U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

Intellectual disability, X-linked 49(MRXSRC)

MedGen UID:
923000
Concept ID:
C0796221
Disease or Syndrome
Synonyms: MENTAL RETARDATION, X-LINKED 15; MRX49; MRXSRC; RAYNAUD-CLAES SYNDROME
SNOMED CT: Raynaud Claes syndrome (1172691004); Chloride voltage-gated channel 4-related X-linked intellectual disability syndrome (1172691004); CLCN4-related X-linked intellectual disability syndrome (1172691004)
 
Gene (location): CLCN4 (Xp22.2)
 
Monarch Initiative: MONDO:0010250
OMIM®: 300114

Disease characteristics

Excerpted from the GeneReview: CLCN4-Related Neurodevelopmental Disorder
CLCN4-related neurodevelopmental disorder (CLCN4-NDD), an X-linked disorder, is characterized in the 36 males reported to date by developmental delay or intellectual disability, behavioral/mental health issues (e.g., autism spectrum disorder, anxiety, hyperactivity, and bipolar disorder), epilepsy, and gastrointestinal dysfunction. The five heterozygous females with a de novo CLCN4 variant reported to date had findings very similar to those of affected males. Twenty-two of 25 heterozygous females identified in family studies following identification of an affected male were unaffected or had only mild specific learning difficulties and/or mental health concerns, whereas three were more severely affected. [from GeneReviews]
Authors:
Elizabeth Emma Palmer  |  Matthew Huu Nguyen  |  Caitlin Forwood, et. al.   view full author information

Additional description

From OMIM
Raynaud-Claes syndrome is an X-linked intellectual developmental disorder characterized by borderline to severe intellectual disability and impaired language development. Additional features include behavioral problems, psychiatric disorders, seizures (variable forms), progressive ataxia, brain abnormalities, and facial dysmorphisms. Some heterozygous females are unaffected, whereas others are affected with a severity spectrum similar to that seen in males (summary by Palmer et al. (2018)).  http://www.omim.org/entry/300114

Clinical features

From HPO
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.
Anxiety
MedGen UID:
1613
Concept ID:
C0003467
Finding
Intense feelings of nervousness, tenseness, or panic, often in reaction to interpersonal stresses; worry about the negative effects of past unpleasant experiences and future negative possibilities; feeling fearful, apprehensive, or threatened by uncertainty; fears of falling apart or losing control.
Bipolar affective disorder
MedGen UID:
2649
Concept ID:
C0005586
Mental or Behavioral Dysfunction
A disorder of the brain that causes unusual shifts in mood, energy, activity levels and the ability to carry out day-to-day tasks. Often these moods range and shift from periods of elation and energized behavior to those of hopelessness and depression.
Depression
MedGen UID:
4229
Concept ID:
C0011581
Mental or Behavioral Dysfunction
Frequent feelings of being down, miserable, and/or hopeless; difficulty recovering from such moods; pessimism about the future; pervasive shame; feeling of inferior self-worth; thoughts of suicide and suicidal behavior.
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Atypical behavior
MedGen UID:
535345
Concept ID:
C0233514
Mental or Behavioral Dysfunction
An abnormality of mental functioning including various affective, behavioural, cognitive and perceptual abnormalities.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Focal impaired awareness seizure
MedGen UID:
543022
Concept ID:
C0270834
Disease or Syndrome
Focal impaired awareness seizure (or focal seizure with impaired or lost awareness) is a type of focal-onset seizure characterized by some degree (which may be partial) of impairment of the person's awareness of themselves or their surroundings at any point during the seizure.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
Progressive cerebellar ataxia
MedGen UID:
140727
Concept ID:
C0393525
Disease or Syndrome
Epileptic encephalopathy
MedGen UID:
452596
Concept ID:
C0543888
Disease or Syndrome
A condition in which epileptiform abnormalities are believed to contribute to the progressive disturbance in cerebral function. Epileptic encephalaopathy is characterized by (1) electrographic EEG paroxysmal activity that is often aggressive, (2) seizures that are usually multiform and intractable, (3) cognitive, behavioral and neurological deficits that may be relentless, and (4) sometimes early death.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
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).
Autistic behavior
MedGen UID:
163547
Concept ID:
C0856975
Mental or Behavioral Dysfunction
Persistent deficits in social interaction and communication and interaction as well as a markedly restricted repertoire of activity and interest as well as repetitive patterns of behavior.
Lower limb spasticity
MedGen UID:
220865
Concept ID:
C1271100
Finding
Spasticity (velocity-dependent increase in tonic stretch reflexes with increased muscle tone and hyperexcitable tendon reflexes) in the muscles of the lower limbs, hips, and pelvis
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Cerebral cortical atrophy
MedGen UID:
1646740
Concept ID:
C4551583
Disease or Syndrome
Atrophy of the cortex of the cerebrum.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Mandibular prognathia
MedGen UID:
98316
Concept ID:
C0399526
Finding
Abnormal prominence of the chin related to increased length of the mandible.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
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).
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.
Midface retrusion
MedGen UID:
339938
Concept ID:
C1853242
Anatomical Abnormality
Posterior positions and/or vertical shortening of the infraorbital and perialar regions, or increased concavity of the face and/or reduced nasolabial angle.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.
Cerebral visual impairment
MedGen UID:
890568
Concept ID:
C4048268
Pathologic Function
A form of loss of vision caused by damage to the visual cortex rather than a defect in the eye.

Professional guidelines

PubMed

DeBrosse SD, Okajima K, Zhang S, Nakouzi G, Schmotzer CL, Lusk-Kopp M, Frohnapfel MB, Grahame G, Kerr DS
Mol Genet Metab 2012 Nov;107(3):394-402. Epub 2012 Sep 7 doi: 10.1016/j.ymgme.2012.09.001. PMID: 23021068

Recent clinical studies

Etiology

Fadiga L, Melo M, Saraiva J, Paiva I
Hormones (Athens) 2022 Mar;21(1):33-40. Epub 2021 Oct 15 doi: 10.1007/s42000-021-00325-y. PMID: 34652632
Huffnagel IC, Dijkgraaf MGW, Janssens GE, van Weeghel M, van Geel BM, Poll-The BT, Kemp S, Engelen M
Orphanet J Rare Dis 2019 Feb 7;14(1):30. doi: 10.1186/s13023-019-1008-6. PMID: 30732635Free PMC Article
Duszyc K, Terczynska I, Hoffman-Zacharska D
J Appl Genet 2015 Feb;56(1):49-56. Epub 2014 Sep 10 doi: 10.1007/s13353-014-0243-8. PMID: 25204757
Philips AK, Sirén A, Avela K, Somer M, Peippo M, Ahvenainen M, Doagu F, Arvio M, Kääriäinen H, Van Esch H, Froyen G, Haas SA, Hu H, Kalscheuer VM, Järvelä I
Orphanet J Rare Dis 2014 Apr 11;9:49. doi: 10.1186/1750-1172-9-49. PMID: 24721225Free PMC Article
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

Diagnosis

Fadiga L, Melo M, Saraiva J, Paiva I
Hormones (Athens) 2022 Mar;21(1):33-40. Epub 2021 Oct 15 doi: 10.1007/s42000-021-00325-y. PMID: 34652632
Philips AK, Sirén A, Avela K, Somer M, Peippo M, Ahvenainen M, Doagu F, Arvio M, Kääriäinen H, Van Esch H, Froyen G, Haas SA, Hu H, Kalscheuer VM, Järvelä I
Orphanet J Rare Dis 2014 Apr 11;9:49. doi: 10.1186/1750-1172-9-49. PMID: 24721225Free PMC Article
Silove N, Collins F, Ellaway C
J Paediatr Child Health 2013 Jul;49(7):519-25. Epub 2013 Apr 19 doi: 10.1111/jpc.12176. PMID: 23600797
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
Van Buggenhout G, Fryns JP
Orphanet J Rare Dis 2006 Jul 10;1:26. doi: 10.1186/1750-1172-1-26. PMID: 16831221Free PMC Article

Therapy

Brousseau M, Nectoux J, Saintpierre B, Lebrun N, Cagnard N, Izac B, Olivier E, Letourneur F, Bienvenu T
Biochim Biophys Acta Mol Basis Dis 2020 Jun 1;1866(6):165730. Epub 2020 Feb 15 doi: 10.1016/j.bbadis.2020.165730. PMID: 32070770
da Silva EM, Strufaldi MW, Andriolo RB, Silva LA
Cochrane Database Syst Rev 2016 Feb 5;2(2):CD008185. doi: 10.1002/14651858.CD008185.pub4. PMID: 26845288Free PMC Article
da Silva EM, Strufaldi MW, Andriolo RB, Silva LA
Cochrane Database Syst Rev 2014 Jan 8;(1):CD008185. doi: 10.1002/14651858.CD008185.pub3. PMID: 24399699
Møller LB, Lenartowicz M, Zabot MT, Josiane A, Burglen L, Bennett C, Riconda D, Fisher R, Janssens S, Mohammed S, Ausems M, Tümer Z, Horn N, Jensen TG
Orphanet J Rare Dis 2012 Jan 22;7:6. doi: 10.1186/1750-1172-7-6. PMID: 22264391Free PMC Article
da Silva EM, Strufaldi MW, Andriolo RB, Silva LA
Cochrane Database Syst Rev 2011 Nov 9;(11):CD008185. doi: 10.1002/14651858.CD008185.pub2. PMID: 22071845

Prognosis

da Silva EM, Strufaldi MW, Andriolo RB, Silva LA
Cochrane Database Syst Rev 2016 Feb 5;2(2):CD008185. doi: 10.1002/14651858.CD008185.pub4. PMID: 26845288Free PMC Article
da Silva EM, Strufaldi MW, Andriolo RB, Silva LA
Cochrane Database Syst Rev 2014 Jan 8;(1):CD008185. doi: 10.1002/14651858.CD008185.pub3. PMID: 24399699
Hung KL, Wang JS, Keng WT, Chen HJ, Liang JS, Ngu LH, Lu JF
Pediatr Neurol 2013 Sep;49(3):185-90. Epub 2013 Jul 5 doi: 10.1016/j.pediatrneurol.2013.04.021. PMID: 23835273
Silove N, Collins F, Ellaway C
J Paediatr Child Health 2013 Jul;49(7):519-25. Epub 2013 Apr 19 doi: 10.1111/jpc.12176. PMID: 23600797
Van Buggenhout G, Fryns JP
Orphanet J Rare Dis 2006 Jul 10;1:26. doi: 10.1186/1750-1172-1-26. PMID: 16831221Free PMC Article

Clinical prediction guides

da Silva EM, Strufaldi MW, Andriolo RB, Silva LA
Cochrane Database Syst Rev 2016 Feb 5;2(2):CD008185. doi: 10.1002/14651858.CD008185.pub4. PMID: 26845288Free PMC Article
da Silva EM, Strufaldi MW, Andriolo RB, Silva LA
Cochrane Database Syst Rev 2014 Jan 8;(1):CD008185. doi: 10.1002/14651858.CD008185.pub3. PMID: 24399699
Hung KL, Wang JS, Keng WT, Chen HJ, Liang JS, Ngu LH, Lu JF
Pediatr Neurol 2013 Sep;49(3):185-90. Epub 2013 Jul 5 doi: 10.1016/j.pediatrneurol.2013.04.021. PMID: 23835273
Silove N, Collins F, Ellaway C
J Paediatr Child Health 2013 Jul;49(7):519-25. Epub 2013 Apr 19 doi: 10.1111/jpc.12176. PMID: 23600797
Zgorzalewicz-Stachowiak M, Stradomska TJ, Bartkowiak Z, Galas-Zgorzalewicz B
Folia Neuropathol 2006;44(4):319-26. PMID: 17183459

Recent systematic reviews

da Silva EM, Strufaldi MW, Andriolo RB, Silva LA
Cochrane Database Syst Rev 2016 Feb 5;2(2):CD008185. doi: 10.1002/14651858.CD008185.pub4. PMID: 26845288Free PMC Article
da Silva EM, Strufaldi MW, Andriolo RB, Silva LA
Cochrane Database Syst Rev 2014 Jan 8;(1):CD008185. doi: 10.1002/14651858.CD008185.pub3. PMID: 24399699
da Silva EM, Strufaldi MW, Andriolo RB, Silva LA
Cochrane Database Syst Rev 2011 Nov 9;(11):CD008185. doi: 10.1002/14651858.CD008185.pub2. PMID: 22071845

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.

    Consumer resources

    Recent activity

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...