Clinical and genetic investigation of a multi-generational Chinese family afflicted with Von Hippel-Lindau disease

Abstract

Background: Von Hippel-Lindau (VHL) disease is a hereditary tumor disorder caused by mutations or deletions of the VHL gene. Few studies have documented the clinical phenotype and genetic basis of the occurrence of VHL disease in China. This study armed to present clinical and genetic analyses of VHL within a five-generation VHL family from Northwestern China, and summarize the VHL mutations and clinical characteristics of Chinese families with VHL according to previous studies.

Methods: An epidemiological investigation of family members was done to collect the general information. A retrospective study of clinical VHL cases was launched to collect the relative clinical data. Genetic linkage and haplotype analysis were used to make sure the linkage of VHL to disease in this family. The VHL gene screening was performed by directly analyzing DNA sequence output. At last, we summarized the VHL gene mutation in China by the literature review.

Results: A five-generation North-western Chinese family afflicted with VHL disease was traced in this research. The family consisted of 38 living family members, of whom nine were affected. The individuals afflicted with VHL exhibited multi-organ tumors that included pheochromocytomas (8), central nervous system hemangioblastomas (3), pancreatic endocrine tumors (2), pancreatic cysts (3), renal cysts (4), and paragangliomas (2). A linkage analysis resulted in a high maximal LOD score of 8.26 (theta = 0.0) for the marker D3S1263, which is in the same chromosome region as VHL. Sequence analysis resulted in the identification of a functional C>T transition mutation (c. 499 C>T, p.R167W) located in exon 3 of the 167 th codon of VHL. All affected individuals shared this mutation, whereas the unaffected family members and an additional 100 unrelated healthy individuals did not. To date, 49 mutations have been associated with this disease in Chinese populations. The most frequent VHL mutations in China are p.S65 W, p.N78 S, p.R161Q and p.R167 W.

Conclusions: The results supported the notion that the genomic sequence that corresponds to the 167 th residue of VHL is a mutational hotspot. Further research is needed to clarify the molecular role of VHL in the development of organ-specific tumors.

Figure 1

Haplotypes of the Chinese family affected by Von Hippel-Lindau (VHL). The open and filled blackened symbols indicated unaffected and affected individuals, respectively. The squares and circles symbolized the males and females, respectively. The proband, IV-3, was indicated by an arrow. The haplotyping was conducted using three polymorphic microsatellite markers. The marker order was determined from the Marshfield map and the UCSC Human Genome database (February 2009). The dark boxes symbolized haplotypes that cosegregated with the affected individuals and suggested linkage of VHL to disease in this family. The boxes with slash symbolized the dead family members.

Figure 2

Representative clinical radiographic data from four patients with Von Hippel-Lindau. (a) Clinical radiograph from the proband (IV-3) who was 41-year-old woman. Contrast-enhanced computerized tomography (CT) scan showed masses in the right adrenal gland (red arrow) and pancreas (yellow arrow) that indicated a right pheochromocytoma and pancreatic endocrine tumors (PETs), respectively. (b) Clinical radiographs from a 37-year-old female patient (IV-5). Contrast-enhanced CT scan showed masses in the pancreas (yellow arrow), and post-operation pathology confirming the PETs. c Clinical radiographs from a 34-year-old female patient (IV-7). Magnetic resonance imaging (MRI) (T2W) showed lesions in the cerebellum that were indicative of hemangioblastoma (green arrow). (d) Clinical radiographs from a 24-year-old male patient (IV-11). Contrast-enhanced CT scan showed masses in the bilateral adrenal glands that were indicative of bilateral pheochromocytomas (red arrow).

Figure 3

Identification of the c. 499C > T (p.R167W) mutation in Von Hippel-Lindau (VHL) in a Chinese family with VHL disease. The DNA sequences of a normal family member (above) and the proband IV-3 (below) were shown. The sequence of codon 167, in which the mutation occurred, was marked with red arrow. The C to T change in the proband resulted in the substitution of an arginine residue (CGG) with a tryptophan residue (TGG) in the VHL protein.