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O que é Coffin-Siris syndrome?
Coffin-Siris syndrome, também conhecido como CSS ou 5 º dígito síndromes, é caracterizado por características faciais ásperas e 5 o dedo da mão ou da mão do pé subdesenvolvido. Sintomas pode variar entre os indivíduos que apresentam o síndromes.
Condições de saúde associadas a Coffin-Siris syndrome pode incluir anormalidades que afetam os olhos, cérebro, coração e rins.
Quais mudanças genéticas causam Coffin-Siris syndrome?
Coffin-Siris syndromeocorre devido a mutações nos seguintes genes: ARID1A, ARID1B, SMARCA4, SMARCB1, DPF2, SMARCE1. É herdado em um padrão autossômico dominante.
No caso de herança autossômica dominante, apenas um dos pais é o portador da mutação do gene e eles têm 50% de chance de passá-la para cada um de seus filhos. Síndromes herdados em uma herança autossômica dominante são causados por apenas uma cópia da mutação do gene.
Genes, localizações e modos de herança:
ARID1A, 1 p36. 11 - Autossômico dominante
ARID2, 1 p36. 11 - Autossômico dominante
SMARCB1, 22 q11. 23 - Autossômico dominante
SOX11, 2 p25. 2 - Autossômico dominante
SMARCA1, Xq25-q26 - Autossômica dominante
SMARCA4, 19 p13. 2 - Autossômica dominante
SMARCA2, 9 p24. 3 - Autossômico dominante
SMARCE1, 17 q21. 2 - Autossômico dominante
ARID1B, 6 q25. 3 - Autossômico dominante
Número OMIM - 135900 (verifique a página OMIM para obter informações atualizadas)
Quais são os principais sintomas de Coffin-Siris syndrome?
Coffin-Siris syndromePrincipal sintomas incluem o que costuma ser descrito como características faciais ásperas - boca e nariz largos, lábios grossos, ponte nasal plana e baixa estatura. O síndromes é caracterizada por crescimento excessivo de cabelo no rosto e no corpo, mas, ao mesmo tempo, crescimento esparso de cabelo no couro cabeludo.
Um 5 º dígito subdesenvolvido na mão ou no pé é o principal sintoma. Outro sintomas pode incluir baixo tônus muscular, baixa estatura, infecções respiratórias e deficiência de crescimento na infância.
Atraso no desenvolvimento e deficiência intelectual são comuns, e atrasos na fala e nas habilidades motoras são comuns.
Como alguém faz o teste de Coffin-Siris syndrome?
O teste inicial para Coffin-Siris syndrome pode começar com a triagem de análise facial, por meio do FDNA Telehealth plataforma telegenética, que pode identificar os principais marcadores do síndromes e delineia a necessidade de mais testes. Seguirá uma consulta com um conselheiro genético e, em seguida, um geneticista.
Com base nesta consulta clínica com um geneticista, as diferentes opções para testes genéticos serão compartilhadas e o consentimento será solicitado para testes adicionais.
Informações médicas sobre Coffin-Siris syndrome
AUTHOR(S): Eline van der Sluijs, Samantha Schrier Vergano, Gijs Santen
KEYWORDS: Intellectual disability, dysmorphic features, hypertrichosis, fifth finger hypoplasia
Coffin Siris Syndrome
SYNDROME OMIM NUMBER-
135900 (ARID1B), 614607 (ARID1A), 614608 (SMARCB1), 614609 (SMARCA4), 616938 (SMARCE1), 617808 (ARID2)
Coffin-Siris syndrome; CSS
FIFTH DIGIT SYNDROME
Coffin-Siris syndrome 1
Coffin-Siris syndrome 2
Coffin-Siris syndrome 3
Coffin-Siris syndrome 4
Coffin-Siris syndrome 5
Coffin-Siris syndrome 6
Coffin Siris Syndrome (CSS) shows autosomal dominant inheritance and is classically characterized by intellectual disability, varying degrees of developmental and speech delay, feeding difficulties, distinct facial features, hypertrichosis and aplasia or hypoplasia of the distal phalanx of the fifth and/or additional fingers and nails. In most patients this syndrome is caused by a mutation in genes (ARID1B, ARID1A, SMARCB1, SMARCA4, SMARCE1, ARID2) encoding components of the BAF (mSWI/SNF) complex, which regulates gene expression through chromatin remodeling. In addition, some CSS patients have mutations in SOX11; SOX11 also influences gene expression since it is a transcriptional factor forming a cross-regulatory network downstream of the PAX6-BAF complex. Mutation in DPF2 have also been described in 8 individuals with a CSS-like phenotype.
ARID1B, ARID1A, SMARCB1, SMARCA4, SMARCE1, ARID2, SOX11 , DPF2
ARID1B (614556), ARID1A (603024), SMARCB1 (601607), SMARCA4 (603254), SMARCE1 (603111), ARID2 (609539), SOX11 (600898), DPF2 (601671)
TYPE OF MUTATION(S)-
ARID1B: almost always truncating mutations or whole gene deletions, one de novo missense in CSS-like patient in literature. Several missense mutations have been reported in patients with isolated short stature.
ARID1A: all described mutations truncating, some are mosaic suggesting that full mutations either give another phenotype or are incompatible with life.
SMARCB1: missense mutations in exon 8/9
SMARCE1: missense mutations in HMG domain
SMARCA4: missense mutations in functional domains of the protein
ARID2: truncating mutations or deletions
SOX11: truncating mutations, deletions or missense variants in HMG DNA binding domain
DPF2: missense, frameshift and splice-site mutations (likely dominant-negative)
There appears to be significant overlap between patients with mutations in the aforementioned genes. In general, patients with mutations in SMARCE1, SMARCB1 or SMARCA4 have more congenital anomalies than patients with mutations in the other genes.
MODE(S) OF INHERITENCE-
Appears to be complete: All published mutations are de novo or inherited from affected parents.
ARID1B mutations are one of the most frequent causes of intellectual disability (up to 1% of patients). More than 200 patients with mutations in the BAF complex have been thus far described.
Due to assessment bias the number of known older patients with mutations in the BAF complex is low. There is currently no evidence for a reduced life expectancy.
AGE OF ONSET-
Agenesis of the corpus callosum may be detected prenatally.
KEY CLINICAL FEATURES/PHENOTYPES:
Abnormality of the face
Coarse facial features HP:0000280
Abnormality of the forehead HP:0000290
Depressed nasal bridge HP:0005280
Wide nose HP:0000445
Abnormality of the philtrum HP:0000288
Wide mouth HP:0000154
Thick lower lip vermilion HP:0000179
Abnormality of the hair
Sparse scalp hair HP:0002209
Thick eyebrows HP:0000574
Abnormality of the voice
Abnormality of the skeletal system
Abnormality of the ear
Abnormality of the pinna HP:0000377
Abnormality of limbs
Aplasia/Hypoplasia of the distal phalanx of the 5th finger HP:0009239
Aplasia/Hypoplasia of the distal phalanx of the 5th toe HP:0100371
Aplasia/Hypoplasia of the distal phalanges of the hand HP:0009835
Small nails HP:0001792
Abnormality of the digestive system HP:0025032
Feeding difficulties HP:0011968
Abnormality of the nervous system
Agenesis of the corpus callosum HP:0001274
(Abnormality of prenatal development or birth)
Abnormality of the genitourinary system
Abnormality of the kidney HP:0000077
Abnormality of the musculature
Muscular hypotonia HP:0001252
Short stature HP:0004322
(Abnormality of the endocrine system)
Abnormality of the respiratory system
Abnormality of the cardiovascular system
Abnormality of the cardiac septa HP:0001671
Abnormality of the heart valves HP:0001654
Abnormality of the eye
(Abnormality of the immune system)
Neurodevelopmental delay HP:0012758
Delayed speech and language development HP:0000750
Motor delay HP:0001270
CLINICAL DESCRIPTION (GENERAL):
In general all CSS patients have developmental and speech delay and intellectual disability, developmental and speech delay, distinct facial features (see CLINICAL DESCRIPTION (BODY SYSTEMS)) and hypertrichosis. Most patients have aplasia or hypoplasia of the distal phalanx of the 5th and/or additional fingers and nails. Some patients have additional congenital anomalies, such as brain, cardiac or renal anomalies
CLINICAL DESCRIPTION (BODY SYSTEMS):
Growth and development
Most patients have a height below the 50th percentile and (± 20% below the 5th percentile). Likewise, development is delayed in patients. In most patients speech is impaired, with no speech development in around 20% of patients. Scoliosis is found in 20-30% of patients.
Features characteristic for CSS patients are coarse facial features, sparse scalp hair, low anterior hairline, thick eyebrows, flat nasal bridge, thick alae nasi, large mouth and thick lower lip vermillion.
Scoliosis is found in 20-30% of patients.
Intellectual disability is reported in (almost) all patients. Hypotonia (±80%) and seizures (20-50%) are seen in a considerable proportion of patients. A variety of brain anomalies have been reported in CSS patients, of which agenesis of the corpus callosum (24-41%) is the most frequent. Other brain anomalies are Dandy Walker, gyri simplification, mega cisterna magna, colpocephaly and delayed myelinization.
A subset of patients have cardiac and/or renal anomalies. Cardiac anomalies include atrial and/or ventricular septal defect, patent ductus arteriosus and tetralogy of Fallot.
Renal and genital anomalies
Renal anomalies include horseshoe kidney, hydronephrotic kidney and urolithiasis. Cryptorchidism is frequently found.
Visual and hearing impairment
Impairment of hearing and/or vision is prevalent among CSS patients. The prevalence of both impairments seem to differ between genes, but in general it appears that vision impairment is slightly more prevalent than hearing impairment. Vision impairment consists mostly of myopia (e.g. 20-30% ARID1B patients have myopia) and hearing problems are in most cases either congenital or related to associated with recurrent upper respiratory tract infections.
Gastrointestinal anomalies consist mainly of feeding and swallowing difficulties, for which a subset of patients needs tube feeding. Other reported anomalies are constipation, gastroesophageal reflux and pyloric stenosis.
Several endocrinological abnormalities have been found in CSS patients, but it is still unclear whether these are part of the spectrum. Hyperinsulinism has been described in two patients with ARID1B mutations and diabetes mellitus in a patient with ARID1A mutation.
Some CSS patients have been reported with malignancies (ARID1B - one patient with papillary thyroid cancer, ARID1A - one with hepatoblastoma and 1 with ALL, a SMARCB1 - one patient with schwannomatosis). An increased cancer risk cannot be ruled out for these patients and therefore the additional value of monitoring potential neoplasm development is not determined yet. A screening program is at present not warranted.
ARID1B patients (which constitute 51-75%1-3 of CSS patients with a known genetic cause) are also characterized by laryngomalacia, agenesis of the corpus callosum, myopia and cryptorchidism. (To be published) Both seizures and scoliosis occur in ±25% of patients.
The main clinical features of individuals with an ARID1A mutation can differ fromare mild to severe intellectual disability with internal complications. Agenesis of the corpus callosum is a frequently reported CNS anomaly among ARID1A patients. Behavioral abnormalities are reported in ±50% of patients. Some individuals also had serious medical complications (e.g., aspiration pneumonia, seizures) leading to death.
Individuals with a pathogenic variant in SMARCB1 typically have a more severely affected phenotype and all have growth impairment, usually mild prenatally and moderate to severe postnatally, with sucking/feeding difficulty. Structural CNS abnormalities with hypotonia and seizures are typical findings accompanied by severe developmental delay/intellectual disability; individuals are typically nonverbal. Scoliosis is a typical skeletal finding. Some individuals may walk independently. Gastrointestinal complications and hernia as well as cardiovascular and genitourinary complications are common.
About half of the patients have severe developmental delay or ID, and occasionally (20–30%) speak no words. Growth impairment is mild prenatally and mild‐to‐moderate postnatally, and difficulty in sucking/feeding is almost always observed. Facial coarseness is evident and a pointed chin in older ages is noted. Internal organs are impaired in most. Patients usually have hypotonia, structural CNS abnormalities, and behavioral abnormalities.
SMARCA4 mutations have been identified in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) tumors. These tumors are rare and usually found in young females. In general, the SMARCA4 variants in these tumors are truncating, while in CSS patients missense or in-frame deletions have been identified. An increased cancer risk in Coffin-Siris syndrome patients with a mutation in SMARCA4 has not been proven.
Individuals with pathogenic SMARCE1 variants tend to have severe intellectual disability, typical facial gestalt, and hypoplastic or absent fifth finger- and toenails associated with hypoplasia of other nails. The hands are characterized by long and slender fingers. Individuals are typically small for gestational age and have postnatal short stature and severe microcephaly, complex congenital heart defects and feeding difficulties.
Most individuals with ARID2 pathogenic variants demonstrate intellectual disability, hypotonia, and behavioral anomalies. Birth defects are not common. Several individuals have demonstrated very mild hypoplasia of the fifth fingernails and hypoplasia of the fifth toenails. Individuals with ARID2 pathogenic variants share some facial features with each other: coarse features, frontal bossing and high forehead, narrow palpebral fissures, flat nasal bridge, slightly broad nose with upturned nasal tip and thick, anteverted alae nasi, prominent philtrum, and a large mouth with a thick lower vermilion.
Individuals display mild to severe intellectual and developmental delay, along with fifth digit nail and distal phalangeal hypoplasia. Neurodevelopmental abnormalities tend to be more prevalent than organ-system or physical complications.
Eight patients had thus far been described, with a phenotype consisting of ‘coarse facial features, global developmental delay, intellectual disability, speech impairment, and hypoplasia of fingernails and toenails.
- Regular evaluation by a developmental pediatrician to assess developmental progress and therapeutic and educational interventions
- Annual follow up with a gastroenterologist and feeding specialists as needed to monitor feeding and weight gain
- Regular follow up of ophthalmologic and/or audiologic abnormalities
Presently a tumor screening program is not warranted, because of the rarity of tumors in CSS. It may be considered to screen SMARCB1 patients for schwannoma’s from 18 years onwards.
MANAGEMENT AND TREATMENT:
At time of diagnosis:
- Consultation with a clinical geneticist and/or genetic counselor
- Neurologic and/or developmental examination to record developmental milestones and identify neurologic symptoms or deficits
- Evaluation for occupational, speech, or physical therapy as needed
- Growth should be monitored closely. Probands should have regular evaluations with gastroenterology or feeding specialists to monitor feeding and weight gain. Nutritional supplementation or G‐tube placement may be necessary to facilitate weight gain.
- Ophthalmologic examination, including a dilated fundus examination and visual acuity
- Audiology evaluation with auditory brain stem response testing and otoacoustic emission testing to assess for hearing loss
- Cardiology evaluations, including an echocardiogram should be considered to assess for structural cardiac anomalies.
- Given the prevalence of both structural kidney and genitourinary anomalies, a renal ultrasound should be considered.
Treatment of manifestations:
- Occupational, physical, and/or speech therapies to optimize developmental outcomes
- Feeding therapy, nutritional supplementation, and/or gastrostomy tube placement as needed to meet nutritional needs
- Spectacles as needed to correct refractive errors and surgery as needed for strabismus and/or ptosis
- Hearing aids as needed
If you have identified patients with mutations in one of the CSS-associated genes we invite you to contact one of the gene-moderators of humandiseasegenes.nl to submit your patient data into an online gene-specific database, which aims to gather more knowledge to improve patients care.
Coffin-Siris syndrome/BAF Pathway Registry - if you have a patient with CSS or mutations in the BAF Pathway, please contact Dr. Samantha Vergano at [email protected] for information on registry enrollment.
Coffin-Siris syndrome Foundation - http://www.coffinsiris.org
Coffin Siris Syndrome:
Schrier Vergano S, Santen G, Wieczorek D, Wollnik B, Matsumoto N, Deardorff MA. Coffin-Siris syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA)1993.
Vergano SS, Deardorff MA. Clinical features, diagnostic criteria, and management of Coffin-Siris syndrome. Am J Med Genet C Semin Med Genet. 2014;166C(3):252-256. PMID: 25169447.
Santen GW, Aten E, Vulto-van Silfhout AT, et al. Coffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients. Hum Mutat. 2013;34(11):1519-1528. PMID: 23929686.
Wieczorek D, Bogershausen N, Beleggia F, et al. A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling. Hum Mol Genet. 2013;22(25):5121-5135. PMID: 23906836.
Tsurusaki Y, Okamoto N, Ohashi H, et al. Coffin-Siris syndrome is a SWI/SNF complex disorder. Clin Genet. 2014;85(6):548-554. PMID: 23815551.
Kosho T, Okamoto N, Coffin-Siris syndrome International C. Genotype-phenotype correlation of Coffin-Siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A. Am J Med Genet C Semin Med Genet. 2014;166C(3):262-275. PMID: 25168959.
Kosho T, Miyake N, Carey JC. Coffin-Siris syndrome and related disorders involving components of the BAF (mSWI/SNF) complex: historical review and recent advances using next generation sequencing. Am J Med Genet C Semin Med Genet. 2014;166C(3):241-251. PMID: 25169878.
Santen GW, Clayton-Smith J, consortium ABC. The ARID1B phenotype: what we have learned so far. Am J Med Genet C Semin Med Genet. 2014;166C(3):276-289. PMID: 25169814.
Bidart M, El Atifi M, Miladi S, et al. Microduplication of the ARID1A gene causes intellectual disability with recognizable syndromic features. Genet Med. 2017;19(6):701-710. PMID: 27906199.
Errichiello E, Mustafa N, Vetro A, et al. SMARCA4 inactivating mutations cause concomitant Coffin-Siris syndrome, microphthalmia and small-cell carcinoma of the ovary hypercalcaemic type. J Pathol. 2017;243(1):9-15. PMID: 28608987.
Zarate YA, Bhoj E, Kaylor J, et al. SMARCE1, a rare cause of Coffin-Siris syndrome: Clinical description of three additional cases. Am J Med Genet A. 2016;170(8):1967-1973. PMID: 27264197.
Bramswig NC, Caluseriu O, Ludecke HJ, et al. Heterozygosity for ARID2 loss-of-function mutations in individuals with a Coffin-Siris syndrome-like phenotype. Hum Genet. 2017;136(3):297-305. PMID: 28124119.
Van Paemel R, De Bruyne P, van der Straaten S, et al. Confirmation of an ARID2 defect in SWI/SNF-related intellectual disability. Am J Med Genet A. 2017;173(11):3104-3108. PMID: 28884947.
Tsurusaki Y, Koshimizu E, Ohashi H, et al. De novo SOX11 mutations cause Coffin-Siris syndrome. Nat Commun. 2014;5:4011. PMID: 24886874.
Hempel A, Pagnamenta AT, Blyth M, et al. Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome. J Med Genet. 2016;53(3):152-162. PMID: 26543203.
Okamoto N, Ehara E, Tsurusaki Y, Miyake N, Matsumoto N. Coffin-Siris syndrome and cardiac anomaly with a novel SOX11 mutation. Congenit Anom (Kyoto). 2017. PMID: 28787104.
Vasileiou G, Vergarajauregui S, Endele S, et al. Mutations in the BAF-Complex Subunit DPF2 Are Associated with Coffin-Siris syndrome. Am J Hum Genet. 2018;102(3):468-479. PMID: 29429572.
* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]
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