Cutaneous and Systemic Findings in Mosaic Neurofibromatosis Type 1

Vázquez‐Osorio, Igor; Duat-Rodríguez, Anna; García‐Martínez, Francisco Javier; Torrelo, Antonio; Noguera‐Morel, Lucero; Hernández‐Martín, Ángela

doi:10.1111/pde.13094

Cited by 15 publications

(8 citation statements)

References 27 publications

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“… 19 , 20 True somatic mosaicism has been well-documented for NF1 and NF2 cancer associated-genes and there has been one documented case for PTEN and Cowden syndrome. 21 – 24 There is a growing literature documenting the detection of mosaic mutations in disease genes detected by NGS, albeit in the context of developmental disorders manifesting in childhood. 25 However, in this study our focus is on the potential that late post-zygotic ACE, limited to the hematologic compartment or to a tumor, may be detected in the blood or saliva in the context of NGS-based testing to detect germline cancer predisposition.…”

Section: Introductionmentioning

confidence: 99%

Somatic TP53 variants frequently confound germ-line testing results

Weitzel

Chao

Nehoray

et al. 2018

Genetics in Medicine

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PurposeBlood/saliva DNA is thought to represent the germline in genetic cancer risk assessment. Cases with pathogenic TP53 variants detected by multi-gene panel tests (MGPT) are often discordant with Li-Fraumeni Syndrome (LFS), raising concern about misinterpretation of acquired aberrant clonal expansions (ACE) with TP53 variants as germline results.MethodsPathogenic TP53 variants with abnormal next-generation sequencing (NGS) metrics (e.g., decreased ratio [<25%] of mutant to wild-type allele, >2 detected alleles) were selected from a CLIA laboratory testing cohort. Alternate tissues and/or close relatives were tested to discern between ACE and germline status. Clinical data and LFS testing criteria were examined.ResultsAmong 114,630 MGPT and 1,454 TP53 gene-specific analyses, abnormal NGS metrics were observed in 20% of 353 TP53 positive results, and ACE was confirmed for 91% of cases with ancillary materials, most due to clonal hematopoiesis. Only four met Chompret criteria. ACE cases were older (50 years vs 33.7; P = 0.02) and were more frequent among MGPT (66/285; 23.2%) vs TP53 gene-specific tests (6/68; 8.8%, P = 0.005).ConclusionACE confounds germline diagnosis, may portend hematologic malignancy, and may result in unwarranted clinical interventions. Ancillary testing to confirm germline status should precede Li-Fraumeni syndrome management.

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Section: Introductionmentioning

confidence: 99%

Somatic TP53 variants frequently confound germ-line testing results

Weitzel

Chao

Nehoray

et al. 2018

Genetics in Medicine

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“…In patients with type-1 neurofibromatosis, cancer susceptibility is a well-known condition, being acute leukemia, chronic myelomonocytic leukemia and NHLs the most frequent hematological neoplasms. 47 At least four previous studies have communicated coincidental expression of cHL and type-1 neurofibromatosis 24–27 but CNVs in 17q have not been analyzed in these works. The main function of the gene product of the NF1 gene (Neurofibromin-1 protein) is the downregulation of RAS-mediated cell proliferation promoting the conversion of the active guanosine-triphosphate (RAS-GTP) form to the inactive guanosine-diphosphate (RAS-GDP) form.…”

Section: Discussionmentioning

confidence: 99%

“…23 Additionally, cancer susceptibility is a well-known condition in patients harboring mutations in the Neurofibromin 1 (NF1) gene and, at least, 4 previous studies have reported coincidental expression of type-1 Neurofibromatosis and cHL. 24–27…”

Section: Introductionmentioning

confidence: 99%

Identification of prognostic factors in classic Hodgkin lymphoma by integrating whole slide imaging and next generation sequencing

et al. 2022

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“…However, not all patients with mosaic NF1 with pigmentary changes develop neurofibromas. Patients may also develop learning difficulties, pseudoarthrosis and malignancy, despite having a milder phenotype 3 , 10 , 11 . Our patient is cognitively normal and had noticed the development of neurofibromas while in his late thirties.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Mosaicism of a novel nonsense variant in the neurofibromin gene underlies a mosaic generalized NF1 phenotype

2021

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Neurofibromatosis 1 (NF1) is a neurocutaneous syndrome characterized by multiple café-au-lait macules, cutaneous neurofibromas or plexiform neurofibromas, iris Lisch nodules, axillary and inguinal freckling. Mosaicism in NF1 can either present as a generalized disease, or in a localized (segmental) manner. Mosaic generalized NF1 may have presentations that are similar to generalized NF1 or have a milder phenotype and hence may be under-recognised in clinical practice. We report a nonsense mutation in the NF1 gene in a 55-year old Chinese male with the mosaic generalized phenotype. He reported noticing increasing numbers of skin-colored papules over his face, neck, back and abdomen when he was about 40 years old. From both next-generation and Sanger sequencing data, the variant appeared to be mosaic and present at about 24%. It is in exon 39 and has not been reported in any database or published literature.

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Cutaneous and Systemic Findings in Mosaic Neurofibromatosis Type 1

Cited by 15 publications

References 27 publications

Somatic TP53 variants frequently confound germ-line testing results

Somatic TP53 variants frequently confound germ-line testing results

Identification of prognostic factors in classic Hodgkin lymphoma by integrating whole slide imaging and next generation sequencing

Case Report: Mosaicism of a novel nonsense variant in the neurofibromin gene underlies a mosaic generalized NF1 phenotype

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