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Fragile X syndrome(FXS)

MedGen UID:
8912
Concept ID:
C0016667
Disease or Syndrome
Synonyms: Fra(X) syndrome; Fragile X syndrome, type A; Marker X syndrome; Martin-Bell syndrome; MENTAL RETARDATION, X-LINKED, ASSOCIATED WITH marXq28; X-linked mental retardation and macroorchidism
SNOMED CT: Fragile X syndrome (613003); Martin-Bell syndrome (613003); Marker X syndrome (613003); FRAXA (fragile X) syndrome (613003)
Modes of inheritance:
X-linked dominant inheritance
MedGen UID:
376232
Concept ID:
C1847879
Finding
Source: Orphanet
A mode of inheritance that is observed for dominant traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked dominant disorders tend to manifest very severely in affected males. The severity of manifestation in females may depend on the degree of skewed X inactivation.
 
Gene (location): FMR1 (Xq27.3)
 
Monarch Initiative: MONDO:0010383
OMIM®: 300624
Orphanet: ORPHA908

Disease characteristics

Excerpted from the GeneReview: FMR1 Disorders
FMR1 disorders include fragile X syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI). Fragile X syndrome occurs in individuals with an FMR1 full mutation or other loss-of-function variant and is nearly always characterized in affected males by developmental delay and intellectual disability along with a variety of behavioral issues. Autism spectrum disorder is present in 50%-70% of individuals with FXS. Affected males may have characteristic craniofacial features (which become more obvious with age) and medical problems including hypotonia, gastroesophageal reflux, strabismus, seizures, sleep disorders, joint laxity, pes planus, scoliosis, and recurrent otitis media. Adults may have mitral valve prolapse or aortic root dilatation. The physical and behavioral features seen in males with FXS have been reported in females heterozygous for the FMR1 full mutation, but with lower frequency and milder involvement. FXTAS occurs in individuals who have an FMR1 premutation and is characterized by late-onset, progressive cerebellar ataxia and intention tremor followed by cognitive impairment. Psychiatric disorders are common. Age of onset is typically between 60 and 65 years and is more common among males who are hemizygous for the premutation (40%) than among females who are heterozygous for the premutation (16%-20%). FXPOI, defined as hypergonadotropic hypogonadism before age 40 years, has been observed in 20% of women who carry a premutation allele compared to 1% in the general population. [from GeneReviews]
Authors:
Jessica Ezzell Hunter  |  Elizabeth Berry-Kravis  |  Heather Hipp, et. al.   view full author information

Additional descriptions

From OMIM
Fragile X syndrome (FXS) is characterized by moderately to severely impaired intellectual development, macroorchidism, and distinct facial features, including long face, large ears, and prominent jaw. In most cases, the disorder is caused by the unstable expansion of a CGG repeat in the FMR1 gene and abnormal methylation, which results in suppression of FMR1 transcription and decreased protein levels in the brain (Devys et al., 1993). Reviews Fragile X syndrome accounts for about one-half of cases of X-linked impaired intellectual development and is the second most common cause of mental impairment after trisomy 21 (190685) (Rousseau et al., 1995). McCabe et al. (1999) summarized the proceedings of a workshop on the fragile X syndrome held in December 1998. Jacquemont et al. (2007) provided a review of fragile X syndrome, which they characterized as a neurodevelopmental disorder, and FXTAS, which they characterized as a neurodegenerative disorder.  http://www.omim.org/entry/300624
From MedlinePlus Genetics
Fragile X syndrome is a genetic condition that causes a range of developmental problems including learning disabilities and cognitive impairment. Usually, males are more severely affected by this disorder than females.

Affected individuals usually have delayed development of speech and language by age 2. Most males with fragile X syndrome have mild to moderate intellectual disability, while about one-third of affected females are intellectually disabled. Children with fragile X syndrome may also have anxiety and hyperactive behavior such as fidgeting or impulsive actions. They may have attention deficit disorder (ADD), which includes an impaired ability to maintain attention and difficulty focusing on specific tasks. About one-third of individuals with fragile X syndrome have features of autism spectrum disorder that affect communication and social interaction. Seizures occur in about 15 percent of males and about 5 percent of females with fragile X syndrome.

Most males and about half of females with fragile X syndrome have characteristic physical features that become more apparent with age. These features include a long and narrow face, large ears, a prominent jaw and forehead, unusually flexible fingers, flat feet, and in males, enlarged testicles (macroorchidism) after puberty.  https://medlineplus.gov/genetics/condition/fragile-x-syndrome

Clinical features

From HPO
Macroorchidism, postpubertal
MedGen UID:
374308
Concept ID:
C1839782
Finding
Congenital macroorchidism
MedGen UID:
870213
Concept ID:
C4024650
Congenital Abnormality
Pes planus
MedGen UID:
42034
Concept ID:
C0016202
Anatomical Abnormality
A foot where the longitudinal arch of the foot is in contact with the ground or floor when the individual is standing; or, in a patient lying supine, a foot where the arch is in contact with the surface of a flat board pressed against the sole of the foot by the examiner with a pressure similar to that expected from weight bearing; or, the height of the arch is reduced.
Metacarpophalangeal joint hyperextensibility
MedGen UID:
870640
Concept ID:
C4025092
Anatomical Abnormality
Increased mobility of one ore more metacarpophalangeal joint.
Mitral valve prolapse
MedGen UID:
7671
Concept ID:
C0026267
Disease or Syndrome
One or both of the leaflets (cusps) of the mitral valve bulges back into the left atrium upon contraction of the left ventricle.
Macrotia
MedGen UID:
488785
Concept ID:
C0152421
Congenital Abnormality
Median longitudinal ear length greater than two standard deviations above the mean and median ear width greater than two standard deviations above the mean (objective); or, apparent increase in length and width of the pinna (subjective).
Autism
MedGen UID:
13966
Concept ID:
C0004352
Mental or Behavioral Dysfunction
Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypic, and ritualized patterns of interests and behavior (Bailey et al., 1996; Risch et al., 1999). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (see ASPG1; 608638) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (Jones et al., 2008). Genetic studies in autism often include family members with these less stringent diagnoses (Schellenberg et al., 2006). Levy et al. (2009) provided a general review of autism and autism spectrum disorder, including epidemiology, characteristics of the disorder, diagnosis, neurobiologic hypotheses for the etiology, genetics, and treatment options. Genetic Heterogeneity of Autism Autism is considered to be a complex multifactorial disorder involving many genes. Accordingly, several loci have been identified, some or all of which may contribute to the phenotype. Included in this entry is AUTS1, which has been mapped to chromosome 7q22. Other susceptibility loci include AUTS3 (608049), which maps to chromosome 13q14; AUTS4 (608636), which maps to chromosome 15q11; AUTS6 (609378), which maps to chromosome 17q11; AUTS7 (610676), which maps to chromosome 17q21; AUTS8 (607373), which maps to chromosome 3q25-q27; AUTS9 (611015), which maps to chromosome 7q31; AUTS10 (611016), which maps to chromosome 7q36; AUTS11 (610836), which maps to chromosome 1q41; AUTS12 (610838), which maps to chromosome 21p13-q11; AUTS13 (610908), which maps to chromosome 12q14; AUTS14A (611913), which has been found in patients with a deletion of a region of 16p11.2; AUTS14B (614671), which has been found in patients with a duplication of a region of 16p11.2; AUTS15 (612100), associated with mutation in the CNTNAP2 gene (604569) on chromosome 7q35-q36; AUTS16 (613410), associated with mutation in the SLC9A9 gene (608396) on chromosome 3q24; AUTS17 (613436), associated with mutation in the SHANK2 gene (603290) on chromosome 11q13; AUTS18 (615032), associated with mutation in the CHD8 gene (610528) on chromosome 14q11; AUTS19 (615091), associated with mutation in the EIF4E gene (133440) on chromosome 4q23; and AUTS20 (618830), associated with mutation in the NLGN1 gene (600568) on chromosome 3q26. (NOTE: the symbol 'AUTS2' has been used to refer to a gene on chromosome 7q11 (KIAA0442; 607270) and therefore is not used as a part of this autism locus series.) There are several X-linked forms of autism susceptibility: AUTSX1 (300425), associated with mutations in the NLGN3 gene (300336); AUTSX2 (300495), associated with mutations in NLGN4 (300427); AUTSX3 (300496), associated with mutations in MECP2 (300005); AUTSX4 (300830), associated with variation in the region on chromosome Xp22.11 containing the PTCHD1 gene (300828); AUTSX5 (300847), associated with mutations in the RPL10 gene (312173); and AUTSX6 (300872), associated with mutation in the TMLHE gene (300777). A locus on chromosome 2q (606053) associated with a phenotype including intellectual disability and speech deficits was formerly designated AUTS5. Folstein and Rosen-Sheidley (2001) reviewed the genetics of autism.
Intellectual disability, moderate
MedGen UID:
7680
Concept ID:
C0026351
Mental or Behavioral Dysfunction
Moderate mental retardation is defined as an intelligence quotient (IQ) in the range of 35-49.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Hyperactivity
MedGen UID:
98406
Concept ID:
C0424295
Finding
Hyperactivity is a condition characterized by constant and unusually high levels of activity, even in situations where it is deemed inappropriate.
Self-biting
MedGen UID:
603118
Concept ID:
C0424375
Finding
Habitual biting of one's own body.
Abnormal head movements
MedGen UID:
96905
Concept ID:
C0476217
Finding
Reduced eye contact
MedGen UID:
303190
Concept ID:
C1445953
Finding
A reduced frequency or duration of eye contact.
Recurrent hand flapping
MedGen UID:
867996
Concept ID:
C4022387
Mental or Behavioral Dysfunction
A type of repetitive behavior in which the affected individual repeatedly waves the hands and/or arms rhythmically.
Periventricular heterotopia
MedGen UID:
1766888
Concept ID:
C5399973
Disease or Syndrome
A form of gray matter heterotopia were the mislocalized gray matter is typically located periventricularly, also sometimes called subependymal heterotopia. Periventricular means beside the ventricles. This is by far the most common location for heterotopia. Subependymal heterotopia present in a wide array of variations. There can be a small single node or a large number of nodes, can exist on either or both sides of the brain at any point along the higher ventricle margins, can be small or large, single or multiple, and can form a small node or a large wavy or curved mass.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Joint hypermobility
MedGen UID:
336793
Concept ID:
C1844820
Finding
The capability that a joint (or a group of joints) has to move, passively and/or actively, beyond normal limits along physiological axes.
Pectus excavatum
MedGen UID:
781174
Concept ID:
C2051831
Finding
A defect of the chest wall characterized by a depression of the sternum, giving the chest ("pectus") a caved-in ("excavatum") appearance.
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Mandibular prognathia
MedGen UID:
98316
Concept ID:
C0399526
Finding
Abnormal prominence of the chin related to increased length of the mandible.
Long face
MedGen UID:
324419
Concept ID:
C1836047
Finding
Facial height (length) is more than 2 standard deviations above the mean (objective); or, an apparent increase in the height (length) of the face (subjective).
Large forehead
MedGen UID:
326962
Concept ID:
C1839783
Finding
Coarse facial features
MedGen UID:
335284
Concept ID:
C1845847
Finding
Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues.
Folate-dependent fragile site at Xq28
MedGen UID:
326579
Concept ID:
C1839785
Finding
The presence of a folate sensitive fragile site at chromosome Xq28.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVFragile X syndrome
Follow this link to review classifications for Fragile X syndrome in Orphanet.

Professional guidelines

PubMed

Aran A, Cayam Rand D
Expert Opin Emerg Drugs 2024 Mar;29(1):65-79. Epub 2024 Jan 23 doi: 10.1080/14728214.2024.2306290. PMID: 38226593
Aishworiya R, Valica T, Hagerman R, Restrepo B
Neurotherapeutics 2022 Jan;19(1):248-262. Epub 2022 Jan 14 doi: 10.1007/s13311-022-01183-1. PMID: 35029811Free PMC Article
Salcedo-Arellano MJ, Hagerman RJ, Martínez-Cerdeño V
Gac Med Mex 2020;156(1):60-66. doi: 10.24875/GMM.19005275. PMID: 32026885

Curated

Jacquemont S, Birnbaum S, Redler S, Steinbach P, Biancalana V
Eur J Hum Genet 2011 Sep;19(9) Epub 2011 May 4 doi: 10.1038/ejhg.2011.55. PMID: 21540884Free PMC Article

American College of Medical Genetics and Genomics Genetic Testing ACT Sheet, Fragile X [FraX] Syndrome, 2012

Recent clinical studies

Etiology

Hunt E, Hogan A, Will EA, Roberts JE
Child Neuropsychol 2023 Jul;29(5):760-786. Epub 2022 Sep 9 doi: 10.1080/09297049.2022.2120605. PMID: 36082630Free PMC Article
Morin-Parent F, Champigny C, Lacroix A, Corbin F, Lepage JF
Transl Psychiatry 2019 Nov 20;9(1):312. doi: 10.1038/s41398-019-0650-z. PMID: 31748507Free PMC Article
Crawford H, Moss J, Oliver C, Riby D
J Neurodev Disord 2017 Sep 25;9(1):9. doi: 10.1186/s11689-017-9189-6. PMID: 28946865Free PMC Article
Sherman SL, Kidd SA, Riley C, Berry-Kravis E, Andrews HF, Miller RM, Lincoln S, Swanson M, Kaufmann WE, Brown WT
Pediatrics 2017 Jun;139(Suppl 3):S183-S193. doi: 10.1542/peds.2016-1159E. PMID: 28814539Free PMC Article
Tassone F
JAMA Neurol 2014 Mar;71(3):355-9. doi: 10.1001/jamaneurol.2013.4808. PMID: 24395328Free PMC Article

Diagnosis

Acero-Garcés DO, Saldarriaga W, Cabal-Herrera AM, Rojas CA, Hagerman RJ
Colomb Med (Cali) 2023 Apr-Jun;54(2):e4005089. Epub 2023 May 20 doi: 10.25100/cm.v54i2.5089. PMID: 37664646Free PMC Article
Ciobanu CG, Nucă I, Popescu R, Antoci LM, Caba L, Ivanov AV, Cojocaru KA, Rusu C, Mihai CT, Pânzaru MC
Int J Mol Sci 2023 May 24;24(11) doi: 10.3390/ijms24119206. PMID: 37298158Free PMC Article
Salcedo-Arellano MJ, Hagerman RJ, Martínez-Cerdeño V
Gac Med Mex 2020;156(1):60-66. doi: 10.24875/GMM.19005275. PMID: 32026885
Reches A
Methods Mol Biol 2019;1942:3-10. doi: 10.1007/978-1-4939-9080-1_1. PMID: 30900171
Hagerman RJ, Berry-Kravis E, Hazlett HC, Bailey DB Jr, Moine H, Kooy RF, Tassone F, Gantois I, Sonenberg N, Mandel JL, Hagerman PJ
Nat Rev Dis Primers 2017 Sep 29;3:17065. doi: 10.1038/nrdp.2017.65. PMID: 28960184

Therapy

Aran A, Cayam Rand D
Expert Opin Emerg Drugs 2024 Mar;29(1):65-79. Epub 2024 Jan 23 doi: 10.1080/14728214.2024.2306290. PMID: 38226593
Aishworiya R, Valica T, Hagerman R, Restrepo B
Neurotherapeutics 2022 Jan;19(1):248-262. Epub 2022 Jan 14 doi: 10.1007/s13311-022-01183-1. PMID: 35029811Free PMC Article
Jakaria M, Azam S, Haque ME, Jo SH, Uddin MS, Kim IS, Choi DK
Redox Biol 2019 Jun;24:101223. Epub 2019 May 21 doi: 10.1016/j.redox.2019.101223. PMID: 31141786Free PMC Article
Sabus A, Feinstein J, Romani P, Goldson E, Blackmer A
Pharmacotherapy 2019 Jun;39(6):645-664. Epub 2019 Mar 27 doi: 10.1002/phar.2238. PMID: 30793794Free PMC Article
Hunter J, Rivero-Arias O, Angelov A, Kim E, Fotheringham I, Leal J
Am J Med Genet A 2014 Jul;164A(7):1648-58. Epub 2014 Apr 3 doi: 10.1002/ajmg.a.36511. PMID: 24700618

Prognosis

Urakami T
Minerva Pediatr 2020 Dec;72(6):472-483. Epub 2020 Aug 4 doi: 10.23736/S0026-4946.20.05971-X. PMID: 32748612
Berry-Kravis E, Kidd SA, Lachiewicz AM, Choo TH, Tartaglia N, Talapatra D, Aguirre-Kolb C, Andrews H, Riley K
J Dev Behav Pediatr 2019 Dec;40(9):751-761. doi: 10.1097/DBP.0000000000000735. PMID: 31593026Free PMC Article
Ciaccio C, Fontana L, Milani D, Tabano S, Miozzo M, Esposito S
Ital J Pediatr 2017 Apr 19;43(1):39. doi: 10.1186/s13052-017-0355-y. PMID: 28420439Free PMC Article
Baujat G, Cormier-Daire V
Orphanet J Rare Dis 2007 Sep 7;2:36. doi: 10.1186/1750-1172-2-36. PMID: 17825104Free PMC Article
Cell 1993 Mar 26;72(6):971-83. doi: 10.1016/0092-8674(93)90585-e. PMID: 8458085

Clinical prediction guides

Aishworiya R, Tak YE, Ponzini MD, Biag HMB, Salcedo-Arellano MJ, Kim K, Tassone F, Schneider A, Thurman AJ, Abbeduto L, Hessl D, Randol JL, Bolduc FV, Lippe S, Hagerman P, Hagerman R
Int J Dev Neurosci 2023 Dec;83(8):715-727. Epub 2023 Sep 19 doi: 10.1002/jdn.10299. PMID: 37724826Free PMC Article
Choo TH, Xu Q, Budimirovic D, Lozano R, Esler AN, Frye RE, Andrews H, Velinov M
Obesity (Silver Spring) 2022 Mar;30(3):743-750. Epub 2022 Feb 16 doi: 10.1002/oby.23368. PMID: 35174658Free PMC Article
Montez ARH, Bizarra MF, Graça SR
Spec Care Dentist 2021 Jan;41(1):13-19. Epub 2020 Oct 26 doi: 10.1111/scd.12529. PMID: 33105044
Niu M, Han Y, Dy ABC, Du J, Jin H, Qin J, Zhang J, Li Q, Hagerman RJ
J Child Neurol 2017 Sep;32(10):903-909. Epub 2017 Jun 15 doi: 10.1177/0883073817712875. PMID: 28617074
Adlof SM, Klusek J, Shinkareva SV, Robinson ML, Roberts JE
J Child Psychol Psychiatry 2015 Jan;56(1):30-9. Epub 2014 Jun 3 doi: 10.1111/jcpp.12267. PMID: 24889646Free PMC Article

Recent systematic reviews

Burack JA, Friedman S, Lessage M, Brodeur D
J Intellect Disabil Res 2023 Mar;67(3):271-288. Epub 2022 Nov 27 doi: 10.1111/jir.12994. PMID: 36437709
Raspa M, Wheeler AC, Riley C
Pediatrics 2017 Jun;139(Suppl 3):S153-S171. doi: 10.1542/peds.2016-1159C. PMID: 28814537Free PMC Article
Rueda JR, Guillén V, Ballesteros J, Tejada MI, Solà I
Cochrane Database Syst Rev 2015 May 19;2015(5):CD010012. doi: 10.1002/14651858.CD010012.pub2. PMID: 25985235Free PMC Article
Hunter J, Rivero-Arias O, Angelov A, Kim E, Fotheringham I, Leal J
Am J Med Genet A 2014 Jul;164A(7):1648-58. Epub 2014 Apr 3 doi: 10.1002/ajmg.a.36511. PMID: 24700618
Rejeb I, Ben Jemaa L, Chaabouni H
Tunis Med 2009 May;87(5):311-8. PMID: 19927760

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.
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      See practice and clinical guidelines in NCBI Bookshelf. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2012
      American College of Medical Genetics and Genomics Genetic Testing ACT Sheet, Fragile X [FraX] Syndrome, 2012
    • EuroGenetest, 2011
      Clinical utility gene card for: fragile X mental retardation syndrome, fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency.

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