Costello syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Costello syndrome is a rare disorder that affects many parts of the body. This condition is characterized by delayed development, loose folds of skin (which are especially noticeable on the hands and feet), unusually flexible joints, heart problems, short stature, and distinctive facial features.

Children with Costello syndrome are often delayed in reaching developmental milestones, such as speaking, sitting, and walking. Affected individuals may also have intellectual disabilities that can vary in severity.

Distinctive facial features in people with Costello syndrome typically include a prominent forehead, full cheeks, and full lips. Infants with Costello syndrome may be larger than average at birth, but most have difficulty eating and grow more slowly than other children. Affected individuals may have gastrointestinal problems that include constipation or a backflow of stomach acids into the esophagus (gastroesophageal reflux or GERD). People with this condition have short stature compared to their family and peers and may have reduced growth hormone levels.

Heart problems are common, including an abnormal heartbeat (arrhythmia), structural heart defects, and a type of heart disease that enlarges and weakens the heart muscle (hypertrophic cardiomyopathy). Neurological problems in people with Costello syndrome include seizures, weak muscle tone (hypotonia), and a structural abnormality of the brain called a Chiari I malformation. Costello syndrome can cause vision problems, such as nearsightedness (myopia), farsightedness (hyperopia), or eyes that do not point in the same direction (strabismus). Hearing loss may also occur.

Other signs and symptoms of Costello syndrome can include tight Achilles tendons (which connect the calf muscles to the heel), recurrent respiratory infections, dry and thickened skin, skeletal abnormalities, and dental problems.

Beginning in early childhood, people with Costello syndrome have a higher risk of developing certain cancerous and noncancerous tumors compared to the general population. The most common noncancerous tumors associated with this condition are papillomas, which are small, wart-like growths that usually develop around the nose and mouth or near the anus. The most common cancerous tumor associated with Costello syndrome is a childhood cancer called rhabdomyosarcoma, which begins in muscle tissue. Neuroblastoma, a tumor that arises in developing nerve cells, has also been reported in children and adolescents with this syndrome. In addition, some teenagers with Costello syndrome have developed transitional cell carcinoma, a form of bladder cancer that is usually seen in older adults.

The signs and symptoms of Costello syndrome overlap significantly with those of two other genetic conditions, cardiofaciocutaneous syndrome (CFC syndrome) and Noonan syndrome. In affected infants, it can be difficult to tell the three conditions apart based on their physical features. However, the conditions can be distinguished by their genetic causes and by the specific patterns of signs and symptoms that develop later in childhood.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also called 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. Variants 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 tumors. It is unclear how variants 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 variant in the HRAS gene. These individuals may actually have CFC syndrome or Noonan syndrome, which are caused by variants 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. This pathway is called the RAS/MAPK signaling pathway, so these three conditions are sometimes referred to as RASopathies. These interactions help explain why variants in different genes can cause conditions with overlapping signs and symptoms.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases of this condition result from new (de novo) variants in the gene that occur during the formation of reproductive cells (eggs or sperm) in an affected individual's parent or in early embryonic development. These affected individuals have no history of the disorder in their family.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

This condition is very rare; it probably affects 100 to 1,500 people worldwide. The estimates of Costello syndrome prevalence range from 1 in 300,000 to 1 in 1.25 million people.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormal fingernail morphology · Very frequent (99-80%)

An abnormality of the fingernails.

Abnormality of the skin · Very frequent (99-80%)

An abnormality of the skin.

Acanthosis nigricans · Very frequent (99-80%)

A dermatosis characterized by thickened, hyperpigmented plaques, typically on the intertriginous surfaces and neck.

Concave nail · Very frequent (99-80%)

The natural longitudinal (posterodistal) convex arch is not present or is inverted.

Deep-set nails · Very frequent (99-80%)

Deeply placed nails.

Delayed skeletal maturation · Very frequent (99-80%)

A decreased rate of skeletal maturation. Delayed skeletal maturation can be diagnosed on the basis of an estimation of the bone age from radiographs of specific bones in the human body.

Depressed nasal bridge · Very frequent (99-80%)

Posterior positioning of the nasal root in relation to the overall facial profile for age.

Feeding difficulties in infancy · Very frequent (99-80%)

Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.

Other findings in the same source

From: Orphanet

Additional reported features include Hyperkeratosis (Very frequent (99-80%)); Macrocephaly (Very frequent (99-80%)); Narrow palate (Very frequent (99-80%)); Ptosis (Very frequent (99-80%)); Pulmonic stenosis (Very frequent (99-80%)); Redundant skin (Very frequent (99-80%)); Short neck (Very frequent (99-80%)); Short stature (Very frequent (99-80%)); Ventricular septal defect (Very frequent (99-80%)); Woolly hair (Very frequent (99-80%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Costello syndrome is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Costello syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.