Simpson-Golabi-Behmel Syndrome Type 1

Clinical characteristics.

Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is characterized by pre- and postnatal macrosomia; distinctive craniofacial features (including macrocephaly, coarse facial features, macrostomia, macroglossia, and palate abnormalities); and, commonly, mild-to-severe intellectual disability with or without structural brain anomalies. Other variable findings include supernumerary nipples, diastasis recti / umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and gastrointestinal issues. Skeletal anomalies can include vertebral fusion, scoliosis, rib anomalies, and congenital hip dislocation. Hand anomalies can include large hands and postaxial polydactyly. Affected individuals are at increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma, and medulloblastoma.

Diagnosis/testing.

The diagnosis of SGBS1 is established in a male proband with suggestive findings and/or a hemizygous pathogenic variant in GPC3 or an intragenic or whole-gene deletion of GPC3 identified by molecular genetic testing. The diagnosis is usually established in a female proband with suggestive findings and a heterozygous pathogenic variant in GPC3 or an intragenic or whole-gene deletion of GPC3 identified by molecular genetic testing.

Management.

Treatment of manifestations: Prompt treatment of neonatal hypoglycemia and airway obstruction resulting from micrognathia and glossoptosis. Treatment of cleft lip and/or cleft palate or macroglossia and related feeding difficulties, obstructive sleep apnea, ophthalmologic issues, hearing loss, heart defects, urogenital abnormalities, skeletal abnormalities, seizures, Wilms tumor, and other types of tumors per standard recommendations by appropriate pediatric specialists. Speech therapy as needed. Neurodevelopmental assessment to determine the need for special education, occupational therapy, and/or physical therapy.

Surveillance: Screening for Wilms tumor and hepatoblastoma with abdominal ultrasound and serum AFP level every three months from time of diagnosis until age four years; renal ultrasound every three months until age seven years; 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. Annual (or as indicated) ophthalmologic and audiologic evaluations in childhood; sleep study if there are concerns about sleep dysregulation including sleep apnea; routine monitoring of kidney function if renal anomalies are present; evaluation for scoliosis at least annually or during periods of rapid growth; monitoring of serum glucose level in the neonatal period; monitoring of developmental progress at each visit through adolescence.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the GPC3 pathogenic variant in the family in order to identify as early as possible those who would benefit from preventive measures such as tumor surveillance.

Pregnancy management: Gestational hypertension, diabetes, preeclampsia, fetal distress, and preterm labor have all been reported in mothers of individuals with SGBS1. Fetal macrocephaly and overgrowth may necessitate cesarean delivery or early induction of labor.

Genetic counseling.

SGBS1 is inherited in an X-linked manner. If the mother of the proband has a pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be carriers, although due to X-chromosome inactivation, carrier females may have manifestations of SGBS1. Males with SGBS1 will pass the pathogenic variant to all their daughters and none of their sons. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible for families in which the pathogenic variant has been identified.

Suggestive Findings

SGBS1 should be suspected in probands with the following clinical findings and family history.

Clinical findings

• Linear somatic overgrowth
• Macrocephaly
• Characteristic facial features
  • Widely spaced eyes, epicanthal folds, and downslanted palpebral fissures
  • Redundant, furrowed skin over the glabella
  • Wide nasal bridge and anteverted nares in infants; broad nose and coarsening of the facial features in older individuals
  • Prominent forehead
  • Macrostomia
  • Macroglossia with or without a midline groove in the lower lip and/or deep furrow in the middle of the tongue
  • Cleft lip and/or submucous cleft palate (with a bifid uvula); high and narrow palate
  • Micrognathia in neonates; macrognathia in older individuals
• Cardiac manifestations. Congenital heart disease (e.g., pulmonary stenosis, cardiomyopathy, ventricular septal defect, patent ductus arteriosus, patent foramen ovale, arrythmias), conduction defects (transient QT interval prolongation)
• Genitourinary manifestations. Renal dysplasia, nephromegaly, duplicated renal system, cryptorchidism or hypospadias in males
• Other features
  • Supernumerary nipples
  • Diastasis recti / umbilical hernia
  • Diaphragmatic hernia
  • Hand and foot anomalies (brachydactyly, cutaneous syndactyly, polydactyly, shortened distal phalanges, fingernail dysplasia)

Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

Male proband. The diagnosis of SGBS1 is established in a male proband with suggestive findings and a hemizygous pathogenic (or likely pathogenic) variant in GPC3 or an intragenic or whole-gene deletion of GPC3 identified by molecular genetic testing (see Table 1).

Female proband. The molecular diagnosis of SGBS1 is usually established in a female proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in GPC3 or an intragenic or whole-gene deletion of GPC3 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a hemizygous or heterozygous variant of uncertain significance in GPC3 does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel, chromosomal microarray analysis) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not.

Option 2

When the diagnosis of SGBS1 has not been considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible. To date, the majority of GPC3 pathogenic variants reported are within the coding or canonical splice site region and are likely to be identified on exome sequencing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Simpson-Golabi-Behmel Syndrome Type 1

Clinical Description

Males and females can present similarly with Simpson-Golabi-Behmel syndrome type 1 (SGBS1). However, there is skewing of males to females in a 9:1 ratio. Individuals of both sexes present with overgrowth, characteristic facial features, skeletal abnormalities, and genitourinary dysfunction. Males often present with cryptorchidism. Females are less likely to present with severe manifestations of SGBS1, potentially due to skewed X-chromosome inactivation. There have not been extensive studies of sex differences in SGBS1 due to the small number of females reported to date and mildly affected or unaffected female carriers who do not present until they have an affected son.

Affected Males

SGBS1 is characterized by pre- and postnatal overgrowth, distinctive facies, and variable visceral, skeletal, and neurodevelopmental abnormalities. To date, 159 individuals have been identified with a pathogenic variant in GPC3 [Klein et al, unpublished data]. The following description of the phenotypic features associated with this condition is based on these reports.

Table 2.

Simpson-Golabi-Behmel Syndrome Type 1: Frequency of Select Features

Overgrowth

• Somatic overgrowth. Virtually all individuals with SGBS1 have either pre- or postnatal overgrowth. 68% of individuals present with postnatal overgrowth and 61% of individuals present with prenatal overgrowth [Klein et al, unpublished data]. At this time, no reference ranges or SGBS1-specific growth curves have been developed. There are currently no reports of hemihypertrophy or lateralized overgrowth.
  As with other overgrowth syndromes, hypoglycemia may be present in the neonatal period; however, hypoglycemia is rare in SGBS1 and is not considered to be a cardinal feature.
• Macrocephaly. Macrocephaly is reported in just over one third of individuals with SGBS1. Most present with macrocephaly in the prenatal period and continue to be macrocephalic throughout their life [Klein et al, unpublished data]. The most common complication of congenital macrocephaly in individuals with SGBS1 is difficulties with vaginal delivery, leading to increased risk of cesarean section deliveries [Klein et al, unpublished data]. Additionally, ventriculomegaly and ventricular hemorrhage, which are seen in some affected individuals, may confound the early identification of macrocephaly [Garganta & Bodurtha 1992, Li & McDonald 2009].

Characteristic facies include the following:

• Widely spaced eyes, epicanthal folds, and downslanted palpebral fissures
• Redundant, furrowed skin over the glabella
• Wide nasal bridge and anteverted nares in infants; broad nose and coarsening of the facial features in older individuals
• Prominent forehead
• Macrostomia
• Macroglossia with or without a midline groove in the lower lip and/or deep furrow in the middle of the tongue
• Cleft lip and/or submucous cleft palate (with a bifid uvula); high and narrow palate
• Micrognathia in neonates; large mandible (macrognathia) in older individuals

Cardiac. A range of cardiac features are seen:

• Congenital heart defects are variable; septal defects are common. Pulmonic stenosis, aortic coarctation, transposition of the great vessels, and patent ductus arteriosus or patent foramen ovale have been reported.
• Conduction defects and arrhythmias have also been described [Lin et al 1999]. Transient QT interval prolongation has also been reported [Gertsch et al 2010], as has AV or right bundle branch block [König et al 1991, Neri et al 2013, Xiang et al 2020].

Genitourinary. Nephromegaly, nephroblastomatosis, multicystic kidneys, hydronephrosis, hydroureter, supernumerary kidneys, and duplicated ureters have been described [Schmidt et al 2017, Reischer et al 2021].

Other genitourinary anomalies include hypospadias, penile hypoplasia, ambiguous genitalia, anal atresia, bifid scrotum, cryptorchidism, hydrocele, and inguinal hernia [Hughes-Benzie et al 1996, Romanelli et al 2007, Villarreal et al 2013, Halayem et al 2016, Magini et al 2016, Fu et al 2019].

Musculoskeletal. Skeletal anomalies can include vertebral fusion, scoliosis, pectus excavatum, rib anomalies (including cervical ribs), congenital hip dislocation [Terespolsky et al 1995, Garavelli et al 2012], small sciatic notches, and flared iliac wings [Chen et al 1993, Garavelli et al 2012]. Extra lumbar vertebrae, spina bifida (open and occulta) [Hughes-Benzie et al 1992, Van Borsel et al 2008], coccygeal skin tag, metaphyseal dysplasia of the femur [Yamashita et al 1995], and bony appendage have also been documented [Golabi & Rosen 1984].

Hand anomalies such as large hands, broad thumbs, and brachydactyly are common. Other findings include syndactyly, clinodactyly, and postaxial polydactyly. Striking index finger hypoplasia with congenital abnormalities of the proximal phalanx have been reported [Verloes et al 1995, Day & Fryer 2005]. Nail dysplasia, hypoplasia (particularly of the index finger), and hypoconvexity are common [Garavelli et al 2012, Cottereau et al 2013, Bu et al 2022].

Advanced bone age, including presence of ossified carpal bones in a newborn, has been described [Chen et al 1993, Watanabe et al 2022].

Neurologic and neurodevelopmental. Neurologic manifestations are perhaps the most variable findings. Hypotonia and absent primitive reflexes, a high-pitched cry in neonates, seizures, and abnormal EEG have all been described.

Normal intelligence has been described, but mild-to-severe intellectual disability is common, with language delay being the most characteristic finding.

Hydrocephalus, epilepsy, and attention-deficit/hyperactivity disorder may also be present [Van Borsel et al 2008, Tenorio et al 2014, Halayem et al 2016].

Brain abnormalities have been reported, including agenesis of the corpus callosum, Chiari malformation, hydrocephalus, and hypoplasia of the cerebellar vermis [Young et al 2006].

Neoplasia. The tumor risk in SGBS1 is estimated to be 11.3%, with the most common types being hepatoblastoma and Wilms tumor [Shimojima et al 2016, Spencer et al 2016]. The median age of neoplastic onset is 17.5 months with a 7:1 male-to-female ratio. With this risk and based on the guidelines for screening in cancer predisposition syndromes that lead to hepatoblastoma and Wilms tumor, individuals with SGBS1 should undergo tumor screening (see Surveillance).

Additionally, several tumors have been reported in single individuals, but it is unknown if they are related to the pathogenesis of SGBS1 or reflect the underlying population-level neoplastic risk. Each of the following has been reported in single individuals:

• Acute lymphoblastic leukemia [Sakazume et al 2007]
• Ameloblastoma [Kaya et al 2019]
• Diffuse neonatal hemangiomatosis [Poetke et al 2002]
• Hepatocellular carcinoma [Lapunzina et al 1998]
• Medulloblastoma [Thomas et al 2012]
• Pancreatic carcinoma [Rodríguez-Criado et al 2005]
• Renal neuroblastoma [Hughes-Benzie et al 1992]

Other manifestations

• Oropharynx. Macroglossia is a characteristic feature. In some cases, the tongue may enlarge such that it interferes with breathing and/or sleeping [Paludetti et al 2003], but the need for surgical intervention has not been determined to date. Other anomalies include various degrees of palatal clefting (including submucous cleft and bifid uvula), laryngeal cleft, and laryngeal web. Obstructive sleep apnea may be present. Silent aspiration leading to chronic respiratory infections and bronchiectasis has also been described [Glamuzina et al 2009, Tenorio et al 2014].
• Eyes. Esotropia, cataracts, and coloboma of the optic disc [Golabi & Rosen 1984] have been noted. Ocular nerve palsies and strabismus can occur.
• Ears. Minor ear abnormalities are frequent, most often preauricular tags, fistulas, ear lobule creases, and helical dimples. Conductive hearing loss has been described, but the incidence is not known. Overall, 37% of individuals have some form of ear deformity or conductive hearing loss [Golabi & Rosen 1984; Garganta & Bodurtha 1992; Griffith et al 2009; Magini et al 2016; Chong et al 2018; Klein et al, unpublished data].
• Neck. Cystic hygroma, thymic hypoplasia, and generalized lymphoid atrophy have been described but are rare [Chen et al 1993].
• Thoracoabdominal wall. Supernumerary nipples are common, either one or multiple, unilateral or bilateral. Diastasis recti and umbilical hernias are observed frequently; however, true omphalocele is rare [Terespolsky et al 1995, Li & McDonald 2009, Schmidt et al 2017].
• Lungs. Abnormal branching of the bronchi and an abnormal lower airway pit have been described in one affected individual [Glamuzina et al 2009]. Diaphragmatic hernia and associated lung hypoplasia have been reported [Chen et al 1993, Shimojima et al 2016, Chong et al 2018, Reischer et al 2021]. See Congenital Diaphragmatic Hernia Overview.
• Gastrointestinal. Gastrointestinal anomalies include pyloric ring, Meckel's diverticulum, intestinal malrotation [Golabi & Rosen 1984], hepatosplenomegaly, pancreatic hyperplasia of islets of Langerhans, choledochal cysts [Kim et al 1999, Shimojima et al 2016], duplication of the pancreatic duct, polysplenia, liver cysts, biliary atresia [Jedraszak et al 2014], inguinal hernia, and supernumerary kidney [Schmidt et al 2017, Chong et al 2018].

Genotype-Phenotype Correlations

There are no known genotype-phenotype correlations for SGBS1 to date.

Penetrance

All males reported with a GPC3 pathogenic variant have clinical findings of SGBS1. Penetrance in heterozygous females is unknown, but unaffected or mildly affected females have been reported [Shimojima et al 2016, Fernandes et al 2021].

Nomenclature

SGBS1 was initially described by Simpson et al [1975], with later accounts by Golabi & Rosen [1984] and Behmel et al [1984].

Terms no longer in use for SGBS1:

• Gigantism-dysplasia syndrome
• Encephalo-tropho-schisis syndrome
• Golabi-Rosen syndrome
• Simpson dysmorphia syndrome

Prevalence

The prevalence of SGBS1 is unknown; however, it is believed to be underdiagnosed due to the wide spectrum of clinical severity.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SGBS1, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Simpson-Golabi-Behmel Syndrome Type 1: Recommended Evaluations Following Initial Diagnosis

Treatment of Manifestations

There is no cure for SGBS1. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Table 5.

Simpson-Golabi-Behmel Syndrome Type 1: Treatment of Manifestations

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Table 6.

Simpson-Golabi-Behmel Syndrome Type 1: Recommended Surveillance for Males

Little information on tumor risk in heterozygous females is available; there are currently only a few reports of tumors in females with SGBS1 (see Clinical Description, Heterozygous Females). However, screening can be considered in affected females.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of older and younger at-risk male and female relatives of an affected individual by molecular genetic testing for the familial SGBS1-related genetic alteration in order to identify as early as possible those who would benefit from preventive measures such as tumor surveillance in males. Specific recommendations depend on the sex of the paternal source of the pathogenic variant and are family specific.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

A number of gestational complications have been reported in the mothers of individuals with SGBS1, including gestational hypertension, diabetes, preeclampsia, fetal distress, and preterm labor. Fetal macrocephaly and overgrowth may necessitate cesarean delivery or early induction of labor [Terespolsky et al 1995, Shimojima et al 2016, Schmidt et al 2017, Ridnõi et al 2018, Fu et al 2019, Toczewski et al 2020].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder, nor will he be hemizygous for the SBGS1-causing genetic alteration; therefore, he does not require further testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote and may demonstrate some features of the condition. Note: If a woman has more than one affected child and no other affected relatives, and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case):
  • The mother may be a heterozygote.
  • The affected male may have a de novo SBGS1-causing genetic alteration (in which case the mother is not a heterozygote). The frequency of de novo SBGS1-causing genetic alterations is about 20%-30% [Tenorio et al 2014].
  • The mother may have somatic/germline mosaicism [Romanelli et al 2007, Yano et al 2011]. The frequency of germline mosaicism is currently unknown.
• Molecular genetic testing capable of detecting the SBGS1-causing genetic alteration identified in the proband is recommended for the mother to confirm her genetic status and to allow reliable recurrence risk assessment.

Parents of a female proband

• A female proband may have inherited the SBGS1-causing genetic alteration from either her mother (who may or may not have manifestations of SBGS1) or her father or the genetic alteration may be de novo.
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a de novo SBGS1-causing genetic alteration from those with an inherited genetic alteration. Molecular genetic testing of the mother (and possibly the father, or subsequently the father) may help determine whether the genetic alteration was inherited.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has an SBGS1-causing genetic alteration, the chance of transmitting the genetic alteration in each pregnancy is 50%.
  • Males who inherit the genetic alteration will be affected.
  • Females who inherit the genetic alteration will be heterozygotes. Due to skewed X-chromosome inactivation, heterozygous females may have manifestations of SBGS1 (see Clinical Description, Heterozygous Females).
• If the proband represents a simplex case and if the SBGS1-causing genetic alteration cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population because of the possibility of maternal germline mosaicism. Maternal germline mosaicism has been reported [Romanelli et al 2007].

Sibs of a female proband. The risk to sibs depends on the genetic status of the parents:

• If the mother of the proband has an SGBS1-causing genetic alteration, the chance of transmitting it in each pregnancy is 50%.
  • Males who inherit the genetic alteration will be affected.
  • Females who inherit the genetic alteration will be heterozygotes. Due to skewed X-chromosome inactivation, heterozygous females may have manifestations of SBGS1 (see Clinical Description, Heterozygous Females).
• If the father of the proband has an SGBS1-causing genetic alteration, he will transmit it to all of his daughters and none of his sons. Transmission from an affected father to his affected daughter has been reported in one family to date [Støve el al 2017].
• If the proband represents a simplex case and if the SGBS1-causing genetic alteration cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism (both maternal and paternal germline mosaicism have been reported in SGBS1 [Romanelli et al 2007, Agatep et al 2014]).

Offspring of a male proband

• Affected males transmit the SGBS1-causing genetic alteration to all of their daughters and none of their sons.
• To date, only one affected male has been reported to reproduce; the affected male was only diagnosed after the fetal demise of the affected child [Støve et al 2017].

Offspring of a female proband. Women with an SGBS1-causing genetic alteration have a 50% chance of transmitting the genetic alteration to each child.

Other family members. The proband's maternal aunts may be at risk of being heterozygous for the SGBS1-causing genetic alteration, and the aunts' offspring may be at risk of having the genetic alteration and being affected.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo SGBS1-causing genetic alteration arose, information that could help determine genetic risk status of the extended family.

Heterozygote Detection

Identification of apparently asymptomatic female heterozygotes requires prior identification of the SGBS1-causing genetic alteration in the family.

Note: Females who are heterozygous for this X-linked disorder may be affected; heterozygous females with features of SGBS1 have been reported (see Clinical Description, Heterozygous Females).

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk male relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or who are at risk of having an SGBS1-causing genetic alteration.

Prenatal Testing and Preimplantation Genetic Testing

High-risk pregnancies. Once the SGBS1-causing genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Low-risk pregnancies. In pregnancies in which SGBS1 is suspected because of fetal overgrowth or congenital anomalies, the use of genomic testing (including chromosomal microarray and exome sequencing) can aid in diagnosis [Kehrer et al 2016].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

GPC3 encodes a glycosylphosphatidylinositol-linked cell surface heparan sulfate proteoglycan, which belongs to the glypican family. Heparan sulfate proteoglycans bind and regulate the activities of a variety of extracellular ligands essential to cellular functions. Glypicans have a role in cell growth and cell division. Abnormal glypican function may affect pathways such as Wnt signaling, the hedgehog pathway, BMP signaling, and FGF signaling [Paine-Saunders et al 2000, Song et al 2005, Ng et al 2009]. Glypican-3 is a glycosylphosphatidylinositol-linked cell surface heparan sulfate proteoglycan [Pilia et al 1996].

Most individuals with Simpson-Golabi-Behmel syndrome type 1 (SGBS1) have pathogenic variants in GPC3. The mechanism by which a pathogenic loss-of-function GPC3 variant leads to the SGBS1 phenotype is unknown. Yano et al [2011] reported that at least 43% loss of functional GPC3 protein is required to develop the SGBS1 phenotype in heterozygous females (total detection rate is unknown) [Yano et al 2011].

GPC3/GPC4 complex copy number abnormalities. Glypican-4, encoded by GPC4, is also a glycosylphosphatidylinositol-linked cell surface heparan sulfate proteoglycan [Veugelers et al 1998]. GPC4 is adjacent to the 3' end of GPC3 and comprises nine exons. Males and female carriers with complex GPC3 and GPC4 copy number abnormalities have been reported [Schirwani et al 2019]. Additional atypical SGBS1 features, such as brain malformations, have been noted in individuals with dual duplications, suggesting that atypical or new features may be associated with duplications of GPC4 [Mujezinović et al 2016]. Mujezinović et al [2016] suggested that the GPC4 duplication could cause a greater disruption of glypican-3 expression, altering the phenotypic expression [Mujezinović et al 2016]. The mechanism by which duplication of GPC3 and GPC4 leads to the SGBS1 phenotype is unknown. Schirwani et al [2019] reported two heterozygous females with 45%-56% of the active X-chromosome-containing complex GPC3/GPC4 duplications. These females manifested mild SGBS1 features including intellectual disability and developmental delay [Schirwani et al 2019]. Duplication of GPC4 without a GPC3 pathogenic variant has been very rarely reported in association with an SGBS1 phenotype [Waterson et al 2010]. However, the mechanism by which duplication of GPC4 leads to the SGBS1 phenotype is unknown. Of note, loss-of-function variants in GPC4 are not associated with SGBS1 [Veugelers et al 2000].

Mechanism of disease causation. Loss of function

Author Notes

Mr Hathaway is a licensed genetic counselor.

Dr Kalish is board certified in pediatrics and clinical genetics and is an Assistant Professor of Pediatrics and Genetics

Dr Kalish (ude.pohc@jhsilak) and Dr Klein (ude.pohc@dsnielk) are actively involved in research regarding individuals with Simpson-Golabi-Behmel syndrome type 1 (SGBS1) and related overgrowth syndromes. They would be happy to communicate with persons who have any questions regarding diagnosis of SGBS1 or other overgrowth syndromes with or without a causative variant identified through molecular genetic testing of known overgrowth genetic or epigenetic causes.

Contact Drs Kalish and Klein to inquire about review of GPC3/GPC4 variants of uncertain significance.

Acknowledgements

We thank the patients who have engaged with our research and the colleagues who have referred patients to the clinic and the research.

Author History

Kathy Culver, MS; California Pacific Medical Center (2006-2011)
Mahin Golabi, MD, MPH; California Pacific Medical Center (2006-2018)
Christina X Gonzalez-Gandolfi, BA; Children's Hospital of Philadelphia (2018-2023)
Evan R Hathaway, MS, LCGC (2018-present)
Aaron James; University of California San Francisco (2006-2011)
Jennifer M Kalish, MD, PhD (2018-present)
Stephen D Klein, MD, PhD (2023-present)
Alva Leung, BS; California Pacific Medical Center (2011-2018)
Christina Lopez, BS; California Pacific Medical Center (2011-2018)
Alex F Nisbet, BS (2023-present)
Brian J Sajorda, BA; Children's Hospital of Philadelphia (2018-2023)

Revision History

• 7 December 2023 (gm) Comprehensive update posted live
• 29 November 2018 (ma) Comprehensive update posted live
• 23 June 2011 (me) Comprehensive update posted live
• 19 December 2006 (me) Review posted live
• 6 July 2006 (kc) Original submission

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