@article {38, title = {Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a multilineage somatic mosaic RASopathy.}, journal = {J Am Acad Dermatol}, volume = {75}, year = {2016}, month = {2016 Aug}, pages = {420-7}, abstract = {

BACKGROUND: We recently demonstrated multilineage somatic mosaicism in cutaneous skeletal hypophosphatemia syndrome (CSHS), which features epidermal or melanocytic nevi, elevated fibroblast growth factor (FGF)-23, and hypophosphatemia, finding identical RAS mutations in affected skin and bone.

OBJECTIVE: We sought to: (1) provide an updated overview of CSHS; (2) review its pathobiology; (3)~present a new patient with CSHS; and (4) discuss treatment modalities.

METHODS: We searched PubMed for "nevus AND rickets," and "nevus AND hypophosphatemia," identifying cases of nevi with hypophosphatemic rickets or elevated serum FGF-23. For our additional patient with CSHS, we performed histopathologic and radiographic surveys of skin and skeletal lesions, respectively. Sequencing was performed for HRAS, KRAS, and NRAS to determine causative mutations.

RESULTS: Our new case harbored somatic activating HRAS p.G13~R mutation in affected tissue, consistent with previous findings. Although the mechanism of FGF-23 dysregulation is unknown in CSHS, interaction between FGF and MAPK pathways may provide insight into pathobiology. Anti-FGF-23 antibody KRN-23 may be useful in managing CSHS.

LIMITATIONS: Multilineage RAS mutation in CSHS was recently identified; further studies on mechanism are unavailable.

CONCLUSION: Patients with nevi in association with skeletal disease should be evaluated for serum phosphate and FGF-23. Further studies investigating the role of RAS in FGF-23 regulation are needed.

}, keywords = {Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Fibroblast Growth Factor-23, Fibroblast Growth Factors, Genes, ras, Humans, Mosaicism, Nevus, Pigmented, Osteomalacia, Rickets, Hypophosphatemic, Skin Neoplasms, Syndrome}, issn = {1097-6787}, doi = {10.1016/j.jaad.2015.11.012}, author = {Lim, Young H and Ovejero, Diana and Derrick, Kristina M and Collins, Michael T and Choate, Keith A} } @article {33, title = {GNA14 Somatic Mutation Causes Congenital and Sporadic Vascular Tumors by MAPK Activation.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Aug 04}, pages = {443-50}, abstract = {

Vascular tumors are among the most common neoplasms in infants and children; 5\%-10\% of newborns present with or develop lesions within the first 3~months of life. Most are benign infantile hemangiomas that typically regress by 5 years of age; other vascular tumors include congenital tufted angiomas (TAs), kaposiform hemangioendotheliomas (KHEs), and childhood lobular capillary hemangiomas (LCHs). Some of these lesions can become locally invasive and unresponsive to pharmacologic intervention, leading to significant complications. Recent investigation has revealed that activating mutations in HRAS, KRAS, NRAS, GNAQ, and GNA11 can cause certain types of rare childhood vascular tumors, and we have now identified causal recurrent somatic activating mutations in GNA14 by whole-exome and targeted sequencing. We found somatic activating GNA14 c.614A>T (p.Gln205Leu) mutations in one KHE, one TA, and one LCH and a GNA11 c.547C>T (p.Arg183Cys) mutation in two LCH lesions. We examined mutation pathobiology via expression of mutant GNA14 or GNA11 in primary human endothelial cells and melanocytes. GNA14 and GNA11 mutations induced changes in cellular morphology and rendered cells growth-factor independent by upregulating the MAPK pathway. Our findings identify GNA14 mutations as a cause of childhood vascular tumors, offer insight into mechanisms of oncogenic transformation by mutations affecting Gaq family members, and identify potential targets for therapeutic intervention.

}, keywords = {Cells, Cultured, Child, Preschool, Enzyme Activation, GTP-Binding Protein alpha Subunits, GTP-Binding Protein alpha Subunits, Gq-G11, Human Umbilical Vein Endothelial Cells, Humans, Infant, Infant, Newborn, Intercellular Signaling Peptides and Proteins, Male, MAP Kinase Signaling System, Melanocytes, Mitogen-Activated Protein Kinases, Mutation, Proto-Oncogene Proteins c-akt, Vascular Neoplasms}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.06.010}, author = {Lim, Young H and Bacchiocchi, Antonella and Qiu, Jingyao and Straub, Robert and Bruckner, Anna and Bercovitch, Lionel and Narayan, Deepak and McNiff, Jennifer and Ko, Christine and Robinson-Bostom, Leslie and Antaya, Richard and Halaban, Ruth and Choate, Keith A} } @article {61, title = {Somatic Mutations in NEK9 Cause Nevus Comedonicus.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 May 05}, pages = {1030-1037}, abstract = {

Acne vulgaris (AV) affects most adolescents, and of those affected, moderate to severe disease occurs in 20\%. Comedones, follicular plugs consisting of desquamated keratinocytes and sebum, are central to its pathogenesis. Despite high heritability in first-degree relatives, AV genetic determinants remain incompletely understood. We therefore employed whole-exome sequencing (WES) in nevus comedonicus (NC), a rare disorder that features comedones and inflammatory acne cysts in localized, linear configurations. WES identified somatic NEK9 mutations, each affecting highly conserved residues within its kinase or RCC1 domains, in affected tissue of three out of three NC-affected subjects. All mutations are gain of function, resulting in increased phosphorylation at Thr210, a hallmark of NEK9 kinase activation. We found that comedo formation in NC is marked by loss of follicular differentiation markers, expansion of keratin-15-positive cells from localization within the bulge to the entire sub-bulge follicle and cyst, and ectopic expression of keratin 10, a marker of interfollicular differentiation not present in normal follicles. These findings suggest that NEK9 mutations in NC disrupt normal follicular differentiation and identify NEK9 as a potential regulator of follicular homeostasis.

}, keywords = {Adolescent, Adult, Child, Female, Fluorescent Antibody Technique, High-Throughput Nucleotide Sequencing, Humans, Male, Mutation, Nevus, NIMA-Related Kinases, Prognosis, Skin Neoplasms, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.03.019}, author = {Levinsohn, Jonathan L and Sugarman, Jeffrey L and McNiff, Jennifer M and Antaya, Richard J and Choate, Keith A} }