title: Genotype-phenotype analysis of von Hippel-Lindau syndrome in fifteen Indian families.
abstract: The general prevalence of the familial multi-organ tumor disorder, von Hippel-Lindau syndrome (VHL), was estimated to be 1 in 25-40,000 in western studies two decades back. Few studies were done in Indian sub-continent, amidst a surge in clinical reports on VHL specific manifestations. The syndrome is correlated with mutations of the gene VHL (located in Chr 3p25.3). We aimed to conduct a prospective case series describing phenotypic and genotypic characteristics in Indian population. The VHL-specific clinical and radiological features were collected from patients and family members. Genotypic changes such as deletion/duplication or point mutation in the VHL locus were identified using sequencing and MLPA. Thirty-one subjects, from fifteen families with diagnosed VHL, were included in the study. Multicystic pancreas was found in 71% (22/31), CNS hemangioblastoma in 68% (21/31), renal cell carcinoma and retinal angiomas in 23% (7/31) each, pheochromocytoma in 9.7% (3/31) of the population and endolymphatic sac tumor in one subject. Four families (9 subjects) had full length deletion of VHL, three families (4 subjects) had a deletion of exon 3, eight families (18 subjects) had different exonic, splice-site and intronic point mutations and one subject had a de novo in-frame indel in exon 1. Multicystic pancreas and CNS hemangioblastomas were the most common manifestations in our population. The phenotypic expression patterns in terms of tumorigenesis, tissue tropism and penetrance in comparison to the genotypic features were found to be different from previous correlative studies.
authors.affiliation: Department of Neurosurgery, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara P.O., Kochi, 682041, India.|Center for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara P.O., Kochi, 682041, India.
authors.forename: Narendranath
authors.initials: N
authors.lastname: Vikkath
authors.affiliation: Mazumdar-Shaw Centre for Translational Research, Mazumdar-Shaw Cancer Centre, Bangalore, India.
authors.forename: Sindhu
authors.initials: S
authors.lastname: Valiyaveedan
authors.affiliation: Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara P.O., Kochi, 682041, India.
authors.forename: Sheela
authors.initials: S
authors.lastname: Nampoothiri
authors.affiliation: Department of Ophthalmology, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara P.O., Kochi, 682041, India.
authors.forename: Natasha
authors.initials: N
authors.lastname: Radhakrishnan
authors.affiliation: Department of Ophthalmology, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara P.O., Kochi, 682041, India.
authors.forename: Gopal S
authors.initials: GS
authors.lastname: Pillai
authors.affiliation: Department of Endocrinology, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara P.O., Kochi, 682041, India.
authors.forename: Vasantha
authors.initials: V
authors.lastname: Nair
authors.affiliation: Department of Urology, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara P.O., Kochi, 682041, India.
authors.forename: Ginil Kumar
authors.initials: GK
authors.lastname: Pooleri
authors.affiliation: Department of Urology, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara P.O., Kochi, 682041, India.
authors.forename: Georgie
authors.initials: G
authors.lastname: Mathew
authors.affiliation: Center for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara P.O., Kochi, 682041, India.
authors.forename: Krishnakumar N
authors.initials: KN
authors.lastname: Menon
authors.affiliation: Department of Neurosurgery, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara P.O., Kochi, 682041, India. prasanthas@aims.amrita.edu.|Center for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara P.O., Kochi, 682041, India. prasanthas@aims.amrita.edu.
authors.forename: Prasanth S
authors.identifier: http://orcid.org/0000-0003-0888-8094
authors.initials: PS
authors.lastname: Ariyannur
authors.affiliation: Department of Neurosurgery, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara P.O., Kochi, 682041, India. brashok@aims.amrita.edu.|Center for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara P.O., Kochi, 682041, India. brashok@aims.amrita.edu.
authors.forename: Ashok B
authors.initials: AB
authors.lastname: Pillai
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D007194:India / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D010641:Phenotype; D011379:Prognosis; D011446:Prospective Studies; D017384:Sequence Deletion; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D055815:Young Adult; D006623:von Hippel-Lindau Disease / Q000453:epidemiology / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
keywords: Genotype–Phenotype correlation; India; Mutation; VHL; von Hippel–Lindau syndrome