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Shprintzen-Goldberg Syndrome

Synonyms: Marfanoid-Craniosynostosis Syndrome, Shprintzen-Goldberg Craniosynostosis Syndrome, Shprintzen-Goldberg Marfanoid Syndrome


Author Information

Initial Posting: ; Last Update: June 13, 2013.

Estimated reading time: 17 minutes


Clinical characteristics.

Shprintzen-Goldberg syndrome (SGS) is characterized by: craniosynostosis of the coronal, sagittal, or lambdoid sutures; dolichocephaly; distinctive craniofacial features; skeletal changes (dolichostenomelia, arachnodactyly, camptodactyly, pes planus, pectus excavatum or carinatum, scoliosis, joint hypermobility or contractures and C1/C2 spine malformation); neurologic abnormalities; intellectual disability; and brain anomalies (hydrocephalus, dilatation of the lateral ventricles, and Chiari 1 malformation). Cardiovascular anomalies may include mitral valve prolapse, mitral regurgitation/incompetence, aortic regurgitation, and aortic root dilatation. Minimal subcutaneous fat, abdominal wall defects, myopia, and cryptorchidism in males are also characteristic findings.


The diagnosis of SGS is suspected in individuals with characteristic clinical findings and radiographic findings showing C1-C2 abnormality, wide anterior fontanel, thin ribs, square-shaped vertebral bodies, and osteopenia. SKI is the only gene in which pathogenic variants are known to cause Shprintzen-Goldberg syndrome.


Treatment of manifestations: If aortic dilatation is present, treatment with beta-adrenergic blockers or other medications should be considered in order to reduce hemodynamic stress; surgical intervention for aneurysms may be indicated. Surgical repair of abdominal hernias; standard management of cleft palate and craniosynostosis; surgical fixation of cervical spine instability; routine management for clubfoot deformity; surgical correction for pectus excavatum (rarely indicated); physiotherapy for joint contractures; developmental assessment with placement in special education programs.

Prevention of secondary complications: Subacute bacterial endocarditis (SBE) prophylaxis is recommended for dental work or other procedures for individuals with cardiac complications.

Surveillance: Management by a cardiologist familiar with this condition is recommended.

Agents/circumstances to avoid: Contact sports; use of agents that stimulate the cardiovascular system; activities that may lead to joint pain and/or injury.

Genetic counseling.

Shprintzen-Goldberg syndrome (SGS), resulting from a heterozygous pathogenic variant in SKI, is inherited in an autosomal dominant manner. Most individuals with SGS have unaffected parents suggesting that the causative variant has occurred either as a de novo event in the affected individual or as a result of germline mosaicism in one of the parents. Affected sibs born to unaffected parents support the occurrence of germline mosaicism in some families with SGS.


Clinical Diagnosis

The diagnosis of Shprintzen-Goldberg syndrome (SGS) is suspected in individuals with a combination of the following major characteristics:

  • Craniosynostosis usually involving the coronal, sagittal, or lambdoid sutures
  • Craniofacial findings
    • Dolichocephaly with or without scaphocephaly
    • Tall or prominent forehead
    • Ocular proptosis
    • Widely spaced eyes
    • Downslanted palpebral fissures
    • Malar flattening
    • High narrow palate with prominent palatine ridges
    • Micrognathia and/or retrognathia
    • Apparently low-set and posteriorly rotated ears
  • Skeletal findings
    • Dolichostenomelia
    • Arachnodactyly
    • Camptodactyly
    • Pes planus
    • Pectus excavatum or carinatum
    • Scoliosis
    • Joint hypermobility or contractures
    • Foot malposition
  • Cardiovascular findings
    • Mitral valve prolapse
    • Mitral regurgitation/incompetence
    • Aortic regurgitation
    • Dilatation of the aortic root
  • Neurologic anomalies
    • Delayed motor and cognitive milestones
    • Mild-to-moderate intellectual disability
  • Brain anomalies
    • Hydrocephalus
    • Dilatation of the lateral ventricles
    • Chiari 1 malformation
  • Radiographic findings
    • Craniosynostosis
    • C1-C2 abnormality
    • Wide anterior fontanel
    • Thin ribs
    • 13 pairs of ribs
    • Square-shaped vertebral bodies
    • Osteopenia
  • Other
    • Arterial tortuosity
    • Other aneurysm
    • Broad/bifid uvula
    • Cleft palate
    • Clubfoot deformity
    • Dural ectasia
    • Hernias
    • Loss of subcutaneous fat
    • Myopia

Molecular Genetic Testing

Gene. SKI is the only gene in which pathogenic variants are known to cause Shprintzen-Goldberg syndrome.

Table 1.

Molecular Genetic Testing Used in Shprintzen-Goldberg syndrome

Gene 1Test MethodPathogenic Variants Detected 2Variant Detection Frequency by Test Method 3
SKISequence analysis 4Sequence variantsSee footnote 5
Deletion/duplication analysis 6Exon or whole-gene deletionsUnknown, none reported 7

See Molecular Genetics for information on allelic variants.


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


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.


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.


No deletions or duplications involving SKI as causative of Shprintzen-Goldberg syndrome have been reported. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

Testing Strategy

Confirming/establishing the diagnosis in a proband. The condition is suspected based on clinical findings. Genetic testing may confirm the diagnosis.

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

The clinical and molecular characterization of 29 individuals with Shprintzen-Goldberg syndrome (SGS) has been reported [Carmignac et al 2012, Doyle et al 2012]. The syndrome is characterized by craniosynostosis, dolichocephaly, distinctive craniofacial features, skeletal changes, hypotonia, intellectual disability, aortic root dilatation, valvular anomalies, and neurologic and brain anomalies (see Clinical Diagnosis). Minimal subcutaneous fat, abdominal wall defects, myopia, and cryptorchidism in males are other characteristic findings. Of note, lens dislocation does not appear to be a feature of SGS.

Both males and females may be affected.

The majority of individuals with Shprintzen-Goldberg syndrome are born at term by spontaneous vaginal delivery, with birth weight greater than 3 kg, birth length greater than 46 cm, and head circumference within the normal range.

Motor and cognitive milestones are delayed and mild-to-moderate intellectual disability appears to be invariable. Although normal intelligence was reported in one man followed from infancy to adulthood, he had academic difficulties and attended a special school [Stoll 2002].

Aortic root dilatation was present in three of 19 affected individuals reported by Carmignac et al [2012] and also in a small proportion of the individuals with SGS reported by Greally et al [1998] and Robinson et al [2005]. In the report of Doyle et al [2012] however, eight of ten individuals with SGS and confirmed pathogenic variants in SKI had aortic root dilatation ± mitral valve prolapse/incompetence. Surgery at age 16 years for aortic dilatation (aortic root dilatation with Z score = 7.014) was reported in one individual with molecularly confirmed SGS [Carmignac et al 2012]. This individual also had vertebrobasilar and internal carotid tortuosity and a dilated pulmonary artery root. Among the affected individuals with molecularly confirmed SGS reported by Doyle et al [2012] one had arterial tortuosity and two had splenic artery aneurysm, one with spontaneous rupture.

In addition to the characteristic skeletal findings, cloverleaf skull [Saal et al 1995], bathrocephaly, abruptly sloping orbital roofs, disharmonic maturation of ossification centers, dislocation of the radial head, anterior subluxation of the wrists, thin proximally placed thumbs, phalangeal hypotubulation and sclerosis, hip subluxation, femur fracture, genu recurvatum, talipes equinovarus, metatarsus adductus, congenital bowing of the ribs and long bones, and hypoplastic hooked clavicles have also been reported [Adès et al 1995].

Other findings include respiratory distress [Hassed et al 1997], strabismus, choanal atresia, hypoplasia of the corpus callosum [Saal et al 1995], intestinal malrotation, anteriorly placed anus, mild cerebral atrophy [Adès et al 1995], abdominal hernia [Stoll 2002,Robinson et al 2005], dural ectasia, cleft palate, and broad/bifid uvula [Doyle et al 2012].

Genotype-Phenotype Correlations

No genotype-phenotype correlation can be made at this time.


Penetrance is unknown.


Anticipation is not observed in Shprintzen-Goldberg syndrome.


Goldberg-Shprintzen syndrome and Shprintzen-Goldberg omphalocele syndrome are separate unrelated syndromes.

Shprintzen-Goldberg syndrome has also been called craniosynostosis with arachnodactyly and abdominal hernias.

The term Furlong syndrome has been used to describe one individual with craniosynostosis, features of SGS, normal intelligence, and aortic enlargement. In 2006 Ades et al reported on two individuals with a phenotype similar to Furlong syndrome. They had the same pathogenic missense variant in TGFBR1, making a diagnosis of Loeys-Dietz syndrome (LDS) type 1 most likely [B Loeys, personal communication]. In the absence of analysis for pathogenic variants in the original individual described as having Furlong syndrome, the existence of this as a separate entity remains unclear.


Approximately 60 cases of SGS have been reported since the original publication of Sugarman & Vogel [1981]. However, some of these individuals have since been found to have other disorders, mainly Loeys-Dietz syndrome or Marfan syndrome.

Differential Diagnosis

The phenotype of Shprintzen-Goldberg syndrome (SGS) is distinctive but shows some overlap with Loeys-Dietz syndrome (LDS) and Marfan syndrome (MFS). Distinguishing features of SGS include hypotonia and intellectual disability, which are rare findings in individuals with LDS and MFS, but appear to be invariably present in those with SGS. Some of the radiographic findings in SGS are distinctive and are rarely found in individuals with either LDS or MFS (e.g., C1/C2 abnormality, 13 pairs of ribs, square-shaped vertebral bodies, Chiari1 malformation). In addition, aortic root dilatation is less frequent is SGS than in LDS or MFS but, when present, it can be severe [Carmignac et al 2012]. One of the hallmarks of LDS is the occurrence of arterial tortuosity and aneurysms in arteries other than the aorta. Arterial tortuosity was found in two individuals with SGS; a further two individuals with SGS were found to have splenic artery aneurysm [Carmignac et al 2012, Doyle et al 2012].

Loeys-Dietz syndrome (LDS) may be difficult to differentiate clinically from SGS. LDS is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections) and skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus). Approximately 75% of affected individuals have LDS type I with craniofacial manifestations (widely spaced eyes, bifid uvula/cleft palate, craniosynostosis); approximately 25% have LDS type II with cutaneous manifestations (velvety and translucent skin; easy bruising; widened, atrophic scars). LDSI and LDSII form a clinical continuum. The natural history of LDS is characterized by aggressive arterial aneurysms (mean age at death 26.1 years) and high incidence of pregnancy-related complications including death and uterine rupture. A minority of affected individuals have developmental delay. Pathogenic variants in TGFBR1, TGFBR2, TGFB2, and SMAD3 have been identified in individuals with Loeys-Dietz syndrome [Loeys et al 2005, Adès et al 2006, Stheneur et al 2008, Tug et al 2010]. LDS is inherited in an autosomal dominant manner.

Adès et al [2005] and Loeys et al [2005] found no pathogenic variants in TGFBR1 and TGFBR2 in their cohort of individuals with SGS.

The phenotype of the individual described by van Steensel et al [2008] included craniosynostosis, scoliosis, pectus excavatum, a mucous pseudocleft of the palate, posterior rotation of the ears, dilatation of the ascending aorta, and normal development. A pathogenic variant in TGFBR2 was found in this individual; thus, despite the absence of arterial tortuosity, it appears to be more likely that this individual had LDS rather than SGS.

Stheneur et al [2008] reported on the phenotype of individuals with aTGFBR1 or TGFBR2 pathogenic variant: one person referred with a diagnosis of SGS because of craniosynostosis, widely spaced eyes, retrognathia, malar flattening, and developmental delay was found to have a TGFBR1 pathogenic variant.

Marfan syndrome is a systemic disorder of connective tissue with a high degree of clinical variability. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. Myopia is the most common ocular feature; displacement of the lens from the center of the pupil, seen in approximately 60% of affected individuals, is a hallmark feature. People with Marfan syndrome are at increased risk for retinal detachment, glaucoma, and early cataract formation. The skeletal system involvement is characterized by bone overgrowth and joint laxity. The extremities are disproportionately long for the size of the trunk (dolichostenomelia). Overgrowth of the ribs can push the sternum in (pectus excavatum) or out (pectus carinatum). Scoliosis is common and can be mild or severe and progressive. The major sources of morbidity and early mortality in the Marfan syndrome relate to the cardiovascular system. Cardiovascular manifestations include dilatation of the aorta at the level of the sinuses of Valsalva, a predisposition for aortic tear and rupture, mitral valve prolapse with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery. With proper management, the life expectancy of someone with Marfan syndrome approximates that of the general population. FBN1 is the gene associated with Marfan syndrome. Inheritance is autosomal dominant.

Pathogenic variants in FBN1 have been reported in three individuals with a clinical diagnosis of Shprintzen-Goldberg syndrome (SGS) [Sood et al 1996, Kosaki et al 2005]:

  • The case of Sood et al [1996] with the p.Cys1223Tyr allele was atypical for both Marfan syndrome and SGS. While the individual reported had ectopia lentis (typical for Marfan syndrome and not SGS), she also had craniosynostosis, strabismus, abnormal ears, hypotonia, and foot deformities (typical of SGS and not Marfan syndrome).
  • The individual described by Kosaki et al [2006] with the p.Cys1223Tyr allele had craniosynostosis, dolichocephaly, mild exophthalmos, downslanted palpebral fissures, pectus carinatum, scoliosis, arachnodactyly with contractures of the interphalangeal joints, developmental delay, minimal enlargement of the aortic root, and mitral valve prolapse, but no evidence of ectopia lentis — that is, findings more typical of SGS.
  • The p.Pro1148Ala pathogenic variant in the other case reported by Sood et al [1996] has been found in aortic aneurysm syndromes, but shows relative enrichment in normal Asian and Hispanic populations and is likely to be a polymorphism [Schrijver et al 1997, Watanabe et al 1997, Whiteman et al 1998].

Adès et al [2005] found no FBN1 pathogenic variants in their cohort of individuals with a clinical diagnosis of SGS.

Congenital contractural arachnodactyly (CCA) is characterized by a Marfan-like appearance (tall, slender habitus in which arm span exceeds height) and long, slender fingers and toes (arachnodactyly). Most affected individuals have "crumpled" ears that present as a folded upper helix of the external ear and most have contractures of major joints (knees and ankles) at birth. The proximal interphalangeal joints also have flexion contractures (i.e., camptodactyly), as do the toes. Hip contractures, adducted thumbs, and clubfoot may occur. The majority of affected individuals have muscular hypoplasia. Contractures usually improve with time. Kyphosis/scoliosis is present in about half of all affected individuals. It begins as early as infancy, is progressive, and causes the greatest morbidity in CCA. Dilatation of the aorta is occasionally present. Infants have been observed with a severe/lethal form characterized by multiple cardiovascular and gastrointestinal anomalies in addition to the typical skeletal findings. FBN2, encoding the extracellular matrix microfibril fibrillin 2, is the only gene known to be associated with CCA. Inheritance is autosomal dominant.

Frontometaphyseal dysplasia (FMD) and Melnick-Needles syndrome (MNS), two disorders in the otopalatodigital spectrum disorders, share skeletal findings with SGS including tall, square-shaped vertebrae, bowed tibiae, and occasionally, fusion of upper cervical vertebrae. The presence of intellectual disability and craniosynostosis usually distinguishes SGS from FMD or MNS. No pathogenic variants in FLNA have been found in SGS [S Robertson and L Adès, personal communication].


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Shprintzen-Goldberg syndrome (SGS), the following evaluations are recommended:

  • Radiographs to detect skeletal manifestations that may require attention by an orthopedist (e.g. severe scoliosis, C1/C2 abnormality)
  • Brain MRI
  • Echocardiogram
  • MRA or CT scan with 3D reconstruction from head to pelvis to identify arterial aneurysms and arterial tortuosity throughout the arterial tree should be considered [Carmignac et al 2012]
  • Surgical evaluation for hernia repair, if indicated
  • Developmental assessment
  • Ophthalmology examination by an ophthalmologist with expertise in connective tissue disorders
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Management of SGS is best conducted through the coordinated input of a multidisciplinary team of specialists including a clinical geneticist, cardiologist, ophthalmologist, orthopedist, cardiothoracic surgeon, and craniofacial team. The following are appropriate.


  • If aortic dilatation is present, treatment with beta-adrenergic blockers or other medications should be considered in order to reduce hemodynamic stress.
  • Surgical intervention for aneurysms may be indicated.

Hernia. Surgical repair of abdominal hernias may be indicated.

Craniofacial. Cleft palate and craniosynostosis require management by a craniofacial team; treatment is the same as in all disorders with these manifestations.


  • Surgical fixation of cervical spine instability may be necessary.
  • Clubfoot deformity may require surgical correction.
  • Pectus excavatum may be severe; rarely, surgical correction is indicated for medical reasons.

Physiotherapy. Physiotherapy may help increase mobility in individuals with joint contractures.

Special education. A developmental assessment will help with placement in a special education center or in a special education program in a regular school.

Prevention of Secondary Complications

Subacute bacterial endocarditis (SBE) prophylaxis is recommended for dental work or other procedures expected to contaminate the bloodstream with bacteria for individuals with cardiac complications.


All individuals with SGS should be managed by a cardiologist who is familiar with this condition.

Agents/Circumstances to Avoid

The following should be avoided:

  • Contact sports, which may lead to catastrophic complications in those with cardiovascular issues or cervical spine anomalies/instability
  • Agents that stimulate the cardiovascular system, including routine use of decongestants
  • Activities that cause joint pain or injury

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search in the US and 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.

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

Shprintzen-Goldberg syndrome (SGS) is caused by a heterozygous pathogenic variant in SKI and is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

Note: (1) Although most individuals diagnosed with SGS do not have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members (2) If the parent is the individual in whom the pathogenic variant first occurred s/he may have somatic mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband

Offspring of a proband. Each child of an individual with SGS has a 50% chance of inheriting the pathogenic variant. To date, all offspring of individuals with SGS have been unaffected, including a son born to Patient 1 of the report of Greally et al [1998].

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk 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 or at risk.

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 SKI pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.


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.

  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free)
  • FACES: The National Craniofacial Association
    PO Box 11082
    Chattanooga TN 37401
    Phone: 800-332-2373 (toll-free)
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • Wide Smiles
    PO Box 5153
    Stockton CA 95205-0153
    Phone: 209-942-2812
    Fax: 209-464-1497

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.

Shprintzen-Goldberg Syndrome: Genes and Databases

GeneChromosome LocusProteinHGMDClinVar
SKI1p36​.33-p36.32Ski oncogeneSKISKI

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 Shprintzen-Goldberg Syndrome (View All in OMIM)


Gene structure. The proto-oncoprotein, SKI, has seven exons; the transcript variant is 5,707 bps. See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic variants. In their report of individuals with SGS, Doyle et al [2012] found pathogenic variants in exon 1 of SKI in all ten individuals: nine missense variants and one 9-bp deletion. The alterations in SKI were found in two distinct N-terminal regions of the protein. The first region is located in the SMAD2/3-binding domain of SKI (residues 17-45) and the second region localizes to a portion of the Daschund-homology domain (DHD) of the SKI protein that mediates binding to SNW1 and N-CoR, proteins essential for recruitment of transcriptional corepressors, such as histone deacetylases [Doyle et al 2012]. Pathogenic variants in exon 1 of SKI were found in 18 of the 19 individuals with SGS reported by Carmignac et al [2012]. A family with five affected individuals had a dominantly inherited heterozygous in-frame deletion in exon 1; a small deletion was also found in a simplex case while the remaining individuals had heterozygous pathogenic missense variants in exon 1, within the R-SMAD-binding domain of SKI.

Normal gene product. The SKI gene product is in the same family as the SnoN protein. The SKI family of proteins negatively regulate SMAD-dependent TGF-β signaling by impeding SMAD2 and SMAD3 (SMAD2/3) activation, preventing nuclear translocation of the receptor-activated SMAD (R-SMAD)-SMAD4 complex and inhibiting TGF-β target gene output by competing with p300/CBP for SMAD binding and recruiting transcriptional repressor proteins, such as mSin3A and HDAC1 [Doyle et al 2012]. SKI has four transcripts (splice site variants): SKI-001, SKI-002, SKI-004 and SKI-005. Only SKI-001 has a protein product.

The SKI protein has a 728 amino-acid sequence with multiple domains and is expressed both inside and outside the cell. The different domains have different functions, with the primary domains interacting with Smad proteins. The SKI oncogene is present in all cells, and is commonly active during development. All pathogenic variants reported to date in SGS were in exon 1, in two distinct N-terminal regions of the protein. The first region is located in the SMAD2/3-binding domain of SKI (residues 17-45) and the second region localizes to a portion of the Daschund-homology domain (DHD) of the SKI protein.

Abnormal gene product. Doyle et al [2012] assessed the functional consequences of SKI pathogenic variants and showed excessive SMAD2/3 and extracellular signal-regulated kinase (ERK1) and ERK2 (ERK1/2) phosphorylation in cells of affected individuals compared to controls, both at baseline and after acute (30-min) stimulation with exogenous TGF-β2. They concluded that this implied loss of suppression of the TGF-β-dependent signaling cascades in SGS cells. The SKI family of proteins negatively regulates SMAD-dependent TGF-β signaling. Pathogenic variants in SKI result in enhanced activation of TGF-β signaling cascades and higher expression of TGF-β-responsive genes relative to control cells. Dysregulation of TGF-β signaling has been implicated in the pathogenesis of syndromic presentations of aneurysm, with excessive TGF-β signaling observed in the aortic wall and other diseased tissue in mouse models of Marfan syndrome. Doyle et al [2012] showed that the multisystem manifestations of SGS are caused by primary pathogenic variants in a prototypical repressor of TGF-β signaling and, from their study, concluded that the gene in which mutation is causative was SKI. Their data supported the conclusion that increased TGF-β signaling is the mechanism underlying SGS.


Literature Cited

  • Adès LC, Biggin A, Holman K, Brett M, Sullivan K, Bennetts B. FBN1, TGFBR1 and TGFBR2 gene screening in Shprintzen-Goldberg syndrome and mutation-negative Marfan syndrome. Poster session 5. Ghent, Belgium: Seventh International Symposium on the Marfan Syndrome; 2005.
  • Adès LC, Morris LL, Power RG, Wilson M, Haan EA, Bateman JF, Milewicz DM, Sillence DO. Distinct skeletal abnormalities in four girls with Shprintzen-Goldberg syndrome. Am J Med Genet. 1995;57:565–72. [PubMed: 7573130]
  • Adès LC, Sullivan K, Biggin A, Haan EA, Brett M, Holman KJ, Dixon J, Robertson S, Holmes AD, Rogers J, Bennetts B. FBN1, TGFBR1, and the Marfan-craniosynostosis/mental retardation disorders revisited. Am J Med Genet A. 2006;140:1047–58. [PubMed: 16596670]
  • Carmignac V, Thevenon J, Adès L, Callewaert B, Julia S, Thauvin-Robinet C, Gueneau L, Courcet JB, Lopez E, Holman K, Renard M, Plauchu H, Plessis G, De Backer J, Child A, Arno G, Duplomb L, Callier P, Aral B, Vabres P, Gigot N, Arbustini E, Grasso M, Robinson PN, Goizet C, Baumann C, Di Rocco M, Sanchez Del Pozo J, Huet F, Jondeau G, Collod-Beroud G, Beroud C, Amiel J, Cormier-Daire V, Rivière JB, Boileau C, De Paepe A, Faivre L. In-frame mutations in exon 1 of SKI cause dominant Shprintzen-Goldberg syndrome. Am J Hum Genet. 2012;91:950–7. [PMC free article: PMC3487125] [PubMed: 23103230]
  • Doyle AJ, Doyle JJ, Bessling SL, Maragh S, Lindsay ME, Schepers D, Gillis E, Mortier G, Homfray T, Sauls K, Norris RA, Huso ND, Leahy D, Mohr DW, Caulfield MJ, Scott AF, Destrée A, Hennekam RC, Arn PH, Curry CJ, Van Laer L, McCallion AS, Loeys BL, Dietz HC. Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nat Genet. 2012;44:1249–54. [PMC free article: PMC3545695] [PubMed: 23023332]
  • Greally MT, Carey JC, Milewicz DM, Hudgins L, Goldberg RB, Shprintzen RJ, Cousineau AJ, Smith WL Jr, Judisch GF, Hanson JW. Shprintzen-Goldberg syndrome: a clinical analysis. Am J Med Genet. 1998;76:202–12. [PubMed: 9508238]
  • Hassed S, Shewmake K, Teo C, Curtis M, Cunniff C. Shprintzen-Goldberg syndrome with osteopenia and progressive hydrocephalus. Am J Med Genet. 1997;70:450–3. [PubMed: 9182791]
  • Kosaki K, Takahashi D, Udaka T, Kosaki R, Matsumoto M, Ibe S, Isobe T, Tanaka Y, Takahashi T. Molecular pathology of Shprintzen-Goldberg syndrome. Am J Med Genet A. 2006;140:104–8. [PubMed: 16333834]
  • Kosaki R, Takahashi D, Udaka T, Matsumoto M, Ibe S, Isobe T, Tanaka Y, Kosaki K. Genetic heterogeneity of Shprintzen-Goldberg syndrome. Abstract 617. Salt Lake City, UT: The American Society of Human Genetics 55th Annual Meeting; 2005.
  • Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, Meyers J, Leitch CC, Katsanis N, Sharifi N, Xu FL, Myers LA, Spevak PJ, Cameron DE, De Backer J, Hellemans J, Chen Y, Davis EC, Webb CL, Kress W, Coucke P, Rifkin DB, De Paepe AM, Dietz HC. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005;37:275–81. [PubMed: 15731757]
  • Robinson PN, Neumann LM, Demuth S, Enders H, Jung U, Konig R, Mitulla B, Muller D, Muschke P, Pfeiffer L, Prager B, Somer M, Tinschert S. Shprintzen-Goldberg syndrome: fourteen new patients and a clinical analysis. Am J Med Genet A. 2005;135:251–62. [PubMed: 15884042]
  • Saal HM, Bulas DI, Allen JF, Vezina LG, Walton D, Rosenbaum KN. Patient with craniosynostosis and marfanoid phenotype (Shprintzen-Goldberg syndrome) and cloverleaf skull. Am J Med Genet. 1995;57:573–8. [PubMed: 7573131]
  • Schrijver I, Liu W, Francke U. The pathogenicity of the Pro1148Ala substitution in the FBN1 gene: causing or predisposing to Marfan syndrome and aortic aneurysm, or clinically innocent? Hum Genet. 1997;99:607–11. [PubMed: 9150726]
  • Sood S, Eldadah ZA, Krause WL, McIntosh I, Dietz HC. Mutation in fibrillin-1 and the Marfanoid-craniosynostosis (Shprintzen-Goldberg) syndrome. Nat Genet. 1996;12:209–11. [PubMed: 8563763]
  • Stheneur C, Collod-Béroud G, Faivre L, Gouya L, Sultan G, Le Parc J-M, Moura B, Attias D, Muti C, Sznajder M, Claustres M, Junien C, Baumann C, Cormier-Daire V, Rio M, Lyonnet S, Plauchu H, Lacombe D, Chevallier B, Jondeau G, Boileau C. Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys-Dietz syndrome and related disorders. Hum Mutat. 2008;29:E284–95. [PubMed: 18781618]
  • Stoll C. Shprintzen-Goldberg marfanoid syndrome: a case followed up for 24 years. Clin Dysmorphol. 2002;11:1–7. [PubMed: 11822698]
  • Sugarman G, Vogel MW. Craniofacial and musculoskeletal abnormalities. A questionable connective tissue disease. Case report 76. Synd Iden. 1981;7:16–7.
  • Tug E, Loeys B, De Paepe A, Aydin H, Gideroglu K. A Turkish patient of typical Loeys-Dietz syndrome with a TGFBR2 mutation. Genet Couns. 2010;21:225–32. [PubMed: 20681224]
  • van Steensel MA, van Geel M, Parren LJ, Schrander-Stumpel CT, Marcus-Soekarman D. Shprintzen-Goldberg syndrome associated with a novel missense mutation in TGFBR2. Exp Dermatol. 2008;17:362–5. [PubMed: 17979970]
  • Watanabe Y, Yano S, Koga Y, Yukizane S, Nishiyori A, Yoshino M, Kato H, Ogata T, Adachi M. P1148A in fibrillin-1 is not a mutation leading to Shprintzen-Goldberg syndrome. Hum Mutat. 1997;10:326–7. [PubMed: 9338588]
  • Whiteman P, Downing AK, Handford PA. NMR analysis of cbEGF domains gives new insights into the structural consequences of a P1148A substitution in fibrillin-1. Protein Eng. 1998;11:957–9. [PubMed: 9876915]

Chapter Notes

Revision History

  • 13 June 2013 (me) Comprehensive update posted live
  • 16 November 2010 (me) Comprehensive update posted live
  • 13 January 2006 (me) Review posted live
  • 2 December 2004 (mtg) Original submission
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