Shprintzen-Goldberg syndrome is a disorder comprising craniosynostosis, a marfanoid habitus, and skeletal, neurologic, cardiovascular, and connective tissue anomalies. There appears to be a characteristic facies involving hypertelorism, downslanting palpebral fissures, high-arched palate, micrognathia, and low-set posteriorly rotated ears. ... Shprintzen-Goldberg syndrome is a disorder comprising craniosynostosis, a marfanoid habitus, and skeletal, neurologic, cardiovascular, and connective tissue anomalies. There appears to be a characteristic facies involving hypertelorism, downslanting palpebral fissures, high-arched palate, micrognathia, and low-set posteriorly rotated ears. Other commonly reported manifestations include hypotonia, developmental delay, and inguinal or umbilical hernia; the most common skeletal manifestations are arachnodactyly, pectus deformity, camptodactyly, scoliosis, and joint hypermobility (summary by Robinson et al., 2005). There is considerable phenotypic overlap between SGS and Marfan syndrome (MFS; 154700) and Loeys-Dietz syndrome (LDS; see 609192): SGS includes virtually all of the craniofacial, skeletal, skin, and cardiovascular manifestations of MFS and LDS, with the additional findings of mental retardation and severe skeletal muscle hypotonia (summary by Doyle et al., 2012).
In 2 unrelated boys, Shprintzen and Goldberg (1982) described a 'new' syndrome of craniosynostosis associated with severe exophthalmos, maxillary and mandibular hypoplasia, soft tissue hypertrophy of the palatal shelves, low-set ears with soft and pliable auricles, multiple abdominal ... In 2 unrelated boys, Shprintzen and Goldberg (1982) described a 'new' syndrome of craniosynostosis associated with severe exophthalmos, maxillary and mandibular hypoplasia, soft tissue hypertrophy of the palatal shelves, low-set ears with soft and pliable auricles, multiple abdominal hernias, arachnodactyly, and camptodactyly. Functional disorders included infantile hypotonia, developmental delay, mental retardation, and obstructive apnea. The marked soft tissue of the palatal shelves created a 'pseudocleft' of the palate. Pectus carinatum was present in one of the boys and pectus excavatum in the other. Gorlin et al. (1990) discussed Shprintzen-Goldberg syndrome (SGS) and related syndromes. Ades et al. (1995) delineated the distinct skeletal abnormalities of the Shprintzen-Goldberg syndrome on the basis of 4 affected girls. Three of them showed bowing of long bones (with a variable degree of progression over time), flare of the metaphyses, a large anterior fontanel with persistent patency into the second to fourth years of life, 13 pairs of ribs, distinct vertebral abnormalities that were absent neonatally but evolved by the second year of life, and progressive osteopenia. Communicating hydrocephalus was present in all 4 cases. Arachnodactyly was illustrated as well as a superior folding of the helix of the ear, reminiscent of that in congenital contractural arachnodactyly (121050). Two of the patients were monozygotic twin girls and another sister was case 4. Apart from this family, all known cases were sporadic. The 3 sibs were products of a nonconsanguineous union, and there had been no previous documented instance of parental consanguinity. Ades et al. (1995) concluded that SGS is probably a generalized connective tissue dysplasia. Saal et al. (1995) reported another female patient with the craniosynostosis and marfanoid phenotype. The disorder was detected prenatally by the presence of a cloverleaf skull. She also had choanal atresia and stenosis. One of the patients reported by Ades et al. (1995) had intestinal malrotation and anteriorly placed anus. Shah et al. (1996) reported an Indian patient with the association of Marfan syndrome (with a dilated aortic root and atlantoaxial dislocation) and the fusion of coronal and sagittal skull sutures. Hassed et al. (1997) described a boy with Shprintzen-Goldberg syndrome, presumably the twelfth patient to be reported. In addition to the commonly described anomalies of individuals with SGS, this patient also had cranial asymmetry, hypotonia, osteopenia, and hydrocephalus. Greally et al. (1998) presented 4 new patients with SGS and reviewed 1 of the patients in the original report of Shprintzen and Goldberg (1982). They concluded that radiologic investigations are particularly helpful in differentiating SGS from other syndromes with craniosynostosis and marfanoid habitus. Abnormality of the first and second cervical vertebrae, hydrocephalus, dilatation of the lateral ventricles, and a Chiari-I malformation of the brain were found only in the patients with Shprintzen-Goldberg syndrome. Pectus excavatum and striking arachnodactyly were pictured. Stoll (2002) reported a 24-year follow-up of a patient with SGS. Dysmorphic features were noted in infancy and became more pronounced over time. These included brachycephaly, posteriorly rotated floppy ears, shallow orbits, hypertelorism, midfacial hypoplasia, a narrow palate, sagittal synostosis, arachnodactyly, camptodactyly, pectus excavatum, scoliosis, bilateral inguinal and crural hernias, fragile skin, and lack of subcutaneous fat. Pectus excavatum was severe and scoliosis worsened during adolescence. Foot deformities included hallux varus, metatarsophalangeal dislocation, hammertoes and tarsometatarsal dislocation. There was also bilateral dislocation of the radial heads. Myopia was present and worsened over time. Height and weight were reduced initially but final adult height was normal. Puberty was delayed. Despite initial psychomotor developmental delay, the patient had no resulting mental retardation. No mutation was found in the gene encoding fibrillin-1. Loeys et al. (2005) compared the clinical features of their series of cases with the Loeys-Dietz syndrome with that of SGS as presented by Greally et al. (1998) and with Marfan syndrome. Cleft palate/bifid uvula was present in 100% of cases of LDS, in none of the MFS patients, and in 1 of 15 SGS cases. Aortic root aneurysm was present in 16 of 16 cases of LDS and 2 of 15 of SGS. Arterial tortuosity was present in 11 of 11 LDS cases and was not associated with the other 2 conditions. Blue sclerae were present in 8 of 13 LDS patients and were not associated with the other 2 conditions. Ectopia lentis was not present in any of the 16 cases of LDS. Patent ductus arteriosus and atrial septal defect were present in 54% and 31%, respectively, of LDS cases but were not associated with the other 2 conditions. Robinson et al. (2005) reported 13 unrelated patients and 1 sib with SGS and compared their clinical findings with those of 23 previously reported individuals. They suggested that there is a characteristic facial appearance, with more than two-thirds of all individuals having hypertelorism, downslanting palpebral fissures, a high-arched palate, micrognathia, and apparently low-set and posteriorly rotated ears. The related disorders SGS and Furlong syndrome (LDS; see 609192) feature marfanoid habitus and craniosynostosis. Megarbane and Hokayem (1998) suggested dividing craniosynostosis with marfanoid habitus into 2 types: type 1, with mental retardation (SGS), and type 2, with normal intelligence and aortic root anomalies (Furlong syndrome). Ades et al. (2006) questioned the diagnosis of SGS in one of the patients of Greally et al. (1998) and in the patient of Stoll (2002).
Doyle et al. (2012) performed whole-exome sequencing in a woman with Shprintzen-Goldberg syndrome and her unaffected parents and identified only 1 variant, a de novo heterozygous missense mutation in the SKI gene (G116E; 164780.0001). The mutation was not ... Doyle et al. (2012) performed whole-exome sequencing in a woman with Shprintzen-Goldberg syndrome and her unaffected parents and identified only 1 variant, a de novo heterozygous missense mutation in the SKI gene (G116E; 164780.0001). The mutation was not present in the unaffected parents or in SNP databases. Subsequent sequencing of SKI in 11 more sporadic cases of SGS revealed heterozygous variants in 9 of the patients, including 7 missense mutations and a 9-bp deletion (see, e.g., 164780.0002-164780.0005). The mutations were not found in SNP databases or in the unaffected parents in the 5 cases in which parental DNA was available. All 10 mutation-positive patients had skeletal muscle hypotonia and developmental delay; 8 of the 10 also had aortic root dilation, 1 had arterial tortuosity, and 2 had splenic artery aneurysm, which spontaneously ruptured in 1 patient. Doyle et al. (2012) stated that despite near-complete phenotypic overlap between Loeys-Dietz syndrome and SGS, the aneurysm phenotype in SGS is less penetrant, less diffuse (generally restricted to the aortic root), and less severe than that seen in LDS. Cultured dermal fibroblasts from mutation-positive SGS patients showed enhanced activation of TGF-beta (TGFB1; 190180) signaling cascades and higher expression of TGF-beta-responsive genes relative to control cells. Doyle et al. (2012) concluded that increased TBF-beta signaling is the mechanism underlying SGS and that high signaling contributes to multiple syndromic presentations of aortic aneurysm. In 18 of 19 patients with characteristic features of SGS who were negative for mutation in the FBN1 (134797), TGFBR1 (190181), and TGFBR2 (190182) genes, including 5 affected individuals over 3 generations in 1 family and another family in which 3 sibs were affected, Carmignac et al. (2012) identified heterozygosity for 2 different in-frame deletions and 10 missense mutations in the SKI gene (see, e.g., 164780.0002, 164780.0004, 164780.0005, and 164780.0007-164780.0010). No SKI mutations were found in a cohort of 11 patients with other marfanoid craniosynostosis syndromes. Carmignac et al. (2012) noted that 3 of the 18 patients with SKI mutations had aortic dilation, 1 of whom also had vertebrobasilar and internal carotid tortuosity and a dilated pulmonary artery root, further highlighting the overlap between SGS and LDS; however, all of the patients with SKI mutations had intellectual disability, supporting the hypothesis that they are distinct syndromes. In patients with Marfan syndrome (154700) who also had features of Shprintzen-Goldberg syndrome, including craniosynostosis and mental retardation, Sood et al. (1996) and Kosaki et al. (2006) identified heterozygous mutations in the FBN1 gene (134707.0022 and 134707.0045). Doyle et al. (2012) stated that it may be significant that both of the identified mutations reside in the same EGF-like domain of fibrillin.
The diagnosis of Shprintzen-Goldberg syndrome (SGS) is suspected in individuals with a combination of the following major characteristics:...
DiagnosisClinical DiagnosisThe 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 suturesCraniofacial findings Dolichocephaly with or without scaphocephaly Tall or prominent forehead Ocular proptosis Widely spaced eyesDownslanted palpebral fissuresMalar flattening High narrow palate with prominent palatine ridges Micrognathia and/or retrognathia Apparently low-set and posteriorly rotated earsSkeletal findings Dolichostenomelia Arachnodactyly Camptodactyly Pes planusPectus excavatum or carinatum Scoliosis Joint hypermobility or contracturesFoot malpositionCardiovascular findings Mitral valve prolapse Mitral regurgitation/incompetence Aortic regurgitationDilatation of the aortic rootNeurologic anomalies Delayed motor and cognitive milestones Mild-to-moderate intellectual disabilityBrain anomalies Hydrocephalus Dilatation of the lateral ventricles Chiari 1 malformationRadiographic findings Craniosynostosis C1-C2 abnormality Wide anterior fontanel Thin ribs 13 pairs of ribs Square-shaped vertebral bodies OsteopeniaOtherArterial tortuosityOther aneurysmBroad/bifid uvulaCleft palateClub foot deformityDural ectasiaHerniasLoss of subcutaneous fatMyopiaMolecular Genetic TestingGene. SKI is the only gene in which mutations are known to cause Shprintzen-Goldberg syndrome. Table 1. Summary of Molecular Genetic Testing Used in Shprintzen-Goldberg syndromeView in own windowGene 1 Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3Test AvailabilitySKISequence analysisSequence variants 4See footnote 5ClinicalDeletion/duplication analysis 6Exonic or whole-gene deletionsUnknown, none reported 71. See Table A. Genes and Databases for chromosome locus and protein name.2. See Molecular Genetics for information on allelic variants. 3. The ability of the test method used to detect a mutation that is present in the indicated gene4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.5. Carmignac et al [2012], Doyle et al [2012]6. Testing that identifies 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.7. 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.Sequence analysis of SKI should be pursued first.If no pathogenic mutation in SKI is found through sequence analysis, deletion/duplication analysis can be considered.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in SKI.
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....
Natural HistoryThe 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 mutations 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].
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]. ...
Differential DiagnosisThe 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 [Loeys & Dietz 2008]. Mutations 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 mutations in TGFBR1 and TGFBR2 in their cohort of patients 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 mutation 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 mutation: 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 mutation.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.Mutations 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 mutation 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 mutations 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 club foot 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 mutations in FLNA have been found in SGS [S Robertson and L Adès, personal communication].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs in an individual diagnosed with Shprintzen-Goldberg syndrome (SGS), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo 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 MRIEchocardiogram 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 indicatedDevelopmental assessmentOphthalmology examination by an ophthalmologist with expertise in connective tissue disordersMedical genetics consultationTreatment of ManifestationsManagement of SGS is best conducted through the coordinated input of a multidisciplinary team of specialists including a medical geneticist, cardiologist, ophthalmologist, orthopedist, cardiothoracic surgeon, and craniofacial team. The following are appropriate:Cardiovascular 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.HerniaSurgical repair of abdominal hernias may be indicated.CraniofacialCleft palate and craniosynostosis require management by a craniofacial team; treatment is the same as in all disorders with these manifestations.SkeletalSurgical 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.PhysiotherapyPhysiotherapy may help increase mobility in individuals with joint contractures.Special educationA developmental assessment will help with placement in a special education center or in a special education program in a regular school.Prevention of Secondary ComplicationsSubacute bacterial endocarditis (SBE) prophylaxis is recommended for dental work or other procedures expected to contaminate the bloodstream with bacteria for individuals with cardiac complications.SurveillanceAll individuals with SGS should be managed by a cardiologist who is familiar with this condition.Agents/Circumstances to AvoidThe 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 decongestantsActivities that cause joint pain or injuryEvaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameHGMDSKI1p36.33Ski oncogeneSKIData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Shprintzen-Goldberg Syndrome (View All in OMIM) View in own window 164780V-SKI AVIAN SARCOMA VIRAL ONCOGENE HOMOLOG; SKI 182212SHPRINTZEN-GOLDBERG CRANIOSYNOSTOSIS SYNDROME; SGSNormal allelic variants. The proto-oncoprotein, SKI, has seven exons; the transcript variant is 5,707 bps. Pathologic allelic variants. In their report of patients with SGS, Doyle et al [2012] found mutations in exon 1 of SKI in all ten patients: nine missense mutations 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]. Mutations in exon 1 of SKI were found in 18 of the 19 patients 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 missense mutations 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 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 mutations 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 mutations 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. Mutations 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 mutations 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.