RESUMEN
Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome are allelic, defined by germline PTEN mutations, and collectively referred to as PTEN hamartoma tumor syndrome. To date, there are no existing criteria based on large prospective patient cohorts to select patients for PTEN mutation testing. To address these issues, we conducted a multicenter prospective study in which 3042 probands satisfying relaxed CS clinical criteria were accrued. PTEN mutation scanning, including promoter and large deletion analysis, was performed for all subjects. Pathogenic mutations were identified in 290 individuals (9.5%). To evaluate clinical phenotype and PTEN genotype against protein expression, we performed immunoblotting (PTEN, P-AKT1, P-MAPK1/2) for a patient subset (n = 423). In order to obtain an individualized estimation of pretest probability of germline PTEN mutation, we developed an optimized clinical practice model to identify adult and pediatric patients. For adults, a semiquantitative score-the Cleveland Clinic (CC) score-resulted in a well-calibrated estimation of pretest probability of PTEN status. Overall, decreased PTEN protein expression correlated with PTEN mutation status; decreasing PTEN protein expression correlated with increasing CC score (p < 0.001), but not with the National Comprehensive Cancer Network (NCCN) criteria (p = 0.11). For pediatric patients, we identified highly sensitive criteria to guide PTEN mutation testing, with phenotypic features distinct from the adult setting. Our model improved sensitivity and positive predictive value for germline PTEN mutation relative to the NCCN 2010 criteria in both cohorts. We present the first evidence-based clinical practice model to select patients for genetics referral and PTEN mutation testing, further supported biologically by protein correlation.
Asunto(s)
Pruebas Genéticas , Síndrome de Hamartoma Múltiple/genética , Fosfohidrolasa PTEN/genética , Selección de Paciente , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Estudios de Cohortes , Femenino , Mutación de Línea Germinal , Síndrome de Hamartoma Múltiple/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Proteínas Quinasas Activadas por Mitógenos/análisis , Proteínas Quinasas Activadas por Mitógenos/genética , Modelos Genéticos , Fosfohidrolasa PTEN/metabolismo , Regiones Promotoras Genéticas/genética , Estudios Prospectivos , Proteínas Proto-Oncogénicas c-akt/análisis , Proteínas Proto-Oncogénicas c-akt/genética , Adulto JovenRESUMEN
BACKGROUND: Lichen planopilaris results in scaling, atrophy, and permanent alopecia with scarring and is thought to be autoimmune in origin. OBJECTIVE: To evaluate the clinical findings of patients with LPP so as to aid in the evaluation and diagnosis of the disease and to review the current effective therapies. METHODS: We reviewed the medical records of 29 patients with LPP that were seen in the Department of Dermatology at The Cleveland Clinic Foundation between 1992 and 2003. RESULTS: Good responses in the active perimeter were seen with topical steroids, intralesional steroids, and tetracycline and in the inactive end-stage with hair transplants and scalp reductions. LIMITATIONS: This study was limited by being retrospective in nature. CONCLUSION: Although topical high-potency and intralesional corticosteroids remain the mainstay for treatment of LPP, the use of tetracycline in this disease may be more helpful than once thought.