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1.
Hum Genet ; 139(4): 461-472, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31980905

RESUMO

SKI pathogenic variations are associated with Shprintzen-Goldberg Syndrome (SGS), a rare systemic connective tissue disorder characterized by craniofacial, skeletal and cardiovascular features. So far, the clinical description, including intellectual disability, has been relatively homogeneous, and the known pathogenic variations were located in two different hotspots of the SKI gene. In the course of diagnosing Marfan syndrome and related disorders, we identified nine sporadic probands (aged 2-47 years) carrying three different likely pathogenic or pathogenic variants in the SKI gene affecting the same amino acid (Thr180). Seven of these molecular events were confirmed de novo. All probands displayed a milder morphological phenotype with a marfanoid habitus that did not initially lead to a clinical diagnosis of SGS. Only three of them had learning disorders, and none had intellectual disability. Six out of nine presented thoracic aortic aneurysm, which led to preventive surgery in the oldest case. This report extends the phenotypic spectrum of variants identified in the SKI gene. We describe a new mutational hotspot associated with a marfanoid syndrome with no intellectual disability. Cardiovascular involvement was confirmed in a significant number of cases, highlighting the importance of accurately diagnosing SGS and ensuring appropriate medical treatment and follow-up.


Assuntos
Aracnodactilia , Craniossinostoses , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Síndrome de Marfan , Mutação , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Adolescente , Adulto , Aracnodactilia/diagnóstico , Aracnodactilia/genética , Aracnodactilia/metabolismo , Criança , Pré-Escolar , Craniossinostoses/diagnóstico , Craniossinostoses/genética , Craniossinostoses/metabolismo , Feminino , Humanos , Masculino , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Síndrome de Marfan/metabolismo , Pessoa de Meia-Idade , Patologia Molecular
2.
Anim Genet ; 51(1): 122-126, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31691328

RESUMO

A GWAS was performed for inborn X-linked facial dysmorphia with severe growth retardation in Labrador Retrievers. This lethal condition was mapped on the X chromosome at 17-21 Mb and supported by eight SNPs in complete LD. Dams of affected male puppies were heterozygous for the significantly associated SNPs and male affected puppies carried the associated alleles hemizygously. In the near vicinity to the associated region, RPS6KA3 was identified as a candidate gene causing facial dysmorphia in humans and mice known as Coffin-Lowry syndrome. Haplotype analysis showed significant association with the phenotypes of all 18 animals under study. This haplotype was validated through normal male progeny from a dam with the not-associated haplotype on both X chromosomes but male affected full-sibs with the associated haplotype.


Assuntos
Craniossinostoses/veterinária , Doenças do Cão/genética , Cães/genética , Genes Letais , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Animais , Craniossinostoses/genética , Feminino , Estudos de Associação Genética/veterinária , Haplótipos , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Cromossomo X/genética
3.
Anim Genet ; 51(1): 127-131, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31774195

RESUMO

Missense variants are associated with various phenotypic traits and disorders in dogs. The canine P2RX7 gene, coding the ATP-gated P2X7 receptor ion channel, contains four known missense variants. The current study aimed to examine the presence of these variants in a random sample of pedigree and mixed-pedigree dogs. Exons 3, 8, 11 and 13 of the P2RX7 gene, encoding these four respective variants, in 65 dogs were assessed by Sanger sequencing and combined with existing sequencing data from another 69 dogs. The distribution of these variants was then evaluated in all 134 dogs combined and separately within individual breeds including 35 different pure breeds. The rs23314713 (p.Phe103Leu) and rs23315462 (p.Pro452Ser) variants were present in 47 and 40% of all dogs studied respectively, with the rs23314713 variant associated with brachycephalic breeds. Among pedigree dogs, the rs23314713 and rs23315462 variants were associated with brachycephalic and non-brachycephalic breeds respectively. The rs851148233 (p.Arg270Cys) and rs850760787 (p.Arg365Gln) variants were present only in dogs of Cocker Spaniel and Labrador Retriever pedigrees respectively. No other missense variants were found in exons 3, 8, 11 and 13 of the P2RX7 gene within the dogs. In conclusion, the rs23314713 and rs23315462 missense variants of the P2RX7 gene are present in a large proportion of dogs, with the rs23314713 variant associated with a number of brachycephalic breeds. However, the association of this variant with dogs of bulldog ancestry, not brachycephaly per se, cannot be excluded.


Assuntos
Craniossinostoses/veterinária , Doenças do Cão/genética , Cães/genética , Mutação de Sentido Incorreto , Receptores Purinérgicos P2X7/genética , Animais , Cruzamento , Craniossinostoses/genética , Linhagem
4.
Neurochirurgie ; 65(5): 246-251, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31568780

RESUMO

INTRODUCTION: The aim of this review was to report on recent advances in trigonocephaly since the last report on craniosynostosis published in 2006. MATERIAL AND METHODS: The review was conducted in accordance with the PRISMA guidelines. Research focused on four main topics: epidemiology, neurodevelopmental disorders, genetics and surgical techniques. RESULTS: Forty reports were included. The prevalence of trigonocephaly increased during the last two decades both in Europe and in the United States, but no clear contributing factors have yet been identified. Neurodevelopmental disorders are frequent in syndromic trigonocephaly and not particularly rare in non-syndromic cases (up to 34%). Developmental retardation (speech, motor or global) was almost always present in children exposed to valproic acid. Chromosomal abnormalities described in metopic synostosis comprised deletion of chromosome 11q24, deletion or trisomy of 9p and deletion of 7p, deletions of 3q, 13q, 12pter, 22q11, and duplication of 15q25. SMAD6 mutations should be systematically screened for in familial cases. Recent advances in surgical techniques have mainly concerned endoscopic-assisted procedures, as they significantly reduce perioperative morbidity. CONCLUSIONS: Neurosurgeons, maxillofacial and plastic surgeons will be increasingly concerned with trigonocephaly because of the increase in prevalence observed over the last two decades. Cytogenetic alterations are probably underestimated in this craniosynostosis, considering the high rate of neurodevelopmental retardation compared to other single-suture synostoses. Genetic counselling is therefore more and more effective in this pathology. An objective method to evaluate the cosmetic results of both endoscopic and open surgeries is necessary, as some under-corrections have been reported with minimally invasive surgery.


Assuntos
Craniossinostoses/cirurgia , Anticonvulsivantes/efeitos adversos , Criança , Pré-Escolar , Craniossinostoses/epidemiologia , Craniossinostoses/genética , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual , Programas de Rastreamento , Procedimentos Cirúrgicos Reconstrutivos , Ácido Valproico/efeitos adversos
5.
Neurochirurgie ; 65(5): 196-201, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31605683

RESUMO

Craniosynostosis (CS) is defined as the premature fusion of cranial sutures, leading to an abnormal skull shape. The overall incidence is between 1: 2,000 and 1: 3,000 live births. Genetic causes are found in 20% of cases. CS can be isolated (non-syndromic CS/NSCS) or they can be part of multiple congenital abnormalities syndromes (syndromic CS/SCS). A few SCS, such as Crouzon, Pfeiffer, Apert and Saethre-Chotzen syndromes, are very well known and their molecular bases have been clarified in the 90s and early 2000s, thus showing the major role of the FGF receptors and TWIST signaling pathways in the etiology of these conditions. The recent availability of powerful molecular tools for genetic diagnosis, such as whole exome or whole genome sequencing, has led to the characterization of the molecular bases of an increasing number of CS, thus emphasizing the significant genetic heterogeneity of these conditions, and blurring the limit between SCS and NSCS. The genetic characterization of patients affected by CS leads to appropriate genetic counseling and provides relevant information concerning comorbidity and prognosis. Nevertheless, this can also lead to the detection of susceptibility factors with low penetrance whose interpretation in genetic counseling is difficult and it raises the question of its cost-effectiveness for health systems. These aspects suggest the need of a patient-tailored clear rationale for performing genetic tests. In this study, we reviewed the main molecular etiologies reported in the last 15 years of either SCS or NSCS, and we propose a systematic multidisciplinary approach as well as a diagnostic flowchart for the genetic evaluation of these patients.


Assuntos
Craniossinostoses/genética , Adulto , Craniossinostoses/diagnóstico , Testes Genéticos , Humanos , Recém-Nascido , Síndrome
6.
Neurochirurgie ; 65(5): 202-209, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31563616

RESUMO

BACKGROUND: Various animal models mimicking craniosynostosis have been developed, using mutant zebrafish and mouse. The aim of this paper is to review the different animal models for syndromic craniosynostosis and analyze what insights they have provided in our understanding of the pathophysiology of these conditions. MATERIAL AND METHODS: The relevant literature for animal models of craniosynostosis was reviewed. RESULTS: Although few studies on craniosynostosis using zebrafish were published, this model appears useful in studying the suture formation mechanisms conserved across vertebrates. Conversely, several mouse models have been generated for the most common syndromic craniosynostoses, associated with mutations in FGFR1, FGFR2, FGFR3 and TWIST genes and also in MSX2, EFFNA, GLI3, FREM1, FGF3/4 genes. The mouse models have also been used to test pharmacological treatments to restore craniofacial growth. CONCLUSIONS: Several zebrafish and mouse models have been developed in recent decades. These animal models have been helpful for our understanding of normal and pathological craniofacial growth. Mouse models mimicking craniosynostoses can be easily used for the screening of drugs as therapeutic candidates.


Assuntos
Craniossinostoses/patologia , Modelos Animais de Doenças , Animais , Craniossinostoses/genética , Humanos , Mutação
7.
Neurochirurgie ; 65(5): 264-268, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31525395

RESUMO

BACKGROUND: Patients with syndromic faciocraniosynostosis due to the mutation of the fibroblast growth factor receptor (FGFR) 2 gene present premature fusion of the coronal sutures and of the cranial base synchondrosis. Cerebrospinal fluid (CSF) circulation disorders and cerebellar tonsil prolapse are frequent findings in faciocraniosynostosis. OBJECTIVE: We reviewed the medical literature on the pathophysiological mechanisms of CSF disorders such as hydrocephalus and of cerebellar tonsil prolapse in FGFR2-related faciocraniosynostosis. DISCUSSION: Different pathophysiological theories have been proposed, but none elucidated all the symptoms present in Apert, Crouzon and Pfeiffer syndromes. The first theory that addressed CSF circulation disruption was the constrictive theory (cephalocranial disproportion): cerebellum and brain stem are constricted by the small volume of the posterior fossa. The second theory proposed venous hyperpressure due to jugular foramens stenosis. The most recent theory proposed a pressure differential between CSF in the posterior fossa and in the vertebral canal, due to foramen magnum stenosis.


Assuntos
Malformação de Arnold-Chiari/etiologia , Malformação de Arnold-Chiari/fisiopatologia , Craniossinostoses/complicações , Craniossinostoses/genética , Hidrocefalia/etiologia , Hidrocefalia/fisiopatologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Acrocefalossindactilia/genética , Humanos
8.
Neurochirurgie ; 65(5): 221-227, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31557489

RESUMO

BACKGROUND: The growth of the posterior fossa in syndromic craniostenosis was studied in many papers. However, few studies described the pathophysiological growth mechanisms in non-operated infants with fibroblast growth factor receptor (FGFR) type 2 mutation (Crouzon, Apert or Pfeiffer syndrome), although these are essential to understanding cranial vault expansion and hydrocephalus treatment in these syndromes. OBJECTIVE: A review of the medical literature was performed, to understand the physiological and pathological growth mechanisms of the posterior fossa in normal infants and infants with craniostenosis related to FGFR2 mutation. DISCUSSION: Of the various techniques for measuring posterior fossa volume, direct slice-by-slice contouring is the most precise and sensitive. Posterior fossa growth follows a bi-phasic pattern due to opening of the petro-occipital, occipitomastoidal and spheno-occipital sutures. Some studies reported smaller posterior fossae in syndromic craniostenosis, whereas direct contouring studies reported no difference between normal and craniostenotic patients. In Crouzon syndrome, synchondrosis fusion occurs earlier than in normal subjects, and follows a precise pattern. This premature fusion in Crouzon syndrome leads to a stenotic foramen magnum and facial retrusion.


Assuntos
Fossa Craniana Posterior/crescimento & desenvolvimento , Fossa Craniana Posterior/patologia , Craniossinostoses/genética , Craniossinostoses/patologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Mutação , Crânio/anormalidades , Síndrome
9.
Genes (Basel) ; 10(9)2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438591

RESUMO

The term linkeropathies (LKs) refers to a group of rare heritable connective tissue disorders, characterized by a variable degree of short stature, skeletal dysplasia, joint laxity, cutaneous anomalies, dysmorphism, heart malformation, and developmental delay. The LK genes encode for enzymes that add glycosaminoglycan chains onto proteoglycans via a common tetrasaccharide linker region. Biallelic variants in XYLT1 and XYLT2, encoding xylosyltransferases, are associated with Desbuquois dysplasia type 2 and spondylo-ocular syndrome, respectively. Defects in B4GALT7 and B3GALT6, encoding galactosyltransferases, lead to spondylodysplastic Ehlers-Danlos syndrome (spEDS). Mutations in B3GAT3, encoding a glucuronyltransferase, were described in 25 patients from 12 families with variable phenotypes resembling Larsen, Antley-Bixler, Shprintzen-Goldberg, and Geroderma osteodysplastica syndromes. Herein, we report on a 13-year-old girl with a clinical presentation suggestive of spEDS, according to the 2017 EDS nosology, in whom compound heterozygosity for two B3GAT3 likely pathogenic variants was identified. We review the spectrum of B3GAT3-related disorders and provide a comparison of all LK patients reported up to now, highlighting that LKs are a phenotypic continuum bridging EDS and skeletal disorders, hence offering future nosologic perspectives.


Assuntos
Fenótipo de Síndrome de Antley-Bixler/genética , Aracnodactilia/genética , Doenças Ósseas/congênito , Craniossinostoses/genética , Nanismo/genética , Glucuronosiltransferase/genética , Síndrome de Marfan/genética , Mutação , Osteocondrodisplasias/genética , Fenótipo , Dermatopatias Genéticas/genética , Adolescente , Fenótipo de Síndrome de Antley-Bixler/patologia , Aracnodactilia/patologia , Doenças Ósseas/genética , Doenças Ósseas/patologia , Craniossinostoses/patologia , Nanismo/patologia , Feminino , Humanos , Síndrome de Marfan/patologia , Osteocondrodisplasias/patologia , Dermatopatias Genéticas/patologia
10.
J Vet Intern Med ; 33(5): 2183-2192, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31454107

RESUMO

BACKGROUND: Brachycephalic dogs have abnormal breathing patterns similar to those in humans with obstructive sleep apnea syndrome. Obstructive sleep apnea syndrome is associated with dyslipidemia, hyperglycemia, and insulin resistance. Despite the fact that anatomic and functional alterations are well described in brachycephalic dogs, little is known about the consequences of upper airway obstruction on systemic inflammatory response and metabolic profile. OBJECTIVES: To describe history, clinical presentation, and anatomic abnormalities; to evaluate systemic inflammatory response and metabolic profile; and to identify possible associations among clinical signs, anatomic abnormalities, inflammatory response, and metabolic profile in brachycephalic dogs with airway obstruction. ANIMALS: Thirty purebred brachycephalic dogs with brachycephalic airway obstructive syndrome (BAOS). METHODS: Prospective study. The following information was recorded and studied: respiratory and digestive signs, airway and digestive endoscopic anomalies, presence or absence of tracheal hypoplasia, histologic evaluation of gastrointestinal tract biopsy specimens, serum concentrations of C-reactive protein (CRP), fructosamine, insulin, glucose, triglyceride, cholesterol, and plasma concentrations of lipoprotein classes. RESULTS: A high proportion of dogs (76.7%) had gastrointestinal signs. Esophageal deviation, atony of the cardia of the stomach, and distal esophagitis were the most common endoscopic anomalies detected. Twenty-six (86.6%) dogs had different degrees of laryngeal collapse. Gastrointestinal histologic evaluation identified mostly chronic inflammation. Glucose, fructosamine, triglycerides, cholesterol, CRP, pre-beta, beta lipoproteins, and chylomicrons were increased to a variable extent. Significant associations among clinical signs, anatomic abnormalities, CRP, and metabolic profile were not found. CONCLUSION AND CLINICAL IMPORTANCE: Despite the presence of inflammation and some mild metabolic derangements, the clinicopathological variables evaluated did not offer valuable information in dogs with BAOS.


Assuntos
Obstrução das Vias Respiratórias/veterinária , Proteína C-Reativa/metabolismo , Doenças do Cão/metabolismo , Metaboloma , Obstrução das Vias Respiratórias/genética , Obstrução das Vias Respiratórias/metabolismo , Animais , Craniossinostoses/genética , Craniossinostoses/veterinária , Doenças do Cão/sangue , Doenças do Cão/genética , Cães , Feminino , Gastroenteropatias/veterinária , Inflamação/veterinária , Masculino , Estudos Prospectivos
11.
Artigo em Russo | MEDLINE | ID: mdl-31339501

RESUMO

The article presents a rare clinical case of isolated sagittal craniosynostosis in dichorionic diamniotic twins. The review addresses issues of epidemiology, etiology, and pathogenesis of craniosynostosis in this group of patients.


Assuntos
Craniossinostoses , Gêmeos Dizigóticos , Craniossinostoses/genética , Craniossinostoses/terapia , Endoscopia , Humanos
12.
PLoS One ; 14(6): e0218286, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31188878

RESUMO

The transcription factor 12 (tcf12) is a basic Helix-Loop-Helix protein (bHLH) of the E-protein family, proven to play an important role in developmental processes like neurogenesis, mesoderm formation, and cranial vault development. In humans, mutations in TCF12 lead to craniosynostosis, a congenital birth disorder characterized by the premature fusion of one or several of the cranial sutures. Current research has been primarily focused on functional studies of TCF12, hence the cellular expression profile of this gene during embryonic development and early stages of ossification remains poorly understood. Here we present the establishment and detailed analysis of two transgenic tcf12:EGFP fluorescent zebrafish (Danio rerio) reporter lines. Using these transgenic lines, we analyzed the general spatiotemporal expression pattern of tcf12 during different developmental stages and put emphasis on skeletal development and cranial suture patterning. We identified robust tcf12 promoter-driven EGFP expression in the central nervous system (CNS), the heart, the pronephros, and the somites of zebrafish embryos. Additionally, expression was observed inside the muscles and bones of the viscerocranium in juvenile and adult fish. During cranial vault development, the transgenic fish show a high amount of tcf12 expressing cells at the growth fronts of the ossifying frontal and parietal bones and inside the emerging cranial sutures. Subsequently, we tested the transcriptional activity of three evolutionary conserved non-coding elements (CNEs) located in the tcf12 locus by transient transgenic assays and compared their in vivo activity to the expression pattern determined in the transgenic tcf12:EGFP lines. We could validate two of them as tcf12 enhancer elements driving specific gene expression in the CNS during embryogenesis. Our newly established transgenic lines enhance the understanding of tcf12 gene regulation and open up the possibilities for further functional investigation of these novel tcf12 enhancer elements in zebrafish.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Embrião não Mamífero/fisiologia , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados/genética , Suturas Cranianas/crescimento & desenvolvimento , Craniossinostoses/genética , Osteogênese/fisiologia , Regiões Promotoras Genéticas/genética , Fatores de Transcrição/genética
14.
Clin Plast Surg ; 46(2): 141-155, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30851747

RESUMO

Management strategies for syndromic craniosynostosis patients require multidisciplinary subspecialty teams to provide optimal care for complex reconstructive approaches. The most common craniosynostosis syndromes include Apert (FGFR2), Crouzon (FGFR2), Muenke (FGFR3), Pfeiffer (FGFR1 and FGFR2), and Saethre-Chotzen (TWIST). Bicoronal craniosynostosis (turribrachycephaly) is most commonly associated with syndromic craniosynostosis. Disease presentation varies from mild sutural involvement to severe pansynostoses, with a spectrum of extracraniofacial dysmorphic manifestations. Understanding the multifaceted syndromic presentations while appreciating the panoply of variable presentations is central to delivering necessary individualized care. Cranial vault remodeling aims to relieve restriction of cranial development and elevated intracranial pressure and restore normal morphology.


Assuntos
Craniossinostoses/cirurgia , Osteotomia/métodos , Procedimentos Cirúrgicos Reconstrutivos/métodos , Crânio/cirurgia , Criança , Suturas Cranianas/anormalidades , Suturas Cranianas/diagnóstico por imagem , Craniossinostoses/diagnóstico por imagem , Craniossinostoses/genética , Feminino , Humanos , Imagem Tridimensional , Lactente , Masculino , Osteotomia de Le Fort/métodos , Procedimentos Cirúrgicos Reconstrutivos/efeitos adversos , Crânio/diagnóstico por imagem , Síndrome , Tomografia Computadorizada por Raios X
15.
Int J Biol Sci ; 15(2): 298-311, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30745822

RESUMO

Craniosynostosis, is the premature fusion of one or more cranial sutures which is the second most common cranial facial anomalies. The premature cranial sutures leads to deformity of skull shape and restricts the growth of brain, which might elicit severe neurologic damage. Craniosynostosis exhibit close correlations with a varieties of syndromes. During the past two decades, as the appliance of high throughput DNA sequencing techniques, steady progresses has been made in identifying gene mutations in both syndromic and nonsyndromic cases, which allow researchers to better understanding the genetic roles in the development of cranial vault. As the enrichment of known mutations involved in the pathogenic of premature sutures fusion, multiple signaling pathways have been investigated to dissect the underlying mechanisms beneath the disease. In addition to genetic etiology, environment factors, especially mechanics, have also been proposed to have vital roles during the pathophysiological of craniosynostosis. However, the influence of mechanics factors in the cranial development remains largely unknown. In this review, we present a brief overview of the updated genetic mutations and environmental factors identified in both syndromic and nonsyndromic craniosynostosis. Furthermore, potential molecular signaling pathways and its relations have been described.


Assuntos
Craniossinostoses/genética , Craniossinostoses/fisiopatologia , Humanos , Mutação/genética , Transdução de Sinais/genética , Crânio/metabolismo
17.
Eur Child Adolesc Psychiatry ; 28(1): 31-42, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29934817

RESUMO

22q11.2 deletion syndrome (22q11.2DS) is the most common known microdeletion in humans occurring in 1 out of 2000-4000 live births, with increasing numbers of individuals with the microdeletion living into adulthood. The aim of the study was to explore the education and employment trajectories of individuals with 22q11.2DS from childhood to adulthood in a large cohort composed of two significant samples. 260 individuals with 22q11.2DS, 134 male and 126 female, aged 5-59 years (mean age 21.3 ± 10.8 years) were evaluated at two sites, Geneva (GVA) and Tel Aviv (TA). Psychiatric comorbidities, IQ score, and adaptive functioning were assessed using gold-standard diagnostic tools. Demographic factors, such as data about education, employment, marital status, and living status, were collected. Children entering elementary school (5-12 years) were significantly more likely to attend a mainstream school, while adolescents were significantly more likely to attend special education schools (p < 0.005). Cognitive abilities, and not adaptive functioning, predicted school placement. Among adults with 22q11.2DS (n = 138), 57 (41.3%) were unemployed, 46 (33.3%) were employed in open market employment, and 35 (25.4%) worked in assisted employment. In adulthood, adaptive functioning more than cognitive abilities predicted employment. Surprisingly, psychotic spectrum disorders were not found to be associated with employment. Individuals with 22q11.2DS are characterized by heterogeneity in educational and employment profiles. We found that cognitive abilities and adaptive functioning, and not the presence of psychiatric disorders, are key factors in school placement and employment. These factors should, therefore, be taken into account when planning optimal development of individuals with 22q11.2DS.


Assuntos
Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/psicologia , Escolaridade , Emprego/estatística & dados numéricos , Transtornos Psicóticos/fisiopatologia , Adolescente , Adulto , Aracnodactilia/genética , Criança , Pré-Escolar , Cognição , Estudos de Coortes , Comorbidade , Craniossinostoses/genética , Síndrome de DiGeorge/complicações , Síndrome de DiGeorge/genética , Feminino , Humanos , Masculino , Síndrome de Marfan/genética , Pessoa de Meia-Idade , Transtornos Psicóticos/etiologia , Adulto Jovem
18.
Congenit Anom (Kyoto) ; 59(4): 132-141, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30132994

RESUMO

The aim of the study was to explore the sonographic findings of fetuses with craniosynostosis and investigate their prognosis. We conducted a 5-year, multicenter retrospective study and collected data on patients with craniosynostosis diagnosed in the perinatal period. Of 41 cases, 30 cases (73%) were syndromic craniosynostosis, eight cases (20%) were non-syndromic craniosynostosis and the other three cases (7%) were secondary craniosynostosis of chromosomal deletion syndromes. The prenatal ultrasound detection rate was 61%. Half of the cases of syndromic craniosynostosis detected during the perinatal period were Pfeiffer syndrome; there were also six cases of Apert syndrome, three cases of Crouzon syndrome and other rare form of syndromic craniosynostosis (Beare-Stevenson syndrome, Saethre-Chotzen syndrome, cranioectodermal dysplasia, and thanatophoric dysplasia). Abnormal shape of the skull was the most common finding leading to prenatal diagnosis of craniosynostosis. Abnormal head biometry, which was the second most frequent finding, was closely correlated with deformation of the cranial shape. Three cases presented with ventriculomegaly and exophthalmos but normal cranial shape and size. The overall survival rate of infants with syndromic craniosynostosis was 79%, while all of the infants with non-syndromic craniosynostosis survived. In conclusion, prenatal diagnosis of craniosynostosis is difficult, especially when dysmorphic change of the fetal cranium is not evident. Abnormal head biometry and ventriculomegaly could potentially be additional markers of fetal craniosynostosis and consequently increase the prenatal detection rate.


Assuntos
Craniossinostoses/diagnóstico , Ultrassonografia Pré-Natal , Acrocefalossindactilia/diagnóstico , Adulto , Aberrações Cromossômicas , Craniossinostoses/genética , Diagnóstico Diferencial , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Assistência Perinatal , Gravidez , Prognóstico , Estudos Retrospectivos , Síndrome , Tomografia Computadorizada Espiral
19.
Eur J Med Genet ; 62(6): 103528, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30142437

RESUMO

Biallelic pathogenic variants in KLHL7 are known to result in Crisponi syndrome (CS)/cold-induced sweating syndrome type 1 (CISS1) like phenotype and Bohring-Opitz-like syndrome. In this report, a trio whole-exome sequencing (WES) was performed in proband with cold-induced sweating, microcephaly, facial dysmorphism, spasticity, failure to thrive, pigmentary abnormalities of the retina, hypoplasia of corpus callosum and periventricular nodular heterotopia. A novel homozygous in-frame deletion was identified in exon 2 of KLHL7, affecting the BTB domain of the protein. Our findings expand the clinical and molecular spectrum of KLHL7-related disorders.


Assuntos
Autoantígenos/genética , Craniossinostoses/genética , Deleção de Genes , Deformidades Congênitas da Mão/genética , Hiperidrose/genética , Deficiência Intelectual/genética , Fenótipo , Trismo/congênito , Autoantígenos/química , Craniossinostoses/patologia , Morte Súbita/patologia , Facies , Deformidades Congênitas da Mão/patologia , Homozigoto , Humanos , Hiperidrose/patologia , Lactente , Deficiência Intelectual/patologia , Masculino , Domínios Proteicos , Trismo/genética , Trismo/patologia
20.
Med Hypotheses ; 122: 180-183, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30593407

RESUMO

Many world-renowned scientists and artists had autism spectrum disorder (ASD). We suggest that the French mathematician and physicist Blaise Pascal (1623-1662) also had ASD. As a boy, he demonstrated his mastery of language, mathematics and science. He showed single-mindedness and obsessive interests in the pursuit of science in his younger years and later he pursued with religion with the same determination. Pascal neglected social interactions; he was cold and aloof and had an obsessive revulsion to any expression of emotional attachment. As shown by his funerary mask and the autopsy report Pascal had craniosynostosis (primary nonsyndromic oxycephaly) with atrophy of the right half of the face. Congenital facial asymmetry due to craniosynostosis has a genetic basis. This suggests that Pascal's facial deformity may betray his propensity to suffer from genetically determined diseases including ASD. Despite the intrinsic limitations of a diagnosis based only on biographical information, we surmise that Pascal had the three key symptoms (obsessive interests, difficulty in social relationship and problems in communicating) that characterize ASD individuals.


Assuntos
Transtorno do Espectro Autista/história , Craniossinostoses/história , Predisposição Genética para Doença , Matemática/história , Transtorno do Espectro Autista/genética , Comunicação , Comorbidade , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/história , Craniossinostoses/genética , Face , Pessoas Famosas , França , História do Século XVII , Humanos , Masculino , Comportamento Obsessivo , Crânio
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