RESUMEN
PURPOSE: Von Hippel-Lindau (VHL) disease is an autosomal-dominantly inherited tumor predisposition syndrome. One of the most common tumors are central nervous system (CNS) hemangioblastomas. Recommendations on the initiation and continuation of the screening and surveillance program for CNS tumors in pediatric VHL patients are based on small case series and thus low evidence level. To derive more robust screening recommendations, we report on the largest monocentric pediatric cohort of VHL patients. METHODS: We performed a retrospective analysis on a pediatric cohort of 99 VHL patients consulted at our VHL center from 1992 to 2023. Clinical, surgical, genetic, and imaging data were collected and statistically analyzed. RESULTS: 42 patients (50% male) developed CNS hemangioblastomas, of whom 18 patients (56% male) underwent hemangioblastoma surgery (mean age at first surgery: 14.9 ± 1.9 years; range 10.2-17). The first asymptomatic patient was operated on at the age of 13.2 years due to tumor progress. Truncating VHL mutation carriers had a significantly higher manifestation rate (HR = 3.7, 95% CI: 1.9-7.4, p < 0.0001) and surgery rate (HR = 3.3, 95% CI: 1.2-8.9, p = 0.02) compared with missense mutation carriers. CONCLUSION: We recommend starting MRI imaging at the age of 12 years with examination intervals every (1-) 2 years depending on CNS involvement. Special attention should be paid to patients with truncating variants. Affected families should be educated regularly on potential tumor-associated symptoms to enable timely MRI imaging and eventually intervention, as CNS hemangioblastoma may develop before screening begins. GERMAN CLINICAL TRIALS REGISTER REGISTRATION NUMBER: DRKS00029553, date of registration 08/16/2022, retrospectively registered.
Asunto(s)
Hemangioblastoma , Enfermedad de von Hippel-Lindau , Humanos , Enfermedad de von Hippel-Lindau/genética , Enfermedad de von Hippel-Lindau/complicaciones , Hemangioblastoma/cirugía , Hemangioblastoma/genética , Hemangioblastoma/patología , Masculino , Femenino , Adolescente , Niño , Estudios Retrospectivos , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/cirugía , Neoplasias Cerebelosas/patología , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/cirugía , Neoplasias del Sistema Nervioso Central/patología , Estudios de Seguimiento , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genéticaRESUMEN
ABSTRACT: Renal hemangioblastoma (HB) is a rare subset of HBs arising outside of the central nervous system (CNS), with its molecular drivers remaining entirely unknown. There were no significant alterations detected in previous studies, including von Hippel-Lindau gene alterations, which are commonly associated with CNS-HB. This study aimed to determine the real molecular identity of renal HB and better understand its relationship with CNS-HB. A cohort of 10 renal HBs was submitted for next-generation sequencing technology. As a control, 5 classic CNS-HBs were similarly analyzed. Based on the molecular results, glycoprotein nonmetastatic B (GPNMB) immunohistochemistry was further performed in the cases of renal HB and CNS-HB. Mutational analysis demonstrated that all 10 renal HBs harbored somatic mutations in tuberous sclerosis complex 1 ( TSC1 , 5 cases), TSC2 (3 cases), and mammalian target of rapamycin (2 cases), with the majority classified as pathogenic or likely pathogenic. The CNS-HB cohort uniformly demonstrated somatic mutations in the von Hippel-Lindau gene. GPNMB was strong and diffuse in all 10 renal HBs and completely negative in CNS-HBs, reinforcing the molecular findings. Our study reveals a specific molecular hallmark in renal HB, characterized by recurrent TSC/mammalian target of rapamycin mutations, which defines it as a unique entity distinct from CNS-HB. This molecular finding potentially expands the therapeutic options for patients with renal HB. GPNMB can be considered for inclusion in immunohistochemical panels to improve renal HB identification.
Asunto(s)
Hemangioblastoma , Neoplasias Renales , Mutación , Serina-Treonina Quinasas TOR , Proteína 2 del Complejo de la Esclerosis Tuberosa , Humanos , Hemangioblastoma/genética , Hemangioblastoma/patología , Hemangioblastoma/química , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/química , Femenino , Masculino , Proteína 2 del Complejo de la Esclerosis Tuberosa/genética , Adulto , Persona de Mediana Edad , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Análisis Mutacional de ADN , Esclerosis Tuberosa/genética , Esclerosis Tuberosa/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Central/química , Inmunohistoquímica , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética , Anciano , Predisposición Genética a la Enfermedad , Adolescente , Fenotipo , Adulto Joven , Niño , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
Von Hippel Lindau disease is a hereditary syndrome characterized by the appearance of benign and malignant tumors in different organs. Its incidence is 1 case per 36000 born alive. We report a family with the disease. The index case was a male with a bilateral pheochromocytoma and cerebelar and retinal hemagioblastomas that had a sudden death due to a cerebrovascular accident at the age of 52 years. One sibling had central nervous system and retinal hemangioblastomas and other was operated for an unilateral pheochromocytoma. Both siblings had the R167Q VHL mutation of the syndrome. Other family members did not have the mutation.
Asunto(s)
Humanos , Masculino , Femenino , Adolescente , Adulto , Enfermedad de von Hippel-Lindau/diagnóstico , Enfermedad de von Hippel-Lindau/genética , Enfermedad de von Hippel-Lindau/complicaciones , Feocromocitoma/genética , Predisposición Genética a la Enfermedad , Hemangioblastoma/genética , Mutación , Neoplasias Cerebelosas/genética , Neoplasias de la Retina/genética , Neoplasias de las Glándulas Suprarrenales/genética , Linaje , Proteína Supresora de Tumores del Síndrome de Von Hippel-LindauRESUMEN
O objetivo dessa apresentação é a discussão do caso de uma paciente com a Síndrome de von Hippel-Lindau, sob os seus diferentes aspectos clínicos, laboratoriais, radiológicos e terapêuticos. A seguir será apresentado o estudo genético realizado na paciente e serão discutidas a principais alterações gênicas envolvidas no aparecimento dessa síndrome clínica.