TY - JOUR
T1 - Costello and cardio-facio-cutaneous syndromes
T2 - Moving toward clinical trials in RASopathies
AU - Rauen, Katherine A
AU - Banerjee, Anuradha
AU - Bishop, W. Robert
AU - Lauchle, Jennifer O.
AU - Mccormick, Frank
AU - Mcmahon, Martin
AU - Melese, Teri
AU - Munster, Pamela N.
AU - Nadaf, Sorena
AU - Packer, Roger J.
AU - Sebolt-Leopold, Judith
AU - Viskochil, David H.
PY - 2011/5/15
Y1 - 2011/5/15
N2 - 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.
AB - 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.
KW - BRAF inhibitor
KW - Cardio-facio-cutaneous syndrome
KW - Clinical trial
KW - Costello syndrome
KW - Farnesyl transferase inhibitor
KW - MEK inhibitor
KW - Neurofibromatosis type 1
KW - Ras/MAPK
KW - RASopathy
KW - Signal transduction pathway
KW - Therapy
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U2 - 10.1002/ajmg.c.30294
DO - 10.1002/ajmg.c.30294
M3 - Article
C2 - 21495172
AN - SCOPUS:79955034369
VL - 157
SP - 136
EP - 146
JO - American Journal of Medical Genetics
JF - American Journal of Medical Genetics
SN - 1552-4825
IS - 2
ER -