Which are the causes of Cloves Syndrome?

Cloves Syndrome, also known as Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, and Scoliosis/Skeletal/Spinal Anomalies and/or Syndactyly, is a rare and complex disorder that affects various parts of the body. It is characterized by the presence of overgrowth of fatty tissue, vascular malformations, epidermal nevi (skin lesions), and skeletal abnormalities. The exact cause of Cloves Syndrome is not yet fully understood, but there are several factors that are believed to contribute to its development.

Mosaic Activating Mutations: One of the primary causes of Cloves Syndrome is thought to be mosaic activating mutations. These mutations occur during early embryonic development and affect a specific group of cells, leading to abnormal growth and development of tissues in various parts of the body. These mutations are not inherited from parents but rather arise spontaneously.

PIK3CA Gene: The majority of individuals with Cloves Syndrome have been found to have mutations in the PIK3CA gene. This gene provides instructions for making a protein that is involved in cell growth and division. Mutations in this gene result in the overactivation of a signaling pathway called the PI3K-AKT-mTOR pathway, which plays a crucial role in regulating cell growth and proliferation. The overactivation of this pathway leads to the abnormal tissue growth observed in Cloves Syndrome.

Mosaicism: Mosaicism refers to the presence of two or more genetically distinct cell populations within an individual. In the case of Cloves Syndrome, the presence of mosaic activating mutations and mosaicism is believed to contribute to the varied and unpredictable nature of the disorder. The extent and distribution of the mutated cells can vary from person to person, leading to differences in the severity and specific features of the syndrome.

Embryonic Development: The abnormal tissue growth and malformations seen in Cloves Syndrome are thought to occur during embryonic development. The specific timing and location of the mutations and abnormal cell growth can influence the affected tissues and organs. The exact mechanisms by which these mutations disrupt normal development are still being studied.

Genetic and Environmental Factors: While the primary cause of Cloves Syndrome is genetic, it is believed that environmental factors may also play a role in the development and progression of the disorder. However, the specific environmental factors that may contribute to the syndrome have not yet been identified.

Other Contributing Factors: In addition to the aforementioned causes, there may be other contributing factors that influence the development of Cloves Syndrome. These factors could include interactions between genetic and environmental factors, as well as other yet unknown biological mechanisms.

In conclusion, Cloves Syndrome is a complex disorder with multiple contributing factors. Mosaic activating mutations, particularly in the PIK3CA gene, are believed to be the primary cause of the syndrome. Mosaicism and abnormal tissue growth during embryonic development further contribute to the varied manifestations of the disorder. While the exact mechanisms and environmental factors involved are still being investigated, ongoing research aims to deepen our understanding of this rare condition.