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Last updated: 2/5/2024
Years published: 2017, 2024
NORD gratefully acknowledges Kayla Nguyen, NORD Editorial Intern, University of Notre Dame; Joseph Farris, NORD Editorial Intern, University of Notre Dame; Barb Calhoun, MSN, RN, NP, Nurse Practitioner and Outreach Coordinator, Boler-Parseghian Center for Rare and Neglected Diseases at the University of Notre Dame; and Hal Dietz, MD, Victor A. McKusick Professor of Medicine and Genetics, Institute of Genetic Medicine, Investigator, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, for the preparation of this report.
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Summary
Shprintzen Goldberg syndrome (SGS) is an extremely rare connective tissue disorder characterized by craniofacial differences as well as skeletal and cardiovascular deformities. Patients with SGS generally present with premature fusion of cranial bones in infancy (craniosynostosis), widely spaced eyes (hypertelorism), distinctive facial features, receding chin (retrognathia), small lower jaw (micrognathia), highly-arched roof of mouth (high, narrow palate), tall skull (dolichocephaly), low-set and rotated ears, elongated fingers (arachnodactyly) and limbs, flat feet (pes planus), low muscle tone (hypotonia), umbilical and abdominal hernias, intellectual disability and heart problems. In addition, individuals with SGS may have brain anomalies including fluid build-up in the brain (hydrocephalus), dilation of the lateral ventricles, and Chiari 1 malformation, a condition where tissue at the base of the brain extends into the spinal cord.
Heart defects found in patients with SGS may include regurgitation or prolapse of heart valves and aortic root aneurysm. SGS is inherited in an autosomal dominant pattern and typically caused by disease-causing (pathogenic) variants of the SKI gene which is important in cell growth and development. Most patients are the first to have the SKI gene variant (de novo) in their family, and SGS has rarely been found to be inherited. As of 2024, there are fewer than 50 patients described in the medical literature.
Introduction
SGS is often misdiagnosed as Marfan syndrome or Loeys-Dietz syndrome due to the similar facial, skeletal and cardiovascular features. However, intellectual disability is uniquely and strongly associated with SGS, and heart defects tend to be less common and less severe than seen in patients with Marfan syndrome or Loeys-Dietz syndrome.
Most newborns with SGS are born full term and have normal weight, height and head circumference. Symptoms begin to appear in the newborn period. Both males and females are affected equally. Craniosynostosis is a common characteristic of SGS. This early fusion of skull bones prevents the skull from growing normally. Individuals with SGS tend to have mild to moderate intellectual and cognitive disabilities even if they do not have craniosynostosis.
SGS patients have distinctive facial features, including a long, narrow head (dolichocephaly); widely spaced eyes (hypertelorism); protruding eyes (exophthalmos); temporal downslanting of the eyes (downslanting palpebral fissures); a high, narrow palate; a small lower jaw (micrognathia); and low-set ears that are rotated backward. While a highly arched palate can be seen in Marfan syndrome and Loeys-Dietz syndrome, patients with SGS often show enlargement of the palatal shelves or enlarged tissues in the throat, leading to a characteristic “Byzantine arch” appearance.
The physical characteristics of someone with SGS are often said to mimic the “marfanoid habitus” (Marfan features) because their bodies resemble those of individuals with Marfan syndrome. Individuals with SGS have unusually long, slender fingers (arachnodactyly) and limbs, sunken chest (pectus excavatum) or protruding chest (pectus carinatum), flat feet (pes planus), malformation of the first two spine vertebrae C1 and C2 (cervical) and an abnormal side-to-side curvature of the spine (scoliosis). Other skeletal abnormalities include one or more fingers that are permanently bent (camptodactyly) and an unusually large range of joint movement (hypermobility).
SGS patients may also have heart anomalies such as valve regurgitation or prolapse and aortic root dilation and aneurysm. Some individuals with SGS have hernias that can be recurrent. Many SGS patients have abnormally low muscle tone generalized throughout the body (hypotonia). In addition, SGS may contribute to gastrointestinal problems such as constipation and delayed gastric emptying (gastroparesis).
Summary of Symptoms
Facial Features
Bone/Skeletal Abnormalities
Heart/Blood Vessel Issues
Possible Brain Abnormalities
Other Characteristics
Neurologic
Gastrointestinal
Other
SGS is one of many diseases that arise from variants in genes that affect the TGF-β signaling pathway. The TGF-β signaling pathway regulates many aspects of early development and tissue homeostasis, and thus SGS patients and people with related diseases have a variety of physical malformations.
SGS is caused by variants in the SKI gene which codes for a protein known to repress TGF-β signaling. Variants in the SKI gene result in production of altered SKI protein. The precise effect of pathogenic variants in SGS tissues throughout the body is not yet fully understood.
Rare individuals thought to have SGS do not have a SKI gene variant, suggesting that other genes not yet identified may be associated with this condition.
SGS is an autosomal dominant genetic condition. Autosomal dominant disorders occur when only a single copy of a disease-causing gene variant is necessary to cause a particular disease. The gene variant can be inherited from either parent or can be the result of a new variant in the affected individual. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
In many individuals, the disorder is due to a spontaneous (de novo) SKI gene variant that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents. In most patients, the SKI gene variants causing SGS appear to be de novo.
SGS affects males and females in equal numbers and occurs worldwide with no ethnic predisposition. As of 2024, there are 44 known patients with SKI pathogenic variants relating to SGS. Because of the similar symptoms, SGS is often misdiagnosed as Loeys-Dietz or Marfan syndrome. The disorder is probably underdiagnosed, making it difficult to determine its true frequency. It is estimated that fewer than 1,000 people in the U.S. have this disease.
Shprintzen Goldberg syndrome is generally diagnosed after a thorough physical examination and the presence of certain craniofacial, skeletal, cardiovascular and neurologic features, brain anomalies and other characteristics such as minimal subcutaneous fat and defects in the abdominal wall and myopia. There is currently no test for SGS other than identification of a pathogenic variant in the SKI gene through genetic testing. To date, this is the only identified gene associated with SGS. Patients with Marfan syndrome and FBN1 gene variants rarely have craniosynostosis and other distinguishing features of SGS.
Treatment
Treatments for SGS are currently limited to symptom management. Management of SGS is best approached through consultation with a variety of specialists including a clinical geneticist, cardiologist, ophthalmologist, orthopedist, neurodevelopmental specialist and craniofacial team. Treatments are primarily surgical: repair of craniofacial or skeletal malformations may be necessary and beneficial. X-ray of the neck and spine should be done annually to assess for skeletal changes and surgical fusion of the cervical vertebrae C1 and C2 may be needed. MRA (magnetic resonance angiography) or CTA (computed tomography angiography) is recommended every 2-3 years to assess the arterial tree from head to pelvis in patients with SGS. Fortunately, aneurysms are relatively rare in this disorder and vascular surgery is rarely indicated.
An MRI is recommended to evaluate for Chiari 1 malformation. A bone density scan should be performed in all people diagnosed with SGS.
Patients often receive occupational, physical and speech therapy and bracing of feet and/or spine may help with walking. CPAP can be used if a patient suffers from obstructive apnea. An eye exam with an ophthalmologist who specializes in connective tissue disease is recommended yearly and glasses may be prescribed for myopia.
Annual exams with a cardiologist are recommended and medications (beta blocker or angiotensin receptor blocker) should be considered for those patients with severe and progressive abnormal aortic growth. Echocardiograms should be conducted yearly to monitor aortic size and heart function.
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For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Chitran P, Nair Sreela LS, Mathew P, Prasad TS. A rare case of Shprintzen-Goldberg syndrome. J Ayub Med Coll Abbottabad. 2021;33(1):155-158.
Trujillo-Quintero JP, Gabau Vila E, Larrañaga Moreira JM, Ruiz Nel Lo A, Monserrat L, Barriales-Villa R. Shprintzen-Goldberg syndrome and aortic dilatation: apropos of 2 new cases. Rev Esp Cardiol (Engl Ed). 2021;74(6):551-553. doi:10.1016/j.rec.2020.11.006.
Takahashi Y, Watanabe K, Yagi M, et al. Early-onset scoliosis associated with Shprintzen-Goldberg syndrome treated with growing rods and required multiple unplanned surgeries: a case report. Spine Surg Relat Res. 2020;5(3):214-217. Published 2020 Aug 20. doi:10.22603/ssrr.2020-0087.
Hambire C. Shprintzen-Goldberg syndrome with plagiocephaly: A case report. Dent Med Probl. 2019;56(3):307-310. doi:10.17219/dmp/109111.
Yadav S, Rawal G. Shprintzen-Goldberg syndrome: a rare disorder. Pan Afr Med J. 2016;23:227. Published 2016 Apr 25. doi:10.11604/pamj.2016.23.227.7482.
Verstraeten A, Alaerts M, Van Laer L and Loeys B. Marfan syndrome and related disorders: 25 years of gene discovery. Hum Mut. 2016:37(6):524-31. https://www.ncbi.nlm.nih.gov/pubmed/26919284.
Doyle AJ, Doyle JJ, Bessling SL, et al. Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nat Gene 2012:44(11):1249-55. https://www.ncbi.nlm.nih.gov/pubmed/23023332.
INTERNET
Shprintzen-Goldberg syndrome. Genetic and Rare Diseases Information Center. https://rarediseases.info.nih.gov/diseases/4861/shprintzen-goldberg-syndrome. Accessed Feb 1, 2024.
Antley-Bixler syndrome – symptoms, causes, treatment: NORD. National Organization for Rare Disorders. 2019. https://rarediseases.org/rare-diseases/antley-bixler-syndrome/ Accessed Feb 1, 2024.
Greally MT. Shprintzen-Goldberg Syndrome. 2006 Jan 13 [Updated 2020 Apr 9]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1277/ Accessed Feb 1, 2024.
Shprintzen-Goldberg Syndrome. Genetics Home Reference. Reviewed: May, 2016. Available at: https://ghr.nlm.nih.gov/condition/shprintzen-goldberg-syndrome Accessed Feb 1, 2024.
Shprintzen Goldberg Syndrome. The Marfan Foundation. Available at: https://www.marfan.org/shprintzen-goldberg-syndrome Accessed Feb 1, 2024.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Shprintzen Goldberg Syndrome; SGS. Entry No: 1182212. Last Edited12/20/2023. Available at: http://www.omim.org/entry/182212 Accessed Feb 1, 2024.
Donovan’s Disease: An educational website developed by a parent to raise awareness about Shprintzen Goldberg syndrome. http://www.donovansdisease.com/ Accessed Feb 1, 2024.
Shprintzen-Goldberg Syndrome Facebook group: https://www.facebook.com/groups/1391983947709314/ Accessed Feb 1, 2024.
Remarkable Rare podcast on Shprintzen-Goldberg Syndrome from the University of Notre Dame: https://youtube.com/playlist?list=PLBAH6o20g8rCMSkPWQScwr2SlmNn-2iMG&si=AVUBRPasOJ2KX-gf Accessed July 10, 2024.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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