What are RASopathies (Ras/mitogen-activated protein kinase pathway disorders)?

RASopathies: Genetic Disorders of the Ras/MAPK Pathway

RASopathies are a group of genetic disorders caused by germline mutations in genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway, resulting in dysregulation of cellular growth, differentiation, and development.

Definition and Pathophysiology

RASopathies represent one of the most prevalent groups of genetic syndromes, affecting more than 1 in 1,000 individuals 1. These disorders share a common underlying biochemical phenotype of Ras/MAPK pathway activation, despite being caused by different genetic mutations 2.

The Ras/MAPK pathway plays essential roles in:

• Cellular growth and differentiation
• Cell cycle regulation
• Senescence and apoptosis
• Normal embryonic and post-natal development

Disorders Classified as RASopathies

The RASopathies include several distinct but overlapping syndromes:

• Neurofibromatosis type 1 (NF1)
• Noonan syndrome (NS)
• Noonan syndrome with multiple lentigines (formerly LEOPARD syndrome)
• Costello syndrome (CS)
• Cardio-facio-cutaneous syndrome (CFC)
• Legius syndrome
• CBL syndrome
• Noonan syndrome-like disorder with loose anagen hair
• Capillary malformation-arteriovenous malformation syndrome
• Gingival fibromatosis 3

Common Clinical Features

Due to their shared pathophysiology, RASopathies exhibit numerous overlapping phenotypic features 4:

1. Craniofacial abnormalities:

   • Hypertelorism (widely spaced eyes)
   • Down-slanting palpebral fissures
   • Ptosis (drooping eyelids)
   • Low-set, posteriorly rotated ears
   • Broad neck with low hairline

2. Growth abnormalities:

   • Proportionate short stature
   • Relative or absolute macrocephaly

3. Cardiovascular abnormalities:

   • Congenital heart defects (especially pulmonary stenosis)
   • Hypertrophic cardiomyopathy

4. Cutaneous manifestations:

   • Various skin and hair abnormalities specific to each syndrome

5. Neurodevelopmental issues:

   • Learning difficulties
   • Variable cognitive impairment

6. Other features:

   • Feeding problems in infancy
   • Cryptorchidism
   • Disorders of pubertal timing
   • Lymphatic anomalies
   • Bleeding diathesis 4

Cancer Predisposition

With the exception of Legius syndrome, children with RASopathies have a significantly increased risk of developing benign and malignant neoplasms compared to the general population 4. The cancer risk varies by specific syndrome:

• Costello syndrome: Highest risk (15% by age 20), particularly for embryonal rhabdomyosarcoma, neuroblastoma, and bladder cancer
• Noonan syndrome with specific PTPN11 or KRAS mutations: High risk for myeloproliferative disorders/juvenile myelomonocytic leukemia (JMML)
• CBL syndrome: High but not precisely defined risk for JMML
• Neurofibromatosis type 1: Increased risk for optic pathway gliomas, plexiform neurofibromas, and malignant peripheral nerve sheath tumors 4

Genetic Basis

RASopathies are caused by mutations in genes encoding components or regulators of the Ras/MAPK pathway. Common genetic mutations include:

• Noonan syndrome: PTPN11 (50%), SOS1 (13%), RAF1 (5%), RIT1 (5%), and less commonly KRAS, NRAS, BRAF, MAP2K1, RRAS, RASA2, A2ML1, SOS2, or LZTR1 4
• Costello syndrome: HRAS mutations
• Cardio-facio-cutaneous syndrome: BRAF, MEK1, MEK2, or rarely KRAS 4
• Neurofibromatosis type 1: NF1 gene mutations 4

Diagnosis

Diagnosis of RASopathies is based on:

1. Clinical features specific to each syndrome
2. Genetic testing to identify causative mutations
3. Differentiation from other RASopathies with overlapping features

The diagnostic criteria for several RASopathies have been updated in recent years, particularly for NF1 in 2021, to better differentiate between syndromes with overlapping features 4.

Management

Management of RASopathies requires a multidisciplinary approach:

1. Cancer surveillance: Tailored to specific syndrome and genetic mutation

   • Regular physical examinations
   • Appropriate imaging studies
   • Laboratory testing as indicated

2. Cardiac monitoring: For congenital heart defects and hypertrophic cardiomyopathy

3. Growth and development monitoring:

   • Regular assessment of growth parameters
   • Neurodevelopmental evaluations

4. Targeted therapies:

   • Emerging molecular therapeutics inhibiting the RAS/MAPK pathway show promise for treating certain manifestations 4

Recent Advances

Recent advances in understanding the RASopathies have led to:

1. Improved diagnostic criteria
2. Better genotype-phenotype correlations
3. Development of targeted therapies that inhibit the Ras/MAPK pathway
4. Clinical trials exploring treatment options for specific manifestations 4, 5

The identification of molecular therapeutics inhibiting the RAS-MAPK pathway has expanded treatment options for patients with certain RASopathies, particularly NF1 with symptomatic, unresectable plexiform neurofibroma or glioma 4.