VHL Germline Mutations in Argentinian Patients with Clinical Diagnoses or Single Typical Manifestations of Type 1 von Hippel-Lindau Disease.
OBJECTIVE
von Hippel-Lindau (VHL) disease is caused by mutations in the VHL tumor suppressor gene. As tumors that develop in the context of VHL also occur in a sporadic context, the frequency of this syndrome may be underestimated. Our aim was to identify VHL gene mutations in Argentinian patients who fulfilled the clinical criteria for type 1 VHL disease and in patients with VHL-associated manifestations that did not meet these criteria.


METHODS
We performed a retrospective cohort study, including patients who met current diagnostic criteria for type 1 VHL (Group 1, n = 19) and patients with VHL-associated manifestations that did not meet these criteria (Group 2, n = 21). Genomic DNA was extracted from peripheral blood leukocytes. Mutation analysis involved DNA sequencing, while large deletions were determined by universal primer quantitative fluorescent multiplex polymerase chain reaction (UPQFM-PCR) and multiplex ligation-dependent probe amplification (MLPA) analysis.


RESULTS
VHL mutations were detected in 16/19 (84.2%) patients in Group 1 and included: gross deletions (4/16); nonsense mutations (6/16); frameshift mutations (4/16); missense mutations (1/16); and splicing mutations (1/16). Three of these mutations were novel. No alterations were found in 3 of 19 VHL patients. In Group 2, one nonsense VHL mutation was detected in a young patient with a solitary central nervous system hemangioblastoma without familial history. A study of 30 first-degree relatives revealed four carriers with VHL mutations.


CONCLUSIONS
We found three novel mutations in the VHL gene in our population. Our results emphasize the importance of a complete genetic study of VHL to confirm type 1 VHL disease, not only in patients with clinical diagnostic criteria but also in those presenting a single typical manifestation.
1 Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE) CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez , CABA, Argentina .
Cecilia
C
Mathó
1 Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE) CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez , CABA, Argentina .
Gabriela
G
Sansó
2 Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia , CABA, Argentina .
Blanca
B
Diez
1 Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE) CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez , CABA, Argentina .
Marta
M
Barontini
1 Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE) CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez , CABA, Argentina .
Patricia A
PA
Pennisi
D000293:Adolescent; D000328:Adult; D000368:Aged; D001118:Argentina; D044466:Asian People / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D018095:Germ-Line Mutation; D018325:Hemangioblastoma / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D012189:Retrospective Studies; D017384:Sequence Deletion; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D006623:von Hippel-Lindau Disease / Q000235:genetics*
D018389:Codon, Nonsense; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
VHL gene; ccRCC; hemangioblastoma; retinal angioma; von Hippel-Lindau disease