Recurrent p.H119Y variant in MAP2K1 expands the phenotypic spectrum of MAP2K1-related RASopathy.

We report three unrelated individuals with atypical clinical findings for cardio-facio-cutaneous (CFC) syndrome, all of whom have the same novel, heterozygous de novo p.H119Y (c.355 C>T) transition variant in MAP2K1, identified by exome sequencing. MAP2K1 encodes MEK1, dual specificity mitogen-activated protein kinase kinase 1, and is one of four genes in the canonical RAS/MAPK signal transduction pathway associated with CFC syndrome. The p.H119Y variant is a non-conservative amino acid substitution that is predicted to impact the tertiary protein structure, and it occurs at a position in the protein kinase domain of MAP2K1 that is highly conserved across species. The clinical findings in these three individuals include facial features that are nonclassical for CFC syndrome, extremely poor weight gain, absence of congenital cardiac defects or cardiomyopathy, normal cognition or only mild intellectual disabilities, normal hair, mild skin abnormalities, and consistent behavioral features of anxiety, photophobia, and sensory hypersensitivities. These individuals expand the phenotypic spectrum of MAP2K1-related RASopathy.

RASopathies - what they reveal about RAS/MAPK signaling in skeletal muscle development.

RASopathies are rare developmental genetic syndromes caused by germline pathogenic variants in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway. Although the incidence of each RASopathy syndrome is rare, collectively, they represent one of the largest groups of multiple congenital anomaly syndromes and have severe developmental consequences. Here, we review our understanding of how RAS/MAPK dysregulation in RASopathies impacts skeletal muscle development and the importance of RAS/MAPK pathway regulation for embryonic myogenesis. We also discuss the complex interactions of this pathway with other intracellular signaling pathways in the regulation of skeletal muscle development and growth, and the opportunities that RASopathy animal models provide for exploring the use of pathway inhibitors, typically used for cancer treatment, to correct the unique skeletal myopathy caused by the dysregulation of this pathway.

Dermoscopic Features of Melanocytic Nevi in Cardiofaciocutaneous and Costello Syndromes.

Importance: Somatic variants in the RAS/MAPK pathway genes are commonly associated with melanocytic nevi and melanoma, whereas germline variants in these genes are associated with RASopathies, syndromes involving multiple organs, including the skin. Nevi counts may be higher in some RASopathies, but studies on features observed through dermoscopy are limited. Objective: To determine the distinguishing dermoscopic features of melanocytic nevi and how the RAS pathway influences them by comparing nevi in patients with cardiofaciocutaneous syndrome (CFC) and Costello syndrome (CS). Design, Setting, and Participants: In this prospective cohort study, patients with CFC and CS, 2 RASopathies caused by variants in the downstream and upstream components of the RAS/MAPK pathway, were recruited from the international CFC and CS family conferences. Some patients with CFC also elected to participate in a longitudinal follow-up study. Main Outcomes and Measures: The main outcomes were dermoscopic features and, in the longitudinal follow-up study, nevi counts, which were recorded over time. Results: A total of 39 patients, 16 with CFC and 23 with CS, were enrolled (overall cohort: 26 [66.7%] female; median [IQR] age, 13.0 [7.6-22.0] years). The 112 nevi overall frequently displayed an organized dermoscopic pattern (CFC, 61 [84.7%]; CS, 34 [85.0%]) rather than a disorganized pattern (CFC, 6 [8.3%]; CS, 1 [2.5%]). Of the organized nevi, homogenous brown was the most common pattern (CFC, 41 [67.2%]; CS, 22 [64.7%]), followed by reticular (CFC, 11 [18.0%]; CS, 7 [20.6%]) and globular (CFC, 9 [14.8%]; CS, 5 [14.7%]). Pigmented networks occurred in 12 nevi in CFC (16.7%) and 6 nevi in CS (15%; P > .99). Of these, 6 CFC-associated nevi (50%) and no CS-associated nevi had atypical networks (P = .05). Six patients with CFC in the follow-up study developed significantly more nevi within 5 years (median [IQR] increase, 24.5 [10-120] nevi; P = .04). Conclusions and Relevance: In this cohort study, the findings suggest that nevi in patients with CFC and CS commonly display organized homogenous brown dermoscopic patterns, and the number of nevi may significantly increase over time in those with CFC. A disorganized pattern and atypical networks may be more frequent in patients with CFC. Future studies are needed to determine the risk of melanoma in individuals with CFC or CS.