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1.
Eur J Med Genet ; 66(8): 104798, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37307869

RESUMO

PTEN hamartoma tumor syndromes (PHTS) comprise hamartomatous overgrowth syndromes associated with PTEN germline mutations. In this case report, we describe a variant identified by next generation sequencing causing peculiar dermatological and skeletal features not yet described in the literature. Being cognizant of such unique disease presentations in PHTS, that manifest at a very young age, could help facilitate a timely diagnosis by clinicians and thus the early education of families on active cancer surveillance. This specific case also strengthens the concept of variable presentation of PHTS and the need for genetic testing early on, even if not all criteria for PHTS are met for a formal clinical diagnosis.


Assuntos
Síndrome do Hamartoma Múltiplo , Humanos , Síndrome do Hamartoma Múltiplo/diagnóstico , Síndrome do Hamartoma Múltiplo/genética , Síndrome do Hamartoma Múltiplo/patologia , PTEN Fosfo-Hidrolase/genética , Testes Genéticos , Mutação em Linhagem Germinativa
2.
Eur J Med Genet ; 57(11-12): 617-20, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25311905

RESUMO

Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant bone dysplasia that until now has only been reported in French Canadian individuals. We have recently identified an intragenic duplication in RUNX2, encompassing exons 3 to 5, as a cause of MDMHB in French Canadian families. Here we describe a 20-year-old Finnish woman who had typical clinical and radiological signs of MDMHB, the first reported individual with MDMHB who is not of French-Canadian origin. Copy number variant assays based on quantitative PCR of genomic DNA showed the presence of three copies within a part of RUNX2. Sequencing RUNX2 cDNA from the skin fibroblasts revealed a duplication of exons 3 to 5. The results demonstrated that the intronic breakpoints of the duplication differed from those previously found in the French Canadian family, but that the consequences on RUNX2 transcript were identical. These findings demonstrate that the MDMHB phenotype results from an intragenic duplication of RUNX2 exons 3 to 5 also outside of the community where the disorder was first identified.


Assuntos
Anormalidades Múltiplas/diagnóstico por imagem , Braquidactilia/diagnóstico por imagem , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Dedos/anormalidades , Maxila/anormalidades , Osteocondrodisplasias/diagnóstico por imagem , Anormalidades Múltiplas/genética , Braquidactilia/genética , Células Cultivadas , Fácies , Feminino , Dedos/diagnóstico por imagem , Finlândia , Duplicação Gênica , Estudos de Associação Genética , Humanos , Maxila/diagnóstico por imagem , Osteocondrodisplasias/genética , Radiografia , Adulto Jovem
3.
Pediatr Endocrinol Rev ; 10 Suppl 2: 397-405, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23858623

RESUMO

Osteogenesis imperfecta (OI), an inherited skeletal disorder characterized by low bone mass, bone fragility, and often short stature. The clinical severity varies widely from being nearly asymptomatic with a mild predisposition to fractures, normal stature and normal lifespan being to profoundly disabling and even lethal. Extra skeletal manifestations may include blue-grey sclera and dental abnormalities. Initially, the classification of OI into four types was based on clinical findings, but more recently additional types OI (types V-XI) have been ascertained, based on the identification of different mutations. While this classification is somewhat controversial, it is described in this article. The treatment of patients with OI is based on the nature and severity of symptoms. The goal of therapy is to prevent fractures and disability, improve function and quality of life. A multidisciplinary approach is needed, and treatment options include medication such as bisphosphonates, surgery, and rehabilitation. Investigations continue to explore gene and cell therapies that may be developed in the future.


Assuntos
Fraturas Ósseas/prevenção & controle , Osteogênese Imperfeita/classificação , Humanos , Osteogênese Imperfeita/fisiopatologia , Osteogênese Imperfeita/terapia
4.
Am J Hum Genet ; 92(2): 252-8, 2013 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-23290074

RESUMO

Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant bone dysplasia characterized by metaphyseal flaring of long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, variable brachydactyly, and dystrophic teeth. We performed genome-wide SNP genotyping in five affected and four unaffected members of an extended family with MDMHB. Analysis for copy-number variations revealed that a 105 kb duplication within RUNX2 segregated with the MDMHB phenotype in a region with maximum linkage. Real-time PCR for copy-number variation in genomic DNA in eight samples, as well as sequence analysis of fibroblast cDNA from one subject with MDMHB confirmed that affected family members were heterozygous for the presence of an intragenic duplication encompassing exons 3 to 5 of RUNX2. These three exons code for the Q/A domain and the functionally essential DNA-binding runt domain of RUNX2. Transfection studies with murine Runx2 cDNA showed that cellular levels of mutated RUNX2 were markedly higher than those of wild-type RUNX2, suggesting that the RUNX2 duplication found in individuals with MDMHB leads to a gain of function. Until now, only loss-of-function mutations have been detected in RUNX2; the present report associates an apparent gain-of-function alteration of RUNX2 function with a distinct rare disease.


Assuntos
Braquidactilia/genética , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Duplicação Gênica/genética , Osteocondrodisplasias/genética , Adolescente , Braquidactilia/diagnóstico por imagem , Cromossomos Humanos Par 6/genética , Éxons/genética , Fácies , Família , Feminino , Dedos/anormalidades , Dedos/diagnóstico por imagem , Genoma Humano/genética , Humanos , Masculino , Maxila/anormalidades , Maxila/diagnóstico por imagem , Osteocondrodisplasias/diagnóstico por imagem , Linhagem , Radiografia , Adulto Jovem
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