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, including dolichocephaly, high prominent forehead, ocular proptosis, hypertelorism, telecanthus, downslanting palpebral fissures, maxillary hypoplasia, high narrow palate with prominent palatine ridges, micrognathia, and apparently low-set and posteriorly rotated ears

• Skeletal findings, including dolichostenomelia, arachnodactyly, camptodactyly, pes planus, pectus excavatum or carinatum, scoliosis, joint hypermobility, or contractures

• Cardiovascular findings, including mitral valve prolapse, mitral regurgitation, and aortic regurgitation
  Note: Current studies suggest that aortic root dilatation is not part of Shprintzen-Goldberg syndrome.

• Neurologic anomalies, including delayed motor and cognitive milestones and mild-to-moderate intellectual disability

• Brain anomalies, including hydrocephalus, dilatation of the lateral ventricles, and Chiari 1 malformation

• Radiographic findings, including craniosynostosis, C1-C2 abnormality, wide anterior fontanel, thin ribs,13 pairs of ribs, square-shaped vertebral bodies, and osteopenia

Molecular Genetic Testing

Gene. Unknown

FBN1. 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 patient 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 patient described by Kosaki et al [2006] with the p.Cys1223Tyr allele had craniosynostosis, dolichocephaly, mild exophthalmos, downslanting 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. This patient was therefore 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].

• The other individual reported by Kosaki et al [2006] had a mutation in TGFBR2 and appeared to have Loeys-Dietz syndrome rather than SGS.

Adès et al [2005] found no FBN1 mutations in their patients with a clinical diagnosis of SGS.

TGFBR1 and TGFBR2. Adès et al [2005] and Loeys et al [2005] found no mutations in TGFBR1 and TGFBR2 in individuals with SGS.

The phenotype of the patient 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 patient; thus, despite the absence of arterial tortuosity, it appears to be more likely that this individual had Loeys-Dietz syndrome (LDS) rather than SGS.

Stheneur et al [2008] reported on the phenotype of patients with aTGFBR1 or TGFBR2 mutation: one person referred with a diagnosis of SGS because of craniosynostosis, ocular hypertelorism, retrognathia, malar hypoplasia, and developmental delay was found to have a TRGFBR1 mutation.

Natural History

Shprintzen-Goldberg syndrome (SGS) is characterized by craniosynostosis, distinctive craniofacial features, skeletal changes, and neurologic and brain anomalies (see Clinical Diagnosis). Cardiovascular anomalies may occur but aortic root dilatation is most likely not found in individuals meeting the diagnostic criteria for SGS. Minimal subcutaneous fat, abdominal wall defects, cryptorchidism in males, and myopia are also 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].

Although reported in a few individuals with Shprintzen-Goldberg syndrome [Greally et al 1998], dilatation of the aorta does not appear to be present in the majority of affected individuals.

In addition to the characteristic skeletal findings, some affected individuals had 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 [Adès et al 1995].

Additional 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], and abdominal hernia [Stoll 2002, Robinson et al 2005].

Genotype-Phenotype Correlations

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

Penetrance

Penetrance is unknown.

Anticipation

Anticipation is not observed in Shprintzen-Goldberg syndrome.

Nomenclature

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 features of SGS, normal intelligence, and aortic enlargement [Adès, personal communication]. It remains unclear whether this represents a distinct clinical entity.

Prevalence

Approximately 42 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.

Evaluations Following Initial Diagnosis

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

• Skeletal survey including skull series

• Brain MRI

• Echocardiogram

• Surgical evaluation for hernia repair, if indicated

Treatment of Manifestations

The following are appropriate:

• Surgical repair of abdominal hernias

• Physiotherapy to increase mobility in individuals with joint contractures

• 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.

Surveillance

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

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 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.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC)
Phone: 800-334-8571 ext. 24640
Email: gentac-registry@rti.org
Web: www.gentac.rti.org

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

The mode of inheritance of Shprintzen-Goldberg syndrome (SGS) is unknown.

Risk to Family Members

Parents of a proband

• To date, most probands with SGS have been simplex cases, i.e., the only affected individual in their families, with the exception of one family in which three siblings were affected [Adès et al 1995].

• Parents of a proband are not affected.

Sibs of a proband

• Familial recurrences of SGS are rare but have been reported [Adès et al 1995, Robinson et al 2005]. Germline mosaicism for a new autosomal dominant mutation, autosomal recessive inheritance, or a cryptic structural abnormality of a chromosome could explain familial recurrence with unaffected parents.

• The risk to sibs of a proband is small, but greater than that of the general population.

Offspring of a proband. 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].

Related Genetic Counseling Issues

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for SGS is not possible at this time.

Literature Cited

1. 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, p.104. Ghent, Belgium: Seventh International Symposium on the Marfan Syndrome; 2005.
2. 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]
3. 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]
4. Greally MT, Carey JC, Milewicz DM, Hudgins L, Goldberg RB, Shprintzen RJ, Cousineau AJ, Smith WL, Judisch GF, Hanson JW. Shprintzen-Goldberg syndrome: a clinical analysis. Am J Med Genet. 1998;76:202–12. [PubMed: 9508238]
5. 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]
6. 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]
7. 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: The American Society of Human Genetics 55th Annual Meeting; 2005.
8. 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]
9. Loeys BL, Dietz HC. Loeys-Dietz syndrome. In: Pagon RA, Bird TC, Dolan CR, Stephens K, eds. GeneReviews at GeneTests: Medical Genetics Information Resources [Internet]. Copyright University of Washington, Seattle. 1997-2010. Available at http://www.ncbi.nlm.nih.gov. 2008. Accessed 12-13-11.
10. 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]
11. 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]
12. 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]
13. 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]
14. 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]
15. Stoll C. Shprintzen-Goldberg marfanoid syndrome: a case followed up for 24 years. Clin Dysmorphol. 2002;11:1–7. [PubMed: 11822698]
16. Sugarman G, Vogel MW. Craniofacial and musculoskeletal abnormalities. A questionable connective tissue disease. Case report 76. Synd Iden. 1981;7:16–7.
17. 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]
18. 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]
19. 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]
20. 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]

Revision History

• 16 November 2010 (me) Comprehensive update posted live

• 13 January 2006 (me) Review posted to live Web site

• 2 December 2004 (mtg) Original submission