A 4-year-old boy presents with failure to thrive, coarse facial features, curly hair, and characteristic perioral papillomas. Genetic testing reveals an activating germline mutation in the HRAS proto-oncogene at the locus marked **A** (11p15.5). Which of the following best describes the pathogenic mechanism underlying Costello syndrome in this patient?
A. Haploinsufficiency of the PTPN11 phosphatase gene causing defective negative feedback in growth signaling
B. Constitutive activation of the RAS-MAPK signaling cascade leading to dysregulated cell proliferation and survival in neural-crest-derived tissues
C. Dominant-negative effect of mutant BRAF kinase on downstream MEK1/2 signaling in cardiac myocytes
Loss of function of the p53 tumor suppressor gene resulting in impaired apoptosis
D.
Explanation
Why "Constitutive activation of the RAS-MAPK signaling cascade..." is right
Costello syndrome is caused by germline activating mutations in HRAS at chromosome 11p15.5 (marked A). The pathogenic mechanism is constitutive (continuous) activation of the RAS-MAPK signaling pathway, which drives dysregulated cell proliferation and survival—particularly in neural-crest-derived tissues. This explains the characteristic features: coarse facies, skin laxity, perioral papillomas, failure to thrive, and the markedly elevated risk of embryonal rhabdomyosarcoma and other malignancies. The p.G12S substitution (found in >80% of cases) locks RAS in its active, GTP-bound state, bypassing normal negative regulation.
Why each distractor is wrong
Loss of function of p53: p53 mutations cause Li-Fraumeni syndrome and hereditary cancer predisposition, not Costello syndrome. Costello is caused by a gain-of-function (activating) mutation in HRAS, not loss of a tumor suppressor.
Haploinsufficiency of PTPN11: PTPN11 mutations cause Noonan syndrome, a different RASopathy. While Noonan shares some features with Costello (short stature, cardiac involvement), it does not present with perioral papillomas or the same malignancy profile. PTPN11 haploinsufficiency is distinct from HRAS activation.
Dominant-negative BRAF on MEK1/2: BRAF mutations cause Cardiofaciocutaneous (CFC) syndrome, not Costello. Although both are RASopathies, CFC is caused by BRAF mutations (7q34), not HRAS mutations. The clinical phenotype and malignancy risk differ significantly.
High-YieldNEET PG
Costello syndrome = HRAS activation at 11p15.5 + RAS-MAPK hyperactivation + perioral papillomas + rhabdomyosarcoma risk; distinguish from Noonan (PTPN11) and CFC (BRAF).
Nelson Textbook of Pediatrics, 21st ed.
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