Mosaik-RASopathies

"RASopathies" refers to a group of diseases surrounding Noonan syndrome that are due to dysregulation of the RAS/RAF pathway by mostly activating constitutional mutations of involved genes.

Common clinical features include:

• cardiovascular abnormalities
• reduced growth
• dysmorphia
• abnormalities of the skin
• developmental disorders of variable severity

In some cases, there is also a tumor disposition. Like the PI3K/AKT pathway, with which it is interconnected, the RAS/RAF pathway stimulates cell growth and is mediated by RAS proteins after binding of growth factors 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 single cells and lead to clonal expansion due to a growth advantage, play a widespread role in oncogenesis (Li S et al. (2018)).

Mosaic RASopathies have a different phenotype than constitutional RASopathies, which are due to postzygotic gain-of-function mutations in RAS/RAF genes that would likely be lethal if they were constitutional (Hafner C et al. 2013). HRAS mutations are an exception. Mutation detection is usually only successful in affected tissue.

Neurocutaneous melanosis affects a small proportion of patients with the common congenital melanocytic nevi (CMN) and is characterized by large (giant) CMN combined with often symptomatic leptomeningeal melanocytosis (Alikhan A et al 2012). It is caused by an early embryonic NRAS mutation in the neuroectoderm. The risk of melanoma depends on the extent of CMN and is circa 1% in CMN in general versus 12% in giant CMN. Neurocutaneous melanosis is also associated with an increased risk of CNS melanoma.

Localized postzygotic mutations in different genes lead to further nevi, for example a keratinocytic epidermal nevus or a nevus sebaceus.

If the mutations occur earlier in development and affect several tissues, syndromic clinical pictures with the main symptom of a specific nevus occur (Lim YH et al. (2017).

These include Schimmelpenning-Feuerstein-Mims syndrome (SFMS), in which the CNS, eyes and skeleton (osteomalacia, hypophosphatemic rickets) can be particularly affected, with evidence of mosaic mutations in HRAS, KRAS and NRAS (Groesser L et al. (2012).

The considerable variability of the clinical symptoms could be explained by the identification as a mosaic disease. Syndromes with congenital abnormalities of the eye and skin have also been identified as mosaic RASopathy:

• oculo-ectodermal syndrome (OES, mutations in KRAS), whose main features are epibulbar dermoids and congenital scalp defects, and
• encephalo-cranio-cutaneous lipomatosis (ECCL, mutations in FGFR1 and KRAS), in which the eponymous lipomas are also present in the CNS (Moog U et al. 2020).

Both syndromes can have other abnormalities of the skin, including a nevus sebaceus. They also include a predisposition to jaw tumors, non-ossifying fibromas and, in the case of ECCL, low-grade gliomas. As it is not always possible to clearly assign previously used clinical diagnoses, the term (KRAS-associated) mosaic RASopathy is often more appropriate.

Vascular malformations: The diagnostic differentiation of the isolated port wine stain (symmetrical nevus flammeus) from the sporadically occurring Sturge-Weber-Krabbe syndrome (SWS) with facial nevus flammeus, intracranial and intraocular vascular malformations is prognostically significant. In Sturge-Weber-Krabbe syndrome, leptomeningeal angiomatosis can lead to epileptic crises as early as the first year of life, affecting psychomotor and mental development. Stroke-like episodes and glaucoma are also among the serious manifestations.

Etiologically, the common port wine stain and the rare Sturge-Weber-Krabbe syndrome are two extreme clinical manifestations of the same molecular mechanism. In malformed capillaries, a specific postzygotic point mutation in the GNAQ gene that activates the RAS/RAF signaling pathway is identified in the majority of cases in both syndromes (Shirley MD et al. 2013). It is likely that non-syndromic port wine stains are caused by a late postzygotic mutation and Sturge-Weber syndrome by an early postzygotic mutation. Mutations in RAS and other genes of the RAS/RAF signaling pathway have also been identified in sporadic vascular malformations (Al-Olabi L et al. 2018).

Pink capillary malformations of the skin in combination with arteriovenous malformations in at least one other family member and occasionally associated hemihyperplasia form a clinically variable clinical picture (CM-AVM), which was only described after the identification of LOF variants in the RASA1 gene (Eerola I et al. 2003). RASA1 is a negative regulator of RAS. Consequently, loss of function also activates the RAS/RAF signaling pathway.

While Sturge-Weber syndrome, which is based on an activating point mutation in the GNAQ gene, is only observed in mosaic form, RASA1-associated phenotypes can follow an autosomal dominant mode of inheritance. In addition to the dominantly inherited mutation in one gene copy, a second newly occurring mutation in the second gene copy leads to loss of function of the RASA1 gene.

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