The albino phenotype in syndromes: from the gene to the clinic
Dr. Maria Cristina Patrosso
Albinism is a rare hereditary disorder characterized by partial or complete absence of the melanin biosynthesis, associated with a general hypopigmentation and specific ocular changes related to the reduction of the melanin pigment during the embryological development and the first months of life. The average incidence on a global scale is 1:20.000.
This disease includes different pathologies due to the different defects of "pathways" of biosynthesis of melanin.
There are three main mechanisms in which changes in different genes result in a lack of pigmentation: the first is in the biochemical pathway of melanin that causes the different forms of Oculocutaneous Albinism (OCA1, OCA2, OCA3 and OCA4) and Ocular Albinism (OA), the second mechanism involves genes implicated in the biogenesis of intracellular organelles whose expression is altered in various tissues, including melanocytes as in Hermansky-Pudlak Syndrome (HPS) and in Chediak-Higashi syndrome (CHS).
A final mechanism concerns the cycle of differentiation of melanocytes, as in Waardenburg syndrome or Waardenburg-Hirschsprung syndrome, where the melanocytes do not reach all areas of pigment in embryogenesis.
Hermansky-Pudlak syndrome (HPS) is a hereditary autosomal recessive disorder characterized by albinism, bleeding diathesis due to a defect in the platelet storage pool and abnormal storage of ceroid-like material throughout the body fat. Three organelles are hit: melanosomes, platelet dense bodies and lysosomes. To date, eight genes were identified in the Hermansky-Pudlak syndrome: HPS1 (10q23.1-q23.3), AP3B1 (5q14.1), HPS3 (3q24), HPS4 (22q11.2-q12.2), HPS5 (11p14), HPS6 (10q24.32), DTNBP1 (6p22.3) and BLOC1S3 (19q13.32). Skin pigmentation may vary in this syndrome. Moreover, the absence of dense bodies in platelets predisposes to bleeding and bruising.
Chediack-Higashi syndrome (CHS) is an autosomal recessive disorder characterized by oculocutaneous albinism and severe immunodeficiency. It can also present an increased susceptibility to infections and a deficiency of the activity of natural killer cells.
The CHS gene, whose mutations cause the disease, is localized in the 1q42.1-q42.2 chromosome and its gene product regulates the passage of various molecules to and from lysosomes. The melanocytes of patients with CHS are characterized by the presence of giant melanosomes and the patients with CHS have hypopigmentation due to these abnormal melanosomes, causing dilution of pigmentation, resulting in hypopigmentation of the hair, skin and fundus.
Waardenburg's syndrome is a rare autosomal dominant hereditary disorder in which melanocytes during embryogenesis do not reach all areas in need of pigment. This disease is characterized by pigment dispersions in the skin, hair and irises, hearing abnormalities, heterochromia of the irises, strabismus and congenital heart disease. In this syndrome are involved six different genes: EDN3 (20 q13.2-q13.3), PAX3 (2q35), MITF (3p14.1-p12.3), EDNRB (13q22), SNAI2 (8q11) and SOX10 (22q13).