Clinical characteristics: While the majority of individuals with HRAS-related Costello syndrome (Costello syndrome) share characteristic findings affecting multiple organ systems, the phenotypic spectrum is wide, ranging from a mild or attenuated phenotype to a severe phenotype with early-lethal complications. Costello syndrome is typically characterized by failure to thrive in infancy as a result of severe postnatal feeding difficulties; short stature; developmental delay or intellectual disability; coarse facial features (full lips, large mouth, full nasal tip); curly or sparse, fine hair; loose, soft skin with deep palmar and plantar creases; papillomata of the face and perianal region; diffuse hypotonia and joint laxity with ulnar deviation of the wrists and fingers; tight Achilles tendons; and cardiac involvement including cardiac hypertrophy (usually hypertrophic cardiomyopathy), congenital heart defects (usually valvular pulmonic stenosis), and arrhythmia (usually supraventricular tachycardia, especially abnormal atrial rhythm / multifocal atrial tachycardia or ectopic atrial tachycardia). Relative or absolute macrocephaly is typical, and postnatal cerebellar overgrowth can result in the development of a Chiari I malformation with associated anomalies including hydrocephalus or syringomyelia. Individuals with Costello syndrome have an approximately 15% lifetime risk for malignant tumors including rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults.
Diagnosis/testing: The diagnosis of Costello syndrome is established in a proband with suggestive clinical findings and a heterozygous HRAS pathogenic variant identified by molecular genetic testing.
Management: Targeted therapy: Trametinib (MEK inhibitor) for treatment of hypertrophic cardiomyopathy with heart failure that is refractory to standard treatment.
Supportive care: Failure to thrive is the most common and challenging clinical problem; most infants require nasogastric or gastrostomy feeding, and many require Nissen fundoplication. Cardiac manifestations and malignancies are managed through standard protocols. Ulnar deviation of the wrists and fingers often requires early bracing and occupational and/or physical therapy; tight Achilles tendons may require surgical tendon lengthening. Developmental delay requires early intervention programs and individualized education strategies. Recurrent facial papillomata may require removal. General anesthesia may pose a risk to those with hypertrophic cardiomyopathy or those predisposed to types of atrial tachycardia.
Surveillance: Monitoring for neonatal hypoglycemia; echocardiography with electrocardiogram at the time of diagnosis with subsequent follow up by a cardiologist; abdominal and pelvic ultrasound examinations to screen for rhabdomyosarcoma and neuroblastoma every three to six months until age eight to ten years may be considered; annual urinalysis for evidence of hematuria to screen for bladder cancer beginning at age ten years.
Genetic counseling: Costello syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, an individual with Costello syndrome has the disorder as the result of an HRAS pathogenic variant inherited from a heterozygous parent; vertical transmission has been reported in two families with the rare, attenuated phenotype of Costello syndrome. If the HRAS pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. Recurrence of Costello syndrome in sibs has been reported and is suspected to be the result of germline mosaicism in a parent. Individuals with classic Costello syndrome typically do not reproduce. If an HRAS pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
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