Costello syndrome

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Costello syndrome
Synonyms	Facio-cutaneous syndrome
Pronounce
Specialty	Medical genetics
Symptoms	Developmental delay, intellectual disability, distinctive facial features, cardiomyopathy, cancer
Complications	N/A
Onset	Infancy
Duration	Lifelong
Types	N/A
Causes	Mutations in the HRAS gene
Risks
Diagnosis	Genetic testing, clinical evaluation
Differential diagnosis	Noonan syndrome, Cardiofaciocutaneous syndrome
Prevention
Treatment	Supportive care, management of symptoms
Medication
Prognosis	Variable, depends on complications
Frequency	Rare, estimated 1 in 1.25 million
Deaths

Alternate names

Faciocutaneoskeletal syndrome; FCS syndrome

Definition

Costello syndrome is a rare condition that affects many different parts of the body. Signs and symptoms generally include developmental delay, intellectual disability, distinctive facial features, loose folds of extra skin (especially on the hands and feet), and unusually flexible joints. Affected people may also have heart abnormalities such as tachycardia, structural heart defects, and hypertrophic cardiomyopathy.

Summary

• Costello syndrome belongs to a group of related conditions called the RASopathies.
• These conditions have some overlapping features and are all caused by genetic changes that disrupt the body's RAS pathway, affecting growth and development. The features of Costello syndrome overlap significantly with two of the RASopathies, cardiofaciocutaneous (CFC) syndrome and Noonan syndrome.

Epidemiology

• This condition is very rare; it probably affects 200 to 300 people worldwide.
• Reported estimates of Costello syndrome prevalence range from 1 in 300,000 to 1 in 1.25 million people.

Cause

• Mutations in the HRAS gene cause Costello syndrome.
• This gene provides instructions for making a protein called H-Ras, which is part of a pathway that helps control cell growth and division.

Gene mutations

• Mutations that cause Costello syndrome lead to the production of an H-Ras protein that is abnormally turned on (active).
• The overactive protein directs cells to grow and divide constantly, which can lead to the development of cancerous and noncancerous tumors.
• It is unclear how mutations in the HRAS gene cause the other features of Costello syndrome, but many of the signs and symptoms probably result from cell overgrowth and abnormal cell division.
• Some people with signs and symptoms like those of Costello syndrome do not have an identified mutation in the HRAS gene.
• These individuals may actually have CFC syndrome or Noonan syndrome, which are caused by mutations in related genes.
• The proteins produced from these genes interact with one another and with the H-Ras protein as part of the same cell growth and division pathway.
• These interactions help explain why mutations in different genes can cause conditions with overlapping signs and symptoms.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

• Costello syndrome is considered to be an autosomal dominant condition, which means one copy of the altered gene in each cell is sufficient to cause the disorder.
• Almost all reported cases have resulted from new gene mutations and have occurred in people with no history of the disorder in their family.

Signs and symptoms

• Signs and symptoms generally include developmental delay, intellectual disability, distinctive facial features, loose folds of extra skin (especially on the hands and feet), and unusually flexible joints.
• Affected people may also have heart abnormalities such as tachycardia, structural heart defects, and hypertrophic cardiomyopathy.
• Beginning in early childhood, people with Costello syndrome additionally have an increased risk to develop certain cancerous and noncancerous tumors.

Clinical presentation

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormal fingernail morphology(Abnormal fingernails)
• Acanthosis nigricans(Darkened and thickened skin)
• Concave nail(Spoon-shaped nails)
• Deep-set nails
• Delayed skeletal maturation(Delayed bone maturation)
• Depressed nasal bridge(Depressed bridge of nose)
• Failure to thrive in infancy(Faltering weight in infancy)
• Hyperkeratosis
• Lack of skin elasticity
• Macrocephaly(Increased size of skull)
• Narrow palate(Narrow roof of mouth)
• Pulmonic stenosis(Narrowing of pulmonic valve)
• Redundant skin(Loose redundant skin)
• Short neck(Decreased length of neck)
• Short stature(Decreased body height)
• Ventricular septal defect(Hole in heart wall separating two lower heart chambers)
• Woolly hair(Kinked hair)

30%-79% of people have these symptoms

• Abnormal dermatoglyphics(Abnormal fingerprints)
• Abnormality of dental enamel(Abnormal tooth enamel)
• Cerebral cortical atrophy(Decrease in size of the outer layer of the brain due to loss of brain cells)
• Cryptorchidism(Undescended testes)
• Epicanthus(Eye folds)
• Full cheeks(Apple cheeks)
• Gastroesophageal reflux(Acid reflux)
• Hypertrophic cardiomyopathy(Enlarged and thickened heart muscle)
• Hypoplastic toenails(Underdeveloped toenails)
• Intellectual disability(Mental deficiency)
• Joint hyperflexibility(Joints move beyond expected range of motion)
• Keratoconus(Bulging cornea)
• Macroglossia(Abnormally large tongue)
• Mitral valve prolapse
• Papilloma
• Polyhydramnios(High levels of amniotic fluid)
• Strabismus(Cross-eyed)
• Thick lower lip vermilion(Increased volume of lower lip)
• Thickened Achilles tendon
• Thickened nuchal skin fold(Thickened skin folds of neck)
• Ulnar deviation of finger(Finger bends toward pinky)

5%-29% of people have these symptoms

• Coarse facial features(Coarse facial appearance)
• Generalized hyperpigmentation
• Large earlobe(Fleshy earlobe)
• Large face(Big face)
• Low-set, posteriorly rotated ears
• Poor suck(Poor sucking)
• Renal insufficiency(Renal failure)

Diagnosis

The diagnosis of Costello syndrome is based on clinical findings and a heterozygous HRAS pathogenic variant an confirmed by molecular genetic testing.[1].

Treatment

• Failure to thrive is the most common and challenging clinical problem[2].
• Most infants require nasogastric or gastrostomy feeding
• Many require Nissen fundoplication.
• Treatment of cardiac manifestations and malignancy is routine.
• 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 disability requires early-intervention programs and individualized education strategies.
• Recurrent facial papillomata may require routine removal with dry ice.
• Hemodynamically significant valvar stenoses require antibiotic prophylaxis for subacute bacterial endocarditis
• Anesthesia may pose a risk to those with hypertrophic cardiomyopathy or those predisposed to some types of atrial tachycardia.

NIH genetic and rare disease info

• NIH info on Costello syndrome

Costello syndrome is a rare disease.

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