Phenotypic heterogeneity of neurofibromatosis type 1 in a large international registry

Tabata, Mika M.; Li, Shufeng; Knight, Pamela; Sarin, Kavita Y.

doi:10.1172/jci.insight.136262

Cited by 20 publications

(27 citation statements)

References 28 publications

(39 reference statements)

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“…Previously studies detected cutaneous neuro broma in more than 80% of patients and plexiform neuro broma in 30-50% of patients [15,16]. Neuro bromas occur in adolescence and after [15,16]. Some patients in our study were in adolescence or older.…”

Section: Discussionsupporting

confidence: 46%

“…All of our patients had greater than/equal to 6 CALMs. Previously studies detected cutaneous neuro broma in more than 80% of patients and plexiform neuro broma in 30-50% of patients [15,16]. Neuro bromas occur in adolescence and after [15,16].…”

Section: Discussionmentioning

confidence: 92%

“…However, optic glioma incidence in NF1 is similar in male and female gender [31,32]. Tabata et al [16] did a cluster analysis in adults with NF 1 and found positive correlations between spinal neuro bromas and optic gliomas; between optic gliomas and sphenoid wing dysplasia. Also, they reported that increasing cutaneous neuro bromas was a risk factor for MPNST [16].…”

Section: Discussionmentioning

confidence: 99%

“…Tabata et al [16] did a cluster analysis in adults with NF 1 and found positive correlations between spinal neuro bromas and optic gliomas; between optic gliomas and sphenoid wing dysplasia. Also, they reported that increasing cutaneous neuro bromas was a risk factor for MPNST [16]. In our study, gender and age were unremarkable in patients with malignancy.…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of the Clinical Profile and Malignancies in Children With Neurofibromatosis Type 1

Şahin¹,

Demırsoy²,

Çorapçıoğlu³

2021

Preprint

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Purpose: Neurofibromatosis type 1 (NF 1) is a significant disease as it is one of the most common autosomal dominant disorders in childhood. Several systems are affected due to significant progression. This study aimed to analyze the clinical findings in children with NF 1 and investigate the characteristics of those with malignancy. Methods: Medical records of 55 children with NF 1 that were followed up for ten years (2004-2015) in our center were analyzed. We assessed clinical and demographical characteristics of patients, presence NF 1 diagnostic criteria, NF 1 related complications, and malignancies. The patients without malignancy are classified in group 1 while patients with malignancy are in group 2. Results: The mean age was 7.68 ± 4.65 years. Female gender was dominant in both groups. Café au lait spots were present in all patients. Axillary-inguinal freckling was observed in 76.4% of patients, followed by neurofibromas in 30.9%, Lisch nodules in 29.1%, bone dysplasia in 14.5%, optic gliomas (OG) in 23.6%, and a history of first degree relative with NF 1 in 63.6%. Central nervous system (CNS) tumors were present in 40%. Tumors beyond CNS were acute myeloid leukemia and schwannoma. None of the diagnostic criteria was a risk factor for malignancy. Having >3 criteria was the risk factor for malignancy in NF-1 (OR:5.891, CI 95%: 1.676-20.705, p=0.006).Conclusions: The major problem is malignancies in NF -1 patients. There are no clearly defined risk factors predicting malignancies in NF-1 at present. However, we found the risk of malignancy higher in patients with more diagnostic criteria.

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Section: Discussionsupporting

confidence: 46%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Evaluation of the Clinical Profile and Malignancies in Children With Neurofibromatosis Type 1

Şahin¹,

Demırsoy²,

Çorapçıoğlu³

2021

Preprint

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“…The pleiotropy of NF1 and the complex pathophysiology mechanisms involved in most NF1-related clinical manifestations underlie the typical largely variable clinical expressivity, which may occur even within the same family for a specific NF1 variant [ 7 ]. However, well-defined clinical hallmarks are recognizable, including distinctive pigmentary defects of the skin (café-au-lait macules—CALMs—and intertriginous freckling, especially axillary and inguinal) and the eye (hamartomas of the iris, known as iris Lisch nodules), as well as typical tumors of the peripheral nervous system (PNSTs) such as cutaneous/subcutaneous (cNFs/sNFs) and plexiform neurofibromas (pNFs) [ 6 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Genotype-Phenotype Correlations in Neurofibromatosis Type 1: A Single-Center Cohort Study

Scala

Schiavetti

Madia

et al. 2021

Cancers

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Neurofibromatosis type 1 (NF1) is a proteiform genetic condition caused by pathogenic variants in NF1 and characterized by a heterogeneous phenotypic presentation. Relevant genotype–phenotype correlations have recently emerged, but only few pertinent studies are available. We retrospectively reviewed clinical, instrumental, and genetic data from a cohort of 583 individuals meeting at least 1 diagnostic National Institutes of Health (NIH) criterion for NF1. Of these, 365 subjects fulfilled ≥2 NIH criteria, including 235 pediatric patients. Genetic testing was performed through cDNA-based sequencing, Next Generation Sequencing (NGS), and Multiplex Ligation-dependent Probe Amplification (MLPA). Uni- and multivariate statistical analysis was used to investigate genotype–phenotype correlations. Among patients fulfilling ≥ 2 NIH criteria, causative single nucleotide variants (SNVs) and copy number variations (CNVs) were detected in 267/365 (73.2%) and 20/365 (5.5%) cases. Missense variants negatively correlated with neurofibromas (p = 0.005). Skeletal abnormalities were associated with whole gene deletions (p = 0.05) and frameshift variants (p = 0.006). The c.3721C>T; p.(R1241*) variant positively correlated with structural brain alterations (p = 0.031), whereas Lisch nodules (p = 0.05) and endocrinological disorders (p = 0.043) were associated with the c.6855C>A; p.(Y2285*) variant. We identified novel NF1 genotype–phenotype correlations and provided an overview of known associations, supporting their potential relevance in the implementation of patient management.

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Analysis of patient‐specific NF1 variants leads to functional insights for Ras signaling that can impact personalized medicine

Long

Liu

et al. 2021

Human Mutation

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We have created a panel of 29 NF1 variant complementary DNAs (cDNAs) representing missense variants, many with clinically relevant phenotypes, in-frame deletions, splice variants, and nonsense variants. We have determined the functional consequences of the variants, assessing their ability to produce mature neurofibromin and restore Ras signaling activity in NF1 null (−/−) cells. cDNAs demonstrate variant-specific differences in neurofibromin protein levels, suggesting that some variants lead to neurofibromatosis type 1 (NF1) gene or protein instability or enhanced degradation. When expressed at high levels, some variant proteins are still able to repress Ras activity, indicating that the NF1 phenotype may be due to low protein abundance. In contrast, other variant proteins are incapable of repressing Ras activity, indicating that some do not functionally engage Ras and stimulate GTPase activity. We observed that effects on protein abundance and Ras activity can be mutually exclusive. These assays allow us to categorize variants by functional effects, may help to classify variants of unknown significance, and may have future implications for more directed therapeutics.

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Phenotypic heterogeneity of neurofibromatosis type 1 in a large international registry

Cited by 20 publications

References 28 publications

Evaluation of the Clinical Profile and Malignancies in Children With Neurofibromatosis Type 1

Evaluation of the Clinical Profile and Malignancies in Children With Neurofibromatosis Type 1

Genotype-Phenotype Correlations in Neurofibromatosis Type 1: A Single-Center Cohort Study

Analysis of patient‐specific NF1 variants leads to functional insights for Ras signaling that can impact personalized medicine

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