies.
PMID:20301398 SUPPORT Human Clinical
"evaluation for scoliosis at least annually or during periods of rapid growth"
Scoliosis carries its own surveillance recommendation, which is why it is modeled separately from the other skeletal anomalies.
Vertebral Fusion OCCASIONAL HP:0002948 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vertebral fusion (HP:0002948). HP:0002948 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301398 SUPPORT Human Clinical
"Skeletal anomalies can include vertebral fusion, scoliosis, rib anomalies, and congenital hip dislocation."
GeneReviews lists vertebral fusion among the skeletal anomalies.
Nervous System 1
Intellectual Disability FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301398 SUPPORT Human Clinical
"commonly, mild-to-severe intellectual disability with or without structural brain anomalies"
GeneReviews records the neurodevelopmental phenotype and its variability.
Prenatal and Birth 1
Polyhydramnios FREQUENT HP:0001561 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polyhydramnios (HP:0001561). HP:0001561 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301398 SUPPORT Human Clinical
"Polyhydramnios has been reported in 68% of pregnancies affected with SGBS1."
Quantifies the prenatal finding that often prompts ascertainment.
Growth 1
Overgrowth VERY_FREQUENT HP:0001548 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Overgrowth (HP:0001548). HP:0001548 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301398 SUPPORT Human Clinical
"Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is characterized by pre- and postnatal macrosomia"
GeneReviews names macrosomia as the defining growth phenotype.
Other 5
Neonatal Hypoglycemia HP:0001998 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neonatal hypoglycemia (HP:0001998), qualified as temporality transient. HP:0001998 is a phenotype from the Human Phenotype Ontology.
Temporal: TRANSIENT
Show evidence (1 reference)
PMID:20301398 SUPPORT INDIRECT Human Clinical
"monitoring of serum glucose level in the neonatal period"
GeneReviews surveillance recommendation, reflecting the neonatal hypoglycemia risk that its management section treats as urgent.
Supernumerary Nipple OCCASIONAL HP:0002558 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Supernumerary nipple (HP:0002558). HP:0002558 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301398 SUPPORT Human Clinical
"Other variable findings include supernumerary nipples, diastasis recti / umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and gastrointestinal issues."
GeneReviews lists supernumerary nipples among the variable findings.
Congenital Diaphragmatic Hernia OCCASIONAL HP:0000776 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital diaphragmatic hernia (HP:0000776). HP:0000776 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301398 SUPPORT Human Clinical
"Other variable findings include supernumerary nipples, diastasis recti / umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and gastrointestinal issues."
GeneReviews lists diaphragmatic hernia among the variable findings.
Hepatoblastoma OCCASIONAL HP:0002884 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatoblastoma (HP:0002884). HP:0002884 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301398 SUPPORT Human Clinical
"Screening for Wilms tumor and hepatoblastoma with abdominal ultrasound and serum AFP level every three months from time of diagnosis until age three years"
Hepatoblastoma is one of the two tumors GeneReviews screens for directly, with a dedicated serum marker.
Visceromegaly FREQUENT HP:0003271 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Visceromegaly (HP:0003271). HP:0003271 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30683921 SUPPORT Human Clinical
"Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked multiple congenital anomalies (MCA) and overgrowth syndrome characterized in males by foetal macrosomia, postnatal overgrowth, macrocephaly, organomegaly"
The clinical utility gene card lists organomegaly among the core male phenotype alongside the overgrowth and macrocephaly already modeled here.
🧬

Genetic Associations

1
GPC3 (Hemizygous loss of function variants and deletions of GPC3 at Xq26 cause Simpson-Golabi-Behmel syndrome type 1.)
Gene: GPC3 hgnc:4451 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GPC3 (hgnc:4451). hgnc:4451 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (4 references)
PMID:8589713 SUPPORT Human Clinical
"GPC3 encodes a putative extracellular proteoglycan, glypican 3, that is inferred to play an important role in growth control in embryonic mesodermal tissues in which it is selectively expressed."
Identifies the gene product and its expression domain.
PMID:9950367 SUPPORT Human Clinical
"We report here a 13 base pair deletion which causes a frameshift and premature termination of the GPC3 gene in the Dutch-Canadian SGBS family in whom the trait was originally mapped. Our analysis shows that a discrete GPC3 disabling mutation is sufficient to cause SGBS."
Establishes that a discrete intragenic GPC3 lesion alone is sufficient to cause the syndrome, ruling out a requirement for a larger contiguous deletion.
PMID:30683921 SUPPORT Human Clinical
"the most prevalent type is large deletions (34.9%) followed by frameshift variants (24.4%), nonsense variants (16.3%), missense variants (8.1%), large duplications (8.1%), splice site variants (4.7%), translocations (2.3%)"
Quantifies the allelic spectrum. Large deletions are the single commonest class, which is what makes sequencing alone an insufficient diagnostic strategy.
+ 1 more reference
💊

Medical Actions

3
Wilms Tumor and Hepatoblastoma Surveillance
Action: Cancer ScreeningNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Cancer Screening (NCIT:C15406). NCIT:C15406 is a clinical intervention from the NCI Thesaurus. NCIT:C15406
Abdominal ultrasound with serum alpha fetoprotein every three months from diagnosis to age three years for Wilms tumor and hepatoblastoma, then renal ultrasound every three months to age seven years. No protocol has been established for the rarer tumors in the spectrum, which are instead covered by six monthly review with a cancer predisposition specialist.
Mechanism Target:
Persistence of Embryonal Progenitor Tissue
Show evidence (2 references)
PMID:20301398 SUPPORT Human Clinical
"Screening for Wilms tumor and hepatoblastoma with abdominal ultrasound and serum AFP level every three months from time of diagnosis until age three years; renal ultrasound every three months until age seven years"
The GeneReviews tumor surveillance protocol.
PMID:20301398 SUPPORT Human Clinical
"no specific tumor screening protocol has been established for neuroblastoma, gonadoblastoma, or medulloblastoma, but follow up with a cancer predisposition specialist every six months is recommended"
Records the limit of the evidence-based protocol, so the entry does not imply surveillance coverage that does not exist.
Neonatal Hypoglycemia and Airway Management
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
The two urgent neonatal problems. Hypoglycemia requires prompt correction and glucose monitoring through the neonatal period; airway obstruction arises from micrognathia and glossoptosis and may require positioning or airway support.
Mechanism Target:
Neonatal Hypoglycemia
Show evidence (1 reference)
PMID:20301398 SUPPORT Human Clinical
"Prompt treatment of neonatal hypoglycemia and airway obstruction resulting from micrognathia and glossoptosis."
The GeneReviews acute neonatal management recommendation.
Longitudinal Cardiac Surveillance
Action: Cardiac Disease ScreeningNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Cardiac Disease Screening (NCIT:C168126). NCIT:C168126 is a clinical intervention from the NCI Thesaurus. NCIT:C168126
Detection of structural heart defects at diagnosis, followed by ongoing cardiac review for conduction and rhythm disturbance. This is the only condition specific longitudinal surveillance besides tumor screening, and the clinical utility gene card links it to premature death.
Mechanism Target:
Congenital Heart Defect
Show evidence (1 reference)
PMID:30683921 SUPPORT Human Clinical
"In addition to the detection of heart defects at the time of the diagnosis, a regular cardiac follow-up is necessary in order to detect and treat heart conduction and rhythm problems."
The clinical utility gene card recommendation for ongoing cardiac follow-up.
🔬

Diagnosis

1
Molecular confirmation of SGBS1
The diagnosis is established by identifying a GPC3 loss of function variant or deletion in a proband with suggestive findings. Because the allelic spectrum is weighted toward gross lesions, sequencing alone is not sufficient: a negative sequencing result is followed by deletion and duplication analysis, and in female probands that order is reversed.
The MLPA snippet above keeps the U+FB01 ligature that PDF extraction left in the cached clinical utility gene card. Replacing it with plain "fi" makes the quote stop matching, because the gating reference validator does not fold ligatures.
Show evidence (2 references)
PMID:20301398 SUPPORT Human Clinical
"The diagnosis of SGBS1 is established in a male proband with suggestive findings and/or a hemizygous pathogenic variant in GPC3 or an intragenic or whole-gene deletion of GPC3 identified by molecular genetic testing."
The GeneReviews statement of how the diagnosis is established.
PMID:30683921 SUPPORT Human Clinical
"In female probands, MLPA would be the first diagnostic step, followed by sequencing."
Records the sex-dependent testing order, which follows from carrier females typically harbouring deletions detectable by dosage analysis.
📊

Prevalence

1
Worldwide
Unknown Not yet documented
No population prevalence estimate has been established. Neither the GeneReviews chapter nor the clinical utility gene card states one, and the deep-research report found none. The record is carried as not yet documented rather than omitted so the absence is visible as a curation fact rather than as silence. It deliberately has no evidence item: nothing in the cached sources asserts a prevalence, and citing a line that merely fails to mention one would misattribute the claim.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Simpson-Golabi-Behmel Syndrome Type 1:

Beckwith-Wiedemann syndrome MONDO:0007534
Overlapping Features The principal differential: the other major overgrowth syndrome with embryonal tumor risk, macroglossia, visceromegaly, and neonatal hypoglycemia. The clinical resemblance is close enough that it drove the original hypothesis that glypican-3 acts on IGF2, since Beckwith-Wiedemann involves biallelic IGF2 expression.
Distinguishing Features
  • X-linked inheritance with affected males favors Simpson-Golabi-Behmel syndrome; 11p15 imprinting disruption favors Beckwith-Wiedemann syndrome.
  • Coarse facial features, postaxial polydactyly, and supernumerary nipples favor Simpson-Golabi-Behmel syndrome.
  • Hemihyperplasia and omphalocele are more characteristic of Beckwith-Wiedemann syndrome.
Show evidence (1 reference)
PMID:10402475 SUPPORT Model Organism
"The clinical features of SGBS are very similar to the more extensively studied Beckwith-Wiedemann syndrome (BWS)."
States the clinical overlap that makes this the primary differential.
🐁

Animal Models

1
Gpc3-null mouse
The loss of function mouse that established GPC3 as sufficient for the overgrowth phenotype and that produced the ligand level result which undercut the IGF2 sequestration model.
Species
Mouse
Genotype
Gpc3 knockout (GPC3-deficient)
Publication
PMID:10402475
Pathograph links
Generalized Prenatal and Postnatal Overgrowth recapitulates fidelity: high The null mouse reproduces the developmental overgrowth together with several other features of the human syndrome, including cystic and dysplastic kidneys and abnormal lung development.
Limitations: Perinatal death in a proportion of mutants limits the study of postnatal and later childhood phenotypes, and the tumor predisposition that defines the human syndrome is not part of the reported phenotype.
Readouts
Developmental overgrowth
Direction: INCREASED
Interpretation: Body size excess as the organism-level correlate of the human phenotype.
Show evidence (1 reference)
PMID:10402475 SUPPORT Model Organism
"we report that GPC3-deficient mice exhibit several of the clinical features observed in SGBS patients, including developmental overgrowth, perinatal death, cystic and dyplastic kidneys, and abnormal lung development."
Reports the overgrowth measurement in the null mouse.
Show evidence (1 reference)
PMID:10402475 SUPPORT Model Organism
"In the particular case of the kidney, we demonstrate that there is an early and persistent developmental abnormality of the ureteric bud/collecting system due to increased proliferation of cells in this tissue element."
Supports treating this model as informative for the overgrowth node, by localizing the proliferative defect to a specific developing compartment.
IGF2 Sequestration by Glypican-3 fails to recapitulate fidelity: low The model does not reproduce what the IGF2 sequestration hypothesis predicts. If glypican-3 restrained IGF-II by binding it, removing glypican-3 should raise ligand levels; in the null mouse they are unchanged.
Limitations: A negative ligand level result does not exclude a local or compartment specific effect on IGF-II availability that a whole animal measurement would miss, so this refutes simple sequestration rather than every possible IGF2 mechanism.
Readouts
Circulating IGF-II level
Direction: UNCHANGED
Interpretation: The prediction of the sequestration model is an increase; the measurement shows no difference from littermate controls.
Show evidence (1 reference)
PMID:10402475 SUPPORT Model Organism
"Unlike the IGF2R-deficient mice, however, the levels of IGF-II in GPC3 knockouts are similar to those of the normal littermates."
The ligand-level measurement itself, reported as unchanged.
Show evidence (1 reference)
PMID:10402475 SUPPORT Model Organism
"Unlike the IGF2R-deficient mice, however, the levels of IGF-II in GPC3 knockouts are similar to those of the normal littermates."
Substantiates the negative claim: this model is informative for the IGF2 node precisely because it fails to show what that model predicts.
{ }

Source YAML

click to show 
name: Simpson-Golabi-Behmel Syndrome Type 1
creation_date: "2026-09-01T00:00:00Z"
category: Mendelian
categories:
- Overgrowth Syndrome
- Cancer Predisposition Syndrome
- Pediatric Cancer
- Multiple Congenital Anomaly Syndrome
parents:
- hereditary cancer-predisposing syndrome
- overgrowth syndrome
disease_term:
  preferred_term: Simpson-Golabi-Behmel syndrome type 1
  term:
    id: MONDO:0020602
    label: Simpson-Golabi-Behmel syndrome type 1
synonyms:
- GPC3 Simpson-Golabi-Behmel syndrome
- Golabi-Rosen syndrome
- SGBS1
- dysplasia gigantism syndrome, X-linked
description: >-
  Simpson-Golabi-Behmel syndrome type 1 is an X-linked overgrowth disorder caused
  by loss of function variants and deletions in GPC3, which encodes the cell
  surface heparan sulfate proteoglycan glypican-3. Affected males show pre and
  postnatal macrosomia, macrocephaly with coarse facial features, visceromegaly,
  and a broad range of congenital anomalies, together with an increased risk of
  embryonal tumors in childhood, principally Wilms tumor and hepatoblastoma.
  The mechanism has been revised since the gene was identified, and the entry is
  curated to reflect that. Glypican-3 was originally proposed to act by binding and
  restraining IGF2, on the strength of a ligand blot interaction and the clinical
  resemblance to Beckwith-Wiedemann syndrome. The Gpc3 null mouse reproduced the
  overgrowth but showed unchanged IGF-II levels, which does not fit a simple ligand
  sequestration model. The mechanism now supported by direct experiment is that
  glypican-3 binds Hedgehog with high affinity, competes with Patched for that
  ligand, and drives Hedgehog endocytosis and degradation, so that losing GPC3
  releases Hedgehog signaling and drives growth. The IGF2 model is retained here as
  an unsupported historical hypothesis rather than deleted, because it is what much
  of the older literature assumes.
inheritance:
- name: X-linked
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  description: >-
    Hemizygous males are affected. Heterozygous carrier females may show
    manifestations because of skewed X chromosome inactivation. Germline mosaicism has
    also been reported and affects recurrence risk counselling; see the notes on the
    GPC3 genetic entry for its attribution.
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SGBS1 is inherited in an X-linked manner."
    explanation: GeneReviews states the mode of inheritance.
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Females who inherit the pathogenic variant will be carriers, although due to X-chromosome inactivation, carrier females may have manifestations of SGBS1."
    explanation: Records manifesting carrier females, which matters for counselling and ascertainment.
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If the mother of the proband has a pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%."
    explanation: The per-pregnancy transmission risk given to a carrier mother.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population prevalence estimate has been established. Neither the GeneReviews
    chapter nor the clinical utility gene card states one, and the deep-research report
    found none. The record is carried as not yet documented rather than omitted so the
    absence is visible as a curation fact rather than as silence. It deliberately has no
    evidence item: nothing in the cached sources asserts a prevalence, and citing a line
    that merely fails to mention one would misattribute the claim.
pathophysiology:
- name: GPC3 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Hemizygous loss of function of GPC3 through point mutation, intragenic
    microdeletion, whole gene deletion, or translocation breakpoint disruption
    removes functional glypican-3 from the cell surface of embryonic mesodermal
    tissues, where it is selectively expressed.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HEMIZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Loss of function alleles of GPC3 spanning point mutations, intragenic and
      whole gene deletions, and X;autosome translocation breakpoints that disrupt
      the locus.
  cellular_components:
  - preferred_term: cell surface glypican-3
    term:
      id: GO:0009986
      label: cell surface
  downstream:
  - target: Loss of Glypican-3 Competition for Hedgehog Ligand
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:8589713
    reference_title: "Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The breakpoints occur near the 5' and 3' ends of a gene, GPC3, that spans more than 500 kilobases in Xq26; in three families, different microdeletions encompassing exons cosegregate with SGBS."
    explanation: >-
      The gene-identification study, establishing GPC3 disruption as the cause through
      both translocation breakpoints and cosegregating microdeletions.
  - reference: PMID:10814714
    reference_title: "Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson-Golabi-Behmel syndrome: identification of loss-of-function mutations in the GPC3 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One frameshift, three nonsense, and one splice mutation predict a loss-of-function of the glypican-3 protein."
    explanation: >-
      Enumerates the loss-of-function allele classes found in SGBS patients, establishing
      loss of function as the mechanism of the point-mutation alleles.
- name: Loss of Glypican-3 Competition for Hedgehog Ligand
  biological_scale: MOLECULAR
  description: >-
    Glypican-3 binds Hedgehog with high affinity and competes with Patched, the
    Hedgehog receptor, for that ligand, then routes the bound Hedgehog to
    endocytosis and degradation. Without glypican-3 this sink is gone and more
    ligand reaches Patched.
  biological_processes:
  - preferred_term: glypican-3 restraint of Hedgehog signaling
    term:
      id: GO:0045879
      label: negative regulation of smoothened signaling pathway
    modifier: DECREASED
  downstream:
  - target: Hedgehog Pathway Hyperactivation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18477453
      reference_title: "Glypican-3 inhibits Hedgehog signaling during development by competing with patched for Hedgehog binding."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here, we show that GPC3 null embryos display increased Hedgehog signaling and that GPC3 inhibits Hedgehog activity in cultured mouse embryonic fibroblasts."
      explanation: >-
        Direct demonstration that removing GPC3 raises Hedgehog signaling, which is the
        causal step this edge asserts.
  evidence:
  - reference: PMID:18477453
    reference_title: "Glypican-3 inhibits Hedgehog signaling during development by competing with patched for Hedgehog binding."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we report that GPC3 interacts with high affinity with Hedgehog but not with its receptor, Patched, and that GPC3 competes with Patched for Hedgehog binding. Furthermore, GPC3 induces Hedgehog endocytosis and degradation."
    explanation: Establishes the competition-and-clearance mechanism at the ligand level.
- name: Hedgehog Pathway Hyperactivation
  biological_scale: CELLULAR
  description: >-
    Released Hedgehog signaling raises the growth set point in embryonic tissues.
    Hedgehog positively regulates body size, so its de-repression is the proposed
    proximate driver of the overgrowth phenotype.
  biological_processes:
  - preferred_term: smoothened signaling pathway
    term:
      id: GO:0007224
      label: smoothened signaling pathway
    modifier: INCREASED
  downstream:
  - target: Excess Embryonic Cell Proliferation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:18477453
    reference_title: "Glypican-3 inhibits Hedgehog signaling during development by competing with patched for Hedgehog binding."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We conclude that GPC3 acts as a negative regulator of Hedgehog signaling during mammalian development and that the overgrowth observed in SGBS patients is, at least in part, the consequence of hyperactivation of the Hedgehog signaling pathway."
    explanation: >-
      The authors' own conclusion tying Hedgehog hyperactivation to the human overgrowth
      phenotype, with the hedged "at least in part" preserved rather than overstated.
- name: Excess Embryonic Cell Proliferation
  biological_scale: CELLULAR
  description: >-
    Increased proliferation in developing mesodermal tissues. In the kidney this was
    localized to the ureteric bud and collecting system in the null mouse, giving an
    early and persistent developmental abnormality rather than a purely postnatal
    growth excess.
  biological_processes:
  - preferred_term: cell population proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
    modifier: INCREASED
  downstream:
  - target: Generalized Prenatal and Postnatal Overgrowth
    causal_link_type: DIRECT
  - target: Persistence of Embryonal Progenitor Tissue
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:10402475
    reference_title: "Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In the particular case of the kidney, we demonstrate that there is an early and persistent developmental abnormality of the ureteric bud/collecting system due to increased proliferation of cells in this tissue element."
    explanation: Localizes the proliferative defect to a specific developing renal compartment.
- name: Generalized Prenatal and Postnatal Overgrowth
  biological_scale: ORGANISM
  description: >-
    The organism level consequence, expressed as macrosomia, macrocephaly,
    visceromegaly, and the characteristic coarse facies.
  downstream:
  - target: Overgrowth
    causal_link_type: DIRECT
  - target: Macrocephaly
    causal_link_type: DIRECT
  - target: Coarse Facial Features
    causal_link_type: DIRECT
  - target: Visceromegaly
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:10402475
    reference_title: "Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we report that GPC3-deficient mice exhibit several of the clinical features observed in SGBS patients, including developmental overgrowth, perinatal death, cystic and dyplastic kidneys, and abnormal lung development."
    explanation: >-
      The null mouse recapitulates the human overgrowth phenotype, supporting GPC3 loss
      as sufficient for it.
- name: Persistence of Embryonal Progenitor Tissue
  biological_scale: TISSUE
  description: >-
    Retained embryonal progenitor populations, notably nephrogenic rests in the
    kidney and hepatic progenitors in the liver, are the substrate on which the
    childhood embryonal tumors of this syndrome arise. This is why tumor
    surveillance is concentrated in the first years of life.
  downstream:
  - target: Nephroblastoma
    causal_link_type: DIRECT
  - target: Hepatoblastoma
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals are at increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma, and medulloblastoma."
    explanation: >-
      Establishes the embryonal tumor spectrum, which is the clinical expression of
      retained embryonal tissue.
- name: IGF2 Sequestration by Glypican-3
  biological_scale: MOLECULAR
  description: >-
    The originally proposed mechanism, in which glypican-3 forms a complex with IGF2
    and restrains its growth promoting action. It is recorded here because much of
    the older literature assumes it, but the ligand level data from the null mouse do
    not support a simple sequestration model. It is deliberately left unconnected to
    the downstream chain, since the evidence does not license an edge.
  mechanism_confidence: HYPOTHETICAL
  biological_processes:
  - preferred_term: insulin-like growth factor receptor signaling pathway
    term:
      id: GO:0048009
      label: insulin-like growth factor receptor signaling pathway
  evidence:
  - reference: PMID:8589713
    reference_title: "Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Initial western- and ligand-blotting experiments suggest that glypican 3 forms a complex with insulin-like growth factor 2 (IGF2), and might thereby modulate IGF2 action."
    explanation: >-
      The original in vitro observation that motivated the IGF2 hypothesis, quoted with
      its own hedging intact.
  - reference: PMID:10402475
    reference_title: "Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "Unlike the IGF2R-deficient mice, however, the levels of IGF-II in GPC3 knockouts are similar to those of the normal littermates."
    explanation: >-
      Argues against simple IGF-II sequestration: if glypican-3 restrained IGF-II by
      binding it, removing glypican-3 should change ligand levels, and it does not.
phenotypes:
- category: Growth
  name: Overgrowth
  description: Pre- and postnatal macrosomia, the defining growth phenotype.
  phenotype_term:
    preferred_term: Overgrowth
    term:
      id: HP:0001548
      label: Overgrowth
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is characterized by pre- and postnatal macrosomia"
    explanation: GeneReviews names macrosomia as the defining growth phenotype.
- category: Craniofacial
  name: Coarse Facial Features
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
  frequency: FREQUENT
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "distinctive craniofacial features (including macrocephaly, coarse facial features, macrostomia, macroglossia, and palate abnormalities)"
    explanation: GeneReviews lists the craniofacial phenotype.
- category: Craniofacial
  name: Macrocephaly
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  frequency: FREQUENT
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "distinctive craniofacial features (including macrocephaly, coarse facial features, macrostomia, macroglossia, and palate abnormalities)"
    explanation: GeneReviews lists macrocephaly among the craniofacial features.
- category: Craniofacial
  name: Macroglossia
  description: >-
    Contributes with micrognathia and glossoptosis to neonatal airway obstruction,
    which is one of the two urgent neonatal problems in this syndrome.
  phenotype_term:
    preferred_term: Macroglossia
    term:
      id: HP:0000158
      label: Macroglossia
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prompt treatment of neonatal hypoglycemia and airway obstruction resulting from micrognathia and glossoptosis."
    explanation: >-
      GeneReviews management text linking the oral and mandibular findings to neonatal
      airway obstruction.
- category: Neurodevelopmental
  name: Intellectual Disability
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: FREQUENT
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "commonly, mild-to-severe intellectual disability with or without structural brain anomalies"
    explanation: GeneReviews records the neurodevelopmental phenotype and its variability.
- category: Metabolic
  name: Neonatal Hypoglycemia
  phenotype_term:
    preferred_term: Neonatal hypoglycemia
    term:
      id: HP:0001998
      label: Neonatal hypoglycemia
    temporality: TRANSIENT
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "monitoring of serum glucose level in the neonatal period"
    directness: INDIRECT
    explanation: >-
      GeneReviews surveillance recommendation, reflecting the neonatal hypoglycemia risk
      that its management section treats as urgent.
- category: Integumentary
  name: Supernumerary Nipple
  phenotype_term:
    preferred_term: Supernumerary nipple
    term:
      id: HP:0002558
      label: Supernumerary nipple
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other variable findings include supernumerary nipples, diastasis recti / umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and gastrointestinal issues."
    explanation: GeneReviews lists supernumerary nipples among the variable findings.
- category: Skeletal
  name: Postaxial Polydactyly
  phenotype_term:
    preferred_term: Postaxial polydactyly
    term:
      id: HP:0100259
      label: Postaxial polydactyly
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hand anomalies can include large hands and postaxial polydactyly."
    explanation: GeneReviews records the hand phenotype.
- category: Respiratory
  name: Congenital Diaphragmatic Hernia
  phenotype_term:
    preferred_term: Congenital diaphragmatic hernia
    term:
      id: HP:0000776
      label: Congenital diaphragmatic hernia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other variable findings include supernumerary nipples, diastasis recti / umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and gastrointestinal issues."
    explanation: GeneReviews lists diaphragmatic hernia among the variable findings.
- category: Prenatal
  name: Polyhydramnios
  phenotype_term:
    preferred_term: Polyhydramnios
    term:
      id: HP:0001561
      label: Polyhydramnios
  frequency: FREQUENT
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Polyhydramnios has been reported in 68% of pregnancies affected with SGBS1."
    explanation: Quantifies the prenatal finding that often prompts ascertainment.
- category: Neoplastic
  name: Nephroblastoma
  description: Wilms tumor, the commonest embryonal tumor in this syndrome.
  phenotype_term:
    preferred_term: Nephroblastoma
    term:
      id: HP:0002667
      label: Nephroblastoma
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals are at increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma, and medulloblastoma."
    explanation: GeneReviews names Wilms tumor first in the embryonal tumor spectrum.
- category: Neoplastic
  name: Hepatoblastoma
  phenotype_term:
    preferred_term: Hepatoblastoma
    term:
      id: HP:0002884
      label: Hepatoblastoma
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Screening for Wilms tumor and hepatoblastoma with abdominal ultrasound and serum AFP level every three months from time of diagnosis until age three years"
    explanation: >-
      Hepatoblastoma is one of the two tumors GeneReviews screens for directly, with a
      dedicated serum marker.
- category: Cardiovascular
  name: Congenital Heart Defect
  description: >-
    Structural cardiac malformation. Cardiac involvement is singled out in the
    clinical utility gene card as needing longitudinal follow up beyond the
    detection of a defect at diagnosis, because conduction and rhythm problems
    develop later and contribute to premature death.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other variable findings include supernumerary nipples, diastasis recti / umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and gastrointestinal issues."
    explanation: GeneReviews lists congenital heart defects among the variable findings.
  - reference: PMID:30683921
    reference_title: "CUGC for Simpson-Golabi-Behmel syndrome (SGBS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to the detection of heart defects at the time of the diagnosis, a regular cardiac follow-up is necessary in order to detect and treat heart conduction and rhythm problems."
    explanation: >-
      Establishes that cardiac involvement is not a one time finding but requires
      ongoing surveillance for conduction and rhythm disease.
- category: Genitourinary
  name: Genitourinary Anomaly
  description: >-
    Structural genitourinary and renal malformation. Renal involvement is also why
    the tumor surveillance protocol continues renal ultrasound to age seven.
  phenotype_term:
    preferred_term: Abnormality of the genitourinary system
    term:
      id: HP:0000119
      label: Abnormality of the genitourinary system
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other variable findings include supernumerary nipples, diastasis recti / umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and gastrointestinal issues."
    explanation: GeneReviews lists genitourinary defects among the variable findings.
- category: Skeletal
  name: Scoliosis
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal anomalies can include vertebral fusion, scoliosis, rib anomalies, and congenital hip dislocation."
    explanation: GeneReviews lists scoliosis among the skeletal anomalies.
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "evaluation for scoliosis at least annually or during periods of rapid growth"
    explanation: >-
      Scoliosis carries its own surveillance recommendation, which is why it is modeled
      separately from the other skeletal anomalies.
- category: Skeletal
  name: Vertebral Fusion
  phenotype_term:
    preferred_term: Vertebral fusion
    term:
      id: HP:0002948
      label: Vertebral fusion
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal anomalies can include vertebral fusion, scoliosis, rib anomalies, and congenital hip dislocation."
    explanation: GeneReviews lists vertebral fusion among the skeletal anomalies.
- category: Growth
  name: Visceromegaly
  description: >-
    Enlargement of the abdominal viscera, part of the generalized overgrowth and
    asserted in this entry's own description of the overgrowth node.
  phenotype_term:
    preferred_term: Visceromegaly
    term:
      id: HP:0003271
      label: Visceromegaly
  frequency: FREQUENT
  evidence:
  - reference: PMID:30683921
    reference_title: "CUGC for Simpson-Golabi-Behmel syndrome (SGBS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked multiple congenital anomalies (MCA) and overgrowth syndrome characterized in males by foetal macrosomia, postnatal overgrowth, macrocephaly, organomegaly"
    explanation: >-
      The clinical utility gene card lists organomegaly among the core male phenotype
      alongside the overgrowth and macrocephaly already modeled here.
- category: Craniofacial
  name: Wide Mouth
  phenotype_term:
    preferred_term: Wide mouth
    term:
      id: HP:0000154
      label: Wide mouth
  frequency: FREQUENT
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "distinctive craniofacial features (including macrocephaly, coarse facial features, macrostomia, macroglossia, and palate abnormalities)"
    explanation: GeneReviews lists macrostomia among the distinctive craniofacial features.
diagnosis:
- name: Molecular confirmation of SGBS1
  description: >-
    The diagnosis is established by identifying a GPC3 loss of function variant or
    deletion in a proband with suggestive findings. Because the allelic spectrum is
    weighted toward gross lesions, sequencing alone is not sufficient: a negative
    sequencing result is followed by deletion and duplication analysis, and in
    female probands that order is reversed.
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of SGBS1 is established in a male proband with suggestive findings and/or a hemizygous pathogenic variant in GPC3 or an intragenic or whole-gene deletion of GPC3 identified by molecular genetic testing."
    explanation: The GeneReviews statement of how the diagnosis is established.
  - reference: PMID:30683921
    reference_title: "CUGC for Simpson-Golabi-Behmel syndrome (SGBS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In female probands, MLPA would be the first diagnostic step, followed by sequencing."
    explanation: >-
      Records the sex-dependent testing order, which follows from carrier females
      typically harbouring deletions detectable by dosage analysis.
  notes: >-
    The MLPA snippet above keeps the U+FB01 ligature that PDF extraction left in the
    cached clinical utility gene card. Replacing it with plain "fi" makes the quote
    stop matching, because the gating reference validator does not fold ligatures.
animal_models:
- name: Gpc3-null mouse
  species: Mouse
  genotype: Gpc3 knockout (GPC3-deficient)
  publication: PMID:10402475
  description: >-
    The loss of function mouse that established GPC3 as sufficient for the overgrowth
    phenotype and that produced the ligand level result which undercut the IGF2
    sequestration model.
  modeled_mechanisms:
  - target: Generalized Prenatal and Postnatal Overgrowth
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The null mouse reproduces the developmental overgrowth together with several
      other features of the human syndrome, including cystic and dysplastic kidneys
      and abnormal lung development.
    limitations: >-
      Perinatal death in a proportion of mutants limits the study of postnatal and
      later childhood phenotypes, and the tumor predisposition that defines the human
      syndrome is not part of the reported phenotype.
    readouts:
    - name: Developmental overgrowth
      target: Generalized Prenatal and Postnatal Overgrowth
      direction: INCREASED
      interpretation: Body size excess as the organism-level correlate of the human phenotype.
      evidence:
      - reference: PMID:10402475
        reference_title: "Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "we report that GPC3-deficient mice exhibit several of the clinical features observed in SGBS patients, including developmental overgrowth, perinatal death, cystic and dyplastic kidneys, and abnormal lung development."
        explanation: Reports the overgrowth measurement in the null mouse.
    evidence:
    - reference: PMID:10402475
      reference_title: "Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In the particular case of the kidney, we demonstrate that there is an early and persistent developmental abnormality of the ureteric bud/collecting system due to increased proliferation of cells in this tissue element."
      explanation: >-
        Supports treating this model as informative for the overgrowth node, by
        localizing the proliferative defect to a specific developing compartment.
  - target: IGF2 Sequestration by Glypican-3
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The model does not reproduce what the IGF2 sequestration hypothesis predicts. If
      glypican-3 restrained IGF-II by binding it, removing glypican-3 should raise
      ligand levels; in the null mouse they are unchanged.
    limitations: >-
      A negative ligand level result does not exclude a local or compartment specific
      effect on IGF-II availability that a whole animal measurement would miss, so this
      refutes simple sequestration rather than every possible IGF2 mechanism.
    readouts:
    - name: Circulating IGF-II level
      target: IGF2 Sequestration by Glypican-3
      direction: UNCHANGED
      interpretation: >-
        The prediction of the sequestration model is an increase; the measurement shows
        no difference from littermate controls.
      evidence:
      - reference: PMID:10402475
        reference_title: "Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Unlike the IGF2R-deficient mice, however, the levels of IGF-II in GPC3 knockouts are similar to those of the normal littermates."
        explanation: The ligand-level measurement itself, reported as unchanged.
    evidence:
    - reference: PMID:10402475
      reference_title: "Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Unlike the IGF2R-deficient mice, however, the levels of IGF-II in GPC3 knockouts are similar to those of the normal littermates."
      explanation: >-
        Substantiates the negative claim: this model is informative for the IGF2 node
        precisely because it fails to show what that model predicts.
genetic:
- name: GPC3
  gene_term:
    preferred_term: GPC3
    term:
      id: hgnc:4451
      label: GPC3
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    Hemizygous loss of function variants and deletions of GPC3 at Xq26 cause
    Simpson-Golabi-Behmel syndrome type 1.
  notes: >-
    The allelic spectrum is broad and skewed toward gross lesions: point mutations,
    single and multi exon deletions, whole gene deletions, and X;autosome
    translocation breakpoints have all been reported. Contiguous deletions may extend
    into the neighbouring GPC4. Quantitatively, large deletions are the commonest single
    class at 34.9%, ahead of frameshift (24.4%) and nonsense (16.3%) variants, which is
    the numeric form of the skew described above and the reason dosage analysis belongs
    in the diagnostic strategy rather than after it.
    A nosological note for whoever revisits this entry: the clinical utility gene card
    argues that SGBS type 2 does not exist as an entity, the cases so designated being
    PIGA-related disease, and concludes that speaking of type 1 is therefore no longer
    justified. This entry keeps the type 1 name because that is the MONDO term it binds,
    not because the two-type division is endorsed.
    Germline mosaicism has been reported in this syndrome
    (Li et al., PMID:17850639), which is why an apparently de novo variant does not
    reduce recurrence risk to background. That report is cited here in prose rather
    than as an evidence item because its PubMed record carries no abstract text, so no
    exact quote can be verified against the cache.
  evidence:
  - reference: PMID:8589713
    reference_title: "Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GPC3 encodes a putative extracellular proteoglycan, glypican 3, that is inferred to play an important role in growth control in embryonic mesodermal tissues in which it is selectively expressed."
    explanation: Identifies the gene product and its expression domain.
  - reference: PMID:9950367
    reference_title: "A small interstitial deletion in the GPC3 gene causes Simpson-Golabi-Behmel syndrome in a Dutch-Canadian family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report here a 13 base pair deletion which causes a frameshift and premature termination of the GPC3 gene in the Dutch-Canadian SGBS family in whom the trait was originally mapped. Our analysis shows that a discrete GPC3 disabling mutation is sufficient to cause SGBS."
    explanation: >-
      Establishes that a discrete intragenic GPC3 lesion alone is sufficient to cause the
      syndrome, ruling out a requirement for a larger contiguous deletion.
  - reference: PMID:30683921
    reference_title: "CUGC for Simpson-Golabi-Behmel syndrome (SGBS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the most prevalent type is large deletions (34.9%) followed by frameshift variants (24.4%), nonsense variants (16.3%), missense variants (8.1%), large duplications (8.1%), splice site variants (4.7%), translocations (2.3%)"
    explanation: >-
      Quantifies the allelic spectrum. Large deletions are the single commonest class,
      which is what makes sequencing alone an insufficient diagnostic strategy.
  - reference: PMID:30683921
    reference_title: "CUGC for Simpson-Golabi-Behmel syndrome (SGBS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As penetrance is complete in male patients and since the disease is present from birth, molecular diagnosis is not used for predictive testing."
    explanation: >-
      Records complete penetrance in males, which is why predictive testing has no role
      and testing is diagnostic or carrier-directed instead.
treatments:
- name: Wilms Tumor and Hepatoblastoma Surveillance
  description: >-
    Abdominal ultrasound with serum alpha fetoprotein every three months from
    diagnosis to age three years for Wilms tumor and hepatoblastoma, then renal
    ultrasound every three months to age seven years. No protocol has been
    established for the rarer tumors in the spectrum, which are instead covered by
    six monthly review with a cancer predisposition specialist.
  treatment_term:
    preferred_term: Cancer Screening
    term:
      id: NCIT:C15406
      label: Cancer Screening
  target_mechanisms:
  - target: Persistence of Embryonal Progenitor Tissue
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Screening for Wilms tumor and hepatoblastoma with abdominal ultrasound and serum AFP level every three months from time of diagnosis until age three years; renal ultrasound every three months until age seven years"
    explanation: The GeneReviews tumor surveillance protocol.
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "no specific tumor screening protocol has been established for neuroblastoma, gonadoblastoma, or medulloblastoma, but follow up with a cancer predisposition specialist every six months is recommended"
    explanation: >-
      Records the limit of the evidence-based protocol, so the entry does not imply
      surveillance coverage that does not exist.
- name: Neonatal Hypoglycemia and Airway Management
  description: >-
    The two urgent neonatal problems. Hypoglycemia requires prompt correction and
    glucose monitoring through the neonatal period; airway obstruction arises from
    micrognathia and glossoptosis and may require positioning or airway support.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Neonatal Hypoglycemia
  evidence:
  - reference: PMID:20301398
    reference_title: "Simpson-Golabi-Behmel Syndrome Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prompt treatment of neonatal hypoglycemia and airway obstruction resulting from micrognathia and glossoptosis."
    explanation: The GeneReviews acute neonatal management recommendation.
- name: Longitudinal Cardiac Surveillance
  description: >-
    Detection of structural heart defects at diagnosis, followed by ongoing cardiac
    review for conduction and rhythm disturbance. This is the only condition specific
    longitudinal surveillance besides tumor screening, and the clinical utility gene
    card links it to premature death.
  treatment_term:
    preferred_term: Cardiac Disease Screening
    term:
      id: NCIT:C168126
      label: Cardiac Disease Screening
  target_mechanisms:
  - target: Congenital Heart Defect
  evidence:
  - reference: PMID:30683921
    reference_title: "CUGC for Simpson-Golabi-Behmel syndrome (SGBS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to the detection of heart defects at the time of the diagnosis, a regular cardiac follow-up is necessary in order to detect and treat heart conduction and rhythm problems."
    explanation: The clinical utility gene card recommendation for ongoing cardiac follow-up.
differential_diagnoses:
- name: Beckwith-Wiedemann syndrome
  disease_term:
    preferred_term: Beckwith-Wiedemann syndrome
    term:
      id: MONDO:0007534
      label: Beckwith-Wiedemann syndrome
  description: >-
    The principal differential: the other major overgrowth syndrome with embryonal
    tumor risk, macroglossia, visceromegaly, and neonatal hypoglycemia. The clinical
    resemblance is close enough that it drove the original hypothesis that
    glypican-3 acts on IGF2, since Beckwith-Wiedemann involves biallelic IGF2
    expression.
  distinguishing_features:
  - X-linked inheritance with affected males favors Simpson-Golabi-Behmel syndrome; 11p15 imprinting disruption favors Beckwith-Wiedemann syndrome.
  - Coarse facial features, postaxial polydactyly, and supernumerary nipples favor Simpson-Golabi-Behmel syndrome.
  - Hemihyperplasia and omphalocele are more characteristic of Beckwith-Wiedemann syndrome.
  evidence:
  - reference: PMID:10402475
    reference_title: "Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The clinical features of SGBS are very similar to the more extensively studied Beckwith-Wiedemann syndrome (BWS)."
    explanation: States the clinical overlap that makes this the primary differential.
references:
- reference: PMID:20301398
  title: Simpson-Golabi-Behmel Syndrome Type 1
  tags:
  - GeneReviews
- reference: PMID:30683921
  title: CUGC for Simpson-Golabi-Behmel syndrome (SGBS)
- reference: DOI:10.1002/humu.23428
  title: "Mutation update for the <i>GPC3</i> gene involved in Simpson-Golabi-Behmel syndrome and review of the literature"
  findings:
  - statement: >-
      Recorded here rather than as an evidence item because the cached record has no
      retrievable body, so no snippet can be verified against it. Do not attempt to
      quote from this reference until the cache carries full text.
📚

References & Deep Research

References

3
PMID:20301398
Simpson-Golabi-Behmel Syndrome Type 1
No top-level findings curated for this source.
PMID:30683921
CUGC for Simpson-Golabi-Behmel syndrome (SGBS)
No top-level findings curated for this source.
DOI:10.1002/humu.23428
Mutation update for the <i>GPC3</i> gene involved in Simpson-Golabi-Behmel syndrome and review of the literature
1 finding
Recorded here rather than as an evidence item because the cached record has no retrievable body, so no snippet can be verified against it. Do not attempt to quote from this reference until the cache carries full text.

Deep Research

1
Falcon ▸
Simpson–Golabi–Behmel Syndrome Type 1: Disease Characteristics Report
Edison Scientific Literature 11 citations 2026-09-01T17:01:28.210901

Simpson–Golabi–Behmel Syndrome Type 1: Disease Characteristics Report

Executive summary

Simpson–Golabi–Behmel syndrome type 1 (SGBS1) is a congenital X-linked overgrowth and multiple-malformation syndrome caused primarily by germline loss-of-function variants in GPC3, which encodes the cell-surface heparan-sulfate proteoglycan glypican-3. Its major manifestations are prenatal and postnatal overgrowth, macrocephaly, organomegaly, characteristic craniofacial and skeletal findings, congenital cardiac/genitourinary/gastrointestinal abnormalities, variable neurodevelopmental impairment, and predisposition to embryonal tumors—especially Wilms tumor and hepatic tumors. Expression is usually greatest in hemizygous males, but symptomatic heterozygous females occur. Prevalence and incidence remain unknown, reflecting extreme rarity, variable expression, early lethality, and probable underdiagnosis. There is no disease-modifying treatment; current practice comprises molecular diagnosis, multidisciplinary supportive care, tumor and cardiac surveillance, and reproductive counseling. (vuillaume2019cugcforsimpsongolabibehmel pages 2-4, vuillaume2019cugcforsimpsongolabibehmel pages 4-5, vuillaume2019cugcforsimpsongolabibehmel pages 1-2)

The principal quantitative genetic dataset available in the retrieved literature comprised 86 distinct GPC3 variants in 120 unrelated families and 152 affected males. Large deletions represented 34.9%, frameshift variants 24.4%, nonsense variants 16.3%, missense variants 8.1%, large duplications 8.1%, splice-site variants 4.7%, translocations 2.3%, and in-frame indels 1.2%. (vuillaume2019cugcforsimpsongolabibehmel pages 1-2)

Domain Key facts Suggested ontology terms Key evidence
Identifiers / synonyms Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is a rare congenital overgrowth-malformation syndrome caused by GPC3 loss of function; OMIM disease identifier #312870; Open Targets disease identifier MONDO:0020602. Common names/synonyms in the literature: Simpson-Golabi-Behmel syndrome, SGBS, SGBS1. Evidence is largely from aggregated disease-level reviews/guidelines plus published case reports/series, not EHR cohorts. MONDO:0020602 (vuillaume2019cugcforsimpsongolabibehmel pages 2-4, vuillaume2019cugcforsimpsongolabibehmel pages 1-2, OpenTargets Search: Simpson-Golabi-Behmel syndrome type 1-GPC3)
Causal gene / inheritance Primary causal gene: GPC3 (glypican 3), Xq26.3; OMIM gene #300037; Open Targets target ENSG00000147257. Inheritance is X-linked; males typically show full penetrance, while female carriers are often asymptomatic or mildly affected, though clinically significant affected females have been reported. HGNC:4451; SO:0001483 loss_of_function_variant (vuillaume2019cugcforsimpsongolabibehmel pages 2-4, vuillaume2019cugcforsimpsongolabibehmel pages 1-2, OpenTargets Search: Simpson-Golabi-Behmel syndrome type 1-GPC3)
Variant spectrum Review data identified 86 distinct GPC3 variants in 120 unrelated families involving 152 male patients. Reported classes: large deletions 34.9%, frameshift 24.4%, nonsense 16.3%, missense 8.1%, large duplications 8.1%, splice-site 4.7%, translocations 2.3%, in-frame indels 1.2%. Variants are predominantly germline loss-of-function defects; only 18% were reported as de novo in the mutation update. SO:0000159 deletion; SO:0001589 frameshift_variant; SO:0001587 stop_gained; SO:0001629 splice_site_variant; SO:1000032 chromosomal_duplication (vuillaume2019cugcforsimpsongolabibehmel pages 1-2, vuillaume2018mutationupdatefor pages 13-14)
Hallmark phenotypes Core phenotype includes fetal macrosomia/pre- and postnatal overgrowth, macrocephaly, organomegaly, coarse/distinctive facies, extremity abnormalities, supernumerary nipples, and variable cardiac, skeletal, gastrointestinal, genitourinary malformations; learning difficulties/intellectual disability occur variably. Typical presentation is from birth/congenital. Suggested HPO terms: overgrowth HP:0001548, fetal macrosomia HP:0001524, macrocephaly HP:0000256, organomegaly HP:0002742, coarse facial features HP:0000280, supernumerary nipple HP:0100807, congenital heart defect HP:0001627, skeletal abnormality HP:0000924, cryptorchidism HP:0000028, intellectual disability HP:0001249. HPO terms listed in cell (vuillaume2019cugcforsimpsongolabibehmel pages 2-4, vuillaume2019cugcforsimpsongolabibehmel pages 1-2, vuillaume2018mutationupdatefor pages 1-2)
Tumor predisposition Documented tumor predisposition is an established component of SGBS1, with emphasis on Wilms tumor and liver tumors/hepatoblastoma; gonadoblastoma surveillance is also recommended in guidance. Exact tumor incidence was not available in the gathered evidence set, so risk should be described qualitatively rather than numerically here. HP:0002669 Neoplasm; NCIT:C3434 Wilms Tumor; NCIT:C3728 Hepatoblastoma; NCIT:C3088 Gonadoblastoma (vuillaume2019cugcforsimpsongolabibehmel pages 4-5, vuillaume2018mutationupdatefor pages 1-2, vuillaume2018mutationupdatefor pages 13-14, vuillaume2019cugcforsimpsongolabibehmel pages 1-2)
Diagnosis Diagnosis combines clinical recognition with molecular confirmation. Reported methods include PCR/direct sequencing (Sanger) and MLPA on peripheral-blood genomic DNA; analytical sensitivity/specificity for coding-exon and flanking-intron variant detection was described as nearly 100% in the clinical utility guideline. Prenatal diagnosis has been reported using ultrasound findings plus molecular testing, including detection of partial GPC3 deletions. NCIT:C16444 Sanger Sequencing; NCIT:C111298 Multiplex Ligation-dependent Probe Amplification (vuillaume2019cugcforsimpsongolabibehmel pages 2-4, vuillaume2019cugcforsimpsongolabibehmel pages 1-2, vuillaume2019cugcforsimpsongolabibehmel pages 5-6)
Management / surveillance Management is multidisciplinary and largely symptomatic: neonatal hypoglycemia treatment, surgery for congenital malformations, specialist management for arrhythmia/conduction disease, and developmental supports (e.g., speech/learning services). Guidance recommends screening in affected males and symptomatic carrier females for Wilms tumors, liver tumors, and gonadoblastoma, plus regular cardiac follow-up. Prenatal molecular diagnosis can be offered to at-risk pregnancies of known female carriers. NCIT:C51932 Supportive Care; NCIT:C17428 Surgical Procedure; NCIT:C15709 Genetic Counseling; NCIT:C47891 Ultrasound (vuillaume2019cugcforsimpsongolabibehmel pages 4-5, vuillaume2019cugcforsimpsongolabibehmel pages 5-6)
Mechanism Causal chain: GPC3 loss-of-function leads to defective cell-surface glypican regulation of morphogen signaling, which leads to dysregulated developmental growth control and organ patterning, resulting in overgrowth, congenital malformations, and tumor susceptibility. The gathered evidence supports dysregulation of WNT, Hedgehog, FGF, and BMP pathways; Hedgehog hyperactivation with elevated Sonic/Indian Hedgehog proteins has been reported in GPC3-null models. Some downstream links to specific human phenotypes remain inferred from model systems rather than directly demonstrated in patient tissues. GO:0060070 canonical Wnt signaling pathway; GO:0007224 smoothened signaling pathway; GO:0008543 fibroblast growth factor receptor signaling pathway; GO:0030509 BMP signaling pathway (vuillaume2018mutationupdatefor pages 1-2, vuillaume2018mutationupdatefor pages 13-14)
Model organisms Gpc3-targeted/deletion mouse models recapitulate major developmental features, including developmental overgrowth, perinatal death, renal dysplasia, accessory spleens, impaired lung development, polydactyly, and placentomegaly. These models support an upstream developmental-regulatory role for GPC3 and are useful for mechanism studies, but they do not fully quantify human neurodevelopmental or tumor outcomes. NCBITaxon:10090; CL/GO not disease-specific here (vuillaume2018mutationupdatefor pages 13-14)
Epidemiology / prognosis Prevalence is unknown and the disorder is likely underdiagnosed. Prognosis is generally favorable in many cases, but can be life-threatening at birth or in infancy because of major congenital malformations, especially severe diaphragmatic or other structural defects; otherwise many patients may have near-normal life expectancy, tempered by cardiac and tumor risks and by variable neurodevelopmental burden. Orphan disease epidemiology not firmly established in gathered evidence (vuillaume2019cugcforsimpsongolabibehmel pages 2-4, vuillaume2019cugcforsimpsongolabibehmel pages 4-5, vuillaume2019cugcforsimpsongolabibehmel pages 1-2)
Recent developments / evidence gaps 2021-2023 literature expanded prenatal diagnosis, familial female expression, and unusual presentations (e.g., disorders of sex development), while 2024 search results indicate continuing phenotype-spectrum work. No SGBS1-specific disease-modifying therapy or interventional trial was identified in the gathered evidence. Important gaps remain in robust prevalence/incidence, tumor-risk quantification, standardized surveillance intervals/ages, natural-history cohorts, and omics-based biomarkers. Oncology trials targeting GPC3 in cancer should not be interpreted as treatments for germline GPC3 deficiency. NCIT:C16084 Clinical Trial; NCIT:C15220 Biomarker (vuillaume2019cugcforsimpsongolabibehmel pages 4-5, OpenTargets Search: Simpson-Golabi-Behmel syndrome type 1-GPC3, vuillaume2018mutationupdatefor pages 13-14)

Table: This table condenses the highest-yield disease knowledge-base fields for Simpson-Golabi-Behmel syndrome type 1, including identifiers, genetics, phenotype, mechanism, management, and evidence gaps. It is aligned to the gathered evidence and highlights the key quantitative variant data needed for structured curation.

1. Disease information

Definition and identifiers

  • Preferred name: Simpson–Golabi–Behmel syndrome type 1
  • Common synonyms: Simpson–Golabi–Behmel syndrome; SGBS; SGBS1; Simpson dysmorphia syndrome; Golabi–Rosen syndrome; bulldog syndrome. The last three are historical terms and are less suitable as preferred labels.
  • MONDO: MONDO:0020602
  • OMIM phenotype: 312870
  • Causal-gene OMIM entry: GPC3, 300037
  • Gene: GPC3, glypican 3; Ensembl ENSG00000147257; chromosome Xq26.3. Open Targets identifies GPC3 as the sole associated target and assigns a target–disease association score of 0.767, driven predominantly by human genetic evidence. (OpenTargets Search: Simpson-Golabi-Behmel syndrome type 1-GPC3)
  • Orphanet: SGBS is represented as a rare genetic overgrowth syndrome, although an exact Orpha identifier was not verified in the retrieved full-text evidence and should be validated directly before database import.
  • ICD: No highly specific ICD-10-CM code was verified. It is generally coded under congenital malformation or overgrowth-syndrome categories. ICD-11 mapping should likewise be verified against the current release rather than inferred.
  • MeSH: No disease-specific MeSH descriptor was established in the retrieved evidence; indexing may use broader headings such as congenital abnormalities, overgrowth, or X-linked genetic diseases.

The evidence base is aggregated disease-level knowledge derived from published families, case series, mutation compilations, clinical-utility guidance, and model systems—not a representative EHR cohort. Consequently, phenotype frequencies are vulnerable to ascertainment and publication bias. The 2019 clinical-utility guideline describes presentation as typically evident from birth. (vuillaume2019cugcforsimpsongolabibehmel pages 2-4, vuillaume2019cugcforsimpsongolabibehmel pages 1-2)

2. Etiology, risk factors, protective factors, and environment

Causal factor

The primary cause is a germline loss-of-function alteration of GPC3. Hemizygous pathogenic variants cause the classical phenotype in males. Most variants truncate the protein or delete one or more exons; pathogenic structural rearrangements also occur. The reviewed gene contains eight exons and produces an approximately 2.3-kb transcript. (vuillaume2019cugcforsimpsongolabibehmel pages 1-2, vuillaume2018mutationupdatefor pages 1-2)

Genetic risk

A pathogenic familial GPC3 allele is the principal risk factor. Under X-linked transmission, a heterozygous mother has, for each pregnancy, a 50% probability of transmitting the altered allele; sons who inherit it are generally affected, while daughters who inherit it are heterozygous and may be asymptomatic or variably affected. Male-to-male transmission does not occur. The mutation update found only 18% of reported variants to be de novo, indicating that familial transmission is important, although this proportion is subject to referral bias. (vuillaume2019cugcforsimpsongolabibehmel pages 2-4, vuillaume2018mutationupdatefor pages 13-14)

Female expression is plausibly influenced by skewed X-chromosome inactivation and variant/rearrangement context, but no validated modifier gene or clinically actionable modifier allele was established in the retrieved evidence. “Complete penetrance in males” is reported in the clinical-utility guideline; expressivity is nevertheless markedly variable. (vuillaume2019cugcforsimpsongolabibehmel pages 2-4)

Environmental, infectious, and lifestyle factors

No toxin, infection, diet, smoking exposure, occupation, or lifestyle factor is established as a cause of SGBS1. Maternal or postnatal environment may alter general outcomes of congenital heart disease, hypoglycemia, respiratory compromise, or cancer, but these are nonspecific modifiers rather than etiologic factors. No replicated gene–environment interaction or protective environmental factor has been demonstrated.

Protective factors

No genetic protective variant, dietary intervention, medication, or exposure is known to prevent expression after inheritance of a pathogenic GPC3 variant. Early recognition and surveillance are risk-mitigating clinical measures, not biological protection against disease onset.

3. Phenotypes

SGBS1 begins during fetal development. Severity ranges from mild dysmorphism and learning difficulty to lethal multisystem malformations. Reliable percentages for most individual manifestations were not recoverable from the available evidence; qualitative frequencies are therefore preferable to invented precision. Core features compiled across the mutation review and clinical guideline include the following. (vuillaume2019cugcforsimpsongolabibehmel pages 1-2, vuillaume2018mutationupdatefor pages 1-2)

  • Prenatal/postnatal overgrowth: congenital physical sign; often fetal macrosomia followed by childhood overgrowth; variable persistence. Suggested HPO: HP:0001524 Fetal macrosomia, HP:0001548 Overgrowth.
  • Macrocephaly: congenital or early-childhood sign, usually stable relative to growth. HP:0000256.
  • Macroglossia: congenital physical manifestation that can impair feeding or airway function. HP:0000158.
  • Organomegaly/visceromegaly: congenital sign involving liver, kidney, spleen, or other viscera. HP:0003270 Organomegaly.
  • Characteristic/coarse facies: broad or coarse face, large mouth, broad nose, and related dysmorphism; usually recognizable from infancy. HP:0000280 Coarse facial features.
  • Supernumerary nipples: congenital, generally stable and medically minor. HP:0002558.
  • Skeletal/limb abnormalities: broad hands, short or broad distal phalanges, syndactyly or polydactyly, rib/vertebral abnormalities, and pectus deformity; congenital and generally nonprogressive. Suggested terms: HP:0010442 Polydactyly, HP:0001159 Syndactyly, HP:0000767 Pectus excavatum, HP:0000924 Abnormality of the skeletal system.
  • Congenital heart disease and electrical disease: structural lesions, cardiomyopathy, conduction abnormalities, or arrhythmias may occur. Severity ranges from incidental to life-threatening. HP:0001627, HP:0011675 Arrhythmia, HP:0001638 Cardiomyopathy. Regular cardiac follow-up is recommended. (vuillaume2019cugcforsimpsongolabibehmel pages 4-5)
  • Diaphragmatic hernia and pulmonary hypoplasia: uncommon but major determinants of neonatal mortality. HP:0000776, HP:0002089. The clinical guideline identifies congenital malformations, especially diaphragmatic hernia, as causes of early life-threatening disease. (vuillaume2019cugcforsimpsongolabibehmel pages 4-5)
  • Genitourinary abnormalities: cryptorchidism, hypospadias, renal anomalies, and occasionally more extensive disorders of sex development. HP:0000028, HP:0000047, HP:0000077.
  • Gastrointestinal abnormalities: congenital structural defects, including anorectal anomalies, may occur. HP:0002027 Abnormality of the gastrointestinal tract.
  • Neonatal hypoglycemia: laboratory abnormality requiring prompt treatment. HP:0001943. (vuillaume2019cugcforsimpsongolabibehmel pages 4-5)
  • Developmental delay, learning difficulty, or intellectual disability: variable, usually mild-to-moderate when present; may impair education, communication, independence, and adult employment. HP:0001263, HP:0001328, HP:0001249. (vuillaume2019cugcforsimpsongolabibehmel pages 4-5)
  • Embryonal tumors: primarily Wilms tumor and liver tumors; gonadoblastoma is also a surveillance concern. HP:0002669 Neoplasm. (vuillaume2019cugcforsimpsongolabibehmel pages 4-5, vuillaume2018mutationupdatefor pages 1-2)

No validated SGBS1-specific EQ-5D, SF-36, PROMIS, or disease-specific quality-of-life study was identified. Quality-of-life burden is therefore inferred from congenital surgery, cardiac disease, developmental disability, cancer surveillance, and family reproductive burden rather than measured with standardized instruments.

4. Genetic and molecular information

GPC3 encodes an approximately 70-kDa glycosylphosphatidylinositol-anchored heparan-sulfate proteoglycan located on the outer plasma membrane. The disease mechanism is predominantly loss of function, not gain of function or dominant negativity. Disease-associated changes include whole/partial-gene deletions, exon-level deletions or duplications, frameshift, nonsense, canonical splice, missense, in-frame indel, and chromosomal rearrangement variants. (vuillaume2018mutationupdatefor pages 1-2, vuillaume2019cugcforsimpsongolabibehmel pages 1-2)

The observed distribution—34.9% large deletions, 24.4% frameshift, and 16.3% nonsense—strongly supports haploinsufficiency/absence of functional protein as the central mechanism. The 86 reported variants span the coding region and include complex rearrangements. (vuillaume2018mutationupdatefor pages 1-2, vuillaume2019cugcforsimpsongolabibehmel pages 1-2)

Variants are constitutional/germline. A tumor arising in an affected person can acquire additional somatic alterations, but a somatic GPC3 variant alone is not equivalent to inherited SGBS1. Pathogenic alleles are expected to be absent or extremely rare from reference populations; however, exact gnomAD allele frequencies must be checked per variant. No single recurrent founder allele or robust population-specific carrier frequency was established.

Large Xq26 rearrangements may encompass neighboring genes, potentially producing a contiguous-gene phenotype. Copy-number analysis is consequently essential. No reproducible GPC3-associated DNA-methylation “episignature,” histone abnormality, or clinically validated epigenetic diagnostic test was found. Likewise, no established human modifier gene explains inter- or intrafamilial variation.

5. Environmental information

SGBS1 is not an environmentally acquired, infectious, occupational, or lifestyle-mediated disease. There is no zoonotic, transmissible, or exposure-related component. Standard avoidance of tobacco, alcohol, radiation, and toxins during pregnancy remains general prenatal-health advice but is not specific prevention for GPC3-associated disease.

6. Mechanism and pathophysiology

Ordered causal chain

  1. A germline hemizygous GPC3 loss-of-function variant leads to absent or deficient functional glypican-3 at the external plasma membrane.
  2. Loss of this heparan-sulfate co-receptor leads to abnormal extracellular presentation, sequestration, or receptor engagement of developmental morphogens.
  3. This results in dysregulated Hedgehog, WNT, FGF, and BMP signaling; Hedgehog hyperactivation with increased Sonic and Indian Hedgehog proteins is demonstrated in Gpc3-null models, whereas the exact direction and magnitude of each pathway in every human tissue remain context-dependent. (vuillaume2018mutationupdatefor pages 1-2, vuillaume2018mutationupdatefor pages 13-14)
  4. Dysregulated morphogen signaling leads to abnormal control of proliferation, apoptosis, polarity, differentiation, and organ patterning during embryogenesis.
  5. Excess developmental growth and disturbed patterning result in fetal/postnatal overgrowth, macrocephaly, visceromegaly, skeletal/limb abnormalities, and cardiac, renal, pulmonary, gastrointestinal, and genital malformations.
  6. Branch: severe structural defects lead to respiratory or cardiac compromise and can result in perinatal death.
  7. Branch: disturbed developmental growth restraint is inferred to increase susceptibility to embryonal neoplasia, resulting particularly in Wilms tumor and hepatic tumors; the complete tumor-initiating sequence in human SGBS1 tissues remains incompletely demonstrated.
  8. Altered nervous-system development is inferred to contribute to variable developmental delay and learning disability.

Upstream events are GPC3 deficiency and morphogen dysregulation; downstream events are altered cellular behavior, malformed organs, overgrowth, and tumor susceptibility. Appropriate GO annotations include GO:0007224 smoothened signaling pathway, GO:0060070 canonical Wnt signaling pathway, GO:0008543 fibroblast growth factor receptor signaling pathway, GO:0030509 BMP signaling pathway, GO:0008283 cell population proliferation, GO:0048513 animal organ development, and GO:0007275 multicellular organism development.

Relevant cell classes are broad rather than a single targeted lineage: embryonic mesenchymal cells (CL:0000134 mesenchymal cell), chondrocytes (CL:0000138), cardiomyocytes (CL:0000746), renal epithelial/nephron progenitor lineages, hepatoblasts, pulmonary epithelial cells, placental trophoblasts, and neural progenitors. These cell assignments are biologically plausible and supported principally by affected-organ and mouse-model phenotypes, not by a definitive human single-cell atlas.

No consistent SGBS1 metabolomic, lipidomic, proteomic, spatial-transcriptomic, or patient single-cell signature has been clinically validated. No SGBS1-specific CRISPR screen, organoid diagnostic assay, or multi-omics classifier was identified. These remain research opportunities rather than current applications.

7. Anatomical structures affected

Primary systems include:

  • Whole-body growth axis and placenta: placentomegaly and fetal overgrowth; UBERON suggestions UBERON:0001987 placenta, UBERON:0000468 multicellular organism.
  • Craniofacial complex and tongue: UBERON:0007811 cranium, UBERON:0001723 tongue.
  • Skeleton and limbs: axial skeleton, ribs, vertebrae, hands, feet, digits; UBERON:0004288 skeleton of hand, UBERON:0001464 skeletal system.
  • Heart: structural myocardium and cardiac conduction system; UBERON:0000948 heart.
  • Kidneys and urinary tract: UBERON:0002113 kidney.
  • Liver and abdominal viscera: UBERON:0002107 liver.
  • Lungs and diaphragm: UBERON:0002048 lung, UBERON:0001103 diaphragm.
  • Gastrointestinal tract: UBERON:0005409 alimentary part of gastrointestinal system.
  • Testes and external genitalia: UBERON:0000473 testis.
  • Central nervous system: developmental involvement underlying variable cognition; UBERON:0000955 brain.

At the subcellular level, the primary compartment is the external side of the plasma membrane/cell surface, where GPI-anchored glypican-3 regulates extracellular morphogens. Suggested GO Cellular Component annotations are GO:0009986 cell surface, GO:0005886 plasma membrane, and GO:0031225 anchored component of membrane. There is no characteristic lateralization; anomalies may be bilateral, unilateral, or asymmetric according to organ and individual.

8. Temporal development

Onset is prenatal, with fetal macrosomia, enlarged organs, increased nuchal thickness, polyhydramnios, or structural malformations sometimes detectable by ultrasound. Ultrasound findings are not pathognomonic, and many diagnoses are made postnatally. Clinically recognizable overgrowth and dysmorphism are usually present at birth. (vuillaume2019cugcforsimpsongolabibehmel pages 2-4, vuillaume2019cugcforsimpsongolabibehmel pages 1-2)

There is no accepted formal staging system. A practical course is:

  1. Prenatal/perinatal phase: overgrowth and congenital malformations; highest risk from diaphragmatic hernia, pulmonary hypoplasia, severe heart disease, and hypoglycemia.
  2. Infancy/childhood: surgical treatment of malformations, developmental assessment, growth monitoring, and intensive embryonal-tumor surveillance.
  3. Later childhood/adolescence: learning, speech, orthopedic, cardiac, and psychosocial needs; some childhood tumor risks decline with age.
  4. Adulthood: congenital traits persist; available natural-history data are sparse, but many less severely affected patients survive with near-normal life expectancy. Cardiac and individual tumor-related follow-up remains clinically relevant. (vuillaume2019cugcforsimpsongolabibehmel pages 4-5)

The condition is lifelong rather than episodic or remitting. Structural anomalies do not spontaneously remit, although treated hypoglycemia or surgically corrected lesions can resolve. The prenatal period and first years of life are the most important intervention windows.

9. Inheritance and population

Inheritance is X-linked, conventionally described as X-linked recessive, although clinically affected heterozygous females demonstrate that the label does not imply absolute female nonpenetrance. Male penetrance is reported as complete, while severity is highly variable. Female carriers are usually asymptomatic or mildly affected. (vuillaume2019cugcforsimpsongolabibehmel pages 2-4, vuillaume2019cugcforsimpsongolabibehmel pages 1-2)

No genetic anticipation is known. Maternal germline mosaicism is biologically possible and should be considered after an apparently de novo result, although its frequency is unknown. Consanguinity is not a major determinant of this X-linked condition. No well-established founder effect, ethnic enrichment, regional endemicity, or reliable carrier frequency has been demonstrated.

Prevalence and incidence are unknown. The literature review identified only 152 affected males across 120 unrelated families, illustrating rarity but not population prevalence. SGBS1 occurs across geographic and ancestral groups. The observed sex ratio is strongly male-biased for clinically recognized classical disease, but this is not evidence that females cannot be affected. (vuillaume2019cugcforsimpsongolabibehmel pages 1-2)

10. Diagnostics

Clinical evaluation

Evaluation should document prenatal and postnatal growth, head circumference, dysmorphism, macroglossia, nipples, hands/feet, chest and spine, genitalia, developmental status, and family history. Initial investigations commonly include glucose assessment in neonates, echocardiography and ECG, abdominal/renal ultrasound, and targeted imaging or functional testing based on malformations. There is no diagnostic serum enzyme assay or validated circulating biomarker.

Genetic-testing strategy

  1. GPC3 sequencing should detect small coding and splice-region variants.
  2. Deletion/duplication analysis by MLPA, exon-level array, or validated NGS copy-number analysis is essential because large deletions are the largest reported variant class.
  3. If negative but suspicion remains high, use a comprehensive overgrowth/malformation panel or exome/genome sequencing with copy-number and structural-variant calling.
  4. Chromosomal microarray is useful for larger Xq26 deletions/duplications and possible contiguous-gene syndromes.
  5. Genome sequencing may resolve complex rearrangements or intronic/regulatory variants missed by conventional tests.
  6. Confirm clinically important variants and test the mother and other at-risk relatives for segregation and counseling.

The clinical-utility guideline reports nearly 100% analytical sensitivity and specificity for detectable coding-exon/flanking-intron variants, but this must not be misread as 100% overall diagnostic yield because promoter, deep-intronic, mosaic, and difficult structural variants can escape a particular assay. PCR, Sanger sequencing, and MLPA were the established methods in the reviewed series. (vuillaume2019cugcforsimpsongolabibehmel pages 2-4, vuillaume2019cugcforsimpsongolabibehmel pages 1-2)

Karyotyping and FISH are not preferred first-line tests but may characterize visible or targeted rearrangements. Mitochondrial-DNA and repeat-expansion testing are not relevant. RNA sequencing may help resolve a suspected splice variant, but it is not routine. There is no established diagnostic proteomic, metabolomic, epigenomic, or liquid-biopsy assay.

Differential diagnosis

The principal differential is Beckwith–Wiedemann spectrum, which shares macrosomia, macroglossia, visceromegaly, neonatal hypoglycemia, and embryonal tumors. Distinguishing features include the X-linked pedigree and GPC3 variant in SGBS1 versus 11p15 imprinting abnormalities or CDKN1C variants in Beckwith–Wiedemann spectrum. Other considerations include Perlman syndrome, Sotos syndrome, Weaver syndrome, Malan syndrome, PI3K-AKT-related overgrowth, and nonsyndromic familial tall stature. The clinical guideline explicitly identifies Beckwith–Wiedemann syndrome as the major differential. (vuillaume2019cugcforsimpsongolabibehmel pages 2-4)

There is no population newborn screen. Appropriate screening is phenotype-triggered testing and cascade testing in an identified family.

11. Outcome and prognosis

Prognosis is heterogeneous. Severe congenital diaphragmatic, pulmonary, cardiac, or other malformations can cause fetal, neonatal, or infant death. In survivors without severe malformations, prognosis is often relatively favorable and life expectancy may be normal, although cardiac complications, tumors, developmental disability, and repeated procedures create substantial morbidity. (vuillaume2019cugcforsimpsongolabibehmel pages 2-4, vuillaume2019cugcforsimpsongolabibehmel pages 4-5)

No reliable 5-year or 10-year survival estimate, disease-specific mortality rate, or validated prognostic calculator exists. Important adverse prognostic factors are severe congenital malformations, respiratory compromise, major heart disease or arrhythmia, malignant tumor development, and more substantial neurodevelopmental impairment. No molecular prognostic biomarker beyond broad genotype/structural-variant context has been validated.

Recovery from the underlying genetic syndrome is not expected. Individual complications—hypoglycemia, hernia, cryptorchidism, congenital cardiac lesions, orthopedic problems, or cancer—may be successfully treated. No standardized long-term disability or quality-of-life dataset was identified.

12. Treatment and real-world implementation

There is no approved etiologic pharmacotherapy, gene therapy, RNA therapy, cell therapy, or GPC3-replacement treatment. Care is individualized and multidisciplinary. (vuillaume2019cugcforsimpsongolabibehmel pages 4-5)

  • Treat neonatal hypoglycemia promptly with glucose-based neonatal protocols. Suggested NCIt concepts: Supportive Care, Glucose Administration.
  • Stabilize airway and respiration; repair diaphragmatic hernia and other structural defects when indicated. NCIt: Surgical Procedure.
  • Manage congenital heart disease, cardiomyopathy, conduction disease, and arrhythmia according to pediatric cardiology standards; maintain longitudinal ECG/echocardiographic follow-up. (vuillaume2019cugcforsimpsongolabibehmel pages 4-5)
  • Correct cryptorchidism, hypospadias, gastrointestinal anomalies, skeletal deformity, and feeding/airway problems when clinically indicated.
  • Provide physical, occupational, speech-language, educational, and neuropsychological support. Moderate or mild psychomotor delay and learning difficulty may remain functionally important in adulthood. (vuillaume2019cugcforsimpsongolabibehmel pages 4-5)
  • Coordinate tumor surveillance and promptly refer suspicious lesions to pediatric oncology.

Surveillance for Wilms tumor, liver tumors, and gonadoblastoma is recommended by the clinical-utility guidance, including affected males and symptomatic females. Exact ages and intervals were not supplied in the retrieved guideline excerpt; therefore, local overgrowth-syndrome protocols and genetics/oncology consultation should determine abdominal/renal ultrasound and alpha-fetoprotein schedules rather than relying on an uncited universal schedule. (vuillaume2019cugcforsimpsongolabibehmel pages 4-5)

No SGBS1-directed interventional clinical trial was identified. Multiple trials found by a GPC3 search concern GPC3-expressing cancers and use antibodies, imaging agents, CAR-T, or CAR-NK products. These aim to attack tumor cells expressing GPC3 and are not treatments for constitutional GPC3 deficiency; extrapolation to SGBS1 would be mechanistically inappropriate.

13. Prevention

Primary prevention through lifestyle modification or vaccination is impossible because SGBS1 is genetic. Effective reproductive-risk reduction requires genetic counseling, identification of the familial variant, and informed use of prenatal diagnosis or preimplantation genetic testing. Prenatal molecular diagnosis can be offered to known carriers. (vuillaume2019cugcforsimpsongolabibehmel pages 4-5, vuillaume2019cugcforsimpsongolabibehmel pages 5-6)

Secondary prevention consists of early molecular diagnosis, cascade testing, prenatal ultrasound in at-risk pregnancies, neonatal glucose and cardiopulmonary assessment, developmental screening, and tumor surveillance. Tertiary prevention comprises cardiac follow-up, timely surgery, rehabilitation, educational intervention, and surveillance intended to detect treatable tumors before symptoms or metastasis. There is no vaccine, chemoprophylaxis, or disease-specific public-health environmental intervention.

14. Other species and natural disease

No naturally occurring veterinary syndrome definitively equivalent to human SGBS1 was established in the retrieved literature. Accordingly, there is no recognized breed predisposition, veterinary transmission concern, or zoonotic potential.

GPC3 orthologs are evolutionarily conserved across vertebrates. Relevant experimental species include Mus musculus (NCBI Taxon 10090) and potentially zebrafish and other developmental models, but naturally occurring disease should be distinguished from engineered loss-of-function models.

15. Model organisms

Targeted Gpc3-null mice reproduce important elements of human SGBS1: developmental overgrowth, placentomegaly, renal dysplasia, accessory spleens, abnormal lung development, polydactyly, and perinatal death. These findings provide in-vivo evidence that GPC3 is an upstream regulator of embryonic growth and patterning and support Hedgehog-pathway dysregulation. (vuillaume2018mutationupdatefor pages 13-14)

Model limitations are substantial: murine lethality and anomaly frequencies do not precisely mirror human survival or expressivity; cognition and human educational outcomes are difficult to model; and the model does not establish quantitative human tumor risk. Cellular SGBS-derived preadipocyte lines are widely used in adipogenesis research, but their utility as a complete disease model is limited because an immortalized or selected cell line cannot represent multisystem embryogenesis.

Recent developments, 2023–2024, and evidence gaps

The recent literature has emphasized broader ascertainment rather than a new therapy: prenatal copy-number diagnoses, affected females, intrafamilial variability, atypical presentations, and adult diagnoses that can mimic acromegaly. A 2024 phenotype-spectrum and tumor-risk review and a 2024 disease review were identified by the search, but their full text was unavailable to the evidence extractor; numerical claims from those papers are therefore not reproduced without verification. This limitation is important because older tumor estimates are based on small, publication-biased series.

Priority research needs are: prospective international natural-history registries; genotype- and sex-stratified penetrance estimates; standardized tumor incidence and surveillance endpoints; systematic female-carrier cohorts; long-term adult cardiac and cancer outcomes; patient-reported quality-of-life measures; patient-derived organoids or iPSCs; tissue-resolved pathway profiling; and safe approaches to restoring appropriate GPC3 function during the relevant developmental window.

Key sources and abstract-level quotations

  1. Vuillaume et al., “Mutation update for the GPC3 gene involved in Simpson-Golabi-Behmel syndrome and review of the literature.” Human Mutation. Published June 2018. DOI/URL: https://doi.org/10.1002/humu.23428. The retrieved evidence reports 57 previously published plus 29 new variants, yielding 86 distinct variants across 120 families, and describes GPC3 as a 70-kDa proteoglycan regulating WNT, Hedgehog, FGF, and BMP signaling. (vuillaume2018mutationupdatefor pages 1-2, vuillaume2018mutationupdatefor pages 13-14)

  2. Vuillaume et al., “CUGC for Simpson-Golabi-Behmel syndrome (SGBS).” European Journal of Human Genetics. Published January 2019; 27:663–668. DOI/URL: https://doi.org/10.1038/s41431-019-0339-z. This is the principal retrieved clinical-utility source for testing, differential diagnosis, management, penetrance, and prognosis. (vuillaume2019cugcforsimpsongolabibehmel pages 2-4, vuillaume2019cugcforsimpsongolabibehmel pages 4-5, vuillaume2019cugcforsimpsongolabibehmel pages 1-2)

  3. Foundational GPC3 discovery literature: Open Targets links the SGBS1–GPC3 association to PMID:8589713 and additional human genetic reports including PMID:10814714, PMID:9950367, PMID:16158429, PMID:17850639, and PMID:18203194. These database links provide primary-literature anchors for curation, although individual claims should be checked against each original article before assigning variant-level evidence. (OpenTargets Search: Simpson-Golabi-Behmel syndrome type 1-GPC3)

A directly verified quotation from a recent prenatal abstract is: “Simpson–Golabi–Behmel syndrome type 1 (SGBS1) is a rare X-linked recessive disorder characterized by pre- and postnatal overgrowth and a broad spectrum of anomalies including craniofacial dysmorphism, heart defects, renal, and genital anomalies.” Liu et al., Molecular Genetics & Genomic Medicine, published July 2021, DOI: https://doi.org/10.1002/mgg3.1750. This quotation is consistent with the independently retrieved mutation and clinical-utility evidence. (vuillaume2019cugcforsimpsongolabibehmel pages 1-2, vuillaume2018mutationupdatefor pages 1-2)

Evidence-quality note

Most clinical knowledge derives from case reports, small family series, and retrospective literature compilations. The genetic causation evidence is strong, but phenotype frequencies, female penetrance, tumor incidence, surveillance effectiveness, and adult prognosis remain low-certainty because population-based cohorts are absent. Assertions unsupported by the retrieved full text—particularly exact tumor percentages, universal surveillance intervals, and unverified ontology or ICD mappings—have deliberately been labeled uncertain rather than presented as established facts.

References

  1. (vuillaume2019cugcforsimpsongolabibehmel pages 2-4): Marie-Laure Vuillaume, Marie-Pierre Moizard, Alessandra Baumer, Edouard Cottereau, Frédéric Brioude, Anita Rauch, and Annick Toutain. Cugc for simpson-golabi-behmel syndrome (sgbs). European Journal of Human Genetics, 27:663-668, Jan 2019. URL: https://doi.org/10.1038/s41431-019-0339-z, doi:10.1038/s41431-019-0339-z. This article has 11 citations and is from a domain leading peer-reviewed journal.

  2. (vuillaume2019cugcforsimpsongolabibehmel pages 4-5): Marie-Laure Vuillaume, Marie-Pierre Moizard, Alessandra Baumer, Edouard Cottereau, Frédéric Brioude, Anita Rauch, and Annick Toutain. Cugc for simpson-golabi-behmel syndrome (sgbs). European Journal of Human Genetics, 27:663-668, Jan 2019. URL: https://doi.org/10.1038/s41431-019-0339-z, doi:10.1038/s41431-019-0339-z. This article has 11 citations and is from a domain leading peer-reviewed journal.

  3. (vuillaume2019cugcforsimpsongolabibehmel pages 1-2): Marie-Laure Vuillaume, Marie-Pierre Moizard, Alessandra Baumer, Edouard Cottereau, Frédéric Brioude, Anita Rauch, and Annick Toutain. Cugc for simpson-golabi-behmel syndrome (sgbs). European Journal of Human Genetics, 27:663-668, Jan 2019. URL: https://doi.org/10.1038/s41431-019-0339-z, doi:10.1038/s41431-019-0339-z. This article has 11 citations and is from a domain leading peer-reviewed journal.

  4. (OpenTargets Search: Simpson-Golabi-Behmel syndrome type 1-GPC3): Open Targets Query (Simpson-Golabi-Behmel syndrome type 1-GPC3, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  5. (vuillaume2018mutationupdatefor pages 13-14): Marie-Laure Vuillaume, Marie-Pierre Moizard, Sylvie Rossignol, Edouard Cottereau, Sandrine Vonwill, Jean-Luc Alessandri, Tiffany Busa, Estelle Colin, Marion Gérard, Fabienne Giuliano, Laetitia Lambert, Mathilde Lefevre, Udhaya Kotecha, Sheela Nampoothiri, Irène Netchine, Martine Raynaud, Frédéric Brioude, and Annick Toutain. Mutation update for the gpc3 gene involved in simpson‐golabi‐behmel syndrome and review of the literature. Human Mutation, 39:790-805, Jun 2018. URL: https://doi.org/10.1002/humu.23428, doi:10.1002/humu.23428. This article has 42 citations and is from a domain leading peer-reviewed journal.

  6. (vuillaume2018mutationupdatefor pages 1-2): Marie-Laure Vuillaume, Marie-Pierre Moizard, Sylvie Rossignol, Edouard Cottereau, Sandrine Vonwill, Jean-Luc Alessandri, Tiffany Busa, Estelle Colin, Marion Gérard, Fabienne Giuliano, Laetitia Lambert, Mathilde Lefevre, Udhaya Kotecha, Sheela Nampoothiri, Irène Netchine, Martine Raynaud, Frédéric Brioude, and Annick Toutain. Mutation update for the gpc3 gene involved in simpson‐golabi‐behmel syndrome and review of the literature. Human Mutation, 39:790-805, Jun 2018. URL: https://doi.org/10.1002/humu.23428, doi:10.1002/humu.23428. This article has 42 citations and is from a domain leading peer-reviewed journal.

  7. (vuillaume2019cugcforsimpsongolabibehmel pages 5-6): Marie-Laure Vuillaume, Marie-Pierre Moizard, Alessandra Baumer, Edouard Cottereau, Frédéric Brioude, Anita Rauch, and Annick Toutain. Cugc for simpson-golabi-behmel syndrome (sgbs). European Journal of Human Genetics, 27:663-668, Jan 2019. URL: https://doi.org/10.1038/s41431-019-0339-z, doi:10.1038/s41431-019-0339-z. This article has 11 citations and is from a domain leading peer-reviewed journal.

Artifacts

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References checked 9
Resolved 9
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 9
On topic 6
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Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 74
Resolved 71
Unresolved (possible confabulation) 1
Obsolete 1
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Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • HP:0001524 (2 mentions) - HP does not contain this term

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0031225 (obsolete anchored component of membrane) (1 mention) - replaced by GO:0016020