RESUMEN
BACKGROUND & AIMS: Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain tumors. There is no satisfactory method for diagnosis of CMMRD because screens for mutations in MMR genes are noninformative for 30% of patients. MMR-deficient cancer cells are resistant to genotoxic agents and have microsatellite instability (MSI), due to accumulation of errors in repetitive DNA sequences. We investigated whether these features could be used to identify patients with CMMRD. METHODS: We examined MSI by PCR analysis and tolerance to methylating or thiopurine agents (functional characteristics of MMR-deficient tumor cells) in lymphoblastoid cells (LCs) from 3 patients with CMMRD and 5 individuals with MMR-proficient LCs (controls). Using these assays, we defined experimental parameters that allowed discrimination of a series of 14 patients with CMMRD from 52 controls (training set). We then used the same parameters to assess 23 patients with clinical but not genetic features of CMMRD. RESULTS: In the training set, we identified parameters, based on MSI and LC tolerance to methylation, that detected patients with CMMRD vs controls with 100% sensitivity and 100% specificity. Among 23 patients suspected of having CMMRD, 6 had MSI and LC tolerance to methylation (CMMRD highly probable), 15 had neither MSI nor LC tolerance to methylation (unlikely to have CMMRD), and 2 were considered doubtful for CMMRD based on having only 1 of the 2 features. CONCLUSION: The presence of MSI and tolerance to methylation in LCs identified patients with CMMRD with 100% sensitivity and specificity. These features could be used in diagnosis of patients.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales/diagnóstico , Resistencia a Antineoplásicos , Pruebas Genéticas , Mutación de Línea Germinal , Linfocitos/efectos de los fármacos , Inestabilidad de Microsatélites , Síndromes Neoplásicos Hereditarios/diagnóstico , Proteínas Adaptadoras Transductoras de Señales/genética , Adenosina Trifosfatasas/genética , Adulto , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Células CACO-2 , Estudios de Casos y Controles , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/tratamiento farmacológico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/metabolismo , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Análisis Mutacional de ADN , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Células HCT116 , Herencia , Humanos , Linfocitos/metabolismo , Masculino , Metilación , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Reacción en Cadena de la Polimerasa Multiplex , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS/genética , Síndromes Neoplásicos Hereditarios/tratamiento farmacológico , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/metabolismo , Síndromes Neoplásicos Hereditarios/patología , Proteínas Nucleares/genética , Fenotipo , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Transfección , Adulto JovenRESUMEN
Erythromelalgia is a rare syndrome with a generally unknown etiology. Whether primary or secondary, this condition is characterized by paroxysmal episodes of erythema, pain, and heat in the extremities. We report two cases of erythromelalgia occurring after the initiation of treatment with infliximab. The first case involves a 38-year-old patient who had been followed since August 2022 for ileocolonic Crohn's disease classified as A2L3B3 according to the Montreal classification, which was resistant to treatment and required infliximab therapy. Two months after the first infusion of infliximab, the patient developed symptoms of erythromelalgia. After ruling out other potential causes through an etiological assessment and conducting a pharmacological investigation, infliximab was considered the most likely cause. Infliximab was discontinued, and symptomatic treatment was initiated, including vascular laser sessions. The patient showed significant clinical improvement. In the second case, a 16-year-old patient with ileocolonic Crohn's disease classified as A1L3B3 according to the Montreal classification was treated with ileocecal resection and received an infusion of infliximab. Sixteen days after the second infusion, she developed clinical symptoms of erythromelalgia. The etiological assessment was inconclusive. Due to a strong suspicion of erythromelalgia secondary to tumor necrosis factor (TNF) alpha inhibitor therapy, infliximab was replaced with ustekinumab. The patient also received symptomatic treatment, and her clinical condition improved, marked by the disappearance of pain.
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Biermer's disease (BD) or pernicious anemia (PA) is an autoimmune atrophic gastritis characterized by the absence of intrinsic factor (IF) secretion, leading to malabsorption of vitamin B12 in the ileum. Its clinical manifestations are primarily hematological, with neuropsychiatric and cardiovascular manifestations being less common. We present the case of a patient with PA diagnosed based on neurological and cardiovascular complications. The patient, a 56-year-old man with no specific medical history, presented with an episode of melena without other associated digestive symptoms. He also complained of memory and gait disturbances. Clinical examination revealed a cerebellar ataxia with impaired proprioceptive and vibratory sensitivity, and a swollen and red right lower limb with a positive Homan sign. The blood count showed macrocytic anemia. Gastroscopy revealed flattened fundic folds resembling a fundus appearance, and histopathological examination confirmed fundic atrophic gastritis with pseudopyloric metaplasia and lymphoplasmacytic infiltration. Anti-intrinsic factor antibodies were positive, while anti-parietal cell antibodies were negative. Vitamin B12 levels were severely low, and vitamin B9 levels were normal. TSH and HbA1c levels were within normal ranges. The abdominal CT scan showed no abnormalities. Lower limb Doppler ultrasound confirmed the diagnosis of deep vein thrombosis (DVT). Cardiac evaluation revealed sinus bradycardia suggestive of secondary dysautonomia. Therapeutically, the patient was started on vitamin B12 supplementation and anticoagulant therapy for DVT, resulting in a good clinical and biological outcome.
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According to the World Health Organization (WHO), tuberculosis (TB) is the 13th cause of death worldwide and the second infectious killer after HIV. It is an endemic disease in Morocco. Isolated appendicular TB is an uncommon form of extrapulmonary TB. We report a case of a 26-year-old woman admitted for acute abdominal pain in the right iliac fossa with fever, vomiting, and diarrhea. Physical examination and abdominal ultrasound confirmed appendicitis. Surgery was performed and revealed on histopathological examination of the resected appendix the diagnosis of tubercular appendicitis. The patient was initiated on the conventional antitubercular regimen for six months and would be followed up appropriately. This case report highlights the importance of histopathological examination of appendicectomy specimens in order to diagnose rare diseases such as primary TB of the appendix.