RESUMEN
Roberts syndrome (RBS) is an autosomal recessive disorder with profound growth deficiency and limb reduction caused by ESCO2 loss-of-function variants. Here, we elucidate the pathogenesis of limb reduction in an Esco2fl/fl;Prrx1-CreTg/0 mouse model using bulk- and single-cell-RNA-seq and gene co-expression network analyses during embryogenesis. Our results reveal morphological and vascular defects culminating in hemorrhage of mutant limbs at E12.5. Underlying this abnormal developmental progression is a pre-apoptotic, mesenchymal cell population specific to mutant limb buds enriched for p53-related signaling beginning at E9.5. We then characterize these p53-related processes of cell cycle arrest, DNA damage, cell death, and the inflammatory leukotriene signaling pathway in vivo. In utero treatment with pifithrin-α, a p53 inhibitor, rescued the hemorrhage in mutant limbs. Lastly, significant enrichments were identified among genes associated with RBS, thalidomide embryopathy, and other genetic limb reduction disorders, suggesting a common vascular etiology among these conditions.
Asunto(s)
Apoptosis , Proteínas Cromosómicas no Histona , Cohesinas , Modelos Animales de Enfermedad , Deformidades Congénitas de las Extremidades , Proteína p53 Supresora de Tumor , Animales , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Apoptosis/genética , Ratones , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Cromosómicas no Histona/genética , Deformidades Congénitas de las Extremidades/genética , Deformidades Congénitas de las Extremidades/patología , Deformidades Congénitas de las Extremidades/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Femenino , Tolueno/análogos & derivados , Tolueno/farmacología , Ectromelia/genética , Ectromelia/metabolismo , Ectromelia/patología , Benzotiazoles/farmacología , Transducción de Señal , Masculino , Daño del ADN , Puntos de Control del Ciclo Celular/genética , Puntos de Control del Ciclo Celular/efectos de los fármacos , Esbozos de los Miembros/metabolismo , Hemorragia/patología , Hemorragia/genética , Hipertelorismo , Proteínas de Homeodominio , Anomalías CraneofacialesRESUMEN
Craniofacial dysmorphisms are among the most common birth defects. Proteasome mutations frequently result in craniofacial dysmorphisms, including lower jaw malformations; however, the underlying mechanisms are unknown. Here, we used a zebrafish proteasome subunit ß 1 (psmb1) mutant to define the cellular mechanisms underlying proteasome mutation-induced craniofacial dysmorphisms. psmb1 mutants exhibited a flattened ceratohyal and smaller Meckel's and palatoquadrate cartilages. Ceratohyal flattening was a result of failed chondrocyte convergent extension, accompanied by reduced numbers of chondrocytes in the lower jaw due to defects in chondrocyte differentiation. Morphogenesis of craniofacial muscles and tendons was similarly perturbed. psmb1 mutants lacked the hyohyal muscles, and craniofacial tendons were shortened and disorganized. We additionally identified a critical period for proteasome function in craniofacial development, specifically during chondrocyte and muscle differentiation. psmb1 overexpression in sox10+ cells of mutant embryos rescued both cartilage and tendon phenotypes but induced only a partial rescue of the muscle phenotype, indicating that psmb1 was required in both tissue-autonomous and nonautonomous fashions during craniofacial development. Overall, our work demonstrates that psmb1 is required for craniofacial cartilage, tendon, and muscle differentiation and morphogenesis.
Asunto(s)
Cartílago , Condrocitos , Morfogénesis , Complejo de la Endopetidasa Proteasomal , Proteínas de Pez Cebra , Pez Cebra , Animales , Pez Cebra/genética , Morfogénesis/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Complejo de la Endopetidasa Proteasomal/genética , Condrocitos/metabolismo , Cartílago/metabolismo , Cartílago/embriología , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patología , Tendones/embriología , Tendones/metabolismo , Tendones/anomalías , Tendones/patología , Diferenciación Celular/genética , Mutación , Regulación del Desarrollo de la Expresión Génica , Condrogénesis/genéticaRESUMEN
Zimmermann-Laband Syndrome (ZLS; MIM 135500) is a rare genetic disorder with the main clinical manifestations of gingival fibromatosis and finger/toe nail hypoplasia. KCNH1 (potassium channel, voltage-gated, subfamily H, member-1), KCNN3 (potassium channel, voltage-gated, subfamily H, member-3) and ATP6V1B2 (ATPase H+ transporting V1 subunit B2) genes are considered causative genes for ZLS. However, there are limited reports about the diverse clinical presentation and genetic heterogeneity. Reporting more information on phenotype-genotype correlation and the treatment of ZLS is necessary. This case reported a 2-year-old patient with gingival enlargement that failure of eruption of the deciduous teeth and severe hypoplasia of nails. Based on a systemic examination and a review of the relevant literature, we made an initial clinical diagnosis of ZLS. A novel pathogenic variant in the KCNH1 gene was identified using whole-exome sequencing to substantiate our preliminary diagnosis. The histopathological results were consistent with gingival fibromatosis. Gingivectomy and gingivoplasty were performed under general anesthesia. After surgery, the gingival appearance improved significantly, and the masticatory function of the teeth was restored. After 2-year follow-up, the gingival showed slightly hyperplasia. Systemic examination and gene sequencing firstly contribute to provide information for an early diagnosis for ZLS, then timely removal of the hyperplastic gingival facilitates the establishment of a normal occlusal relationship and improves oral aesthetics.
Asunto(s)
Fibromatosis Gingival , Humanos , Fibromatosis Gingival/genética , Preescolar , Deformidades Congénitas de la Mano/genética , Anomalías Múltiples/genética , Masculino , Gingivectomía/métodos , Femenino , Uñas Malformadas/genética , Anomalías CraneofacialesRESUMEN
Selective serotonin re-uptake inhibitors (SSRI) widely used in the treatment of depression, anxiety, obsessive compulsive disorder, fibromyalgia, and migraine are among the most heavily prescribed drug class in the United States (US). Along with an overall rise in SSRI use, these medications are increasingly used by pregnant individuals and recent preclinical and clinical studies have indicated that SSRIs may increase the prevalence of congenital abnormalities and birth defects of the craniofacial region. Our group has developed pre-clinical models of study, including those that mimic the clinical use of SSRI in mice. Here we designed a study to interrogate a commonly prescribed SSRI drug, Citalopram, for its effects on craniofacial and dental development when introduced in utero. Pre-natal exposure to a clinically relevant dose of citalopram resulted in changes in craniofacial form identified by an increase in endocast volume in SSRI exposed postnatal day 15 mouse pups. More specifically, cranial length and synchondrosis length increased in SSRI exposed pups as compared to control pups of the same age. Additionally, growth center (synchondrosis) height and width and palate length and width decreased in SSRI exposed pups as compared to control un-exposed pups. Effects of SSRI on the molars was minimal. Craniofacial growth and development continue to be an area of interest in the investigation of in utero pharmaceutical drug exposure. Altogether these data indicate that prenatal SSRI exposure affects craniofacial form in multiple tissues and specifically at growth sites and centers of the skull.
Asunto(s)
Citalopram , Anomalías Craneofaciales , Inhibidores Selectivos de la Recaptación de Serotonina , Cráneo , Animales , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Ratones , Femenino , Embarazo , Citalopram/farmacología , Cráneo/efectos de los fármacos , Anomalías Craneofaciales/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Modelos Animales de Enfermedad , MasculinoRESUMEN
Due to abnormal prenatal ultrasound findings of femoral shortening and flattened facial profile, a G2P0 pregnant patient underwent an amniocentesis at 15 weeks of gestation for proband-only exome sequencing. Bioinformatic filtering for genes included on the laboratory's extended skeletal dysplasia panel identified a heterozygous, likely pathogenic, frameshift variant in DVL1 NM_001330311.2:c.1575_1582dup; (p.Pro528ArgfsTer149). Pathogenic variants in DVL1 are associated with autosomal dominant Robinow syndrome (ADRS), a genetic disorder characterized by skeletal dysplasia with genital and craniofacial abnormalities. Prenatal ultrasound in the third trimester noted shortened long bones (first percentile for gestational age), macrocephaly with frontal bossing, short and upturned nose with a wide nasal root, triangular mouth, low pedal arches concerning for rocker-bottom feet, and ambiguous genitalia. A postnatal exam by Medical Genetics confirmed the prenatal findings in addition to hypertelorism, brachydactyly with broad thumbs and halluces, clinodactyly of second fingers, rigid gums with a frontal frenulum, and a sacral dimple. This case describes a novel variant in DVL1 identified in a fetus with prenatal and postnatal phenotypic features consistent with ADRS. To our knowledge, this is the first reported case of a prenatal molecular diagnosis of the dominant form of Robinow syndrome and the third case to describe prenatal ultrasound findings associated with this diagnosis.
Asunto(s)
Anomalías Craneofaciales , Proteínas Dishevelled , Deformidades Congénitas de las Extremidades , Adulto , Femenino , Humanos , Embarazo , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/diagnóstico , Anomalías Craneofaciales/diagnóstico por imagen , Proteínas Dishevelled/genética , Enanismo/genética , Enanismo/diagnóstico , Enanismo/diagnóstico por imagen , Mutación del Sistema de Lectura , Deformidades Congénitas de las Extremidades/genética , Deformidades Congénitas de las Extremidades/diagnóstico , Deformidades Congénitas de las Extremidades/diagnóstico por imagen , Fenotipo , Ultrasonografía Prenatal , Anomalías UrogenitalesRESUMEN
Rho-associated protein kinase-2 (ROCK2) is a critical player in many cellular processes and was incriminated in cardiovascular and neurological disorders. Recent evidence has shown that non-selective pharmacological blockage of ROCKs ameliorates behavioral alterations in a mouse model of 16p11.2 haploinsufficiency. We had revealed that 16p11.2-deficient mice also display cerebrovascular abnormalities, including endothelial dysfunction. To investigate whether genetic blockage of ROCK2 also exerts beneficial effects on cognition and angiogenesis, we generated mice with both 16p11.2 and Rock2 haploinsufficiency (16p11.2df/+;Rock2+/-). We find that Rock2 heterozygosity on a 16p11.2df/+ background significantly improved recognition memory. Furthermore, brain endothelial cells from 16p11.2df/+;Rock2+/- mice display improved angiogenic capacity compared to cells from 16p11.2df/+ littermates. Overall, this study implicates Rock2 gene as a modulator of 16p11.2-associated alterations, highlighting its potential as a target for treatment of autism spectrum disorders.
Asunto(s)
Trastorno Autístico , Deleción Cromosómica , Trastornos de los Cromosomas , Cromosomas Humanos Par 16 , Modelos Animales de Enfermedad , Quinasas Asociadas a rho , Animales , Quinasas Asociadas a rho/genética , Quinasas Asociadas a rho/metabolismo , Cromosomas Humanos Par 16/genética , Ratones , Trastorno Autístico/genética , Trastornos de los Cromosomas/genética , Heterocigoto , Reconocimiento en Psicología/fisiología , Células Endoteliales/metabolismo , Haploinsuficiencia , Masculino , Ratones Endogámicos C57BL , Anomalías Craneofaciales/genética , Discapacidad Intelectual/genéticaRESUMEN
The shift to a genotype-first approach in genetic diagnostics has revolutionized our understanding of neurodevelopmental disorders, expanding both their molecular and phenotypic spectra. Kleefstra syndrome (KLEFS1) is caused by EHMT1 haploinsufficiency and exhibits broad clinical manifestations. EHMT1 encodes euchromatic histone methyltransferase-1-a pivotal component of the epigenetic machinery. We have recruited 209 individuals with a rare EHMT1 variant and performed comprehensive molecular in silico and in vitro testing alongside DNA methylation (DNAm) signature analysis for the identified variants. We (re)classified the variants as likely pathogenic/pathogenic (molecularly confirming Kleefstra syndrome) in 191 individuals. We provide an updated and broader clinical and molecular spectrum of Kleefstra syndrome, including individuals with normal intelligence and familial occurrence. Analysis of the EHMT1 variants reveals a broad range of molecular effects and their associated phenotypes, including distinct genotype-phenotype associations. Notably, we showed that disruption of the "reader" function of the ankyrin repeat domain by a protein altering variant (PAV) results in a KLEFS1-specific DNAm signature and milder phenotype, while disruption of only "writer" methyltransferase activity of the SET domain does not result in KLEFS1 DNAm signature or typical KLEFS1 phenotype. Similarly, N-terminal truncating variants result in a mild phenotype without the DNAm signature. We demonstrate how comprehensive variant analysis can provide insights into pathogenesis of the disorder and DNAm signature. In summary, this study presents a comprehensive overview of KLEFS1 and EHMT1, revealing its broader spectrum and deepening our understanding of its molecular mechanisms, thereby informing accurate variant interpretation, counseling, and clinical management.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 9 , Anomalías Craneofaciales , Metilación de ADN , Estudios de Asociación Genética , N-Metiltransferasa de Histona-Lisina , Discapacidad Intelectual , Fenotipo , Humanos , N-Metiltransferasa de Histona-Lisina/genética , Anomalías Craneofaciales/genética , Discapacidad Intelectual/genética , Cromosomas Humanos Par 9/genética , Metilación de ADN/genética , Femenino , Masculino , Niño , Preescolar , Antígenos de Histocompatibilidad/genética , Adolescente , Cardiopatías Congénitas/genética , Haploinsuficiencia/genética , MutaciónRESUMEN
Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, â¼15% of KMT2C PTVs were inherited. Although the most highly expressed KMT2C transcript consists of only the last four exons, pathogenic PTVs were found in almost all the exons of this large gene. KMT2C variant interpretation can be challenging due to segmental duplications and clonal hematopoesis-induced artifacts. Using samples from 27 affected individuals, divided into discovery and validation cohorts, we generated a moderate strength disorder-specific KMT2C DNA methylation (DNAm) signature and demonstrate its utility in classifying non-truncating variants. Based on 81 individuals with pathogenic/likely pathogenic variants, we demonstrate that the KMT2C-related NDD is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, hypotonia, seizures, short stature, and other comorbidities. The facial module of PhenoScore, applied to photographs of 34 affected individuals, reveals that the KMT2C-related facial gestalt is significantly different from the general NDD population. Finally, using PhenoScore and DNAm signatures, we demonstrate that the KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes. Overall, we define the clinical features, molecular spectrum, and DNAm signature of the KMT2C-related NDD and demonstrate they are distinct from Kleefstra and Kabuki syndromes highlighting the need to rename this condition.
Asunto(s)
Anomalías Múltiples , Deleción Cromosómica , Cromosomas Humanos Par 9 , Anomalías Craneofaciales , Metilación de ADN , Proteínas de Unión al ADN , Cara , Enfermedades Hematológicas , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Enfermedades Vestibulares , Humanos , Anomalías Múltiples/genética , Enfermedades Vestibulares/genética , Discapacidad Intelectual/genética , Cara/anomalías , Cara/patología , Proteínas de Unión al ADN/genética , Masculino , Femenino , Enfermedades Hematológicas/genética , Trastornos del Neurodesarrollo/genética , Anomalías Craneofaciales/genética , Cromosomas Humanos Par 9/genética , Niño , Metilación de ADN/genética , Preescolar , Proteínas de Neoplasias/genética , Adolescente , Hipertricosis/genética , Mutación , Insuficiencia de Crecimiento/genética , N-Metiltransferasa de Histona-Lisina/genética , Cardiopatías CongénitasRESUMEN
This article reports on the clinical and genetic characteristics of monozygotic twins with Marshall-Smith syndrome (MRSHSS) due to a mutation in the NFIX gene, along with a review of related literature. Both patients presented with global developmental delays, a prominent forehead, shallow eye sockets, and pectus excavatum. Genetic testing revealed a heterozygous splicing site mutation c.697+1G>A in both children, with parents showing wild-type at this locus. According to the guidelines of the American College of Medical Genetics and Genomics, this mutation is considered likely pathogenic and has not been previously reported in the literature. A review of the literature identified 32 MRSHSS patients with splicing/frameshift mutations. Accelerated bone maturation and moderate to severe global developmental delay/intellectual disability are the primary clinical manifestations of patients with MRSHSS. Genetic testing results are crucial for the diagnosis of this condition.
Asunto(s)
Mutación , Factores de Transcripción NFI , Gemelos Monocigóticos , Humanos , Factores de Transcripción NFI/genética , Gemelos Monocigóticos/genética , Anomalías Múltiples/genética , Masculino , Femenino , Anomalías Craneofaciales/genética , Preescolar , Enfermedades del Desarrollo Óseo , Displasia Septo-ÓpticaRESUMEN
Robinow syndrome is a rare disease caused by variants of seven WNT pathway genes. Craniofacial features include widening of the nasal bridge and jaw hypoplasia. We used the chicken embryo to test whether two missense human FZD2 variants (1301G>T, p.Gly434Val; 425C>T, p.Pro142Lys) were sufficient to change frontonasal mass development. In vivo, the overexpression of retroviruses with wild-type or variant human FZD2 inhibited upper beak ossification. In primary cultures, wild-type and variant human FZD2 significantly inhibited chondrogenesis, with the 425C>T variant significantly decreasing activity of a SOX9 luciferase reporter compared to that for the wild type or 1301G>T. Both variants also increased nuclear shuttling of ß-catenin (CTNNB1) and increased the expression of TWIST1, which are inhibitory to chondrogenesis. In canonical WNT luciferase assays using frontonasal mass cells, the variants had dominant-negative effects on wild-type FZD2. In non-canonical assays, the 425C>T variant failed to activate the reporter above control levels and was unresponsive to exogenous WNT5A. This is the first single amino acid change to selectively alter ligand binding in a FZD receptor. Therefore, FZD2 missense variants are pathogenic and could lead to the altered craniofacial morphogenesis seen in Robinow syndrome.
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Condrogénesis , Anomalías Craneofaciales , Receptores Frizzled , Animales , Embrión de Pollo , Humanos , Pico , beta Catenina/metabolismo , Núcleo Celular/metabolismo , Condrogénesis/genética , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patología , Enanismo , Receptores Frizzled/genética , Receptores Frizzled/metabolismo , Deformidades Congénitas de las Extremidades , Cráneo/patología , Cráneo/embriología , Proteína 1 Relacionada con Twist/metabolismo , Proteína 1 Relacionada con Twist/genética , Anomalías Urogenitales , Vía de Señalización WntRESUMEN
INTRODUCTION: Little is known about rates of suicidal ideation and behavior among youth with cleft lip and/or palate (CLP) and other craniofacial conditions. METHODS: Records of patients ages 6 and older who were administered the Columbia-Suicide Severity Rating Scale (C-SSRS) Lifetime Version during routine multidisciplinary cleft or craniofacial team visits between 2019 and 2023 were examined. Demographics information, C-SSRS data, and diagnoses were assessed with statistics including t tests, the Fisher exact test, and odds ratios. RESULTS: A total of 1140 C-SSRS questionnaires across 602 (433 CLP and 169 craniofacial) patients with an average age of 11.2±3.7 years were included. Eighty-four (13.6%) patients endorsed lifetime suicidal ideation, 9 (1.5%) had at least one instance of suicidal behavior, 30 (5.0%) endorsed nonsuicidal self-injury, and 2 (0.3%) engaged in self-injurious behavior. Compared with CLP, those with other craniofacial conditions had similar odds of endorsing suicidal ideation and behavior ( P ≥0.05). Compared with those with isolated cleft palates, CLP had greater odds of endorsing suicidal ideation and behavior, though those differences were not significant ( P ≥0.05). Incidence of suicidality was unchanged before, during, and after the COVID-19 pandemic ( P ≥0.05). Dividing patients by sex or insurance type revealed no difference in suicidality ( P ≥0.05). CONCLUSION: Patients with CLP and craniofacial conditions have a high incidence of suicidal ideation and behavior, though levels are similar between these groups. Suicidality in these patients was not negatively impacted by the COVID-19 pandemic. Early identification of safety risks and psychosocial challenges through regular screening can facilitate connection with appropriate clinical interventions.
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Labio Leporino , Fisura del Paladar , Ideación Suicida , Humanos , Femenino , Masculino , Niño , Labio Leporino/psicología , Fisura del Paladar/psicología , Adolescente , COVID-19/psicología , COVID-19/epidemiología , Encuestas y Cuestionarios , Anomalías Craneofaciales/psicología , Conducta Autodestructiva/psicología , Conducta Autodestructiva/epidemiologíaRESUMEN
BACKGROUND: Minor physical anomalies (MPAs) are congenital morphological abnormalities linked to disruptions of fetal development. MPAs are common in 22q11.2 deletion syndrome (22q11DS) and psychosis spectrum disorders (PS) and likely represent a disruption of early embryologic development that may help identify overlapping mechanisms linked to psychosis in these disorders. METHODS: Here, 2D digital photographs were collected from 22q11DS (n = 150), PS (n = 55), and typically developing (TD; n = 93) individuals. Photographs were analyzed using two computer-vision techniques: (1) DeepGestalt algorithm (Face2Gene (F2G)) technology to identify the presence of genetically mediated facial disorders, and (2) Emotrics-a semi-automated machine learning technique that localizes and measures facial features. RESULTS: F2G reliably identified patients with 22q11DS; faces of PS patients were matched to several genetic conditions including FragileX and 22q11DS. PCA-derived factor loadings of all F2G scores indicated unique and overlapping facial patterns that were related to both 22q11DS and PS. Regional facial measurements of the eyes and nose were smaller in 22q11DS as compared to TD, while PS showed intermediate measurements. CONCLUSIONS: The extent to which craniofacial dysmorphology 22q11DS and PS overlapping and evident before the impairment or distress of sub-psychotic symptoms may allow us to identify at-risk youths more reliably and at an earlier stage of development.
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Anomalías Craneofaciales , Síndrome de DiGeorge , Trastornos Psicóticos , Humanos , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/fisiopatología , Trastornos Psicóticos/genética , Femenino , Masculino , Adolescente , Niño , Anomalías Craneofaciales/genética , Adulto Joven , Adulto , Aprendizaje Automático , Procesamiento de Imagen Asistido por ComputadorRESUMEN
BACKGROUND: Frontonasal dysplasia (FND) is a rare congenital anomaly resulting from the underdevelopment of the frontonasal process, and it can be syndromic or nonsyndromic. The typical features of FND include a deformed nose and ocular hypertelorism, which are sometimes associated with cleft lip and/or palate. Only approximately 10 cases of prenatally diagnosed nonsyndromic FND have been reported in the past 30 years. CASE PRESENTATION: A 33-year-old woman (G2P1) was referred to our center at 20 gestational weeks for bilateral hydrocephaly. We detected typical features of FND, including severe hypertelorism, median nasal bifidity, a minor cleft lip, and multiple limb anomalies using three-dimensional (3D) ultrasound. A hypoplastic corpus callosum, unilateral microtia, and a ventricular septal defect were also detected. Genetic testing, including karyotype analysis, copy number variation (CNV) analysis, trio-whole exome sequencing (trio-WES), and trio-whole-gene sequencing (trio-WGS), was performed; however, we did not find any de novo gene variants in the fetus as compared to the parents. Postmortem examination confirmed the prenatal diagnosis of FND. CONCLUSION: The present case expands the wide phenotypic spectrum of prenatal FND patients. 3D ultrasound is a useful tool for detecting facial and limb deformities.
Asunto(s)
Agenesia del Cuerpo Calloso , Anomalías Craneofaciales , Cara , Hidrocefalia , Imagenología Tridimensional , Deformidades Congénitas de las Extremidades , Ultrasonografía Prenatal , Humanos , Femenino , Adulto , Embarazo , Anomalías Craneofaciales/diagnóstico por imagen , Agenesia del Cuerpo Calloso/diagnóstico por imagen , Agenesia del Cuerpo Calloso/genética , Deformidades Congénitas de las Extremidades/diagnóstico por imagen , Deformidades Congénitas de las Extremidades/genética , Cara/anomalías , Cara/diagnóstico por imagen , Hidrocefalia/diagnóstico por imagen , Defectos del Tabique Interventricular/diagnóstico por imagen , Defectos del Tabique Interventricular/genética , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/genéticaRESUMEN
Schinzel-Giedion syndrome (SGS) is a severe multisystem disorder characterized by distinctive facial features, profound intellectual disability, refractory epilepsy, cortical visual impairment, hearing loss, and various congenital anomalies. SGS is attributed to gain-of-function (GoF) variants in the SETBP1 gene, with reported variants causing canonical SGS located within a 12 bp hotspot region encoding SETBP1 residues aa868-871 (degron). Here, we describe a case of typical SGS caused by a novel heterozygous missense variant, D874V, adjacent to the degron. The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart disease, consistent with canonical SGS. This is the first report of a typical SGS caused by a, SETBP1 non-degron missense variant. This case expands the genetic spectrum of SGS and provides new insights into genotype-phenotype correlations.
Asunto(s)
Anomalías Múltiples , Proteínas Portadoras , Deformidades Congénitas de la Mano , Mutación Missense , Uñas Malformadas , Humanos , Femenino , Anomalías Múltiples/genética , Proteínas Portadoras/genética , Recién Nacido , Proteínas Nucleares/genética , Discapacidad Intelectual/genética , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/complicaciones , Pie Equinovaro/genética , Fenotipo , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/complicaciones , DegronesRESUMEN
Pediatric craniomaxillofacial reconstruction must be approached through the lens of growth and durability. A systematic approach of matching defects to donor tissue drives the selection of autologous reconstructive technique. The menu of available methods for reconstruction can be organized in a manner similar to adults, with special considerations for growth and development. Reconstructive surgeons have the opprtunity to promote and maintain young patients' sense of identity during psychosocial development.
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Procedimientos de Cirugía Plástica , Humanos , Procedimientos de Cirugía Plástica/métodos , Niño , Anomalías Craneofaciales/cirugía , Cráneo/cirugíaRESUMEN
When searching over associations between congenital ear abnormalities, especially microtia and affiliated deformities like cleft lip or palate and congenital heart diseases, some clinical analysis and genetic theories are found. A 10-year-old boy sent to the plastic surgery hospital was puzzled by a congenital anterior auricular fistula with fluid trace for more than 9 years. The preoperative diagnoses were branchial cleft fistula and congenital left ear deformity with postoperation of TOF. By browsing over studies on genetic concerns and clinical performance, it may be attributed to a possible association between microtia, branchial cleft fistula, and tetralogy of Fallot, though whose fundamental mechanisms remain concerned.
Asunto(s)
Región Branquial , Microtia Congénita , Tetralogía de Fallot , Humanos , Masculino , Tetralogía de Fallot/cirugía , Región Branquial/anomalías , Región Branquial/cirugía , Niño , Microtia Congénita/cirugía , Fístula/cirugía , Fístula/congénito , Enfermedades Faríngeas , Anomalías CraneofacialesRESUMEN
SATB2-associated syndrome (SAS, glass syndrome, OMIM#612313) is a neurodevelopmental autosomal dominant disorder with frequent craniofacial abnormalities including palatal and dental anomalies. To assess the role of Satb2 in craniofacial development, we analyzed mutant mice at different stages of development. Here, we show that Satb2 is broadly expressed in early embryonic mouse development including the mesenchyme of the second and third arches. Satb2-/- mutant mice exhibit microglossia, a shortened lower jaw, smaller trigeminal ganglia, and larger thyroids. We correlate these findings with the detailed clinical phenotype of four individuals with SAS and remarkable craniofacial phenotypes with one requiring mandibular distraction in childhood. We conclude that the mouse and patient data presented support less well-described phenotypic aspects of SAS including mandibular morphology and thyroid anatomical/functional issues.
Asunto(s)
Región Branquial , Proteínas de Unión a la Región de Fijación a la Matriz , Fenotipo , Factores de Transcripción , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Animales , Humanos , Ratones , Factores de Transcripción/genética , Región Branquial/anomalías , Región Branquial/patología , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patología , Femenino , Masculino , Ratones Noqueados , Síndrome , Mandíbula/anomalías , Mandíbula/patologíaRESUMEN
Harold (Hal) C. Slavkin, DDS, the 22nd president of the American Association for Dental, Oral, and Craniofacial Research (1993 to 1994), died on December 22, 2023. During a career that spanned almost 6 decades, Hal distinguished himself as an international authority on craniofacial biology and an advocate for oral health equity. He served as dean of the University of Southern California's dental school, founded the school's Center for Craniofacial Molecular Biology, created the nation's first PhD program in craniofacial biology, and served as the sixth director of the National Institute of Dental and Craniofacial Research. Hal's studies of the molecular and cellular underpinnings of craniofacial malformations prepared him to champion translational research later in his career, when his work with patient advocates revealed the importance of applying new discoveries to clinical practice. A visionary thinker, skilled administrator, progressive educator, compelling communicator, researcher, scholar, and mentor, Hal was known as a Renaissance leader. He rejoiced in fostering collaborative synergies among people and organizations. Throughout his life, family was his central grounding force. He and his wife, Lois, advanced a wide range of social and community initiatives and took great pride in their children, grandchildren, and great-grandchildren. We remember Hal for his indelible spirit, unflappable enthusiasm for science, fierce advocacy for social justice, and infectious zest for life. Here, we outline his multidimensional accomplishments through the lenses of academia, government, and nonprofit organizations. Although it is with heavy hearts that we bid goodbye to this remarkable man, our spirits are lightened by the many gifts he left behind.