Heterochromia is a variation in

color Color (or colour in English in the Commonwealth of Nations, Commonwealth English; American and British English spelling differences#-our, -or, see spelling differences) is the visual perception based on the electromagnetic spectrum. Though co ...

ation most often used to describe color differences of the iris, but can also be applied to color variation of

hair Hair is a protein filament that grows from follicles found in the dermis. Hair is one of the defining characteristics of mammals. The human body, apart from areas of glabrous skin, is covered in follicles which produce thick terminal and ...

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...

. Heterochromia is determined by the production, delivery, and concentration of

melanin Melanin (; ) is a family of biomolecules organized as oligomers or polymers, which among other functions provide the pigments of many organisms. Melanin pigments are produced in a specialized group of cells known as melanocytes. There are ...

pigment A pigment is a powder used to add or alter color or change visual appearance. Pigments are completely or nearly solubility, insoluble and reactivity (chemistry), chemically unreactive in water or another medium; in contrast, dyes are colored sub ...

). It may be inherited, or caused by genetic mosaicism, chimerism,

disease A disease is a particular abnormal condition that adversely affects the structure or function (biology), function of all or part of an organism and is not immediately due to any external injury. Diseases are often known to be medical condi ...

, or

injury Injury is physiological damage to the living tissue of any organism, whether in humans, in other animals, or in plants. Injuries can be caused in many ways, including mechanically with penetration by sharp objects such as teeth or with ...

. It occurs in humans and certain breeds of domesticated animals. Heterochromia of the

eye An eye is a sensory organ that allows an organism to perceive visual information. It detects light and converts it into electro-chemical impulses in neurons (neurones). It is part of an organism's visual system. In higher organisms, the ey ...

is called heterochromia iridum (heterochromia between the two eyes) or heterochromia iridis (heterochromia within one eye). It can be complete, sectoral, or central. In complete heterochromia, one iris is a different color from the other. In sectoral heterochromia, part of one iris is a different color from its remainder. In central heterochromia, there is a ring around the pupil or possibly spikes of different colors radiating from the pupil. Though multiple causes have been posited, the scientific consensus is that a lack of

genetic diversity Genetic diversity is the total number of genetic characteristics in the genetic makeup of a species. It ranges widely, from the number of species to differences within species, and can be correlated to the span of survival for a species. It is d ...

is the primary reason behind heterochromia, at least in domestic animals. This is due to a mutation of the genes that determine melanin distribution at the 8-HTP pathway, which usually only become corrupted due to chromosomal homogeneity. Though common in some breeds of cats, dogs, cattle and horses due to inbreeding, heterochromia is uncommon in humans, affecting fewer than 200,000 people in the United States, and is not associated with lack of genetic diversity. The affected eye may be hyperpigmented (hyperchromic) or hypopigmented (hypochromic). In humans, an increase of melanin production in the eyes indicates

hyperplasia Hyperplasia (from ancient Greek ὑπέρ ''huper'' 'over' + πλάσις ''plasis'' 'formation'), or hypergenesis, is an enlargement of an organ or tissue caused by an increase in the amount of Tissue (biology), organic tissue that results from ...

of the iris tissues, whereas a lack of melanin indicates

hypoplasia Hypoplasia (; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.Ancient Greek Ancient Greek (, ; ) includes the forms of the Greek language used in ancient Greece and the classical antiquity, ancient world from around 1500 BC to 300 BC. It is often roughly divided into the following periods: Mycenaean Greek (), Greek ...

: , "different" and , "color".

Background

Eye color Eye color is a polygene, polygenic phenotypic trait determined by two factors: the pigmentation of the eye's Iris (anatomy), iris and the frequency-dependence of the scattering of light by the Turbidity, turbid medium in the Stroma of iris, str ...

, specifically the color of the irises, is determined primarily by the concentration and distribution of melanin. Although the processes determining eye color are not fully understood, it is known that inherited eye color is determined by multiple

genes In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. Environmental or acquired factors can alter these inherited traits. The color of the mammalian, including human, iris is very variable. However, there are only two pigments present,

eumelanin Melanin (; ) is a family of biomolecules organized as oligomers or polymers, which among other functions provide the pigments of many organisms. Melanin pigments are produced in a specialized group of cells known as melanocytes. There are ...

and

pheomelanin Melanin (; ) is a family of biomolecules organized as oligomers or polymers, which among other functions provide the Biological pigment, pigments of many organisms. Melanin pigments are produced in a specialized group of cells known as melan ...

. The overall concentration of these pigments, the ratio between them, variation in the distribution of pigment in the layers of the stroma of the iris and the effects of light scattering all play a part in determining eye color. In the United States, July 12 is observed by some as National Different Colored Eyes Day.National Day Calenda
"National Different Colored Eyes Day - July 12"
''National Day Calendar.'' November 8, 2022. Retrieved July 12, 2023.

Classification

Heterochromia is classified primarily by onset: as either genetic or acquired. Although a distinction is frequently made between heterochromia that affects an eye completely or only partially (sectoral heterochromia), it is often classified as either genetic (due to mosaicism or

congenital A birth defect is an abnormal condition that is present at childbirth, birth, regardless of its cause. Birth defects may result in disability, disabilities that may be physical disability, physical, intellectual disability, intellectual, or dev ...

) or acquired, with mention as to whether the affected iris or portion of the iris is darker or lighter.Swann P
"Heterochromia."
''Optometry Today.'' January 29, 1999. Retrieved November 1, 2006. Most cases of heterochromia are hereditary, or caused by genetic factors such as chimerism, and are entirely benign and unconnected to any pathology, but some are associated with certain diseases and syndromes. Sometimes one eye may change color following disease or injury.

Genetic

Abnormal iris darker

* Lisch nodules – iris

hamartoma A hamartoma is a mostly benign, local malformation of cells that resembles a neoplasm of local tissue but is usually due to an overgrowth of multiple aberrant cells, with a basis in a systemic genetic condition, rather than a growth descended fr ...

s seen in

neurofibromatosis Neurofibromatosis (NF) refers to a group of three distinct genetic conditions in which tumors grow in the nervous system. The tumors are non-cancerous (benign) and often involve the skin or surrounding bone. Although symptoms are often mild, e ...

. * Ocular melanosis – a condition characterized by increased pigmentation of the uveal tract, episclera, and anterior chamber angle. * Oculodermal melanocytosis (nevus of Ota) *

Pigment dispersion syndrome Pigment dispersion syndrome (PDS) is an eye disorder that can lead to a form of glaucoma known as pigmentary glaucoma. It takes place when pigment cells slough off from the back of the iris and float around in the aqueous humor. Over time, the ...

– a condition characterized by loss of pigmentation from the posterior iris surface which is disseminated intraocularly and deposited on various intraocular structures, including the anterior surface of the iris. *

Sturge–Weber syndrome Sturge–Weber syndrome, sometimes referred to as encephalotrigeminal angiomatosis, is a rare congenital neurocutaneous disorder (also known as phakomatoses). It is often associated with port-wine stains of the face, glaucoma, seizures, intellect ...

– a syndrome characterized by a port-wine stain nevus in the distribution of the trigeminal nerve,

ipsilateral Standard anatomical terms of location are used to describe unambiguously the anatomy of humans and other animals. The terms, typically derived from Latin or Greek roots, describe something in its standard anatomical position. This position prov ...

leptomeningeal angiomas with intracranial calcification and neurologic signs, and angioma of the choroid, often with secondary glaucoma.

Abnormal iris lighter

*Simple heterochromia – a rare condition characterized by the absence of other ocular or systemic problems. The lighter eye is typically regarded as the affected eye as it usually shows iris

hypoplasia Hypoplasia (; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.Congenital Horner's syndrome – sometimes inherited, although usually acquired. *

Waardenburg syndrome Waardenburg syndrome is a group of rare genetic conditions characterised by at least some degree of congenital hearing loss and pigmentation deficiencies, which can include bright blue eyes (or Heterochromia iridum, one blue eye and one brown ey ...

– a syndrome in which heterochromia is expressed as a bilateral iris hypochromia in some cases. A Japanese review of 11 children with albinism found that the condition was present. All had sectoral/partial heterochromia. * Piebaldism – similar to Waardenburg's syndrome, a rare disorder of melanocyte development characterized by a white forelock and multiple symmetrical hypopigmented or depigmented macules. *

Hirschsprung's disease Hirschsprung's disease (HD or HSCR) is a birth defect in which nerves are missing from parts of the intestine. The most prominent symptom is constipation. Other symptoms may include vomiting, abdominal pain, diarrhea and slow growth. Most child ...

– a bowel disorder associated with heterochromia in the form of a sector hypochromia. The affected sectors have been shown to have reduced numbers of melanocytes and decreased stromal pigmentation. * Incontinentia pigmenti * Parry–Romberg syndrome

Acquired

Acquired heterochromia is usually due to injury, inflammation, the use of certain eyedrops that damage the iris, or tumors, both benign and malignant.

Abnormal iris darker

*Deposition of material ** Siderosis – iron deposition within ocular tissues due to a penetrating injury and a retained iron-containing, intraocular foreign body. ** Hemosiderosis – long standing hyphema (blood in the anterior chamber) following blunt trauma to the eye may lead to iron deposition from blood products. *Certain eyedrops – prostaglandin analogues (

latanoprost Latanoprost, sold under the brand name Xalatan among others, is a medication used to treat increased pressure inside the eye (intraocular pressure). This includes ocular hypertension and open-angle glaucoma. Latanaprost is applied as eye d ...

, isopropyl unoprostone,

travoprost Travoprost, sold under the brand name Travatan among others, is a medication used to treat high pressure inside the eye including glaucoma. Specifically it is used for open angle glaucoma when other agents are not sufficient. It is used as an ...

, and bimatoprost) are used topically to lower

intraocular pressure Intraocular pressure (IOP) is the fluid pressure inside the eye. Tonometry is the method eye care professionals use to determine this. IOP is an important aspect in the evaluation of patients at risk of glaucoma. Most tonometers are calibrated t ...

glaucoma Glaucoma is a group of eye diseases that can lead to damage of the optic nerve. The optic nerve transmits visual information from the eye to the brain. Glaucoma may cause vision loss if left untreated. It has been called the "silent thief of ...

patients. A concentric heterochromia has developed in some patients applying these drugs. A stimulation of melanin synthesis within iris melanocytes has been postulated. *

Neoplasm A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

– Nevi and melanomatous tumors. *Iridocorneal endothelium syndrome *Iris ectropion syndrome

Abnormal iris lighter

Fuchs heterochromic iridocyclitis Fuchs heterochromic iridocyclitis (FHI) is a chronic unilateral uveitis appearing with the triad of heterochromia, predisposition to cataract and glaucoma, and keratitic precipitates on the posterior corneal surface. Patients are often asymptomati ...

– a condition characterized by a low grade, asymptomatic

uveitis Uveitis () is inflammation of the uvea, the pigmented layer of the eye between the inner retina and the outer fibrous layer composed of the sclera and cornea. The uvea consists of the middle layer of pigmented vascular structures of the eye and ...

in which the iris in the affected eye becomes hypochromic and has a washed-out, somewhat moth eaten appearance. The heterochromia can be very subtle, especially in patients with lighter colored irides. It is often most easily seen in daylight. The prevalence of heterochromia associated with Fuchs has been estimated in various studies with results suggesting that there is more difficulty recognizing iris color changes in dark-eyed individuals. * Acquired Horner's syndrome – usually acquired, as in

neuroblastoma Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the head, neck, chest, abdomen, or Vertebral column, spine. Symptoms may include ...

, although sometimes inherited. *

–

Melanoma Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...

s can also be very lightly pigmented, and a lighter colored iris may be a rare manifestation of metastatic disease to the eye. * Parry–Romberg syndrome – due to tissue loss. Heterochromia has also been observed in those with

Duane syndrome Duane syndrome is a congenital rare type of strabismus most commonly characterized by the inability of the human eye, eye to move outward. The syndrome was first described by ophthalmologists Jakob Stilling (1887) and Siegmund Türk (1896), and s ...

. *Chronic

iritis Uveitis () is inflammation of the uvea, the pigmented layer of the eye between the inner retina and the outer fibrous layer composed of the sclera and cornea. The uvea consists of the middle layer of pigmented vascular structures of the eye and i ...

*Juvenile xanthogranuloma *

Leukemia Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...

and

lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). The name typically refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlarged lymph node ...

Partial heterochromia – different colors in the same iris

Partial heterochromia is most often a benign trait of genetic origins, but, like complete heterochromia, can be acquired or be related to clinical syndromes.

Sectoral

In sectoral heterochromia, areas of the same iris contain two different colors, the contrasting colors being demarcated in a radial, or sectoral, manner. Sectoral heterochromia may affect one or both eyes. It is unknown how rare sectoral heterochromia is in humans, but it is considered to be less common than complete heterochromia.

Central

Central heterochromia is also an eye condition where there are two colors in the same iris; but the arrangement is concentric, rather than sectoral. The central (pupillary) zone of the iris is a different color than the mid-peripheral (ciliary) zone. Central heterochromia is more noticeable in irises containing low amounts of

In history and culture

Heterochromia of the eye was first described as a human condition by

Aristotle Aristotle (; 384–322 BC) was an Ancient Greek philosophy, Ancient Greek philosopher and polymath. His writings cover a broad range of subjects spanning the natural sciences, philosophy, linguistics, economics, politics, psychology, a ...

, who termed it ''heteroglaucos''. Notable historical figures thought to have heterochromia include the

Byzantine emperor The foundation of Constantinople in 330 AD marks the conventional start of the Eastern Roman Empire, which Fall of Constantinople, fell to the Ottoman Empire in 1453 AD. Only the emperors who were recognized as legitimate rulers and exercised s ...

Anastasius the First, dubbed ''dikoros'' (Greek for 'having two pupils'). "His right eye was light blue, while the left was black, nevertheless his eyes were most attractive", is the description of the historian

John Malalas John Malalas (; ; – 578) was a Byzantine chronicler from Antioch in Asia Minor. Life Of Syrian descent, Malalas was a native speaker of Syriac who learned how to write in Greek later in his life. The name ''Malalas'' probably derive ...

. A more recent example is the German poet, playwright, novelist, scientist, statesman, theatre director, and critic,

Johann Wolfgang Goethe Johann Wolfgang (von) Goethe (28 August 1749 – 22 March 1832) was a German polymath who is widely regarded as the most influential writer in the German language. His work has had a wide-ranging influence on literary, political, and philosoph ...

. The '' Alexander Romance'', an early literary treatment of the life of

Alexander the Great Alexander III of Macedon (; 20/21 July 356 BC – 10/11 June 323 BC), most commonly known as Alexander the Great, was a king of the Ancient Greece, ancient Greek kingdom of Macedonia (ancient kingdom), Macedon. He succeeded his father Philip ...

, attributes heterochromia to him. In it he is described as having one eye light and one eye dark. However, no ancient historical source mentions this. It is used to emphasise the otherworldly and heroic qualities of Alexander. In the

Ars Amatoria The (''The Art of Love'') is an instructional elegy series in three books by the ancient Roman poet Ovid. It was written in 2 AD. Content Book one of was written to show a man how to find a woman. In book two, Ovid shows how to keep her. These ...

, the Roman poet

Ovid Publius Ovidius Naso (; 20 March 43 BC – AD 17/18), known in English as Ovid ( ), was a Augustan literature (ancient Rome), Roman poet who lived during the reign of Augustus. He was a younger contemporary of Virgil and Horace, with whom he i ...

describes the witch Dipsas as having 'double pupils'. Kirby Flower Smith suggested that this could be understood as heterochromia, though other scholars have disagreed. The Roman jurist and writer

Cicero Marcus Tullius Cicero ( ; ; 3 January 106 BC – 7 December 43 BC) was a Roman statesman, lawyer, scholar, philosopher, orator, writer and Academic skeptic, who tried to uphold optimate principles during the political crises tha ...

also mentions the same feature of 'double pupils' as being found in some Italic women.

Pliny the Elder Gaius Plinius Secundus (AD 23/24 79), known in English as Pliny the Elder ( ), was a Roman Empire, Roman author, Natural history, naturalist, and naval and army commander of the early Roman Empire, and a friend of the Roman emperor, emperor Vesp ...

related this feature to the concept of 'the

evil eye The evil eye is a supernatural belief in a curse brought about by a malevolent glaring, glare, usually inspired by envy. Amulets to Apotropaic, protect against it have been found dating to around 5,000 years ago. It is found in many cultures i ...

'. The twelfth-century scholar Eustathius, in his commentary on the Iliad, reports a tradition in which the

Thracian The Thracians (; ; ) were an Indo-European speaking people who inhabited large parts of Southeast Europe in ancient history.. "The Thracians were an Indo-European people who occupied the area that today is shared between north-eastern Greece, ...

Thamyris In Greek mythology, Thamyris (Ancient Greek: Θάμυρις, ''Thámuris'') was a Thrace, Thracian singer. He is notable in Greek mythology for reportedly being a lover of Hyacinth (mythology), Hyacinth and thus to have been the first male to hav ...

(son of the nymph Argiope), who was famed for his musical abilities, had one eye that was grey, whilst the other was black. W. B. McDaniel suggests that this should be interpreted as heterochromia.

In other animals

Although infrequently seen in humans, complete heterochromia is more frequently observed in species of domesticated mammals. The blue eye occurs within a white spot, where melanin is absent from the skin and hair (see

Leucism Leucism () is a wide variety of conditions that result in partial loss of pigmentation in an animal—causing white, pale, or patchy coloration of the skin, hair, feathers, scales, or cuticles, but not the eyes. It is occasionally spelled ''le ...

). These species include the

cat The cat (''Felis catus''), also referred to as the domestic cat or house cat, is a small domesticated carnivorous mammal. It is the only domesticated species of the family Felidae. Advances in archaeology and genetics have shown that the ...

, particularly breeds such as

Turkish Van The Turkish Van is a semi-long-haired, standardised breed of domestic cat, which was developed in the United Kingdom from a selection of cats obtained from various cities of modern Turkey, especially southeast Turkey. The breed is rare, This s ...

, Khao Manee and (rarely)

Japanese Bobtail The is a breed of domestic cat with an unusual bobtail more closely resembling the tail of a rabbit than that of other cats. The breed was first developed in Japan, and registered officially in the 1960s. The breed has been known in Japan for c ...

. These so-called odd-eyed cats are white, or mostly white, with one normal eye (copper, orange, yellow, green), and one blue eye. Among

dog The dog (''Canis familiaris'' or ''Canis lupus familiaris'') is a domesticated descendant of the gray wolf. Also called the domestic dog, it was selectively bred from a population of wolves during the Late Pleistocene by hunter-gatherers. ...

s, complete heterochromia is seen often in the

Siberian Husky The Siberian Husky is a dog breed, breed of medium-sized Working dog, working sled dog. The breed belongs to the Spitz genetic family. It is recognizable by its thickly furred Coat (dog), double coat, erect triangular ears, and distinctive mark ...

and few other breeds, usually

Australian Shepherd The Australian Shepherd is a breed of herding dog from the United States. The name of the breed is technically a misnomer, as it was developed in California in the 19th century. It is believed to have its origins in sheepdog breeds from northwe ...

and Catahoula Leopard Dog and rarely in Shih Tzu. Horses with complete heterochromia have one brown and one white, gray, or blue eye—complete heterochromia is more common in horses with pinto coloring. Complete heterochromia occurs also in

cattle Cattle (''Bos taurus'') are large, domesticated, bovid ungulates widely kept as livestock. They are prominent modern members of the subfamily Bovinae and the most widespread species of the genus '' Bos''. Mature female cattle are calle ...

and even

water buffalo The water buffalo (''Bubalus bubalis''), also called domestic water buffalo, Asian water buffalo and Asiatic water buffalo, is a large bovid originating in the Indian subcontinent and Southeast Asia. Today, it is also kept in Italy, the Balkans ...

. It can also be seen in ferrets with

, although it can be very hard to tell at times as the eye color is often a midnight blue. Sectoral heterochromia, usually sectoral hypochromia, is often seen in

s, specifically in breeds with

merle Merle may refer to: People and fictional characters *Merle (given name), a list of men, women and fictional characters *Merle (surname), a list of people Others *Merle (dog coat), a pattern in dogs’ coats *Merle (grape), another name for the w ...

coats. These breeds include the

Border Collie The Border Collie is a British list of dog breeds, breed of herding dog of the collie type of medium size. It originates in the region of the Anglo-Scottish border, and descends from the traditional Sheep dog, sheepdogs once found all over the ...

Collie Collies form a distinctive type of herding dogs, including many related landraces and standardized breeds. The type originated in Scotland and Northern England. Collies are medium-sized, fairly lightly-built dogs, with pointed snouts. Many type ...

, Shetland Sheepdog, Welsh Corgi, Pyrenean Shepherd, Mudi,

Beauceron The Beauceron () is a herding dog breed originating from the plains of Central France. The Beauceron is also known as Berger de Beauce (, sheepdog from Beauce) or Bas Rouge (, red-stockings). Description Appearance This breed stands in height ...

, Catahoula Cur, Dunker,

Great Dane The Great Dane is a German list of dog breeds, breed of large mastiff-sighthound, which descends from hunting dogs of the Middle Ages used to hunt bears, wild boar, and deer. They were also used as guardian dogs of German nobility. It is one o ...

Dachshund The dachshund ( or ; German: 'badger dog'), also known as the wiener dog or sausage dog, badger dog, doxen and doxie, is a short-legged, long-bodied, hound-type dog breed. The dog may be smooth-haired, wire-haired, or long-haired, with varie ...

and Chihuahua. It also occurs in certain breeds that do not carry the merle trait, such as the

, Dalmatian, and rarely, Shih Tzu. There are examples of cat breeds that have the condition such as Van cat.

References

External links

* {{Medicine Disturbances of pigmentation Eye color Eye diseases Genodermatoses Medical signs

Background

Classification

Genetic

Abnormal iris darker

Abnormal iris lighter

Acquired

Abnormal iris darker

Abnormal iris lighter

Partial heterochromia – different colors in the same iris

Sectoral

Central

In history and culture

In other animals

See also

References

External links