Patient improved
Patient improved
Patient fully recovered

At day +46 after treatment initiation, a ventriculoperitoneal shunt was placed in order to manage the intraventricular hemorrhage and a red blood cell unit was transfused. After surgery, we observed rapid worsening of CHF (nt-pro-BNP increased from 2049 pg/mL to 47,000 pg/mL) as well as respiratory deterioration, requiring again mechanical ventilator support. Pulmonary artery dilation, stable until then, increased to 18 mm (+5.7 SDS) and death from untreatable CHF with hypoxic respiratory failure occurred on day +57.This case report was extracted from a published article. The reference information for this article is: Mussa A, Carli D, Giorgio E, Villar AM, Cardaropoli S, Carbonara C, Campagnoli MF, Galletto P, Palumbo M, Olivieri S, Isella C, Andelfinger G, Tartaglia M, Botta G, Brusco A, Medico E, Ferrero GB. MEK Inhibition in a Newborn with RAF1-Associated Noonan Syndrome Ameliorates Hypertrophic Cardiomyopathy but Is Insufficient to Revert Pulmonary Vascular Disease. Genes (Basel). 2021 Dec 21;13(1):6. doi: 10.3390/genes13010006. PMID: 35052347; PMCID: PMC8774485.The free full text of the article is available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC8774485/

After treatment initiation there was a prompt improvement in clinical conditions (ROSS score from IV to III), allowing progressive and rapid withdrawal of inotropes in the next 4 days and weaning from mechanical ventilation a week later. Consistent with HCM stabilization, nt-pro-BNP decreased from 30,805 to 2355 pg/mL, and the patient was placed in non-invasive ventilator support and restricted fluid intake, with furosemide administration “as needed”. During the next month, treatment with Trametinib was continued without relevant side effects. ROSS score was II at 1 month. Liver enzymes, complete blood count, clotting tests, electrolytes, renal function were regularly monitored with no substantial modifications from baseline nor effects attributable to Trametinib administration. Echocardiography showed a tendency to HCM improvement with reduction of the septal thickness from treatment start to day +23. We also noted sudden dilation of the pulmonary artery dilation (14 mm, +3.5 SDS) at day 23. Despite of this finding, clinical conditions were stable in the following days and non-invasive ventilatory support was progressively reduced in terms of oxygen flow and fraction.

Hypertrophic cardiomyopathy (with symptoms)

This case report was extracted from a published article. The reference information for the article is: Leegaard A, Gregersen PA, Nielsen TØ, Bjerre JV, Handrup MM. Succesful MEK-inhibition of severe hypertrophic cardiomyopathy in RIT1-related Noonan Syndrome. Eur J Med Genet. 2022 Nov;65(11):104630. doi: 10.1016/j.ejmg.2022.104630. Epub 2022 Sep 30. PMID: 36184070.The free full-text of the article is available at: https://www.sciencedirect.com/science/article/pii/S1769721222002117?via%3Dihub

After one month of treatment HCM regressed by 30% (left ventricular (LV) wall thickness from ten mm to seven mm). After 21 months of treatment HCM was no longer present. At 30 months of age the echocardiography showed no presence of HCM

At dose of 0.025 mg/kg patient had clinically significant rhabdomyolysis with myoglobinuria. She had an elevated troponin which lead to temporary discontinuation of medication. While off trametinib patient continued to have intermittent elevated troponins, though to be due to her congenital heart disease and not trametinib. Did not have rhabdomyolysis at 0.0125 mg/kg dose. Checked patient's pharmacogenomics as well as trametinib level at the time of rhabdomyolysis which was normal.

Respiratory support, BNP, Echocardiography


increased dose 3 times. now we are giving her 500 mg. We also give it all in one dose in the morning as her school would not administer it. Although it works great all in the morning.

increased language, awareness of the world, increased processing time

Symptoms come back as soon as we stop. We also see less benefits when taking generic brand of Tanganil.

Improved clarity, Improved following directions


Clobetasol propionate 0.05% topical; Keratosis pillaris and hyperkeratosis were described as "Dermatologic condition including rough, dry areas on the skin of his arms and legs gradually developed into blisters with surrounding erythema and subsequent scaling, multiple cup-shaped hyperkeratotic, inflammatory papules with significant scale on his scalp, face, trunk, and upper and lower limbs, all the lesions had a ‘‘nutmeg grater’’ texture"

Hypotonia; Cortical atrophy; Bilateral ptosis; Atrophic right testicle; Keratosis pillaris; Hyperkeratosis; Dysmorphic coarse facial features; Sparse scalp hair and no eyelashes, eyebrows, or body hair; Bitemporal constriction; Prominent philtrum; Micrognathia; Posteriorly rotated ears; Hyperhidrosis; Heat intolerance of more severe skin lesions; Histopathologic findings including eccrine squamous metaplasia; Histopathologic findings including periadnexal granuloma


The hypertrophic cardiomyopathy had decreased by 7 days after ACTH treatment was discontinued. Left ventricular stroke volume decreased from 10.5 to 5.9 mL.


The patient was diagnosed with diabetes insipidus, likely related to the poorly visualised posterior pituitary bright spot on brain MRI. The patient responded appropriately to a 3-day long desmopressin infusion, confirming the diagnosis of central diabetes insipidus, which turned out to be transient and did not require further desmopressin treatment.


We noticed a failure of all topical (steroids, calcineurin inhibitors, and vitamin D3 analogues) or systemic medications (acitretin up to 0.5 mg/kg, methotrexate 20 mg/week, subcutaneous injections of ustekinumab 45 mg every 12 weeks).Despite dupilumab therapy being capable of inducing drastic reductions of IgE synthesis in patients with atopic dermatitis (13), the reduction of IgE concentrations at 18 months of treatment is moderate in this case of CFC. This is in contrast with the observed strong and durable improvement of skin symptoms.This case report was extracted from the published literature. The reference information for the publication is: Altandi SA, Apoil PA, Mazereeuw-Hautier J, Severino-Freire M. Cardio-facio-cutaneous Syndrome with Severe Inflammatory Cutaneous Lesions: Dramatic Effect of Dupilumab. Acta Derm Venereol. 2024 Sep 5;104:adv40465. doi: 10.2340/actadv.v104.40465. PMID: 39235050; PMCID: PMC11388110.The free full text of the article is available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC11388110/

After 3 months (T2) there was a dramatic reduction in skin lesions and pruritus, permitting a complete cessation of topical steroid use.

Inflammatory dermatitis; Diffuse erythematous lesions covered by thick scales; Yellowish palmoplantar keratoderma; Coarse and unruly hair; Thick hyperkeratotic scalp plaques; Severe Itching; Skin Pustules/blisters; Staphylococcus superinfections; Sleep disturbance; Dysmorphic facies; Macroglossia; Very thin eyebrows and scarce hair


Diffuse erythematous lesions covered with thick scales had fully resolved after 3 month of Dupilumab treatment.

Diffuse erythematous lesions covered by thick scales


Patient born with severe hypertrophic cardiomyopathy with obstruction. Patient had open heart surgery (myectomy) at two months old 12/2019.  Everolimus started in February 2020. Continued medication with titrations until April 2022. No significant changes in hypertrophic cardiomyopathy. Decided to discontinue Everolimus to see impact on patient’s condition. Patient currently 4 yrs old and hypertrophic cardiomyopathy consider considered mild to moderate. No scientific evidence Everolimus contributed to HCM stabilization, but hopeful!


Hydrocortisone 2.5% topical; Keratosis pillaris and hyperkeratosis were described as "Dermatologic condition including rough, dry areas on the skin of his arms and legs gradually developed into blisters with surrounding erythema and subsequent scaling, multiple cup-shaped hyperkeratotic, inflammatory papules with significant scale on his scalp, face, trunk, and upper and lower limbs, all the lesions had a ‘‘nutmeg grater’’ texture"


One month following the initiation of treatment, testosterone went from a mid-pubertal level of 4.41 nmol/L to an early pubertal level of 1.43 nmol/L.At the 3-month follow-up visit, the testicular volumes had decreased to 4–5 and 5–6 cc. The monthly leuprolide depot injections were continued at the same dose. The testosterone level decreased to a near pre-pubertal level of 0.93 nmol/L and the gonadotropin levels decreased as expected.

craniofacial and cutaneous features characteristic of CFCS, including bitemporal narrowing, a short broad nose, and sparse and curly hair; idiopathic central precocious puberty; hypernatremia on 2 occasions despite good ability to produce concentrated urine; asymptomatic hyperprolactinemia


Used in combination with midazolam, phenobarbital and valproic acid to try to control refractory seizures.

Status epilepticus was treated with multiple doses of intravenous midazolam and the patient was then started on a combination of levetiracetam, phenobarbital and valproic acid. Several anticonvulsants are often required to control refractory seizures in CFCS. Four months following diagnosis, the patient was readmitted to the hospital for treatment of status epilepticus following an anticonvulsant weaning attempt.


Used in combination with levetiracetam, phenobarbital and valproic acid to try to control refractory seizures.


Mometasone furoate 0.1% topical; Keratosis pillaris and hyperkeratosis were described as "Dermatologic condition including rough, dry areas on the skin of his arms and legs gradually developed into blisters with surrounding erythema and subsequent scaling, multiple cup-shaped hyperkeratotic, inflammatory papules with significant scale on his scalp, face, trunk, and upper and lower limbs, all the lesions had a ‘‘nutmeg grater’’ texture"


Used in combination with midazolam, levetiracetam, and valproic acid


Pimecrolimus 1% topical treatment; Keratosis pillaris and hyperkeratosis were described as: "Dermatologic condition including rough, dry areas on the skin of his arms and legs gradually developed into blisters with surrounding erythema and subsequent scaling, multiple cup-shaped hyperkeratotic, inflammatory papules with significant scale on his scalp, face, trunk, and upper and lower limbs, all the lesions had a ‘‘nutmeg grater’’ texture"


Tacrolimus 0.1% topical; Although persistent, the lesions showed marked improvement with heat avoidance, including the lack of development of new skin lesions. This case was unique in that it reported previously unreported histopathologic findings in CFC of eccrine squamous metaplasia and periadnexal granuloma. Keratosis pillaris and hyperkeratosis were described in the article as "Dermatologic condition including rough, dry areas on the skin of his arms and legs gradually developed into blisters with surrounding erythema and subsequent scaling, multiple cup-shaped hyperkeratotic, inflammatory papules with significant scale on his scalp, face, trunk, and upper and lower limbs, all the lesions had a ‘‘nutmeg grater’’ texture."This case report was extracted from a published article. The article's reference information is: Jeffries ML, Aleck KA, Bernert RA, Hansen RC. Eccrine squamous metaplasia and periadnexal granulomas: new cutaneous histopathologic findings in cardiofaciocutaneous syndrome. Pediatr Dermatol. 2010 May-Jun;27(3):274-8. doi: 10.1111/j.1525-1470.2009.00982.x. Epub 2009 Oct 4. PMID: 19804494.The full text of the article is available at: https://onlinelibrary.wiley.com/doi/10.1111/j.1525-1470.2009.00982.x


Developmental delays (gross motor, fine motor, speech)


At day of life 3, she developed frequent atrial ectopy with rapid atrial rate and numerous P wave morphologies. Echocardiogram was performed and demonstrated early hypertrophic cardiomyopathy with concentric left ventricular hypertrophy, pulmonary valve stenosis, and atrial septal defect. Based on the cardiac manifestations, macrocephaly, and widely spaced nipples, a RASopathy sequencing panel was performed, revealing a RAF1 c.770C>T pathogenic variant. She was started onpropranolol and discharged on home oxygen at 4 weeks. At 6 weeks, she presented with respiratory failure because of coronavirus HKU1 requiring intubation. Her arrhythmias and hypertrophic cardiomyopathy progressed, and she was diagnosed with MAT. The MAT frequently degenerated to atrial flutter/fibrillation with rapid ventricular response requiring multiple cardioversions. Progressive escalation of antiarrhythmic therapies included esmolol infusion, nadolol, amiodarone, and flecainide without successful rhythm or rate control. She developed chylothoraces requiring pleural tubes with inability to extubate because of congestive heart failure and severe left mainstem bronchomalacia. At 17 weeks, she had 2 cardiac arrests caused by degeneration of her MAT in the setting of high antiarrhythmic doses, resulting in polymorphic ventricular tachycardia requiring defibrillation. Her flecainide was transitioned to diltiazem infusion while continuing on amiodarone and nadolol. Because of her recalcitrant MAT and progressive biventricular hypertrophy, management options were discussed including cardiac transplantation, and the decision was made to pursue compassionate use of pharmacological MEK inhibition.While on trametinib, she developed severe diarrhea for which her trametinib was held for 3 days and dose was reduced to 0.01875 mg/kg per day, during which atrial ectopy briefly returned. Amiodarone and diltiazem were slowly weaned and discontinued. She remained on trametinib and nadolol with trivial residual atrial ectopy <1% of beats. This case was reported in the published literature. The article reference information is: Meisner JK, Bradley DJ, Russell MW. Molecular Management of Multifocal Atrial Tachycardia in Noonan's Syndrome With MEK1/2 Inhibitor Trametinib. Circ Genom Precis Med. 2021;14(5):e003327. doi:10.1161/CIRCGEN.121.003327. PMID: 34463117. The free full text link to the article is: https://www.ahajournals.org/doi/10.1161/CIRCGEN.121.003327?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

Ectopic and Multifocal Atrial Tachycardias; Congestive Heart Failure; Biventricular Hypertrophy; Atrial Ectopy


Cardiac magnetic resonance imaging at 2 days and 6 months after initiation and serial echocardiograms demonstrated initially moderate asymmetrical septal and biventricular hypertrophy that improved over the initial 6 months


Within 48 hours of initiation, her MAT resolved without appreciable conduction abnormalities

Ectopic and Multifocal Atrial Tachycardias


Patient was intubated during treatment due to respiratory distress. Because of multifocal atrial tachycardia with rapid ventricular response, propranolol (1 mg/kg t.i.d.) was introduced and serial 24 h ECG Holter monitoring was indicated. For the persistence of subentrant episodes of MAT, flecainide (5 mg/kg b.i.d.) and then intravenous amiodarone (5 mcg/kg minute) were added on top of beta-blocker therapy. Because the patient showed a persistent need for mechanical ventilation and severe bilateral involvement was detected on chest HRCT, treatment with dexamethasone was started, with partial recovery of respiratory parameters. Trametinib was added at week 9 to this background regimen because of sub-entrant, drug-resistant episodes of MAT and progressive decline in respiratory function. This case report was extracted from an article in the published literature. The article's reference information is: Lioncino M, Fusco A, Monda E, Colonna D, Sibilio M, Caiazza M, Magri D, Borrelli AC, D'Onofrio B, Mazzella ML, Colantuono R, Arienzo MR, Sarubbi B, Russo MG, Chello G, Limongelli G. Severe Lymphatic Disorder and Multifocal Atrial Tachycardia Treated with Trametinib in a Patient with Noonan Syndrome and SOS1 Mutation. Genes (Basel). 2022 Aug 23;13(9):1503. doi: 10.3390/genes13091503. PMID: 36140671; PMCID: PMC9498305.The free full text of the article is available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC9498305/

Week 12 Follow-up chest CT scan showed a significant reduction in lung consolidation areas

Acute respiratory distress; Bilateral parenchymal lung consolidation; Pleural effusion


After 4 days of treatment, lung ultrasound examination showed the absence of pleural effusion.


This case report was extracted from a published article. The reference information for the article is: Leegaard A, Gregersen PA, Nielsen TØ, Bjerre JV, Handrup MM. Succesful MEK-inhibition of severe hypertrophic cardiomyopathy in RIT1-related Noonan Syndrome. Eur J Med Genet. 2022 Nov;65(11):104630. doi: 10.1016/j.ejmg.2022.104630. Epub 2022 Sep 30. PMID: 36184070.The free full-text of the article is available at: https://www.sciencedirect.com/science/article/pii/S1769721222002117?via%3Dihub

Although she was well and thriving with a normal growth (weight and length: 50th percentile) before starting trametinib, we saw an improved growth (weight: 75th to 90th percentile, length: 75th percentile) after treatment was initiated.


At day +46 after treatment initiation, a ventriculoperitoneal shunt was placed in order to manage the intraventricular hemorrhage and a red blood cell unit was transfused. After surgery, we observed rapid worsening of CHF (nt-pro-BNP increased from 2049 pg/mL to 47,000 pg/mL) as well as respiratory deterioration, requiring again mechanical ventilator support. Pulmonary artery dilation, stable until then, increased to 18 mm (+5.7 SDS) and death from untreatable CHF with hypoxic respiratory failure occurred on day +57.This case report was extracted from a published article. The reference information for this article is: Mussa A, Carli D, Giorgio E, Villar AM, Cardaropoli S, Carbonara C, Campagnoli MF, Galletto P, Palumbo M, Olivieri S, Isella C, Andelfinger G, Tartaglia M, Botta G, Brusco A, Medico E, Ferrero GB. MEK Inhibition in a Newborn with RAF1-Associated Noonan Syndrome Ameliorates Hypertrophic Cardiomyopathy but Is Insufficient to Revert Pulmonary Vascular Disease. Genes (Basel). 2021 Dec 21;13(1):6. doi: 10.3390/genes13010006. PMID: 35052347; PMCID: PMC8774485.The free full text of the article is available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC8774485/

Pulmonary hypertension; Congestive heart failure; Pulmonary artery aneurysm; Posthemorrhagic hydrocephalus; Pulmonary artery dilation; Pulmonary capillary hemangiomatosis; Mild mitral regurgitation; Aortic valve with thickened cusps; Pulmonary artery dilation;


Right ventricular outlet tract obstruction

After two months of treatment the RVOT gradient had declined from 90 mmHg to 60 mmHg, and after ten months it further declined to 50 mmHg before stabilizing. At 30 months of age the echocardiography showed no presence of HCM and a RVOT gradient of 20–25 mmHg.

Right Ventricular Outflow Tract Obstruction (RVOTO)


Triamcinolone 0.1% topical. Keratosis pillaris and hyperkeratosis were described in the article as "Dermatologic condition including rough, dry areas on the skin of his arms and legs gradually developed into blisters with surrounding erythema and subsequent scaling, multiple cup-shaped hyperkeratotic, inflammatory papules with significant scale on his scalp, face, trunk, and upper and lower limbs, all the lesions had a ‘‘nutmeg grater’’ texture". This case report was extracted from a published article. The article's reference information is: Jeffries ML, Aleck KA, Bernert RA, Hansen RC. Eccrine squamous metaplasia and periadnexal granulomas: new cutaneous histopathologic findings in cardiofaciocutaneous syndrome. Pediatr Dermatol. 2010 May-Jun;27(3):274-8. doi: 10.1111/j.1525-1470.2009.00982.x. Epub 2009 Oct 4. PMID: 19804494.The full text of the article is available at: https://onlinelibrary.wiley.com/doi/10.1111/j.1525-1470.2009.00982.x


Used in combination with midazolam, levetiracetam, and phenobarbital for control of refractory seizures.This case report was extracted from the published literature. The reference information for the case is: Lenet S, Polychronakos C. Endocrine abnormalities in cardiofaciocutaneous syndrome: a case of precocious puberty, hyperprolactinemia and diabetes insipidus. BMJ Case Rep. 2019 Jun 18;12(6):e229032. doi: 10.1136/bcr-2018-229032. PMID: 31217210; PMCID: PMC6586202.The full text of the article is available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC6586202/


The patient was treated with antiepileptic drugs (levetiracetam, zonisamide, clonazepam, topiramate, phenobarbital, and lamotrigine), intravenous immunoglobulin, thyrotropin-releasing hormone, and a ketogenic diet but showed no decrease in clinical seizures or improvement in EEG findings. Finally, we decided to administer vigabatrin with the consent of our hospital’s ethics committee and written informed consent from theparents, because vigabatrin has not been approved for use in Japan.This case report was extracted from the published literature. The reference information for the published case is: Hatori T, Sugiyama Y, Yamashita S, Hirakubo Y, Nonaka K, Ichihashi K. Vigabatrin Therapy for Infantile Spasms in a Case of Cardiofaciocutaneous Syndrome with Cardiac Hypertrophy Developing during Adrenocorticotropic Hormone Treatment. J Nippon Med Sch. 2016;83(4):167-71. doi: 10.1272/jnms.83.167. PMID: 27680485.The free full text of the article is available at: https://www.jstage.jst.go.jp/article/jnms/83/4/83_167/_article


After the dosage had been increased to 140 mg/kg/day, seizures became nonclustered spasms and the EEG findings improved (Fig. 1C). Although the patient continued to have severe psychomotor retardation and was unable to smile or control her head, she did not require mechanical ventilation or tube feeding.