Mosaik-RASopathies

Last updated on: 12.04.2022

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Definition
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"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.

Clinical picture
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If the mutations occur earlier in development and affect multiple tissues, syndromal syndromes occur with the leading symptom being a specific nevus (Lim YH et al (2017).

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

The remarkable variability of clinical symptoms could be explained by identifying it as a mosaic disorder. 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 may have other abnormalities of the skin, including a nevus sebaceus. Furthermore, they include a predisposition to jaw tumors, non-osseous fibromas, and, in the case of ECCL, low-grade gliomas. Since it is not always possible to clearly assign previously used clinical diagnoses, the term (KRAS-associated) mosaic RASopathy will often be more accurate.

Vascular malformations: The diagnostic differentiation of the isolated port wine stain (nevus flammeus symmetric) from the sporadic 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 intellectual 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 pathway is identified in the majority of cases in both syndromes (Shirley MD et al. 2013). It is likely that nonsyndromic port wine stains arise from a late postzygotic mutation and Sturge-Weber syndrome from an early postzygotic mutation. Mutations in RAS and other genes of the RAS/RAF pathway have also been identified in sporadic vascular malformations (Al-Olabi L et al. 2018).

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

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

Literature
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Last updated on: 12.04.2022