Heterochromia (Eyes of different colors)

Eye pigmentation is determined by melanocytes. The presence of melanocytes in the iris is dependent on innervation by sympathetic nerves, which grow out of the spinal cord (anterior roots of the first and second thoracic segments) and follow the carotid artery to the head. Thus, one way to develop heterochromia is to have an injury to this portion of the nervous system. Congenital cases are generally inherited as autosomal dominant traits.

Heterochromia is usually (and maybe always) associated with Horner syndrome, Waardenburg syndrome, or piebald syndrome.

Horner syndrome is the result of damage or paralysis of the sympathetic nerves in one side of the face. In addition to heterochromia (with the affected side blue, i.e. little or no pigment), other symptoms include sunken eyeball, small iris, droopy eyelid (ptosis), and lack of sweating on that side of the face. Horner described this syndrome in 1869; it is inherited, but can also result from injury at birth. At least one case of Horner syndrome acquired from an accident as a teenager.

Waardenburg syndrome: "The features of Waardenburg syndrome are wide bridge of the nose owing to lateral displacement of the inner canthus of each eye, pigmentary disturbance (frontal white blaze of hair, heterochromia iridis, white eye lashes, leukoderma--white patches on the skin), and cochlear deafness. The severity varies widely and some affected persons escape deafness." (from OMIM 193500) The gene involved, PAX3 (also called HUP2), was cloned originially in the mouse, and corresponds to the mouse mutant Splotch, which has a similar phenotype. The protein has two DNA binding domains, a paired domain and a homeodomain. Mutations mostly alter these regions. Although the molecular mechanism of pathogenesis isn't completely clear, it seems that PAX3 activates MITF, which in turn activates tyrosinase, an essential enzyme for melanin production and melanocyte differentiation. There are many alleles of PAX3, and the phenotype is also modified by many other genes, giving rise to the observed variation in severity.

Piebald trait: "The features are white forelock and absence of pigmentation of the medial portion of the forehead, eyebrows and chin and of the ventral chest, abdomen, and extremities. The borders of unpigmented areas are hyperpigmented. Heterochromia iridis occurs in some." (from OMIM 172800) A white forelock is a common symptom. Deafness is usually not associated with this trait. Piebald is common among mammalian species, and probably involves a defect in the migration of the neural crest cells (which include the melanocytes), but the exact mechanism is not clear. The homologous gene in mice is W, dominant white spotting. A similar gene has also been studied in pigs. The trait is dominant in humans: homozygotes are rare and are completely lacking in pigment in hair and eyes. The gene involved is the KIT protooncogene, whose viral homologue is in feline sarcoma virus. The cellular gene encodes a transmembrane tyrosine kinase that is a receptor for stem cell factor (SCFR), which is necesary for normal melanogenesis, as well as blood cell formation (hematopoiesis) and germ cell differentiation (gametogenesis).