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Mosaicism in von Hippel-Lindau disease: an event important to recognize.

Santarpia L, Sarlis NJ, Santarpia M, Sherman SI, Trimarchi F, Benvenga S - J. Cell. Mol. Med. (2007 Nov-Dec)

Bottom Line: The mosaic subject was found to have a cyst of the kidney and an angioma of the glans penis and had had surgery for a mandibular cyst and epididymal cystadenomas.Our results strongly suggest a complete and extensive clinical examination in the parents of each patient affected by an apparently de novo VHL germline mutation.We recommend performing a mutation screening of both parents of a proband with techniques that permit detection of low percentages of mosaicism before concluding that the proband has a de novo VHL mutation.

View Article: PubMed Central - PubMed

Affiliation: Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA.

ABSTRACT
von Hippel-Lindau disease (VHL) is an autosomal dominant, familial neoplastic disorder with variable interfamilial and intrafamilial expression. VHL is characterized by pre-disposition to development of a combination of benign and malignant tumours affecting multiple organs. We provide molecular evidence of somatic mosaicism in nearly asymptomatic man whose daughter had VHL. The mosaic subject was found to have a cyst of the kidney and an angioma of the glans penis and had had surgery for a mandibular cyst and epididymal cystadenomas. Mosaicism could provide a genetic explanation for the clinical heterogeneity and variable severity of VHL. The real incidence of mosaicism is still unclear and the identification of mosaicism has important consequences in genetic counseling of VHL patients who appear to have de novo VHL mutations and should be considered when evaluating patients with isolated VHL-related tumours. Our results strongly suggest a complete and extensive clinical examination in the parents of each patient affected by an apparently de novo VHL germline mutation. We recommend performing a mutation screening of both parents of a proband with techniques that permit detection of low percentages of mosaicism before concluding that the proband has a de novo VHL mutation.

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Denaturing high-performance liquid chromatography (DHPLC) analysis of exon 3 of the von Hippel-Lindau disease (VHL) gene in all the family members. (A) DHPLC analysis of the PCR products of exon 3 of the VHL gene in the pro-band (DHPLC 3), her father (DHPLC 1), her mother (DHPLC 2) and her brother and sister (DHPLC 4, 5). In the first-degree pedigree of this family, the pro-band is indicated by number 03, while her father, mother, sister and brother are indicated by the numbers 01, 02, 04 and 05, respectively. The dashed symbol for the pro-band's father indicates genetic mosaicism. DNA was extracted from peripheral blood lymphocytes (PBLs) in all five individuals. DHPLC analysis of the pro-band's DNA shows an extra peak that is barely visible (but reproducibly so) in her father's DNA. (B) DHPLC analysis of DNA extracted from a normal control (NC) sample, the father's PBLs, and the father's oral mucosa (tissue 1), hair roots (tissue 2) and fibroblasts (tissue 3).
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fig02: Denaturing high-performance liquid chromatography (DHPLC) analysis of exon 3 of the von Hippel-Lindau disease (VHL) gene in all the family members. (A) DHPLC analysis of the PCR products of exon 3 of the VHL gene in the pro-band (DHPLC 3), her father (DHPLC 1), her mother (DHPLC 2) and her brother and sister (DHPLC 4, 5). In the first-degree pedigree of this family, the pro-band is indicated by number 03, while her father, mother, sister and brother are indicated by the numbers 01, 02, 04 and 05, respectively. The dashed symbol for the pro-band's father indicates genetic mosaicism. DNA was extracted from peripheral blood lymphocytes (PBLs) in all five individuals. DHPLC analysis of the pro-band's DNA shows an extra peak that is barely visible (but reproducibly so) in her father's DNA. (B) DHPLC analysis of DNA extracted from a normal control (NC) sample, the father's PBLs, and the father's oral mucosa (tissue 1), hair roots (tissue 2) and fibroblasts (tissue 3).

Mentions: The VHL gene sequence was altered in both the proband and her father, though to different extents in each. DHPLC analysis of VHL exon 3 PBLs DNA showed quantitative differences in the DNA elution profiles between daughter and father (Fig. 2A). This finding suggested a heterozygous mutation in both relatives and mosaicism in the father. To test for mosaicism, molecular analysis was performed on tissues of various embryonic origins. DNA exon 3 amplicons extracted from the father's buccal mucosa, hair roots, and skin fibroblasts showed different levels of intensity of the same altered DHPLC peaks, although the intensity of the peaks in these tissues was comparable to that seen in the PBL DNA (Fig. 2B).


Mosaicism in von Hippel-Lindau disease: an event important to recognize.

Santarpia L, Sarlis NJ, Santarpia M, Sherman SI, Trimarchi F, Benvenga S - J. Cell. Mol. Med. (2007 Nov-Dec)

Denaturing high-performance liquid chromatography (DHPLC) analysis of exon 3 of the von Hippel-Lindau disease (VHL) gene in all the family members. (A) DHPLC analysis of the PCR products of exon 3 of the VHL gene in the pro-band (DHPLC 3), her father (DHPLC 1), her mother (DHPLC 2) and her brother and sister (DHPLC 4, 5). In the first-degree pedigree of this family, the pro-band is indicated by number 03, while her father, mother, sister and brother are indicated by the numbers 01, 02, 04 and 05, respectively. The dashed symbol for the pro-band's father indicates genetic mosaicism. DNA was extracted from peripheral blood lymphocytes (PBLs) in all five individuals. DHPLC analysis of the pro-band's DNA shows an extra peak that is barely visible (but reproducibly so) in her father's DNA. (B) DHPLC analysis of DNA extracted from a normal control (NC) sample, the father's PBLs, and the father's oral mucosa (tissue 1), hair roots (tissue 2) and fibroblasts (tissue 3).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401302&req=5

fig02: Denaturing high-performance liquid chromatography (DHPLC) analysis of exon 3 of the von Hippel-Lindau disease (VHL) gene in all the family members. (A) DHPLC analysis of the PCR products of exon 3 of the VHL gene in the pro-band (DHPLC 3), her father (DHPLC 1), her mother (DHPLC 2) and her brother and sister (DHPLC 4, 5). In the first-degree pedigree of this family, the pro-band is indicated by number 03, while her father, mother, sister and brother are indicated by the numbers 01, 02, 04 and 05, respectively. The dashed symbol for the pro-band's father indicates genetic mosaicism. DNA was extracted from peripheral blood lymphocytes (PBLs) in all five individuals. DHPLC analysis of the pro-band's DNA shows an extra peak that is barely visible (but reproducibly so) in her father's DNA. (B) DHPLC analysis of DNA extracted from a normal control (NC) sample, the father's PBLs, and the father's oral mucosa (tissue 1), hair roots (tissue 2) and fibroblasts (tissue 3).
Mentions: The VHL gene sequence was altered in both the proband and her father, though to different extents in each. DHPLC analysis of VHL exon 3 PBLs DNA showed quantitative differences in the DNA elution profiles between daughter and father (Fig. 2A). This finding suggested a heterozygous mutation in both relatives and mosaicism in the father. To test for mosaicism, molecular analysis was performed on tissues of various embryonic origins. DNA exon 3 amplicons extracted from the father's buccal mucosa, hair roots, and skin fibroblasts showed different levels of intensity of the same altered DHPLC peaks, although the intensity of the peaks in these tissues was comparable to that seen in the PBL DNA (Fig. 2B).

Bottom Line: The mosaic subject was found to have a cyst of the kidney and an angioma of the glans penis and had had surgery for a mandibular cyst and epididymal cystadenomas.Our results strongly suggest a complete and extensive clinical examination in the parents of each patient affected by an apparently de novo VHL germline mutation.We recommend performing a mutation screening of both parents of a proband with techniques that permit detection of low percentages of mosaicism before concluding that the proband has a de novo VHL mutation.

View Article: PubMed Central - PubMed

Affiliation: Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA.

ABSTRACT
von Hippel-Lindau disease (VHL) is an autosomal dominant, familial neoplastic disorder with variable interfamilial and intrafamilial expression. VHL is characterized by pre-disposition to development of a combination of benign and malignant tumours affecting multiple organs. We provide molecular evidence of somatic mosaicism in nearly asymptomatic man whose daughter had VHL. The mosaic subject was found to have a cyst of the kidney and an angioma of the glans penis and had had surgery for a mandibular cyst and epididymal cystadenomas. Mosaicism could provide a genetic explanation for the clinical heterogeneity and variable severity of VHL. The real incidence of mosaicism is still unclear and the identification of mosaicism has important consequences in genetic counseling of VHL patients who appear to have de novo VHL mutations and should be considered when evaluating patients with isolated VHL-related tumours. Our results strongly suggest a complete and extensive clinical examination in the parents of each patient affected by an apparently de novo VHL germline mutation. We recommend performing a mutation screening of both parents of a proband with techniques that permit detection of low percentages of mosaicism before concluding that the proband has a de novo VHL mutation.

Show MeSH
Related in: MedlinePlus