Familial cylindromatosis is a rare disorder; its prevalence is unknown.

Familial cylindromatosis is caused by mutations in the CYLD gene. This gene provides instructions for making a protein that helps regulate nuclear factor-kappa-B. Nuclear factor-kappa-B is a group of related proteins that help protect cells from self-destruction (apoptosis) in response to certain signals. In regulating the action of nuclear factor-kappa-B, the CYLD protein allows cells to respond properly to signals to self-destruct when appropriate, such as when the cells become abnormal. By this mechanism, the CYLD protein acts as a tumor suppressor, which means that it helps prevent cells from growing and dividing too fast or in an uncontrolled way.

People with familial cylindromatosis are born with a mutation in one of the two copies of the CYLD gene in each cell. This mutation prevents the cell from making functional CYLD protein from the altered copy of the gene. However, enough protein is usually produced from the other, normal copy of the gene to regulate cell growth effectively. For tumors to develop, a second mutation or deletion of genetic material involving the other copy of the CYLD gene must occur in certain cells during a person's lifetime.

When both copies of the CYLD gene are mutated in a particular cell, that cell cannot produce any functional CYLD protein. The loss of this protein allows the cell to grow and divide in an uncontrolled way to form a tumor. In people with familial cylindromatosis, a second CYLD mutation typically occurs in multiple cells over an affected person's lifetime. The loss of CYLD protein in these cells leads to the growth of skin appendage tumors.

Some researchers consider familial cylindromatosis and two related conditions called multiple familial trichoepithelioma and Brooke-Spiegler syndrome, which are also caused by CYLD gene mutations, to be different forms of the same disorder. It is unclear why mutations in the CYLD gene cause different patterns of skin appendage tumors in each of these conditions, or why the tumors are generally confined to the skin in these disorders.