Neurofibromatosis–Noonan syndrome: Molecular evidence of the concurrence of both disorders in a patient

@article{Bertola2005NeurofibromatosisNoonanSM,
  title={Neurofibromatosis–Noonan syndrome: Molecular evidence of the concurrence of both disorders in a patient},
  author={D{\'e}bora Romeo Bertola and A C Pereira and Fabio Passetti and Paulo S L de Oliveira and Ludwine M Messiaen and Bruce D. Gelb and Chong Ae Kim and Jos{\'e} Eduardo Krieger},
  journal={American Journal of Medical Genetics Part A},
  year={2005},
  volume={136A}
}
Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, facial anomalies, webbed neck, sternal deformity, heart defects, and, in males, cryptorchidism. PTPN11 encodes SHP2, an important component of several signal transduction pathways that acts as a positive regulator of RAS‐mitogen activated protein kinase signaling. Neurofibromatosis type 1 (NF1) is another autosomal dominant disorder characterized by hamartomas in multiple organs. The NF1 gene encodes a GAP… 
Lethal presentation of neurofibromatosis and Noonan syndrome
TLDR
This case suggests that a double genetic defect resulting in the hypersignaling of the Ras pathway may lead to complex cardiovascular abnormalities, cardiomyopathy, refractory arrhythmia, severe neurological phenotype, and early death.
Noonan syndrome and neurofibromatosis type I in a family with a novel mutation in NF1
TLDR
Noonan syndrome is characterized by short stature, heart defect, pectus deformity and facial dysmorphism, whereas skin manifestations, skeletal defects, Lisch nodules and neurofibromas are characteristic of NF1.
Novel association of neurofibromatosis type 1‐causing mutations in families with neurofibromatosis‐noonan syndrome
TLDR
The results support the notion that NFNS represents a variant ofNF1, genetically distinct from NS, and is caused by mutations in NF1, some of which also cause classical NF1.
Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis
TLDR
A single missense mutation in SHOC2, which encodes a cytoplasmic scaffold positively controlling RAF1 activation, has been discovered to cause a closely related phenotype previously termed Noonan-like syndrome with loose anagen hair, demonstrating that the substantial phenotypic variation characterizing NS and related conditions can be ascribed, in part, to the gene mutated and even the specific molecular lesion involved.
NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome.
TLDR
The view that NFNS represents a variant of NF1 and is caused by mutations of the NF1 gene, some of which have been demonstrated to cause classic NF1 in other individuals is supported.
Neurofibromatosis 1 in the setting of dual diagnosis: Diagnostic and management conundrums
TLDR
Clinicians should have high index of suspicion to exclude coexisting disorders, as apart from providing comprehensive medical care, in order to differentiate from an extreme phenotypic spectrum of NF1.
Independent NF1 and PTPN11 mutations in a family with neurofibromatosis‐Noonan syndrome
TLDR
It is speculated that absence of cutaneous neurofibromas is not solely associated with the recurrent 3‐bp in‐frame deletion in exon 17, and suggests that the index patient's typical NFNS phenotype is caused by an additive effect of mutations in both NF1 and PTPN11.
Clinical variability of neurofibromatosis 1: A modifying role of cooccurring PTPN11 variants and atypical brain MRI findings
TLDR
It is found that functionally relevant PTPN11 variants occur in a small but significant proportion of subjects with NF1 modulating disease presentation, suggesting a model in which the clinical expression of pathogenic NF1 variants is modified by concomitant dysregulation of protein(s) functionally linked to neurofibromin.
A variable combination of features of Noonan syndrome and neurofibromatosis type I are caused by mutations in the NF1 gene
TLDR
Seven novel patients from five unrelated families with variable phenotypes of the NF1‐NS spectrum are described which were systematically analyzed for mutations in the disease‐causing genes NF1 for NF1 and PTPN11 for NS to support the hypothesis that variable phenotypic overlap of NS and NF1 represents variants of NF1.
Is Neurofibromatosis Type 1-Noonan Syndrome a Phenotypic Result of Combined Genetic and Epigenetic Factors?
TLDR
The NFNS phenotype may be the result of both a genetic factor (mutation in the NF1 gene) and an epigenetic/environmental factor (e.g. hydantoin) due to exposure to that anticonvulsant during fetal development.
...
...

References

SHOWING 1-10 OF 34 REFERENCES
PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.
TLDR
The spectrum and distribution of PTPN11 mutations in a large, well-characterized cohort with NS revealed that pulmonic stenosis was more prevalent among the group of subjects with NS who had PTP N11 mutations than it was in the group without them, andotype-phenotype analysis revealed that hypertrophic cardiomyopathy was less prevalent among those with PTPn11 mutations.
Novel recurrent nonsense mutation causing neurofibromatosis type 1 (NF1) in a family segregating both NF1 and Noonan syndrome.
TLDR
Clinical and molecular analyses of this four-generation family demonstrated that the NF-NS phenotype was additive, being the result of both classical NF1 and NS, which suggests the presence of an NS locus on 17q, which might be of interest for further linkage studies.
Different mutations in the NF1 gene are associated with Neurofibromatosis–Noonan syndrome (NFNS)
TLDR
The results show that NFNS can in some cases result from different mutations in the NF1 gene and therefore represents a variant form of NF1.
Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene.
TLDR
It is demonstrated that ML/LEOPARD syndrome and NS are allelic disorders and the detected mutations suggest that distinct molecular and pathogenetic mechanisms cause the peculiar cutaneous manifestations of the ML/LeOPARD-syndrome subtype of NS.
Absence of PTPN11 mutations in 28 cases of cardiofaciocutaneous (CFC) syndrome
TLDR
The results showed no abnormalities in the coding region of the PTPN11 gene in any CFC patient, nor any evidence of major deletions within the gene suggesting that mutations in other gene(s) are responsible for this syndrome.
Exclusion of allelism of Noonan syndrome and neurofibromatosis-type 1 in a large family with Noonan syndrome-neurofibromatosis association.
TLDR
Results suggest that two mutations at two independent but closely linked loci are the cause of neurofibromatosis-Noonan syndrome (NF-NS) association in this family.
Phenotypic and genotypic characterisation of Noonan-like/multiple giant cell lesion syndrome
TLDR
The phenotype of three sporadic cases of NS/MGCLS and the results of mutation analysis of the PTPN11 and SH3BP2 genes are presented and the clinical features of the three patients are summarised.
The Genetic Aspects of Neurofibromatosis a
TLDR
The segmental form of NF is of interest as cases of this presentation may be helpful in studying the hypothesis of human somatic mutation when DNA analysis is available, and an age-of-onset penetrance curve for NF could be constructed for genetic counseling purposes.
Exclusion of PTPN11 mutations in Costello syndrome: further evidence for distinct genetic etiologies for Noonan, cardio–facio–cutaneous and Costello syndromes
TLDR
Screening for PTPN11 mutations in Costello syndrome patients using denaturing high performance liquid chromatography analysis suggested distinct genetic etiologies for Noonan, CFC and Costello syndromes.
Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome
TLDR
It is shown that missense mutations in PTPN11—a gene encoding the nonreceptor protein tyrosine phosphatase SHP-2, which contains two Src homology 2 (SH2) domains—cause Noonan syndrome and account for more than 50% of the cases that were examined.
...
...