Costello syndrome results from pathogenic variants in the HRAS gene (chromosome 11), the sole gene associated with this condition at DEFINITIVE evidence strength per ClinGen classification. HRAS encodes a protein in the RAS signaling pathway; pathogenic HRAS variants lead to constitutive activation of this cascade, driving abnormal cell growth across multiple tissue types. The condition belongs to the RASopathy group of disorders, as reflected in active clinical trial designations in this packet. Penetrance is documented at 100% in GeneReviews, meaning all individuals with a pathogenic HRAS variant develop features of Costello syndrome. A systematic review of 146 individuals with HRAS pathogenic variants found no apparent genotype-phenotype correlation for major cardiac features including hypertrophic cardiomyopathy, multifocal tachycardia, and aortic dilatation, per GeneReviews. The range of manifestations among affected individuals reflects variable expressivity rather than differences in penetrance.

No consensus clinical diagnostic criteria for Costello syndrome have been published, per GeneReviews. Suspicion is based on prenatal and postnatal clinical findings together with family history. Prenatal features include polyhydramnios and characteristic ulnar deviation of the wrists on ultrasound. Postnatal clinical findings include diffuse hypotonia, feeding difficulties, characteristic facial features, papillomata, joint laxity, soft skin changes, and the multisystem involvement described in the disease definition. Molecular genetic testing identifying a pathogenic variant in HRAS confirms the diagnosis. Costello syndrome shares clinical overlap with cardiofaciocutaneous syndrome and Noonan syndrome, which can be difficult to distinguish clinically, particularly in infancy. Multidisciplinary evaluation addressing cardiac, neurological, growth, and tumor-risk aspects is part of the initial assessment process described in GeneReviews clinical management guidelines.

No FDA-approved treatments specifically for Costello syndrome are available in this packet. Clinical practice guidelines for management of Costello syndrome have been published, as referenced in GeneReviews. Management involves multidisciplinary evaluation and care directed at individual system manifestations. Initial assessments following diagnosis address the extent of involvement across cardiac, neurological, growth, musculoskeletal, cutaneous, and tumor-risk domains. Supportive care targeting specific manifestations represents the general approach to management. Tumor surveillance is a recognized component of long-term management given the increased lifetime tumor risk documented in the disease definition. GeneReviews also notes that aggressive feeding therapy in infancy is not expected to improve oral intake and may result in oral aversion, providing context for management decisions around the characteristic early feeding difficulties.

Natural history data specific to Costello syndrome are not certified in this packet. The condition follows a multisystem course characterized by the features described in the disease definition and GeneReviews clinical description. Cardiac involvement and the increased lifetime tumor risk are recognized as clinically significant determinants of long-term outcomes. Outcomes vary across affected individuals. Penetrance is 100% per GeneReviews documentation, but variable expressivity means the specific combination and severity of manifestations differ among those affected.

Several clinical trials are currently investigating Costello syndrome within the broader RASopathy research framework. Active studies include a clinical and genetic epidemiological study of RASopathies (NCT04888936), a solid tumor study in RASopathies (NCT05761314), a biorepository for RASopathy research (NCT04395495), and a caregiver-focused acceptance and commitment therapy study (NCT05361811). A clinical genetics eligibility screening survey (NCT07005297) is also listed. Active clinical trials for this condition are listed on ClinicalTrials.gov.