Clinical and molecular aspects of an informative family with neurofibromatosis type 1 and Noonan phenotype

Stevenson, David A.; Viskochil, David; Rope, Alan F.; Carey, John C.

doi:10.1111/j.1399-0004.2006.00576.x

Cited by 38 publications

(35 citation statements)

References 39 publications

(60 reference statements)

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“…Mutations with (*) have also been identified in classical NF1 patients as reported in the Human Gene Mutation Database professional release 2008.2 (41). The c.2970delAAT (**) has been associated with WS (33), NFNS (20) and with mild NF1 lacking cutaneous neurofibromas (39). Below : The highly conserved motif and the novel mutation p.L1390F identified in the present study which resides within the motif.…”

Section: Discussionsupporting

confidence: 53%

Noonan syndrome and neurofibromatosis type I in a family with a novel mutation in NF1

et al. 2009

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Noonan syndrome (NS) and neurofibromatosis type I (NF1) belong to a group of clinically related disorders that share a common pathogenesis, dysregulation of the RAS-MAPK pathway. NS 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. Both disorders display considerable clinical variability. Features of NS have been observed in individuals with NF1 -a condition known as neurofibromatosis-Noonan syndrome (NFNS). The major gene causing NFNS is NF1. Rarely, a mutation in PTPN11 in addition to an NF1 mutation is present. We present the clinical and molecular characterization of a family displaying features of both NS and NF1, with complete absence of neurofibromas. To investigate the etiology of the phenotype, mutational analysis of NF1 was conducted, revealing a novel missense mutation in exon 24, p.L1390F, affecting the GAP-domain. Additional RAS-MAPK pathway genes were examined, but no additional mutations were identified. We confirm that NF1 mutations are involved in the etiology of NFNS. Furthermore, based on our results and previous studies we suggest that evaluation of the GAP-domain of NF1 should be prioritized in NFNS.

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Section: Discussionsupporting

confidence: 53%

Noonan syndrome and neurofibromatosis type I in a family with a novel mutation in NF1

et al. 2009

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“…The overlap of disease phenotype within the disorders of the Ras-MAPK pathway is well established (Brems et al, 2007; Pasmant et al, 2009; Spurlock et al 2009; Stevenson et al, 2008; Stevenson et al, 2006; Nyström et al, 2003; Johnson et al, 1998; Lopez-Rangel, 2007; Diglio et al, 2002; Tassabehji et al, 1993; Allanson et al, 1991). One of the most common Ras-MAPK pathway disorders is NF1.…”

Section: Discussionmentioning

confidence: 99%

SPRED 1 Mutations in a Neurofibromatosis Clinic

et al. 2010

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Legius syndrome, caused by SPRED1 mutations, has phenotypic overlap with neurofibromatosis type 1 (NF1) without tumorigenic manifestations. Patients fulfilling the NIH diagnostic criteria for NF1 were enrolled from the University of Utah NF Clinic and SPRED1 mutation analysis performed in order to identify the frequency of Legius syndrome within an NF1 clinic population. SPRED1 sequencing was performed on 151 individuals with the clinical diagnosis of NF1 and 2 individuals (1.3%) were found to have novel SPRED1 mutations, p.R18X and p.Q194X. The phenotypes for the two individuals with SPRED1 mutations included altered pigmentation without tumorigenesis. A specific SPRED1 haplotype allele was identified in 27 individuals. The frequency of SPRED1 mutations in patients meeting diagnostic criteria for NF1 in a hospital-based clinic is 1–2%. The likelihood an individual is harboring a SPRED1 mutation increases with age if multiple, non-pigmentary NF1 findings are absent. Legius syndrome patients may benefit from altered medical surveillance.

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“…Although these are the signs and symptoms most commonly associated with NF1, individuals with NF1 may have other manifestations of the disorder, including cardiac malformations, cardiovascular disease, vasculopathy, hypertension, vitamin D deficiency, brain malformations, and seizures. They may also have dysmorphic craniofacial features reminiscent of NS (27, 57), mild neurocognitive impairment, and a predisposition to developing certain malignancies. Segmental and mosaic forms of NF1 are not uncommon, and gonadal mosaicism has been documented.…”

Section: The Rasopathiesmentioning

confidence: 99%

The RASopathies

Rauen

2013

Annu. Rev. Genom. Hum. Genet.

728

736

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The RASopathies are a clinically defined group of medical genetic syndromes caused by germline mutations in genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. These disorders include neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentigines, capillary malformation–arteriovenous malformation syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, and Legius syndrome. Because of the common underlying Ras/MAPK pathway dysregulation, the RASopathies exhibit numerous overlapping phenotypic features. The Ras/MAPK pathway plays an essential role in regulating the cell cycle and cellular growth, differentiation, and senescence, all of which are critical to normal development. Therefore, it is not surprising that Ras/MAPK pathway dysregulation has profound deleterious effects on both embryonic and later stages of development. The Ras/MAPK pathway has been well studied in cancer and is an attractive target for small-molecule inhibition to treat various malignancies. The use of these molecules to ameliorate developmental defects in the RASopathies is under consideration.

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Clinical and molecular aspects of an informative family with neurofibromatosis type 1 and Noonan phenotype

Cited by 38 publications

References 39 publications

Noonan syndrome and neurofibromatosis type I in a family with a novel mutation in NF1

Noonan syndrome and neurofibromatosis type I in a family with a novel mutation in NF1

SPRED 1 Mutations in a Neurofibromatosis Clinic

The RASopathies

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