2.1 Brooke-Spiegler Syndrome

At least 20 CYLD gene mutations have been identified in individuals with Brooke-Spiegler syndrome. This condition is characterized by multiple noncancerous (benign) tumors that develop in structures associated with the skin (skin appendages), such as sweat glands and hair follicles. People with Brooke-Spiegler syndrome may develop several types of skin appendage tumors, including growths called spiradenomas, trichoepitheliomas, and cylindromas. Spiradenomas are tumors of the sweat glands. Trichoepitheliomas arise from the hair follicles. While previously thought to derive from sweat glands, cylindromas are now generally believed to begin in hair follicles.

People with Brooke-Spiegler syndrome 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. These genetic changes are called somatic mutations and are not inherited.

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 impairs the regulation of nuclear factor-kappa-B, allowing the cell to grow and divide in an uncontrolled way to form a tumor. In people with Brooke-Spiegler syndrome, second CYLD mutations typically occur in different types of cells in the skin over an affected person's lifetime, leading to the growth of multiple types of skin appendage tumors.

2.2 Familial Cylindromatosis

More than 30 CYLD gene mutations have been identified in individuals with familial cylindromatosis. People with this disorder typically develop large numbers of cylindromas.

As in Brooke-Spiegler syndrome, people with familial cylindromatosis are born with one mutated copy of the CYLD gene in each cell, and 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 particular hair follicle cells, those cells cannot produce any functional CYLD protein. The loss of this protein allows the cells to grow and divide in an uncontrolled way to form cylindromas.

2.3 Multiple Familial Trichoepithelioma

At least 22 mutations in the CYLD gene have been identified in individuals with multiple familial trichoepithelioma. People with this disorder typically develop large numbers of trichoepitheliomas.

As in Brooke-Spiegler syndrome and familial cylindromatosis, people with CYLD-related multiple familial trichoepithelioma are born with one mutated copy of the CYLD gene in each cell, and 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 particular hair follicle cells, those cells cannot produce any functional CYLD protein. The loss of this protein allows the cells to grow and divide in an uncontrolled way to form trichoepitheliomas.

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

2.4 Cancers

Somatic mutations and reduced activity (expression) of the CYLD gene have also been identified in certain cancerous tumors. These cancers include multiple myeloma, which starts in cells of the bone marrow, and cancers of the kidney, liver, uterus, and colon. These genetic changes likely impair the tumor suppressor function of the CYLD protein, allowing cells to grow and divide in an uncontrolled way and become cancerous.