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FRAXE(MRX109; XLID109)

MedGen UID:
155512
Concept ID:
C0751157
Disease or Syndrome
Synonyms: Fragile XE syndrome; FRAXE intellectual disability; Intellectual developmental disorder, X-linked 109; Intellectual disability, X-linked, FRAXE type
SNOMED CT: FRAXE (254288000)
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Source: Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
 
Gene (location): AFF2 (Xq28)
 
Monarch Initiative: MONDO:0010659
OMIM®: 309548
Orphanet: ORPHA100973

Definition

Intellectual developmental disorder-109 (MRX109) is characterized by mildly to moderately impaired intellectual development associated with learning difficulties, communication deficits, attention problems, hyperactivity, and autistic behavior (summary by Bensaid et al., 2009). The disorder, which is associated with a fragile site on chromosome Xq28 (FRAXE), can be caused either by silencing of the FMR2 gene as a consequence of a CCG expansion located upstream of this gene or by deletion within the gene (Stettner et al., 2011). [from OMIM]

Additional description

From MedlinePlus Genetics
Fragile XE syndrome is a genetic disorder that impairs thinking ability and cognitive functioning. Most affected individuals have mild intellectual disability. In some people with this condition, cognitive function is described as borderline, which means that it is below average but not low enough to be classified as an intellectual disability. Females are rarely diagnosed with fragile XE syndrome, likely because the signs and symptoms are so mild that the individuals function normally.

Learning disabilities are the most common sign of impaired cognitive function in people with fragile XE syndrome. The learning disabilities are likely a result of communication and behavioral problems, including delayed speech, poor writing skills, hyperactivity, and a short attention span. Some affected individuals display autistic behaviors, such as hand flapping, repetitive behaviors, and intense interest in a particular subject. Unlike some other forms of intellectual disability, cognitive functioning remains steady and does not decline with age in fragile XE syndrome.  https://medlineplus.gov/genetics/condition/fragile-xe-syndrome

Clinical features

From HPO
Fetal growth restriction
MedGen UID:
4693
Concept ID:
C0015934
Pathologic Function
An abnormal restriction of fetal growth with fetal weight below the tenth percentile for gestational age.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
Aggressive behavior can denote verbal aggression, physical aggression against objects, physical aggression against people, and may also include aggression towards oneself.
Impulsivity
MedGen UID:
43850
Concept ID:
C0021125
Mental or Behavioral Dysfunction
Acting on the spur of the moment in response to immediate stimuli; acting on a momentary basis without a plan or consideration of outcomes; difficulty establishing or following plans; a sense of urgency and self-harming behavior under emotional distress.
Agitation
MedGen UID:
88447
Concept ID:
C0085631
Sign or Symptom
A state of exceeding restlessness and excessive motor activity associated with mental distress or a feeling of inner tension.
Hyperactivity
MedGen UID:
98406
Concept ID:
C0424295
Finding
Hyperactivity is a state of constantly being unusually or abnormally active, including in situations in which it is not appropriate.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Poor coordination
MedGen UID:
107874
Concept ID:
C0563243
Finding
Compulsive behaviors
MedGen UID:
109373
Concept ID:
C0600104
Mental or Behavioral Dysfunction
Recurrent obsessions or compulsions that are severe enough to be time consuming (i.e., they take more than 1 hour a day) or cause marked distress or significant impairment (DSM-IV).
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
Recurrent hand flapping
MedGen UID:
867996
Concept ID:
C4022387
Mental or Behavioral Dysfunction
A type of stereotypic behavior in which the affected individual repeatedly waves the hands up and down.
Stereotypical body rocking
MedGen UID:
868614
Concept ID:
C4023013
Mental or Behavioral Dysfunction
Habitual repetitive movement of the body.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Hoarse voice
MedGen UID:
5602
Concept ID:
C0019825
Sign or Symptom
Hoarseness refers to a change in the pitch or quality of the voice, with the voice sounding weak, very breathy, scratchy, or husky.
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Thick vermilion border
MedGen UID:
332232
Concept ID:
C1836543
Finding
Increased width of the skin of vermilion border region of upper lip.
Prominent nasal bridge
MedGen UID:
343051
Concept ID:
C1854113
Finding
Anterior positioning of the nasal root in comparison to the usual positioning for age.
Long upper lip
MedGen UID:
462845
Concept ID:
C3151495
Finding
Increased width of the upper lip.
Fetal distress
MedGen UID:
5164
Concept ID:
C0015930
Pathologic Function
An intrauterine state characterized by suboptimal values in the fetal heart rate, oxygenation of fetal blood, or other parameters indicative of compromise of the fetus. Signs of fetal distress include repetitive variable decelerations, fetal tachycardia or bradycardia, late decelerations, or low biophysical profile.

Professional guidelines

PubMed

Liu T, Wang FS, Cheah FSH, Gu Y, Shaw M, Law HY, Tay SKH, Lee CG, Nelson DL, Gecz J, Chong SS
J Mol Diagn 2021 Aug;23(8):941-951. Epub 2021 Jun 7 doi: 10.1016/j.jmoldx.2021.04.015. PMID: 34111553
Steiner CE, Guerreiro MM, Marques-de-Faria AP
Arq Neuropsiquiatr 2003 Jun;61(2A):176-80. Epub 2003 Jun 9 doi: 10.1590/s0004-282x2003000200003. PMID: 12806492
Patsalis PC, Sismani C, Hettinger JA, Boumba I, Georgiou I, Stylianidou G, Anastasiadou V, Koukoulli R, Pagoulatos G, Syrrou M
Am J Med Genet 1999 May 28;84(3):184-90. PMID: 10331587

Recent clinical studies

Etiology

Costa A, Gao L, Carrillo F, Cáceres-Redondo MT, Carballo M, Díaz-Martín J, Gómez-Garre P, Sobrino F, Lucas M, López-Barneo J, Mir P, Pintado E
Parkinsonism Relat Disord 2011 May;17(4):281-4. Epub 2011 Jan 22 doi: 10.1016/j.parkreldis.2010.12.013. PMID: 21257332
Lukusa T, Fryns JP
Biochim Biophys Acta 2008 Jan;1779(1):3-16. Epub 2007 Dec 3 doi: 10.1016/j.bbagrm.2007.10.005. PMID: 18078840
Debacker K, Kooy RF
Hum Mol Genet 2007 Oct 15;16 Spec No. 2:R150-8. Epub 2007 Jun 13 doi: 10.1093/hmg/ddm136. PMID: 17567780
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Hum Mutat 1999;13(2):166-9. doi: 10.1002/(SICI)1098-1004(1999)13:2<166::AID-HUMU10>3.0.CO;2-X. PMID: 10094554
Chan SY, Wong V
Clin Genet 1998 Mar;53(3):179-83. doi: 10.1111/j.1399-0004.1998.tb02673.x. PMID: 9630071

Diagnosis

Liu T, Wang FS, Cheah FSH, Gu Y, Shaw M, Law HY, Tay SKH, Lee CG, Nelson DL, Gecz J, Chong SS
J Mol Diagn 2021 Aug;23(8):941-951. Epub 2021 Jun 7 doi: 10.1016/j.jmoldx.2021.04.015. PMID: 34111553
Lukusa T, Fryns JP
Biochim Biophys Acta 2008 Jan;1779(1):3-16. Epub 2007 Dec 3 doi: 10.1016/j.bbagrm.2007.10.005. PMID: 18078840
Sutherland GR
Cytogenet Genome Res 2003;100(1-4):77-84. doi: 10.1159/000072840. PMID: 14526166
Youings SA, Murray A, Dennis N, Ennis S, Lewis C, McKechnie N, Pound M, Sharrock A, Jacobs P
J Med Genet 2000 Jun;37(6):415-21. doi: 10.1136/jmg.37.6.415. PMID: 10851251Free PMC Article
Chan SY, Wong V
Clin Genet 1998 Mar;53(3):179-83. doi: 10.1111/j.1399-0004.1998.tb02673.x. PMID: 9630071

Therapy

Probst FJ, Roeder ER, Enciso VB, Ou Z, Cooper ML, Eng P, Li J, Gu Y, Stratton RF, Chinault AC, Shaw CA, Sutton VR, Cheung SW, Nelson DL
Am J Med Genet A 2007 Jun 15;143A(12):1358-65. doi: 10.1002/ajmg.a.31781. PMID: 17506108
Syrrou M, Georgiou I, Grigoriadou M, Petersen MB, Kitsiou S, Pagoulatos G, Patsalis PC
Genet Epidemiol 1998;15(1):103-9. doi: 10.1002/(SICI)1098-2272(1998)15:1<103::AID-GEPI8>3.0.CO;2-8. PMID: 9523214
Subramanian PS, Nelson DL, Chinault AC
Am J Hum Genet 1996 Aug;59(2):407-16. PMID: 8755928Free PMC Article
Wang Q, Green E, Barnicoat A, Garrett D, Mullarkey M, Bobrow M, Mathew CG
Lancet 1993 Oct 23;342(8878):1025-6. doi: 10.1016/0140-6736(93)92882-t. PMID: 8105267

Prognosis

Gu Y, Nelson DL
Cytogenet Genome Res 2003;100(1-4):129-39. doi: 10.1159/000072847. PMID: 14526173
Zucchi I, Jones J, Affer M, Montagna C, Redolfi E, Susani L, Vezzoni P, Parvari R, Schlessinger D, Whyte MP, Mumm S
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Elbaz A, Suédois J, Duquesnoy M, Beldjord C, Berchel C, Mérault G
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Am J Med Genet 1997 Dec 31;73(4):463-9. doi: 10.1002/(sici)1096-8628(19971231)73:4<463::aid-ajmg16>3.0.co;2-p. PMID: 9415475
Sutherland GR, Mulley JC
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Clinical prediction guides

Gu Y, Nelson DL
Cytogenet Genome Res 2003;100(1-4):129-39. doi: 10.1159/000072847. PMID: 14526173
Barros Santos C, Gonçalves Pimentel MM
Int J Mol Med 2003 Sep;12(3):385-9. PMID: 12883656
Murray A, Macpherson JN, Pound MC, Sharrock A, Youings SA, Dennis NR, McKechnie N, Linehan P, Morton NE, Jacobs PA
Hum Mol Genet 1997 Feb;6(2):173-84. doi: 10.1093/hmg/6.2.173. PMID: 9063737
Lubs HA, Chiurazzi P, Arena JF, Schwartz C, Tranebjaerg L, Neri G
Am J Med Genet 1996 Jul 12;64(1):147-57. doi: 10.1002/(SICI)1096-8628(19960712)64:1<147::AID-AJMG25>3.0.CO;2-M. PMID: 8826465
Bates G, Lehrach H
Bioessays 1994 Apr;16(4):277-84. doi: 10.1002/bies.950160411. PMID: 8031305

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