MEK Inhibition in a Newborn with RAF1-Associated Noonan Syndrome Ameliorates Hypertrophic Cardiomyopathy but Is Insufficient to Revert Pulmonary Vascular Disease

Mussa, Alessandro; Carli, Diana; Giorgio, Elisa; Villar, Anna Maria; Cardaropoli, Simona; Carbonara, Caterina; Campagnoli, Maria Francesca; Galletto, Paolo; Palumbo, Martina; Olivieri, Simone; Isella, Claudio; Andelfinger, Grégor; Tartaglia, Marco; Botta, Giovanni; Brusco, Alfredo; Medico, Enzo

doi:10.3390/genes13010006

Cited by 40 publications

(36 citation statements)

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“…Head MRI examination suggested that the cerebral haemorrhage had recovered. However, the child developed hypertrophic cardiomyopathy, which was consistent with Mussa A, who discovered the RAF1:c.770C > T (Ser257Leu) mutation [6], but the patient [6] developed myocardial hypertrophy and pulmonary hypertension during the neonatal period, resulting in death during the neonatal period. However, no effective treatment has been found for myocardial hypertrophy caused by RAF1, and its clinical study is currently underway [22].…”

Section: Follow-upsupporting

confidence: 80%

“…Mutation in the RAF1 gene has been connected with a variety of maladies covering hypertrophic cardiomyopathy, mental retardation, short stature, and Noonan-like skin features associated with freckle syndrome (multiple freckles, nevi cafe-au-lait, multiple nevi). More than 90% of NS patients with mutations in conserved region 2 of RAF1 suffer from severe hypertrophic cardiomyopathy, resulting from abnormal ERK5 and MEK1/2 signalling [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

“…Factor XIII deficiency can cause massive uncontrolled bleeding. For this reason, infusion of cryoprecipitate or fresh frozen plasma containing cryoprecipitate is required for effective haemostasis [ 6 ]. Therefore, it is not convincing to think that the lack of coagulation factors leads to bleeding in the patient.…”

Section: Discussionmentioning

confidence: 99%

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Noonan syndrome with RAF1 gene mutations in a newborn with cerebral haemorrhage

et al. 2022

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Background Noonan syndrome is an autosomal dominant genetic disorder that can occur in men and women and has a sporadic or family history. NS can lead to abnormal bleeding, but cerebral haemorrhage is rare. This is the first case of cerebral haemorrhage with a RAF1 gene mutation that originated in the neonatal period. Case presentation This case presents a newborn with a RAF1 gene mutation resulting in NS complicated with an abnormality of chromosome 46, X, del (Y) (q12). In the course of treatment, the baby's breathing suddenly increased. After an MRI examination of the skull, haemorrhaging was found in multiple parts of the brain. Conclusions After symptomatic treatment, the baby recovered well, but the main cause of cerebral haemorrhage was not found.

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Section: Follow-upsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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Noonan syndrome with RAF1 gene mutations in a newborn with cerebral haemorrhage

et al. 2022

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“…It is encouraging that much progress has been made in our understanding of the molecular genetic causes of NS, and novel therapeutic drugs have been given to patients. To date, there are some publications describing the use of RAS pathway inhibition as useful for NS ( Andelfinger et al, 2019 ; Mek Inhibitor Reverses Hypertrophic Cardiomyopathy, 2019 ; Dori et al, 2020 ; Meisner et al, 2021 ; Mussa et al, 2021 ; Kontaridis et al, 2022 ). Trametinib, a MEK-inhibitor approved for treatment of RAS/MAPK-mutated cancers, is an emerging treatment option for HCM in NS.…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular Abnormalities and Gene Mutations in Children With Noonan Syndrome

et al. 2022

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Background: Common cardiac abnormalities in Noonan syndrome (NS) include congenital heart diseases (CHD), pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). Molecular diagnoses are enabling earlier and more precise diagnosis of patients who have a subtle or atypical presentation. The aims of this study were to investigate genotype-phenotype associations with respect to Noonan syndrome (NS)-associated cardiac abnormalities and catheter or surgery-based interventions conditions.Methods: From January 2019 to December 2021, 22 children with a confirmed molecular diagnosis of NS combined with cardiovascular abnormalities were consecutively enrolled into the current study. A comprehensive review was carried out of echocardiography and electrocardiogram results, second-generation whole-exome sequencing results and catheter or surgery-based interventions conditions.Results: The main manifestations of electrocardiogram abnormalities were QTc prolongation, abnormal Q wave in the precordial lead and limb lead, right ventricular hypertrophy and left or right deviation of the electrical axis. The most commonly detected abnormality was pulmonary valve dysplasia with stenosis, seen in 15 (68.2%) patients, followed by atrial septal defect in 11 (50%) patients. Seven genes (RAF1, RIT1, SOS1, PTPN11, BRAF, SOS2, and LZTR1) were found to contain disease-associated variants. The most commonly observed genetic mutations were PTPN11 (27%) and RAF1 (27%). Each genotype was associated with specific phenotypic findings. RIT1, SOS1, PTPN11, and SOS2 had common echocardiography features characterized by pulmonary valve stenosis, while RAF1 was characterized by HCM. Interestingly, patients with BRAF mutations were not only characterized by HCM, but also by pulmonary valve stenosis. In the cohort there was only one patient carrying a LZTR1 mutation characterized by left ventricle globose dilation. Ten cases underwent catheter or surgery-based interventions. All the operations had immediate results and high success rates. However, some of the cases had adverse outcomes during extended follow-up. Based on the genotype-phenotype associations observed during follow-up, BRAF and RAF1 genotypes seem to be poor prognostic factors, and multiple interventions may be required for NS patients with severe pulmonary stenosis or myectomy for HCM.Conclusions: The identification of causal genes in NS patients has enabled the evaluation of genotype-cardiac phenotype relationships and prognosis of the disease. This may be beneficial for the development of therapeutic approaches.

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“…The somatic oncogenic variant (COSM13036) we identified in the PTPN11 gene is potentially actionable as treatment with MEK‐inhibitors could be envisioned. Actually, response to MEK‐inhibition was observed in patients with pediatric low grade gliomas with RAS/MAPK/pathway activation 21 as well as in complicated NS patients, 22 suggesting this strategy could be promising. Theoretically, the case here presented could benefit the most from such treatment, being carrier of two mutations in this cascade, with the somatic PTPN11 variant affecting part of the body—including tumor tissue—and a variant in FGFR1 detected only in tumor tissue.…”

Section: Discussionmentioning

confidence: 99%

Lateralized overgrowth with vascular malformation caused by a somaticPTPN11pathogenic variant: Another piece added to the puzzle of mosaicRASopathies

Mussa

Turchiano

Cardaropoli³

et al. 2022

Genes Chromosomes & Cancer

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Lateralized/segmental overgrowth disorders (LOs) encompass a heterogeneous group of congenital conditions with excessive body tissue growth. Documented molecular alterations in LOs mostly consist of somatic variants in genes of the PI3KCA/AKT/mTOR pathway or of chromosome band 11p15.5 imprinted region anomalies. In some cases, somatic pathogenic variants in genes of the RAS/MAPK pathway have been reported. We present the first case of a somatic pathogenic variant (T507K) in PTPN11 causing a LO phenotype characterized by severe lateralized overgrowth, vascular proliferation, and cerebral astrocytoma. The T507K variant was detected in DNA from overgrown tissue in a leg with capillary malformation. The astrocytoma tissue showed a higher PTPN11 variant allele frequency. A pathogenic variant in FGFR1 was also found in tumor tissue, representing a second hit on the RAS/MAPK pathway. These findings indicate that RAS/MAPK cascade overactivation can cause mosaic overgrowth phenotypes resembling PIK3CA‐related overgrowth disorders (PROS) with cancer predisposition and are consistent with the hypothesis that RAS/MAPK hyperactivation can be involved in the pathogenesis of astrocytoma. This observation raises the issue of cancer predisposition in patients with RAS/MAPK pathway gene variants and expands genotype spectrum of LOs and the treatment options for similar cases through inhibition of the RAS/MAPK oversignaling.

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MEK Inhibition in a Newborn with RAF1-Associated Noonan Syndrome Ameliorates Hypertrophic Cardiomyopathy but Is Insufficient to Revert Pulmonary Vascular Disease

Cited by 40 publications

References 50 publications

Noonan syndrome with RAF1 gene mutations in a newborn with cerebral haemorrhage

Noonan syndrome with RAF1 gene mutations in a newborn with cerebral haemorrhage

Cardiovascular Abnormalities and Gene Mutations in Children With Noonan Syndrome

Lateralized overgrowth with vascular malformation caused by a somaticPTPN11pathogenic variant: Another piece added to the puzzle of mosaicRASopathies

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