Identification of a novel de novo mutation in SOX4 for syndromic tooth agenesis.

OBJECTIVES: Coffin-Siris Syndrome (CSS) is a congenital disorder characterized by delayed growth, dysmorphic facial features, hypoplastic nails and phalanges of the fifth digit, and dental abnormalities. Tooth agenesis has been reported in CSS patients, but the mechanisms regulating this syndromic tooth agenesis remain largely unknown. This study aims to identify the pathogenic mutation of CSS presenting tooth genesis and explore potential regulatory mechanisms. MATERIALS AND METHODS: We utilized whole-exome sequencing to identify variants in a CSS patient, followed by Sanger validation. In silico analysis including conservation analysis, pathogenicity predictions, and 3D structural assessments were carried out. Additionally, single-cell RNA sequencing and fluorescence in situ hybridization (FISH) were applied to explore the spatio-temporal expression of Sox4 expression during murine tooth development. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to examine the functional role of SOX4. RESULTS: A novel de novo SOX4 missense mutation (c.1255C > G, p.Leu419Val) was identified in a Chinese CSS patient exhibiting tooth agenesis. Single-cell RNA sequencing and FISH further verified high expression of Sox4 during murine tooth development, and WGCNA confirmed its central role in tooth development pathways. Enriched functions included cell-substrate junctions, focal adhesion, and RNA splicing. CONCLUSIONS: Our findings link a novel SOX4 mutation to syndromic tooth agenesis in CSS. This is the first report of SOX4 missense mutation causing syndromic tooth agenesis. CLINICAL RELEVANCE: This study not only enhances our understanding of the pathogenic mutation for syndromic tooth agenesis but also provides genetic diagnosis and potential therapeutic insights for syndromic tooth agenesis.

ARID2, a milder cause of Coffin-Siris Syndrome? Broadening the phenotype with 17 additional individuals.

Coffin-Siris Syndrome (CSS, MIM 135900) is now a well-described genetic condition caused by pathogenic variants in the Bromocriptine activating factor (BAF) complex, including ARID1B, ARID1A, ARID2, SMARCA4, SMARCE1, SMARCB1, SOX11, SMARCC2, DPF2, and more recently, BICRA. Individuals with CSS have a spectrum of various medical challenges, most often evident at birth, including feeding difficulties, hypotonia, organ-system anomalies, and learning and developmental differences. The classic finding of fifth digit hypo- or aplasia is seen variably. ARID2, previously described, is one of the less frequently observed gene changes in CSS. Although individuals with ARID2 have been reported to have classic features of CSS including hypertrichosis, coarse facial features, short stature, and fifth digit anomalies, as with many of the other CSS genes, there appears to be a spectrum of phenotypes. We report here a cohort of 17 individuals with ARID2 variants from the Coffin-Siris/BAF clinical registry and detail their medical challenges as well as developmental progress. Feeding difficulties, hypotonia, and short stature occur often, and hip dysplasia appears to occur more often than with other genes, however more severe medical challenges such as significant brain and cardiac malformations are rarer. Individuals appear to have mild to moderate intellectual impairment and may carry additional diagnoses such as ADHD. Further phenotypic description of this gene will aid clinicians caring for individuals with this rarer form of CSS.

Prenatal Coffin-Siris Syndrome: Expanding the Phenotypic and Genotypic Spectrum of the Disease.

Coffin-Siris syndrome is an autosomal dominant disorder with neurological, cardiovascular, and gastrointestinal symptoms. Patients with Coffin-Siris syndrome typically have variable degree of developmental delay or intellectual disability, muscular hypotonia, dysmorphic facial features, sparse scalp hair, but otherwise hirsutism and fifth digit nail or distal phalanx hypoplasia or aplasia. Coffin-Siris syndrome is caused by pathogenic variants in 12 different genes including SMARCB1 and ARID1A. Pathogenic SMARCB1 gene variants cause Coffin-Siris syndrome 3 whereas pathogenic ARID1A gene variants cause Coffin-Siris syndrome 2. Here, we present two prenatal Coffin-Siris syndrome cases with autosomal dominant pathogenic variants: SMARCB1 gene c.1066_1067del, p.(Leu356AspfsTer4) variant, and a novel ARID1A gene c.1920+3_1920+6del variant. The prenatal phenotype in Coffin-Siris syndrome has been rarely described. This article widens the phenotypic spectrum of prenatal Coffin-Siris syndrome with severely hypoplastic right ventricle with VSD and truncus arteriosus type III, persisting left superior and inferior caval vein, bilateral olfactory nerve aplasia, and hypoplastic thymus. A detailed clinical description of the patients with ultrasound, MRI, and post mortem pictures of the affected fetuses showing the wide phenotypic spectrum of the disease is presented.

Delineation of the adult phenotype of Coffin-Siris syndrome in 35 individuals.

Coffin-Siris syndrome (CSS) is a rare multisystemic autosomal dominant disorder. Since 2012, alterations in genes of the SWI/SNF complex were identified as the molecular basis of CSS, studying largely pediatric cohorts. Therefore, there is a lack of information on the phenotype in adulthood, particularly on the clinical outcome in adulthood and associated risks. In an international collaborative effort, data from 35 individuals ≥ 18 years with a molecularly ascertained CSS diagnosis (variants in ARID1B, ARID2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, BICRA) using a comprehensive questionnaire was collected. Our results indicate that overweight and obesity are frequent in adults with CSS. Visual impairment, scoliosis, and behavioral anomalies are more prevalent than in published pediatric or mixed cohorts. Cognitive outcomes range from profound intellectual disability (ID) to low normal IQ, with most individuals having moderate ID. The present study describes the first exclusively adult cohort of CSS individuals. We were able to delineate some features of CSS that develop over time and have therefore been underrepresented in previously reported largely pediatric cohorts, and provide recommendations for follow-up.

Reabilitação com prótese bucomaxilofacial: revisão de literatura / Rehabilitation with maxillofacial prosthetics

A odontologia reabilitadora tem como um dos seus ramos a especialidade de Prótese Bucomaxilofacial (PBMF), que visa restaurar ou substituir estruturas perdidas na região facial e no sistema estomatognático artificialmente, podendo ser ou não removidos pelo paciente. O presente trabalho objetiva revisar a leitura a respeito da reabilitação com PBMF e a sua aplicabilidade na clínica odontológica. Os indivíduos com alguma perda de estrutura na região de cabeça e pescoço, devido a traumas físicos e/ou químicos, defeitos congênitos, doenças autoimunes, neoplasias, infecções e parasitas, são pacientes para os quais há a indicação da reposição da parte ausente. As reconstruções podem ser perdas intraorais (área da maxila, mandíbula), extraorais (oculopalpebral, ocular, nasal, facial extensa e auricular) ou conjugadas. Esse é um trabalho multidisciplinar, com especialistas de áreas abrangentes e todos os especialistas trabalham de forma conjunta. Pode-se concluir que, embora seja uma das especialidades mais nobres da odontologia, ainda é muito desconhecida por parte dos estudantes e profissionais das áreas da saúde e são próteses absolutamente fundamentais para a reabilitação e qualidade de vida dos indivíduos que tem a necessidade do uso da prótese PBMF(AU)

Rehabilitating dentistry has as one of its branches the specialty of Oral and Maxillofacial Prosthesis (PBMF), which aims to restore or replace structures lost in the facial region and in the stomatognathic system artificially, which may or may not be removed by the patient. The present study aims to review the reading about rehabilitation with PBMF and its applicability in dental clinic. Individuals with some loss of structure in the head and neck region, due to physical and/or chemical trauma, birth defects, autoimmune diseases, neoplasms, infections and parasites, are patients in whom there is an indication for replacement of the absent part. Reconstructions can be intraoral (maximal area, mandible), extraoral (oculopalpebral, ocular, nasal, extensive facial and auricular) or conjugated losses. It is a multidisciplinary work, with specialists from the comprehensive areas and that all specialists work together. It can be concluded that although it is one of the noblest specialties of dentistry, it is still very unknown to students and health professionals, and they are absolutely fundamental prostheses for the rehabilitation and quality of life of individuals who need the use the PBMFprosthesis(AU)

Congenital diaphragmatic hernia in Coffin Siris syndrome: Further evidence from two cases.

Coffin-Siris Syndrome (CSS) is a rare multi-system dominant condition with a variable clinical presentation mainly characterized by hypoplasia/aplasia of the nail and/or distal phalanx of the fifth digit, coarse facies, hirsutism/hypertrichosis, developmental delay and intellectual disability of variable degree and growth impairment. Congenital anomalies may include cardiac, genitourinary and central nervous system malformations whereas congenital diaphragmatic hernia (CDH) is rarely reported. The genes usually involved in CSS pathogenesis are ARID1B (most frequently), SMARCA4, SMARCB1, ARID1A, SMARCE1, DPF2, and PHF6. Here, we present two cases of CSS presenting with CDH, for whom Whole Exome Sequencing (WES) identified two distinct de novo heterozygous causative variants, one in ARID1B (case 1) and one in SMARCA4 (case 2). Due to the rarity of CDH in CSS, in both cases the occurrence of CDH did not represent a predictive sign of CSS but, on the other hand, prompted genetic testing before (case 1) or independently (case 2) from the clinical hypothesis of CSS. We provide further evidence of the association between CSS and CDH, reviewed previous cases from literature and discuss possible functional links to related conditions.

Two SOX11 variants cause Coffin-Siris syndrome with a new feature of sensorineural hearing loss.

Coffin-Siris syndrome (CSS, OMIM#135900) is a rare congenital disorder associated with neurodevelopmental and dysmorphic features. The primary cause of CSS is pathogenic variants in any of 9 BAF chromatin-remodeling complex encoding genes or the genes SOX11 and PHF6. Herein, we performed whole-exome sequencing (WES) and a series of analyses of growth-related, auditory, and radiological findings in two probands with syndromic sensorineural hearing loss and inner ear malformations who exhibited distinctive facial features, intellectual disability, growth retardation, and fifth finger malformation. Two de novo variants in the SOX11 gene (c.148A>C:p.Lys50Asn; c.811_814del:p.Asn271Serfs*10) were detected in these probands and were identified as pathogenic variants as per ACMG guidelines. These probands were diagnosed as having CSS based upon clinical and genetic findings. This is the first report of CSS caused by variants in SOX11 gene in Chinese individuals. Deleterious SOX11 variants can result in sensorineural hearing loss with inner ear malformation, potentially extending the array of phenotypes associated with these pathogenic variants. We suggest that both genetic and clinical findings be considered when diagnosing syndromic hearing loss.

Congenital Midline Cervical Cleft (CMCC): Z-Plasty Versus Linear Cutaneous Repair.

Congenital midline cervical cleft (CMCC) is a rare congenital difference. Accurate diagnosis is important to ensure appropriate treatment. CMCC results in both functional and esthetic concerns addressed by surgical management. While the majority of reported CMCC cases have been treated with a z-plasty, the best method of repair has been debated in the literature. The authors present a case of CMCC and review of the literature.

Epilepsy in Coffin-Siris syndrome: A report from the international CSS registry and review of the literature.

Coffin-Siris syndrome (CSS, MIM135900) is a rare multiple congenital anomaly syndrome caused by pathogenic variants in the BAF complex; up to 28% of patients have previously been reported to have seizures, however, a comprehensive review of epilepsy has not been undertaken in this population. The International CSS Patient Report Database was queried for patients with self-reported seizures, epilepsy, and EEG results. Data gathered included demographic data, pathogenic gene variants, seizure characteristics and treatments, and EEG findings. In addition, a PubMed search was performed using keywords "Coffin-Siris syndrome" and "epilepsy," "seizures," or "EEG." Results from relevant papers are reported. Twenty-four (7.2%) of 334 patients in the database reported having seizures, EEG abnormalities, and/or epilepsy. Median age of seizure onset was 2. 7 years. Fifteen of the 23 patients with seizures or epilepsy had an ARID1B causative variant. Seventeen patients (5.1%) reported EEG abnormalities, the majority of which were described as focal or multifocal (87.5%). In all but one patient, seizures were controlled on antiseizure medications (ASMs). The literature review yielded 311 unique CSS patients, 82 of which (26.4%) carried diagnoses of seizures or epilepsy. Details on seizure type(s), EEG findings, and response to treatment were limited.

Severe coarctation of the aorta, developmental delay, and multiple dysmorphic features in a child with SMAD6 and SMARCA4 variants.

Pathogenic variants in SMARCA4 cause Coffin-Siris syndrome (CSS) while those in SMAD6 lead to aortic valve disease and other dysmorphisms. We identified a 6-year-old Thai boy with features of CSS alongside unusual manifestations including, very severe coarctation of the aorta (CoA) requiring coarctectomy in the neonatal period and bilateral radioulnar synostoses. Trio exome sequencing revealed that the patient harbored two de novo variants, a missense c.2475G > T, p.(Trp825Cys) in SMARCA4 and a nonsense c.652C > T, p.(Gln218Ter) in SMAD6. Both of which have never been previously reported. The clinical presentations in our patient are a result of the combinational features of each genetic variant: the SMARCA4 p.(Trp825Cys) variant leads to facial features of Coffin Siris syndrome and Dandy-Walker malformation, while the SMAD6 p.(Gln218Ter) variant underlies radioulnar synostosis. Interestingly, the severity of CoA in the proband is beyond the phenotypic spectra of each genetic variant and may be a result of the synergistic effects of both variants. Here, we report a child with variants in SMARCA4 or SMAD6 with combined features of each plus a severe CoA, possibly due to an additive effect of each variant.

"Cancer in ARID1A-Coffin-Siris syndrome: Review and report of a child with hepatoblastoma".

Coffin-Siris syndrome (CSS) is a rare neurodevelopmental and multisystemic disorder with wide genetic heterogeneity and phenotypic variability caused by pathogenic variants in the BAF complex with 341 cases enrolled in the CSS/BAF-related disorders registry by 2021. Pathogenic variants of ARID1A account for 7-8% of cases with CSS phenotype. Malignancy has been previously reported in six individuals with CSS associated with BAF mutations. Two of these malignancies including one acute lymphoid leukemia and one hepatoblastoma were reported in ARID1A-associated CSS (ARID1A-CSS). Alterations in ARID1A are among the most common molecular aberrations in human cancer. Somatic deletion of 1p and specifically of 1p36.11 containing ARID1A is frequently seen in hepatoblastoma and has been associated with high-risk features. Here we report a child with CSS Phenotype and a novel de novo variant of ARID1A with hepatoblastoma. Because hepatoblastoma has an incidence of 1 per million children, the presence of hepatoblastoma in 2 of 30 known cases of ARID1A-CSS is significant. ARID1A-CSS should be included among the cancer predisposition syndromes associated with an increased risk of hepatoblastoma and tumour surveillance considered for these patients. The role of ARID1A in the pathogenesis and outcome of hepatoblastoma deserves further investigation.

Short stature and melanocytic nevi in a girl with ARID1B-related Coffin-Siris syndrome: a case report.

BACKGROUND: Coffin-Siris syndrome (CSS) is a rare autosomal dominant disorder characterized by intellectual disability, developmental delay, and characteristic facial features. Few patients with cutaneous phenotype in this rare syndrome have been reported. CASE PRESENTATION: Herein, we describe a 12-year-old Chinese girl diagnosed with CSS, who was referred to our hospital because of intellectual disability and short stature. Prominent characteristics of the cutaneous system were observed: (1) A congenital giant nevus from the left frontal and temporal regions to the entire left scalp; and (2) multiple melanocytic nevi on the face and trunk. Whole exome sequencing revealed a novel heterozygous variant in the ARID1B gene. Recombinant human growth hormone (rhGH) was given for short stature, and resulted in significantly improved height. No enlargement or malignant transformation of nevi occurred within 4 years of follow-up. CONCLUSION: The symptoms in cutaneous system is noteworthy,which may be a neglected phenotype in CSS.The therapeutic response of growth hormone is effective in this patient and no tumor related signs were found.

[Clinical features and genetic analysis of two Chinese patients with Coffin Siris syndrome-1].

OBJECTIVE: To explore the genetic basis for two unrelated patients with global developmental delay and coarse facial features. METHODS: Clinical data and family history of the two pedigrees were collected. Whole exome sequencing and Sanger sequencing were carried out to detect potential variants. RESULTS: The two patients have presented with global developmental delay, coarse facies, muscular hypotonia, congenital heart disease, and pectus excavatum, and were found to harbor two de novo loss-of-function variants of the ARID1B gene, namely c.3586delC (p.Gln1196Serfs*15) and c.4954_4957delACGT (p.Thr1652Glyfs*31). Both variants were unreported previously. CONCLUSION: The nonsense variants of the ARID1B gene probably underlay the etiology in these patients. Above finding has enriched the genotypic and phenotypic spectrum of the disease and provided a basis for prenatal diagnosis.

Evidence for an association between Coffin-Siris syndrome and congenital diaphragmatic hernia.

Coffin-Siris syndrome (CSS) is an autosomal dominant neurodevelopmental syndrome that can present with a variety of structural birth defects. Pathogenic variants in 12 genes have been shown to cause CSS. Most of these genes encode proteins that are a part of the mammalian switch/sucrose non-fermentable (mSWI/SNF; BAF) complex. An association between genes that cause CSS and congenital diaphragmatic hernia (CDH) has been suggested based on case reports and the analysis of CSS and CDH cohorts. Here, we describe an unpublished individual with CSS and CDH, and we report additional clinical information on four published cases. Data from these individuals, and a review of the literature, provide evidence that deleterious variants in ARID1B, ARID1A, SMARCB1, SMARCA4, SMARCE1, ARID2, DPF2, and SMARCC2, which are associated with CSS types 1-8, respectively, are associated with the development of CDH. This suggests that additional genetic testing to identify a separate cause of CDH in an individual with CSS may be unwarranted, and that comprehensive genetic testing for individuals with non-isolated CDH should include an evaluation of CSS-related genes. These data also suggest that the mSWI/SNF (BAF) complex may play an important role in diaphragm development.

Neurocognitive, behavioral and socio-adaptive functioning assessment in a case of Coffin-Siris syndrome: A holistic approach/perspective beyond the identification of the disorder.

PURPOSE: Coffin-Siris syndrome (CSS) is a rare genetic disorder characterized by the presence of particular facies, congenital malformations, intellectual developmental disorder, behavioral issues, and speech and language impairment. Thorough neuropsychological assessments in the case of CSS have been reported infrequently, and its subdomains are poorly defined. A detailed description of the clinical, neurocognitive, behavioral, socio-adaptive sequelae of the patient with CSS is provided. RESULTS: The clinical diagnosis in the patient was confirmed by genetic analysis, which identified the presence of mutation of ARID1B gene; the parents' Sanger sequencing reported normal. The neuropsychological assessments revealed borderline intellectual functioning (IQ-75, verbal > performance) with a mild socio-adaptive deficit score of 64 as suggested by the adaptive scale. The behavioral profile reported that the child had significant difficulties in the attention subdomain with concern in social and thought subdomains. The child met the profile for mild severity of Autism Spectrum Disorder and did not meet the criteria for Attention Deficit Hyperactivity Disorder. In addition, the child had scholastic difficulties in reading and mathematical skills. CONCLUSION: Neurocognitive, behavioral, socio-adaptive functioning and comorbidity assessment in order to provide holistic management of such children after thorough evaluation is essential for their overall functioning.

Cochlear nerve deficiency in SOX11-related Coffin-Siris syndrome.

The phenotypic spectrum of SOX11-related Coffin-Siris syndrome (CSS) is expanding with reports of new associations. SOX11 is implicated in neurogenesis and inner ear development. Cochlear nerve deficiency, absence or hypoplasia, is commonly associated with cochlear canal stenosis or with CHARGE syndrome, a monogenic condition that affects inner ear development. SOX11 is a transcription factor essential for neuronal identity, highly correlated with the expression of CHD7, which regulates SOX11. We present two unrelated probands, each with novel de novo SOX11 likely pathogenic variants and phenotypic manifestations of CSS including global developmental delay, growth deficiency, and hypoplastic nails. They have unilateral sensorineural hearing loss due to cochlear nerve deficiency confirmed on MRI. SOX11 is implicated in sensory neuron survival and maturation. It is highly expressed in the developing inner ear. Homozygous ablation of SOX11 in a mouse model resulted in a reduction in sensory neuron survival and decreased axonal growth. A heterozygous knockout mice model had hearing impairment with grossly normal inner ear structures like the two probands reported. We propose cochlear nerve deficiency as a new phenotypic feature of SOX11-related CSS. Magnetic resonance imaging is useful in delineating the cochlear nerve deficiency and other CSS-related brain malformations.

De Novo SMARCC2 Variant in a Chinese Woman with Coffin-Siris Syndrome 8: a Case Report with Mild Intellectual Disability and Endocrinopathy.

Coffin-Siris syndrome (CSS) is a neurodevelopmental disorder characterized by cognitive disability, coarse facial features, hypertrichosis, and somatic dysmorphic features. It is caused by mutations in the BAF-complex or SOX gene. Here, a Chinese woman presenting with neurodevelopmental delay, mild intellectual disability, speech delay, dysmorphic features, obesity, scoliosis, hypotonia, seizures, skin problems, hypokalemia, and endocrine dysfunction is described. Whole exome sequencing (WES) identified a heterozygous missense variant, c.2074G > C (p. Ala692Pro), in the SMARCC2 gene of the proband. Affecting chromatin structure, SMARCC2 plays an essential role in modulating cortical neurogenesis, and controlling cortical size and thickness. Moreover, it is associated with tumor suppression, and SMARCC2 mutations have been observed with high frequency in human cancers. While this is the second report of SMARCC2 mutations in patients with detailed phenotypes, this is the first describing the observation of electrolyte disturbances and endocrinopathy. These findings expanded the genetic and clinical spectrum of SMARCC2-related Coffin-Siris syndrome.