PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype–phenotype correlation in Korean patients with Noonan syndrome

Ko, Jung Min; Kim, Jae-Min; Kim, Gu-Hwan; Yoo, Han‐Wook

doi:10.1007/s10038-008-0343-6

Cited by 91 publications

(93 citation statements)

References 36 publications

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“…Different groups of clinicians reported a lower prevalence of short stature in patients with SOS1 mutations, compared with NS subjects harboring other genotypes [16][17][18][19]. In agreement, Malaquias et al, recently observed in 14 SOS1 patients a mean height SDS of +0.4 (±0.8) compared to NS standard (which is thus composed, in majority, of subjects mutated in PTPN11) [14].…”

Section: Influence Of Genotype On Spontaneous Growth In Subjects With Nssupporting

confidence: 60%

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

Raynal¹

2014

Horm Stud

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Short stature is a frequent feature of Noonan syndrome (NS), a disease caused by mutations of genes encoding components of the Ras/mitogen-activated protein kinases (MAPK) signalling pathway. To date numerous patients have been treated with growth hormone (GH) in various countries. However this treatment is still controversial, as its efficacy is a matter of debate. The final height gain of GH therapy represents 5 to 10 cm, at best, which is disappointing considering the length and burden of the treatment. The reasons explaining this lack of efficiency are poorly understood and they seemed to involve a waning effect after the first year of GH treatment or acceleration of bone maturation in patients on GH. Moreover, GH therapy raises questions about its safety, especially in subjects with NS who are at risk for cardiac defects and malignancies. Cases of severe adverse effects were described, yet too sporadically to conclude that they were certainly caused by GH therapy. Novels insights in understanding the dysfunction of GH-dependent processes in NS were recently reported and this manuscript aims at reviewing the latest advances. Clinical data suggested that growth retardation could be caused by a partial postreceptor resistance to GH, an impaired sensitivity to GH which could also explain the modest efficiency of GH therapy in NS patients. Similar observations were also obtained in a NS mouse model harboring a mutation in the gene encoding the tyrosine phosphatase Shp2. In the mouse, the mechanism of GH resistance is thought to involve upregulation by mutated Shp2 of GH-induced Ras/MAPK, a signaling pathway which seemed to play a negative regulatory role in the production of GH mediators involved in bone growth. Despite these recent finding, the underlying mechanisms of growth retardation and GH therapy in NS remain to be further explored in order to improve treatment for short stature.

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Section: Influence Of Genotype On Spontaneous Growth In Subjects With Nssupporting

confidence: 60%

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

Raynal¹

2014

Horm Stud

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“…Indeed, the most frequent mutation found in NS is p .N308D (10,19). Mutation p.N308S has also been found in several studied patients (10,(19)(20)(21)(22)(23).…”

Section: Discussionmentioning

confidence: 87%

Co-occurring PTPN11 and SOS1 gene mutations in Noonan syndrome: does this predict a more severe phenotype?

Brasil

Malaquias²,

Wanderley

et al. 2010

Arq Bras Endocrinol Metab

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Noonan syndrome (NS) is an autosomal dominant disorder, with variable phenotypic expression, characterized by short stature, facial dysmorphisms and heart disease. Different genes of the RAS/MAPK signaling pathway are responsible for the syndrome, the most common are: PTPN11, SOS1, RAF1, and KRAS. The objective of this study was to report a patient with Noonan syndrome presenting mutations in two genes of RAS/MAPK pathway in order to establish whether these mutations lead to a more severe expression of the phenotype. We used direct sequencing of the PTPN11, SOS1, RAF1, and KRAS genes. We have identified two described mutations in heterozygosity: p.N308D and p.R552G in the genes PTPN11 and SOS1, respectively. The patient has typical clinical features similar to the ones with NS and mutation in only one gene, even those with the same mutation identified in this patient. A more severe or atypical phenotype was not observed, suggesting that these mutations do not exhibit an additive effect.

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“…Whether the PTPN11 mutation or other mutations in the RAS-MAPK pathway are correlated with the growth response to rhGH treatment up to final height, merits further evaluation in larger prospective and representative studies [28,29]. Screening for mutations of the RAF1 and HRAS genes before rhGH therapy is important due to the development of progressive ventricular hypertrophy in NS children with RAF1 mutation [10,30] and the susceptibility to tumor growth in patients with Costello syndrome [31]. Recently, it has been reported that risk of cancer in patients carrying a mutation in PTPN11 is higher than the general population, particularly hematological malignancies.…”

Section: Discussionmentioning

confidence: 99%

Response to Growth Hormone Therapy in Children with Noonan Syndrome: Correlation with or without <b><i>PTPN11</i></b> Gene Mutation

et al. 2012

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Background/Aims: The objective of this study was to evaluate the efficacy of recombinant human growth hormone (rhGH) therapy and the influence of genotype on the response to rhGH therapy in children with Noonan syndrome (NS). Methods: 14 male and 4 female subjects with NS with short stature, whose height was <3rd percentile, were included. The rhGH was subcutaneously administered at a dose of 66 µg/kg/day. Mutations in the PTPN11 gene were identified in 10 subjects (55.6%). Mutations in the SOS1 (2 children, 11.1%), MEK1 (1 child, 5.6%) and KRAS (1 child, 5.6%) genes were also found. Results: Height SDS increased from –2.8 ± 0.9 at the start of rhGH therapy to –2.0 ± 0.9 12 months later (p < 0.001). Height velocity increased from 5.0 ± 0.9 cm/year in the year before treatment to 8.9 ± 1.6 during treatment (p < 0.001). Changes in height SDS, height velocity, and serum IGF-1 level did not differ significantly between those children with or without PTPN11 mutations. Conclusion: The rhGH therapy significantly improved the growth velocity and increased the serum IGF-1 level. Long-term correlation between genotype and rhGH therapy responsiveness needs to be addressed in a large population.

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PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype–phenotype correlation in Korean patients with Noonan syndrome

Cited by 91 publications

References 36 publications

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

Co-occurring PTPN11 and SOS1 gene mutations in Noonan syndrome: does this predict a more severe phenotype?

Response to Growth Hormone Therapy in Children with Noonan Syndrome: Correlation with or without <b><i>PTPN11</i></b> Gene Mutation

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