Severe Lymphatic Disorder and Multifocal Atrial Tachycardia Treated with Trametinib in a Patient with Noonan Syndrome and SOS1 Mutation.

Noonan syndrome (NS) is a multisystemic disorder caused by germline mutations in the Ras/MAPK cascade, causing a broad spectrum of phenotypical abnormalities, including abnormal facies, developmental delay, bleeding diathesis, congenital heart disease (mainly pulmonary stenosis and hypertrophic cardiomyopathy), lymphatic disorders, and uro-genital abnormalities. Multifocal atrial tachycardia has been associated with NS, where it may occur independently of hypertrophic cardiomyopathy. Trametinib, a highly selective MEK1/2 inhibitor currently approved for the treatment of cancer, has been shown to reverse left ventricular hypertrophy in two RIT1-mutated newborns with NS and severe hypertrophic cardiomyopathy. Severe lymphatic abnormalities may contribute to decreased pulmonary compliance in NS, and pulmonary lymphangiectasias should be included in the differential diagnosis of a newborn requiring prolonged oxygen administration. Herein we report the case of a pre-term newborn who was admitted to our unit for the occurrence of severe respiratory distress and subentrant MAT treated with trametinib.

Minimal disease activity in Gaucher disease: criteria for definition.

Gaucher disease type I is a metabolic disorder caused by a genetic deficiency of lysosomal ß-glucocerebrosidase that leads to accumulation of glucocerebroside in macrophages, thus causing damage in different organ systems. Enzyme replacement therapy with imiglucerase improves organ impairment and clinical manifestations, but patients differ in response to treatment. While clinical remission is the most desirable therapeutic outcome, a more realistic goal in patients with high disease burden is reasonably good clinical status despite persistence of residual biochemical or imaging abnormalities. Therefore, the concept of minimal disease activity--used in certain haematological or rheumatologic conditions--needs to be introduced in Gaucher disease, with a level of disease activity that patients and physicians consider a useful treatment target. In this paper, we propose specific parameters and criteria for defining minimal disease activity in Gaucher disease and its stability over time, based on three major systemic domains typically involved: haematological, visceral, and skeletal. Biomarker parameters were not included as criteria, because currently they do not adequately reflect disease evolution in individual patients. Neurological and respiratory domains were also excluded, as their involvement per se indicates severe disease unlikely to respond to enzyme replacement therapy and achieve minimal disease status. Our goal in defining minimal disease activity and stability is to identify a tool to facilitate treatment decisions in clinical practice.

Molecular markers for the follow-up of enzyme-replacement therapy in mucopolysaccharidosis type VI disease.

MPS VI (mucopolysaccharidosis type VI) is a lysosomal storage disease in which deficient activity of the enzyme N-acetylgalactosamine 4-sulfatase [ASB (arylsulfatase B)] impairs the stepwise degradation of the GAG (glycosaminoglycan) dermatan sulfate. Clinical studies of ERT (enzyme replacement therapy) by using rhASB (recombinant human ASB) have been reported with promising results. The release of GAG into the urine is currently used as a biomarker of disease, reflecting in some cases disease severity and in all cases therapeutic responsiveness. Using RNA studies in four Italian patients undergoing ERT, we observed that TNFalpha (tumour necrosis factor alpha) might be a biomarker for MPS VI responsive to therapy. In addition to its role as a potential biomarker, TNFalpha expression could provide insights into the possible pathophysiological mechanisms underlying the mucopolysaccharidoses.