RESUMO
INTRODUCTION: Pitt-Hopkins syndrome (PTHS) is a rare genetic syndrome associated with neurodevelopmental disorders and craniofacial dysmorphisms caused by variations in the TCF4 transition factor. The aim of this article was to report the case of two twin infants diagnosed with PTHS, confirmed by the identification of a heterozygous pathogenic variant in the TCF4 gene through DNA extracted from a buccal swab. CASE PRESENTATION: Both infants presented with craniofacial asymmetry with a metopic crest and cranial deformity. During the diagnostic investigation, computed tomography with three-dimensional reconstruction of the skull showed premature fusion of the left coronal and metopic sutures in both twins. They underwent craniofacial reconstruction at the 9th month of age using a combination of techniques. The postoperative outcomes were satisfactory in both cases. CONCLUSION: To the best of our knowledge, this is the first case report to describe the occurrence of complex craniosynostosis (CCS) in children with PTHS. Further studies are needed to determine whether the co-occurrence of PTHS and CCS described here indicates an association or is explained by chance.
Assuntos
Craniossinostoses , Hiperventilação , Deficiência Intelectual , Humanos , Craniossinostoses/cirurgia , Craniossinostoses/diagnóstico por imagem , Craniossinostoses/genética , Craniossinostoses/complicações , Deficiência Intelectual/genética , Hiperventilação/genética , Lactente , Feminino , Masculino , Fator de Transcrição 4/genética , Fácies , Doenças em Gêmeos/cirurgia , Doenças em Gêmeos/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
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.
Assuntos
Craniossinostoses , Sequência de Bases , Criança , Craniossinostoses/genética , Estudos Transversais , Proteínas de Ligação a DNA/genética , Família , Humanos , Mutação de Sentido Incorreto/genética , Fatores de Transcrição/genéticaRESUMO
Crouzon syndrome is a rare form of syndromic craniosynostosis (SC) characterized by premature fusion of the cranial and facial sutures, elevated intracranial pressure, varying degrees of ocular exposure due to exorbitism, and airway compromise caused by midface retrusion. Craniolacunae and upper and lower extremity anomalies are not frequently found in Crouzon syndrome. We present a girl with Crouzon syndrome caused by c.1040 C > G, p.Ser347Cys, a pathogenic mutation in the FGFR2 gene with atypical characteristics, including craniolacunae resembling severe Swiss cheese type of bone formation, and upper and lower extremity anomalies which are more commonly associated with Pfeiffer syndrome patients. Distinguishing between severe Crouzon syndrome patients and patients who have mild and/or moderate Pfeiffer syndrome can be challenging even for an experienced craniofacial surgeon. An accurate genotype diagnosis is essential to distinguishing between these syndromes, as it provides predictors for neurosurgical complications and facilitates appropriate family counseling related to long-term outcomes.
Assuntos
Acrocefalossindactilia , Disostose Craniofacial , Craniossinostoses , Disostose Craniofacial/diagnóstico por imagem , Disostose Craniofacial/genética , Craniossinostoses/genética , Feminino , Humanos , Extremidade Inferior , Mutação/genética , Fenótipo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
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.
Assuntos
Humanos , Criança , Craniossinostoses/genética , Fatores de Transcrição/genética , Sequência de Bases , Família , Estudos Transversais , Mutação de Sentido Incorreto/genética , Proteínas de Ligação a DNA/genéticaRESUMO
BACKGROUND: Craniosynostosis is one of the major genetic disorders affecting 1 in 2,100-2,500 live newborn children. Environmental and genetic factors are involved in the manifestation of this disease. The suggested genetic causes of craniosynostosis are pathogenic variants in FGFR1, FGFR2, FGFR3, and TWIST1 genes. METHODS: In order to describe their major clinical characteristics and the presence of pathogenic variants, a sample of 36 Mexican patients with craniosynostosis diagnosed as: Crouzon (OMIM 123,500), Pfeiffer (OMIM 101,600), Apert (OMIM 101,200), Saethre-Chotzen (OMIM 101,400), and Muenke (OMIM 602,849) was analyzed. RESULTS: In addition to craniosynostosis, most of the patients presented hypertelorism, midface hypoplasia, and abnormalities in hands and feet. To detect the pathogenic variants p.Pro252Arg FGFR1 (OMIM 136,350), p.Ser252Trp, p.Pro253Arg FGFR2 (OMIM 176,943), p.Pro250Arg, FGFR3 (OMIM 134,934), and p.Gln119Pro TWIST1 (OMIM 601,622), PCR amplification and restriction enzyme digestion were performed. Four and two patients with Apert presented the pathogenic variants p.Ser252Trp and p.Pro253Arg in FGFR2, respectively (with a frequency of 11.1% and 5.5%). The p.Pro250Arg pathogenic variant of FGFR3 was found in a patient with Muenke (with a frequency of 2.8%). The above percentages were calculated with the total number of patients. CONCLUSION: The contribution of this work is discreet, since only 4 genes were analyzed and sample size is small. However, this strategy could be improved by sequencing the FGFR1, FGFR2, FGFR3, and TWIST1 genes, to determine different pathogenic variants. On the other hand, it would be important to include other genes, such as TCF12 (OMIM 600,480), MSX2 (OMIM 123,101), RAB23 (OMIM 606,144), and EFNB1 (OMIM 300,035), to determine their participation in craniosynostosis in the Mexican population.
Assuntos
Craniossinostoses/genética , Proteínas Nucleares/genética , Fenótipo , Receptores de Fatores de Crescimento de Fibroblastos/genética , Proteína 1 Relacionada a Twist/genética , Adulto , Criança , Pré-Escolar , Craniossinostoses/patologia , Feminino , Frequência do Gene , Humanos , Lactente , Masculino , México , Mutação de Sentido IncorretoRESUMO
BACKGROUND: Chromosome 22q11.2 microdeletion syndrome, a disorder caused by heterozygous loss of genetic material in chromosome region 22q11.2, has a broad range of clinical symptoms. The most common congenital anomalies involve the palate in 80% of patients, and the heart in 50-60% of them. The cause of the phenotypic variability is unknown. Patients usually harbor one of three common deletions sizes: 3, 2 and 1.5 Mb, between low copy repeats (LCR) designated A-D, A-C and A-B, respectively. This study aimed to analyze the association between these 3 deletion sizes and the presence of congenital cardiac and/or palatal malformations in individuals with this condition. A systematic review and meta-analysis were conducted, merging relevant published studies with data from Chilean patients to increase statistical power. RESULTS: Eight articles out of 432 were included; the data from these studies was merged with our own, achieving a total of 1514 and 487 patients to evaluate cardiac and palate malformations, respectively. None of the compared deleted chromosomal segments were statistically associated with cardiac defects (ORAB v/s AC-AD: 0.654 [0.408-1.046]; OR AD v/s AB-AC: 1.291 [0.860-1.939]) or palate anomalies (ORAB v/s AC-AD: 1.731 [0.708-4.234]; OR AD v/s AB-AC: 0.628 [0.286-1.382]). CONCLUSIONS: The lack of association between deletion size and CHD or PA found in this meta-analysis suggests that deletion size does not explain the incomplete penetrance of these 2 major manifestations, and that the critical region for the development of heart and palatal abnormalities is within LCR A-B, the smallest region of overlap among the three deletion sizes.
Assuntos
Aracnodactilia/genética , Deleção Cromossômica , Craniossinostoses/genética , Síndrome de Marfan/genética , Humanos , FenótipoRESUMO
We report the case of a 14 years and 8 months girl, who is the first child of nonconsanguineous parents, with short stature, obstructive hypertrophic cardiomyopathy, multiple facial lentigines, high and wide forehead, downslanting palpebral fissures, low-set ears, short neck, and pectus excavatum; all features suggestive of Noonan syndrome with multiple lentigines (NSML). In addition, the patient exhibited craniosynostosis. Molecular analysis of rats sarcoma (RAS)/mitogen-activated protein kinase (MAPK) pathway genes with high-resolution melting curve analysis followed by sequencing showed a RAF1 amino acid substitution of valine to glycine at position 263 (p.V263G). The present report provides clinical data regarding the first association of a RAF1 variant and craniosynostosis in a patient with clinical diagnosis of NSML.
Assuntos
Craniossinostoses/diagnóstico , Craniossinostoses/genética , Variação Genética , Síndrome LEOPARD/diagnóstico , Síndrome LEOPARD/genética , Fenótipo , Proteínas Proto-Oncogênicas c-raf/genética , Adolescente , Alelos , Substituição de Aminoácidos , Éxons , Fácies , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , MutaçãoRESUMO
We describe a patient severely affected with multiple congenital anomalies, including brain malformations and skeletal dysplasia suggestive of cranioectodermal dysplasia (CED) ciliopathy, who unusually carries several homozygosity tracts involving homozygous missense mutations in SPAG17 (exon 8; c.1069G > C; p.Asp357His) and WDR35 (exon 13; c.1415G > A; p.Arg472Gln) as revealed by homozygosity mapping and next generation sequencing. SPAG17 is essential for the function and structure of motile cilia, while WDR35 belongs to the same intraflagellar transport (IFT) gene family whose protein products are part of functional IFT A and B complexes. Formerly, SPAG17 was related - through polymorphic variants - to an influence on individuals' height; more recently, Spag17-/- mice models were reported to present skeletal and bone defects, reduced mucociliary clearance, respiratory distress, and cerebral ventricular enlargement. Homozygous or compound heterozygous mutations in WDR35 have mainly been related to CED2 or short-rib thoracic dysplasia 7, with only three cases showing some brain anomalies. Given that our patient presents these clinical features and the close functional relationship between SPAG17 and WDR35, it is feasible that the combined effects from both mutations contribute to his phenotype. To our knowledge, this patient is the first to harbor a likely pathogenic homozygous mutation in both genes at the same time. Thus, the resulting complex phenotype of this patient illustrates the heterogeneity associated with ciliopathies and further expands the clinical and mutational spectrum of these diseases. Finally, we highlight the combined use of high-throughput tools to diagnose and support the proper handling of this and other patients.
Assuntos
Anormalidades Múltiplas/genética , Osso e Ossos/anormalidades , Encefalopatias/genética , Ciliopatias/genética , Craniossinostoses/genética , Displasia Ectodérmica/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação de Sentido Incorreto , Proteínas/genética , Anormalidades Múltiplas/patologia , Adolescente , Osso e Ossos/patologia , Encefalopatias/complicações , Encefalopatias/patologia , Criança , Ciliopatias/complicações , Ciliopatias/patologia , Craniossinostoses/complicações , Craniossinostoses/patologia , Proteínas do Citoesqueleto , Displasia Ectodérmica/complicações , Displasia Ectodérmica/patologia , Feminino , Proteínas Hedgehog , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , FenótipoRESUMO
Hypochondroplasia (HCH) is a skeletal dysplasia caused by an abnormal function of the fibroblast growth factor receptor 3. Although believed to be relatively common, its prevalence and phenotype are not well established owing to its clinical, radiological, and genetic heterogeneity. Here we report on a molecularly proven HCH family with an affected father and two children. The siblings (male and female) with HCH also had craniosynostosis and cleft palate, respectively. The present report supports the conclusion that the full clinical spectrum of HCH is not completely delineated. It also suggests that secondary, as yet unknown, modifying factors can influence the final phenotype.
Assuntos
Osso e Ossos/anormalidades , Fissura Palatina/diagnóstico , Fissura Palatina/genética , Craniossinostoses/diagnóstico , Craniossinostoses/genética , Nanismo/diagnóstico , Nanismo/genética , Estudos de Associação Genética , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/genética , Lordose/diagnóstico , Lordose/genética , Adulto , Criança , Fácies , Feminino , Genótipo , Humanos , Cariótipo , Masculino , México , Mutação , Fenótipo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Análise de Sequência de DNA , Síndrome , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVES: The objective is to describe a new surgical procedure developed in the San Jose Pediatric University Hospital for the management of syndromic synostosis of the metopic suture in a patient clinically diagnosed with Saethre-Chotzen syndrome. METHODS: The diagnosis of Saethre-Chotzen syndrome, bilateral coronal sutures, and metopic suture synostoses was made through photographic, anthropometric, exophthalmometric, and computed tomography analysis. The keel-like frontal bone deformity was corrected following resection using a fusiform osteotomy, remodelling was obtained by milling the edges, and the bony fragments were repositioned and fixed on the posterior wall of the frontal bone. Additionally, a fronto-orbital advancement with a self-stabilizing bar was performed. RESULTS: The 1-year postoperative results showed improvement in the position of the fronto-orbital bar, adequate cranial expansion, satisfactory correction of the upper facial third alteration, and correction of the keel-like deformity. CONCLUSIONS: The surgical approach has not previously been described in the literature and offers an alternative management for syndromic craniosyntostosis of the metopic suture, avoiding skull irregularities.