Severe intellectual disability-progressive spastic diplegia syndrome: Difference between revisions

Severe intellectual disability-progressive spastic diplegia syndrome
Severe intellectual disability-progressive spastic diplegia syndrome
Other names	CTNNB1 syndrome, CTNNB1-related intellectual disability, Intellectual disability, autosomal dominant 19
Specialty	Medical genetics, Pediatry
Causes	Genetic mutation
Prevention	none
Prognosis	good
Frequency	rare, only 1 out of 50,000 live births have this condition
Deaths	-

Browse history interactively

← Previous edit Next edit →

Content deleted Content added

VisualWikitext

Inline

Revision as of 05:20, 6 September 2022

Severe intellectual disability-progressive spastic diplegia syndrome is a rare novel genetic disorder characterized by severe intellectual disabilities, ataxia, craniofacial dysmorphisms, and muscle spasticity.^[2]It is a type of autosomal dominant syndromic intellectual disability.^[3]^[4]^[5]^[6]^[7]

Signs and symptoms

Individuals with this condition typically show severe intellectual disability, motor delays, severe speech delay and difficulties, infancy-onset hypotonia affecting the trunk, progressive hypertonia affecting the distal limbs, severe progressive microcephaly, autistic-like symptoms, aggresive behavior towards others and/or oneself, sleep abnormalities, and mild facial dysmorphisms such as broad nose, hypoplastic alae nasi, elongated/flattened philtrum, and thin upper lip.^[8]^[9]

Other symptoms include seizures, nearsightedness, farsightedness, strabismus, syringomyelia, ventriculomegaly, corpus callosum hypoplasia, hearing difficulties, and delay of CNS myelination.^[10]

In rarer cases, a child with the condition might be born with polydactyly.^[11]

Complications

Most symptoms which characterize this condition arise as a result of the profound intellectual disability associated with this condition, these symptoms can cause more complications, such as communication difficulties, poor school performance, etc.^[8]

Diagnosis

This condition can be diagnosed through physical examination and genetic testing.

Genetics

This condition is caused by heterozygous mutations in the CTNNB1 gene, located in the short arm of chromosome 3.^[12]^[13]^[14]^[15]^[16] The condition, although genetic, is typically not inherited, except in rare cases where it is^[17], as it is usually the result of a de novo mutation.^[18] Insertions, deletions, and other types of mutations have been reported.^[19]

This gene produces a protein called "beta-catenin", which is present in various cells and tissues within the body. It is important for cell adhesion, cell communication, cell signaling, and in the normal development and function of hair follicles.^[20]^[21]^[22]

Treatment

Treatment methods include occupational therapy, physical therapy, speech therapy, assistive services, constant monitoring and family counseling.^[23]^[24]

Prevalence

This condition affects 1 out of 50,000 children worldwide.^[25]

Cases

The following list comprises some cases of severe intellectual disability-progressive spastic diplegia syndrome (from the OMIM page for this condition):

2012: de Ligt et al. describes 2 patients from a group of 100 patients with severe intellectual disability, said 2 patients had a mutation in the CTNNB1 gene. One of these patients was a 29 year old woman (named patient 70) who started showing signs of developmental regression when she was 6 months old, which was then followed by a moderate-severe developmental delay. She hit the milestone of sitting at the age of 2 years old and learned how to walk at the age of 12. Her first words were spoken between the ages of 9 and 10. She started showing behavioral anomalies at a young age, which consisted in aggressive behavior, self-harming behavior by automutilation, and her recurrent acts of smearing fecal matter on nearby surfaces. She was affected by microcephaly and short stature at the age of 29. She also had other mild facial dysmorphisms, such as high-arched, narrow palate, posteriorly rotated small ears, long philtrum, and low columella. They also found another patient with CTNNB1 mutation out of a group of 785 patients with intellectual disability. All of these patients had severe intellectual disabilities, speech delays, microcephaly, spasticity, and walking difficulties.^[26]

2014: Tucci et al. describes a fourth affected patient. The patient suffered from microcephaly, thin upper lip, autism, early-onset hypotonia, progressive spastic diplegia, and from hypoplasia of the corpus callosum.^[27]

2014: Dubruc et al. describes a 5 and a half year old girl of Caucasian descent born to healthy, un-related parents. She was affected by fetal/antenatal growth delays. Her birth was eventful, as her umbilical cord ended up wrapped around her neck and consequently, in neonatal respiratory distress syndrome. She started showing symptoms such as progressive microcephaly, hypotonia of the trunk, psychomotor delays, and speech impairments. She had a friendly and energetic personality, the latter of which was due to her hyperactivity. She had fair skin, sparse, thin hair, low-set ears, ataxia, spasticity, hyperreflexia, thin lips, a sacral dimple, and was farsighted. Genetic testing found a heterozygous 333-kb deletion in chromosome 3 which deleted the entire CTNNB1 gene and the last 3 exons of the ULK4 gene, his deleterious mutation was not found in both of her parents, thus leaving with the conclusion that it was sporadic, and not inherited.^[28]

2015: Kuechler et al. describes 16 patients from 15 families who were confirmed to have the disorder through genetic testing, there was an equal distribution of affected males and affected females (8 girls and 8 boys). The following paragraph comprises the symptoms, with the ones listed at the top being the most prevalent ones and the ones listed at the bottom being the least prevalent ones; intellectual disabilities, infancy-onset psychomotor delays, speech impairments, facial dysmorphisms, spasticity, visual refractory errors, autistic-like symptoms with aggression, and microcephaly. Seizures and hearing impairments were not observed.^[29]

2017: Kharbanda et al. describes 11 patients with the condition identified through interrogation of the DECIPHER database. Said patients had a mutation of the inactivating kind in the CTNNB1 gene. Out of the 11 patients, 10 had available medical details, these included intellectual disabilities, progressive microcephaly, hypotonia of the trunk, peripheral spasticity, behavioral problems, mild facial dysmorphisms, fair skin and hair, and abnormal hair patterns.^[30]

2017: Li et al. describes a 1 year, 3 month old boy of Chinese descent who suffered from retinal detachment and vitreous and lens opacity. He had no reaction to light. After testing negative for the mutations involved in exudative vitreoretinopathy, Li et al. found a heterozygous de novo nonsense mutation in his CTNNB1 gene. Other features exhibited by the child included developmental delays, mild thumb adduction, and microcephaly.^[31]

2017: Panagiotou et al. describes a 3 year old boy of Chinese descent who suffered from exudative vitreoretinopathy, developmental delays, and facial dysmorphisms who was later found to have a de novo 1 bp insertion in his CTNNB1 gene.^[32]

Animal model

In 2004, Tucci et al. made an animal model consisting of mice (named "batface") with a heterozygous mutation (later named "T653K") located in the C-terminal amardillo repeat of the CTNNB1 gene. Said mice exhibited craniofacial dysmorphisms such as short nose, broad face, short anteroposterior axis. Altered brain morphology with signs such as larger structures of the deep brain, reduced volume of the cerebellum and the olfactory bulb, and corpus callosum hypoplasia. Altered behavior and cognitive function with signs such as motor defects, less complexity in vocalization, poor hippocampus-dependant memory, and deficits in pre+pulse inhibition. In vitro studies revealed that the T653K mutation 'disrupted the association between CTNNB1 and cadherin', which was consistent wuth a "dominant-negative effect". Abnormally high length and number of neurons, alongside diminished dendritic branching was present in the brains of heterozygous mutant mice. CTNNB1 knockdown (by the usage of siRNA) resulted in decreasing of neuronal processes and length, which lead the researchers to believe T653K is a loss-of-function type of mutation. Electrophysiologic tests showed that the neurons of mutated mice exhibited higher neural network excitability alongside decreased efficiency of functional connectivity. These results showed that CTNNB1 is important in various aspects of neurodevelopmental and synaptic function.^[27]

Organizations

The following list comprises some of the organizations which help patients with this condition:

The CTNNB1 Foundation is an organization for the parents of children with the condition whose main goal is to be able to give children with CTNNB1 syndrome the opportunity of a gene therapy treatment.^[33]

The CTNNB1 Syndrome Awareness Worldwide is an organization which aims at increasing awareness of this condition across the world. It also provides information on CTNNB1 syndrome to parents of children with the condition.^[34]

The CureCTNNB1 is an organization which helps raise funding for research on CTNNB1 syndrome.^[35]

Media coverage

This condition has been covered by a small number of news networks from Spain.^[36]^[37]^[38]^[39]^[40]

References

^ https://rarediseases.org/gard-rare-disease/severe-intellectual-disability-progressive-spastic-diplegia-syndrome/
^ "Severe intellectual disability-progressive spastic diplegia syndrome (Concept Id: C3554449) - MedGen - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-09-05.
^ Winczewska-Wiktor A, Badura-Stronka M, Monies-Nowicka A, Nowicki MM, Steinborn B, Latos-Bieleńska A, Monies D (March 2016). "A de novo CTNNB1 nonsense mutation associated with syndromic atypical hyperekplexia, microcephaly and intellectual disability: a case report". BMC Neurology. 16 (1): 35. doi:10.1186/s12883-016-0554-y. PMC 4788907. PMID 26968164.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Verhoeven WM, Egger JI, Jongbloed RE, van Putten MM, de Bruin-van Zandwijk M, Zwemer AS, et al. (2020-10-07). "A de novo CTNNB1 Novel Splice Variant in an Adult Female with Severe Intellectual Disability". International Medical Case Reports Journal. 13: 487–492. doi:10.2147/IMCRJ.S270487. PMID 33116939.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ "KEGG DISEASE: Autosomal dominant intellectual developmental disorder". www.genome.jp. Retrieved 2022-09-05.
^ "autosomal dominant intellectual developmental disorder 19 Disease Ontology Browser - DOID:0070049". www.informatics.jax.org. Retrieved 2022-09-05.
^ "Open Targets Platform". platform.opentargets.org. Retrieved 2022-09-05.
^ ^a ^b INSERM US14. "Orphanet: Severe intellectual disability progressive spastic diplegia syndrome". www.orpha.net. Retrieved 2022-09-05.{{cite web}}: CS1 maint: numeric names: authors list (link)
^ "Urban's story – CTNNB1 Foundation". Retrieved 2022-09-05.
^ "Severe intellectual disability-progressive spastic diplegia syndrome - About the Disease - Genetic and Rare Diseases Information Center". rarediseases.info.nih.gov. Retrieved 2022-09-05.
^ Ke Z, Chen Y (2020). "Case Report: A de novo CTNNB1 Nonsense Mutation Associated With Neurodevelopmental Disorder, Retinal Detachment, Polydactyly". Frontiers in Pediatrics. 8: 575673. doi:10.3389/fped.2020.575673/full. PMID 33425807.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ "Severe Intellectual Disability-Progressive Spastic Diplegia Syndrome". DoveMed. Retrieved 2022-09-05.
^ "Severe intellectual disability-progressive spastic diplegia syndrome". Rare Hematology News. Retrieved 2022-09-05.
^ "Deletion of CTNNB1 in inhibitory circuitry contributes to autism-associated behavioral defects". academic.oup.com. Retrieved 2022-09-05.
^ Verhoeven WM, Egger JI, Jongbloed RE, van Putten MM, de Bruin-van Zandwijk M, Zwemer AS, et al. (2020-10-07). "A de novo CTNNB1 Novel Splice Variant in an Adult Female with Severe Intellectual Disability". International Medical Case Reports Journal. 13: 487–492. doi:10.2147/IMCRJ.S270487. PMID 33116939.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Sun W, Xiao X, Li S, Jia X, Wang P, Zhang Q (January 2019). "Germline Mutations in CTNNB1 Associated With Syndromic FEVR or Norrie Disease". Investigative Ophthalmology & Visual Science. 60 (1): 93–97. doi:10.1167/iovs.18-25142. PMID 30640974.
^ Wang H, Zhao Y, Yang L, Han S, Qi M (August 2019). "Identification of a novel splice mutation in CTNNB1 gene in a Chinese family with both severe intellectual disability and serious visual defects". Neurological Sciences. 40 (8): 1701–1704. doi:10.1007/s10072-019-03823-5. PMC 6647480. PMID 30929091.
^ Ho SK, Tsang MH, Lee M, Cheng SS, Luk HM, Lo IF, Chung BH (1993). "CTNNB1 Neurodevelopmental Disorder". In Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, Amemiya A (eds.). GeneReviews. Seattle (WA): University of Washington, Seattle. PMID 35593792. Retrieved 2022-09-05.
^ "Entry - #615075 - NEURODEVELOPMENTAL DISORDER WITH SPASTIC DIPLEGIA AND VISUAL DEFECTS; NEDSDV - OMIM". omim.org. Retrieved 2022-09-05.
^ "CTNNB1 gene: MedlinePlus Genetics". medlineplus.gov. Retrieved 2022-09-05.
^ "CTNNB1 Gene - GeneCards | CTNB1 Protein | CTNB1 Antibody". www.genecards.org. Retrieved 2022-09-05.
^ "CTNNB1".
^ Byrd F. "Intellectual Disability in Children". WebMD. Retrieved 2022-09-05.
^ Patel DR, Cabral MD, Ho A, Merrick J (February 2020). "A clinical primer on intellectual disability". Translational Pediatrics. 9 (Suppl 1): S23–S35. doi:10.21037/tp.2020.02.02. PMID 32206581.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ "CTNNB1 syndrome – CTNNB1 Foundation". Retrieved 2022-09-05.
^ de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, et al. (November 2012). "Diagnostic exome sequencing in persons with severe intellectual disability". The New England Journal of Medicine. 367 (20): 1921–1929. doi:10.1056/NEJMoa1206524. PMID 23033978.
^ ^a ^b Tucci V, Kleefstra T, Hardy A, Heise I, Maggi S, Willemsen MH, et al. (April 2014). "Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features". The Journal of Clinical Investigation. 124 (4): 1468–1482. doi:10.1172/JCI70372. PMC 3973091. PMID 24614104.
^ Dubruc E, Putoux A, Labalme A, Rougeot C, Sanlaville D, Edery P (June 2014). "A new intellectual disability syndrome caused by CTNNB1 haploinsufficiency". American Journal of Medical Genetics. Part A. 164A (6): 1571–1575. doi:10.1002/ajmg.a.36484. PMID 24668549.
^ Kuechler A, Willemsen MH, Albrecht B, Bacino CA, Bartholomew DW, van Bokhoven H, et al. (January 2015). "De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum". Human Genetics. 134 (1): 97–109. doi:10.1007/s00439-014-1498-1. PMID 25326669.
^ Kharbanda M, Pilz DT, Tomkins S, Chandler K, Saggar A, Fryer A, et al. (February 2017). "Clinical features associated with CTNNB1 de novo loss of function mutations in ten individuals". European Journal of Medical Genetics. 60 (2): 130–135. doi:10.1016/j.ejmg.2016.11.008. PMC 6070129. PMID 27915094.
^ Li N, Xu Y, Li G, Yu T, Yao RE, Wang X, Wang J (May 2017). "Exome sequencing identifies a de novo mutation of CTNNB1 gene in a patient mainly presented with retinal detachment, lens and vitreous opacities, microcephaly, and developmental delay: Case report and literature review". Medicine. 96 (20): e6914. doi:10.1097/MD.0000000000006914. PMC 5440144. PMID 28514307.
^ Panagiotou ES, Sanjurjo Soriano C, Poulter JA, Lord EC, Dzulova D, Kondo H, et al. (June 2017). "Defects in the Cell Signaling Mediator β-Catenin Cause the Retinal Vascular Condition FEVR". American Journal of Human Genetics. 100 (6): 960–968. doi:10.1016/j.ajhg.2017.05.001. PMC 5473728. PMID 28575650.
^ "CTNNB1 Foundation – CTNNB1 Syndrome". Retrieved 2022-09-05.
^ "CTNNB1 Syndrome | Ctnnb1.org | About Us". ctnnb1. Retrieved 2022-09-05.
^ "Advancing CTNNB1 Cures & Treatments | Be Part of the Cure". Advancing CTNNB1 Cures & Treatments. Retrieved 2022-09-05.
^ Menni R. "Paula nació con síndrome CTNNB1. Nuestra Unidad Infantil de Bilbao la ayuda a vivir mejor | Red Menni" (in European Spanish). Retrieved 2022-09-05.
^ "¿Qué es el síndrome CTNNB1, el trastorno que se confunde con el autismo?". Mundo Deportivo (in Spanish). 2021-05-26. Retrieved 2022-09-05.
^ "Regusa solidaria - Dando a conocer el síndrome CTNNB1". Regusa (in Spanish). 2022-05-05. Retrieved 2022-09-05.
^ "«Si mi hija consigue andar y hablar sería algo grandioso»". El Correo (in Spanish). 2021-07-12. Retrieved 2022-09-05.
^ "Diez familias se unen para dar a conocer un síndrome que se confunde con el autismo". Salud (in European Spanish). 2021-05-23. Retrieved 2022-09-05.

[1] ttps://rarediseases.org/gard-rare-disease/severe-intellectual-disability-progressive-spastic-diplegia-syndrome/

[2] "Severe intellectual disability-progressive spastic diplegia syndrome (Concept Id: C3554449) - MedGen - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-09-05.

[3] Winczewska-Wiktor A, Badura-Stronka M, Monies-Nowicka A, Nowicki MM, Steinborn B, Latos-Bieleńska A, Monies D (March 2016). "A de novo CTNNB1 nonsense mutation associated with syndromic atypical hyperekplexia, microcephaly and intellectual disability: a case report". BMC Neurology. 16 (1): 35. doi:10.1186/s12883-016-0554-y. PMC 4788907. PMID 26968164.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[4] Verhoeven WM, Egger JI, Jongbloed RE, van Putten MM, de Bruin-van Zandwijk M, Zwemer AS, et al. (2020-10-07). "A de novo CTNNB1 Novel Splice Variant in an Adult Female with Severe Intellectual Disability". International Medical Case Reports Journal. 13: 487–492. doi:10.2147/IMCRJ.S270487. PMID 33116939.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[5] "KEGG DISEASE: Autosomal dominant intellectual developmental disorder". www.genome.jp. Retrieved 2022-09-05.

[6] "autosomal dominant intellectual developmental disorder 19 Disease Ontology Browser - DOID:0070049". www.informatics.jax.org. Retrieved 2022-09-05.

[7] "Open Targets Platform". platform.opentargets.org. Retrieved 2022-09-05.

[:0-8] INSERM US14. "Orphanet: Severe intellectual disability progressive spastic diplegia syndrome". www.orpha.net. Retrieved 2022-09-05.{{cite web}}: CS1 maint: numeric names: authors list (link)

[9] "Urban's story – CTNNB1 Foundation". Retrieved 2022-09-05.

[10] "Severe intellectual disability-progressive spastic diplegia syndrome - About the Disease - Genetic and Rare Diseases Information Center". rarediseases.info.nih.gov. Retrieved 2022-09-05.

[11] Ke Z, Chen Y (2020). "Case Report: A de novo CTNNB1 Nonsense Mutation Associated With Neurodevelopmental Disorder, Retinal Detachment, Polydactyly". Frontiers in Pediatrics. 8: 575673. doi:10.3389/fped.2020.575673/full. PMID 33425807.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[12] "Severe Intellectual Disability-Progressive Spastic Diplegia Syndrome". DoveMed. Retrieved 2022-09-05.

[13] "Severe intellectual disability-progressive spastic diplegia syndrome". Rare Hematology News. Retrieved 2022-09-05.

[14] "Deletion of CTNNB1 in inhibitory circuitry contributes to autism-associated behavioral defects". academic.oup.com. Retrieved 2022-09-05.

[15] Verhoeven WM, Egger JI, Jongbloed RE, van Putten MM, de Bruin-van Zandwijk M, Zwemer AS, et al. (2020-10-07). "A de novo CTNNB1 Novel Splice Variant in an Adult Female with Severe Intellectual Disability". International Medical Case Reports Journal. 13: 487–492. doi:10.2147/IMCRJ.S270487. PMID 33116939.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[16] Sun W, Xiao X, Li S, Jia X, Wang P, Zhang Q (January 2019). "Germline Mutations in CTNNB1 Associated With Syndromic FEVR or Norrie Disease". Investigative Ophthalmology & Visual Science. 60 (1): 93–97. doi:10.1167/iovs.18-25142. PMID 30640974.

[17] Wang H, Zhao Y, Yang L, Han S, Qi M (August 2019). "Identification of a novel splice mutation in CTNNB1 gene in a Chinese family with both severe intellectual disability and serious visual defects". Neurological Sciences. 40 (8): 1701–1704. doi:10.1007/s10072-019-03823-5. PMC 6647480. PMID 30929091.

[18] Ho SK, Tsang MH, Lee M, Cheng SS, Luk HM, Lo IF, Chung BH (1993). "CTNNB1 Neurodevelopmental Disorder". In Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, Amemiya A (eds.). GeneReviews. Seattle (WA): University of Washington, Seattle. PMID 35593792. Retrieved 2022-09-05.

[:2-19] "Entry - #615075 - NEURODEVELOPMENTAL DISORDER WITH SPASTIC DIPLEGIA AND VISUAL DEFECTS; NEDSDV - OMIM". omim.org. Retrieved 2022-09-05.

[20] "CTNNB1 gene: MedlinePlus Genetics". medlineplus.gov. Retrieved 2022-09-05.

[21] "CTNNB1 Gene - GeneCards | CTNB1 Protein | CTNB1 Antibody". www.genecards.org. Retrieved 2022-09-05.

[22] "CTNNB1".

[23] Byrd F. "Intellectual Disability in Children". WebMD. Retrieved 2022-09-05.

[24] Patel DR, Cabral MD, Ho A, Merrick J (February 2020). "A clinical primer on intellectual disability". Translational Pediatrics. 9 (Suppl 1): S23–S35. doi:10.21037/tp.2020.02.02. PMID 32206581.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[25] "CTNNB1 syndrome – CTNNB1 Foundation". Retrieved 2022-09-05.

[26] Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, et al. (November 2012). "Diagnostic exome sequencing in persons with severe intellectual disability". The New England Journal of Medicine. 367 (20): 1921–1929. doi:10.1056/NEJMoa1206524. PMID 23033978.

[:1-27] Tucci V, Kleefstra T, Hardy A, Heise I, Maggi S, Willemsen MH, et al. (April 2014). "Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features". The Journal of Clinical Investigation. 124 (4): 1468–1482. doi:10.1172/JCI70372. PMC 3973091. PMID 24614104.

[28] Dubruc E, Putoux A, Labalme A, Rougeot C, Sanlaville D, Edery P (June 2014). "A new intellectual disability syndrome caused by CTNNB1 haploinsufficiency". American Journal of Medical Genetics. Part A. 164A (6): 1571–1575. doi:10.1002/ajmg.a.36484. PMID 24668549.

[29] Kuechler A, Willemsen MH, Albrecht B, Bacino CA, Bartholomew DW, van Bokhoven H, et al. (January 2015). "De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum". Human Genetics. 134 (1): 97–109. doi:10.1007/s00439-014-1498-1. PMID 25326669.

[30] Kharbanda M, Pilz DT, Tomkins S, Chandler K, Saggar A, Fryer A, et al. (February 2017). "Clinical features associated with CTNNB1 de novo loss of function mutations in ten individuals". European Journal of Medical Genetics. 60 (2): 130–135. doi:10.1016/j.ejmg.2016.11.008. PMC 6070129. PMID 27915094.

[31] Li N, Xu Y, Li G, Yu T, Yao RE, Wang X, Wang J (May 2017). "Exome sequencing identifies a de novo mutation of CTNNB1 gene in a patient mainly presented with retinal detachment, lens and vitreous opacities, microcephaly, and developmental delay: Case report and literature review". Medicine. 96 (20): e6914. doi:10.1097/MD.0000000000006914. PMC 5440144. PMID 28514307.

[32] Panagiotou ES, Sanjurjo Soriano C, Poulter JA, Lord EC, Dzulova D, Kondo H, et al. (June 2017). "Defects in the Cell Signaling Mediator β-Catenin Cause the Retinal Vascular Condition FEVR". American Journal of Human Genetics. 100 (6): 960–968. doi:10.1016/j.ajhg.2017.05.001. PMC 5473728. PMID 28575650.

[33] "CTNNB1 Foundation – CTNNB1 Syndrome". Retrieved 2022-09-05.

[34] "CTNNB1 Syndrome | Ctnnb1.org | About Us". ctnnb1. Retrieved 2022-09-05.

[35] "Advancing CTNNB1 Cures & Treatments | Be Part of the Cure". Advancing CTNNB1 Cures & Treatments. Retrieved 2022-09-05.

[36] Menni R. "Paula nació con síndrome CTNNB1. Nuestra Unidad Infantil de Bilbao la ayuda a vivir mejor | Red Menni" (in European Spanish). Retrieved 2022-09-05.

[37] "¿Qué es el síndrome CTNNB1, el trastorno que se confunde con el autismo?". Mundo Deportivo (in Spanish). 2021-05-26. Retrieved 2022-09-05.

[38] "Regusa solidaria - Dando a conocer el síndrome CTNNB1". Regusa (in Spanish). 2022-05-05. Retrieved 2022-09-05.

[39] "«Si mi hija consigue andar y hablar sería algo grandioso»". El Correo (in Spanish). 2021-07-12. Retrieved 2022-09-05.

[40] "Diez familias se unen para dar a conocer un síndrome que se confunde con el autismo". Salud (in European Spanish). 2021-05-23. Retrieved 2022-09-05.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

@@ Line 34: / Line 34: @@
 }}
-'''Severe intellectual disability-progressive spastic diplegia syndrome''' is a rare novel [[genetic disorder]] characterized by severe [[intellectual disabilities]], [[ataxia]], [[Dysmorphic feature|craniofacial dysmorphisms]], and muscle [[spasticity]].<ref>{{Cite web |title=Severe intellectual disability-progressive spastic diplegia syndrome (Concept Id: C3554449) - MedGen - NCBI |url=https://www.ncbi.nlm.nih.gov/medgen/767363 |access-date=2022-09-05 |website=www.ncbi.nlm.nih.gov |language=en}}</ref>It is a type of autosomal dominant syndromic intellectual disability.<ref>{{Cite journal |last=Winczewska-Wiktor |first=Anna |last2=Badura-Stronka |first2=Magdalena |last3=Monies-Nowicka |first3=Anna |last4=Nowicki |first4=Michal Maciej |last5=Steinborn |first5=Barbara |last6=Latos-Bieleńska |first6=Anna |last7=Monies |first7=Dorota |date=2016-03-12 |title=A de novo CTNNB1 nonsense mutation associated with syndromic atypical hyperekplexia, microcephaly and intellectual disability: a case report |url=https://doi.org/10.1186/s12883-016-0554-y |journal=BMC Neurology |volume=16 |issue=1 |pages=35 |doi=10.1186/s12883-016-0554-y |issn=1471-2377 |pmc=PMC4788907 |pmid=26968164}}</ref><ref>{{Cite journal |last=Verhoeven |first=Willem MA |last2=Egger |first2=Jos IM |last3=Jongbloed |first3=Rob E. |last4=Putten |first4=Marloes Meijer van |last5=Zandwijk |first5=Marieke de Bruin-van |last6=Zwemer |first6=Anne-Suus |last7=Pfundt |first7=Rolph |last8=Willemsen |first8=Marjolein H. |date=2020-10-07 |title=A de novo CTNNB1 Novel Splice Variant in an Adult Female with Severe Intellectual Disability |url=https://www.dovepress.com/a-de-novo-ctnnb1-novel-splice-variant-in-an-adult-female-with-severe-i-peer-reviewed-fulltext-article-IMCRJ |journal=International Medical Case Reports Journal |language=English |volume=13 |pages=487–492 |doi=10.2147/IMCRJ.S270487}}</ref><ref>{{Cite web |title=KEGG DISEASE: Autosomal dominant intellectual developmental disorder |url=https://www.genome.jp/dbget-bin/www_bget?H00773 |access-date=2022-09-05 |website=www.genome.jp}}</ref><ref>{{Cite web |title=autosomal dominant intellectual developmental disorder 19 Disease Ontology Browser - DOID:0070049 |url=http://www.informatics.jax.org/disease/DOID:0070049 |access-date=2022-09-05 |website=www.informatics.jax.org}}</ref><ref>{{Cite web |title=Open Targets Platform |url=https://platform.opentargets.org/ |access-date=2022-09-05 |website=platform.opentargets.org |language=en}}</ref>
+'''Severe intellectual disability-progressive spastic diplegia syndrome''' is a rare novel [[genetic disorder]] characterized by severe [[intellectual disabilities]], [[ataxia]], [[Dysmorphic feature|craniofacial dysmorphisms]], and muscle [[spasticity]].<ref>{{Cite web |title=Severe intellectual disability-progressive spastic diplegia syndrome (Concept Id: C3554449) - MedGen - NCBI |url=https://www.ncbi.nlm.nih.gov/medgen/767363 |access-date=2022-09-05 |website=www.ncbi.nlm.nih.gov |language=en}}</ref>It is a type of autosomal dominant syndromic intellectual disability.<ref>{{cite journal | vauthors = Winczewska-Wiktor A, Badura-Stronka M, Monies-Nowicka A, Nowicki MM, Steinborn B, Latos-Bieleńska A, Monies D | title = A de novo CTNNB1 nonsense mutation associated with syndromic atypical hyperekplexia, microcephaly and intellectual disability: a case report | journal = BMC Neurology | volume = 16 | issue = 1 | pages = 35 | date = March 2016 | pmid = 26968164 | pmc = 4788907 | doi = 10.1186/s12883-016-0554-y }}</ref><ref>{{cite journal | vauthors = Verhoeven WM, Egger JI, Jongbloed RE, van Putten MM, de Bruin-van Zandwijk M, Zwemer AS, Pfundt R, Willemsen MH | display-authors = 6 | title = A de novo <i>CTNNB1</i> Novel Splice Variant in an Adult Female with Severe Intellectual Disability | language = English | journal = International Medical Case Reports Journal | volume = 13 | pages = 487–492 | date = 2020-10-07 | pmid = 33116939 | doi = 10.2147/IMCRJ.S270487 }}</ref><ref>{{Cite web |title=KEGG DISEASE: Autosomal dominant intellectual developmental disorder |url=https://www.genome.jp/dbget-bin/www_bget?H00773 |access-date=2022-09-05 |website=www.genome.jp}}</ref><ref>{{Cite web |title=autosomal dominant intellectual developmental disorder 19 Disease Ontology Browser - DOID:0070049 |url=http://www.informatics.jax.org/disease/DOID:0070049 |access-date=2022-09-05 |website=www.informatics.jax.org}}</ref><ref>{{Cite web |title=Open Targets Platform |url=https://platform.opentargets.org/ |access-date=2022-09-05 |website=platform.opentargets.org |language=en}}</ref>
 == Signs and symptoms ==
-Individuals with this condition typically show severe intellectual disability, [[psychomotor retardation|motor delays]], severe [[speech delay]] and difficulties, infancy-onset hypotonia affecting the [[trunk]], progressive hypertonia affecting the distal limbs, severe progressive [[microcephaly]], [[Autism|autistic-like symptoms]], aggresive behavior towards others and/or [[Self harm|oneself]], sleep abnormalities, and mild facial dysmorphisms such as broad nose, hypoplastic [[alae nasi]], elongated/flattened [[philtrum]], and thin upper lip.<ref name=":0">{{Cite web |last=RESERVED |first=INSERM US14-- ALL RIGHTS |title=Orphanet: Severe intellectual disability progressive spastic diplegia syndrome |url=https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=404473 |access-date=2022-09-05 |website=www.orpha.net |language=en}}</ref><ref>{{Cite web |title=Urban’s story – CTNNB1 Foundation |url=https://ctnnb1-foundation.org/urbans-story/ |access-date=2022-09-05 |language=en-GB}}</ref>
+Individuals with this condition typically show severe intellectual disability, [[psychomotor retardation|motor delays]], severe [[speech delay]] and difficulties, infancy-onset hypotonia affecting the [[trunk]], progressive hypertonia affecting the distal limbs, severe progressive [[microcephaly]], [[Autism|autistic-like symptoms]], aggresive behavior towards others and/or [[Self harm|oneself]], sleep abnormalities, and mild facial dysmorphisms such as broad nose, hypoplastic [[alae nasi]], elongated/flattened [[philtrum]], and thin upper lip.<ref name=":0">{{Cite web  | author = INSERM US14  |title=Orphanet: Severe intellectual disability progressive spastic diplegia syndrome |url=https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=404473 |access-date=2022-09-05 |website=www.orpha.net |language=en}}</ref><ref>{{cite web |title=Urban’s story – CTNNB1 Foundation |url=https://ctnnb1-foundation.org/urbans-story/ |access-date=2022-09-05 |language=en-GB}}</ref>
 Other symptoms include [[seizures]], [[nearsightedness]], [[farsightedness]], [[strabismus]], [[syringomyelia]], [[ventriculomegaly]], [[corpus callosum]] hypoplasia, hearing difficulties, and delay of CNS myelination.<ref>{{Cite web |title=Severe intellectual disability-progressive spastic diplegia syndrome - About the Disease - Genetic and Rare Diseases Information Center |url=https://rarediseases.info.nih.gov/diseases/3505/severe-intellectual-disability-progressive-spastic-diplegia-syndrome |access-date=2022-09-05 |website=rarediseases.info.nih.gov |language=en}}</ref>
-In rarer cases, a child with the condition might be born with [[polydactyly]].<ref>{{Cite journal |last=Zhongling |first=KE, |last2=Yanhui |first2=CHEN, |date=2020 |title=Case Report: A de novo CTNNB1 Nonsense Mutation Associated With Neurodevelopmental Disorder, Retinal Detachment, Polydactyly |url=https://www.frontiersin.org/articles/10.3389/fped.2020.575673/full |journal=Frontiers in Pediatrics |language=English |volume=0 |doi=10.3389/fped.2020.575673/full |issn=2296-2360}}</ref>
+In rarer cases, a child with the condition might be born with [[polydactyly]].<ref>{{cite journal | vauthors = Ke Z, Chen Y | title = Case Report: A <i>de novo</i> CTNNB1 Nonsense Mutation Associated With Neurodevelopmental Disorder, Retinal Detachment, Polydactyly | language = English | journal = Frontiers in Pediatrics | volume = 8 | pages = 575673 | date = 2020 | pmid = 33425807 | doi = 10.3389/fped.2020.575673/full }}</ref>
 == Complications ==
@@ Line 54: / Line 54: @@
 == Genetics ==
-This condition is caused by heterozygous mutations in the [[CTNNB1]] gene, located in the short arm of [[chromosome 3]].<ref>{{Cite web |title=Severe Intellectual Disability-Progressive Spastic Diplegia Syndrome |url=http://www.dovemed.com/diseases-conditions/severe-intellectual-disability-progressive-spastic-diplegia-syndrome/ |access-date=2022-09-05 |website=DoveMed |language=en}}</ref><ref>{{Cite web |title=Severe intellectual disability-progressive spastic diplegia syndrome |url=https://www.rarehematologynews.com/rarediseases/severe-intellectual-disability-progressive-spastic-diplegia-syndrome/ |access-date=2022-09-05 |website=Rare Hematology News |language=en-US}}</ref><ref>{{Cite web |title=Deletion of CTNNB1 in inhibitory circuitry contributes to autism-associated behavioral defects |url=https://academic.oup.com/hmg/article/25/13/2738/2525756 |access-date=2022-09-05 |website=academic.oup.com}}</ref><ref>{{Cite journal |last=Verhoeven |first=Willem MA |last2=Egger |first2=Jos IM |last3=Jongbloed |first3=Rob E. |last4=Putten |first4=Marloes Meijer van |last5=Zandwijk |first5=Marieke de Bruin-van |last6=Zwemer |first6=Anne-Suus |last7=Pfundt |first7=Rolph |last8=Willemsen |first8=Marjolein H. |date=2020-10-07 |title=A de novo CTNNB1 Novel Splice Variant in an Adult Female with Severe Intellectual Disability |url=https://www.dovepress.com/a-de-novo-ctnnb1-novel-splice-variant-in-an-adult-female-with-severe-i-peer-reviewed-fulltext-article-IMCRJ |journal=International Medical Case Reports Journal |language=English |volume=13 |pages=487–492 |doi=10.2147/IMCRJ.S270487}}</ref><ref>{{Cite journal |last=Sun |first=Wenmin |last2=Xiao |first2=Xueshan |last3=Li |first3=Shiqiang |last4=Jia |first4=Xiaoyun |last5=Wang |first5=Panfeng |last6=Zhang |first6=Qingjiong |date=2019-01-02 |title=Germline Mutations in CTNNB1 Associated With Syndromic FEVR or Norrie Disease |url=https://iovs.arvojournals.org/article.aspx?articleid=2720409 |journal=Investigative Ophthalmology & Visual Science |language=en |volume=60 |issue=1 |pages=93–97 |doi=10.1167/iovs.18-25142 |issn=1552-5783}}</ref> The condition, although genetic, is typically not inherited, except in rare cases where it is<ref>{{Cite journal |last=Wang |first=Hui |last2=Zhao |first2=Yiqi |last3=Yang |first3=Liwei |last4=Han |first4=Shuai |last5=Qi |first5=Ming |date=2019-08-01 |title=Identification of a novel splice mutation in CTNNB1 gene in a Chinese family with both severe intellectual disability and serious visual defects |url=https://doi.org/10.1007/s10072-019-03823-5 |journal=Neurological Sciences |language=en |volume=40 |issue=8 |pages=1701–1704 |doi=10.1007/s10072-019-03823-5 |issn=1590-3478 |pmc=PMC6647480 |pmid=30929091}}</ref>, as it is usually the result of a [[de novo mutation]].<ref>{{Citation |last=Ho |first=Stephanie KL |title=CTNNB1 Neurodevelopmental Disorder |date=1993 |url=http://www.ncbi.nlm.nih.gov/books/NBK580527/ |work=GeneReviews® |editor-last=Adam |editor-first=Margaret P. |place=Seattle (WA) |publisher=University of Washington, Seattle |pmid=35593792 |access-date=2022-09-05 |last2=Tsang |first2=Mandy HY |last3=Lee |first3=Mianne |last4=Cheng |first4=Shirley SW |last5=Luk |first5=Ho-ming |last6=Lo |first6=Ivan FM |last7=Chung |first7=Brian HY |editor2-last=Everman |editor2-first=David B. |editor3-last=Mirzaa |editor3-first=Ghayda M. |editor4-last=Pagon |editor4-first=Roberta A.}}</ref> [[Indels|Insertions]], deletions, and other types of mutations have been reported.<ref name=":2">{{Cite web |title=Entry - #615075 - NEURODEVELOPMENTAL DISORDER WITH SPASTIC DIPLEGIA AND VISUAL DEFECTS; NEDSDV - OMIM |url=https://omim.org/entry/615075 |access-date=2022-09-05 |website=omim.org |language=en-us}}</ref>
+This condition is caused by heterozygous mutations in the [[CTNNB1]] gene, located in the short arm of [[chromosome 3]].<ref>{{Cite web |title=Severe Intellectual Disability-Progressive Spastic Diplegia Syndrome |url=http://www.dovemed.com/diseases-conditions/severe-intellectual-disability-progressive-spastic-diplegia-syndrome/ |access-date=2022-09-05 |website=DoveMed |language=en}}</ref><ref>{{Cite web |title=Severe intellectual disability-progressive spastic diplegia syndrome |url=https://www.rarehematologynews.com/rarediseases/severe-intellectual-disability-progressive-spastic-diplegia-syndrome/ |access-date=2022-09-05 |website=Rare Hematology News |language=en-US}}</ref><ref>{{Cite web |title=Deletion of CTNNB1 in inhibitory circuitry contributes to autism-associated behavioral defects |url=https://academic.oup.com/hmg/article/25/13/2738/2525756 |access-date=2022-09-05 |website=academic.oup.com}}</ref><ref>{{cite journal | vauthors = Verhoeven WM, Egger JI, Jongbloed RE, van Putten MM, de Bruin-van Zandwijk M, Zwemer AS, Pfundt R, Willemsen MH | display-authors = 6 | title = A de novo <i>CTNNB1</i> Novel Splice Variant in an Adult Female with Severe Intellectual Disability | language = English | journal = International Medical Case Reports Journal | volume = 13 | pages = 487–492 | date = 2020-10-07 | pmid = 33116939 | doi = 10.2147/IMCRJ.S270487 }}</ref><ref>{{cite journal | vauthors = Sun W, Xiao X, Li S, Jia X, Wang P, Zhang Q | title = Germline Mutations in CTNNB1 Associated With Syndromic FEVR or Norrie Disease | journal = Investigative Ophthalmology & Visual Science | volume = 60 | issue = 1 | pages = 93–97 | date = January 2019 | pmid = 30640974 | doi = 10.1167/iovs.18-25142 }}</ref> The condition, although genetic, is typically not inherited, except in rare cases where it is<ref>{{cite journal | vauthors = Wang H, Zhao Y, Yang L, Han S, Qi M | title = Identification of a novel splice mutation in CTNNB1 gene in a Chinese family with both severe intellectual disability and serious visual defects | journal = Neurological Sciences | volume = 40 | issue = 8 | pages = 1701–1704 | date = August 2019 | pmid = 30929091 | pmc = 6647480 | doi = 10.1007/s10072-019-03823-5 }}</ref>, as it is usually the result of a [[de novo mutation]].<ref>{{cite book | vauthors = Ho SK, Tsang MH, Lee M, Cheng SS, Luk HM, Lo IF, Chung BH | chapter = CTNNB1 Neurodevelopmental Disorder |date=1993 | chapter-url= http://www.ncbi.nlm.nih.gov/books/NBK580527/ | veditors = Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, Amemiya A | title = GeneReviews |place=Seattle (WA) |publisher=University of Washington, Seattle |pmid=35593792 |access-date=2022-09-05 }}</ref> [[Indels|Insertions]], deletions, and other types of mutations have been reported.<ref name=":2">{{Cite web |title=Entry - #615075 - NEURODEVELOPMENTAL DISORDER WITH SPASTIC DIPLEGIA AND VISUAL DEFECTS; NEDSDV - OMIM |url=https://omim.org/entry/615075 |access-date=2022-09-05 |website=omim.org |language=en-us}}</ref>
 This gene produces a protein called "beta-catenin", which is present in various cells and tissues within the body. It is important for cell adhesion, cell communication, cell signaling, and in the normal development and function of hair follicles.<ref>{{Cite web |title=CTNNB1 gene: MedlinePlus Genetics |url=https://medlineplus.gov/genetics/gene/ctnnb1/ |access-date=2022-09-05 |website=medlineplus.gov |language=en}}</ref><ref>{{Cite web |title=CTNNB1 Gene - GeneCards {{!}} CTNB1 Protein {{!}} CTNB1 Antibody |url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=CTNNB1 |access-date=2022-09-05 |website=www.genecards.org}}</ref><ref>{{Cite web |title=CTNNB1 |url=https://www.sigmaaldrich.com/MX/es/genes/ctnnb1}}</ref>
@@ Line 60: / Line 60: @@
 == Treatment ==
-Treatment methods include [[occupational therapy]], [[physical therapy]], [[speech therapy]], assistive services, constant monitoring and family counseling.<ref>{{Cite web |last=Byrd |first=Florence |title=Intellectual Disability in Children |url=https://www.webmd.com/parenting/baby/child-intellectual-disability |access-date=2022-09-05 |website=WebMD |language=en}}</ref><ref>{{Cite journal |last=Patel |first=Dilip R. |last2=Cabral |first2=Maria Demma |last3=Ho |first3=Arlene |last4=Merrick |first4=Joav |date=2020-02-01 |title=A clinical primer on intellectual disability |url=https://tp.amegroups.com/article/view/36118 |journal=Translational Pediatrics |language=en |volume=9 |issue=S1 |pages=S23–S2S35 |doi=10.21037/tp.2020.02.02 |issn=2224-4344}}</ref>
+Treatment methods include [[occupational therapy]], [[physical therapy]], [[speech therapy]], assistive services, constant monitoring and family counseling.<ref>{{Cite web | vauthors = Byrd F |title=Intellectual Disability in Children |url=https://www.webmd.com/parenting/baby/child-intellectual-disability |access-date=2022-09-05 |website=WebMD |language=en}}</ref><ref>{{cite journal | vauthors = Patel DR, Cabral MD, Ho A, Merrick J | title = A clinical primer on intellectual disability | journal = Translational Pediatrics | volume = 9 | issue = Suppl 1 | pages = S23-S35 | date = February 2020 | pmid = 32206581 | doi = 10.21037/tp.2020.02.02 }}</ref>
 == Prevalence ==
@@ Line 70: / Line 70: @@
 The following list comprises some cases of severe intellectual disability-progressive spastic diplegia syndrome (from the OMIM page for this condition):
-*2012: de Ligt et al. describes 2 patients from a group of 100 patients with severe intellectual disability, said 2 patients had a mutation in the CTNNB1 gene. One of these patients was a 29 year old woman (named ''patient 70'') who started showing signs of [[developmental regression]] when she was 6 months old, which was then followed by a moderate-severe [[developmental delay]]. She hit the milestone of sitting at the age of 2 years old and learned how to walk at the age of 12. Her first words were spoken between the ages of 9 and 10. She started showing behavioral anomalies at a young age, which consisted in aggressive behavior, self-harming behavior by automutilation, and her recurrent acts of smearing fecal matter on nearby surfaces. She was affected by [[microcephaly]] and [[short stature]] at the age of 29. She also had other mild facial dysmorphisms, such as [[high-arched palate|high-arched]], [[narrow palate|narrow]] palate, posteriorly rotated [[microtia|small ears]], long [[philtrum]], and low [[columella]]. They also found another patient with CTNNB1 mutation out of a group of 785 patients with intellectual disability. All of these patients had severe intellectual disabilities, speech delays, microcephaly, spasticity, and walking difficulties.<ref>{{Cite journal |last=de Ligt |first=Joep |last2=Willemsen |first2=Marjolein H. |last3=van Bon |first3=Bregje W. M. |last4=Kleefstra |first4=Tjitske |last5=Yntema |first5=Helger G. |last6=Kroes |first6=Thessa |last7=Vulto-van Silfhout |first7=Anneke T. |last8=Koolen |first8=David A. |last9=de Vries |first9=Petra |last10=Gilissen |first10=Christian |last11=del Rosario |first11=Marisol |last12=Hoischen |first12=Alexander |last13=Scheffer |first13=Hans |last14=de Vries |first14=Bert B. A. |last15=Brunner |first15=Han G. |date=2012-11-15 |title=Diagnostic exome sequencing in persons with severe intellectual disability |url=https://pubmed.ncbi.nlm.nih.gov/23033978/ |journal=The New England Journal of Medicine |volume=367 |issue=20 |pages=1921–1929 |doi=10.1056/NEJMoa1206524 |issn=1533-4406 |pmid=23033978}}</ref>
+*2012: de Ligt et al. describes 2 patients from a group of 100 patients with severe intellectual disability, said 2 patients had a mutation in the CTNNB1 gene. One of these patients was a 29 year old woman (named ''patient 70'') who started showing signs of [[developmental regression]] when she was 6 months old, which was then followed by a moderate-severe [[developmental delay]]. She hit the milestone of sitting at the age of 2 years old and learned how to walk at the age of 12. Her first words were spoken between the ages of 9 and 10. She started showing behavioral anomalies at a young age, which consisted in aggressive behavior, self-harming behavior by automutilation, and her recurrent acts of smearing fecal matter on nearby surfaces. She was affected by [[microcephaly]] and [[short stature]] at the age of 29. She also had other mild facial dysmorphisms, such as [[high-arched palate|high-arched]], [[narrow palate|narrow]] palate, posteriorly rotated [[microtia|small ears]], long [[philtrum]], and low [[columella]]. They also found another patient with CTNNB1 mutation out of a group of 785 patients with intellectual disability. All of these patients had severe intellectual disabilities, speech delays, microcephaly, spasticity, and walking difficulties.<ref>{{cite journal | vauthors = de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C, del Rosario M, Hoischen A, Scheffer H, de Vries BB, Brunner HG, Veltman JA, Vissers LE | display-authors = 6 | title = Diagnostic exome sequencing in persons with severe intellectual disability | journal = The New England Journal of Medicine | volume = 367 | issue = 20 | pages = 1921–1929 | date = November 2012 | pmid = 23033978 | doi = 10.1056/NEJMoa1206524 }}</ref>
-*2014: Tucci et al. describes a fourth affected patient. The patient suffered from [[microcephaly]], thin upper lip, [[autism]], early-onset hypotonia, progressive [[spastic diplegia]], and from hypoplasia of the corpus callosum.<ref name=":1">{{Cite journal |last=Tucci |first=Valter |last2=Kleefstra |first2=Tjitske |last3=Hardy |first3=Andrea |last4=Heise |first4=Ines |last5=Maggi |first5=Silvia |last6=Willemsen |first6=Marjolein H. |last7=Hilton |first7=Helen |last8=Esapa |first8=Chris |last9=Simon |first9=Michelle |last10=Buenavista |first10=Maria-Teresa |last11=McGuffin |first11=Liam J. |last12=Vizor |first12=Lucie |last13=Dodero |first13=Luca |last14=Tsaftaris |first14=Sotirios |last15=Romero |first15=Rosario |date=April 2014 |title=Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features |url=https://pubmed.ncbi.nlm.nih.gov/24614104/ |journal=The Journal of Clinical Investigation |volume=124 |issue=4 |pages=1468–1482 |doi=10.1172/JCI70372 |issn=1558-8238 |pmc=3973091 |pmid=24614104}}</ref>
+*2014: Tucci et al. describes a fourth affected patient. The patient suffered from [[microcephaly]], thin upper lip, [[autism]], early-onset hypotonia, progressive [[spastic diplegia]], and from hypoplasia of the corpus callosum.<ref name=":1">{{cite journal | vauthors = Tucci V, Kleefstra T, Hardy A, Heise I, Maggi S, Willemsen MH, Hilton H, Esapa C, Simon M, Buenavista MT, McGuffin LJ, Vizor L, Dodero L, Tsaftaris S, Romero R, Nillesen WN, Vissers LE, Kempers MJ, Vulto-van Silfhout AT, Iqbal Z, Orlando M, Maccione A, Lassi G, Farisello P, Contestabile A, Tinarelli F, Nieus T, Raimondi A, Greco B, Cantatore D, Gasparini L, Berdondini L, Bifone A, Gozzi A, Wells S, Nolan PM | display-authors = 6 | title = Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features | journal = The Journal of Clinical Investigation | volume = 124 | issue = 4 | pages = 1468–1482 | date = April 2014 | pmid = 24614104 | pmc = 3973091 | doi = 10.1172/JCI70372 }}</ref>
-*2014: Dubruc et al. describes a 5 and a half year old girl of Caucasian descent born to healthy, un-related parents. She was affected by fetal/antenatal growth delays. Her birth was eventful, as her umbilical cord ended up wrapped around her neck and consequently, in [[neonatal respiratory distress syndrome]]. She started showing symptoms such as progressive microcephaly, hypotonia of the trunk, psychomotor delays, and speech impairments. She had a friendly and energetic personality, the latter of which was due to her [[hyperactivity]]. She had [[fair skin]], sparse, thin hair, [[low-set ears]], ataxia, spasticity, hyperreflexia, thin lips, a [[sacral dimple]], and was farsighted. Genetic testing found a heterozygous 333-kb deletion in [[chromosome 3]] which deleted the entire CTNNB1 gene and the last 3 exons of the ULK4 gene, his deleterious mutation was not found in both of her parents, thus leaving with the conclusion that it was sporadic, and not inherited.<ref>{{Cite journal |last=Dubruc |first=Estelle |last2=Putoux |first2=Audrey |last3=Labalme |first3=Audrey |last4=Rougeot |first4=Christelle |last5=Sanlaville |first5=Damien |last6=Edery |first6=Patrick |date=June 2014 |title=A new intellectual disability syndrome caused by CTNNB1 haploinsufficiency |url=https://pubmed.ncbi.nlm.nih.gov/24668549/ |journal=American Journal of Medical Genetics. Part A |volume=164A |issue=6 |pages=1571–1575 |doi=10.1002/ajmg.a.36484 |issn=1552-4833 |pmid=24668549}}</ref>
+*2014: Dubruc et al. describes a 5 and a half year old girl of Caucasian descent born to healthy, un-related parents. She was affected by fetal/antenatal growth delays. Her birth was eventful, as her umbilical cord ended up wrapped around her neck and consequently, in [[neonatal respiratory distress syndrome]]. She started showing symptoms such as progressive microcephaly, hypotonia of the trunk, psychomotor delays, and speech impairments. She had a friendly and energetic personality, the latter of which was due to her [[hyperactivity]]. She had [[fair skin]], sparse, thin hair, [[low-set ears]], ataxia, spasticity, hyperreflexia, thin lips, a [[sacral dimple]], and was farsighted. Genetic testing found a heterozygous 333-kb deletion in [[chromosome 3]] which deleted the entire CTNNB1 gene and the last 3 exons of the ULK4 gene, his deleterious mutation was not found in both of her parents, thus leaving with the conclusion that it was sporadic, and not inherited.<ref>{{cite journal | vauthors = Dubruc E, Putoux A, Labalme A, Rougeot C, Sanlaville D, Edery P | title = A new intellectual disability syndrome caused by CTNNB1 haploinsufficiency | journal = American Journal of Medical Genetics. Part A | volume = 164A | issue = 6 | pages = 1571–1575 | date = June 2014 | pmid = 24668549 | doi = 10.1002/ajmg.a.36484 }}</ref>
-*2015: Kuechler et al. describes 16 patients from 15 families who were confirmed to have the disorder through genetic testing, there was an equal distribution of affected males and affected females (8 girls and 8 boys). The following paragraph comprises the symptoms, with the ones listed at the top being the most prevalent ones and the ones listed at the bottom being the least prevalent ones; intellectual disabilities, infancy-onset psychomotor delays, speech impairments, facial dysmorphisms, spasticity, visual refractory errors, autistic-like symptoms with aggression, and [[microcephaly]]. Seizures and hearing impairments were not observed.<ref>{{Cite journal |last=Kuechler |first=Alma |last2=Willemsen |first2=Marjolein H. |last3=Albrecht |first3=Beate |last4=Bacino |first4=Carlos A. |last5=Bartholomew |first5=Dennis W. |last6=van Bokhoven |first6=Hans |last7=van den Boogaard |first7=Marie Jose H. |last8=Bramswig |first8=Nuria |last9=Büttner |first9=Christian |last10=Cremer |first10=Kirsten |last11=Czeschik |first11=Johanna Christina |last12=Engels |first12=Hartmut |last13=van Gassen |first13=Koen |last14=Graf |first14=Elisabeth |last15=van Haelst |first15=Mieke |date=January 2015 |title=De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum |url=https://pubmed.ncbi.nlm.nih.gov/25326669/ |journal=Human Genetics |volume=134 |issue=1 |pages=97–109 |doi=10.1007/s00439-014-1498-1 |issn=1432-1203 |pmid=25326669}}</ref>
+*2015: Kuechler et al. describes 16 patients from 15 families who were confirmed to have the disorder through genetic testing, there was an equal distribution of affected males and affected females (8 girls and 8 boys). The following paragraph comprises the symptoms, with the ones listed at the top being the most prevalent ones and the ones listed at the bottom being the least prevalent ones; intellectual disabilities, infancy-onset psychomotor delays, speech impairments, facial dysmorphisms, spasticity, visual refractory errors, autistic-like symptoms with aggression, and [[microcephaly]]. Seizures and hearing impairments were not observed.<ref>{{cite journal | vauthors = Kuechler A, Willemsen MH, Albrecht B, Bacino CA, Bartholomew DW, van Bokhoven H, van den Boogaard MJ, Bramswig N, Büttner C, Cremer K, Czeschik JC, Engels H, van Gassen K, Graf E, van Haelst M, He W, Hogue JS, Kempers M, Koolen D, Monroe G, de Munnik S, Pastore M, Reis A, Reuter MS, Tegay DH, Veltman J, Visser G, van Hasselt P, Smeets EE, Vissers L, Wieland T, Wissink W, Yntema H, Zink AM, Strom TM, Lüdecke HJ, Kleefstra T, Wieczorek D | display-authors = 6 | title = De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum | journal = Human Genetics | volume = 134 | issue = 1 | pages = 97–109 | date = January 2015 | pmid = 25326669 | doi = 10.1007/s00439-014-1498-1 }}</ref>
-*2017: Kharbanda et al. describes 11 patients with the condition identified through interrogation of the [[DECIPHER]] database. Said patients had a mutation of the inactivating kind in the CTNNB1 gene. Out of the 11 patients, 10 had available medical details, these included [[intellectual disabilities]], progressive [[microcephaly]], hypotonia of the trunk, peripheral spasticity, behavioral problems, mild facial dysmorphisms, fair skin and hair, and abnormal hair patterns.<ref>{{Cite journal |last=Kharbanda |first=Mira |last2=Pilz |first2=Daniela T. |last3=Tomkins |first3=Susan |last4=Chandler |first4=Kate |last5=Saggar |first5=Anand |last6=Fryer |first6=Alan |last7=McKay |first7=Victoria |last8=Louro |first8=Pedro |last9=Smith |first9=Jill Clayton |last10=Burn |first10=John |last11=Kini |first11=Usha |last12=De Burca |first12=Anna |last13=FitzPatrick |first13=David R. |last14=Kinning |first14=Esther |last15=DDD Study |date=February 2017 |title=Clinical features associated with CTNNB1 de novo loss of function mutations in ten individuals |url=https://pubmed.ncbi.nlm.nih.gov/27915094/ |journal=European Journal of Medical Genetics |volume=60 |issue=2 |pages=130–135 |doi=10.1016/j.ejmg.2016.11.008 |issn=1878-0849 |pmc=6070129 |pmid=27915094}}</ref>
+*2017: Kharbanda et al. describes 11 patients with the condition identified through interrogation of the [[DECIPHER]] database. Said patients had a mutation of the inactivating kind in the CTNNB1 gene. Out of the 11 patients, 10 had available medical details, these included [[intellectual disabilities]], progressive [[microcephaly]], hypotonia of the trunk, peripheral spasticity, behavioral problems, mild facial dysmorphisms, fair skin and hair, and abnormal hair patterns.<ref>{{cite journal | vauthors = Kharbanda M, Pilz DT, Tomkins S, Chandler K, Saggar A, Fryer A, McKay V, Louro P, Smith JC, Burn J, Kini U, De Burca A, FitzPatrick DR, Kinning E | display-authors = 6 | title = Clinical features associated with CTNNB1 de novo loss of function mutations in ten individuals | journal = European Journal of Medical Genetics | volume = 60 | issue = 2 | pages = 130–135 | date = February 2017 | pmid = 27915094 | pmc = 6070129 | doi = 10.1016/j.ejmg.2016.11.008 }}</ref>
-*2017: Li et al. describes a 1 year, 3 month old boy of Chinese descent who suffered from [[retinal detachment]] and vitreous and lens opacity. He had no reaction to light. After testing negative for the mutations involved in [[exudative vitreoretinopathy]], Li et al. found a heterozygous de novo nonsense mutation in his CTNNB1 gene. Other features exhibited by the child included [[developmental delays]], mild [[thumb adduction]], and [[microcephaly]].<ref>{{Cite journal |last=Li |first=Niu |last2=Xu |first2=Yufei |last3=Li |first3=Guoqiang |last4=Yu |first4=Tingting |last5=Yao |first5=Ru-En |last6=Wang |first6=Xiumin |last7=Wang |first7=Jian |date=May 2017 |title=Exome sequencing identifies a de novo mutation of CTNNB1 gene in a patient mainly presented with retinal detachment, lens and vitreous opacities, microcephaly, and developmental delay: Case report and literature review |url=https://pubmed.ncbi.nlm.nih.gov/28514307/ |journal=Medicine |volume=96 |issue=20 |pages=e6914 |doi=10.1097/MD.0000000000006914 |issn=1536-5964 |pmc=5440144 |pmid=28514307}}</ref>
+*2017: Li et al. describes a 1 year, 3 month old boy of Chinese descent who suffered from [[retinal detachment]] and vitreous and lens opacity. He had no reaction to light. After testing negative for the mutations involved in [[exudative vitreoretinopathy]], Li et al. found a heterozygous de novo nonsense mutation in his CTNNB1 gene. Other features exhibited by the child included [[developmental delays]], mild [[thumb adduction]], and [[microcephaly]].<ref>{{cite journal | vauthors = Li N, Xu Y, Li G, Yu T, Yao RE, Wang X, Wang J | title = Exome sequencing identifies a de novo mutation of CTNNB1 gene in a patient mainly presented with retinal detachment, lens and vitreous opacities, microcephaly, and developmental delay: Case report and literature review | journal = Medicine | volume = 96 | issue = 20 | pages = e6914 | date = May 2017 | pmid = 28514307 | pmc = 5440144 | doi = 10.1097/MD.0000000000006914 }}</ref>
-*2017: Panagiotou et al. describes a 3 year old boy of Chinese descent who suffered from exudative vitreoretinopathy, developmental delays, and facial dysmorphisms who was later found to have a de novo 1 bp insertion in his CTNNB1 gene.<ref>{{Cite journal |last=Panagiotou |first=Evangelia S. |last2=Sanjurjo Soriano |first2=Carla |last3=Poulter |first3=James A. |last4=Lord |first4=Emma C. |last5=Dzulova |first5=Denisa |last6=Kondo |first6=Hiroyuki |last7=Hiyoshi |first7=Atsushi |last8=Chung |first8=Brian Hon-Yin |last9=Chu |first9=Yoyo Wing-Yiu |last10=Lai |first10=Connie H. Y. |last11=Tafoya |first11=Mark E. |last12=Karjosukarso |first12=Dyah |last13=Collin |first13=Rob W. J. |last14=Topping |first14=Joanne |last15=Downey |first15=Louise M. |date=2017-06-01 |title=Defects in the Cell Signaling Mediator β-Catenin Cause the Retinal Vascular Condition FEVR |url=https://pubmed.ncbi.nlm.nih.gov/28575650/ |journal=American Journal of Human Genetics |volume=100 |issue=6 |pages=960–968 |doi=10.1016/j.ajhg.2017.05.001 |issn=1537-6605 |pmc=5473728 |pmid=28575650}}</ref>
+*2017: Panagiotou et al. describes a 3 year old boy of Chinese descent who suffered from exudative vitreoretinopathy, developmental delays, and facial dysmorphisms who was later found to have a de novo 1 bp insertion in his CTNNB1 gene.<ref>{{cite journal | vauthors = Panagiotou ES, Sanjurjo Soriano C, Poulter JA, Lord EC, Dzulova D, Kondo H, Hiyoshi A, Chung BH, Chu YW, Lai CH, Tafoya ME, Karjosukarso D, Collin RW, Topping J, Downey LM, Ali M, Inglehearn CF, Toomes C | display-authors = 6 | title = Defects in the Cell Signaling Mediator β-Catenin Cause the Retinal Vascular Condition FEVR | journal = American Journal of Human Genetics | volume = 100 | issue = 6 | pages = 960–968 | date = June 2017 | pmid = 28575650 | pmc = 5473728 | doi = 10.1016/j.ajhg.2017.05.001 }}</ref>
 == Animal model ==
@@ Line 100: / Line 100: @@
 == Media coverage ==
-This condition has been covered by a small number of news networks from [[Spain]].<ref>{{Cite web |last=Menni |first=Red |title=Paula nació con síndrome CTNNB1. Nuestra Unidad Infantil de Bilbao la ayuda a vivir mejor {{!}} Red Menni |url=https://xn--daocerebral-2db.es/paula-nacio-con-sindrome-ctnnb1-nuestra-unidad-infantil-de-bilbao-la-ayuda-a-vivir-mejor/ |access-date=2022-09-05 |language=es-ES}}</ref><ref>{{Cite web |date=2021-05-26 |title=¿Qué es el síndrome CTNNB1, el trastorno que se confunde con el autismo? |url=https://www.mundodeportivo.com/vidae/salud/20210526/493941347676/sindrome-ctnnb1-trastorno-alteracion-cromosoma-autismo-act-pau.html |access-date=2022-09-05 |website=Mundo Deportivo |language=es}}</ref><ref>{{Cite web |date=2022-05-05 |title=Regusa solidaria - Dando a conocer el síndrome CTNNB1 |url=https://gruporegusa.com/2022/05/05/regusa-solidaria-dando-a-conocer-el-sindrome-ctnnb1/ |access-date=2022-09-05 |website=Regusa |language=es}}</ref><ref>{{Cite web |date=2021-07-12 |title=«Si mi hija consigue andar y hablar sería algo grandioso» |url=https://www.elcorreo.com/bizkaia/nervion/hija-consigue-andar-20210713210131-nt.html |access-date=2022-09-05 |website=El Correo |language=es}}</ref><ref>{{Cite web |date=2021-05-23 |title=Diez familias se unen para dar a conocer un síndrome que se confunde con el autismo |url=https://www.20minutos.es/noticia/4705798/0/diez-familias-se-unen-para-dar-a-conocer-un-sindrome-que-se-confunde-con-el-autismo/ |access-date=2022-09-05 |website=Salud |language=es-ES}}</ref>
+This condition has been covered by a small number of news networks from [[Spain]].<ref>{{Cite web | vauthors = Menni R |title=Paula nació con síndrome CTNNB1. Nuestra Unidad Infantil de Bilbao la ayuda a vivir mejor {{!}} Red Menni |url=https://xn--daocerebral-2db.es/paula-nacio-con-sindrome-ctnnb1-nuestra-unidad-infantil-de-bilbao-la-ayuda-a-vivir-mejor/ |access-date=2022-09-05 |language=es-ES}}</ref><ref>{{Cite web |date=2021-05-26 |title=¿Qué es el síndrome CTNNB1, el trastorno que se confunde con el autismo? |url=https://www.mundodeportivo.com/vidae/salud/20210526/493941347676/sindrome-ctnnb1-trastorno-alteracion-cromosoma-autismo-act-pau.html |access-date=2022-09-05 |website=Mundo Deportivo |language=es}}</ref><ref>{{Cite web |date=2022-05-05 |title=Regusa solidaria - Dando a conocer el síndrome CTNNB1 |url=https://gruporegusa.com/2022/05/05/regusa-solidaria-dando-a-conocer-el-sindrome-ctnnb1/ |access-date=2022-09-05 |website=Regusa |language=es}}</ref><ref>{{Cite web |date=2021-07-12 |title=«Si mi hija consigue andar y hablar sería algo grandioso» |url=https://www.elcorreo.com/bizkaia/nervion/hija-consigue-andar-20210713210131-nt.html |access-date=2022-09-05 |website=El Correo |language=es}}</ref><ref>{{Cite web |date=2021-05-23 |title=Diez familias se unen para dar a conocer un síndrome que se confunde con el autismo |url=https://www.20minutos.es/noticia/4705798/0/diez-familias-se-unen-para-dar-a-conocer-un-sindrome-que-se-confunde-con-el-autismo/ |access-date=2022-09-05 |website=Salud |language=es-ES}}</ref>
 == See also ==