Clinical characteristics.

Shprintzen-Goldberg syndrome (SGS) is characterized by: delayed motor and cognitive milestones and mild-to-moderate intellectual disability; craniosynostosis of the coronal, sagittal, or lambdoid sutures; distinctive craniofacial features; and musculoskeletal findings including olichostenomelia, arachnodactyly, camptodactyly, pectus excavatum or carinatum, scoliosis, joint hypermobility or contractures, pes planus, foot malposition, and C1-C2 spine malformation. Cardiovascular anomalies may include mitral valve prolapse, secundum atrial septal defect, and aortic root dilatation. Minimal subcutaneous fat, abdominal wall defects, and myopia are also characteristic findings.

Diagnosis/testing.

The diagnosis of SGS is established in a proband with a heterozygous pathogenic variant in SKI identified by molecular genetic testing.

Management.

Treatment of manifestations: Early intervention for developmental delay with placement in special education programs; standard management of cleft palate and craniosynostosis; surgical fixation may be necessary for cervical spine instability; routine management for scoliosis; surgical correction for pectus excavatum is rarely indicated; physiotherapy for joint contractures; clubfoot deformity may require surgical correction. 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; treatment of myopia as per ophthalmologist; surgical repair of abdominal hernias as indicated.

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

Surveillance: Developmental assessment with each visit; cervical spine evaluation and clinical evaluation for scoliosis as recommended by orthopedist; imaging per cardiologist familiar with this condition; ophthalmology exams as recommended by ophthalmologist.

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.

SGS, caused by a heterozygous pathogenic variant in SKI, is an autosomal dominant disorder. 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. Once a SKI pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

SGS should be suspected in individuals with a combination of the following clinical (see Figure 1) and radiographic features:

Figure 1.

Clinical features of Shprintzen-Goldberg syndrome. Note craniosynostosis with typical craniofacial features including dolichocephaly, proptosis, hypertelorism, low-set ears, and retrognathia. Hand and foot images show arachnodactyly and camptodactyly. (more...)

• Neurodevelopment. Hypotonia, delayed motor and cognitive milestones, mild-to-moderate intellectual disability
• Craniosynostosis usually involving the coronal, sagittal, or lambdoid sutures
• Craniofacial findings
  • Dolichocephaly with or without scaphocephaly
  • Tall or prominent forehead
  • Hypertelorism
  • Downslanting palpebral fissures
  • Ocular proptosis
  • Malar flattening
  • High narrow palate with prominent palatine ridges
  • Micrognathia and/or retrognathia
  • Apparently low-set and posteriorly rotated ears
• Musculoskeletal findings
  • Dolichostenomelia
  • Arachnodactyly
  • Camptodactyly
  • Pectus excavatum or carinatum
  • Scoliosis
  • Joint hypermobility or contractures
  • Pes planus
  • Foot malposition/talipes equinovarus/club foot
  • C1-C2 spine malformation
• Cardiovascular anomalies. Mitral valve prolapse/valvular anomalies, secundum atrial septal defect, aortic root dilatation
• Brain anomalies. Chiari I malformation
• Other. Minimal subcutaneous fat, abdominal wall defects, and myopia

Establishing the Diagnosis

The diagnosis of SGS is established in a proband with a heterozygous pathogenic (or likely pathogenic) variant in SKI 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 section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous SKI variant of uncertain significance 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) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of SGS is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with craniosynostosis and additional congenital anomalies are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

To date, 44 individuals have been identified with a pathogenic variant in SKI [Carmignac et al 2012, Doyle et al 2012, Au et al 2014, Schepers et al 2015, Saito et al 2017, O'Dougherty et al 2019, Zhang et al 2019]. The following description of the phenotypic features associated with this condition is based on these reports.

Neurodevelopment. Motor and cognitive milestones are delayed and intellectual disability is usually mild to moderate. To date, three individuals with Shprintzen-Goldberg syndrome (SGS) and a confirmed SKI pathogenic variant were reported to have normal intelligence [Doyle et al 2012, Schepers et al 2015, Zhang et al 2019].

Craniosynostosis usually involves the coronal, sagittal, or lambdoid sutures. The sutures are fused at birth and craniosynostosis can usually be suspected from the abnormal skull shape. A single suture or multiple sutures may be involved [Au et al 2014]. Information on individuals with SGS who underwent surgery for craniosynostosis in unavailable.

Characteristic craniofacial features include hypertelorism, downslanting palpebral fissures, ocular proptosis, high narrow palate, micrognathia, and low-set posteriorly rotated ears. Cleft palate was reported in three of 17 individuals with SGS [Doyle et al 2012, Schepers et al 2015, O'Dougherty et al 2019]. Broad/bifid uvula has been reported in two of 12 individuals [Doyle et al 2012, O'Dougherty et al 2019].

Musculoskeletal. Arachnodactyly, camptodactyly, pectus deformities, and clubfeet are common features and are present at birth. Joint contractures are often present at birth or in the neonatal period, with the ankle joint most frequently affected [Au et al 2014, Saito et al 2017]. Joint hypermobility also occurs in individuals with SGS and is typically present from birth. Joint dislocation and instability reported by O'Dougherty et al [2019] included involvement of the left patella, thumb, and foot and C1-C2 instability. Au et al [2014] reported subluxing patellae. Pes planus becomes evident later in childhood; one or both feet may be affected. Scoliosis may be severe [Au et al 2014].

Cardiovascular. Aortic root dilatation was present in three of 18 affected individuals reported by Carmignac et al [2012]. 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 with or without 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.

Ocular. Myopia was reported in ten of 19 individuals [Carmignac et al 2012, Au et al 2014, O'Dougherty et al 2019]. Ectopia lentis has not been reported in the 16 individuals with SGS who were evaluated for this finding [Doyle et al 2012, Schepers et al 2015].

Minimal subcutaneous fat and/or marfanoid habitus was reported in nine of 20 individuals [Carmignac et al 2012, Au et al 2014].

Abdominal wall defects were reported in 14 of 23 individuals [Carmignac et al 2012, Au et al 2014, Schepers et al 2015, Saito et al 2017, O'Dougherty et al 2019].

Other

• Dural ectasia (5/8 individuals) [Doyle et al 2012, Schepers et al 2015, O'Dougherty et al 2019]
• Chiari I malformation (2/3 individuals) [Au et al 2014, O'Dougherty et al 2019]
• Cryptorchidism (1/1 male) [Saito et al 2017]

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Penetrance

Penetrance is unknown.

Nomenclature

Goldberg-Shprintzen syndrome and Shprintzen-Goldberg omphalocele syndrome are separate syndromes, not related to SGS.

Other names that have been used to refer to SGS:

• Craniosynostosis with arachnodactyly and abdominal hernias
• Marfanoid-craniosynostosis syndrome
• Shprintzen-Goldberg craniosynostosis syndrome
• Shprintzen-Goldberg marfanoid syndrome

The term Furlong syndrome has been used to describe one individual with craniosynostosis, features of SGS, normal intelligence, and aortic enlargement. Adès et al [2006] 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 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.

Prevalence

SGS is a rare disorder and the prevalence is unknown. A SKI pathogenic variant has been identified in 44 individuals with SGS to date.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Shprintzen-Goldberg syndrome (SGS), the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

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.

Prevention of Secondary Complications

For individuals with cardiac complications, subacute bacterial endocarditis prophylaxis is recommended for dental work or other procedures expected to contaminate the bloodstream with bacteria.

Surveillance

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 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

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

Risk to Family Members

Parents of a proband

• To date, most probands diagnosed with SGS represent simplex cases (i.e., a single occurrence in a family) and are assumed to have the disorder as a result of a de novo pathogenic variant.
• Rarely, an individual diagnosed with SGS has the disorder as the result of an inherited pathogenic variant. Recurrence of SGS was reported in a three-generation family with SGS [Carmignac et al 2012] (family 3).
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Parental germline mosaicism could explain familial recurrence with unaffected parents. See Carmignac et al [2012] (family 4: individuals 8, 9, 10), Schepers et al [2015] (individuals 10, 11).
• The family history of some individuals diagnosed with SGS may appear to be negative because of a milder phenotypic presentation in an affected family member. Therefore, an apparently negative family history cannot be confirmed until appropriate clinical evaluation and/or molecular genetic testing has been performed.
• If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.

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

• If a parent of the proband is heterozygous for the pathogenic variant identified in the proband, the risk to the sibs is 50%. Multigenerational familial recurrence of SGS is rare but has been reported [Carmignac et al 2012].
• If the proband has a known SKI pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Carmignac et al 2012, Schepers et al 2015].
• If the parents have not been tested for the SKI pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for SGS because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.

Offspring of a proband. Each child of an individual with SGS has a 50% chance of inheriting the pathogenic variant and having SGS.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, members of the parent's family 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 identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

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 at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the SKI pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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

Molecular Pathogenesis

SKI encodes the nuclear protooncogene protein homolog of avian sarcoma viral (v-ski) oncogene, which functions as a repressor of TGF-β signaling. The SKI family of proteins negatively regulate SMAD-dependent TGF-β signaling by 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.

The SKI oncogene is present in all cells, and is commonly active during development. It has a 728 amino-acid sequence with multiple domains and is expressed both inside and outside the cell. The different domains have different functions, including interaction with SMAD proteins.

Mechanism of disease causation. Cultured dermal fibroblasts from individuals with molecularly confirmed SGS showed enhanced activation of TGF-β signaling cascades and higher expression of TGF-β-responsive genes relative to control cells. Doyle et al [2012] concluded that increased TBF-β signaling is the mechanism underlying SGS.

TGF-β signaling is crucial to normal development and maintenance of various organs, including the vasculature. SKI exerts a negative regulatory effect on TGF-β signaling by interacting with other cellular partners, such as SMAD proteins and transcriptional co-regulators. All pathogenic variants of SKI are located in exon 1 and cluster into two domains: the R-SMAD binding domain and daschund homology domain (DHD). Zebrafish studies indicate that SKI plays crucial roles in aortic morphogenesis and homeostasis, and that aortic aneurysm formation in individujals with SGS is a result of increased TGF-β signaling, similar to aortopathies in Marfan syndrome and Loeys-Dietz syndrome [Takeda et al 2018]. For a review of the regulatory effects of transcriptional cofactors Ski (Sloan-Kettering Institute) and SnoN (Ski novel) on the TGF-β signaling pathway in health and disease, see Tecalco-Cruz et al [2018].

SKI-specific laboratory technical considerations. The majority of pathogenic variants are missense and are located in exon 1 of SKI [Carmignac et al 2012]. A mutational hot spot has been identified in the R-SMAD domain of exon 1 with 24 (73%) of 33 unrelated individuals having a pathogenic variant within a stretch of five residues (from Ser31 to Pro35). A smaller number of individuals with pathogenic variants in the DHD domain have been reported, suggesting a second mutational hotspot in this domain [Zhang et al 2019].

Revision History

• 9 April 2020 (sw) Comprehensive update posted live
• 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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