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Simpson-Golabi-Behmel Syndrome Type 1

, MD, MPH, , BS, and , BS.

Author Information

Initial Posting: ; Last Update: June 23, 2011.

Summary

Clinical characteristics.

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

Diagnosis/testing.

The diagnosis of SGBS1 is based on clinical findings, family history consistent with X-linked inheritance, and molecular genetic testing. GPC3 and GPC4 are the only two genes in which pathogenic variants are known to cause SGBS1.

Management.

Treatment of manifestations: Prompt treatment of neonatal hypoglycemia and airway obstruction resulting from micrognathia and glossoptosis. Care of cleft lip and/or cleft palate or macroglossia and related feeding difficulties, heart defects, skeletal abnormalities, and urogenital abnormalities by appropriate pediatric specialists. Speech therapy as needed. Neurodevelopmental assessment to determine need for special education, occupational therapy, and/or physical therapy.

Prevention of secondary complications: For those with congenital heart disease: anticoagulation and antibiotic prophylaxis as needed.

Surveillance: For hypoglycemia (newborn period); scoliosis (during accelerated growth); hearing and speech difficulties (especially in those with cleft palate); sleep apnea (especially for those with hypotonia and macroglossia, from newborn period through the end of the child’s growth spurt); and Wilms tumor, gonadoblastoma, hepatocellular carcinoma, neuroblastoma, nephroblastomatosis, and hepatoblastoma (starting in the newborn period).

Genetic counseling.

Simpson-Golabi-Behmel syndrome type 1 is inherited in an X-linked manner. If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers. Due to X-chromosome inactivation, carrier females may have manifestations of SGBS1. Males with SGBS1 will pass the pathogenic variant to all of their daughters and none of their sons. Carrier testing for at-risk relatives and prenatal testing for at-risk pregnancies may be available through laboratories offering either testing for the gene of interest or custom testing.

Diagnosis

Clinical Diagnosis

The diagnosis of Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is based on clinical findings, family history consistent with X-linked inheritance, and molecular genetic testing.

No clinical diagnostic criteria have been established. The diagnosis is suspected in males with the following:

  • Macrosomia (weight or length ≥95th percentile when adjusted for sex and age)
  • Characteristic facial features
    • Macrocephaly (occipitofrontal circumference [OFC] ≥95th percentile when adjusted for sex and age)
    • Ocular hypertelorism, epicanthal folds, and downslanting palpebral fissures
    • Redundant, furrowed skin over the glabella
    • Wide nasal bridge and anteverted nares in infants; broad nose and "coarse" facial appearance in older individuals
    • Macrostomia (abnormally large mouth)
    • Macroglossia (abnormally large tongue)
    • Dental malocclusion
    • 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 [Hughes-Benzie et al 1996]
    • Small mandible (micrognathia) in neonates; macrognathia in older individuals
  • Multiple congenital anomalies (see Clinical Description)
    • Congenital heart disease
    • Conduction defects (transient QT interval prolongation)
    • Supernumerary nipples
    • Diastasis recti/umbilical hernia
    • Diaphragmatic hernia
    • Renal dysplasia/nephromegaly
    • Cryptorchidism/hypospadias
    • Hand anomalies (brachydactyly, cutaneous syndactyly, polydactyly)

Molecular Genetic Testing

Genes

  • GPC3, encoding glypican-3, was the first gene known to be associated with Simpson-Golabi-Behmel syndrome type 1 (SGBS1).
  • GPC4, encoding glypican-4, flanks the centromeric end of GPC3 on Xq26 [Waterson et al 2010].

Clinical testing

Table 1.

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

Gene 1Test MethodVariants Detected 2Variant Detection Frequency by Test Method 3
MalesHeterozygous Females
GPC3Sequence analysis 4Sequence variants37%-70% 5, 6, 7Unknown 8
Deletion/duplication analysis 9(Multi)exon or whole-gene deletion 10Unknown 11Unknown
GPC4Deletion/duplication analysis 9(Multi)exon or whole-gene duplicationUnknown
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on allelic variants.

3.

The ability of the test method used to detect a variant that is present in the indicated gene

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

26/37 individuals with SGBS1 [Lin et al 1999]; 7/10 [Veugelers et al 2000]; 7/19 [Li et al 2001]. Note: (1) Lin et al [1999] hypothesized that the high detection rate may reflect sampling bias. (2) In the study by Li et al [2001], two individuals clinically diagnosed with Perlman syndrome and Sotos syndrome prior to the availability of molecular genetic testing were found to have a GPC3 pathogenic variant.

6.

Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis.

7.

Includes the variant detection frequency using deletion/duplication analysis

8.

Sequence analysis of genomic DNA cannot detect deletion of one or more exons or of the entire X-linked gene in a heterozygous female.

9.

Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

10.

A contiguous deletion of GPC3 and GPC4 has been identified in one family with SGBS1 [Veugelers et al 1998].

11.

Duplication of exons 1-9 in GPC4 without deletion or mutation of GPC3 was found in the original family described by Golabi & Rosen [1984] in which no GPC3 pathogenic variant had been identified [Waterson et al 2010].

Testing Strategy

To confirm/establish the diagnosis in an individual with findings consistent with SGBS1:

1.

Sequence analysis of GPC3

2.

If no pathogenic variant is identified, deletion/duplication analysis of GPC3

3.

If no pathogenic variant in GPC3 is detected, deletion/duplication analysis of GPC4.

Carrier testing for at-risk relatives requires prior identification of the pathogenic variant in the family.

Note: (1) Carriers are heterozygotes for this X-linked disorder and may have clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the pathogenic variant in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no pathogenic variant is identified, by methods to detect gross structural abnormalities.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant in the family.

Clinical Characteristics

Clinical Description

Males

Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is characterized by pre- and postnatal macrosomia, distinctive facies, and variable visceral, skeletal, and neurodevelopmental abnormalities.

Macrosomia. Virtually all persons with SGBS1 have pre- and postnatal overgrowth. As with other macrosomic syndromes, hypoglycemia may be present in the neonatal period.

Macrocephaly. See Clinical Diagnosis.

Characteristic facies. See Clinical Diagnosis.

Eyes. Esotropia, cataracts, and coloboma of the optic disc [Golabi & Rosen 1984] have been noted. Ocular nerve palsies and strabismus can occur.

Ears. Minor ear abnormalities are frequent, most often preauricular tags, fistulas, ear lobule creases, and helical dimples. Conductive hearing loss has been described [Golabi & Rosen 1984].

Neck. Cystic hygroma has been described [Chen et al 1993].

Thoracoabdominal wall. Supernumerary nipples are common, either one or multiple, unilateral or bilateral. Diastasis recti and umbilical hernias are observed frequently; however, true omphalocele is rare.

Cardiothoracic. Congenital heart defects are variable; septal defects are common. Pulmonic stenosis, aortic coarctation, transposition of the great vessels, and patent ductus arteriosus or patent foramen ovale have been reported.

Conduction defects and arrhythmias have frequently been described [Lin et al 1999]. Transient QT interval prolongation has been reported [Gertsch et al 2010].

Genitourinary. Nephromegaly, multicystic kidneys, hydronephrosis, hydroureter, and duplicated ureters are described. Other genitourinary anomalies include hypospadias, bifid scrotum, cryptorchidism, hydrocele, and inguinal hernia [Hughes-Benzie et al 1996].

Gastrointestinal. GI anomalies include pyloric ring, Meckel's diverticulum, intestinal malrotation [Golabi & Rosen 1984], hepatosplenomegaly, pancreatic hyperplasia of islets of Langerhans, choledochal cysts [Kim et al 1999], duplication of the pancreatic duct, and polysplenia.

Skeletal. Skeletal anomalies can include vertebral fusion, scoliosis, pectus excavatum, rib anomalies (including cervical ribs), winged scapula, congenital hip dislocation [Terespolsky et al 1995], small sciatic notches, and flared iliac wings [Chen et al 1993]. Extra lumbar vertebrae, spina bifida occulta, coccygeal skin tag, and bony appendage have also been documented [Golabi & Rosen 1984].

Hand anomalies, including large hands, broad thumbs, and brachydactyly, are common. Other findings include syndactyly, clinodactyly, and postaxial polydactyly. Striking index finger hypoplasia with congenital abnormalities of the proximal phalanx has been reported [Day & Fryer 2005]. Nail dysplasia, hypoplasia (particularly of the index finger), and hypoconvexity are common.

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

Central nervous system (CNS). Normal intelligence has been described, but mild to severe intellectual disability is common, with language delay being the most characteristic description.

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

CNS malformations include agenesis of the corpus callosum, Chiari malformation and hydrocephalus [Young et al 2006], and aplasia of the cerebellar vermis.

Neoplasia. An absolute incidence and relative risk for tumors has not been established; however, in a review of more than 100 persons with SGBS1, Li et al [2001] found a tumor frequency of about 10%. At least five tumor types have been described [Lapunzina et al 1998, Li et al 2001, Lapunzina 2005]

  • Wilms tumor (4 cases)
  • Hepatoblastoma (2)
  • Adrenal neuroblastoma (1)
  • Gonadoblastoma (1)
  • Hepatocellular carcinoma (1)

See Wilms Tumor Overview.

Other

Heterozygous Females

Due to skewed X-chromosome inactivation, carrier females can have manifestations of SBGS including macrosomia, macrocephaly, hypertelorism, broad and upturned nasal tip with prominent columella, macrostomia, prominent chin, hypoplastic fingernails, coccygeal skin tag and bony appendage, extra lumbar and thoracic vertebrae, and accessory nipples [Golabi & Rosen 1984]. Tall stature, course facial features, and developmental delay have also been reported [Gertsch et al 2010].

Two female carriers with a GPC3 pathogenic variant were reported to have two different types of cancer: one had a sero-papilliferous cystoadenoma, a low-grade ovarian carcinoma; the other had breast cancer [Gurrieri et al 2011]. Information was not sufficient to exclude other possible genetic causes for breast/ovarian cancer in the family.

Genotype-Phenotype Correlations

In a study of genotype-phenotype correlations, Mariani et al [2003] determined that all deletions and single-nucleotide variants occurring in the eight GPC3 exons result in loss of function with no phenotypic distinctions based on size or position of a deletion or single-nucleotide variant.

Penetrance

To date, all males with a GPC3 pathogenic variant have had clinical findings of SGBS1 [Authors, personal observation].

Penetrance in heterozygous females is unknown.

Nomenclature

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

Terms no longer in use for SGBS:

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

Prevalence

The prevalence of SGBS1 is unknown; however, it is believed to be underdiagnosed [Author, personal observation].

Differential Diagnosis

Simpson-Golabi-Behmel syndrome type 2, also known as the infantile lethal variant, maps to Xp22 and is postulated to be a distinct disorder with overlapping phenotypic features. Clinical features described in four individuals include hydrops fetalis, jaundice, brisk deep tendon reflexes, seizures, and trilobate left lung [Terespolsky et al 1995, Brzustowicz et al 1999]. Budny et al [2006] identified a CXORF5 pathogenic variant in one family.

Beckwith-Wiedemann syndrome (BWS) is characterized by macrosomia, macroglossia, visceromegaly, embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma), omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, and renal abnormalities (e.g., medullary dysplasia, nephrocalcinosis, medullary sponge kidney, and nephromegaly). BWS is associated with abnormal regulation of gene transcription by any one of a number of mechanisms in an imprinted domain on chromosome 11p15.5. BWS demonstrates the greatest number of clinical similarities with SGBS1 including macrosomia, macroglossia, ear anomalies, genitourinary malformations, and an increased incidence of tumors. However, the facies in these two syndromes are appreciably different, the skeletal abnormalities seen in SGBS1 are not present in BWS, and omphalocele seen in BWS is rare in SGBS1. Additionally, the X-linked inheritance of SGBS1 may help to differentiate these two overgrowth syndromes [Pilia et al 1996].

Sotos syndrome is characterized by a typical facial appearance, intellectual impairment, and overgrowth involving both height and head circumference. It is associated with neonatal jaundice, scoliosis, seizures, strabismus, conductive hearing loss, congenital cardiac anomalies, renal anomalies, and behavioral problems. The risk for sacrococcygeal teratoma and neuroblastoma is slightly increased. About 80%-90% of individuals with Sotos syndrome have a demonstrable pathogenic variant or deletion of NSD1. Inheritance is autosomal dominant.

Weaver syndrome shares clinical features of overgrowth, umbilical hernia, ear anomalies, hypotonia, advanced bone age, vertebral defects, and hypertelorism, but has different facies and more prominent psychomotor delay. The diagnosis of Weaver syndrome is made on clinical grounds [Weaver et al 1974]. See EZH2-Related Overgrowth.

Nevoid basal cell carcinoma syndrome (NBCCS, Gorlin syndrome) is characterized by multiple jaw keratocysts frequently beginning in the second decade of life and/or basal cell carcinomas usually from the third decade onwards. About 60% of individuals have a recognizable appearance with macrocephaly, bossing of the forehead, coarse facial features, and facial milia. Most individuals with NBCCS have skeletal anomalies such as bifid ribs or wedge-shaped vertebrae. Other less common findings include ectopic calcification, particularly in the falx; cardiac and ovarian fibromas; and medulloblastoma (primitive neuroectodermal tumor [PNET]) in early childhood. In about 60%-85% of individuals fulfilling diagnostic criteria, it is possible to identify a germline pathogenic variant of PTCH. Inheritance is autosomal dominant.

Fryns syndrome, an autosomal recessive multiple congenital anomaly syndrome, is characterized by coarse facies, diaphragmatic hernia with lung hypoplasia, distal limb hypoplasia and malformations of the cardiovascular system, gastrointestinal system, genitourinary system (renal cystic dysplasia), and central nervous system (arrhinencephaly, Dandy-Walker anomaly, agenesis of the corpus callosum).

Other syndromes that may share overlapping features:

  • Perlman syndrome, a rare autosomal recessive condition, with macrosomia and a high incidence of Wilms tumor; facial features are distinctive and neonatal mortality is high.
  • Nevo syndrome, an autosomal recessive condition that shares vertebral anomalies, ear malformations, cryptorchidism, overgrowth, and intellectual disability with SGBS1. Nevo syndrome manifestations further include accelerated osseous maturation, large extremities, and hypotonia. This condition is caused by pathogenic variants in exon 9 of PLOD1 [Giunta et al 2005]. (See Ehlers-Danlos Syndrome, Kyphoscoliotic Form.)
  • Marshall-Smith syndrome, which shares advanced bone age and intellectual disability with SGBS1; differences include facial features and predisposition to fractures.
  • Elejalde syndrome (acrocephalopolydactylous dysplasia). Infrequently described, Elejalde syndrome includes findings of macrosomia, abnormal facies, craniosynostosis with acrocepaly, omphalocele, organomegaly, cystic renal dysplasia, and polydactyly.
  • Infant of a diabetic mother syndrome. Infants born to diabetic mothers (IDM) have a higher rate of congenital malformations. Sacral agenesis or hypogenesis and/or caudal dysgenesis are classic findings [Williamson 1970], but other frequently observed anomalies include congenital heart defects, renal anomalies, vertebral anomalies, limb defects, and structural brain abnormalities.
  • Mosaic trisomy 8. Phenotype is variable, with characteristic findings of advanced growth, long slender trunk with multiple skeletal abnormalities (spinal deformities, contractures of fingers and toes), absence of the corpus callosum, and moderate intellectual disability. Typical facial features include high, prominent forehead, hypertelorism, full lips, and micrognathia.
  • Mosaic tetrasomy 12p (or Pallister-Killian syndrome), characterized by variegated skin pigmentation, facial anomalies including prominent forehead with sparse anterior scalp hair, ocular hypertelorism, short nose with anteverted nares, flat nasal bridge, as well as developmental delay

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with Simpson-Golabi-Behmel syndrome type 1 (SGBS1), the following evaluations are recommended:

  • Assessment of neonates for hypoglycemia
  • Assessment for upper airway sufficiency if macroglossia is present
  • Evaluation of young children with hypotonia and macroglossia for sleep apnea
  • Evaluation by a craniofacial team, including a feeding specialist if orofacial clefting is present
  • Hearing evaluation
  • Eye examination
  • Cardiac evaluation for structural defects and conduction abnormalities including chest radiograph, electrocardiogram, and echocardiogram
  • Renal ultrasound examination to evaluate for genitourinary malformations
  • Abdominal/pelvic ultrasound examination to evaluate for intra-abdominal tumors
  • Abdominal ultrasound examination to evaluate for visceral anomalies; further studies (e.g., MRI) if findings are suspicious
  • Examination for evidence of skeletal anomalies requiring intervention (e.g., scoliosis during period of rapid growth rate)
  • Development assessment including speech and language assessment
  • Neurology evaluation / MRI of the brain if seizures are present

Treatment of Manifestations

The following are appropriate:

  • Prompt treatment of hypoglycemia if present
  • Prompt treatment of upper airway obstruction resulting from macroglossia, micrognathia, and/or glossoptosis
  • Referral of children to the following pediatric specialists as needed:
    • Craniofacial team for management of cleft lip and/or palate, or macroglossia and related feeding difficulties
    • Audiologist, otolaryngologist, and speech therapy for management of hearing loss
    • Ophthalmologist for management of vision problems
    • Cardiologist for management of congenital heart defects and/or cardiac conduction defects
    • Orthopedist for the treatment of vertebral malformations and scoliosis if present
    • Urologist for surgical correction of anomalies such as hypospadias and cryptorchidism
    • Neurologist if seizures are present
    • Oncologist if a tumor is identified
  • Neurodevelopmental follow up for individual treatment plan that may include special education, occupational therapy, and physical therapy

Prevention of Secondary Complications

Routine pre- and post-surgical preparation and monitoring for individuals with congenital heart disease and/or conduction defects

Surveillance

For males with SGBS1:

  • Monitoring for hypoglycemia in the newborn period
  • Physical examination to monitor for scoliosis during period of rapid growth rate; radiographs as needed
  • If development appears to be normal on initial assessment, routine monitoring of social and intellectual development
  • Monitoring of renal function if renal anomalies are present
  • Physical examinations to monitor for tumor risk [Lapunzina 2005]:
    • Every three months until age four years
    • Every four months from age four to seven years
    • Biannually after age seven years

The following screening recommendations require further study to determine benefit. The clinician and family should discuss the methods to be used:

  • Wilms tumor. Abdominal ultrasound examination every three or four months from birth until at least age seven or eight years, and yearly thereafter [Choyke et al 1999, Lapunzina 2005]. Abdominal ultrasound examination should assess for both Wilms tumor and hepatic tumors.
    Note: When associated with an overgrowth syndrome, the risk for Wilms tumor decreases after age eight years [Beckwith 1998].
  • Gonadoblastoma or hepatocellular carcinoma. Serial measurement of serum alpha fetoprotein and beta human chorionic gonadotropin concentrations with the following suggested frequency [Lapunzina 2005]:
    • Every four months until age four years
    • Every six months between ages four and seven years
    • Annually after age seven years
  • Neuroblastoma. Measurements of urinary catecholamine metabolites including vanillylmandelic acid and homovanillic acid as well as urinary free fractionated catecholamines with the following suggested frequency [Lapunzina 2005]:
    • Every four months until age four years
    • Every six months from age four to seven years
    • Annually after age seven years
      Annual lifelong chest radiograms have also been suggested [Lapunzina 2005].

Evaluation of Relatives at Risk

Early diagnosis of affected males in a family helps identify those who will benefit from early diagnosis and intervention to reduce morbidity and mortality.

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

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

  • The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant.
  • In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
  • If pedigree analysis reveals that the proband is the only affected family member, the mother may be a carrier or the affected male may have a de novo pathogenic variant, in which case the mother is not a carrier. The frequency of de novo pathogenic variants is not known.
  • Because some female carriers have physical findings of SGBS1, physical examination of the proband's mother for features of SGBS1 is helpful.
  • If a woman has more than one affected son and the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism.
  • When an affected male represents a simplex case (i.e., the only affected individual in the family), several possibilities regarding his mother's carrier status need to be considered:
    • He has a de novo disease-causing alteration in GPC3 or GPC4 and his mother is not a carrier.
    • His mother has a de novo disease-causing alterations in GPC3 or GPC4, either (a) as a "germline pathogenic variant" (i.e., present at the time of her conception and therefore in every cell of her body); or (b) as "germline mosaicism" (i.e., present in some of her germ cells only).
    • His mother has a pathogenic variant that she inherited from a maternal female ancestor.

Sibs of a proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother of the proband has a pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Male sibs who inherit the variant will be affected; female sibs who inherit the variant will be carriers and will usually not be affected.
  • Germline mosaicism has been demonstrated. Thus, even if the pathogenic variant present in the proband has not been identified in the mother's DNA, sibs of the proband are still at increased risk of inheriting the pathogenic variant.

Offspring of a proband. Males with SGBS1 will pass the pathogenic variant to all of their daughters and none of their sons. Thus, female offspring of the proband will be carriers, while male offspring of the proband will not be affected.

Other family members of a proband. The proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the GPC3 pathogenic variant has been identified in an affected family member.

If the pathogenic variant has not been identified in the family, physical examination of at-risk female relatives and X-chromosome inactivation studies to determine if skewing of X-chromosome inactivation is present may identify some possible carriers [Author, personal observation].

Related Genetic Counseling Issues

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

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal 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, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variant has been identified in a family member, prenatal testing is possible for a pregnancy at increased risk and preimplantation genetic diagnosis for SGBS1 are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Simpson-Golabi-Behmel Syndrome Type 1: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
GPC3Xq26​.2Glypican-3GPC3 databaseGPC3GPC3
GPC4Xq26​.2Glypican-4GPC4 @ LOVDGPC4GPC4

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Simpson-Golabi-Behmel Syndrome Type 1 (View All in OMIM)

300037GLYPICAN 3; GPC3
300168GLYPICAN 4; GPC4
312870SIMPSON-GOLABI-BEHMEL SYNDROME, TYPE 1; SGBS1

GPC3

Gene structure. GPC3 comprises eight exons that span more than 500 kb. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. All eight exons of GPC3 have been found to harbor either deletions or single-nucleotide variants that lead to the Simpson-Golabi-Behmel syndrome type 1 (SGBS1) phenotype.

Approximately 50% of GPC3 deletions involve exon 8 [Veugelers et al 2000]. Single-nucleotide variants include splice site, frameshift, missense, and nonsense variants [Veugelers et al 2000]. Single-nucleotide variants have been described in all exons; as expected, most occur in exon 3, the largest exon.

Normal gene product. Glypican-3 is a glycosylphosphatidylinositol-linked cell surface heparan sulfate proteoglycan [Pilia et al 1996]. Heparan sulfate proteoglycans bind and regulate the activities of a variety of extracellular ligands essential to cellular functions. Glypicans have a role in cell growth and cell division.

Abnormal gene product. The mechanism by which a pathogenic loss-of-function GPC3 variant leads to the SGBS1 phenotype is unknown. At least 43% loss of functional GPC3 protein is required to develop the SGBS1 phenotype in heterozygous females (total number of detection rate is unknown) [Yano et al 2011].

GPC4

Gene structure. GPC4 is adjacent to the 3' end of GPC3 and comprises nine exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Duplication of exons 1-9 of GPC4 without a GPC3 pathogenic variant leads to the SGBS1 phenotype [Waterson et al 2010]. Note: Loss-of-function variants in GPC4 are not associated with SGBS1 [Veugelers et al 2000].

Normal gene product. Glypican-4 is also a glycosylphosphatidylinositol-linked cell surface heparan sulfate proteoglycan [Veugelers et al 1998].

Abnormal gene product. The mechanism by which a pathogenic loss-of-function GPC4 variant leads to the SGBS1 phenotype is unknown.

References

Literature Cited

  • Beckwith JB. Nephrogenic rests and the pathogenesis of Wilms tumor: developmental and clinical considerations. Am J Med Genet. 1998;79:268–73. [PubMed: 9781906]
  • Behmel A, Plochl E, Rosenkranz W. A new X-linked dysplasia gigantism syndrome: identical with the Simpson dysplasia syndrome? Hum Genet. 1984;67:409–13. [PubMed: 6490008]
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Suggested Reading

  • Gurrieri F, Cappa M, Neri G. Further delineation of the Simpson-Golabi-Behmel (SGB) syndrome. Am J Med Genet. 1992;44:136–7. [PubMed: 1456280]
  • Sapienza C, Hall JG. Genome imprinting in human disease. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 15.
  • Zarate YA, Mena R, Martin LJ, Steele P, Tinkle BT, Hopkin RJ. Experience with hemihyperplasia and Beckwith-Wiedemann syndrome surveillance protocol. Am J Med Genet A. 2009;149A:1691–7. [PubMed: 19610116]

Chapter Notes

Author Notes

Mahin Golabi, MD, MPH, is board certified in Medical Genetics and Pediatrics, and former clinical professor in Clinical Genetics at University of California, San Francisco.

Author History

Kathy Culver, MS; California Pacific Medical Center (2006-2011)
Mahin Golabi, MD, MPH (2006-present)
Aaron James; University of California San Francisco (2006-2011)
Alva Leung, BS (2011-present)
Christina Lopez, BS (2011-present)

Revision History

  • 23 June 2011 (me) Comprehensive update posted live
  • 19 December 2006 (me) Review posted to live Web site
  • 6 July 2006 (kc) Original submission
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