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BMC Medical Genomics May 2024Coffin-Siris syndrome (CSS) is a rare autosomal dominant inheritance disorder characterized by distinctive facial features, hypoplasia of the distal phalanx or nail of...
Coffin-Siris syndrome (CSS) is a rare autosomal dominant inheritance disorder characterized by distinctive facial features, hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, hypotonia, hirsutism/hypertrichosis, sparse scalp hair and varying kind of congenital anomalies. CSS can easily be misdiagnosed as other syndromes or disorders with a similar clinical picture because of their genetic and phenotypic heterogeneity. We describde the genotype-phenotype correlation of one patient from a healthy Chinese family with a novel genotype underlying CSS, who was first diagnosed in the ophthalmology department as early-onset high myopia (eoHM). Comprehensive ophthalmic tests as well as other systemic examinations were performed on participants to confirm the phenotype. The genotype was identified using whole exome sequencing, and further verified the results among other family members by Sanger sequencing. Real-time quantitative PCR (RT-qPCR) technology was used to detect the relative mRNA expression levels of candidate genes between proband and normal family members. The pathogenicity of the identified variant was determined by The American College of Medical Genetics and Genomics (ACMG) guidelines. STRING protein-protein interactions (PPIs) network analysis was used to detect the interaction of candidate gene-related proteins with high myopia gene-related proteins. The patient had excessive eoHM, cone-rod dystrophy, coarse face, excessive hair growth on the face, sparse scalp hair, developmental delay, intellectual disability, moderate hearing loss, dental hypoplasia, patent foramen ovale, chronic non-atrophic gastritis, bilateral renal cysts, cisterna magna, and emotional outbursts with aggression. The genetic assessment revealed that the patient carries a de novo heterozygous frameshift insertion variant in the ARID1B c.3981dup (p.Glu1328ArgfsTer5), which are strongly associated with the typical clinical features of CSS patients. The test results of RT-qPCR showed that mRNA expression of the ARID1B gene in the proband was approximately 30% lower than that of the normal control in the family, suggesting that the variant had an impact on the gene function at the level of mRNA expression. The variant was pathogenic as assessed by ACMG guidelines. Analysis of protein interactions in the STRING online database revealed that the ARID1A protein interacts with the high myopia gene-related proteins FGFR3, ASXL1, ERBB3, and SOX4, whereas the ARID1A protein antagonizes the ARID1B protein. Therefore, in this paper, we are the first to report a de novo heterozygous frameshift insertion variant in the ARID1B gene causing CSS with excessive eoHM. Our study extends the genotypic and phenotypic spectrums for ARID1B-CSS and supplies evidence of significant association of eoHM with variant in ARID1B gene. As CSS has high genetic and phenotypic heterogeneity, our findings highlight the importance of molecular genetic testing and an interdisciplinary clinical diagnostic workup to avoid misdiagnosis as some disorders with similar manifestations of CSS.
Topics: Humans; Intellectual Disability; Transcription Factors; Face; Male; Micrognathism; Pedigree; Female; Hand Deformities, Congenital; Myopia; DNA-Binding Proteins; Neck; Abnormalities, Multiple; Adult; Asian People; Genetic Association Studies; China; Phenotype; Exome Sequencing; Mutation; East Asian People
PubMed: 38790056
DOI: 10.1186/s12920-024-01904-9 -
European Journal of Medical Genetics Jun 2024Anorectal malformations (ARMs) represent a wide spectrum of congenital anomalies of the anus and rectum, of which more than half are syndromic. Their etiology is highly... (Review)
Review
Anorectal malformations (ARMs) represent a wide spectrum of congenital anomalies of the anus and rectum, of which more than half are syndromic. Their etiology is highly heterogeneous and still poorly understood. We report a 4-year-old girl who initially presented with an isolated ARM, and subsequently developed a global developmental delay as part of an ARID1B-related Coffin-Siris syndrome (CSS). A co-occurrence of ARMs and CSS in an individual by chance is unexpected since both diseases are very rare. A review of the literature enabled us to identify 10 other individuals with both CSS and ARMs. Among the ten individuals reported in this study, 8 had a variant in ARID1A, 2 in ARID1B, and 1 in SMARCA4. This more frequent than expected association between CSS and ARM indicates that some ARMs are most likely part of the CSS spectrum, especially for ARID1A-related CSS.
Topics: Humans; Female; Micrognathism; Child, Preschool; Intellectual Disability; Transcription Factors; Neck; Hand Deformities, Congenital; Abnormalities, Multiple; DNA-Binding Proteins; Anorectal Malformations; Face; DNA Helicases; Nuclear Proteins; Anal Canal; Phenotype
PubMed: 38735569
DOI: 10.1016/j.ejmg.2024.104948 -
European Journal of Medical Genetics Jun 2024To date 11 patients with Coffin-Siris syndrome type 7 (OMIM 618027) have been described since the first literature report. All reported patients carried de novo variants...
To date 11 patients with Coffin-Siris syndrome type 7 (OMIM 618027) have been described since the first literature report. All reported patients carried de novo variants with presumed dominant negative effect, which localized in the PHD1/PHD2 domains of DPF2. Here we report on the first familial case of Coffin-Siris syndrome type 7. The index patient presented during the 1st year of life with failure to thrive and ectodermal anomalies. The genetic analysis using whole exome sequencing showed a likely pathogenic missense variant in the PHD1 region. The family analysis showed that the mother as well as the older brother of the index patient also carried the detected DPF2 variant in heterozygous state. The mother had a history of school difficulties but no history of failure to thrive and was overall mildly affected. The brother showed developmental delay with autistic features, ectodermal anomalies and overlapping morphologic features but did not have a history of growth failure problems. To our knowledge this is the first report of an inherited likely pathogenic variant in DPF2, underlining the variability of the associated phenotype as well as the importance of considering inherited DPF2 variants during the variant filtering strategy of whole exome data.
Topics: Humans; Male; Micrognathism; Intellectual Disability; Hand Deformities, Congenital; Face; Transcription Factors; Female; Abnormalities, Multiple; Pedigree; Neck; Mutation, Missense; DNA-Binding Proteins; Phenotype; Infant; Adult
PubMed: 38697389
DOI: 10.1016/j.ejmg.2024.104945 -
Clinical Oral Investigations Apr 2024Craniofacial anomalies are widely discussed as predisposing factors of breathing disorders. Since many more cofactors exist, this study investigated the association...
OBJECTIVE
Craniofacial anomalies are widely discussed as predisposing factors of breathing disorders. Since many more cofactors exist, this study investigated the association between maxillary micrognathia and morphological changes of posterior airway space and adenoids in these patients.
MATERIAL AND METHODS
Cephalometric radiographs of n = 73 patients were used for data acquisition. The patients were divided into two groups according to certain skeletal characteristics: maxillary micrognathia (n = 34, 16 female, 18 male; mean age 10.55 ± 3.03 years; defined by a SNA angle < 79°) and maxillary eugnathia (n = 39, 19 female, 20 male; mean age 10.93 ± 3.26 years; defined by a SNA angle > 79°). The evaluation included established procedures for measurements of the maxilla, posterior airway space and adenoids. Statistics included Kolmogorov-Smirnov-, T- and Mann-Whitney-U-Tests for the radiographs. The level of significance was set at p < 0.05.
RESULTS
The cephalometric analysis showed differences in the superior posterior face height and the depth of the posterior airway space at palatal level among the two groups. The depth of the posterior airway space at mandibular level was the same for both groups, just as the size of the area taken by adenoids in the nasopharynx.
CONCLUSIONS
Skeletal anomalies affect the dimension of the posterior airway space. There were differences among the subjects with maxillary micrognathia and these with a normal maxilla. However, the maxilla was only assessed in the sagittal direction, not in the transverse. This study showed that the morphology of the maxilla relates to the posterior airway space whereas the adenoids seem not to be affected.
CLINICAL RELEVANCE
Maxillary micrognathia is significantly associated with a smaller depth of the posterior airway space at the palatal level compared to patients with maxillary eugnathia.
Topics: Humans; Male; Female; Child; Adolescent; Adenoids; Micrognathism; Nasopharynx; Maxilla; Respiratory System; Cephalometry
PubMed: 38627272
DOI: 10.1007/s00784-024-05657-8 -
Molecular Genetics & Genomic Medicine Apr 2024Auriculocondylar syndrome (ARCND) is a rare congenital craniofacial developmental malformation syndrome of the first and second pharyngeal arches with external ear... (Review)
Review
BACKGROUND
Auriculocondylar syndrome (ARCND) is a rare congenital craniofacial developmental malformation syndrome of the first and second pharyngeal arches with external ear malformation at the junction between the lobe and helix, micromaxillary malformation, and mandibular condylar hypoplasia. Four subtypes of ARCND have been described so far, that is, ARCND1 (OMIM # 602483), ARCND2 (ARCND2A, OMIM # 614669; ARCND2B, OMIM # 620458), ARCND3 (OMIM # 615706), and ARCND4 (OMIM # 620457).
METHODS
This study reports a case of ARCND2 resulting from a novel pathogenic variant in the PLCB4 gene, and summarizes PLCB4 gene mutation sites and phenotypes of ARCND2.
RESULTS
The proband, a 5-day-old male neonate, was referred to our hospital for respiratory distress. Micrognathia, microstomia, distinctive question mark ears, as well as mandibular condyle hypoplasia were identified. Trio-based whole-exome sequencing identified a novel missense variant of NM_001377142.1:c.1928C>T (NP_001364071.1:p.Ser643Phe) in the PLCB4 gene, which was predicted to impair the local structural stability with a result that the protein function might be affected. From a review of the literature, only 36 patients with PLCB4 gene mutations were retrieved.
CONCLUSION
As with other studies examining familial cases of ARCND2, incomplete penetrance and variable expressivity were observed within different families' heterozygous mutations in PLCB4 gene. Although, motor and intellectual development are in the normal range in the vast majority of patients with ARCND2, long-term follow-up and assessment are still required.
Topics: Humans; Infant, Newborn; Male; China; Ear; Ear Diseases; Micrognathism; Phospholipase C beta; East Asian People
PubMed: 38618928
DOI: 10.1002/mgg3.2441 -
Genes Dec 2023Nager syndrome is a rare human developmental disorder characterized by craniofacial defects including the downward slanting of the palpebral fissures, cleft palate, limb... (Review)
Review
Nager syndrome is a rare human developmental disorder characterized by craniofacial defects including the downward slanting of the palpebral fissures, cleft palate, limb deformities, mandibular hypoplasia, hypoplasia or absence of thumbs, microretrognathia, and ankylosis of the temporomandibular joint. The prevalence is very rare and the literature describes only about a hundred cases of Nager syndrome. There is evidence of autosomal dominant and autosomal recessive inheritance for Nager syndrome, suggesting genetic heterogeneity. The majority of the described causes of Nager syndrome include pathogenic variants in the gene, which encodes a component of the spliceosome; therefore, the syndrome belongs to the spliceosomopathy group of diseases. The diagnosis is made on the basis of physical and radiological examination and detection of mutations in the gene. Due to the diversity of defects associated with Nager syndrome, patients require multidisciplinary, complex, and long-lasting treatment. Usually, it starts from birth until the age of twenty years. The surgical procedures vary over a patient's lifetime and are related to the needed function. First, breathing and feeding must be facilitated; then, oral and facial clefts should be addressed, followed by correcting eyelid deformities and cheekbone reconstruction. In later age, a surgery of the nose and external ear is performed. Speech and hearing disorders require specialized logopedic treatment. A defect of the thumb is treated by transplanting a tendon and muscle or transferring the position of the index finger. In addition to surgery, in order to maximize a patient's benefit and to reduce functional insufficiency, complementary treatments such as rehabilitation and physiotherapy are recommended. In our study, we describe eight patients of different ages with various cases of Nager syndrome. The aim of our work was to present the actual genetic knowledge on this disease and its treatment procedures.
Topics: Child; Humans; Young Adult; Adult; Mandibulofacial Dysostosis; Cleft Palate; Micrognathism; Syndrome; RNA Splicing Factors
PubMed: 38254920
DOI: 10.3390/genes15010029 -
Pediatric and Developmental Pathology :... 2024Coffin-Siris syndrome is an autosomal dominant disorder with neurological, cardiovascular, and gastrointestinal symptoms. Patients with Coffin-Siris syndrome typically...
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 and . Pathogenic gene variants cause Coffin-Siris syndrome 3 whereas pathogenic gene variants cause Coffin-Siris syndrome 2. Here, we present two prenatal Coffin-Siris syndrome cases with autosomal dominant pathogenic variants: gene c.1066_1067del, p.(Leu356AspfsTer4) variant, and a novel 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 pictures of the affected fetuses showing the wide phenotypic spectrum of the disease is presented.
Topics: Humans; Intellectual Disability; Abnormalities, Multiple; Face; Phenotype; Hand Deformities, Congenital; Micrognathism; Neck
PubMed: 37981638
DOI: 10.1177/10935266231210155 -
Indian Journal of Dental Research :... 2023SAMS syndrome is a rare genetic disorder characterized by midline facial clefting, skeletal anomalies, and other defects.
RATIONALE
SAMS syndrome is a rare genetic disorder characterized by midline facial clefting, skeletal anomalies, and other defects.
SALIENT FEATURES
Among the craniofacial manifestations of SAMS syndrome is the presence of a median mandibular cleft (MMC). MMC is a rare occurrence and in this syndrome, it poses a complex challenge for both functional and aesthetic reasons. Patient.
FINDINGS
This rare case report describes the successful correction of an MMC in an 18-month-old child diagnosed with SAMS syndrome.
TREATMENT
This report describes the presentation, diagnosis and treatment. The surgical intervention involved a meticulous, single stage, osseous reconstruction. The mechanism of MMC in SAMS syndrome is discussed.
OUTCOMES
Early intervention for MMC in SAMS syndrome patients can offer promising outcomes.
Topics: Humans; Infant; Cleft Palate; Face; Micrognathism; Syndrome
PubMed: 37787217
DOI: 10.4103/ijdr.ijdr_461_23 -
The Laryngoscope Apr 2024Surgically assisted rapid palatal expansion (SARPE) addresses transverse maxillary deficiency, a known contributor to nasal obstruction. The purpose of this study was to...
OBJECTIVE
Surgically assisted rapid palatal expansion (SARPE) addresses transverse maxillary deficiency, a known contributor to nasal obstruction. The purpose of this study was to assess the feasibility, preliminary outcomes, and safety of posterior palatal expansion via subnasal endoscopy (2PENN), a modified SARPE procedure, aimed at achieving anterior and posterior maxillary expansion.
METHODS
This prospective case series included consecutive adult patients with findings of transverse maxillary deficiency that underwent the 2PENN procedure from 4/2021 to 4/2022. Patients completed pre- and post-operative clinical evaluations, Nasal Obstruction and Septoplasty Effectiveness (NOSE) questionnaires, and computed tomography (CT), with measures including expansion at the level of the posterior nasal spine (PNS), first maxillary inter-molar distance (IMD), and anterior nasal spine (ANS).
RESULTS
The cohort (N = 20) was middle-aged (39 ± 11 years), predominantly male (80%), and overweight (BMI 28 ± 4 kg/m ). The majority (85%) of patients had sleep breathing issues, of which 10 (59%) had polysomnography-confirmed obstructive sleep apnea (OSA). Full anterior-posterior separation of the mid-palatal suture line was evident on all post-operative CT scans, with mean expansion at the PNS of 3.6 ± 1.3 mm, IMD of 6.1 ± 1.6 mm and ANS of 7.0 ± 1.6 mm (p < 0.001). Following surgery, mean NOSE scores improved from 57 ± 23 to 14 ± 13 (p < 0.001). One patient required maxillary antrostomy for post-operative sinusitis.
CONCLUSION
2PENN is an effective and safe technique for achieving both anterior and posterior maxillary expansion in patients with transverse maxillary deficiency. Further study is warranted to better understand the effect of 2PENN in patients with OSA, particularly as it relates to improving pharyngeal patency.
LEVEL OF EVIDENCE
4 Laryngoscope, 134:1970-1977, 2024.
Topics: Adult; Middle Aged; Humans; Male; Female; Palatal Expansion Technique; Pilot Projects; Nasal Obstruction; Sleep Apnea, Obstructive; Endoscopy, Gastrointestinal; Micrognathism; Maxilla
PubMed: 37772955
DOI: 10.1002/lary.31060 -
American Journal of Medical Genetics.... Sep 2023Heterozygous ARID1B variants result in Coffin-Siris syndrome. Features may include hypoplastic nails, slow growth, characteristic facial features, hypotonia,...
Heterozygous ARID1B variants result in Coffin-Siris syndrome. Features may include hypoplastic nails, slow growth, characteristic facial features, hypotonia, hypertrichosis, and sparse scalp hair. Most reported cases are due to ARID1B loss of function variants. We report a boy with developmental delay, feeding difficulties, aspiration, recurrent respiratory infections, slow growth, and hypotonia without a clinical diagnosis, where a previously unreported ARID1B missense variant was classified as a variant of uncertain significance. The pathogenicity of this variant was refined through combined methodologies including genome-wide methylation signature analysis (EpiSign), Machine Learning (ML) facial phenotyping, and LIRICAL. Trio exome sequencing and EpiSign were performed. ML facial phenotyping compared facial images using FaceMatch and GestaltMatcher to syndrome-specific libraries to prioritize the trio exome bioinformatic pipeline gene list output. Phenotype-driven variant prioritization was performed with LIRICAL. A de novo heterozygous missense variant, ARID1B p.(Tyr1268His), was reported as a variant of uncertain significance. The ACMG classification was refined to likely pathogenic by a supportive methylation signature, ML facial phenotyping, and prioritization through LIRICAL. The ARID1B genotype-phenotype has been expanded through an extended analysis of missense variation through genome-wide methylation signatures, ML facial phenotyping, and likelihood-ratio gene prioritization.
Topics: Male; Humans; DNA-Binding Proteins; Muscle Hypotonia; Transcription Factors; Face; Abnormalities, Multiple; Micrognathism; Intellectual Disability; Hand Deformities, Congenital; Neck
PubMed: 37654076
DOI: 10.1002/ajmg.c.32056