Costello syndrome: Clinical phenotype, genotype, and management guidelines

Abstract

Costello syndrome (CS) is a RASopathy caused by activating germline mutations in HRAS. Due to ubiquitous HRAS gene expression, CS affects multiple organ systems and individuals are predisposed to cancer. Individuals with CS may have distinctive craniofacial features, cardiac anomalies, growth and developmental delays, as well as dermatological, orthopedic, ocular, and neurological issues; however, considerable overlap with other RASopathies exists. Medical evaluation requires an understanding of the multifaceted phenotype. Subspecialists may have limited experience in caring for these individuals because of the rarity of CS. Furthermore, the phenotypic presentation may vary with the underlying genotype. These guidelines were developed by an interdisciplinary team of experts in order to encourage timely health care practices and provide medical management guidelines for the primary and specialty care provider, as well as for the families and affected individuals across their lifespan. These guidelines are based on expert opinion and do not represent evidence-based guidelines due to the lack of data for this rare condition.

Keywords: Costello syndrome; HRAS mutation; RAS/MAPK; RASopathy; management guidelines.

FIGURE 1

Images of an individual male with the most common heterozygous HRAS p.G12S missense mutation. The images demonstrate the classical Costello syndrome craniofacial phenotype. This figure depicts the evolution of his features from birth (a), to 5 months of age (b), one and one-half years of age (c), four and one-half years of age (d), 15 years of age (e), and 23 years of age (f)

FIGURE 2

Images of individuals with rarer HRAS missense mutations. (a) A 3-year-old boy with a heterozygous HRAS p.F156L missense mutation. (b) A 3-year-old girl with a heterozygous HRAS p.Q22K missense mutation. (c) A three and one-half-year-old boy with a heterozygous HRAS p.G12A missense mutation. (d) A five and one-half-year-old girl with a heterozygous HRAS p.G12C missense mutation. (e) A 6-year-old girl with a heterozygous HRAS p.G13C missense mutation. (f) A 26-year-old man with a heterozygous HRAS p.G13D missense mutation