Nonreentrant atrial tachycardia occurs independently of hypertrophic cardiomyopathy in RASopathy patients.

Multifocal atrial tachycardia (MAT) has a well-known association with Costello syndrome, but is rarely described with related RAS/MAPK pathway disorders (RASopathies). We report 11 patients with RASopathies (Costello, Noonan, and Noonan syndrome with multiple lentigines [formerly LEOPARD syndrome]) and nonreentrant atrial tachycardias (MAT and ectopic atrial tachycardia) demonstrating overlap in cardiac arrhythmia phenotype. Similar overlap is seen in RASopathies with respect to skeletal, musculoskeletal and cutaneous abnormalities, dysmorphic facial features, and neurodevelopmental deficits. Nonreentrant atrial tachycardias may cause cardiac compromise if sinus rhythm is not restored expeditiously. Typical first-line supraventricular tachycardia anti-arrhythmics (propranolol and digoxin) were generally not effective in restoring or maintaining sinus rhythm in this cohort, while flecainide or amiodarone alone or in concert with propranolol were effective anti-arrhythmic agents for acute and chronic use. Atrial tachycardia resolved in all patients. However, a 4-month-old boy from the cohort was found asystolic (with concurrent cellulitis) and a second patient underwent cardiac transplant for heart failure complicated by recalcitrant atrial arrhythmia. While propranolol alone frequently failed to convert or maintain sinus rhythm, fleccainide or amiodarone, occasionally in combination with propranolol, was effective for RASopathy patient treatment for nonreentrant atrial arrhythmia. Our analysis shows that RASopathy patients may have nonreentrant atrial tachycardia with and without associated cardiac hypertrophy. While nonreentrant arrhythmia has been traditionally associated with Costello syndrome, this work provides an expanded view of RASopathy cardiac arrhythmia phenotype as we demonstrate mutant proteins throughout this signaling pathway can also give rise to ectopic and/or MAT.

Recombinant growth hormone therapy in a girl with Costello syndrome: a 4-year observation.

BACKGROUND: Costello syndrome is a rare syndrome of multiple congenital anomalies. The typical clinical traits include dysmorphic craniofacial features, skin hyperpigmentation and excess, feeding difficulties leading to severe postnatal growth retardation, short stature, joint hypermobility, and delayed psychomotor development. Additionally, Costello syndrome may present with an increased incidence of congenital heart disease, hypertrophic cardiomyopathy, and increased risk of both benign and malignant tumors. Furthermore, cases of patients with endocrine disorders such as adrenal insufficiency and endogenous growth hormone deficiency have also been documented. CASE PRESENTATION: We present a patient with Costello syndrome who has been successfully treated with recombinant human growth hormone (rhGH) for almost 4 years. CONCLUSIONS: The possibility of growth hormone (GH) treatment can be considered in cases of documented GH deficiency in patients with Costello syndrome, but only under close oncologic and cardiologic supervision.

Growth hormone replacement therapy in Costello syndrome.

Costello syndrome (CS) is considered an overgrowth disorder given the macrosomia that is present at birth .However, shortly after birth the weight drops dramatically and the patients are usually referred for failure to thrive. Subsequently, affected patients develop the distinctive coarse facial appearance and are at risk for cardiac anomalies and solid tumor malignancies. Various endocrine disorders, although not very often, have been reported in patients with CS, including growth hormone deficiency, hypoglycemia, ACTH deficiency, cryptorchidism and hypothyroidism. We report a case of Costello syndrome with hypothyroidism, cryptorchidism and growth hormone deficiency and we evaluate the long-term safety and efficacy of growth hormone replacement therapy. The index patient is a paradigm of successful and safe treatment with growth hormone for almost 7 years. Since patients with CS are at increased risk for cardiac myopathy and tumor development they deserve close monitoring during treatment.

Antioxidant effects of potassium ascorbate with ribose in costello syndrome.

BACKGROUND: Costello syndrome is a rare genetic condition characterized by coarse facies, short stature, loose folds of skin especially on hands and feet, severe feeding difficulties and failure to thrive. Other features include cardiac anomalies, developmental disability and increased risk of neoplasms. Given the link between oxidative stress (OS) and carcinogenesis, we tested the hypothesis that OS occurs in this syndrome, supposing its role both in cancer development and in other clinical features. PATIENTS AND METHODS: We describe four cases with Costello syndrome in which we verified the presence of OS by measuring a redox biomarker profile including total hydroperoxides, non-protein-bound iron, advanced oxidation protein products, thyols, carbonyl groups and isoprostanes. Thus, we introduced an antioxidant agent, namely potassium ascorbate with ribose (PAR) into the therapy and monitored the redox profile every three months to verify its efficacy. RESULTS: A progressive decrease in OS biomarkers occurred, together with an improvement in the clinical features of the patients. CONCLUSION: OS was proven in all four cases of Costello syndrome. The antioxidant therapy with PAR demonstrated positive effects. These promising results need further research to confirm the relevance of OS and the efficacy of PAR therapy in Costello syndrome.

Costello and cardio-facio-cutaneous syndromes: Moving toward clinical trials in RASopathies.

The RASopathies, one of the largest groups of multiple congenital anomaly syndromes known, are caused by germline mutations in various genes encoding components of the Ras/mitogen-activated protein kinase (MAPK) pathway. The RASopathies have many overlapping characteristics, including craniofacial manifestations, cardiac malformations, cutaneous, musculoskeletal, gastrointestinal, and ocular abnormalities, neurocognitive impairment, hypotonia, and an increased risk of developing cancer. Costello syndrome (CS) and cardio-facio-cutaneous (CFC) syndrome are two of the more rare RASopathies. CS is caused by activating mutations in HRAS, and CFC is caused by dysregulation of signaling in the Ras/MAPK pathway due to mutations in BRAF, MEK1, or MEK2. The Ras/MAPK pathway, which has been well-studied in cancer, is an attractive target for inhibition in the treatment of various malignancies utilizing small molecule therapeutics that specifically inhibit the pathway. With many inhibitors of the Ras/MAPK pathway in clinical trials, the notion of using these molecules to ameliorate developmental defects in CS and CFC is under consideration. CS and CFC, like other syndromes in their class, have a progressive phenotype and may be amenable to inhibition or normalization of signaling.