Importance of molecular identification in type 1 VHL

MATHÓ, CECILIA; VIEITES, ANA; DIEZ, BLANCA; BARONTINI, MARTA; PENNISI, PATRICIA; SANSÓ, GABRIELA

Playa del Carmen

Congreso; XXIV Reunión Anual de la Sociedad Latinoamericana de Endocrinología Pediátrica (SLEP); 2014

Sociedad Latinoamericana de Endocrinología Pediátrica (SLEP)

Introduction: von Hippel-Lindau disease is an autosomal dominant cancer syndrome characterized by the development of SNC and retina hemangioblastomas, renal tumours or cysts, pheochromocytoma, pancreatic tumours or cysts and epididymal cysts. Its incidence is 1 in 35000 live births. The disease is classified into two subtypes according to the absence (type 1) or presence (type 2) of pheochromocytoma. In non-mosaic patients with classical VHL disease germline mutation detection is 95%.In 10-40% of patients with apparently sporadic hemangioblastomas VHL gene mutations have been detected. Recently, our laboratory has implemented the analysis of large deletions, that together with point mutations and small deletions analysis enables the complete study of the gene, and thus the molecular identification of type 1 VHL disease. Aim: To detect alterations in the VHL gene in patients with clinical diagnostic criteria of type 1 VHL or any of its characteristic manifestations. Patients: In this study 24 unrelated patients were included, ages 3-55 years (median=26.5), at clinical manifestation. 11 of them fulfilled the clinical diagnostic criteria of type 1 VHL, while 13 presented a single type 1 VHL typical tumour. Furthermore, 25 first grade relatives were studied. Methods: Genomic DNA was extracted from peripheral blood leukocytes. Complete genetic analysis of the VHL gene was performed using the PCR amplification techniques and automatic sequencing for the study of point mutations and small deletions. MLPA and UPQFM-PCR for the study of large deletions. In those with positive results, the study was extended to their first grade relatives. All patients signed an informed consent. Results: In 9/11 patients who fulfilled the clinical diagnostic criteria of type 1 VHL the following mutations we found: p.R161*(n=3), p.W88*(n=1), p.G144*(n=1), p.C162W (n=1), and the deletion IVS1_Ex3del (c.554-?_c.810+?) (n=1), previously described by other groups, and two novel mutations: p.Q73Pfs*58 (n=1), and c219_232del GGTCATCTTCTGCA (n=1). After the identification of index cases, the genetic study was extended to 25 relatives, of which 5 were positive for the corresponding mutation. In the group of patients with a single manifestation of disease (n=13), p.W88* mutation was detected in one patient with cerebellar hemangioblastoma. Conclusions: Our results underline the importance of the complete genetic study of the VHL gene for the confirmation of von Hippel-Lindau disease, not only in patients with clinical diagnostic criteria, but also in those patients presenting a single typical manifestation, enabling their correct diagnosis and follow-up. Two novel germline mutations were detected in VHL patients with no family history of VHL disease.