Costello Syndrome: Symptoms, Types, Causes and Treatment

Costello syndrome is a rare genetic disorder that affects multiple body systems and presents a unique set of challenges for individuals and their families. Characterized by distinctive facial features, developmental delays, cardiac complications, and a predisposition to certain tumors, Costello syndrome is part of a group of conditions known as RASopathies. Understanding its symptoms, types, underlying causes, and approaches to treatment is essential for clinicians, caregivers, and those seeking to improve the lives of affected individuals.

Symptoms of Costello Syndrome

Costello syndrome manifests through a broad spectrum of symptoms, often evident from early infancy. These symptoms affect physical appearance, growth, neurological development, and various organ systems. Recognizing these features is crucial for early diagnosis and timely intervention.

Symptom	Description	Prevalence/Significance	Source(s)
Facial	Coarse face, macrocephaly, depressed nasal bridge	Highly characteristic; present in most cases	1 2 10 13
Skin	Loose, redundant skin; papillomata, cutis laxa	Common, includes risk of warts	1 2 11
Growth	Prenatal overgrowth, postnatal growth retardation	Failure to thrive; short stature	1 3 17
Neurological	Developmental delay, intellectual disability, seizures	Ranges from mild to severe	3 10 12
Cardiac	Cardiomyopathy, arrhythmias, structural defects	Frequent and clinically significant	1 6 13 14
Musculoskeletal	Hypotonia, joint laxity, skeletal deformities	Orthopedic complications common	4
Tumor Risk	Predisposition to rhabdomyosarcoma, other tumors	Increased risk; needs surveillance	1 9 11 13
Behavior	Friendly, outgoing, but also irritability in infancy	Noted in infancy, sociable later	1 3
Feeding	Severe feeding difficulties, failure to thrive	Often requires tube feeding	3 17

Table 1: Key Symptoms

Facial and Skin Features

Costello syndrome is often recognized by its distinct facial appearance—coarse features, macrocephaly (large head), a depressed nasal bridge, and thick lips. The skin tends to be loose and redundant, resembling cutis laxa, and many individuals develop small benign growths called papillomata, especially around the mouth and nostrils. These facial and skin signs are often the first clues for clinicians 1 2 10 11 13.

Growth and Feeding

Affected infants may be larger than average at birth (prenatal overgrowth), but they soon experience significant postnatal growth retardation. Feeding difficulties are often severe, leading to failure to thrive and the need for tube feeding in infancy 1 3 17. Short stature is a persistent issue throughout life.

Neurodevelopmental and Behavioral Aspects

Developmental delay is a hallmark, with intellectual disability ranging from mild to severe. While many children are described as sociable and friendly, infants can exhibit unexpected irritability, hypersensitivity to stimuli, sleep disturbances, and shyness—symptoms that tend to resolve by early childhood 3 12. Seizures and structural brain abnormalities, including macrocephaly and cerebellar overgrowth, are common 3 10 12.

Cardiac and Musculoskeletal Complications

Cardiac involvement includes hypertrophic cardiomyopathy, arrhythmias, and congenital heart defects. These can be life-threatening and require close monitoring 1 6 13 14. Musculoskeletal findings include hypotonia (low muscle tone), joint laxity, scoliosis, kyphosis, contractures, and distinctive hand and foot deformities. Osteopenia and osteoporosis are also noted 4.

Tumor Predisposition

Children with Costello syndrome face a higher risk of developing certain tumors, especially rhabdomyosarcoma and other embryonal tumors. The estimated risk is about 15-17%, emphasizing the importance of regular cancer screening 1 9 11 13.

Types of Costello Syndrome

While Costello syndrome is a single clinical entity, its manifestations can vary based on the specific mutation in the HRAS gene. Understanding these types helps tailor care and anticipate complications.

Type/Variant	HRAS Mutation	Distinct Features	Source(s)
Classic	p.Gly12Ser (G12S)	Most common; typical phenotype	5 7 8 11 13
Rare Variants	p.Gly12Asp/Cys (G12D/C), p.Gly13Asp/Cys (G13D/C), K117R, etc.	Atypical features, variable tumor risk	5 8 11
Severe Neonatal	Rare mutations (G12D, G12C, others)	Severe cardiomyopathy, multisystem disease	5 8 11
Mosaic	Somatic mosaicism for HRAS variant	Milder/atypical presentation	8

Table 2: Types and Genetic Variants

Classic Costello Syndrome

The majority of Costello syndrome cases—more than 80%—are caused by a specific mutation in the HRAS gene, p.Gly12Ser (G12S). These individuals tend to display the full spectrum of features described above, including coarse facial features, skin abnormalities, growth failure, intellectual disability, and tumor risk 5 7 11 13.

Rare HRAS Variants and Phenotypic Spectrum

Other, less common mutations (such as p.Gly12Asp, p.Gly12Cys, p.Gly13Asp, and K117R) are associated with atypical or more severe presentations. For example, certain rare mutations may result in less coarse facial features, slower growing and unusual hair, or a reduced risk of malignancy 8 11. Conversely, some variants (e.g., G12D, G12C) have been linked with particularly severe neonatal disease, including profound cardiac and pulmonary complications 5 8 11.

Severe Neonatal Cases

Severe neonatal forms of Costello syndrome are typically associated with rare HRAS mutations. These infants may present with life-threatening cardiomyopathy, hypoglycemia, renal and respiratory abnormalities, and multisystem disease shortly after birth. Recognizing these variants is essential for prognosis and management 5.

Mosaic and Mild Presentations

Somatic mosaicism—where only a proportion of the body's cells carry the HRAS mutation—can lead to milder or atypical forms of Costello syndrome 8. These cases may be more challenging to diagnose and may not exhibit the full classic phenotype.

Causes of Costello Syndrome

Costello syndrome is rooted in genetics, with a single gene—HRAS—responsible for the disorder. Advances in molecular genetics have revealed how specific mutations disrupt cellular pathways, leading to the diverse clinical picture observed in affected individuals.

Cause	Description	Mechanism/Consequence	Source(s)
HRAS Mutation	Heterozygous de novo missense mutations	Dysregulated Ras/MAPK pathway	7 9 11 13
Germline Origin	Usually paternal germline; not inherited	De novo, not familial	9 11 13
Cellular Effect	Constitutive HRAS activation	Abnormal cell growth/differentiation	7 12 13
Pathway	Ras/MAPK pathway dysregulation	Affects heart, brain, tumor risk	12 13 16

Table 3: Causes and Mechanisms

HRAS Gene Mutations

Costello syndrome is caused by heterozygous missense mutations in the proto-oncogene HRAS, located on chromosome 11. The most common substitution is p.Gly12Ser (G12S), but multiple other activating mutations have been identified 7 9 11 13. These mutations are almost always de novo, meaning they arise spontaneously and are not inherited from the parents.

Molecular and Cellular Effects

The HRAS mutations lead to constitutive or prolonged activation of the HRAS protein, a crucial regulator of the Ras/mitogen-activated protein kinase (MAPK) pathway. This pathway governs cell proliferation, differentiation, and survival. Dysregulation results in abnormal development of multiple organ systems, underpinning the multisystem features of Costello syndrome 7 12 13.

Germline versus Somatic Mutations

While HRAS mutations are well known in cancer biology as drivers of tumorigenesis, in Costello syndrome these mutations occur in the germline and affect all or most cells of the body. Notably, these are typically introduced in the paternal germline 9 13. The same mutations, when occurring somatically (in only certain tissues), are associated with cancers rather than congenital syndromes.

Impact on Organ Systems

Excessive HRAS signaling affects the timing and pattern of brain development, leading to intellectual disability, as well as heart development, causing congenital heart disease and cardiomyopathy. The mutation also impairs mitochondrial function, contributing to cardiac and muscle problems, and increases the risk of certain tumors 12 13 16.

Treatment of Costello Syndrome

There is no cure for Costello syndrome, but management focuses on addressing the multisystem complications through coordinated, multidisciplinary care. Advances in understanding its molecular basis are opening doors to new therapeutic possibilities.

Treatment	Purpose/Target	Special Considerations	Source(s)
Cardiac Care	Manage cardiomyopathy, arrhythmias	Regular monitoring, specialized care	6 14
Tumor Surveillance	Early detection of malignancies	Routine imaging, clinical exams	9 11 13
Orthopedic Management	Address skeletal/joint issues	Surgery, physiotherapy, screening	4
Growth Hormone Therapy	Treat growth hormone deficiency	Only with close cardiac/oncology supervision	15 17 18
Feeding Support	Ensure adequate nutrition	Tube feeding in infancy, gastrostomy	3 17
Neurodevelopmental Support	Address developmental delays	Early intervention, special education	3 12
Potential Targeted Therapies	Mitochondrial modulators, signaling inhibitors	Experimental, under investigation	12 14 16

Table 4: Treatment Approaches

Cardiac and Tumor Management

Given the high frequency and seriousness of cardiac complications, individuals with Costello syndrome require ongoing cardiology care, including regular echocardiograms and electrocardiograms. Arrhythmias and hypertrophic cardiomyopathy are treated according to standard protocols, but with heightened vigilance due to the underlying genetic predisposition 6 14.

Because of the increased tumor risk, annual abdominal and pelvic ultrasounds (and other imaging as needed) are recommended to enable early detection and treatment of rhabdomyosarcoma and other malignancies 9 11 13.

Orthopedic and Growth Management

Orthopedic complications—such as scoliosis, hip dysplasia, and joint contractures—often require intervention. Early and regular evaluation by an orthopedic surgeon is advised, and physiotherapy can help maintain mobility. Surgical correction may be needed for severe deformities 4.

Some children have documented growth hormone deficiency and may benefit from recombinant growth hormone therapy. However, GH treatment must be approached with caution, given the increased risk for cardiac complications and tumors; close monitoring by endocrinology, cardiology, and oncology is essential 15 17 18.

Nutritional and Developmental Support

Feeding difficulties are prominent in infancy; tube feeding or gastrostomy may be necessary to ensure adequate nutrition and growth 3 17. Early intervention programs, speech therapy, occupational therapy, and individualized education plans help address developmental delays and optimize functional outcomes 3 12.

Emerging and Experimental Therapies

Research into the molecular underpinnings of Costello syndrome has identified new therapeutic targets. Treatments aimed at improving mitochondrial function and modulating abnormal signaling pathways (e.g., using mitochondrial modulators or Ras/MAPK pathway inhibitors) show promise in preclinical models 12 14 16. These approaches may one day provide more effective management of the syndrome’s core features.

Conclusion

Costello syndrome is a rare, multisystem disorder rooted in HRAS gene mutations that disrupt cellular signaling and development. While challenging, advances in research and multidisciplinary care are improving outcomes and quality of life for those affected.

Key Takeaways:

• Symptoms include distinctive facial features, loose skin, growth failure, developmental delay, cardiac disease, orthopedic complications, and increased tumor risk.
• Types are defined by specific HRAS mutations, with the classic G12S variant being most common; rare mutations can lead to atypical or severe neonatal presentations.
• Causes are heterozygous de novo mutations in HRAS, leading to dysregulation of the Ras/MAPK pathway and multisystem effects.
• Treatment focuses on proactive management of cardiac, tumor, orthopedic, growth, nutritional, and developmental issues, with emerging molecular therapies on the horizon.

Comprehensive, coordinated care and ongoing research are essential for meeting the complex needs of individuals with Costello syndrome and their families.