ABSTRACT
Current understanding of the genetic factors contributing to the etiology of non-syndromic craniosynostosis (NSC) remains scarce. The present work investigated the presence of variants in ALX4, EFNA4, and TWIST1 genes in children with NSC to verify if variants within these genes may contribute to the occurrence of these abnormal phenotypes. A total of 101 children (aged 45.07±40.94 months) with NSC participated in this cross-sectional study. Parents and siblings of the probands were invited to participate. Medical and family history of craniosynostosis were documented. Biological samples were collected to obtain genomic DNA. Coding exons of human TWIST1, ALX4, and EFNA4 genes were amplified by polymerase chain reaction and Sanger sequenced. Five missense variants were identified in ALX4 in children with bilateral coronal, sagittal, and metopic synostosis. A de novo ALX4 variant, c.799G>A: p.Ala267Thr, was identified in a proband with sagittal synostosis. Three missense variants were identified in the EFNA4 gene in children with metopic and sagittal synostosis. A TWIST1 variant occurred in a child with unilateral coronal synostosis. Variants were predicted to be among the 0.1% (TWIST1, c.380C>A: p. Ala127Glu) and 1% (ALX4, c.769C>T: p.Arg257Cys, c.799G>A: p.Ala267Thr, c.929G>A: p.Gly310Asp; EFNA4, c.178C>T: p.His60Tyr, C.283A>G: p.Lys95Glu, c.349C>A: Pro117Thr) most deleterious variants in the human genome. With the exception of ALX4, c.799G>A: p.Ala267Thr, all other variants were present in at least one non-affected family member, suggesting incomplete penetrance. Thus, these variants may contribute to the development of craniosynostosis, and should not be discarded as potential candidate genes in the diagnosis of this condition.
Subject(s)
Humans , Child , Craniosynostoses/genetics , Transcription Factors/genetics , Base Sequence , Family , Cross-Sectional Studies , Mutation, Missense/genetics , DNA-Binding Proteins/geneticsABSTRACT
BACKGROUND : 677C to T allele in the 5, 10‑methylenetetrahydrofolate reductase (MTHFR) gene has been implicated in the etiology of various syndromes and nonsyndromic diseases but till date no direct studies have been reported with craniosynostosis. OBJECTIVES: The aim was to study the family‑based association of MTHFR polymorphism in different categories of craniosynostosis patients. MATERIALS AND METHODS: This was a cross‑sectional study in which 30 patients classified as Apert syndrome, Pfeiffr syndrome and nonsyndromic craniosynostosis patients with their family were recruited. A sample of 3 ml intravenous blood was taken from patients and from their family members (father and mother) in ethylenediaminetetraacetic acid‑anticoagulated vacutainer for the purpose of the study. Genomic DNA was extracted from peripheral blood lymphocytes by phenol chloroform extraction method. Primers for MTHFR gene were designed. The polymerase chain reaction was carried out. After successful amplification, a small aliquot (5 µl) of the MTHFR reaction mixture was treated with 1 units of Hinf I restriction enzyme (NEB). Results were obtained and compiled. RESULTS: A total of 30 patients/participants with craniosynostosis of Indian descent and their parents formed the study group. The genotyping did not confirm an association between the MTHFR 677C to T polymorphism and between different categories of craniosynostosis. When comparing the offspring of mothers statistically significant differences were found. CONCLUSION: C667T polymorphism of the MTHFR gene is unlikely to play a role in the pathogenesis of craniosynostosis though maternal MTHFR C677T polymorphism may be a genetic risk factor.
Subject(s)
Child , Craniosynostoses/diagnosis , Craniosynostoses/epidemiology , Craniosynostoses/etiology , Craniosynostoses/genetics , Craniosynostoses/history , Humans , India , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , /genetics , RiskABSTRACT
OBJECTIVE: The Objective of this study was to identify the association of mutation of fibroblast growth factor receptor 1 (FGFR1), FGFR2 genes with syndromic as well as non‑syndromic craniosynostosis in Indian population. MATERIALS AND METHODS: Retrospective analysis of our records from January 2008 to December 2012 was done. A total of 41 cases satisfying the inclusion criteria and 51 controls were taken for the study. A total volume of 3 ml blood from the patient as well as parents was taken. Deoxyribonucleic acid extracted using phenol chloroform extraction method followed by polymerase chain reaction‑restriction fragment length polymorphism method. RESULTS: There were 33 (80.4%) non‑syndromic cases of craniosynostosis while 8 (19.5%) were syndromic. Out of these 8 syndromic cases, 4 were Apert syndrome, 3 were Crouzon syndrome and 1 Pfeiffer syndrome. Phenotypically the most common non‑syndromic craniosynostosis was scaphocephaly (19, 57.7%) followed by plagiocephaly in (14, 42.3%). FGFR1 mutation (Pro252Arg) was seen in 1 (2.4%) case of non‑syndromic craniosynostosis while no association was noted either with FGFR1 or with FGFR2 mutation in syndromic cases. None of the control group showed any mutation. CONCLUSION: Our study proposed that FGFR1, FGFR2 mutation, which confers predisposition to craniosynostosis does not exist in Indian population when compared to the western world.
Subject(s)
Adult , Child , Child, Preschool , Craniosynostoses/blood , Craniosynostoses/genetics , Female , Humans , India , Infant , Male , Receptors, Fibroblast Growth Factor/classification , Receptors, Fibroblast Growth Factor/genetics , SyndromeABSTRACT
Introdução: A síndrome de Saethre-Chotzen é um distúrbio raro de herança autossômica dominante causada por mutações no gene TWIST, localizado no lócus 7p21; os pacientes apresentam defeitos na cabeça (plagiocefalia e assimetría facial) e na parte distal das extremidades, dedos encurtados e ligados pela persistência de uma membrana entre eles (sindactilia). Objetivo: Apresentar um relato de caso da síndrome de Saethre-Chotzen, discutindo as características diagnósticas que diferenciam essa síndrome dos outros tipos de craniossinostoses e o diagnóstico diferencial. Descrição: Estudante de 11 anos apresentando os seguintes sinais clínicos: plagiocefalia decorrente de craniossinostose, acrobraquicefalia, assimetria facial e hemimelia, com ausência da porção distal do antebraço direito. Comentários: Apresentamos um caso ilustrativo da síndrome de Saethre-Chotzen, que constitui a mais frequente das doenças com craniossinostoses e descrevemos as importantes alterações faciais dismórficas da síndrome.
Subject(s)
Humans , Male , Child , Acrocephalosyndactylia/diagnosis , Acrocephalosyndactylia/genetics , Craniosynostoses/diagnosis , Craniosynostoses/geneticsABSTRACT
Craniosynsostosis syndromes exhibit considerable phenotypic and genetic heterogeneity. Sagittal synostosis is common form of isolated craniosynostosis. The sutures involved, the shape of the skull and associated malformations give a clue to the specific diagnosis. Crouzon syndrome is one of the most common of the craniosynostosis syndromes. Apert syndrome accounts for 4.5% of all craniosynostoses and is one of the most serious of these syndromes. Most syndromic craniosynostosis require multidisciplinary management. The following review provides a brief appraisal of the various genes involved in craniosynostosis syndromes, and an approach to diagnosis and genetic counseling.
Subject(s)
Acrocephalosyndactylia/epidemiology , Acrocephalosyndactylia/genetics , Child , Cranial Sutures/abnormalities , Craniosynostoses/epidemiology , Craniosynostoses/genetics , Humans , Hydrocephalus/epidemiology , Hydrocephalus/genetics , Plagiocephaly/geneticsABSTRACT
Las displasias esqueléticas son un grupo muy heterogéneo de trastornos que se caracterizan por una alteración en la organización del tejido óseo, lo que causa una distorsión en su patrón de crecimiento y desarrollo. En 1998, se descibió el caso de cuatro hermanos japoneses, tres varones y una hembra que presentaban una displasia espóndilo-epifisiaria, no descrita anteriormente, asociada con cráneo-sinostosis, cataratas, paladar hendido y retardo mental de diferente grado. Se planteó una probable herencia autosómica recesiva, debido a que las alteraciones afectaban a ambos sexos y los padres eran fenotípicamente sanos, aunque con discreto retardo mental; sin embargo, no fue posible descartar un mosaicismo germinal. El caso que se presenta, trata de un paciente con signos clínicos y radiológicos que coinciden con los previamente descritos. Es producto de padres consanguíneos en la segunda generación, lo cual se sumaría a la presunción ya postulada, de una probable mutación de herencia autosómica recesiva. La presente comunicación, representa el segundo reporte en la literatura, del quinto caso descrito y el segundo grupo familiar con la afección mencionada.
Skeletal dysplasias are a heterogeneous group of disorders characterized by an alteration of the organization of osseous tissue causing a distortion on the growth and development pattern of bones. In 1998, four Japanese sibs were described by the first time, three males and one female who presented a previously undescribed spondylo-epiphyseal dysplasia associated with craniosynostosis, cataracts, cleft palate and different grades of mental retardation. A probable autosomic recessive inheritance was suggested, but a germinal mosaicism could not be discarded. This is a case report of a patient with clinical and radiological findings similar to the ones previously described, born to second degree consanguineous parents. This supports the postulated presumption of a mutation with an autosomic recesive inheritance. The present comunication represents the fifth case reported in the literature and the second familiar group affected.
Subject(s)
Adult , Female , Humans , Infant, Newborn , Male , Abnormalities, Multiple/genetics , Cleft Palate/genetics , Craniosynostoses/genetics , Intellectual Disability/genetics , Osteochondrodysplasias/genetics , Abortion, Spontaneous , Consanguinity , Cataract/genetics , Cleft Lip/genetics , Collagen/genetics , Genes, Recessive , Growth Disorders/genetics , Pedigree , SyndromeABSTRACT
The Muenke syndrome (MS) is characterized by unicoronal or bicoronal craniosynostosis, midfacial hypoplasia, ocular hypertelorism, and a variety of minor abnormalities associated with a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. The birth prevalence is approximately one in 10,000 live births, accounting for 8-10% of patients with coronal synostosis. Although MS is a relatively common diagnosis in patients with craniosynostosis syndromes, with autosomal dominant inheritance, there has been no report of MS, in an affected Korean family with typical cephalo-facial morphology that has been confirmed by molecular studies. Here, we report a familial case of MS in a female patient with a Pro250Arg mutation in exon 7 (IgII-IGIII linker domain) of the FGFR3 gene. This patient had mild midfacial hypoplasia, hypertelorism, downslanting palpebral fissures, a beak shaped nose, plagio-brachycephaly, and mild neurodevelopmental delay. The same mutation was confirmed in the patient's mother, two of the mother's sisters and the maternal grandfather. The severity of the cephalo-facial anomalies was variable among these family members.
Subject(s)
Adult , Child, Preschool , Female , Humans , Male , Asian People/genetics , Craniosynostoses/genetics , DNA Mutational Analysis , Hypertelorism/genetics , Korea , Mutation , Pedigree , Phenotype , Receptor, Fibroblast Growth Factor, Type 3/genetics , Skull/abnormalities , Syndrome , Treatment OutcomeABSTRACT
TEMA: aspectos sobre o desenvolvimento de linguagem oral em craniossinostoses sindrômicas. As craniossinostoses (fusão precoce das suturas cranianas) apresentam incidência em torno de 0,4 a 1/1.000 nativivos. Estas podem ocorrer devido a fatores ambientais ou genéticos. Com relação à forma de apresentação, estas podem ocorrer de maneira isolada ou associada a outros defeitos congênitos. Neste último grupo, destacam-se as acrocefalossindactilias, condições geneticamente determinadas, que apresentam similaridade fenotípica, sendo estas as síndromes de Saethre-Chotzen, Apert, Crouzon e Pfeiffer. Diante destas condições complexas que envolvem o arcabouço craniofacial, é possível encontrar interferências anatômicas e funcionais que determinem atrasos e/ou desvios de linguagem. OBJETIVO: revisar a literatura acerca dos aspectos fonoaudiológicos relacionados ao desenvolvimento normal da linguagem oral e descrever as principais características associadas a ela apresentadas por crianças com síndromes de Apert, Crouzon, Pfeiffer e Saethre-Chotzen. Foi realizada revisão sistemática de estudos sobre as craniossinostoses sindrômicas e dados referentes a linguagem oral nestes casos. Para isso, utilizou-se pesquisa na base de dados Medline e Lilacs, assim como outras publicações importantes para a conclusão do artigo. CONCLUSÃO: diversas manifestações relacionadas à audição e linguagem podem estar presentes em craniossinostoses sindrômicas. Destacam-se as alterações do sistema de condução do som, levando à perda auditiva, o que conseqüentemente prejudica a aquisição e desenvolvimento pleno da linguagem. Deste modo, recomenda-se o diagnóstico e tratamento fonoaudiológico adequados e precoces, eliminando ou minimizando os prejuízos para a aquisição e desenvolvimento da linguagem oral.
BACKGROUND: aspects of language development in craniosynostosis. Craniosynostosis (premature fusion of the cranial sutures) has an incidence of 0.4 to 1/1.000 newborns. Etiology for this congenital anomaly includes environmental and genetic factors. Regarding the form of presentation, it can occur in its isolated form or associated to other congenital anomalies. For this last group, acrocephalosyndactilies are observed. These are genetically determined conditions which present phenotypic similarity, including the following syndromes: Saethre-Chotzen, Apert, Crouzon e Pfeiffer. As all of these conditions affect the craniofacial development, it is possible to find anatomic and functional interferences which determine language delays and/or deficits. AIM: to revise the literature concerning aspects related to normal verbal language development and to describe the main characteristics associated to this condition in children who present Apert, Crouzon, Pfeiffer and Saethre-Chotzen syndromes. A systematic review on syndromic craniosynostosis and oral language was performed, consulting Medline, Lilacs and other important references on this theme. CONCLUSION: several manifestations related to hearing and language have been detected in individuals with syndromic craniosynostosis. The most important are alterations in the sound conduction system, leading to hearing losses, and consequently interfering in language acquisition and development. For this reason, speech-language diagnosis and early intervention are recommended in order to eliminate or minimize damages in language acquisition and development.
Subject(s)
Child , Humans , Craniosynostoses/genetics , Language Development , Speech-Language PathologyABSTRACT
A síndrome de Prader-Willi é afecção genética de deficiência mental associada a hipogonadismo hipogonadotrófico, hiperfagia e obesidade. Descrevemos o caso de menino de 4 anos de idade, filho de casal consangüíneo, apresentando três condições clínicas não relacionadas: síndrome de Prader-Willi, cariótipo 47,XXY (compatível com síndrome de Klinefelter) e craniossinostose coronal. Ao nosso conhecimento, não foi relatado caso semelhante previamente na literatura.
Subject(s)
Child, Preschool , Humans , Male , Craniosynostoses/genetics , Klinefelter Syndrome/genetics , Prader-Willi Syndrome/genetics , Craniosynostoses/complications , Klinefelter Syndrome/complications , Prader-Willi Syndrome/complicationsABSTRACT
El Síndrome de Seckel es una enfermedad congénita, un trastorno autosónico recesivo y la forma más frecuente de enanismo osteodisplásico microcefálico. Fue descrita por primera vez como "enanismo de cabeza de pájaro" por Rudolf Virchow en 1982, posteriormente en 1960 Helmut Seckel caracterizó el síndrome tal como conocemos en la actualidad (1), con retraso del crecimiento intrauterino, microcefalia, dwarfismo (forma de enanismo proporcionado), y facie peculiar (4).
Subject(s)
Humans , Female , Child, Preschool , Dwarfism/diagnosis , Dwarfism/genetics , Dwarfism , Bone Diseases, Developmental/diagnosis , Bone Diseases, Developmental/pathology , Microcephaly/diagnosis , Fetal Growth Retardation/genetics , Facial Asymmetry/etiology , Craniosynostoses/genetics , CraniosynostosesABSTRACT
La craneosinostosis secundaria a la obliteración prematura de una o varias suturas craneales, da lugar a deformidad de la bóveda y/o la base del cráneo. Las neurofibromatosis son trastornos genéticos del sistema nervioso. La acidosis tubular renal esta caracterizada por hipercalciuria y acidemia (8). Paciente femenina de 6 años de edad, con diagnóstico clínico radiológico de craneosinostosis turricefálica sin compromiso neurológico desde 6 meses de edad. Referida al CRN "Dr. Pastor Oropeza", allí se diagnóstica neurofibromatosis y acidosis tubular renal. Intervención neuroquirúrgica a los 4 años de edad en Caracas, el procedimiento se realizo sin complicaciones. La turricefália se produce por el cierre completo de la sutura coronal, presentándose un cráneo en torre con disminución de su diámetro antero posterior y alargado en altura.(3). En estudios realizados se ha observado la asociación con neurofibromatosis en baja proporción; sin embargo no se han descrito casos con acidosis tubular renal. La importancia de este caso radica en que la literatura no reporta un síndrome con las características clínicas de esta niña; siendo infrecuente dicha asociación de patologías en un mismo paciente; en la actualidad la niña presenta un desarrollo psicosocial e intelectual normal.
Subject(s)
Humans , Female , Child , Craniosynostoses/diagnosis , Craniosynostoses/genetics , Craniosynostoses/pathology , Microcephaly/diagnosis , Cranial Sutures/anatomy & histology , Acidosis, Renal Tubular/pathology , Hydrocephalus/diagnosis , Infant, Premature , Neurofibromatoses/pathologyABSTRACT
The Antley-Bixler syndrome is a rare multiple congenital anomaly with a high mortality rate. The characteristic manifestations include craniosynostosis, radiohumeral synostosis, midface hypoplasia, joint contractures and arachnodactyly. We report two new cases of this syndrome and address the diagnostic features, associated malformations, inheritance patterns, prenatal findings, and briefly review the literature.
Subject(s)
Abnormalities, Multiple/genetics , Contracture/genetics , Craniosynostoses/genetics , Humans , Infant , Male , Marfan Syndrome/genetics , Syndrome , Synostosis/geneticsABSTRACT
Craniossinostose caracteriza-se pelo fechamento prematuro de uma ou mais suturas cranianas. As craniossinostoses formam um grupo bastante heterogeneo, com incidencia de um para 2000-3000 nascimentos...
Subject(s)
Humans , Craniosynostoses/diagnosis , Genetic Counseling , Risk Factors , Craniosynostoses/genetics , Diagnosis, DifferentialABSTRACT
The post eighteen months have been exciting time for craniosynostosis research. In a rapid flurry of publications, mutations of fibroblast growth factor receptors (FGFRs) have been identified in three of the best known craniosynostosis syndromes, namely Apert, Crouzon and Pfeiffer syndromes, as well as in Jackson-Weiss syndrome and thanatophoric dysplasia. These findings open many new avenues for craniosynostosis research including studies of diagnosis, pathogenesis, and mutagenesis. Here the major findings and their implications have been briefly reviewed.
Subject(s)
Craniosynostoses/genetics , Humans , India , Mutation/genetics , Receptors, Fibroblast Growth Factor/genetics , Research , SyndromeABSTRACT
Introducción. La displasia craneofrontonasal es un síndrome malformativo donde coexisten craneosinostosis e hipertelorismo y anomalías extracraneales en pacientes femeninos, cuyo mecanismo hereditario está aún en discusión. Material y métodos. Se estudió clínica, radiológica y citogenéticamente a 43 pacientes afectados, incluyendo 7 casos familiares, lo que permitió el estudio del patrón hereditario. Resultados. Se demostró que el espectro clínico completo incluye hallazgos no reportados o cuya frecuencia se ha descrito como menor: cabello crespo, rizado, de origen no familiar y de inicio tardío; fisuras faciales pterigium colli y/o axilar, clavículas anómalas, hipoplasia mamaria inilareral y acortamiento ispilateral de la extremidad pélvica; se corroboraron radiográficamente las fisuras faciales y las alteraciones esqueléticas óseas. Se describen formas frustras o de afección mínima en mujeres. El cariotipo fue normal en todos los casos. Conclusiones. El estudio familiar detectó formas mínimas, además de expresión diferencial en ambos sexos, y que el gen responsable está localizado en el cromosoma X
Subject(s)
Infant, Newborn , Infant , Child, Preschool , Child , Adolescent , Adult , Middle Aged , Humans , Male , Female , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Cleidocranial Dysplasia/genetics , Skull/abnormalities , Craniofacial Dysostosis , Craniosynostoses/diagnosis , Craniosynostoses/genetics , Hypertelorism/etiologyABSTRACT
Presentamos una revisión bibliográfica actualizada de las alteraciones craneofaciales congénitas y proponemos una clasificación que incluye 4 categorías: fisuras craneofaciales, craneosinostosis, defectos de la dentición y otras alteraciones craneofaciales. Cada una de ellas puede ser malformaciones, deformaciones y disrupciones, presentarse aisladas o formando parte de alteraciones múltiples (defectos politópicos de campo, secuencias o asociaciones). Es importante conocer la causa precisa en cada caso individual para de acuerdo con ello brindar el adecuado asesoramiento genético y la corrección quirúrgica, si es necesario