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Rett syndrome, congenital variant

MedGen UID:
462055
Concept ID:
C3150705
Disease or Syndrome
Synonym: RETT SYNDROME, CONGENITAL VARIANT
SNOMED CT: FOXG1 syndrome (702450004)
 
Gene (location): FOXG1 (14q12)
 
Monarch Initiative: MONDO:0013270
OMIM®: 613454

Definition

The congenital variant of Rett syndrome is a severe neurodevelopmental disorder with features of classic Rett syndrome (RTT; 312750), but earlier onset in the first months of life. Classic Rett syndrome shows later onset and is caused by mutation in the MECP2 gene (300005). [from OMIM]

Additional description

From MedlinePlus Genetics
FOXG1 syndrome is a condition characterized by impaired development and structural brain abnormalities. Affected infants are small at birth, and their heads grow more slowly than normal, leading to an unusually small head size (microcephaly) by early childhood. The condition is associated with a particular pattern of brain malformations that includes a thin or underdeveloped connection between the right and left halves of the brain (a structure called the corpus callosum), reduced folds and grooves (gyri) on the surface of the brain, and a smaller than usual amount of brain tissue known as white matter.

FOXG1 syndrome affects most aspects of development, and children with the condition typically have severe intellectual disability. Abnormal or involuntary movements, such as jerking movements of the arms and legs and repeated hand motions, are common, and most affected children do not learn to sit or walk without assistance. Babies and young children with FOXG1 syndrome often have feeding problems, sleep disturbances, seizures, irritability, and excessive crying. Affected individuals may have autism spectrum disorder, which is characterized by limited communication and social interaction, including poor eye contact and a near absence of speech and language skills. 

FOXG1 syndrome was previously described as a congenital variant of Rett syndrome, which is a similar disorder of brain development. Both disorders are characterized by impaired development, intellectual disability, and problems with communication and language. However, Rett syndrome is diagnosed almost exclusively in females, while FOXG1 syndrome affects both males and females. Rett syndrome also involves a period of apparently normal early development that does not occur in FOXG1 syndrome. Because of these differences, physicians and researchers now usually consider FOXG1 syndrome to be distinct from Rett syndrome.  https://medlineplus.gov/genetics/condition/foxg1-syndrome

Clinical features

From HPO
Clubfoot
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
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.
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Infrequent or difficult evacuation of feces.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Gastroesophageal reflux
MedGen UID:
1368658
Concept ID:
C4317146
Finding
A condition in which the stomach contents leak backwards from the stomach into the esophagus through the lower esophageal sphincter.
Protruding ear
MedGen UID:
343309
Concept ID:
C1855285
Finding
Angle formed by the plane of the ear and the mastoid bone greater than the 97th centile for age (objective); or, outer edge of the helix more than 2 cm from the mastoid at the point of maximum distance (objective).
Apraxia
MedGen UID:
8166
Concept ID:
C0003635
Mental or Behavioral Dysfunction
A defect in the understanding of complex motor commands and in the execution of certain learned movements, i.e., deficits in the cognitive components of learned movements.
Athetosis
MedGen UID:
2115
Concept ID:
C0004158
Disease or Syndrome
A slow, continuous, involuntary writhing movement that prevents maintenance of a stable posture. Athetosis involves continuous smooth movements that appear random and are not composed of recognizable sub-movements or movement fragments. In contrast to chorea, in athetosis, the same regions of the body are repeatedly involved. Athetosis may worsen with attempts at movement of posture, but athetosis can also occur at rest.
Bruxism
MedGen UID:
676
Concept ID:
C0006325
Mental or Behavioral Dysfunction
Bruxism is characterized by the grinding of the teeth including the clenching of the jaw and typically occur during sleep, but also can occur while the affected individual is awake.
Chorea
MedGen UID:
3420
Concept ID:
C0008489
Disease or Syndrome
Chorea (Greek for 'dance') refers to widespread arrhythmic involuntary movements of a forcible, jerky and restless fashion. It is a random-appearing sequence of one or more discrete involuntary movements or movement fragments. Movements appear random because of variability in timing, duration or location. Each movement may have a distinct start and end. However, movements may be strung together and thus may appear to flow randomly from one muscle group to another. Chorea can involve the trunk, neck, face, tongue, and extremities.
Dyskinesia
MedGen UID:
8514
Concept ID:
C0013384
Disease or Syndrome
A movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements.
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.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
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.
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
Severe mental retardation is defined as an intelligence quotient (IQ) in the range of 20-34.
Sleep abnormality
MedGen UID:
52372
Concept ID:
C0037317
Finding
An abnormal pattern in the quality, quantity, or characteristics of sleep.
Motor stereotypies
MedGen UID:
21318
Concept ID:
C0038271
Individual Behavior
Use of the same abnormal action in response to certain triggers or at random. They may be used as a way to regulate one's internal state but must otherwise have no apparent functional purpose.
EEG abnormality
MedGen UID:
56235
Concept ID:
C0151611
Finding
Abnormality observed by electroencephalogram (EEG), which is used to record of the brain's spontaneous electrical activity from multiple electrodes placed on the scalp.
Delayed ability to walk
MedGen UID:
66034
Concept ID:
C0241726
Finding
A failure to achieve the ability to walk at an appropriate developmental stage. Most children learn to walk in a series of stages, and learn to walk short distances independently between 12 and 15 months.
Macrogyria
MedGen UID:
120579
Concept ID:
C0266483
Congenital Abnormality
Pachygyria is a malformation of cortical development with abnormally wide gyri with sulci 1,5-3 cm apart and abnormally thick cortex measuring more than 5 mm (radiological definition). See also neuropathological definitions for 2-, 3-, and 4-layered lissencephaly.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
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.
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.
Focal-onset seizure
MedGen UID:
199670
Concept ID:
C0751495
Disease or Syndrome
A focal-onset seizure is a type of seizure originating within networks limited to one hemisphere. They may be discretely localized or more widely distributed, and may originate in subcortical structures.
Inappropriate crying
MedGen UID:
810697
Concept ID:
C0860609
Sign or Symptom
Uncontrolled episodes of crying occur without any apparent motivating stimuli.
Reduced eye contact
MedGen UID:
303190
Concept ID:
C1445953
Finding
A reduced frequency or duration of eye contact.
Tongue thrusting
MedGen UID:
473491
Concept ID:
C1829460
Finding
Pressing forward of the tongue in the mouth, a retained motoric habit from infantile swallowing patterns
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Hypoplasia of the frontal lobes
MedGen UID:
341396
Concept ID:
C1849172
Finding
Underdevelopment of the frontal lobe of the cerebrum.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
Simplified gyral pattern
MedGen UID:
413664
Concept ID:
C2749675
Finding
An abnormality of the cerebral cortex with fewer gyri but with normal cortical thickness. This pattern is usually often associated with congenital microcephaly.
Delayed CNS myelination
MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Delayed myelination in the central nervous system.
Reduced social responsiveness
MedGen UID:
868342
Concept ID:
C4022736
Finding
A reduced ability to participate in the back-and-forth flow of social interaction appropriate to culture and developmental level, which is normally characterized by an influence of the behavior of one person on the behavior of another person. This results in difficulty interacting with others through emotional, physical, or verbal communication.
Delayed ability to sit
MedGen UID:
1368737
Concept ID:
C4476710
Finding
A failure to achieve the ability to sit at an appropriate developmental stage. Most children sit with support at 6 months of age and sit steadily without support at 9 months of age.
Kyphosis
MedGen UID:
44042
Concept ID:
C0022821
Anatomical Abnormality
Exaggerated anterior convexity of the thoracic vertebral column.
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.
Progressive microcephaly
MedGen UID:
340542
Concept ID:
C1850456
Anatomical Abnormality
Progressive microcephaly is diagnosed when the head circumference falls progressively behind age- and gender-dependent norms.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Neonatal hypotonia
MedGen UID:
412209
Concept ID:
C2267233
Disease or Syndrome
Muscular hypotonia (abnormally low muscle tone) manifesting in the neonatal period.
Aspiration
MedGen UID:
751786
Concept ID:
C2712334
Finding
Inspiration of a foreign object into the airway.
Drooling
MedGen UID:
8484
Concept ID:
C0013132
Finding
Habitual flow of saliva out of the mouth.
Bulbous nose
MedGen UID:
66013
Concept ID:
C0240543
Finding
Increased volume and globular shape of the anteroinferior aspect of the nose.
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
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.
Thin upper lip vermilion
MedGen UID:
355352
Concept ID:
C1865017
Finding
Height of the vermilion of the upper lip in the midline more than 2 SD below the mean. Alternatively, an apparently reduced height of the vermilion of the upper lip in the frontal view (subjective).

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVRett syndrome, congenital variant

Professional guidelines

PubMed

Tzetis M, Kitsiou-Tzeli S, Frysira H, Xaidara A, Kanavakis E
Expert Rev Mol Diagn 2012 Jun;12(5):449-57. doi: 10.1586/erm.12.40. PMID: 22702362

Recent clinical studies

Etiology

Mazel B, Delanne J, Garde A, Racine C, Bruel AL, Duffourd Y, Lopergolo D, Santorelli FM, Marchi V, Pinto AM, Mencarelli MA, Canitano R, Valentino F, Papa FT, Fallerini C, Mari F, Renieri A, Munnich A, Niclass T, Le Guyader G, Thauvin-Robinet C, Philippe C, Faivre L
Am J Med Genet B Neuropsychiatr Genet 2024 Sep;195(6):e32970. Epub 2024 Mar 8 doi: 10.1002/ajmg.b.32970. PMID: 38459409
Croci S, Carriero ML, Capitani K, Daga S, Donati F, Papa FT, Frullanti E, Lopergolo D, Lamacchia V, Tita R, Giliberti A, Benetti E, Niccheri F, Furini S, Lo Rizzo C, Conticello SG, Renieri A, Meloni I
Eur J Hum Genet 2020 Oct;28(10):1446-1458. Epub 2020 Jun 15 doi: 10.1038/s41431-020-0652-6. PMID: 32541681Free PMC Article
Shiohama T, Levman J, Takahashi E
Int J Dev Neurosci 2019 Apr;73:83-88. Epub 2019 Jan 25 doi: 10.1016/j.ijdevneu.2019.01.005. PMID: 30690146Free PMC Article
Ariani F, Hayek G, Rondinella D, Artuso R, Mencarelli MA, Spanhol-Rosseto A, Pollazzon M, Buoni S, Spiga O, Ricciardi S, Meloni I, Longo I, Mari F, Broccoli V, Zappella M, Renieri A
Am J Hum Genet 2008 Jul;83(1):89-93. Epub 2008 Jun 19 doi: 10.1016/j.ajhg.2008.05.015. PMID: 18571142Free PMC Article
Muhle R, Trentacoste SV, Rapin I
Pediatrics 2004 May;113(5):e472-86. doi: 10.1542/peds.113.5.e472. PMID: 15121991

Diagnosis

Ghirardo S, Sabatini L, Onofri A, Testa MBC, Paglietti MG, Diodato D, Travaglini L, Stregapede F, Ciofi Degli Atti ML, Cherchi C, Cutrera R
Ital J Pediatr 2022 Sep 7;48(1):167. doi: 10.1186/s13052-022-01359-7. PMID: 36071486Free PMC Article
Kobayashi Y, Ohashi T, Akasaka N, Tohyama J
Brain Dev 2012 Aug;34(7):601-4. Epub 2011 Oct 15 doi: 10.1016/j.braindev.2011.09.014. PMID: 22001500
Rajaei S, Erlandson A, Kyllerman M, Albage M, Lundstrom I, Karrstedt EL, Hagberg B
J Child Neurol 2011 Jan;26(1):65-71. doi: 10.1177/0883073810374125. PMID: 21212452
Le Guen T, Bahi-Buisson N, Nectoux J, Boddaert N, Fichou Y, Diebold B, Desguerre I, Raqbi F, Daire VC, Chelly J, Bienvenu T
Neurogenetics 2011 Feb;12(1):1-8. Epub 2010 Aug 24 doi: 10.1007/s10048-010-0255-4. PMID: 20734096
Muhle R, Trentacoste SV, Rapin I
Pediatrics 2004 May;113(5):e472-86. doi: 10.1542/peds.113.5.e472. PMID: 15121991

Therapy

Leoncini S, De Felice C, Signorini C, Pecorelli A, Durand T, Valacchi G, Ciccoli L, Hayek J
Redox Rep 2011;16(4):145-53. doi: 10.1179/1351000211Y.0000000004. PMID: 21888765Free PMC Article
Hoffbuhr KC, Moses LM, Jerdonek MA, Naidu S, Hoffman EP
Ment Retard Dev Disabil Res Rev 2002;8(2):99-105. doi: 10.1002/mrdd.10026. PMID: 12112735

Prognosis

Mazel B, Delanne J, Garde A, Racine C, Bruel AL, Duffourd Y, Lopergolo D, Santorelli FM, Marchi V, Pinto AM, Mencarelli MA, Canitano R, Valentino F, Papa FT, Fallerini C, Mari F, Renieri A, Munnich A, Niclass T, Le Guyader G, Thauvin-Robinet C, Philippe C, Faivre L
Am J Med Genet B Neuropsychiatr Genet 2024 Sep;195(6):e32970. Epub 2024 Mar 8 doi: 10.1002/ajmg.b.32970. PMID: 38459409
Ellaway CJ, Ho G, Bettella E, Knapman A, Collins F, Hackett A, McKenzie F, Darmanian A, Peters GB, Fagan K, Christodoulou J
Eur J Hum Genet 2013 May;21(5):522-7. Epub 2012 Sep 12 doi: 10.1038/ejhg.2012.208. PMID: 22968132Free PMC Article
Tzetis M, Kitsiou-Tzeli S, Frysira H, Xaidara A, Kanavakis E
Expert Rev Mol Diagn 2012 Jun;12(5):449-57. doi: 10.1586/erm.12.40. PMID: 22702362
Le Guen T, Bahi-Buisson N, Nectoux J, Boddaert N, Fichou Y, Diebold B, Desguerre I, Raqbi F, Daire VC, Chelly J, Bienvenu T
Neurogenetics 2011 Feb;12(1):1-8. Epub 2010 Aug 24 doi: 10.1007/s10048-010-0255-4. PMID: 20734096
Mencarelli MA, Kleefstra T, Katzaki E, Papa FT, Cohen M, Pfundt R, Ariani F, Meloni I, Mari F, Renieri A
Eur J Med Genet 2009 Mar-Jun;52(2-3):148-52. Epub 2009 Mar 19 doi: 10.1016/j.ejmg.2009.03.004. PMID: 19303466

Clinical prediction guides

Harada K, Yamamoto M, Konishi Y, Koyano K, Takahashi S, Namba M, Kusaka T
Brain Dev 2018 Jan;40(1):49-52. Epub 2017 Aug 7 doi: 10.1016/j.braindev.2017.07.007. PMID: 28781028
Bertossi C, Cassina M, Cappellari A, Toldo I, Nosadini M, Rigon C, Suppiej A, Sartori S
Neuropediatrics 2015 Feb;46(1):56-64. Epub 2015 Jan 7 doi: 10.1055/s-0034-1395345. PMID: 25565401
De Filippis R, Pancrazi L, Bjørgo K, Rosseto A, Kleefstra T, Grillo E, Panighini A, Cardarelli F, Meloni I, Ariani F, Mencarelli MA, Hayek J, Renieri A, Costa M, Mari F
Clin Genet 2012 Oct;82(4):395-403. Epub 2011 Dec 13 doi: 10.1111/j.1399-0004.2011.01810.x. PMID: 22091895
Leoncini S, De Felice C, Signorini C, Pecorelli A, Durand T, Valacchi G, Ciccoli L, Hayek J
Redox Rep 2011;16(4):145-53. doi: 10.1179/1351000211Y.0000000004. PMID: 21888765Free PMC Article
Le Guen T, Bahi-Buisson N, Nectoux J, Boddaert N, Fichou Y, Diebold B, Desguerre I, Raqbi F, Daire VC, Chelly J, Bienvenu T
Neurogenetics 2011 Feb;12(1):1-8. Epub 2010 Aug 24 doi: 10.1007/s10048-010-0255-4. PMID: 20734096

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