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Last updated: 8/7/2023
Years published: 1991, 1999, 2007, 2008, 2012, 2015, 2018, 2023
NORD gratefully acknowledges Michael J. Lyons, MD, Associate Clinical Geneticist, Greenwood Genetic Center, for assistance in the preparation of this report.
FG syndrome type 1 (FGS1) is an X-linked genetic disorder that is characterized by poor muscle tone (hypotonia), intellectual disability, constipation and or anal anomalies and complete or partial absence of the part of the brain that connects the two hemispheres of the brain (corpus callosum). Other features of the disorder are small and simple ears, tall and prominent forehead, wide and flat thumbs and great toes and down slanting eyes. FGS1 is an X-linked genetic disorder typically caused by a change (variant or mutation) in the MED12 gene. The spectrum of disorders caused by variants in this gene is still being defined. Some individuals previously diagnosed with FGS1 do not have a MED12 gene variant and, therefore, probably have a different reason for intellectual disability.
FG syndrome type 1 (FGS1) is an X-linked genetic disorder that is characterized by poor muscle tone (hypotonia), intellectual disability, constipation and or anal anomalies and complete or partial absence of the part of the brain that connects the two hemispheres of the brain (corpus callosum). Other features of the disorder are small and simple ears, tall and prominent forehead, wide and flat thumbs and great toes and down slanting eyes. Additional features may include a large head (macrocephaly), widely spaced eyes (ocular hypertelorism) and upswept frontal hair. Seizures and congenital heart defects have also been reported.
Individuals with FGS1 often have characteristic behaviors that can include hyperactivity, friendliness and attention seeking.
FGS1 is typically caused by a variant in the MED12 gene on the X chromosome located at Xq13.1. The MED12 gene is responsible for production of the MED12 (TRAP230) protein that is involved in the regulation of transcription.
FGS1 is an X-linked genetic disorder. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and occur mostly in males. Females that have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes, and one is inactivated so that the genes on that chromosome are nonfunctioning. It is usually the X chromosome with the abnormal gene that is inactivated. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease gene, he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
Males with X-linked disorders pass the disease gene to all of their daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
The prevalence of FGS1 is unknown. The spectrum of disorders caused by variants in this gene is still being defined. Some individuals previously diagnosed with FGS1 do not have a MED12 gene variant and, therefore, probably have a different reason for intellectual disability.
FGS1 syndrome is suspected based on the presence of physical characteristics. Molecular genetic testing for the MED12 gene is available and is the only way to confirm the diagnosis.
Treatment
The symptoms of FGS1 syndrome are treated individually. This usually involves care by a team of healthcare providers including a pediatrician, neurologist, cardiologist, surgeon, gastroenterologist and psychologist. Early intervention with physical, occupational and speech therapy should be initiated as soon as possible.
Genetic counseling is recommended for affected individuals and their family members.
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 web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
FG Syndrome Type 1 Resources
TEXTBOOKS
Graham JM Jr. FG Syndrome In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:193-4.
JOURNAL ARTICLES
Maia N, Ibarluzea N, Misra-Isrie M, Koboldt DC, Marques I, Soares G, Santos R, Marcelis CLM, Keski-Filppula R, Guitart M, Gabau Vila E, Lehman A, Hickey S, Mori M, Terhal P, Valenzuela I, Lasa-Aranzasti A, Cueto-Gonzalez AM, Chhouk BH, Yeh RC, Neil JE, Abu-Libde B, Kleefstra T, Elting MW, Csaszar A, Karteszi J, Bessenyei B, van Bokhoven H, Jorge P, van Hagen JM, de Brouwer APM. Missense MED12 variants in 22 males with intellectual disability: From nonspecific symptoms to complete syndromes. Am J Med Genet A 2023 Jan;191(1):135-143.
Srivastava S, Niranjan T, May MM, Tarpey P, Allen W, Hackett A, Jouk PS, Raymond L, Briault S, Skinner C, Toutain A, Gecz J, Heath W, Stevenson RE, Schwartz CE, Wang T. Dysregulations of sonic hedgehog signaling in MED12-related X-linked intellectual disability disorders. Mol Genet Genomic Med. 2019 Apr;7(4):e00569.
Narayanan DL, Phadke SR. A novel variant in MED12 gene: Further delineation of phenotype. Am J Med Genet A. 2017 Aug;173(8):2257-60.
Prontera P, Ottaviani V, Rogaia D, et al. A novel MED12 mutation: Evidence for a fourth phenotype. Am J Med Genet A. 2016 Sep;170(9):2377-82.
Isidor B, Lefebvre T, Le Vaillant C, et al. Blepharophimosis, short humeri, developmental delay and Hirschsprung disease: expanding the phenotypic spectrum of MED12 mutations. Am J Med Genet A 2014 164A:1821-5.
Lesca G, Moizard MP, Bussy G, et al. Clinical and neurocognitive characterization of a family with a novel MED12 gene frameshift mutation. Am J Med Genet A. 2013 Dec;161A(12):3063-71.
Vulto-van Silfhout AT, de Vries BB, van Bon BW, et al. Mutations in MED12 cause X-linked Ohdo syndrome. Am J Hum Genet. 2013 92:401-6.
Graham JM Jr, Schwartz CE. MED12 related disorders. Am J Med Genet A. 2013 Nov;161A(11):2734-40.
Rump P, Niessen RC, Verbruggen KT, et al. A novel mutation in MED12 causes FG syndrome (Opitz-Kaveggia syndrome). Clin Genet. 2011 Feb;79(2):183-8.
Clark RD, Graham JM Jr, et al. FG syndrome, an X-linked multiple congenital anomaly syndrome: The clinical phenotype and an algorithm for diagnostic testing. Genet Med. 2009 Nov;11(11):769-77.
Risheg H, Graham JM, Clark RD, et al. A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome. Nat Genet 2007;39:451-3.
Schwartz CE, Tarpay PS, Lubs HA, et al. The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene. J Med Genet A 2007;44:472-7.
Battaglia A, Chines C and Carey JC. The FG syndrome: Report of a large Italian series. Am J Med Genet 2006;140A:2075-9.
Jehee, FS, Rosenberg C, Krepischi-Santos, AC, et al. An Xq22.3 duplication detected by comparative genomic hybridization microarray (Array-CGH) defines in a new locus (FGS5) for FG syndrome. Am J Med Genet 2005;139A:221-6.
Piluso G, Carella M, DโAvanzo M, et al. Genetic heterogeneity of FG syndrome: a fourth locus (FGS4) maps to Xp11.4-p11.3 in an Italian family. Hum Genet 2003;112(2):124-30.
Ozonoff S, Williams BJ, Rauch AM, et al. Behavioral phenotype of FG syndrome: cognition, personality and behavior in eleven boys. Am J Med Genet 2000;97:112-118.
Meroni G, Cainarca S, Berti C, et al. Identification and characterization of proteins that interact with midin, the Opitz syndrome gene product. Am Soc Hum Genet Program and Abstract 2000;abstract 959: p. 183.
Graham JM Jr, Superneau D, Rogers RC, et al. Clinical and behavioral characteristics in FG syndrome. Am J Med Genet 1999;85:470-475.
Opitz JM, Richieri-da Costa A, Aase JM, et al. FG syndrome update 1998: note of 5 new patients and bibliography. Am J Med Genet 1998;30:309-328.
Graham JM Jr, Tackels, D, Dibbern K, et al. FG syndrome: report of three new families with linkage to Xq12-q21.1 Am J Med Genet 1998;80:145-156.Briault S, Hill R, Shrimpton A, et al. A gene for FG syndrome maps in the Xq12-X21.31 region. Am J Med Genet 1997;73:87-90.
Briault S, Hill R, Shrimpton A, et al. A gene for FG syndrome maps in the Xq12-X21.31 region. Am J Med Genet 1997;73:87-90.
Kato R, Niikawa N, Nagai T, et al. Japanese kindred with FG syndrome [letter]. Am J Med Genet 1994;52:242-243.
INTERNET
Lyons MJ. MED12-Related Disorders. 2008 Jun 23 [Updated 2021 Aug 12]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1676/ Accessed August 7, 2023.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University; Entry No. 305450; Last Update06/06/2023. https://omim.org/entry/305450 Accessed August 7, 2023.
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The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
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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