Neurofibromatosis in Monozygotic Twins: <i>A Case Report</i>

Åkesson, Hans Olof; Axelsson, Rolf; Samuelsson, Birgitta

doi:10.1017/s0001566000005109

Cited by 9 publications

(11 citation statements)

References 6 publications

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“…Whole body MRI of the remaining twins could be helpful in determining if paraspinal tumors exist in other twin pairs and if they are concordant. Malignancy, particularly MPNST, was discordant in one of our teenaged twin pairs (the pair with extensive paraspinal tumors) as well as one pair reported in the literature [Akesson et al, 1983], again supporting a random second hit event hypothesis. However, the sample size is small and it is therefore difficult to draw conclusions.…”

Section: Discussionsupporting

confidence: 80%

“…The skewed sex ratio with 90% female in our report is likely due to the small sample size since this ratio has not been previously described in twins with NF1. In reviewing the published cases where gender was reported, 6 of 13 pairs (46%) of MZ NF1 twins were of male gender, not different from the population ratio [Vaughn et al, 1981;Cartwright, 1982;Akesson et al, 1983;Crawford and Buckler, 1983;Pascual-Castroviejo et al, 1988;Craigen and Clarke, 1995;Kelly et al, 1998;Koul et al, 2000;Tubridy et al, 2001;Payne et al, 2003;Lubinsky, 2006;Kaplan et al, 2010]. Fifty percent of twin pairs in our study were de novo mutations, as expected with the known new mutation rate of the NF1 gene.…”

Section: Discussionsupporting

confidence: 72%

“…Reports of discordance include plexiform neurofibromas, cutaneous and mesenteric neurofibromas [Bauer et al, 1988;Easton et al, 1993;Tubridy et al, 2001;Payne et al, 2003;Lubinsky, 2006], MPNST [Akesson et al, 1983], scoliosis [Easton et al, 1993], OPG [Vaughn et al, 1981;Akesson et al, 1983;Kelly et al, 1998;Tubridy et al, 2001], congenital glaucoma [Payne et al, 2003], and ulnar pseudarthrosis [Craigen and Clarke, 1995]. Additionally, of twins with OPG [Crawford and Buckler, 1983] or plexiform neurofibromas [Akesson et al, 1983], there have been discrepancies between symptomatic and asymptomatic tumors. Of interest is a set of MZ twins reported by Kaplan et al [2010] who were discordant for clinical diagnosis of NF1.…”

Section: Discussionmentioning

confidence: 99%

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Variable expression of neurofibromatosis 1 in monozygotic twins

Rieley

Stevenson

Viskochil

et al. 2011

American J of Med Genetics Pt A

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Neurofibromatosis 1 (NF1) is a common autosomal dominant disorder with high penetrance but extreme variability of expression. Monozygotic (MZ) twins with NF1 who have phenotypic discordances are a useful tool in evaluating which traits are influenced by non-hereditary influences such as second hit somatic events, environmental agents, epigenetic modification, or post-zygotic mutations. We evaluated nine sets of MZ twins and one set of MZ triplets, ages 4-18 years, for NF1 features and calculated probandwise concordance (P C ) for each feature. MZ twins were highly concordant in numbers of cafe-au-lait spots (P C ¼ 0.89) and cutaneous neurofibromas. IQ scores were within 10 points for all twin pairs tested, and similar patterns of learning disabilities and speech disorders were observed. Twin pairs showed significant discordance for tumors, particularly plexiform neurofibromas (P C ¼ 0.40) and malignant peripheral nerves sheath tumors (MPNST), as expected if post-natal second -hit events were contributing to these features. One set of twins was concordant for multiple, large paraspinal neurofibromas, suggesting that there may be more hereditary factors involved in production of paraspinal neurofibromas. Four sets were concordant for pectus deformities of the chest (P C ¼ 0.80). Three sets of twins were discordant for scoliosis (P C ¼ 0.40); an additional set was concordant for scoliosis but differed in presence of dystrophic features and need for surgery. Our data suggest there are additional non-hereditary factors modifying the NF1 phenotype and causing discordancies between MZ twins. Future studies may focus on differences in epigenetic changes or somatic mosaicism which have been documented for other disease genes in MZ twins.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

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Variable expression of neurofibromatosis 1 in monozygotic twins

Rieley

Stevenson

Viskochil

et al. 2011

American J of Med Genetics Pt A

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“…Twin studies have historically been a valuable tool for studying genetic disorders. The literature reports at least 30 pairs of proven MZ twins with NF1 [Brady, ; Vaughn et al, ; Cartwright, ; Akesson et al, ; Crawford and Buckler, ; Bauer et al, ; Pascual‐Castroviejo et al, ; Craigen and Clarke, ; Kelly et al, ; Tubridy et al, ; Koul et al, ; Payne et al, ; Lubinski, ; Sabbagh et al, ; Rieley et al, ]. In a population of 175 individuals from 48 families with NF1, Easton et al [1993] found that phenotypic features varied to a greater degree with increasing distance from a proband, with six pairs of MZ twins having the closest agreement in traits such as presence of neurofibromas, head circumference and learning disabilities, compared to more distant relatives with NF1.…”

Section: Introductionmentioning

confidence: 99%

Analysis of copy number variants in 11 pairs of monozygotic twins with neurofibromatosis type 1

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Smolarek

Martin

et al. 2016

American J of Med Genetics Pt A

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Phenotypic variability among individuals with neurofibromatosis type 1 (NF1) has long been a challenge for clinicians and an enigma for researchers. Members of the same family and even identical twins with NF1 often demonstrate variable disease expression. Many mechanisms for this variability have been proposed. We have performed an exploratory study of copy number variants (CNVs) as a possible source of phenotypic variability in NF1. We enrolled 11 pairs of monozygotic (MZ) twins with NF1 and their parents, catalogued their clinical characteristics, and utilized a single nucleotide polymorphism (SNP) microarray to identify CNVs in blood and saliva. The 11 twin pairs showed high concordance for presence and number of café-au-lait spots, cutaneous neurofibromas, IQ, and ADHD. They were more likely to be discordant for optic pathway glioma, plexiform neurofibromas, skeletal manifestations, and malignancy. Microarray analysis identified a total of 81 CNVs meeting our conservative criteria, 37 of which overlap known genes. Of interest, three CNVs were previously unreported. Microarray analysis failed to ascertain any CNV differences within twin pairs, between twins and parents, or between tissues in any one individual. Results of this small pilot study did not demonstrate any de novo CNV events in our MZ twin pairs, nor were de novo CNVs overrepresented in these individuals with NF1. A much larger sample size would be needed to form any conclusions about the role of CNVs in NF1 variable expressivity. Alternative explanations for discordant phenotypes include epigenetic changes, smaller genetic alterations, or environmental factors. © 2016 Wiley Periodicals, Inc.

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“…In principle, this concordance is readily explicable, not simply in terms of the presence of identical mutations in the MZ, but also as a consequence of the virtual genetic identity of the MZ genome-wide, and their shared experience of very similar pre-and peri-natal environments. Cases of MZ with NF1 who differ quite markedly with respect to the clinical manifestations of the disease have however also been reported [Akesson et al, 1983;Bauer et al, 1988;Kelly et al, 1998;Koul et al, 2000;Detjen et al, 2007] testifying to the likely complexity of the underlying biology. However, the causative mutation has not been identified in such cases and the nature of the factors responsible for bringing about the discordance of clinical symptoms in these MZ twin pairs has remained enigmatic.…”

Section: Introductionmentioning

confidence: 99%

Monozygotic twins discordant for neurofibromatosis type 1 due to a postzygotic NF1 gene mutation

Vogt

Kohlhase²,

Morlot

et al. 2011

Hum. Mutat.

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ABSTRACT:The analysis of monozygotic twins (MZ) concordant for neurofibromatosis type 1 (NF1) has indicated that genetic factors exert a major influence on the clinical variability (e.g. the number of café-au-lait spots and/or neurofibromas) evident in this disease. Here, we report on a pair of monozygotic, dichorionic twins who are phenotypically discordant with respect to NF1. Whereas DNA sequence analysis indicated somatic mosaicism for the NF1 nonsense mutation, c.4108C>T (p.Q1370X), in the affected twin II/1, this lesion was apparently absent in his unaffected brother. The observation of heterozygosity for flanking SNP and microsatellite markers rendered it most unlikely that the observed mosaicism with normal cells was due to mutation reversion brought about either by gene conversion or mitotic recombination. Instead, we conclude that the twinning event, which would have taken place within three days post-fertilization, must have preceded the c.4108C>T mutation which is therefore predicted to have occurred during the blastocyst stage, leading to somatic mosaicism with normal cells lacking the mutation. This is the first reported case of monozygotic twins discordant for NF1 in whom mosaicism for a postzygotic NF1 gene mutation has been observed in the affected but not the unaffected twin. ©2011 Wiley-Liss, Inc.

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Neurofibromatosis in Monozygotic Twins: A Case Report

Cited by 9 publications

References 6 publications

Variable expression of neurofibromatosis 1 in monozygotic twins

Variable expression of neurofibromatosis 1 in monozygotic twins

Analysis of copy number variants in 11 pairs of monozygotic twins with neurofibromatosis type 1

Monozygotic twins discordant for neurofibromatosis type 1 due to a postzygotic NF1 gene mutation

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