RESUMO
Amish and Mennonite children with severe combined immune deficiency (SCID) often die without treatment as a result of delayed diagnoses and prohibitive costs of therapy. In this detailed case report, we describe the novel use of DNA microarrays to improve the diagnosis and management of an Amish infant with SCID. Using 10,000 single nucleotide polymorphism (SNP) genotypes from the patient, her parents, and seven siblings, we identified the recombinase activating genes for diagnostic sequencing, and then characterized a novel pathogenic variant in RAG1 (c.2974A>G). The same genotype data were used to identify a sibling stem cell donor who was haplo-identical at human leukocyte antigen (HLA) and blood group (ABO) loci. Autozygosity and linkage analysis of SNP genotypes within a family narrows the search for SCID candidate genes and provides a relatively simple and inexpensive way to identify potential tissue donors among biological siblings.
Assuntos
Antígenos HLA/genética , Teste de Histocompatibilidade , Técnicas de Diagnóstico Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Imunodeficiência Combinada Severa/genética , Transplante de Medula Óssea , Feminino , Genes RAG-1 , Genótipo , Haplótipos , Humanos , Lactente , Recém-Nascido , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Imunodeficiência Combinada Severa/fisiopatologia , Imunodeficiência Combinada Severa/terapiaRESUMO
The Clinic for Special Children (CSC) has integrated biochemical and molecular methods into a rural pediatric practice serving Old Order Amish and Mennonite (Plain) children. Among the Plain people, we have used single nucleotide polymorphism (SNP) microarrays to genetically map recessive disorders to large autozygous haplotype blocks (meanâ=â4.4 Mb) that contain many genes (meanâ=â79). For some, uninformative mapping or large gene lists preclude disease-gene identification by Sanger sequencing. Seven such conditions were selected for exome sequencing at the Broad Institute; all had been previously mapped at the CSC using low density SNP microarrays coupled with autozygosity and linkage analyses. Using between 1 and 5 patient samples per disorder, we identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. Our results reveal the power of coupling new genotyping technologies to population-specific genetic knowledge and robust clinical data.
Assuntos
Mapeamento Cromossômico/métodos , Exoma/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos , Aminoacil-tRNA Sintetases , Amish/genética , Proteína Adaptadora de Sinalização CRADD , Criança , Pré-Escolar , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Epilepsia/genética , Etnicidade/genética , Estudos de Associação Genética/métodos , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana Transportadoras/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Nucleares/genética , Transtornos Parkinsonianos/genética , Proteínas de Ligação a RNA , Receptores Virais/genética , Convulsões/genética , Síndromes de Usher/genéticaRESUMO
The dura is traditionally viewed as a supportive fibrous covering of the brain containing the dural venous sinuses but otherwise devoid of vessels and lacking any specific function. However, review of the embryology and anatomy reveals the dura to be a complex, vascularized and innervated structure, not a simple fibrous covering. The dura contains an inner vascular plexus that is larger in the infant than in the adult, and this plexus likely plays a role in CSF absorption. This role could be particularly important in the infant whose arachnoid granulations are not completely developed. Although subdural hemorrhage is frequently traumatic, there are nontraumatic conditions associated with subdural hemorrhage, and the inner dural plexus is a likely source of bleeding in these nontraumatic circumstances. This review outlines the development and age-specific vascularity of the dura and offers an alternative perspective on the role of the dura in homeostasis of the central nervous system.
Assuntos
Líquido Cefalorraquidiano/fisiologia , Hematoma Subdural/fisiopatologia , Meninges/anatomia & histologia , Criança , Pré-Escolar , Dura-Máter/anatomia & histologia , Humanos , Lactente , Recém-Nascido , Meninges/irrigação sanguínea , Meninges/embriologia , Meninges/fisiopatologia , Espaço Subdural/anatomia & histologiaRESUMO
Mucinous cystic neoplasms (MCNs) make up a morphologic family of similar appearing tumors arising in the ovary and various extraovarian sites, including the pancreas, hepatobiliary tract, paratesticular soft tissues, and mesentery. Other than the uncommon mucinous cystadenoma of the ovary presenting in adolescence, MCNs are rarely seen by the pediatric pathologist. The present case is a 5-year-old boy with an abdominal mass appearing to arise in the mesentery of the small intestine. Because of its unresectability, a generous biopsy was performed and disclosed a MCN with focal complex papillary architecture in the absence of appreciable cytologic atypia or invasion into the wall. Like other MCNs, this tumor had an inhibin-positive, ovarian-like stroma that was nonreactive for estrogen and progesterone receptors. Only 1 other case of a mesenteric MCN has been reported to date in a child and none in a male. The MCN of the mesentery joins other, somewhat more common cystic lesions of the omentum and mesentery presenting in childhood.