NORD gratefully acknowledges Joseph Farris, NORD Editorial Intern from the 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.
Shprintzen Goldberg syndrome (SGS) is an extremely rare connective tissue disorder characterized by craniofacial, skeletal, and cardiovascular deformities. Patients with SGS generally present with premature fusion of cranial bones in infancy (craniosynostosis), distinctive facial features, elongated fingers and limbs, umbilical and abdominal hernias, developmental delays, intellectual disability, and cardiac 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 caused by the skull at the nape pushing brain tissue into the spinal column. Cardiovascular anomalies found in patients with SGS may include regurgitation or prolapse of the valves and aortic root enlargement and aneurysm. SGS is inherited as an autosomal dominant trait and thought to be caused by changes (mutations) of the SKI gene, important in cell growth and development. Currently, there are fewer than 50 patients described in the medical literature.
SGS is often misdiagnosed as Marfan syndrome or Loeys-Dietz syndrome due to the similar presentation of facial, skeletal and cardiovascular features. However, intellectual disability is uniquely and strongly associated with SGS, and cardiovascular abnormalities tend to be less common and less severe than seen in patients with Marfan syndrome or Loeys-Dietz syndrome.
Most SGS newborns are born full term and have normal weight, height, and head circumference parameters. Both males and females may be affected. Craniosynostosis is a common characteristic of SGS. This early fusion prevents the skull from growing normally. Individuals with SGS tend to have mild to moderate intellectual and cognitive disabilities that can be seen in the absence of craniosynostosis.
SGS patients present with distinctive facial features, including a long, narrow head; widely spaced eyes (hypertelorism); protruding eyes (exophthalmos); outside corners of the eyes that point downward (downslanting palpebral fissures); a high, narrow palate; a small lower jaw (micrognathia); and low-set ears that are rotated backward. While highly arched palate can be seen in Marfan syndrome and Loeys-Dietz syndrome, patients with SGS often show prominence at the base of the palate, leading to a characteristic “Byzantine arch” appearance.
The physical characteristics of 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), 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 present with cardiac anomalies such as valve regurgitation or prolapse and aortic root dilation and aneurysm. Some individuals with SGS present with respiratory distress, abdominal hernias, translucent skin that bruises easily, and hypotonia. In addition, SGS may contribute to gastrointestinal problems such as constipation and delayed gastric emptying (gastroparesis).
Summary of symptoms identified in patients with SGS:
• A long, narrow head (dolichocephaly)
• High prominent forehead
• Widely spaced eyes (hypertelorism)
• Protruding or bulging eyes (exophthalmos, ocular proptosis)
• Wandering eye (strabismus)
• Outside corners of the eyes point downward (down-slanting palpebral fissures)
• Increased angle of the eyelids (telecanthus)
• A high, narrow palate (roof of the mouth
• Wide or split uvula (exceedingly rare when compared to Loeys-Dietz syndrome)
• Under-developed jaw bones (maxillary hypoplasia)
• Small lower jaw (micrognathia)
• Low-set ears that are rotated backward
• Increased angle of the eyelids (telecanthus)
• Smaller than normal tongue (microglossia/retroglossia)
• Premature fusion of one or more sutures of skull (craniosynostosis)
• Abnormalities of the cervical spine (C1 C2)
• Curvature of the spine (scoliosis)
• Slippage of the vertebrae (spondylolisthesis)
• Square-shaped vertebral bodies
• Limbs are unusually long (dolichostenomelia)
• Fingers and toes are unusually long and narrow (arachnodactyly)
• Abnormal bending of joint of finger (camptodactyly)
• Flat feet (pes planus)
• Thin ribs
• 13 pairs of ribs
• Chest wall is “sunken in” or “sticking out” due to abnormal development of breast bone and ribs (pectus excavatum or carinatum)
• Hypermobility of joints
• Malposition of foot (clubfoot)
• Bone loss (osteopenia)
Heart/blood vessel issues noted with SGS
• Mitral valve prolapse
• Mitral and aortic valve regurgitation
• Aortic root enlargement
• Aortic Regurgitation
• Aneurysms in arteries besides the aorta (rare)
Possible brain abnormalities
• Brain anomalies, including water on the brain (hydrocephalus)
• Enlargement (dilatation) of the lateral ventricles
• Brain tissue protrudes into the spinal canal (Chiari 1 malformation)
• Widening of the Dural sac surrounding the spinal cord (dural ectasia)
• Delayed motor and cognitive milestones
• Mild-to-moderate intellectual disability
• Umbilical and abdominal hernias
• Nearsighted vision (myopia)
• Loss of subcutaneous fat
• Loss of respiratory function at puberty (due to skeletal abnormalities)
SGS is one of many diseases that arise from genetic mutations that affect the TGF-β signaling pathway. The TGF-β signaling pathway regulates many aspects of early development, and thus SGS patients and people with related diseases display a variety of physical malformations.
SGS is caused by mutations in the SKI gene, which codes for a protein known to repress TGF-β signaling. Mutations in the SKI gene result in production of altered SKI proteins that allow TGF-β signaling to continue uncontrolled. This leads to abnormal development of many body systems.
Rare individuals thought to have SGS do not have a SKI gene mutation, suggesting that other genes may be associated with this condition that have not yet been identified.
SGS is an autosomal dominant genetic condition. Autosomal dominant disorders occur when only a single copy of an altered gene is necessary to cause a particular disease. The altered gene can be inherited from either parent or can be the result of a new mutation in the affected individual. The risk of passing the altered gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation 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 mutations causing SGS appear to be de novo mutations.
SGS affects males and females in equal numbers and occurs worldwide with no ethnic predisposition. There are currently approximately 40 known patients in the general population. 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.
Shprintzen Goldberg syndrome is generally diagnosed after a thorough physical examination and the presence of certain craniofacial, skeletal, cardiovascular, neurologic features and brain anomalies. There is currently no test for SGS other than identification of mutations in the SKI gene. To date, this is the only identified gene associated with SGS.
Treatments for SGS are currently limited to symptom management. Treatments are primarily surgical: repair of aneurysms and heart valves and correction of craniofacial, spinal, or chest 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 two years to assess from head to pelvis in patients with SGS. 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 ambulation. Feeding may need to come exclusively or be supplemented by a feeding tube. CPAP can be used if patient suffers from obstructive apnea. Tracheostomy or tracheostomy may be needed if airway is obstructed by abnormality in the structure of bone or tissue at the back of nasal passage (choanal atresia). An eye exam with an ophthalmologist that 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 abnormal aortic growth. Echocardiograms should be conducted yearly to monitor aortic size and heart function.
Current investigational therapies have focused on down-regulating the TGF-β pathway after it was identified as the biochemical pathway important for causing SGS and related diseases. These treatments include β-blockers and losartan, which may show the potential to suppress abnormal aortic growth through a variety of potential mechanisms. Early analysis of these treatments has yielded varying results.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll free: (800) 411-1222
TTY: (866) 411-1010
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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
Greally MT. Shprintzen-Goldberg Syndrome. 2006 Jan 13 [Updated 2013 Jun 13]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1277/ Accessed May 1, 2017.
Shprintzen-Goldberg Syndrome. Genetics Home Reference. Reviewed: May, 2016. Available at: https://ghr.nlm.nih.gov/condition/shprintzen-goldberg-syndrome Accessed May 1, 2017.
Shprintzen Goldberg Syndrome. The Marfan Foundation. Available at: https://www.marfan.org/shprintzen-goldberg-syndrome Accessed May 1, 2017.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Shprintzen Goldberg Syndrome; SGS. Entry No: 1182212. Last Edited 08/04/2016. Available at: http://www.omim.org/entry/182212 Accessed May 1, 2017.
Donovan’s Disease: An educational website developed by a parent to raise awareness about Shprintzen Goldberg syndrome. http://www.donovansdisease.com/
Facebook group: https://www.facebook.com/groups/1391983947709314/
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100