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SynopsisCostello syndrome is a congenital multisystem disorder caused by a heterozygous germline mutation in HRAS, a proto-oncogene on chromosome 11p15. The majority of patients with Costello syndrome have a de novo autosomal dominant mutation that leads to dysregulation of the Ras / mitogen-activated protein kinase (MAPK) pathway, which regulates cellular differentiation and proliferation.
The syndrome presents with characteristic coarse facial features, distinctive hand posture, intellectual disability, severe feeding difficulty, failure to thrive, short stature, cardiac problems, and a predisposition to neoplasia.
Costello syndrome is very rare: approximately 300 patients have been reported. Boys and girls are equally affected.
Q87.89 – Other specified congenital malformation syndromes, not elsewhere classified
309776008 – Costello syndrome
Differential Diagnosis & PitfallsCostello syndrome belongs to the RASopathies, a class of genetic syndromes that are caused by dysregulation of the Ras / MAPK pathway and that includes Noonan syndrome and cardiofaciocutaneous syndrome. The RASopathies have overlapping features.
- Cardiofaciocutaneous syndrome – Caused by mutations in BRAF, MEK1, MEK2, or KRAS genes; characterized by a distinctive craniofacial appearance, cutaneous abnormalities, congenital heart defects, growth retardation, and intellectual disability; in contrast to Costello syndrome, hair is more consistently sparse / curly, and papillomata and malignant tumors are not seen.
- Noonan syndrome – Caused by mutations in PTPN11 gene; characterized by distinctive facial features, short stature, congenital heart defects, and chest deformity with superior pectus carinatum and inferior pectus excavatum; in contrast to Costello syndrome, failure to thrive and feeding difficulties are less severe.