Costello Syndrome

Costello syndrome is an autosomal dominant RASopathy caused by activating HRAS variants (usually p.Gly12Ser), with coarse facies, loose skin, feeding difficulty, hypertrophic cardiomyopathy, arrhythmia, developmental delay and a predisposition to tumours. Variants are de novo.

Pathophysiology. Activating HRAS variants lead to constitutive RAS-MAPK signalling, driving overgrowth of some tissues and tumour formation, while impairing growth overall.

Infants have severe feeding problems and failure to thrive, with relative macrosomia in the neonatal period.

Tumour risk is raised throughout life, and surveillance begins in early childhood.

• Coarse facies, full lips, wide mouth, macrocephaly and curly sparse hair
• Loose, soft skin with deep palmar and plantar creases, and papillomata around the mouth and nose
• Severe feeding difficulty and failure to thrive in infancy
• Short stature, relative macrocephaly
• Cardiac disease: hypertrophic cardiomyopathy, pulmonary stenosis, atrial tachycardia
• Developmental delay and intellectual disability, with friendly personality
• Chiari malformation, hydrocephalus and seizures in some
• Hypoglycaemia in infancy and endocrine problems (growth hormone deficiency)
• Tumours: rhabdomyosarcoma, neuroblastoma, bladder carcinoma
• Hypotonia, joint contractures and tight Achilles tendon

• HRAS sequencing (the p.Gly12Ser variant accounts for most cases) or a RASopathy panel.
• Clinical diagnosis from facies, skin and cardiac findings.
• Echocardiography and ECG at diagnosis, with Holter monitoring.
• Brain MRI for Chiari malformation or hydrocephalus.
• Endocrine assessment: glucose in infancy, growth and thyroid tests.
• Baseline abdominal and pelvic ultrasound for tumour surveillance, with urinary catecholamines.

Differential diagnosis.

• Cardiofaciocutaneous syndrome and Noonan syndrome
• Noonan syndrome with multiple lentigines
• Beckwith-Wiedemann syndrome (neonatal macrosomia and hypoglycaemia)
• Pachydermoperiostosis and cutis laxa
• Mucopolysaccharidoses and other storage disorders (coarse facies)
• Rubinstein-Taybi syndrome

• Tumour surveillance: abdominal and pelvic ultrasound every 3 to 4 months to age 8 to 10 years, with urinary catecholamine metabolites at the same intervals (neuroblastoma), then urine dipstick for haematuria yearly from age 10 (bladder cancer) and clinical review. Investigate any new mass promptly.
• Cardiac care: echocardiography and ECG every 6 to 12 months. For hypertrophic cardiomyopathy use propranolol 1 mg/kg daily in two to three divided doses increasing to 4 mg/kg daily. For atrial tachycardia use sotalol or flecainide in specialist care.
• Feeding and growth: nasogastric or gastrostomy feeding in infancy, with omeprazole 0.7 to 1 mg/kg daily for reflux and dietetic support. Treat hypoglycaemia with glucose 2 mL/kg of 10% dextrose and frequent feeds.
• Neurological care: surgery for symptomatic Chiari malformation or hydrocephalus, and levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily for seizures.
• Orthopaedic care: physiotherapy and surgery for contractures and tight Achilles tendon.
• Skin: topical treatment or excision of troublesome papillomata.
• Endocrine care: treat growth hormone deficiency when proved, with cardiology agreement given the cardiomyopathy.
• Development: early intervention, speech therapy and special education.
• Genetic counselling: recurrence risk is very low for de novo variants.

Special groups.

• Adults: continue cardiac and bladder cancer surveillance, and plan transition to adult services.

Monitoring. Abdominal and pelvic ultrasound with urinary catecholamines every 3 to 4 months to age 8 to 10 years, cardiology every 6 to 12 months, and growth, development and feeding review at every visit.

Referral and escalation. Refer to clinical genetics, paediatric cardiology and oncology. Emergency for arrhythmia, syncope, abdominal mass or haematuria.