Costello syndrome

Costello syndrome is inherited in an autosomal dominant manner. The recurrence risk to siblings of a proband is low but not negligible if neither parent carries the pathogenic variant, owing to the possibility of parental germline mosaicism. Each child of an affected individual has a 50% risk of inheriting the variant. Prenatal molecular testing is possible once the familial pathogenic variant has been identified.

Diagnosis is established by molecular genetic testing identifying a pathogenic variant in HRAS. Clinical suspicion arises from the combination of severe feeding difficulties, characteristic facial features, perioral and perianal papillomata, and cardiac involvement.

Main differential diagnoses include:

• : shares hypotonia, feeding difficulties, hypertrophic cardiomyopathy and pulmonic valve stenosis; distinguished by absence of papillomata and a much lower malignancy risk; BRAF, KRAS, MAP2K1, MAP2K2.
• : shares short stature, developmental delay and overlapping cardiac defects; distinguished by pectus deformity, broad/webbed neck and lymphatic dysplasia; PTPN11, SOS1, RAF1, RIT1 and others.
• Beckwith-Wiedemann syndrome: shares neonatal overgrowth, coarse facial features and embryonal tumour predisposition; distinguished by macroglossia, omphalocele and visceromegaly; 11p15.5 imprinting alterations or CDKN1C pathogenic variants.

• Establishing the diagnosis: A confirmed molecular diagnosis ends the diagnostic odyssey, clarifies prognosis and informs clinical management.
• Specific and individualised surveillance: A molecular diagnosis enables condition-specific surveillance, including cardiac follow-up and tumour screening, and is a prerequisite for targeted medical care planned by the treating physicians in consultation with the affected individual.
• Family member testing: Identification of the familial pathogenic HRAS variant allows targeted testing of at-risk relatives and informed genetic counselling.

• Gripp KW, Weaver KN. HRAS-related Costello syndrome. 2006 Aug 29 [updated 2026 May 21]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: 20301680.
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• Leoni C, Viscogliosi G, Tartaglia M, Aoki Y, Zampino G. Multidisciplinary management of Costello syndrome: current perspectives. J Multidiscip Healthc. 2022;15:1277-1296. PMID: .
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