RESUMO
Smith-Kingsmore syndrome (SKS) OMIM #616638, also known as MINDS syndrome (ORPHA 457485), is a rare autosomal dominant disorder reported so far in 23 patients. SKS is characterized by intellectual disability, macrocephaly/hemi/megalencephaly, and seizures. It is also associated with a pattern of facial dysmorphology and other non-neurological features. Germline or mosaic mutations of the mTOR gene have been detected in all patients. The mTOR gene is a key regulator of cell growth, cell proliferation, protein synthesis and synaptic plasticity, and the mTOR pathway (PI3K-AKT-mTOR) is highly regulated and critical for cell survival and apoptosis. Mutations in different genes in this pathway result in known rare diseases implicated in hemi/megalencephaly with epilepsy, as the tuberous sclerosis complex caused by mutations in TSC1 and TSC2, or the PIK3CA-related overgrowth spectrum (PROS). We here present 4 new cases of SKS, review all clinical and molecular aspects of this disorder, as well as some characteristics of the patients with only brain mTOR somatic mutations.
Assuntos
Encéfalo/metabolismo , Megalencefalia/genética , Síndrome de Smith-Lemli-Opitz/genética , Serina-Treonina Quinases TOR/genética , Adolescente , Encéfalo/fisiopatologia , Proliferação de Células/genética , Criança , Classe I de Fosfatidilinositol 3-Quinases/genética , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Megalencefalia/diagnóstico por imagem , Megalencefalia/fisiopatologia , Mutação , Plasticidade Neuronal/genética , Proteínas Proto-Oncogênicas c-akt/genética , Síndrome de Smith-Lemli-Opitz/diagnóstico por imagem , Síndrome de Smith-Lemli-Opitz/fisiopatologia , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genéticaRESUMO
Cryptorchidism is the most common congenital disorder in boys, but the cause for most cases remains unknown. Patients with Noonan Syndrome are characterized by a typical face, growth retardation, congenital heart defects, learning disabilities and cryptorchidism. Copy number variations of Ras/MAPK pathway genes are unusual in patients with several clinical features of Noonan Syndrome; however, they have not been studied in patients with only one feature of this condition, such as cryptorchidism. Our aim was to determine whether patients with isolated cryptorchidism exhibit Ras/MAPK pathway gene copy number variations (CNVs). Fifty-nine patients with isolated cryptorchidism and negative for mutations in genes associated with Noonan Syndrome were recruited. Determination of Ras/MAPK pathway gene CNVs was performed by Comparative Genome Hybridization array. A CNV was identified in two individuals, a ~175 kb microduplication at 3p25.2, partially including RAF1. A similar RAF1 microduplication has been observed in a patient with testicular aplasia. This suggests that some patients with isolated cryptorchidism may harbor Ras/MAPK pathway gene CNVs.
Assuntos
Criptorquidismo/genética , Dosagem de Genes , Sistema de Sinalização das MAP Quinases/genética , Adolescente , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Duplicação Gênica , Genes ras , Humanos , Lactente , Masculino , Linhagem , Testosterona/sangueAssuntos
Anormalidades Múltiplas/genética , Coloboma/genética , Cardiopatias Congênitas/genética , Mutação , Fatores de Processamento de RNA/genética , Proteínas Repressoras/genética , Anormalidades Múltiplas/metabolismo , Pré-Escolar , Coloboma/metabolismo , Feminino , Cardiopatias Congênitas/metabolismo , Humanos , Masculino , Análise de Sequência de DNARESUMO
INTRODUCTION: Cardiomyelic syndromes encompass congenital heart disease and skeletal malformations of the upper limbs and are related to mutations in transcription factors with T-Box domains. Holt-Oram syndrome is caused by a dominant mutation in the TBX5 gene that alters the three-dimensional structure of the protein and its DNA binding function. Several point mutations and deletions in TBX5 have been reported in patients with the Holt-Oram syndrome phenotype. PATIENTS AND METHODS: The proband was a boy with a large atrial septal defect ostium secundum type and a ventricular septal defect, diagnosed by clinical findings (heart murmur) and echocardiography. He also presented slightly hypoplastic thumbs with distal bilateral placement and an implantation index of 0.19 (compared with an average of 0.50 for his gestational age at birth). The boy was referred to the department of medical genetics to rule out 22q11.2 microdeletion syndrome. RESULTS: Karyotype and fluorescence in situ hybridization at locus D22S75 were both normal. Because of his clinical findings, molecular study for Holt-Oram syndrome was indicated, leading to the finding of a mutation at intron 7 of TBX5, probably producing a splicing alteration of the gene and resulting in a protein truncated at its C-terminal end. The proband's parents presented the wild type sequence of the gene, thus indicating that the mutation was produced de novo, although a possible germinal mosaicism in the parents could not be ruled out. CONCLUSIONS: Holt-Oram syndrome is the most frequent cause of cardiomyelic syndrome. All children with heart malformations and abnormalities of the upper limbs such as absent, hypoplastic, distally placed or triphalangic thumbs should undergo molecular studies for this syndrome.