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1.
Eur J Med Genet ; 62(6): 103534, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30189253

RESUMO

TARP syndrome (TARPS) is an X-linked syndromic condition including Robin sequence, congenital heart defects, developmental delay, feeding difficulties and talipes equinovarus, as major features. The disease is caused by inactivating mutations in RBM10 which encodes for a RNA binding motif protein involved in transcript processing. We herein report a male born from healthy and non-consanguineous parents, presenting prenatal record of intrauterine fetal growth retardation, and postnatal features including growth and developmental delays, CNS abnormalities, facial dysmorphisms, bilateral syndactyly at the hands, talipes equinovarus and congenital heart defects. By using trio-based Whole Exome Sequencing approach, a maternally inherited RBM10 frameshift variant causing decay of the RBM10 transcript was identified. Despite the syndrome is considered lethal in affected males, our subject with molecularly confirmed TARPS is still alive at 11 years of age supporting the chance of surviving. Long-term surviving in TARPS is extremely rare and should be considered in genetic counselling and clinical follow up of the syndrome. We provide the natural history of the syndrome, reviewing the major clinical characteristics. Congenital heart defects are confirmed as specific diagnostic markers for the syndrome. In addition, cardiac anatomical details are defining a possible clinical overlap with syndromic conditions related to the hedgehog pathway and/or primary cilium anomalies as Oral-Facial-Digital or Smith-Lemli-Opitz syndromes.


Assuntos
Pé Torto Equinovaro/genética , Cardiopatias Congênitas/genética , Síndrome de Pierre Robin/genética , Proteínas de Ligação a RNA/genética , Criança , Pé Torto Equinovaro/patologia , Diagnóstico Diferencial , Cardiopatias Congênitas/patologia , Humanos , Masculino , Síndrome de Pierre Robin/patologia
2.
Am J Med Genet A ; 176(12): 2911-2914, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30450804

RESUMO

TARP syndrome (talipes equinovarus, atrial septal defect, Robin sequence, and persistent left superior vena cava) is a rare X-linked condition. As more patients are identified through genetic testing, it is increasingly clear that the original TARP acronym does not fully describe the complete phenotypic spectrum of this syndrome. The presented patient had genetically confirmed TARP syndrome and demonstrated new findings of hydronephrosis and hemodynamically significant hypertrophic obstructive cardiomyopathy. The patient also had physical findings common with previously reported individuals with TARP syndrome in the literature but not described by the TARP acronym. These features include central nervous system dysfunction, renal abnormalities, cardiac lesions other than atrial septal defect or persistent left superior vena cava, and distal limb defects other than talipes equinovarus. By adding to the known spectrum of the TARP phenotype, this report will aid clinicians as they care for patients with this rare condition.


Assuntos
Pé Torto Equinovaro/diagnóstico , Pé Torto Equinovaro/genética , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Síndrome de Pierre Robin/diagnóstico , Síndrome de Pierre Robin/genética , Causas de Morte , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Mutação , Fenótipo , Prognóstico , Proteínas de Ligação a RNA/genética
3.
Am J Med Genet A ; 176(12): 2915-2918, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30462380

RESUMO

TARP syndrome (talipes equinovarus, atrial septal defect, Robin sequence, and persistence of the left superior vena cava) is a rare X-linked syndrome often resulting in pre- or post-natal lethality in affected males. In 2010, RBM10 was identified as the disease-causing gene, and we describe the first adult patient with TARP syndrome at age 28 years, hereby expanding the phenotypic spectrum. Our patient had Robin sequence, atrial septal defect, intellectual disability, scoliosis, and other findings previously associated with TARP syndrome. In addition, he had a prominent nose and nasal bridge, esotropia, displacement of lacrimal points in the cranial direction, small teeth, and chin dimple, which are the findings that have not previously been associated with TARP syndrome. Our patient was found to carry a hemizygous c.273_283delinsA RBM10 mutation in exon 4, an exon skipped in three of five protein-coding transcripts, suggesting a possible explanation for our patient surviving to adulthood. Direct sequencing of maternal DNA indicated possible mosaicism, which was confirmed by massive parallel sequencing. One of two sisters were heterozygous for the mutation. Therefore, we recommend sisters of patients with TARP syndrome be carrier tested before family planning regardless of carrier testing results of the mother. Based on our patient and previously reported patients, we suggest TARP syndrome be considered as a possible diagnosis in males with severe or profound intellectual disability combined with septal heart defect, and Robin sequence, micrognathia, or cleft palate.


Assuntos
Pé Torto Equinovaro/diagnóstico , Pé Torto Equinovaro/genética , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Síndrome de Pierre Robin/diagnóstico , Síndrome de Pierre Robin/genética , Adulto , Pé Torto Equinovaro/terapia , Análise Mutacional de DNA , Facies , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Cardiopatias Congênitas/terapia , Humanos , Mutação com Perda de Função , Masculino , Fases de Leitura Aberta , Linhagem , Fenótipo , Síndrome de Pierre Robin/terapia , Proteínas de Ligação a RNA/genética
4.
Am J Med Genet A ; 176(10): 2135-2139, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30380189

RESUMO

The 22q11.2 Deletion Syndrome (22q11.2DS) occurs in ~1:3,000-6,000 individuals. Features less typically associated with 22q11.2DS, such as orthopedic manifestations, may be overlooked or may not lead to appropriate diagnostic testing. Club foot has a general population prevalence of ~1:1,000 and has been occasionally described in association with 22q11.2DS. Our hypothesis is that the prevalence of club foot is higher in patients with 22q11.2DS. We performed a retrospective review in two specialized 22q11.2DS centers to determine the prevalence of club foot. "True club foot" requires treatment (either conservative or surgical), therefore we only included those patients with proof of treatment. We investigated whether congenital heart disease (CHD) and/or cleft palate were associated with the presence of club foot within 22q11.2DS. The records of 1,466 patients were reviewed. Of these, 48 (3.3%) had confirmation of club foot (95% Confidence Interval: 2.4-4.3): 22 (46%) had a bilateral, 12 (25%) left, and 14 (29%) right club foot. Within our study, neither a CHD and/or a cleft palate were associated with a club foot. The prevalence of club foot in 22q11.2DS is 30 times higher than that observed in the general population. This suggests the diagnosis of club foot, especially in the face of other typically associated abnormalities of 22q11.2DS, should provoke consideration of 22q11.2DS as an underlying diagnosis, particularly in the neonatal setting.


Assuntos
Pé Torto Equinovaro/genética , Síndrome de DiGeorge/complicações , Pé Torto Equinovaro/complicações , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Masculino
5.
Int J Mol Sci ; 19(8)2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30071673

RESUMO

Lymphedema is characterized by chronic swelling of any body part caused by malfunctioning or obstruction in the lymphatic system. Primary lymphedema is often considered genetic in origin. VEGFC, which is a gene encoding the ligand for the vascular endothelial growth factor receptor 3 (VEGFR3/FLT4) and important for lymph vessel development during lymphangiogenesis, has been associated with a specific subtype of primary lymphedema. Through Sanger sequencing of a proband with bilateral congenital pedal edema resembling Milroy disease, we identified a novel mutation (NM_005429.2; c.361+5G>A) in VEGFC. The mutation induced skipping of exon 2 of VEGFC resulting in a frameshift and the introduction of a premature stop codon (p.Ala50ValfsTer18). The mutation leads to a loss of the entire VEGF-homology domain and the C-terminus. Expression of this Vegfc variant in the zebrafish floorplate showed that the splice-site variant significantly reduces the biological activity of the protein. Our findings confirm that the splice-site variant, c.361+5G>A, causes the primary lymphedema phenotype in the proband. We examine the mutations and clinical phenotypes of the previously reported cases to review the current knowledge in this area.


Assuntos
Artrogripose/genética , Fissura Palatina/genética , Pé Torto Equinovaro/genética , Mutação da Fase de Leitura , Deformidades Congênitas da Mão/genética , Processamento de RNA/genética , Fator C de Crescimento do Endotélio Vascular/genética , Animais , Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/metabolismo , Artrogripose/metabolismo , Artrogripose/patologia , Pré-Escolar , Fissura Palatina/metabolismo , Fissura Palatina/patologia , Pé Torto Equinovaro/metabolismo , Pé Torto Equinovaro/patologia , Feminino , Deformidades Congênitas da Mão/metabolismo , Deformidades Congênitas da Mão/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Domínios Proteicos , Fator C de Crescimento do Endotélio Vascular/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
6.
J Orthop Surg Res ; 13(1): 206, 2018 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-30134936

RESUMO

BACKGROUND: Also known as clubfoot, idiopathic congenital talipes equinovarus (ICTEV) is the most common pediatric deformity and occurs in 1 in every 1000 live births. Even though it has been widely researched, the etiology of ICTEV remains poorly understood and is often described as being based on a multifactorial genesis. Genetic and environmental factors seem to have a major role in the development of this disease. Thus, the aim of this review is to analyze the available literature to document the current evidence on ICTEV etiology. METHODS: The literature on ICTEV etiology was systematically reviewed using the following inclusion criteria: studies of any level of evidence, reporting clinical or preclinical results, published in the last 20 years (1998-2018), and dealing with the etiology of ICTEV. RESULTS: A total of 48 articles were included. ICTEV etiology is still controversial. Several hypotheses have been researched, but none of them are decisive. Emerging evidence suggests a role of several pathways and gene families associated with limb development (HOX family; PITX1-TBX4), the apoptotic pathway (caspases), and muscle contractile protein (troponin and tropomyosin), but a major candidate gene has still not been identified. Strong recent evidence emerging from twin studies confirmed major roles of genetics and the environment in the disease pathogenesis. CONCLUSIONS: The available literature on the etiology of ICTEV presents major limitations in terms of great heterogeneity and a lack of high-profile studies. Although many studies focus on the genetic background of the disease, there is lack of consensus on one or multiple targets. Genetics and smoking seem to be strongly associated with ICTEV etiology, but more studies are needed to understand the complex and multifactorial genesis of this common congenital lower-limb disease.


Assuntos
Pé Torto Equinovaro/genética , Pé Torto Equinovaro/etiologia , Interação Gene-Ambiente , Humanos
7.
Clin Dysmorphol ; 27(4): 116-121, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29912011

RESUMO

We report on a family with three siblings, male and female, affected by congenital bilateral limitation of vocal cord abduction, with the additional finding of clubfeet in two. The paternal family history suggests an autosomal dominant inheritance. The siblings and father also have mild craniofacial features, which may be an expression of variability or may be unrelated. The association between congenital vocal cord paralysis and clubfeet has been reported with additional major features or in the context of Charcot-Marie-Tooth disease. However, the two in isolation have only been reported in one other family previously. Genomic analyses of the family, including chromosomal microarray and exome sequencing, showed neither a likely pathogenic variant in a known disease gene nor a compelling candidate gene variant. We propose that the association of these two findings constitutes a novel recognizable phenotype, for which a genetic cause remains undetermined.


Assuntos
Paralisia das Pregas Vocais/fisiopatologia , Adulto , Criança , Pré-Escolar , Pé Torto Equinovaro/etiologia , Pé Torto Equinovaro/genética , Anormalidades Craniofaciais/genética , Família , Feminino , Humanos , Masculino , Linhagem , Fenótipo , Paralisia das Pregas Vocais/genética , Prega Vocal/fisiopatologia
8.
Development ; 145(3)2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29439133

RESUMO

Genetic factors underlying the human limb abnormality congenital talipes equinovarus ('clubfoot') remain incompletely understood. The spontaneous autosomal recessive mouse 'peroneal muscular atrophy' mutant (PMA) is a faithful morphological model of human clubfoot. In PMA mice, the dorsal (peroneal) branches of the sciatic nerves are absent. In this study, the primary developmental defect was identified as a reduced growth of sciatic nerve lateral motor column (LMC) neurons leading to failure to project to dorsal (peroneal) lower limb muscle blocks. The pma mutation was mapped and a candidate gene encoding LIM-domain kinase 1 (Limk1) identified, which is upregulated in mutant lateral LMC motor neurons. Genetic and molecular analyses showed that the mutation acts in the EphA4-Limk1-Cfl1/cofilin-actin pathway to modulate growth cone extension/collapse. In the chicken, both experimental upregulation of Limk1 by electroporation and pharmacological inhibition of actin turnover led to defects in hindlimb spinal motor neuron growth and pathfinding, and mimicked the clubfoot phenotype. The data support a neuromuscular aetiology for clubfoot and provide a mechanistic framework to understand clubfoot in humans.


Assuntos
Doença de Charcot-Marie-Tooth/embriologia , Pé Torto Equinovaro/embriologia , Pé Torto Equinovaro/genética , Quinases Lim/genética , Mutação , Animais , Axônios , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Embrião de Galinha , Mapeamento Cromossômico , Pé Torto Equinovaro/patologia , Modelos Animais de Doenças , Feminino , Membro Posterior/anormalidades , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , Neurônios Motores/patologia , Músculo Esquelético/anormalidades , Músculo Esquelético/inervação , Nervo Fibular/anormalidades , Fenótipo , Gravidez , Receptor EphA4/deficiência , Receptor EphA4/genética , Nervo Isquiático/anormalidades , Regulação para Cima
9.
Eur J Med Genet ; 61(2): 107-113, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28919208

RESUMO

Clubfoot or talipes equinovarus (TEV) is an inborn three-dimensional deformity of leg, ankle and foot. It results from structural defects of several tissues of foot and lower leg leading to abnormal positioning of foot and ankle joints. TEV can lead to long-lasting functional disability, malformation and discomfort if left untreated. Substantial progress has been achieved in the management and diagnosis of limb defects; however, not much is known about the molecular players and signalling pathways underlying TEV disorder. The homeostasis and development of the limb depends on the complex interactions between the lateral plate mesoderm cells and outer ectoderm. These complex interactions include HOX signalling and PITX1-TBX4 pathways. The susceptibility to develop TEV is determined by a number of environmental and genetic factors, although the nature and level of interplay between them remains unclear. Familial occurrence and inter and intra phenotypic variability of TEV is well documented. Variants in genes that code for contractile proteins of skeletal myofibers might play a role in the aetiology of TEV but, to date, no strong candidate genes conferring increased risk have emerged, although variants in TBX4, PITX1, HOXA, HOXC and HOXD clusters genes, NAT2 and others have been shown to be associated with TEV. The mechanisms by which variants in these genes confer risk and the nature of the physical and genetic interaction between them remains to be determined. Elucidation of genetic players and cellular pathways underlying TEV will certainly increase our understanding of the pathophysiology of this deformity.


Assuntos
Pé Torto Equinovaro/genética , Pé Torto Equinovaro/epidemiologia , Pé Torto Equinovaro/patologia , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Humanos
10.
J Cell Biochem ; 119(5): 3809-3818, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29274279

RESUMO

RBM10 is an RNA binding motif (RBM) protein expressed in most, if not all, human and animal cells. Interest in RBM10 is rapidly increasing and its clinical importance is highlighted by its identification as the causative agent of TARP syndrome, a developmental condition that significantly impacts affected children. RBM10's cellular functions are beginning to be explored, with initial studies demonstrating a tumor suppressor role. Very recently, however, contradictory results have emerged, suggesting a tumor promoter role for RBM10. In this review, we describe the current state of knowledge on RBM10, and address this dichotomy in RBM10 function. Furthermore, we discuss what may be regulating RBM10 function, particularly the importance of RBM10 alternative splicing, and the relationship between RBM10 and its paralogue, RBM5. As RBM10-related work is gaining momentum, it is critical that the various aspects of RBM10 molecular biology revealed by recent studies be considered moving forward. It is only if these recent advances in RBM10 structure and function are considered that a clearer insight into RBM10 function, and the disease states with which RBM10 mutation is associated, will be gained.


Assuntos
Processamento Alternativo , Pé Torto Equinovaro , Cardiopatias Congênitas , Mutação , Síndrome de Pierre Robin , Proteínas de Ligação a RNA , Animais , Pé Torto Equinovaro/genética , Pé Torto Equinovaro/metabolismo , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Humanos , Síndrome de Pierre Robin/genética , Síndrome de Pierre Robin/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Relação Estrutura-Atividade
11.
Clin Genet ; 93(4): 800-811, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29112243

RESUMO

Richieri-Costa-Pereira syndrome is a rare autosomal recessive acrofacial dysostosis that has been mainly described in Brazilian individuals. The cardinal features include Robin sequence, cleft mandible, laryngeal anomalies and limb defects. A biallelic expansion of a complex repeated motif in the 5' untranslated region of EIF4A3 has been shown to cause this syndrome, commonly with 15 or 16 repeats. The only patient with mild clinical findings harbored a 14-repeat expansion in 1 allele and a point mutation in the other allele. This proband is described here in more details, as well as is his affected sister, and 5 new individuals with Richieri-Costa-Pereira syndrome, including a patient from England, of African ancestry. This study has expanded the phenotype in this syndrome by the observation of microcephaly, better characterization of skeletal abnormalities, less severe phenotype with only mild facial dysmorphisms and limb anomalies, as well as the absence of cleft mandible, which is a hallmark of the syndrome. Although the most frequent mutation in this study was the recurrent 16-repeat expansion in EIF4A3, there was an overrepresentation of the 14-repeat expansion, with mild phenotypic expression, thus suggesting that the number of these motifs could play a role in phenotypic delineation.


Assuntos
Pé Torto Equinovaro/genética , RNA Helicases DEAD-box/genética , Fator de Iniciação 4A em Eucariotos/genética , Deformidades Congênitas da Mão/genética , Laringe/fisiopatologia , Deformidades Congênitas dos Membros/genética , Síndrome de Pierre Robin/genética , Adolescente , Adulto , Alelos , Brasil/epidemiologia , Criança , Pé Torto Equinovaro/epidemiologia , Pé Torto Equinovaro/fisiopatologia , Expansão das Repetições de DNA/genética , Inglaterra/epidemiologia , Extremidades/fisiopatologia , Feminino , Genótipo , Deformidades Congênitas da Mão/epidemiologia , Deformidades Congênitas da Mão/fisiopatologia , Humanos , Laringe/anormalidades , Deformidades Congênitas dos Membros/fisiopatologia , Masculino , Fenótipo , Síndrome de Pierre Robin/epidemiologia , Síndrome de Pierre Robin/fisiopatologia , Mutação Puntual/genética , Adulto Jovem
12.
J Hum Genet ; 62(12): 1073-1078, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28855715

RESUMO

We have recently described a family with a condition (Santos syndrome (SS; MIM 613005)) characterized by fibular agenesis/hypoplasia, hypoplastic femora and grossly malformed/deformed clubfeet with severe oligodactyly, ungual hypoplasia/anonychia, sometimes associated with mild brachydactyly and occasional pre-axial polydactyly. Autosomal dominant inheritance with incomplete penetrance was suggested, but autosomal recessive inheritance could not be ruled out, due to the high frequency of consanguineous matings in the region where the family lived. This report deals with linkage studies and exome sequencing, disclosing a novel variant in WNT7A, c.934G>A (p.Gly312Ser), as the cause of this syndrome. This variant was present in homozygous state in five individuals typically affected by the SS syndrome, and in heterozygous state in the son of one affected homozygous individual. The heterozygous boy presented only unilateral complex polysyndactyly and we hypothesize that he either presents a distinct defect or that his phenotype results from a rare, mild clinical manifestation of the variant in heterozygous state. Variants in WNT7A are known to cause at least two other limb defect disorders, the syndromes of Fuhrmann and Al-Awadi/Raas-Rothschild. Despite their variable degree of expressivity and overlap, the three related conditions can be differentiated phenotypically in most instances.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Pé Torto Equinovaro/genética , Fíbula/anormalidades , Dedos/anormalidades , Marcadores Genéticos/genética , Deformidades Congênitas dos Membros/genética , Unhas Malformadas/genética , Polidactilia/genética , Proteínas Wnt/genética , Sequência de Aminoácidos , Consanguinidade , Feminino , Ligação Genética , Homozigoto , Humanos , Masculino , Repetições de Microssatélites/genética , Mutação , Linhagem , Fenótipo , Alinhamento de Sequência
13.
Am J Med Genet A ; 173(10): 2798-2802, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28815864

RESUMO

Interstitial deletions of the short and long arms of chromosome 5 are rare cytogenetic abnormalities. The 5p distal deletion is a genetic disorder characterized by a high-pitched cat-like cry, microcephaly, epicanthal folds, micrognathia, severe intellectual disability and motor delays. Previously, more than 46 patients with the 5q deletion have been reported. Here, we report de novo interstitial deletions involving 5p14.1-p15.2 and 5q14.3-q23.2 in a patient with multiple congenital abnormalities, including blepharophimosis, arthrogryposis, short neck, round face, pelvic kidney, agenesis of the corpus callosum, and clubfoot. The deletions were characterized using GTG banding and aCGH microarray analysis. Concurrent 5p and 5q interstitial deletions in humans have not been previously reported. We also discussed the relationship between the 5q deleted region and clubfeet.


Assuntos
Artrogripose/genética , Blefarofimose/genética , Deleção Cromossômica , Cromossomos Humanos Par 5 , Pé Torto Equinovaro/genética , Anormalidades Congênitas/genética , Adulto , Artrogripose/complicações , Artrogripose/patologia , Blefarofimose/complicações , Blefarofimose/patologia , Pré-Escolar , Pé Torto Equinovaro/complicações , Pé Torto Equinovaro/patologia , Anormalidades Congênitas/patologia , Feminino , Humanos , Lactente , Masculino , Prognóstico
14.
BMC Med Genet ; 18(1): 60, 2017 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-28577551

RESUMO

BACKGROUND: Diagnostic Exome Sequencing (DES) has been shown to be an effective tool for diagnosis individuals with suspected genetic conditions. CASE PRESENTATION: We report a male infant born with multiple anomalies including bilateral dysplastic kidneys, cleft palate, bilateral talipes, and bilateral absence of thumbs and first toes. Prenatal testing including chromosome analysis and microarray did not identify a cause for the multiple congenital anomalies. Postnatal diagnostic exome studies (DES) were utilized to find a molecular diagnosis for the patient. Exome sequencing of the proband, mother, and father showed a previously unreported maternally inherited RNA binding motif protein 10 (RBM10) c.1352_1353delAG (p.E451Vfs*66) alteration. Mutations in RBM10 are associated with TARP syndrome, an X-linked recessive disorder originally described with cardinal features of talipes equinovarus, atrial septal defect, Robin sequence, and persistent left superior vena cava. CONCLUSION: DES established a molecular genetic diagnosis of TARP syndrome for a neonatal patient with a poor prognosis in whom traditional testing methods were uninformative and allowed for efficient diagnosis and future reproductive options for the parents. Other reported cases of TARP syndrome demonstrate significant variability in clinical phenotype. The reported features in this infant including multiple hemivertebrae, imperforate anus, aplasia of thumbs and first toes have not been reported in previous patients, thus expanding the clinical phenotype for this rare disorder.


Assuntos
Pé Torto Equinovaro/diagnóstico , Pé Torto Equinovaro/genética , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Síndrome de Pierre Robin/diagnóstico , Síndrome de Pierre Robin/genética , Proteínas de Ligação a RNA/genética , Exoma , Evolução Fatal , Humanos , Lactente , Masculino , Mutação , Fenótipo , Prognóstico , Análise de Sequência de DNA
15.
Neuron ; 93(5): 989-991, 2017 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-28279361

RESUMO

In this issue of Neuron, Ben-Yaacov et al. (2017) dissect the interaction between AMPA receptors and auxiliary (TARP) subunits, revealing essential roles for the receptor transmembrane and cytoplasmic domains, as well as for the TARP extracellular EX2 loop.


Assuntos
Canais de Cálcio/metabolismo , Pé Torto Equinovaro/metabolismo , Cardiopatias Congênitas/metabolismo , Neurônios/metabolismo , Síndrome de Pierre Robin/metabolismo , Subunidades Proteicas/metabolismo , Receptores de AMPA/metabolismo , Animais , Pé Torto Equinovaro/genética , Cardiopatias Congênitas/genética , Humanos , Proteínas de Membrana/metabolismo , Síndrome de Pierre Robin/genética
16.
Physiol Res ; 66(3): 403-410, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28248538

RESUMO

Idiopathic pes equinovarus (clubfoot) is a congenital deformity of the foot and lower leg defined as a fixation of the foot in plantar flexion, adduction, supination and varus. The deformity does not affect only the foot position, which is usually investigated by radiography, CT, micro-CT, MRI or ultrasound but logically influence the whole gait biomechanics. It is supposed, that clubfoot belongs to a group of fibroproliferative disorders whose origin and multi-hierarchical effect remain unknown. It has been suggested that fibroblasts and growth factors may be involved. To gain a more global view, direct analysis of the protein composition of extracellular matrix, a proteomic approach was used. At present two principle methods are mostly used for the treatment of clubfoot: physiotherapy and the Ponseti method. The determination of the general biological and biomechanical parameters for various regions of the clubfoot can potentially help in the understanding of the mechanisms participating on this serious anomaly and thus contribute to the development of the more efficient therapeutic approach. This review summarizes the present knowledge on the possible pathogenetic mechanisms participating in the development of the clubfoot and their possible relation to the new therapeutic approaches.


Assuntos
Pé Torto Equinovaro/genética , Pé Torto Equinovaro/terapia , Colágeno/genética , Pé Torto Equinovaro/patologia , Terapia por Exercício/métodos , Fibroblastos/patologia , Órtoses do Pé/estatística & dados numéricos , Marcha/fisiologia , Humanos , Resultado do Tratamento
17.
Hum Mol Genet ; 26(12): 2177-2191, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28334780

RESUMO

Biallelic loss-of-function mutations in the RNA-binding protein EIF4A3 cause Richieri-Costa-Pereira syndrome (RCPS), an autosomal recessive condition mainly characterized by craniofacial and limb malformations. However, the pathogenic cellular mechanisms responsible for this syndrome are entirely unknown. Here, we used two complementary approaches, patient-derived induced pluripotent stem cells (iPSCs) and conditional Eif4a3 mouse models, to demonstrate that defective neural crest cell (NCC) development explains RCPS craniofacial abnormalities. RCPS iNCCs have decreased migratory capacity, a distinct phenotype relative to other craniofacial disorders. Eif4a3 haploinsufficient embryos presented altered mandibular process fusion and micrognathia, thus recapitulating the most penetrant phenotypes of the syndrome. These defects were evident in either ubiquitous or NCC-specific Eif4a3 haploinsufficient animals, demonstrating an autonomous requirement of Eif4a3 in NCCs. Notably, RCPS NCC-derived mesenchymal stem-like cells (nMSCs) showed premature bone differentiation, a phenotype paralleled by premature clavicle ossification in Eif4a3 haploinsufficient embryos. Likewise, nMSCs presented compromised in vitro chondrogenesis, and Meckel's cartilage was underdeveloped in vivo. These findings indicate novel and essential requirements of EIF4A3 for NCC migration and osteochondrogenic differentiation during craniofacial development. Altogether, complementary use of iPSCs and mouse models pinpoint unique cellular mechanisms by which EIF4A3 mutation causes RCPS, and provide a paradigm to study craniofacial disorders.


Assuntos
Pé Torto Equinovaro/genética , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Fator de Iniciação 4A em Eucariotos/genética , Fator de Iniciação 4A em Eucariotos/metabolismo , Deformidades Congênitas da Mão/genética , Síndrome de Pierre Robin/genética , Animais , Osso e Ossos/metabolismo , Região Branquial/metabolismo , Diferenciação Celular/genética , Movimento Celular , Condrogênese/genética , Pé Torto Equinovaro/metabolismo , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/metabolismo , Modelos Animais de Doenças , Deformidades Congênitas da Mão/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Crista Neural/crescimento & desenvolvimento , Crista Neural/metabolismo , Osteogênese/genética , Síndrome de Pierre Robin/metabolismo
18.
Clin Orthop Relat Res ; 475(6): 1716-1725, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28236079

RESUMO

BACKGROUND: Clubfoot is one of the most common pediatric orthopaedic disorders. While the Ponseti method has revolutionized clubfoot treatment, it is not effective for all patients. When the Ponseti method does not correct the foot, patients are at risk for lifelong disability and may require more-extensive surgery. QUESTIONS/PURPOSES: (1) What genetic and morphologic abnormalities contribute to the development of clubfoot? (2) How can this information be used to devise personalized treatment paradigms for patients with clubfoot? METHODS: Human gene sequencing, molecular genetic engineering of mouse models of clubfoot, MRI of clubfoot, and development of new treatment methods all have been used by our group to understand the biological basis and improve therapy for this group of disorders. RESULTS: We gained new insight into clubfoot pathogenesis from our discovery that mutations in the PITX1-TBX4-HOXC transcriptional pathway cause familial clubfoot and vertical talus in a small number of families, with the unique lower limb expression of these genes providing an explanation for the lack of upper extremity involvement in these disorders. MRI studies revealed corresponding morphologic abnormalities, including hypomorphic muscle, bone, and vasculature, that are not only associated with these gene mutations, but also are biomarkers for treatment-resistant clubfoot. CONCLUSIONS: Based on an understanding of the underlying biology, we improved treatment methods for neglected and syndromic clubfoot, developed new treatment for congenital vertical talus based on the principles of the Ponseti method, and designed a new dynamic clubfoot brace to improve strength and compliance.


Assuntos
Pé Torto Equinovaro/genética , Pé Torto Equinovaro/terapia , Procedimentos Ortopédicos/métodos , Medicina de Precisão/métodos , Pesquisa Médica Translacional , Animais , Distinções e Prêmios , Braquetes , Criança , Pré-Escolar , Pé Chato , Deformidades Congênitas do Pé/genética , Deformidades Congênitas do Pé/terapia , Redes Reguladoras de Genes/genética , Proteínas de Homeodomínio/genética , Humanos , Lactente , Camundongos , Fatores de Transcrição Box Pareados/genética , Análise de Sequência de DNA , Proteínas com Domínio T/genética
19.
J Pediatr Endocrinol Metab ; 30(3): 361-364, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28222034

RESUMO

BACKGROUND: Gordon syndrome (GS) is a rare form of monogenic hypertension characterized by low renin hypertension, hyperkalemia, hyperchloremic metabolic acidosis, and normal glomerular filtration rate. To date, four genes causing GS have been identified as: WNK1, WNK4, CUL3, and KLHL3. CASE PRESENTATION: We report three cases of GS in two families. All patients presented with typical clinical features of GS and had a known dominant KLHL3 mutation. Oral thiazide treatment with low salt diet resulted in normalization of blood pressure and serum electrolytes in all three cases. CONCLUSIONS: GS should be considered in patients with low renin hypertension and hyperkalemia. Although it is a rare disease, the correct diagnosis of GS is clinically important, as it can easily be treated with a low sodium diet or thiazides. In addition, family studies can identify individuals with undiagnosed GS as all mutations causing this disease, except for some recessive KLHL3 mutations, are dominant mutations.


Assuntos
Artrogripose/genética , Artrogripose/patologia , Biomarcadores/metabolismo , Proteínas de Transporte/genética , Fissura Palatina/genética , Fissura Palatina/patologia , Pé Torto Equinovaro/genética , Pé Torto Equinovaro/patologia , Genes Dominantes/genética , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/patologia , Mutação/genética , Adulto , Pré-Escolar , Feminino , Humanos , Lactente , Fenótipo , Prognóstico
20.
Am J Med Genet A ; 173(1): 254-259, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27714920

RESUMO

Gordon syndrome or distal arthrogryposis type 3 is a rare autosomal dominant disorder characterized by contractures of upper and lower limbs. It is distinguishable from other forms of distal arthrogryposis by cleft palate and short stature. Recently, Gordon syndrome has been associated to heterozygous mutations in the piezo-type mechanosensitive ion channel component 2 gene (PIEZO2). Different mutations of this gene also cause distal arthrogryposis type 5 and Marden-Walker syndrome. Dysfunction of this ion channel provides pleiotropic effects on joints, ocular muscles, and bone development. Here, we present a family with three affected individuals exhibiting multiple contractures (metacarpo-phalangeal and interphalangeal joints as well as elbow, shoulder, knee, and ankle joints), clubfeet, short stature, bifid uvula/cleft palate, and a distinct facial phenotype including ptosis. In addition, mild intellectual disability and delay in psychomotor development are obvious. The multigenerational phenotypic spectrum of Gordon syndrome is present in the 37-year-old father, his 4-year-old son and a male neonate showing typical signs of arthrogryposis in the prenatal ultrasound examination already seen at 13 week of gestation. In all affected family members, we identified the PIEZO2 mutation c.8057G>A (p.Arg2686His) by Sanger sequencing. Our analysis indicated that mild delay in psychomotor development and intellectual disability could be part of the phenotypic spectrum of Gordon syndrome. © 2016 Wiley Periodicals, Inc.


Assuntos
Artrogripose/diagnóstico , Artrogripose/genética , Fissura Palatina/diagnóstico , Fissura Palatina/genética , Pé Torto Equinovaro/diagnóstico , Pé Torto Equinovaro/genética , Estudos de Associação Genética , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/genética , Canais Iônicos/genética , Mutação , Adulto , Alelos , Substituição de Aminoácidos , Pré-Escolar , Códon , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Éxons , Facies , Genótipo , Humanos , Recém-Nascido , Masculino , Linhagem , Fenótipo , Ultrassonografia Pré-Natal
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