Schinzel-Giedion syndrome is a severe condition that is apparent at birth and affects many body systems. Signs and symptoms of this condition include distinctive facial features, neurological problems, and organ and bone abnormalities. Because of their serious health problems, most affected individuals do not survive past childhood.

Children with Schinzel-Giedion syndrome can have a variety of distinctive features. In most affected individuals, the middle of the face looks as though it has been drawn inward (midface retraction). Other facial features include a large or bulging forehead; wide-set eyes (ocular hypertelorism); a short, upturned nose; and a wide mouth with a large tongue (macroglossia). Affected individuals can have other distinctive features, including larger than normal gaps between the bones of the skull in infants (fontanelles), a short neck, low-set ears, and an inability to secrete tears (alacrima). Babies with Schinzel-Giedion syndrome often have excessive hairiness (hypertrichosis) that usually disappears in infancy.

Children with Schinzel-Giedion syndrome have severe developmental delay. Other neurological problems can include severe feeding problems, seizures, or visual or hearing impairment. They may also experience short pauses in breathing during sleep (sleep apnea).

Affected individuals can also have abnormalities of organs such as the heart, kidneys, or genitals. Heart defects include problems with the heart valves, which control blood flow in the heart; the chambers of the heart that pump blood to the body (ventricles); or the dividing wall between the sides of the heart (the septum). Most children with Schinzel-Giedion syndrome have an accumulation of urine in the kidneys (hydronephrosis), which can occur in one or both kidneys. Affected individuals can have genital abnormalities such as underdevelopment (hypoplasia) of the genitals. Affected boys may have the opening of the urethra on the underside of the penis (hypospadias).

Bone abnormalities are common in people with Schinzel-Giedion syndrome. The bones at the base of the skull are often abnormally hard or thick (sclerotic), or the joint between the bones at the base of the skull (occipital synchondrosis) can be abnormally wide. In addition, affected individuals may have broad ribs, abnormal collarbones (clavicles), inward- and upward-turning feet (clubfeet), or shortened bones in the arms or legs or at the ends of the fingers (hypoplastic distal phalanges).

Children with Schinzel-Giedion syndrome who survive past infancy have a higher than normal risk of developing certain types of brain tumors called neuroepithelial tumors.

Schinzel-Giedion syndrome is very rare, although the exact prevalence is unknown. At least 50 cases of the condition have been reported in the scientific literature.

Schinzel-Giedion syndrome is caused by mutations in the SETBP1 gene. This gene provides instructions for making a protein that attaches (binds) to certain regions of DNA to increase gene activity (expression). The SETBP1 protein is found throughout the body, but protein levels are highest during brain development before birth. During this time, nerve cells grow and divide (proliferate) and move (migrate) to their proper location in the brain. The SETBP1 protein is thought to control the activity of genes involved in these developmental processes.

The SETBP1 gene mutations that have been identified in Schinzel-Giedion syndrome are described as "gain-of-function" mutations because they increase the activity of the SETBP1 protein. Increased SETBP1 activity likely alters the expression of other genes, particularly genes involved in development before birth. Researchers are working to understand how mutations in the SETBP1 gene cause the signs and symptoms of Schinzel-Giedion syndrome.

Genetic Testing Information

• Genetic Testing Registry: Schinzel-Giedion syndrome

Genetic and Rare Diseases Information Center

• Schinzel-Giedion syndrome

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• SCHINZEL-GIEDION MIDFACE RETRACTION SYNDROME

Scientific Articles on PubMed

• PubMed

• Acuna-Hidalgo R, Deriziotis P, Steehouwer M, Gilissen C, Graham SA, van Dam S, Hoover-Fong J, Telegrafi AB, Destree A, Smigiel R, Lambie LA, Kayserili H, Altunoglu U, Lapi E, Uzielli ML, Aracena M, Nur BG, Mihci E, Moreira LM, Borges Ferreira V, Horovitz DD, da Rocha KM, Jezela-Stanek A, Brooks AS, Reutter H, Cohen JS, Fatemi A, Smitka M, Grebe TA, Di Donato N, Deshpande C, Vandersteen A, Marques Lourenco C, Dufke A, Rossier E, Andre G, Baumer A, Spencer C, McGaughran J, Franke L, Veltman JA, De Vries BB, Schinzel A, Fisher SE, Hoischen A, van Bon BW. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies. PLoS Genet. 2017 Mar 27;13(3):e1006683. doi: 10.1371/journal.pgen.1006683. eCollection 2017 Mar. Citation on PubMed or Free article on PubMed Central
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• Atlas of Genetics and Cytogenetics in Oncology and Haematology: Schinzel-Giedion Midface Retraction Syndrome
• Herenger Y, Stoetzel C, Schaefer E, Scheidecker S, Maniere MC, Pelletier V, Alembik Y, Christmann D, Clavert JM, Terzic J, Fischbach M, De Saint Martin A, Dollfus H. Long term follow up of two independent patients with Schinzel-Giedion carrying SETBP1 mutations. Eur J Med Genet. 2015 Sep;58(9):479-87. doi: 10.1016/j.ejmg.2015.07.004. Epub 2015 Jul 15. Citation on PubMed
• Hoischen A, van Bon BW, Gilissen C, Arts P, van Lier B, Steehouwer M, de Vries P, de Reuver R, Wieskamp N, Mortier G, Devriendt K, Amorim MZ, Revencu N, Kidd A, Barbosa M, Turner A, Smith J, Oley C, Henderson A, Hayes IM, Thompson EM, Brunner HG, de Vries BB, Veltman JA. De novo mutations of SETBP1 cause Schinzel-Giedion syndrome. Nat Genet. 2010 Jun;42(6):483-5. doi: 10.1038/ng.581. Epub 2010 May 2. Citation on PubMed
• Lehman AM, McFadden D, Pugash D, Sangha K, Gibson WT, Patel MS. Schinzel-Giedion syndrome: report of splenopancreatic fusion and proposed diagnostic criteria. Am J Med Genet A. 2008 May 15;146A(10):1299-306. doi: 10.1002/ajmg.a.32277. Citation on PubMed
• Liu WL, He ZX, Li F, Ai R, Ma HW. Schinzel-Giedion syndrome: a novel case, review and revised diagnostic criteria. J Genet. 2018 Mar;97(1):35-46. Citation on PubMed
• Piazza R, Magistroni V, Redaelli S, Mauri M, Massimino L, Sessa A, Peronaci M, Lalowski M, Soliymani R, Mezzatesta C, Pirola A, Banfi F, Rubio A, Rea D, Stagno F, Usala E, Martino B, Campiotti L, Merli M, Passamonti F, Onida F, Morotti A, Pavesi F, Bregni M, Broccoli V, Baumann M, Gambacorti-Passerini C. SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub. Nat Commun. 2018 Jun 6;9(1):2192. doi: 10.1038/s41467-018-04462-8. Citation on PubMed or Free article on PubMed Central