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      Comparison of effectiveness of growth hormone therapy according to disease-causing genes in children with Noonan syndrome

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          Abstract

          Purpose

          To analyze the growth response to growth hormone (GH) therapy in prepubertal patients with Noonan syndrome (NS) harboring different genetic mutations.

          Methods

          Twenty-three patients with prepubertal NS treated at Pusan National University Children’s Hospital between March 2009 and July 2017 were enrolled. According to the disease-causing genes identified, the patients with NS were divided into 4 groups. Three groups were positive for mutations of the PTPN11, RAF1, and SOS1 genes. The five genes undetected (FGU) group was negative for PTPN11, RAF1, SOS1, KRAS, and BRAF gene mutations. The influence of genotype was retrospectively analyzed by comparing the growth parameters after GH therapy.

          Results

          The mean chronological age at the start of GH treatment was 5.85±2.67 years. At the beginning of the GH treatment, the height standard deviation score (SDS), growth velocity (GV), and lower levels of insulin-like growth factor-1 (IGF)-1 levels were not statistically different among the groups. All the 23 NS patients had significantly increased height SDS and serum IGF-1 level during the 3 years of treatment. GV was highest during the first year of treatment. During the 3 years of GH therapy, the PTPN11, RAF1, and SOS1 groups showed less improvement in height SDS, IGF-1 SDS, and GV, and less increase in bone age-to-chronological age ratio than the FGU group.

          Conclusion

          The 3-year GH therapy in the 23 prepubertal patients with NS was effective in improving height SDS, GV, and serum IGF-1 levels. The FGU group showed a better response to recombinant human GH therapy than the PTPN11, RAF1, and SOS1 groups.

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          MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1(L613V) mutation.

          Matthew Simpson, X. Wu, Peter Backx … (2011)
          Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden death in children and young adults. Abnormalities in several signaling pathways are implicated in the pathogenesis of HCM, but the role of the RAS-RAF-MEK-ERK MAPK pathway has been controversial. Noonan syndrome (NS) is one of several autosomal-dominant conditions known as RASopathies, which are caused by mutations in different components of this pathway. Germline mutations in RAF1 (which encodes the serine-threonine kinase RAF1) account for approximately 3%-5% of cases of NS. Unlike other NS alleles, RAF1 mutations that confer increased kinase activity are highly associated with HCM. To explore the pathogenesis of such mutations, we generated knockin mice expressing the NS-associated Raf1(L613V) mutation. Like NS patients, mice heterozygous for this mutation (referred to herein as L613V/+ mice) had short stature, craniofacial dysmorphia, and hematologic abnormalities. Valvuloseptal development was normal, but L613V/+ mice exhibited eccentric cardiac hypertrophy and aberrant cardiac fetal gene expression, and decompensated following pressure overload. Agonist-evoked MEK-ERK activation was enhanced in multiple cell types, and postnatal MEK inhibition normalized the growth, facial, and cardiac defects in L613V/+ mice. These data show that different NS genes have intrinsically distinct pathological effects, demonstrate that enhanced MEK-ERK activity is critical for causing HCM and other RAF1-mutant NS phenotypes, and suggest a mutation-specific approach to the treatment of RASopathies.
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            Clinical and molecular studies in a large Dutch family with Noonan syndrome.

            I der Weid, Sjef van der Linden, Paul B. Hamel … (1994)
            We describe the largest Noonan syndrome (NS) family reported to date. The manifestations of the affected relatives are discussed. In the absence of a biochemical marker NS is still a clinical diagnosis. The diagnostic criteria that were used are presented compared with other published criteria for diagnosing NS. The large size of this family enabled us to test the possible involvement of candidate regions by multipoint linkage analysis. Both the region surrounding the NF1 locus on chromosome 17 and the proximal part of chromosome 22 could be excluded. Since NS may well be heterogeneous, the use of such a large family in linkage studies of NS should prove indispensable.
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              Next-generation sequencing identifies rare variants associated with Noonan syndrome.

              Peng-Chieh Chen, Jiani Yin, Hui-Wen Yu … (2014)
              Noonan syndrome (NS) is a relatively common genetic disorder, characterized by typical facies, short stature, developmental delay, and cardiac abnormalities. Known causative genes account for 70-80% of clinically diagnosed NS patients, but the genetic basis for the remaining 20-30% of cases is unknown. We performed next-generation sequencing on germ-line DNA from 27 NS patients lacking a mutation in the known NS genes. We identified gain-of-function alleles in Ras-like without CAAX 1 (RIT1) and mitogen-activated protein kinase kinase 1 (MAP2K1) and previously unseen loss-of-function variants in RAS p21 protein activator 2 (RASA2) that are likely to cause NS in these patients. Expression of the mutant RASA2, MAP2K1, or RIT1 alleles in heterologous cells increased RAS-ERK pathway activation, supporting a causative role in NS pathogenesis. Two patients had more than one disease-associated variant. Moreover, the diagnosis of an individual initially thought to have NS was revised to neurofibromatosis type 1 based on an NF1 nonsense mutation detected in this patient. Another patient harbored a missense mutation in NF1 that resulted in decreased protein stability and impaired ability to suppress RAS-ERK activation; however, this patient continues to exhibit a NS-like phenotype. In addition, a nonsense mutation in RPS6KA3 was found in one patient initially diagnosed with NS whose diagnosis was later revised to Coffin-Lowry syndrome. Finally, we identified other potential candidates for new NS genes, as well as potential carrier alleles for unrelated syndromes. Taken together, our data suggest that next-generation sequencing can provide a useful adjunct to RASopathy diagnosis and emphasize that the standard clinical categories for RASopathies might not be adequate to describe all patients.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Korean J Pediatr
                Journal ID (iso-abbrev): Korean J Pediatr
                Journal ID (publisher-id): KJP
                Title: Korean Journal of Pediatrics
                Publisher: Korean Pediatric Society
                ISSN (Print): 1738-1061
                ISSN (Electronic): 2092-7258
                Publication date (Print): July 2019
                Publication date (Electronic): 3 December 2018
                Volume: 62
                Issue: 7
                Pages: 274-280
                Affiliations
                [1 ]Department of Pediatrics, Pusan National University Children’s Hospital, Yangsan, Korea
                [2 ]Department of Pediatrics, Chungnam National University Hospital, Daejeon, Korea
                [3 ]Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
                [4 ]Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea
                Author notes
                Corresponding author: Chong Kun Cheon, MD Division of Pediatric Endocrinology, Department of Pediatrics, Pusan National University Children’s Hospital, Pusan National University School of Medicine, Geumo-ro 20, Yangsan 50612, Korea Tel: +82-55-360-3158 Fax: +82-55-360-2181 E-mail: chongkun@ 123456pusan.ac.kr
                Author information
                http://orcid.org/0000-0002-8609-5826
                Article
                Publisher ID: kjp-2018-06842
                DOI: 10.3345/kjp.2018.06842
                PMC ID: 6642922
                PubMed ID: 30514065
                SO-VID: 695ad16c-42b6-4be0-bc8f-9cd59c21d3ed
                Copyright © Copyright © 2019 by The Korean Pediatric Society
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 1 August 2018
                Date revision received : 15 November 2018
                Date accepted : 3 December 2018
                Categories
                Subject: Original Article
                Subject: Endocrinology

                ScienceOpen disciplines: Pediatrics
                Keywords: noonan syndrome,recombinant human growth hormone,mutations
                Data availability:
                ScienceOpen disciplines: Pediatrics
                Keywords: noonan syndrome, recombinant human growth hormone, mutations

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