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Genotype–phenotype analysis of von Hippel–Lindau syndrome in fifteen Indian families

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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.

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Acknowledgments

The authors wish to acknowledge Dr. Catherine Stolle of Children’s Hospital of Philadelphia for her contributions on the design and analyses of VHL genotyping. The authors also wish to acknowledge Mrs. Krishna Chandra and Mrs. Gisha Girish for their contributions in the VHL clinic coordination and SciGenome Laboratories, Kakkanad Kochi India for their contributions in sequencing. The study was supported by Kerala State Council for Science, Technology and Environment (222/SRSLS/2004/CSTE) and Indian Council of Medical Research (54/18/2011-HUM/BMS), Internal seed grant from Amrita Institute of Medical Sciences and VHL Family Alliance to ABP. Research fellowship to NV was funded by Council of Scientific and Industrial Research, India (09/963(0009)/2011-EMR-I).

Conflict of interest

The authors declare that there is no conflict of interest.

Ethical standard

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Authors and Affiliations

  1. Department of Neurosurgery, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara P.O., Kochi, 682041, India

    Narendranath Vikkath, Prasanth S. Ariyannur & Ashok B. Pillai

  2. Mazumdar-Shaw Centre for Translational Research, Mazumdar-Shaw Cancer Centre, Bangalore, India

    Sindhu Valiyaveedan

  3. Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara P.O., Kochi, 682041, India

    Sheela Nampoothiri

  4. Department of Ophthalmology, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara P.O., Kochi, 682041, India

    Natasha Radhakrishnan & Gopal S. Pillai

  5. Department of Endocrinology, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara P.O., Kochi, 682041, India

    Vasantha Nair

  6. Department of Urology, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara P.O., Kochi, 682041, India

    Ginil Kumar Pooleri & Georgie Mathew

  7. Center for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara P.O., Kochi, 682041, India

    Narendranath Vikkath, Krishnakumar N. Menon, Prasanth S. Ariyannur & Ashok B. Pillai

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  1. Narendranath Vikkath
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  2. Sindhu Valiyaveedan
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Correspondence to Prasanth S. Ariyannur or Ashok B. Pillai.

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Vikkath, N., Valiyaveedan, S., Nampoothiri, S. et al. Genotype–phenotype analysis of von Hippel–Lindau syndrome in fifteen Indian families. Familial Cancer 14, 585–594 (2015). https://doi.org/10.1007/s10689-015-9806-z

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