Abstract
Patients with typical features of neurofibromatosis type 1 (NF1) limited to a specific body segment are usually referred to as having “segmental NF1”, which is generally assumed to be the result of somatic mosaicism for a NF1 mutation. Mosaicism has also been demonstrated at the molecular level in some sporadic cases with phenotypically classic NF1. In the present report, we describe a patient with NF1 disease manifestations throughout the whole body, but leaving a few sharply delineated segments of the skin unaffected, suggestive of revertant mosaicism. A large intragenic deletion was found by mutation analysis using long-range RT-PCR. The intra-exonic breakpoints were characterized in exon 13 and exon 28, resulting in a deletion of 99,571 bp at the genomic level. The presence of two genetically distinct cell populations, confirming mosaicism for this NF1 mutation, was shown by analysis of several tissues. Revertant mosaicism was excluded by demonstrating heterozygosity for markers residing in the deletion region. The findings in this patient demonstrate two things: (1) although the entire body is affected, mosaicism can still be suspected at clinical examination and proven by DNA analysis and skin biopsies; (2) long-range RT-PCR is a feasible method for demonstrating large intragenic deletions in NF1.
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References
Ainsworth PJ, Chakraborty PK, Weksberg R (1997) Example of somatic mosaicism in a series of de novo neurofibromatosis type 1 cases due to a maternally derived deletion. Hum Mutat 9:452–457
Ariga T, Kondoh T, Yamaguchi K, Yamada M, Sasaki S, Nelson DL, Ikeda H, Kobayashi K, Moriuchi H, Sakiyama Y (2001) Spontaneous in vivo reversion of an inherited mutation in the Wiskott-Aldrich syndrome. J Immunol 166:5245–5249
Colman SD, Rasmussen SA, Ho VT, Abernathy CR, Wallace MR (1996) Somatic mosaicism in a patient with neurofibromatosis type 1. Am J Hum Genet 58:484–490
Darling TN, Yee C, Bauer JW, Hintner H, Yancey KB (1999) Revertant mosaicism: partial correction of a germ-line mutation in COL17A1 by a frame-restoring mutation. J Clin Invest 103:1371–1377
den Dunnen JT, Antonarakis SE (2001) Nomenclature for the description of human sequence variations. Hum Genet 109:121–124
Ellis NA, Ciocci S, German J (2001) Back mutation can produce phenotype reversion in Bloom syndrome somatic cells. Hum Genet 108:167–173
Friedman JM, Gutmann DH, Maccollin M, Riccardi VM (1999) Neurofibromatosis: phenotype, natural history, and pathogenesis, 3rd edn. Johns Hopkins University Press, Baltimore
Gregory JJ Jr, Wagner JE, Verlander PC, Levran O, Batish SD, Eide CR, Steffenhagen A, Hirsch B, Auerbach AD (2001) Somatic mosaicism in Fanconi anemia: evidence of genotypic reversion in lymphohematopoietic stem cells. Proc Natl Acad Sci USA 98:2532–2537
Happle R (1993) Mosaicism in human skin. Understanding the patterns and mechanisms. Arch Dermatol 129:1460–1470
Hirschhorn R, Yang DR, Israni A, Huie ML, Ownby DR (1994) Somatic mosaicism for a newly identified splice-site mutation in a patient with adenosine deaminase-deficient immunodeficiency and spontaneous clinical recovery. Am J Hum Genet 55:59–68
Huson SM, Ruggieri M (2000) The neurofibromatoses. In: Harper J, Oranje JM, Rose M (eds) Textbook of pediatric dermatology, vol 2. Blackwell Science, Oxford
Ingordo V, D’Andria G, Mendicini S, Grecucci M, Baglivo A (1995) Segmental neurofibromatosis: is it uncommon or underdiagnosed? Arch Dermatol 131:959–60
Jonkman MF (1999) Revertant mosaicism in human genetic disorders. Am J Med Genet 85:361–364
Jonkman MF, Scheffer H, Stulp R, Pas HH, Nijenhuis M, Heeres K, Owaribe K, Pulkkinen L, Uitto J (1997) Revertant mosaicism in epidermolysis bullosa caused by mitotic gene conversion. Cell 88:543–551
Kvittingen EA, Rootwelt H, Berger R, Brandtzaeg P (1994) Self-induced correction of the genetic defect in tyrosinemia type I. J Clin Invest 94:1657–1661
Lazaro C, Gaona A, Ravella A, Volpini V, Casals T, Fuentes JJ, Estivill X (1993a) Novel alleles, hemizygosity and deletions at an Alu-repeat within the neurofibromatosis type 1 (NF1) gene. Hum Mol Genet 2:725–730
Lazaro C, Gaona A, Xu G, Weiss R, Estivill X (1993b) A highly informative CA/GT repeat polymorphism in intron 38 of the human neurofibromatosis type 1 (NF1) gene. Hum Genet 92:429–430
Lazaro C, Gaona A, Estivill X (1994) Two CA/GT repeat polymorphisms in intron 27 of the human neurofibromatosis (NF1) gene. Hum Genet 93:351–352
Lo Ten Foe JR, Kwee ML, Rooimans MA, Oostra AB, Veerman AJ, van Weel M, Pauli RM, Shahidi NT, Dokal I, Roberts I, Altay C, Gluckman E, Gibson RA, Mathew CG, Arwert F, Joenje H (1997) Somatic mosaicism in Fanconi anemia: molecular basis and clinical significance. Eur J Hum Genet 5:137–148
Lopez Correa C, Brems H, Lazaro C, Estivill X, Clementi M, Mason S, Rutkowski JL, Marynen P, Legius E (1999) Molecular studies in 20 submicroscopic neurofibromatosis type 1 gene deletions. Hum Mutat 14:387–393
Messiaen LM, Callens T, Mortier G, Beysen D, Vandenbroucke I, Van Roy N, Speleman F, De Paepe A (2000) Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat 15:541–555
Povey S, Lovering R, Bruford E, Wright M, Lush M, Wain H (2001) The HUGO Gene Nomenclature Committee (HGNC). Hum Genet 109:678–680
Rasmussen SA, Colman SD, Ho VT, Abernathy CR, Arn PH, Weiss L, Schwartz C, Saul RA, Wallace MR (1998) Constitutional and mosaic large NF1 gene deletions in neurofibromatosis type 1. J Med Genet 35:468–471
Riva P, Corrado L, Natacci F, Castorina P, Wu BL, Schneider GH, Clementi M, Tenconi R, Korf BR, Larizza L (2000) NF1 microdeletion syndrome: refined FISH characterization of sporadic and familial deletions with locus-specific probes. Am J Hum Genet 66:100–109
Ruggieri M, Huson SM (2001) The clinical and diagnostic implications of mosaicism in the neurofibromatoses. Neurology 56:1433–1443
Ruggieri M, Polizzi A (2000) Segmental neurofibromatosis. J Neurosurg 93:530–532
Stephan V, Wahn V, Le Deist F, Dirksen U, Broker B, Muller-Fleckenstein I, Horneff G, Schroten H, Fischer A, de Saint Basile G (1996) Atypical X-linked severe combined immunodeficiency due to possible spontaneous reversion of the genetic defect in T cells. N Engl J Med 335:1563–1567
Streubel B, Latta E, Kehrer-Sawatzki H, Hoffmann GF, Fonatsch C, Rehder H (1999) Somatic mosaicism of a greater than 1.7-Mb deletion of genomic DNA involving the entire NF1 gene as verified by FISH: further evidence for a contiguous gene syndrome in 17q11.2. Am J Med Genet 87:12–16
Tinschert S, Naumann I, Stegmann E, Buske A, Kaufmann D, Thiel G, Jenne DE (2000) Segmental neurofibromatosis is caused by somatic mutation of the neurofibromatosis type 1 (NF1) gene. Eur J Hum Genet 8:455–459
Tonsgard JH, Yelavarthi KK, Cushner S, Short MP, Lindgren V (1997) Do NF1 gene deletions result in a characteristic phenotype? Am J Med Genet 73:80–86
Wada T, Schurman SH, Otsu M, Garabedian EK, Ochs HD, Nelson DL, Candotti F (2001) Somatic mosaicism in Wiskott-Aldrich syndrome suggests in vivo reversion by a DNA slippage mechanism. Proc Natl Acad Sci USA 98:8697–8702
Waisfisz Q, Morgan NV, Savino M, de Winter JP, van Berkel CG, Hoatlin ME, Ianzano L, Gibson RA, Arwert F, Savoia A, Mathew CG, Pronk JC, Joenje H (1999) Spontaneous functional correction of homozygous fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism. Nat Genet 22:379–383
Wolkenstein P, Mahmoudi A, Zeller J, Revuz J (1995) More on the frequency of segmental neurofibromatosis. Arch Dermatol 131:1465
Wu BL, Boles RG, Yaari H, Weremowicz S, Schneider GH, Korf BR (1997) Somatic mosaicism for deletion of the entire NF1 gene identified by FISH. Hum Genet 99:209–213
Xu GF, Nelson L, O’Connell P, White R (1991) An Alu polymorphism intragenic to the neurofibromatosis type 1 gene (NF1). Nucleic Acids Res 19:3764
Acknowledgements
The authors would like to thank M.F. Jonkman for insightful discussions. This work was supported by a grant of the Ghent University (BOF 01107799 and 011D3801 to I.V. and L.M.), by a grant of the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen KAN 1.5.135.03 (I.V. and L.M.) and by the Interuniversity Attraction Poles (IUAP nr. P5/25 (L.M.).
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Vandenbroucke, I., van Doorn, R., Callens, T. et al. Genetic and clinical mosaicism in a patient with neurofibromatosis type 1. Hum Genet 114, 284–290 (2004). https://doi.org/10.1007/s00439-003-1047-9
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DOI: https://doi.org/10.1007/s00439-003-1047-9