Costello syndrome is a rare, congenital disorder that is part of a larger group of genetic conditions known as the RASopathies. This group, which also includes conditions like Noonan syndrome and cardiofaciocutaneous (CFC) syndrome, is characterized by mutations in genes that are part of a critical cell signaling pathway called the RAS/MAPK pathway.

To understand what goes wrong, it is helpful to use an analogy.

• Think of the RAS/MAPK pathway as a crucial “Go!” signal inside every cell. It is like a cascade of falling dominoes that relays messages from the cell’s surface down to its nucleus, telling the cell when to grow, divide, and differentiate into different types of tissue.
• In a healthy person, this “Go!” signal is tightly controlled. The dominoes only fall when they are supposed to.
• In Costello syndrome, a mutation affects a gene called HRAS, which creates one of the first and most powerful dominoes in this chain.
• This mutation makes the HRAS domino “stuck” in the “on” position. It is constantly tipping over, keeping the “Go!” signal permanently active.
• This uncontrolled and relentless growth signal disrupts the normal, orderly development of many tissues throughout the body, leading to the characteristic features of the syndrome, including the cardiac issues, skin changes, and an increased risk of certain tumors.

In my experience, Costello syndrome often becomes evident in early infancy when a child presents with feeding difficulties, developmental delays, and unusual facial features.

The cause of Costello syndrome is a specific mutation in the HRAS gene. The HRAS gene is a type of gene known as a proto-oncogene. In its normal state, it plays a vital role as a master switch in controlling cell growth and division.

When a mutation occurs in the HRAS gene, it produces a protein that is permanently “switched on.” This leads to the continuous activation of the RAS/MAPK signaling pathway, resulting in uncontrolled cell growth and division. This is not only what disrupts normal development in the womb but is also what underlies the increased lifetime risk of developing certain types of cancer that is associated with the syndrome.

In my experience, parents are often surprised to learn that the condition results from a spontaneous mutation, not something inherited from either parent.

Costello syndrome is a genetic disorder that is present from birth. It is not contagious. How it occurs is a crucial point for parents to understand.

Virtually all cases of Costello syndrome are caused by a de novo (new) mutation.

• This means that the mutation in the HRAS gene is a new, random error that occurred for the first time in that individual. It happened by complete chance during the formation of either the egg or the sperm cell of a parent, or very early in embryonic development.
• The parents have normal genes, and there is absolutely nothing they did or did not do before or during the pregnancy to cause the condition.
• When a condition is de novo, the risk of the parents having another child with the same syndrome is extremely low (less than 1%).

Because the condition is caused by a mutation in just one copy of the HRAS gene, it is an autosomal dominant condition. This means that in the extremely rare instance that an individual with Costello syndrome has children, they would have a 50% chance of passing the condition on.

In my experience, it usually arises sporadically. Most cases are not inherited but occur due to a new mutation during early embryonic development.

Costello syndrome is a multi-system disorder that affects many parts of the body. The signs and symptoms can be variable, but there is a recognizable pattern of features.

Feeding and Growth

• Severe Feeding Difficulties: This is a hallmark and often the most immediate and challenging issue in infancy. Babies with Costello syndrome typically have very low muscle tone (hypotonia), a poor suck, and severe gastroesophageal reflux, making feeding extremely difficult.
• Failure to Thrive: As a result of the severe feeding problems, infants have profound difficulty gaining weight and growing in the first year of life, a condition known as failure to thrive.

Distinctive Craniofacial Features

Many children with Costello syndrome share a characteristic facial appearance.

• A large head (macrocephaly) relative to their body size.
• Coarse facial features.
• A large mouth with full lips.
• A broad nasal bridge.

Skin and Musculoskeletal Features

• Loose, Soft Skin: The skin is often very soft and redundant, with deep creases on the palms of the hands and soles of the feet.
• Hypermobile Joints: Very loose or “double-jointed” joints.
• Papillomas: Small, benign, wart-like growths often develop around the nose, mouth, or anus later in childhood.
• Tight Achilles Tendons.

Cardiac Abnormalities

Heart problems are very common, affecting a majority of individuals.

• Hypertrophic Cardiomyopathy (HCM): A thickening of the heart muscle is the most common cardiac finding.
• Pulmonary Stenosis: A narrowing of the valve leading to the lungs.
• Arrhythmias: Abnormal heart rhythms, like chaotic atrial tachycardia, are a serious concern.

Developmental and Neurological Features

• Developmental Delay: Delays in reaching milestones are universal.
• Intellectual Disability: Most individuals have some degree of intellectual disability, which is typically in the moderate to severe range.
• Friendly Personality: Many parents and doctors note that children with Costello syndrome have a characteristically cheerful, outgoing, and friendly personality.

Increased Cancer Risk

Individuals with Costello syndrome have a significantly increased lifetime risk (estimated around 15%) of developing certain types of childhood cancers.

• The most common tumors are rhabdomyosarcoma (a cancer of soft tissue) and neuroblastoma (a cancer of nerve tissue).

Clinically, I’ve seen signs like short stature, hypertrophic cardiomyopathy, and papillomas around the nose and mouth, making early diagnosis important for screening complications.

The diagnostic journey for Costello syndrome often begins when a baby presents with severe failure to thrive and the characteristic facial and skin features. Diagnosis is usually suspected by a clinical geneticist.

• Clinical Distinction from other RASopathies: Costello syndrome shares many features with Noonan syndrome and CFC syndrome. A geneticist will carefully evaluate the child for the specific features that point more toward Costello, such as the severe feeding issues, the particular skin characteristics, and the hoarse cry.
• Molecular Genetic Testing: The Costello syndrome diagnosis is definitively confirmed with a molecular genetic test from a blood sample. A doctor will order sequencing of the HRAS gene. If a known disease-causing mutation is identified in this gene, the diagnosis is confirmed. This is often done as part of a larger RASopathy gene panel or through Whole Exome Sequencing (WES).
• Comprehensive Evaluation: Once a diagnosis is made, a child must undergo a thorough baseline evaluation by a team of specialists to screen for all the potential associated health issues. This includes an echocardiogram, an abdominal ultrasound, a developmental assessment, and an eye exam.

In my experience, diagnosis sometimes takes time due to overlap with other RASopathies like Noonan or CFC syndrome, facial features and tumor risk often guide testing.

There is no cure for the underlying genetic cause of Costello syndrome. Therefore, management is a lifelong, proactive, and supportive process focused on anticipating, monitoring for, and treating the many health and developmental challenges. This requires a dedicated multidisciplinary team of specialists.

The key management strategies include:

• Feeding and Nutritional Support: This is the most critical intervention in infancy. Due to the severe feeding difficulties, the vast majority of infants with Costello syndrome will require a gastrostomy tube (G-tube) or nasogastric tube (NG-tube) for feeding. This is essential to provide adequate nutrition for growth and to prevent the dangerous complication of aspiration.
• Cardiac Care: Lifelong monitoring by a pediatric cardiologist is essential. This includes regular echocardiograms to monitor the development or progression of hypertrophic cardiomyopathy and to watch for arrhythmias. Medications may be needed.
• Cancer Surveillance: This is a cornerstone of proactive care. Children with Costello syndrome typically follow a surveillance protocol that includes regular abdominal and pelvic ultrasounds (e.g., every 3-6 months) throughout childhood to screen for the early development of tumors like rhabdomyosarcoma and neuroblastoma.
• Developmental Therapies: Intensive early intervention is crucial to help a child reach their maximum potential. This includes:
  • Physical Therapy to manage low muscle tone and improve motor skills.
  • Occupational Therapy to help with fine motor skills, sensory issues, and daily activities.
  • Speech Therapy to address communication and oral-motor feeding challenges.
• Orthopedic Care: Regular monitoring for the development of tight Achilles tendons or scoliosis is needed.
• Educational Support: All children will require an individualized education plan (IEP) and a supportive, specialized school environment.

I’ve found that managing this condition requires a multidisciplinary approach, developmental therapy, cardiac monitoring, dermatologic care, and regular tumor screening are essential.

A diagnosis of Costello syndrome presents a family with a profound and lifelong journey of medical and developmental care. This very rare genetic disorder, caused by a mutation in the HRAS gene, brings with it a host of significant challenges, from severe feeding difficulties in infancy to a constant need for cardiac and cancer surveillance. However, a definitive diagnosis, while difficult to hear, provides families with a crucial roadmap. It replaces uncertainty with a clear action plan. While there is no cure, a proactive, loving, and team-based approach to care can successfully manage complex health needs. In my experience, families benefit most from early intervention and coordinated care. Though the condition is complex, timely management greatly improves outcomes.

National Organization for Rare Disorders (NORD). (2023). Costello Syndrome. Retrieved from https://rarediseases.org/rare-diseases/costello-syndrome/

National Institutes of Health, Genetic and Rare Diseases Information Center (GARD). (2023). Costello syndrome. Retrieved from https://rarediseases.info.nih.gov/diseases/6188/costello-syndrome

Costello Syndrome Family Network (CSFN). (n.d.). What is Costello syndrome?. Retrieved from https://costellosyndrome.org/