RESUMEN
BACKGROUND: Cutaneous leiomyomatosis has been associated with multiple uterine myomas and, more recently, with germline heterozygous mutations of the FH gene and certain types of renal cancer. Despite the growing amount of knowledge concerning this genodermatosis, its clinical spectrum remains incompletely characterized. OBJECTIVE: We report the observation of a patient with multiple cutaneous and uterine leiomyomatosis (MCUL) with unusual gastrointestinal manifestations. METHODS AND RESULTS: A gastric leiomyoma was diagnosed on a 38-year-old female MCUL patient on endoscopy performed because of mild dyspepsia. Furthermore, routine colonoscopy disclosed hyperplastic polyposis. Genetic testing revealed a previously not reported mutation of the FH gene. CONCLUSION: Gastrointestinal lesions such as the present ones are frequently asymptomatic and probably underdiagnosed. As the phenotypical spectrum associated with mutations of the FH gene keeps expanding, clinicians should keep in mind that, besides renal cancer, other unexpected tumors could also arise in this setting.
Asunto(s)
Poliposis Adenomatosa del Colon/diagnóstico , Fumarato Hidratasa/genética , Leiomioma/diagnóstico , Leiomiomatosis/diagnóstico , Neoplasias Gástricas/diagnóstico , Poliposis Adenomatosa del Colon/genética , Poliposis Adenomatosa del Colon/cirugía , Adulto , Codón , Colonoscopía , Endoscopía Gastrointestinal , Femenino , Humanos , Leiomioma/genética , Leiomioma/cirugía , Leiomiomatosis/genética , Leiomiomatosis/cirugía , Mutación , Neoplasias Gástricas/genética , Neoplasias Gástricas/cirugíaRESUMEN
BACKGROUND: Mutations in the subunits B, C, and D of succinate dehydrogenase (SDH) mitochondrial complex II have been associated with the development of paragangliomas (PGL), gastrointestinal stromal tumors, papillary thyroid and renal carcinoma (SDHB), and testicular seminoma (SDHD). AIM: Our aim was to examine the possible causative link between SDHD inactivation and somatotropinoma. PATIENTS AND METHODS: A 37-yr-old male presented with acromegaly and hypertension. Other family members were found with PGL. Elevated plasma and urinary levels of catecholamines led to the identification of multiple PGL in the proband in the neck, thorax, and abdomen. Adrenalectomy was performed for bilateral pheochromocytomas (PHEO). A GH-secreting macroadenoma was also found and partially removed via transsphenoidal surgery (TTS). Genetic analysis revealed a novel SDHD mutation (c.298_301delACTC), leading to a frame shift and a premature stop codon at position 133 of the protein. Loss of heterozygosity for the SDHD genetic locus was shown in the GH-secreting adenoma. Down-regulation of SDHD protein in the GH-secreting adenoma by immunoblotting and immunohistochemistry was found. A literature search identified other cases of multiple PGL and/or PHEO in association with pituitary tumors. CONCLUSION: We describe the first kindred with a germline SDHD pathogenic mutation, inherited PGL, and acromegaly due to a GH-producing pituitary adenoma. SDHD loss of heterozygosity, down-regulation of protein in the GH-secreting adenoma, and decreased SDH enzymatic activity supports SDHD's involvement in the pituitary tumor formation in this patient. Older cases of multiple PGL and PHEO and pituitary tumors in the literature support a possible association between SDH defects and pituitary tumorigenesis.
Asunto(s)
Acromegalia/genética , Adenoma/genética , Hormona del Crecimiento/metabolismo , Hipertensión/genética , Neoplasias Hipofisarias/genética , Succinato Deshidrogenasa/genética , Acromegalia/metabolismo , Adenoma/metabolismo , Adulto , Codón sin Sentido , Mutación del Sistema de Lectura , Sitios Genéticos , Mutación de Línea Germinal , Humanos , Hipertensión/metabolismo , Pérdida de Heterocigocidad , Masculino , Neoplasias Hipofisarias/metabolismo , Succinato Deshidrogenasa/metabolismoRESUMEN
Gastrointestinal stromal tumors (GISTs) may be caused by germline mutations of the KIT and platelet-derived growth factor receptor-alpha (PDGFRA) genes and treated by Imatinib mesylate (STI571) or other protein tyrosine kinase inhibitors. However, not all GISTs harbor these genetic defects and several do not respond to STI571 suggesting that other molecular mechanisms may be implicated in GIST pathogenesis. In a subset of patients with GISTs, the lesions are associated with paragangliomas; the condition is familial and transmitted as an autosomal-dominant trait. We investigated 11 patients with the dyad of 'paraganglioma and gastric stromal sarcoma'; in eight (from seven unrelated families), the GISTs were caused by germline mutations of the genes encoding subunits B, C, or D (the SDHB, SDHC and SDHD genes, respectively). In this report, we present the molecular effects of these mutations on these genes and the clinical information on the patients. We conclude that succinate dehydrogenase deficiency may be the cause of a subgroup of GISTs and this offers a therapeutic target for GISTs that may not respond to STI571 and its analogs.
Asunto(s)
Tumores del Estroma Gastrointestinal/enzimología , Tumores del Estroma Gastrointestinal/genética , Mutación de Línea Germinal , Proteínas Hierro-Azufre/genética , Proteínas de la Membrana/genética , Síndromes Neoplásicos Hereditarios/enzimología , Síndromes Neoplásicos Hereditarios/genética , Paraganglioma/enzimología , Paraganglioma/genética , Succinato Deshidrogenasa/genética , Adolescente , Adulto , Alelos , Antineoplásicos/uso terapéutico , Secuencia de Bases , Benzamidas , Niño , Cartilla de ADN/genética , ADN de Neoplasias/genética , Femenino , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/patología , Genes Dominantes , Heterocigoto , Humanos , Mesilato de Imatinib , Pérdida de Heterocigocidad , Masculino , Síndromes Neoplásicos Hereditarios/tratamiento farmacológico , Síndromes Neoplásicos Hereditarios/patología , Paraganglioma/tratamiento farmacológico , Paraganglioma/patología , Piperazinas/uso terapéutico , Pirimidinas/uso terapéuticoRESUMEN
CONTEXT: Gastrointestinal stromal tumors (GISTs) may be caused by somatic or germline mutations of the KIT and PDGFRA genes, but most GISTs associated with neuroendocrine tumors (NETs) are not, suggesting that other molecular pathways are implicated in their pathogenesis. OBJECTIVE: In the course of investigating NETs and GIST genetics, we encountered a patient who had a unique combination of multiple fibrous polyps and lipomas of the small intestine and several gastric GISTs. DESIGN: The study included the clinical description of a unique patient, DNA sequencing of germline and tumor DNA, and comparative genomic hybridization (CGH) and allelic marker analysis of tumor DNA. RESULTS: The patient was found to carry a germline PDGFRA mutation (V561D) in the heterozygote state; it has only been seen rarely before and only in the somatic state in sporadic GISTs. CGH identified losses of chromosomal regions 1p33-36, 9q12-24, 11q13, and 16q; loss of the 14q region that is commonly lost in NETs and GISTs was shown by DNA marker analysis. These changes are likely to point to secondary and tertiary genetic hits involved in the formation of these rare tumors. CONCLUSIONS: Multiple GISTs and other tumors may be caused by germline PDGFRA gene mutations; the V561D mutation can occur in the germline state and lead to a syndrome that should not be confused with other genetic conditions associated with a predisposition to NETs and other tumors. A number of chromosomal loci are likely to be involved in the PDGFRA V561D-dependent tumorigenesis, as shown by CGH and other DNA analyses.
Asunto(s)
Tumores del Estroma Gastrointestinal/genética , Mutación de Línea Germinal , Neoplasias Primarias Múltiples/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Ácido Aspártico/genética , Secuencia de Bases , Análisis Mutacional de ADN , Femenino , Humanos , Persona de Mediana Edad , Valina/genéticaRESUMEN
BACKGROUND: Germline mutations of the SDHD, SDHB and SDHC genes, encoding three of the four subunits of succinate dehydrogenase, are a major cause of hereditary paraganglioma and pheochromocytoma, and demonstrate that these genes are classic tumor suppressors. Succinate dehydrogenase is a heterotetrameric protein complex and a component of both the Krebs cycle and the mitochondrial respiratory chain (succinate:ubiquinone oxidoreductase or complex II). METHODS: Using conformation sensitive gel electrophoresis (CSGE) and direct DNA sequencing to analyse genomic DNA from peripheral blood lymphocytes, here we describe the mutation analysis of the SDHB and SDHC genes in 37 patients with sporadic (i.e. no known family history) head and neck paraganglioma and five pheochromocytoma and/or paraganglioma families. RESULTS: Two sporadic patients were found to have a SDHB splice site mutation in intron 4, c.423+1G>A, which produces a mis-spliced transcript with a 54 nucleotide deletion, resulting in an 18 amino acid in-frame deletion. A third patient was found to carry the c.214C>T (p.Arg72Cys) missense mutation in exon 4 of SDHC, which is situated in a highly conserved protein motif that constitutes the quinone-binding site of the succinate: ubiquinone oxidoreductase (SQR) complex in E. coli. Together with our previous results, we found 27 germline mutations of SDH genes in 95 cases (28%) of sporadic head and neck paraganglioma. In addition all index patients of five families showing hereditary pheochromocytoma-paraganglioma were found to carry germline mutations of SDHB: four of which were novel, c.343C>T (p.Arg115X), c.141G>A (p.Trp47X), c.281G>A (p.Arg94Lys), and c.653G>C (p.Trp218Ser), and one reported previously, c.136C>T, p.Arg46X. CONCLUSION: In conclusion, these data indicate that germline mutations of SDHB and SDHC play a minor role in sporadic head and neck paraganglioma and further underline the importance of germline SDHB mutations in cases of familial pheochromocytoma-paraganglioma.