What is RASopathy (Ras/mitogen-activated protein kinase pathway disorder)?

What is RASopathy?

RASopathies are a group of genetic disorders caused by germline mutations in genes encoding components of the Ras/mitogen-activated protein kinase (RAS/MAPK) signaling pathway, resulting in constitutional dysregulation of this critical cellular pathway. 1

Genetic Basis and Mechanism

• RASopathies result from mutations in genes that encode proteins within the RAS/MAPK pathway, which plays an essential role in regulating the cell cycle, cellular growth, differentiation, and senescence—all critical to normal development 1

• The pathway dysregulation occurs through germline (constitutional) mutations, distinguishing these conditions from somatic mutations seen in cancer 1

• Inheritance is typically autosomal dominant, with approximately 50% of cases arising from de novo mutations and generally complete penetrance with variable expressivity 1

Specific Syndromes Included

The RASopathy spectrum encompasses multiple distinct but overlapping syndromes 1:

• Neurofibromatosis type 1 (NF1): Among the most common, with birth prevalence of 1/2,000 to 1/3,000 persons 1

• Noonan syndrome (NS): Caused by mutations in PTPN11 (50%), SOS1 (13%), RAF1 (5%), RIT1 (5%), or more rarely KRAS, NRAS, BRAF, MAP2K1, RRAS, RASA2, A2ML1, SOS2, or LZTR1 1

• Costello syndrome (CS): Associated with 15% cancer risk by age 20 years 1

• Cardio-facio-cutaneous syndrome (CFC): Caused by mutations in BRAF, MEK1, MEK2, or rarely KRAS genes 1

• Noonan syndrome with multiple lentigines (formerly LEOPARD syndrome) 2

• Legius syndrome: Caused by SPRED1 mutations, notably without increased cancer risk 1

• CBL syndrome: Associated with high but not precisely defined JMML risk 1

Common Clinical Features

Because all RASopathies share dysregulation of the same cellular pathway, they exhibit numerous overlapping phenotypic features 1:

Craniofacial Dysmorphology

• Hypertelorism with down-slanting palpebral fissures 1
• Ocular ptosis 1
• Low-set, posteriorly rotated ears 1
• Broad neck with low posterior hairline 1

Growth Abnormalities

• Proportionate short stature 1
• Relative or absolute macrocephaly 1

Cardiovascular Manifestations

• Congenital heart defects, most commonly pulmonary stenosis or hypertrophic cardiomyopathy 1, 2
• Aortic dilatation with increased risk of dissection, aneurysm, rupture 1
• Mitral valve abnormalities 1

Additional Features

• Thorax deformity 1
• Abnormal skin and adnexa (dermatologic abnormalities) 1
• Learning difficulties and developmental delay 1
• Feeding problems in infancy and failure to thrive 1
• Cryptorchidism 1
• Lymphatic anomalies 1
• Bleeding diathesis 1

Cancer Predisposition

A critical distinguishing feature of most RASopathies (except Legius syndrome) is increased cancer risk, though the magnitude varies by specific syndrome 1:

• Children with Noonan syndrome face approximately 8-fold increased risk for cancers including gliomas, acute lymphoblastic leukemia, neuroblastoma, and rhabdomyosarcoma 1

• Specific PTPN11 or KRAS mutations confer high risk of myeloproliferative disorder/juvenile myelomonocytic leukemia (JMML) 1

• Costello syndrome carries 15% cancer risk by age 20 years, including embryonal rhabdomyosarcoma, neuroblastoma, and bladder cancer 1

• NF1 patients have significantly increased risk of benign and malignant neoplasms, with malignant peripheral nerve sheath tumors representing the most significant malignant risk in adolescence and young adulthood 1

Diagnostic Considerations

• Differentiating between specific RASopathies can be challenging, particularly in the newborn period, due to overlapping phenotypic features 1

• Molecular diagnosis through multigene RAS/MAPK pathway panel testing is recommended, with approximately 80% mutation detection rate for CFC 1

• Genotype-phenotype associations have been described for some variants, but for the majority, expressivity cannot be predicted based on the specific variant 1

• Somatic mosaicism is well documented, particularly in NF1, and mosaic individuals may have variable to few clinical features 1

Clinical Management Implications

• The availability of targeted therapies inhibiting the RAS-MAPK pathway has transformed management, particularly for NF1 patients with symptomatic, unresectable plexiform neurofibromas or gliomas, making early detection through structured surveillance increasingly important 1, 3

• Multidisciplinary care from specialists is essential, including genetics, cardiology, oncology, neurology, and other subspecialties as clinically indicated 1

• Cancer surveillance protocols vary by specific syndrome and mutation, with some requiring intensive monitoring (physical exam and imaging every 3-4 months in early childhood for certain high-risk variants) while others require only baseline evaluation 1