RESUMO
Townes-Brocks syndrome (TBS) is an autosomal dominant disorder characterised by the triad of anorectal, thumb, and ear malformations. It may also be accompanied by defects in kidney, heart, eyes, hearing, and feet. TBS has been demonstrated to result from heterozygous variants in the SALL1 gene, which encodes zinc finger protein believed to function as a transcriptional repressor. The clinical characteristics of an atypical TBS phenotype patient from a Chinese family are described, with predominant manifestations including external ear dysplasia, unilateral renal hypoplasia with mild renal dysfunction, and hearing impairment. A novel heterozygous variant c.3060T>A (p.Tyr1020*) in exon 2 of the SALL1 gene was identified in this proband. Pyrosequencing of the complementary DNA of the proband revealed that the variant transcript accounted for 48% of the total transcripts in peripheral leukocytes, indicating that this variant transcript has not undergone nonsense-mediated mRNA decay. This variant c.3060T > A is located at the terminal end of exon 2, proximal to the 3' end of the SALL1 gene, and exerts a relatively minor impact on protein function. We suggest that the atypical TBS phenotype observed in the proband may be attributed to the truncated protein retaining partial SALL1 function.
Assuntos
Anormalidades Múltiplas , Perda Auditiva Neurossensorial , Fatores de Transcrição , Feminino , Humanos , Masculino , Anormalidades Múltiplas/genética , Anus Imperfurado/genética , Anus Imperfurado/diagnóstico , China , Análise Mutacional de DNA , Orelha/anormalidades , População do Leste Asiático/genética , Predisposição Genética para Doença , Hereditariedade , Heterozigoto , Mutação , Linhagem , Fenótipo , Polegar/anormalidades , Fístula Traqueoesofágica/genética , Fatores de Transcrição/genéticaRESUMO
We report a 2.2 year-old-boy, born of consanguineous marriage, referred for short stature, with history of neonatal death and skeletal deformities in his older sibling. Rhizo-mesomelic dwarfism was detected antenatally. Within 24 hours of birth, he developed multiple seizures. Examination revealed severe short stature, dolichocephaly, broad forehead, deep set eyes, low set ears, bulbous nose, small, irregular teeth, pointed chin, and triangular facies. He had rhizomelic shortening, stubby fingers, pes planus, and scanty hair. Neurological evaluation revealed ataxia, hypotonia, and global developmental delay. Skeletal survey radiograph revealed shallow acetabuli, short femurs and humerus, short, broad metacarpals and short cone-shaped phalanges with cupping of phalangeal bases. Clinical exome analysis revealed homozygous mutations involving the POC1A gene and the SLC13A5 gene responsible for SOFT syndrome and Kohlschutter-Tonz syndrome respectively, which were inherited from the parents. Both these syndromes are extremely rare, and their co-occurrence is being reported for the first time.
Assuntos
Anormalidades Múltiplas , Amelogênese Imperfeita , Demência , Nanismo , Epilepsia , Osteocondrodisplasias , Simportadores , Masculino , Recém-Nascido , Humanos , Pré-Escolar , Amelogênese Imperfeita/genética , Anormalidades Múltiplas/genética , Osteocondrodisplasias/genética , Nanismo/genética , Nanismo/diagnóstico , Proteínas do Citoesqueleto , Proteínas de Ciclo CelularRESUMO
Loss-of-function mutations in chromatin remodeler gene ARID1A are a cause of Coffin-Siris syndrome, a developmental disorder characterized by dysgenesis of corpus callosum. Here, we characterize Arid1a function during cortical development and find unexpectedly selective roles for Arid1a in subplate neurons (SPNs). SPNs, strategically positioned at the interface of cortical gray and white matter, orchestrate multiple developmental processes indispensable for neural circuit wiring. We find that pancortical deletion of Arid1a leads to extensive mistargeting of intracortical axons and agenesis of corpus callosum. Sparse Arid1a deletion, however, does not autonomously misroute callosal axons, implicating noncell-autonomous Arid1a functions in axon guidance. Supporting this possibility, the ascending axons of thalamocortical neurons, which are not autonomously affected by cortical Arid1a deletion, are also disrupted in their pathfinding into cortex and innervation of whisker barrels. Coincident with these miswiring phenotypes, which are reminiscent of subplate ablation, we unbiasedly find a selective loss of SPN gene expression following Arid1a deletion. In addition, multiple characteristics of SPNs crucial to their wiring functions, including subplate organization, subplate axon-thalamocortical axon cofasciculation ("handshake"), and extracellular matrix, are severely disrupted. To empirically test Arid1a sufficiency in subplate, we generate a cortical plate deletion of Arid1a that spares SPNs. In this model, subplate Arid1a expression is sufficient for subplate organization, subplate axon-thalamocortical axon cofasciculation, and subplate extracellular matrix. Consistent with these wiring functions, subplate Arid1a sufficiently enables normal callosum formation, thalamocortical axon targeting, and whisker barrel development. Thus, Arid1a is a multifunctional regulator of subplate-dependent guidance mechanisms essential to cortical circuit wiring.
Assuntos
Córtex Cerebral/metabolismo , Cromatina/química , Corpo Caloso/metabolismo , Proteínas de Ligação a DNA/genética , Mutação com Perda de Função , Tálamo/metabolismo , Fatores de Transcrição/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Animais , Córtex Cerebral/patologia , Cromatina/metabolismo , Conectoma , Corpo Caloso/patologia , Proteínas de Ligação a DNA/deficiência , Face/anormalidades , Face/patologia , Deleção de Genes , Regulação da Expressão Gênica , Substância Cinzenta/metabolismo , Substância Cinzenta/patologia , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/metabolismo , Deformidades Congênitas da Mão/patologia , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Camundongos , Camundongos Transgênicos , Micrognatismo/genética , Micrognatismo/metabolismo , Micrognatismo/patologia , Pescoço/anormalidades , Pescoço/patologia , Vias Neurais/metabolismo , Vias Neurais/patologia , Neurônios/metabolismo , Neurônios/patologia , Tálamo/patologia , Fatores de Transcrição/deficiência , Vibrissas/metabolismo , Vibrissas/patologia , Substância Branca/metabolismo , Substância Branca/patologiaRESUMO
RATIONALE: The karyotype 49,XXXXY is a rare form of Klinefelter syndrome usually presenting with ambiguous genitalia, facial dysmorphism, mental retardation, and a combination of cardiac, skeletal, and other malformations. PATIENT CONCERNS: We describe a 19-year-old man, whose chromosomal analysis of peripheral blood revealed a karyotype of 49,XXXXY. His mental development and motor ability were significantly delayed. At the age of 19, he had failed to develop secondary sexual characteristics. His random blood glucose level was 19.61âmmol/L, and he showed dry mouth, polydipsia, and polyuria. He had a characteristic facial appearance with prognathism, widened nasal bridge, and strabismus. His bilateral elbow rotation was limited. He had atrophic testes with micropenis. Ophthalmic examination revealed a polar cataract in both eyes. DIAGNOSIS: He was diagnosed with Klinefelter syndrome associated with cleft palate, hypothyroidism, cataracts, diabetes, and other anomalies. INTERVENTIONS: After the initial diagnosis, the patient received intensive insulin therapy to correct hyperglycemia, and he received calcium and vitamin D supplements. The patient also received testosterone and thyroid hormone replacement therapy for primary hypogonadism. OUTCOMES: The patient was discharged 12 days after receiving treatment; meanwhile, there were no clinical symptoms of dry mouth, polyuria and polyuria, and his blood glucose level was controlled. LESSONS: The combination of cleft palate, hypothyroidism, cataracts, diabetes, and osteoporosis in 49,XXXXY syndrome has not yet been reported. Early treatment and appropriate care can significantly improve the patient's quality of life and prevent serious consequences.
Assuntos
Catarata/congênito , Fissura Palatina/genética , Hipotireoidismo Congênito/genética , Diabetes Mellitus/congênito , Transtornos dos Cromossomos Sexuais/complicações , Anormalidades Múltiplas/genética , Aneuploidia , Cromossomos Humanos X/genética , Humanos , Cariotipagem , Masculino , Aberrações dos Cromossomos Sexuais , Transtornos dos Cromossomos Sexuais/genética , Adulto JovemRESUMO
OBJECTIVE: Identify, diagnose, and document oral clinical and radiographic evidence associated with the genetic condition known as special AT-rich sequence-binding protein 2 (SATB2)-associated syndrome. Through identifying and publishing these common dental and behavioral findings, we hope to educate oral and medical healthcare providers to identify this condition in an attempt to develop meaningful comprehensive care to this patient population. METHODS: A total of 37 patients (19 female), ranging from ages 2 to 20 were evaluated at Arkansas Children's Hospital in Little Rock, Arkansas. Patient geographic distribution included: the United States, Canada, Portugal, Spain, and the Netherlands. Patients were clinically and radiographically examined for oral findings. Panoramic radiographs were obtained when patient's behavior allowed. Patient's parents or guardians were also interviewed concerning dental, medical, and behavioral histories. RESULTS: Clinical findings included delayed tooth eruption, bruxism, sialorrhea, larger than normal teeth with an increased propensity for maxillary anterior tooth trauma due to unsteady ambulation. Radiographic findings included delayed permanent root formation, significantly delayed or missing second bicuspids, malformed teeth, and taurodontism. Medical and behavioral issues included: insomnia, hyperphagia, cognitive delays, and an extremely high pain threshold. CONCLUSION: Patients with SATB2-associated syndrome have shown to have a consistent and unique set of dental findings both clinically and radiographically. A thorough health and dental history along with the aforementioned results of the study may facilitate a diagnosis of this syndrome. Due to the complexity of the patient's dental needs and behavior, a health practitioner with special needs care experience on a comprehensive craniofacial team would be optimal.
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Proteínas de Ligação à Região de Interação com a Matriz/genética , Doenças da Boca/diagnóstico , Doenças da Boca/genética , Fatores de Transcrição/genética , Adolescente , Arkansas , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Radiografia Panorâmica , Síndrome , Adulto JovemRESUMO
PURPOSE OF REVIEW: The group of sclerosing bone disorders encompasses a variety of disorders all marked by increased bone mass. In this review, we give an overview of the genetic causes of this heterogeneous group of disorders and briefly touch upon the value of these findings for the development of novel therapeutic agents. RECENT FINDINGS: Advances in the next-generation sequencing technologies are accelerating the molecular dissection of the pathogenic mechanisms underlying skeletal dysplasias. Throughout the years, the genetic cause of these disorders has been extensively studied which resulted in the identification of a variety of disease-causing genes and pathways that are involved in bone formation by osteoblasts, bone resorption by osteoclasts, or both processes. Due to this rapidly increasing knowledge, the insights into the regulatory mechanisms of bone metabolism are continuously improving resulting in the identification of novel therapeutic targets for disorders with reduced bone mass and increased bone fragility.
Assuntos
Hiperostose/genética , Osteíte Deformante/genética , Osteosclerose/genética , Picnodisostose/genética , Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Remodelação Óssea/genética , Reabsorção Óssea/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deficiência Intelectual/genética , Melorreostose/genética , Osteoblastos , Osteoclastos , Osteogênese/genética , Osteopetrose/genética , Osteopecilose/genéticaRESUMO
INTRODUCTION: The term 'RASopathies' covers a series of diseases that present mutations in the genes that code for the proteins of the RAS/MAPK pathway. These diseases include neurofibromatosis type 1, Noonan syndrome, Legius syndrome, LEOPARD syndrome, Costello syndrome and cardiofaciocutaneous syndrome. Involvement of the RAS/MAPK pathway not only increases predisposition to develop tumours, but also determines the presence of phenotypic anomalies and alterations in learning processes. AIM: To review the use of therapeutic strategies with mechanisms that have a selective action on RASopathies. DEVELOPMENT: The fact that the RAS pathway is involved in a third of all neoplasms has led to the development and study of different drugs at this level. Some of these pharmaceutical agents have been tested in RASopathies, mainly in neurofibromatosis type 1. Here we analyse the use of different antitarget treatments: drugs that act on the membrane receptors, such as tyrosine kinase inhibitors, in the mTOR pathway or MEK inhibitors. These latter have shown potential benefits in recent studies conducted on different RASopathies. CONCLUSIONS: Today, thanks to the results from the first studies conducted with MEK inhibitor based mainly on animal models, a number of promising clinical trials are being carried out.
TITLE: Actualizacion del tratamiento de las rasopatias.Introduccion. El termino 'rasopatias' agrupa una serie de enfermedades que presentan mutaciones en genes que codifican las proteinas de la via RAS/MAPK. Estas enfermedades incluyen la neurofibromatosis de tipo 1, el sindrome de Noonan, el sindrome de Legius, el sindrome LEOPARD, el sindrome de Costello y el sindrome cardiofaciocutaneo. La afectacion de la via RAS/MAPK no solo aumenta la predisposicion a desarrollar tumores, sino que tambien determina la presencia de anomalias fenotipicas y alteraciones en los procesos de aprendizaje. Objetivo. Revisar el papel del uso de estrategias terapeuticas con mecanismos de accion selectivo en las rasopatias. Desarrollo. El hecho de que la via RAS participe en un tercio de las neoplasias ha motivado el desarrollo y el estudio de distintos farmacos a este nivel. Algunos de estos farmacos han sido probados en las rasopatias, principalmente en la neurofibromatosis de tipo 1. Analizamos el uso de distintos tratamientos antidiana: farmacos que actuan en los receptores de membrana, como los inhibidores de la tirosincinasa, en la via mTOR o los inhibidores de MEK. Existe un potencial beneficio de estos ultimos en estudios recientes realizados en distintas rasopatias. Conclusiones. Actualmente, gracias a los resultados de los primeros trabajos desarrollados con inhibidor de MEK basados principalmente en modelos animales, se estan realizando multiples ensayos clinicos prometedores.
Assuntos
Anormalidades Múltiplas/tratamento farmacológico , Genes ras , Doenças Genéticas Inatas/tratamento farmacológico , Sistema de Sinalização das MAP Quinases , Terapia de Alvo Molecular , Proteínas ras/antagonistas & inibidores , Anormalidades Múltiplas/classificação , Anormalidades Múltiplas/genética , Animais , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Doenças Genéticas Inatas/classificação , Doenças Genéticas Inatas/genética , Humanos , MAP Quinase Quinase Quinases/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Síndromes Neoplásicas Hereditárias/tratamento farmacológico , Síndromes Neoplásicas Hereditárias/genética , Neurofibromatose 1/tratamento farmacológico , Neurofibromatose 1/genética , Síndrome de Noonan/tratamento farmacológico , Síndrome de Noonan/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Síndrome , Serina-Treonina Quinases TOR/antagonistas & inibidores , Proteínas ras/genéticaRESUMO
Dysregulation of histone methylation has emerged as a major driver of neurodevelopmental disorders including intellectual disabilities and autism spectrum disorders. Histone methyl writer and eraser enzymes generally act within multisubunit complexes rather than in isolation. However, it remains largely elusive how such complexes cooperate to achieve the precise spatiotemporal gene expression in the developing brain. Histone H3K4 methylation (H3K4me) is a chromatin signature associated with active gene-regulatory elements. We review a body of literature that supports a model in which the RAI1-containing H3K4me writer complex counterbalances the LSD1-containing H3K4me eraser complex to ensure normal brain development. This model predicts H3K4me as the nexus of previously unrelated neurodevelopmental disorders.
Assuntos
Encéfalo/metabolismo , Histonas/metabolismo , Anormalidades Múltiplas/genética , Animais , Transtornos Cromossômicos/genética , Duplicação Cromossômica/genética , Ritmo Circadiano/genética , Proteínas Correpressoras/genética , Expressão Gênica , Proteínas de Grupo de Alta Mobilidade/genética , Histona Desmetilases/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Metilação , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas do Tecido Nervoso/genética , Síndrome de Smith-Magenis/genética , Transativadores , Fatores de Transcrição/genéticaRESUMO
Although mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of genetic Parkinson's disease, their function is largely unknown. LRRK2 is pleiotropic in nature, shown to be involved in neurodegeneration and in more peripheral processes, including kidney functions, in rats and mice. Recent studies in zebrafish have shown conflicting evidence that removal of the LRRK2 WD40 domain may or may not affect dopaminergic neurons and/or locomotion. This study shows that â¼50% LRRK2 knockdown in zebrafish causes not only neuronal loss but also developmental perturbations such as axis curvature defects, ocular abnormalities, and edema in the eyes, lens, and otic vesicles. We further show that LRRK2 knockdown results in significant neuronal loss, including a reduction of dopaminergic neurons. Immunofluorescence demonstrates that endogenous LRRK2 is expressed in the lens, brain, heart, spinal cord, and kidney (pronephros), which mirror the LRRK2 morphant phenotypes observed. LRRK2 knockdown results further in the concomitant upregulation of ß-synuclein, PARK13, and SOD1 and causes ß-synuclein aggregation in the diencephalon, midbrain, hindbrain, and postoptic commissure. LRRK2 knockdown causes mislocalization of the Na(+) /K(+) ATPase protein in the pronephric ducts, suggesting that the edema might be linked to renal malfunction and that LRRK2 might be associated with pronephric duct epithelial cell differentiation. Combined, our study shows that LRRK2 has multifaceted roles in zebrafish and that zebrafish represent a complementary model to further our understanding of this central protein. © 2016 Wiley Periodicals, Inc.
Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Doenças Neurodegenerativas/genética , Neurônios/patologia , Proteínas de Peixe-Zebra/genética , beta-Sinucleína/genética , Sequência de Aminoácidos , Animais , Química Encefálica/genética , Neurônios Dopaminérgicos , Técnicas de Silenciamento de Genes , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/biossíntese , Locomoção , Mutação/genética , Doenças Neurodegenerativas/patologia , Doença de Parkinson/genética , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/biossínteseRESUMO
BACKGROUND: We describe a male with functionally impairing radial deviation of the thumb who presented to us at 24 years of age. Two sclerotic skin lesions had been excised 7 years before because of consecutive skin contracture. Latest radiological examination showed a spotted pattern consistent with osteopoikilosis. CASE PRESENTATION: A corrective osteotomy of the thumb was carried out due to the patients discomfort. Facing the simultaneous osteo-cutaneous malformation we postulated a Buschke-Ollendorff syndrome. Buschke-Ollendorff syndrome is a rare autosomal-dominant hereditary disorder of connective tissue with typical osteo-cutaneous manifestations. To explore our hypothesis, biopsies were taken from the affected bone lesions and surrounding skin and soft tissue for histological investigation and genetic testing of the LEMD3 gene was performed on blood of the patient. The histology showed typical changes of the bone architecture and a fibrotic collagenous nodule of the skin. The genetic testing on DNA extracted from peripheral blood leucocytes confirmed a heterozygous loss of function mutation in the LEM domain-containing protein 3 (LEMD3) gene coding for the inner nuclear membrane protein MAN1, which causes osteopoikilosis by antagonizing transforming growth factor ß (TGF-ß) and bone morphogenetic protein (BMP) signalling. CONCLUSIONS: In atypical cases of simultaneous occurrence of fibrotic skin lesions and a spotted pattern in the X-ray we recommend the genetic screening of the LEMD3 gene. A correct diagnosis of Buschke-Ollendorff syndrome is necessary to spare patients from expensive investigations and to provide reassurance about the benign nature of the disease.
Assuntos
Anormalidades Múltiplas/patologia , Osteopecilose/patologia , Anormalidades da Pele , Dermatopatias Genéticas/patologia , Polegar/anormalidades , Anormalidades Múltiplas/genética , Sequência de Bases , Análise Mutacional de DNA/métodos , Proteínas de Ligação a DNA , Humanos , Masculino , Proteínas de Membrana/genética , Mutação , Proteínas Nucleares/genética , Osteopecilose/genética , Homologia de Sequência do Ácido Nucleico , Dermatopatias Genéticas/genética , Polegar/cirurgia , Adulto JovemRESUMO
BACKGROUND: Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome is an autosomal dominant disorder. We report the first detailed case of hypoparathyroidism complicated by biliary atresia. CASE PRESENTATION: A 1-year-old Japanese girl was admitted to our hospital for living donor liver transplantation. She suffered from obstructive jaundice owing to biliary atresia. She also had persistent hypocalcemia. Despite oral calcium and abundant vitamin D supplementation, a laboratory test showed hypocalcemia (1.4 mmol/l) and hyperphosphatemia (2.6 mmol/l). The intact parathyroid hormone level was normal (66 ng/l) with severe vitamin D deficiency (25-hydroxy vitamin D: undetectable levels). There were no rachitic changes in metaphysis on X-rays. Her family history showed that her mother had sensorineural deafness, a low serum calcium level (2.1 mmol/l), hypoplastic left kidney, and a past history of an operation for right vesicoureteral reflux. We suspected that this patient and her mother have hypoparathyroidism, sensorineural deafness, and renal dysplasia syndrome. A heterozygous GATA3 gene mutation (c.736delGinsAT) was found in this patient and her mother, but not in her father. CONCLUSION: This familial case confirms the importance of family history in the diagnosis of HDR syndrome. Regardless of marked vitamin D deficiency, the complication of hypoparathyroidism prevented the onset of vitamin D deficiency rickets in our patient.
Assuntos
Anormalidades Múltiplas/diagnóstico , Atresia Biliar/diagnóstico , Perda Auditiva Neurossensorial/diagnóstico , Hipoparatireoidismo/diagnóstico , Nefrose/diagnóstico , Anormalidades Múltiplas/genética , Atresia Biliar/genética , Feminino , Mutação da Fase de Leitura , Fator de Transcrição GATA3/genética , Marcadores Genéticos , Perda Auditiva Neurossensorial/genética , Humanos , Hipoparatireoidismo/genética , Lactente , Nefrose/genéticaRESUMO
Cortical development is a complex process where a multitude of factors, including cadherins, plays an important role and where disruptions are known to have far reaching effects in neural development and cortical patterning. Cadherins play a central role in structural left-right differentiation during brain and body development, but their effect on a functional level remains elusive. We addressed this question by examining functional cerebral asymmetries in a patient with Van Maldergem Syndrome (VMS) (MIM#601390), which is caused by mutations in DCHS1-FAT4 cadherins, using a dichotic listening task. Using neurophysiological (EEG) data, we show that when key regulators during mammalian cerebral cortical development are disrupted due to DCHS1-FAT4 mutations, functional cerebral asymmetries are stronger. Basic perceptual processing of biaurally presented auditory stimuli was unaffected. This suggests that the strength and emergence of functional cerebral asymmetries is a direct function of proliferation and differentiation of neuronal stem cells. Moreover, these results support the recent assumption that the molecular mechanisms establishing early left-right differentiation are an important factor in the ontogenesis of functional lateralization.
Assuntos
Anormalidades Múltiplas/fisiopatologia , Anormalidades Múltiplas/psicologia , Caderinas/fisiologia , Córtex Cerebral/fisiopatologia , Anormalidades Craniofaciais/fisiopatologia , Anormalidades Craniofaciais/psicologia , Deformidades Congênitas do Pé/fisiopatologia , Deformidades Congênitas do Pé/psicologia , Deformidades Congênitas da Mão/fisiopatologia , Deformidades Congênitas da Mão/psicologia , Deficiência Intelectual/fisiopatologia , Deficiência Intelectual/psicologia , Instabilidade Articular/fisiopatologia , Instabilidade Articular/psicologia , Proteínas Supressoras de Tumor/fisiologia , Anormalidades Múltiplas/genética , Estimulação Acústica , Adolescente , Proteínas Relacionadas a Caderinas , Caderinas/genética , Criança , Anormalidades Craniofaciais/genética , Testes com Listas de Dissílabos , Eletroencefalografia , Potenciais Evocados Auditivos , Deformidades Congênitas do Pé/genética , Lateralidade Funcional , Deformidades Congênitas da Mão/genética , Humanos , Deficiência Intelectual/genética , Instabilidade Articular/genética , Masculino , Mutação , Proteínas Supressoras de Tumor/genéticaRESUMO
Growth hormone deficiency affects roughly between one in 3000 and one in 4000 children with most instances of growth hormone deficiency being idiopathic. Growth hormone deficiency can also be associated with genetic diseases or chromosome abnormalities. Association of growth hormone deficiency together with hypothalamic-pituitary axis malformation and Cat-Eye syndrome is a very rare condition. We report a family with two brothers presenting with growth delay due to a growth hormone deficiency associated with a polymalformation syndrome. They both displayed pre-auricular pits and tags, imperforate anus and Duane retraction syndrome. Both parents and a third unaffected son displayed normal growth pattern. Cerebral MRI showed a hypothalamic-pituitary axis malformation in the two affected brothers. Cytogenetic studies revealed a type I small supernumerary marker chromosome derived from chromosome 22 resulting in a tetrasomy 22pter-22q11.21 characteristic of the Cat-Eye syndrome. The small supernumerary marker chromosome was present in the two affected sons and the mother in a mosaic state. Patients with short stature due to growth hormone deficiency should be evaluated for chromosomal abnormality. Family study should not be underestimated.
Assuntos
Transtornos Cromossômicos/diagnóstico , Anormalidades do Olho/diagnóstico , Hormônio do Crescimento Humano/deficiência , Hipófise/anormalidades , Anormalidades Múltiplas/genética , Aneuploidia , Aberrações Cromossômicas , Transtornos Cromossômicos/tratamento farmacológico , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 22/genética , Anormalidades do Olho/tratamento farmacológico , Anormalidades do Olho/genética , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Hipotálamo/anormalidades , Hibridização in Situ Fluorescente , Recém-Nascido , Cariotipagem , MasculinoRESUMO
BACKGROUND: Kabuki syndrome is a multi-system disorder with peculiar facial features, and ophthalmic abnormalities are frequently involved. This case report of a child with Kabuki syndrome describes two new previously unreported ophthalmic conditions. CASE PRESENTATION: A 3-year-old Taiwanese boy with Kabuki syndrome had a short stature, spinal dysraphism, intellectual disability and typical facial features. Ophthalmic findings which have been previously reported in the literature and in this patient, included ptosis, esotropia, coloboma of the iris, retina, choroid and optic disc, and microcornea. The newly identified ophthalmic features in this patient included colobomatous microphthalmos and a dysplastic and elevated disc without central cupping. The genetic analysis identified an MLL2 gene mutation. CONCLUSION: The presentations of a dysplastic disc and colobomatous microphthalmia are rarely reported in patients with Kabuki syndrome, but these ophthalmic abnormalities may affect vision. Detailed ophthalmic evaluations in children with Kabuki syndrome are advised.
Assuntos
Anormalidades Múltiplas/diagnóstico , Coloboma/diagnóstico , Face/anormalidades , Doenças Hematológicas/diagnóstico , Microftalmia/diagnóstico , Disco Óptico/anormalidades , Doenças Vestibulares/diagnóstico , Anormalidades Múltiplas/genética , Pré-Escolar , Coloboma/genética , Proteínas de Ligação a DNA/genética , Doenças Hematológicas/genética , Humanos , Masculino , Microftalmia/genética , Mutação/genética , Proteínas de Neoplasias/genética , Tomografia Computadorizada por Raios X , Doenças Vestibulares/genéticaRESUMO
The 5q14.3 deletion syndrome is a rare chromosomal disorder characterized by moderate to severe intellectual disability, seizures and dysmorphic features. We report a 14-year-old boy with 5q14.3 deletion syndrome who carried a heterozygous deletion of the myocyte-specific enhancer factor 2c (MEF2C) gene. In addition to the typical neurodevelopmental features of 5q14.3 deletion syndrome, he showed recurrent hypoglycemia, appetite loss and hypothermia. Hormonal loading tests using insulin, arginine and growth hormone-releasing factor revealed that growth hormone was insufficiently released into serum in response to these stimuli, thus disclosing the hypothalamic dysfunction in the present case. To uncover the biological roles of MEF2C in the hypothalamus, we studied its expression in the postnatal mouse brain. Notably, neuropeptide Y (NPY)-positive interneurons in the hypothalamic arcuate nuclei highly expressed MEF2C. In contrast, the Rett syndrome-associated protein, Methyl-CpG binding Protein 2 (MECP2) was barely expressed in these neurons. MEF2C knockdown or overexpression experiments using Neuro2a cells revealed that MEF2C activated the endogenous transcription of NPY. Conversely, siRNA-mediated knockdown of MECP2 led to derepression of the Npy gene. These data support the concept that MEF2C and MECP2 share common molecular pathways regulating the homeostatic expression of NPY in the adult hypothalamus. We propose that individuals with 5q14.3 deletion syndrome may exhibit neuroendocrine phenotypes through the functional loss of MEF2C in the postnatal hypothalamus.
Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 5/genética , Deleção de Genes , Hipotálamo/metabolismo , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Animais , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/metabolismo , Feminino , Humanos , Hipoglicemia/diagnóstico , Hipoglicemia/genética , Hipotálamo/crescimento & desenvolvimento , Hipotermia/diagnóstico , Hipotermia/genética , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/metabolismo , Camundongos , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Fenótipo , SíndromeRESUMO
Maternal supplementation with folic acid is known to reduce the incidence of neural tube defects (NTDs) by as much as 70%. Despite the strong clinical link between folate and NTDs, the biochemical mechanisms through which folic acid acts during neural tube development remain undefined. The Mthfd1l gene encodes a mitochondrial monofunctional 10-formyl-tetrahydrofolate synthetase, termed MTHFD1L. This gene is expressed in adults and at all stages of mammalian embryogenesis with localized regions of higher expression along the neural tube, developing brain, craniofacial structures, limb buds, and tail bud. In both embryos and adults, MTHFD1L catalyzes the last step in the flow of one-carbon units from mitochondria to cytoplasm, producing formate from 10-formyl-THF. To investigate the role of mitochondrial formate production during embryonic development, we have analyzed Mthfd1l knockout mice. All embryos lacking Mthfd1l exhibit aberrant neural tube closure including craniorachischisis and exencephaly and/or a wavy neural tube. This fully penetrant folate-pathway mouse model does not require feeding a folate-deficient diet to cause this phenotype. Maternal supplementation with sodium formate decreases the incidence of NTDs and partially rescues the growth defect in embryos lacking Mthfd1l. These results reveal the critical role of mitochondrially derived formate in mammalian development, providing a mechanistic link between folic acid and NTDs. In light of previous studies linking a common splice variant in the human MTHFD1L gene with increased risk for NTDs, this mouse model provides a powerful system to help elucidate the specific metabolic mechanisms that underlie folate-associated birth defects, including NTDs.
Assuntos
Anormalidades Múltiplas/genética , Aminoidrolases/genética , Anormalidades Craniofaciais/genética , Desenvolvimento Embrionário/genética , Formiato-Tetra-Hidrofolato Ligase/genética , Metilenotetra-Hidrofolato Desidrogenase (NADP)/genética , Complexos Multienzimáticos/genética , Defeitos do Tubo Neural/genética , Aminoidrolases/deficiência , Animais , Primers do DNA/genética , Desenvolvimento Embrionário/efeitos dos fármacos , Formiato-Tetra-Hidrofolato Ligase/deficiência , Formiatos/administração & dosagem , Formiatos/farmacologia , Deleção de Genes , Genótipo , Immunoblotting , Redes e Vias Metabólicas/fisiologia , Metilenotetra-Hidrofolato Desidrogenase (NADP)/deficiência , Camundongos , Camundongos Knockout , Complexos Multienzimáticos/deficiência , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: COQ4 encodes a protein that organises the multienzyme complex for the synthesis of coenzyme Q(10) (CoQ(10)). A 3.9 Mb deletion of chromosome 9q34.13 was identified in a 3-year-old boy with mental retardation, encephalomyopathy and dysmorphic features. Because the deletion encompassed COQ4, the patient was screened for CoQ(10) deficiency. METHODS: A complete molecular and biochemical characterisation of the patient's fibroblasts and of a yeast model were performed. RESULTS: The study found reduced COQ4 expression (48% of controls), CoQ(10) content and biosynthetic rate (44% and 43% of controls), and activities of respiratory chain complex II+III. Cells displayed a growth defect that was corrected by the addition of CoQ(10) to the culture medium. Knockdown of COQ4 in HeLa cells also resulted in a reduction of CoQ(10.) Diploid yeast haploinsufficient for COQ4 displayed similar CoQ deficiency. Haploinsufficency of other genes involved in CoQ(10) biosynthesis does not cause CoQ deficiency, underscoring the critical role of COQ4. Oral CoQ(10) supplementation resulted in a significant improvement of neuromuscular symptoms, which reappeared after supplementation was temporarily discontinued. CONCLUSION: Mutations of COQ4 should be searched for in patients with CoQ(10) deficiency and encephalomyopathy; patients with genomic rearrangements involving COQ4 should be screened for CoQ(10) deficiency, as they could benefit from supplementation.
Assuntos
Anormalidades Múltiplas/genética , Haploinsuficiência , Proteínas Mitocondriais/genética , Ubiquinona/análogos & derivados , Anormalidades Múltiplas/tratamento farmacológico , Anormalidades Múltiplas/enzimologia , Proliferação de Células/efeitos dos fármacos , Pré-Escolar , Hibridização Genômica Comparativa , Transporte de Elétrons , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Fibroblastos/enzimologia , Fibroblastos/metabolismo , Células HeLa , Humanos , Masculino , Proteínas Mitocondriais/metabolismo , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/genética , Transcrição Gênica , Ubiquinona/deficiência , Ubiquinona/farmacologia , Ubiquinona/uso terapêuticoRESUMO
BACKGROUND AND OBJECTIVES: Matrix γ-carboxyglutamate protein (MGP), a vitamin K-dependent protein, is recognized as a potent local inhibitor of vascular calcification. Studying patients with Keutel syndrome (KS), a rare autosomal recessive disorder resulting from MGP mutations, provides an opportunity to investigate the functions of MGP. The purpose of this study was (i) to investigate the phenotype and the underlying MGP mutation of a newly identified KS patient, and (ii) to investigate MGP species and the effect of vitamin K supplements in KS patients. METHODS: The phenotype of a newly identified KS patient was characterized with specific attention to signs of vascular calcification. Genetic analysis of the MGP gene was performed. Circulating MGP species were quantified and the effect of vitamin K supplements on MGP carboxylation was studied. Finally, we performed immunohistochemical staining of tissues of the first KS patient originally described focusing on MGP species. RESULTS: We describe a novel homozygous MGP mutation (c.61+1G>A) in a newly identified KS patient. No signs of arterial calcification were found, in contrast to findings in MGP knockout mice. This patient is the first in whom circulating MGP species have been characterized, showing a high level of phosphorylated MGP and a low level of carboxylated MGP. Contrary to expectations, vitamin K supplements did not improve the circulating carboxylated mgp levels. phosphorylated mgp was also found to be present in the first ks patient originally described. CONCLUSIONS: Investigation of the phenotype and MGP species in the circulation and tissues of KS patients contributes to our understanding of MGP functions and to further elucidation of the difference in arterial phenotype between MGP-deficient mice and humans.
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Anormalidades Múltiplas/tratamento farmacológico , Calcinose/tratamento farmacológico , Proteínas de Ligação ao Cálcio/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/genética , Doenças das Cartilagens/tratamento farmacológico , Proteínas da Matriz Extracelular/efeitos dos fármacos , Proteínas da Matriz Extracelular/genética , Deformidades Congênitas da Mão/tratamento farmacológico , Estenose da Valva Pulmonar/tratamento farmacológico , Vitamina K/uso terapêutico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Artérias , Calcinose/genética , Calcinose/patologia , Proteínas de Ligação ao Cálcio/sangue , Doenças das Cartilagens/genética , Doenças das Cartilagens/patologia , Proteínas da Matriz Extracelular/sangue , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/patologia , Homozigoto , Humanos , Mutação , Estenose da Valva Pulmonar/genética , Estenose da Valva Pulmonar/patologia , Proteína de Matriz GlaRESUMO
BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is characterized by alveolar hypoventilation and autonomic dysregulation. PURPOSE: (1) To demonstrate the importance of PHOX2B testing in diagnosing and treating patients with CCHS, (2) to summarize recent advances in understanding how mutations in the PHOX2B gene lead to the CCHS phenotype, and (3) to provide an update on recommendations for diagnosis and treatment of patients with CCHS. METHODS: Committee members were invited on the basis of their expertise in CCHS and asked to review the current state of the science by independently completing literature searches. Consensus on recommendations was reached by agreement among members of the Committee. RESULTS: A review of pertinent literature allowed for the development of a document that summarizes recent advances in understanding CCHS and expert interpretation of the evidence for management of affected patients. CONCLUSIONS: A PHOX2B mutation is required to confirm the diagnosis of CCHS. Knowledge of the specific PHOX2B mutation aids in anticipating the CCHS phenotype severity. Parents of patients with CCHS should be tested for PHOX2B mutations. Maintaining a high index of suspicion in cases of unexplained alveolar hypoventilation will likely identify a higher incidence of milder cases of CCHS. Recommended management options aimed toward maximizing safety and optimizing neurocognitive outcome include: (1) biannual then annual in-hospital comprehensive evaluation with (i) physiologic studies during awake and asleep states to assess ventilatory needs during varying levels of activity and concentration, in all stages of sleep, with spontaneous breathing, and with artificial ventilation, and to assess ventilatory responsiveness to physiologic challenges while awake and asleep, (ii) 72-hour Holter monitoring, (iii) echocardiogram, (iv) evaluation of ANS dysregulation across all organ systems affected by the ANS, and (v) formal neurocognitive assessment; (2) barium enema or manometry and/or full thickness rectal biopsy for patients with a history of constipation; and (3) imaging for neural crest tumors in individuals at greatest risk based on PHOX2B mutation.
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/terapia , Hipoventilação/diagnóstico , Hipoventilação/terapia , Anormalidades Múltiplas/genética , Adulto , Criança , Pré-Escolar , Eletroforese em Gel de Poliacrilamida , Feminino , Predisposição Genética para Doença/genética , Proteínas de Homeodomínio/genética , Humanos , Hipoventilação/congênito , Lactente , Masculino , Mutação/genética , Fenótipo , Respiração Artificial/métodos , Sociedades Médicas , Síndrome , Traqueotomia/métodos , Fatores de Transcrição/genética , Estados UnidosRESUMO
BACKGROUND: Fetuses with increased nuchal translucency but apparently normal karyotypes may have small genetic defects that are undetectable by conventional cytogenetic studies. Microarray comparative genomic hybridization (array comparative genomic hybridization) may help prenatal diagnosis by revealing small genetic defects. CASE: A patient presented with a fetus with large nuchal translucency and ambiguous genitalia at 13 weeks of gestation. Conventional fetal karyotype by chorionic villus sampling was 46,XY,inv (1)(p31q42). The inversion was de novo. Further analysis by array comparative genomic hybridization revealed a single-copy ZEB2 gene deletion at 2q22.3 consistent with Mowat-Wilson syndrome. Ultrasonography at 17 weeks revealed a reduced nuchal fold of 5 mm. The patient decided to terminate the pregnancy, which was completed uneventfully at 17 weeks of gestation. CONCLUSION: Array comparative genomic hybridization is a useful complementary diagnostic tool in fetuses with increased nuchal translucency but apparently normal karyotypes.