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

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1879
Author(s):  
Marcello Scala ◽  
Irene Schiavetti ◽  
Francesca Madia ◽  
Cristina Chelleri ◽  
Gianluca Piccolo ◽  
...  
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Copy Number Variations ◽  
Single Nucleotide Variants ◽  
Multivariate Statistical ◽  
Gene Deletions ◽  
Pathogenic Variants ◽  
Lisch Nodules ◽  
Next Generation Sequencing Ngs

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.

scholarly journals Do non-pathogenic variants of DNA mismatch repair genes modify neurofibroma load in neurofibromatosis type 1?

2022 ◽  
Author(s):  
Anja Harder
Keyword(s):  
Mismatch Repair ◽  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Tumour Suppressor Genes ◽  
Gene Variants ◽  
Single Nucleotide Variants ◽  
Dna Mismatch ◽  
Pathogenic Variants ◽  
Patients At Risk

AbstractNon-pathogenic mismatch repair (MMR) gene variants can be associated with decreased MMR capacity in several settings. Due to an increased mutation rate, reduced MMR capacity leads to accumulation of somatic sequence changes in tumour suppressor genes such as in the neurofibromatosis type 1 (NF1) gene. Patients with autosomal dominant NF1 typically develop neurofibromas ranging from single to thousands. Concerning the number of neurofibromas NF1 patients face a situation that is still not predictable. A few studies suggested that germline non-pathogenic MMR gene variants modify the number of neurofibromas in NF1 and by this mechanism may promote the extent of neurofibroma manifestation. This review represents first evidence that specific non-pathogenic single nucleotide variants of MMR genes act as a modifier of neurofibroma manifestation in NF1, highlighting MSH2 re4987188 as the best analysed non-pathogenic variant so far. In summary, besides MSH2 promotor methylation, specific non-pathogenic germline MSH2 variants are associated with the extent of neurofibroma manifestation. Those variants can serve as a biomarker to facilitate better mentoring of NF1 patients at risk.

scholarly journals Challenges in the diagnosis of neurofibromatosis type 1 (NF1) in young children facilitated by means of revised diagnostic criteria including genetic testing for pathogenic NF1 gene variants

2021 ◽  
Author(s):  
Hildegard Kehrer-Sawatzki ◽  
David N. Cooper
Keyword(s):  
Young Children ◽  
Diagnostic Criteria ◽  
Neurofibromatosis Type 1 ◽  
Early Adulthood ◽  
Neurofibromatosis Type ◽  
Clinical Feature ◽  
Pathogenic Variants ◽  
Legius Syndrome ◽  
Nf1 Gene

AbstractNeurofibromatosis type 1 (NF1) is the most frequent disorder associated with multiple café-au-lait macules (CALM) which may either be present at birth or appear during the first year of life. Other NF1-associated features such as skin-fold freckling and Lisch nodules occur later during childhood whereas dermal neurofibromas are rare in young children and usually only arise during early adulthood. The NIH clinical diagnostic criteria for NF1, established in 1988, include the most common NF1-associated features. Since many of these features are age-dependent, arriving at a definitive diagnosis of NF1 by employing these criteria may not be possible in infancy if CALM are the only clinical feature evident. Indeed, approximately 46% of patients who are diagnosed with NF1 later in life do not meet the NIH diagnostic criteria by the age of 1 year. Further, the 1988 diagnostic criteria for NF1 are not specific enough to distinguish NF1 from other related disorders such as Legius syndrome. In this review, we outline the challenges faced in diagnosing NF1 in young children, and evaluate the utility of the recently revised (2021) diagnostic criteria for NF1, which include the presence of pathogenic variants in the NF1 gene and choroidal anomalies, for achieving an early and accurate diagnosis.

Neurofibromatosis Type 1

2017 ◽  
Author(s):  
David S. Wolf
Keyword(s):  
Learning Disabilities ◽  
Neurofibromatosis Type 1 ◽  
Autosomal Dominant ◽  
Neurofibromatosis Type ◽  
Vascular Abnormalities ◽  
Hyperactivity Disorder ◽  
Café Au Lait Spots ◽  
Lisch Nodules ◽  
Neurocutaneous Disorder

Neurofibromatosis type 1 is a common, autosomal dominant, monogenetic neurocutaneous disorder. It is characterized by café au lait spots, axillary and inguinal freckling, Lisch nodules, optic pathway gliomas, neurofibromas, and distinctive bony abnormalities. Also associated with this condition are other central nervous system tumors, scoliosis, hypertension, vascular abnormalities, and cognitive issues such as learning disabilities and attention deficit-hyperactivity disorder.

Structure of Lisch nodules in neurofibromatosis Type 1

1991 ◽  
Vol 12 (1) ◽  
pp. 11-17 ◽  
Author(s):  
T. H. Williamson ◽  
A. Garner ◽  
A. T. Moore
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Lisch Nodules

scholarly journals Neurofibromatosis Type 1 Complicated by Atypical Coarctation of the Thoracic Aorta

2013 ◽  
Vol 2013 ◽  
pp. 1-4
Author(s):  
Masato Kimura ◽  
Shuhei Kakizaki ◽  
Kengo Kawano ◽  
Shinichi Sato ◽  
Shigeo Kure
Keyword(s):  
Thoracic Aorta ◽  
Neurofibromatosis Type 1 ◽  
Aortic Coarctation ◽  
Autosomal Dominant ◽  
Genetic Disorder ◽  
Neurofibromatosis Type ◽  
Lisch Nodules ◽  
Atypical Coarctation ◽  
Graft Interposition

Neurofibromatosis type 1 (NF1) is a relatively common autosomal dominant genetic disorder with a prevalence of 1 in 3,000 (0.03%) at birth. Clinical features are café-au-lait macules, intertriginous freckling, dermal neurofibroma, iris hamartoma (Lisch nodules), and learning disability. NF1 vasculopathy is a serious but underrecognized complication involving the cerebrovascular and cardiovascular systems. The incidence of hypertension in patients with NF1 is around 1% and is associated mainly with renal artery stenosis in children. Only a few cases of thoracic aortic coarctation in association with hypertension and neurofibromatosis have been reported. Here we describe the case of a 4-year-old girl who presented with NF1 and hypertension due to atypical coarctation of the thoracic aorta. The diagnosis of coarctation of the thoracic aorta at the Th5-to-Th6 level was made following catheterization with a pressure gradient of 40 mmHg. The patient underwent surgery comprising resection of the coarctation of the thoracic aorta and graft interposition. On the basis of our findings, annual assessment of blood pressure is advised for patients with NF1.

Lisch Nodules in Neurofibromatosis Type 1

1991 ◽  
Vol 324 (18) ◽  
pp. 1264-1266 ◽  
Author(s):  
Marie-Louise E. Lubs ◽  
Mislen S. Bauer ◽  
Maria E. Formas ◽  
Borivoje Djokic
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Lisch Nodules

Diagnostic Outcome in Children With Multiple Café au Lait Spots

PEDIATRICS ◽  
1992 ◽  
Vol 90 (6) ◽  
pp. 924-927
Author(s):  
Bruce R. Korf
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Initial Visit ◽  
Definite Diagnosis ◽  
Skin Fold ◽  
Lisch Nodules ◽  
Multiple Lentigines ◽  
Diagnostic Outcome

Forty-one children, ranging in age from 1 month to 14 years, had six or more café au lait spots at their initial visit and were examined annually. Signs of neurofibromatosis type 1 eventually developed in 24. The most common feature to appear to confirm the diagnosis was skin-fold freckling, which occurred in 18 subjects. Diagnosis was based on the appearance of Lisch nodules in 5, and on neurofibromas in 3. In most instances, diagnosis was established within 3 years of initial evaluation, usually before 5 years of age. Six children had a segmental distribution of café au lait spots, suggesting segmental neurofibromatosis. In 3, diagnoses other than neurofibromatosis type 1 were established (Bannayan-Riley-Rulvalcaba syndrome, multiple lentigines syndrome, and fibrous dysplasia). In 8 subjects only multiple café au lait spots are present, and no definite diagnosis has been established. It is concluded that with regular follow-up, including physical and ophthalmological examinations, a definite diagnosis, most commonly neurofibromatosis type 1, can be established for most children having multiple café au lait spots.

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