Rasopathies (overview)

The term "RASopathies ", also known as"neuro-cardio-facio-cutaneous syndromes", is used to describe a group of diseases associated with Noonan syndrome that are based on a dysregulation of the RAS/RAF signaling pathway, usually caused by activating, constitutional mutations in the genes involved. In some cases, there is also a tumor predisposition. Like the PI3K/AKT signaling pathway, to which it is linked, the RAS/RAF signaling pathway stimulates cell growth and is mediated by RAS proteins after growth factors bind to receptors on the cell surface. The classical RAS proteins are encoded by the HRAS, KRAS and NRAS genes. Somatic mutations in these genes, which occur spontaneously in individual cells and lead to clonal expansion due to a growth advantage, play a widespread role in oncogenesis.

RASopathies are characterized by symptoms in several organ systems. These include:

• the skin organ
• the cardiovascular system
• skeleton
• musculature
• gastrointestinal tract
• the central nervous system and
• the eyes.

The following diseases are classified as RASopathies:

• Neurofibromatosis type I (NF1 gene).
• Legius syndrome (SPRED1 gene), a syndrome similar to neurofibromatosis type I with a different mutation (see above)
• Lelis syndrome(palmo-plantar hyperkeratoses, acanthosis nigricans, nail dystrophies, mental retardation)
• Naxos syndrome (mutation of the JUP gene, which codes for phacoglobin, an integral component of desmosomes) palmo-plantar hyperkeratoses, frizz hair, right cardiac cardiomyopathy)
• Carvajal syndrome (mutation of the DSP gene, which also encodes phacoglobin) palmo-plantar hyperkeratosis, frizzy hair, left cardiac cardiomyopathy occurring in early childhood)
• Rothmund-Thomson syndrome
• Costello syndrome (among others, a heterozygous missense mutation c.34G>A (p.Gly12Ser) in exon 2 has been detected; mutations in sections of the HRAS gene are rarer )
• Cardiofasciocutaneous syndrome(Noonan-related syndromes: short stature, mental retardation, facial dysmorphia, cardiac anomalies, hyperextensible joints, cutis laxa, hyperkeratoses, hyperhidrosis, curly hair that is usually easily epilated(loose anagen hair syndrome), acanthosis nigricans, nail dystrophies)
• CFC syndrome (cardio-facio-cutaneous syndrome)

For clarification, a step-by-step diagnosis using next generation sequencing (NGS) should be performed.

1. Costello JM (1971) A new sydrnome. NZ Med J 74:397
2. Wirtz M et al (2015) Costello syndrome, a rare RASopathy with cutaneous symptoms, dermatologist 66:225-228