Heterochromia

Etiology

Most cases of heterochromia are sporadic and isolated benign conditions without any clinical significance.

The most important group of conditions with heterochromia are congenital heterochromia which may be the only presentation of congenital Horner syndrome. There may be associated miosis, partial ptosis, and facial anhidrosis. Not all of these signs need to be present to be diagnosed as congenital Horner syndrome. The iris stromal melanocytes derive from neurocrest cells in embryological development. The sympathetic neurons also derive from neurocrest cells. Any disruption of sympathetic innervation of the iris melanocytes due to disruption of the post-ganglionic cervical sympathetic pathways, especially early in life as in congenital Horner syndrome, will result in decreased brown melanin color of one iris and heterochromia. Any syndromic illness associated with impaired neurocrest cells or tissues development and migration may also cause heterochromia, such as Waardenburg syndrome and Parry-Romberg syndrome. Other congenital diseases include ocular melanosis and neurocutaneous syndromes such as Sturge-Weber syndrome (abnormal hyperpigmented iris), oculodermal melanocytosis (nevus of Ota), and neurofibromatosis type I (von Recklinghausen disease, iris hamartoma).[1]

Congenital Causes of Heterochromia

• Benign heterochromia
• Congenital Horner syndrome: with other presentations of miosis, partial ptosis, and/or impaired facial sweating (anhydrosis)[7][5]
• Waardenburg syndrome: hearing loss, heterochromia, lateral displacement of medial canthus, hypertrichosis of medial eyebrows, and prominent broad nasal root[8]
• Parry-Romberg syndrome: progressive facial hemiatrophy[9]
• Sturge-Weber syndrome: facial port-wine stain with meningeal angiomatosis. Patients may present with unilateral neurological deficits, seizures, and a large facial nevus. The ipsilateral eye may have melanocytosis of the uveal coat and retina. Glaucoma is not an uncommon complication.[10]
• Neurofibromatosis I: Lisch nodules in the iris associated with other clinical features. Children with NF1 may also develop optic nerve pathway glioma, which can be detected by simple ophthalmoscopy showing the absence of red reflex in one eye.[11]
• Oculodermal melanocytosis: hamartomatous congenital melanocytosis[12]
• Iridocorneal endothelial (ICE) syndromes[13]
• Iris ectropion syndrome
• Incontinentia pigmenti[14]

Acquired Causes of Heterochromia

• Acquired Horner syndrome
• Other causes of sympathetic heterochromia such as neuroblastoma or paravertebral neurilemmoma[15][16]
• Ocular trauma
• Fuchs heterochromic iridocyclitis[17] (Fuchs heterochromic uveitis)
• foreign body including use of colored contact lens
• Iron deposition: siderosis and hemosiderosis
• Melanocyte infiltration as in diffuse nevus or melanoma
• Local iris tumors
• Certain eyedrops such as prostaglandin analogs[18][19]

Epidemiology

Heterochromia is an uncommon sign. There is no widely reported prevalence.

Pathophysiology

Human iris color exists in a continuum from light blue to dark brown. The most common description uses three shades, including blue, green-hazel, and brown. As discussed above, the most important determining factors for human iris color are the iris stromal texture and stromal melanocytes. The stromal melanocytes are derived from embryological neurocrest cells, which migrate through the uveal tract to the iris during fetal development. Subsequently, the iris stromal melanocytes are also under the trophic influence of the post-ganglionic cervical sympathetic pathway. Consequently, any unilateral lesion affecting the cervical sympathetic (Horner syndrome), either congenital or acquired within the first two years of life, will lead to heterochromia.[5] 

Very rarely, longstanding Horner syndrome may also result in heterochromia. Other diseases related to neurocrest cell development and migration may cause heterochromia, such as Waardenburg syndrome and Perry-Romberg syndrome.[8][9] 

In addition to diseases primarily involving the iris melanocytes, any local eye or iris disease that causes a unilateral change in colors such as trauma with bleeding, melanoma and other tumors, and Fuchs heterochromic iridocyclitis.[17]

History and Physical

History

• Onset: acute, subacute versus chronic - important in differentiating local eye disease vs. genetic causes. Progressive facial hemiatrophy is typical for Parry-Romberg syndrome.
• Any local eye symptoms such as pain, redness, and visual disturbances suggest local eye diseases.
• History of trauma.
• History of use of eye drops, especially used in one eye, causing discoloration of that eye such as latanoprost and other prostaglandin analog eyedrops.[18]
• Family history of neurofibromatosis type I

Physical

• Most important: Review old photos, especially childhood pictures. Look for the presence of heterochromia in the past and signs of Horner syndrome such as miosis and partial ptosis.
• Look for other signs of Horner syndrome - miosis and ptosis.
• Look for signs of specific syndromes such as cutaneous neurofibromata, facial hemiatrophy, facial port-wine stains, hearing loss, and broad facial features.
• Careful exam of the eye, especially the iris, anterior chamber, pupil size and responses, corneal conditions, and intraocular pressure measurement.[12]

Evaluation

Eye examination by an ophthalmologist with a slit lamp examination. Clinical exam, especially to look for other signs of Horner syndrome.[16]

Clinicians can use urinary catecholamines, VMA, etc., for excessive sympathetic activities in children to rule out underlying neuroblastoma and other neurocrest derived tumors.

CT chest and abdomen to causes of Horner syndrome or possible neuroblastoma or other tumors in children and infants.[20] CT angiogram and CT skull base for hypoplasia of the internal carotid artery as proof of congenital Horner syndrome, or evidence of carotid dissection in chronic acquired Horner syndrome.

Most of the time, with obviously isolated heterochromia and no other abnormal findings on physical exam, the diagnosis will be benign heterochromia. However, no further evaluation plus reassurance is adequate for the management of the patient.

Treatment / Management

Heterochromia is a sign and not by itself a disease. There is no specific treatment of heterochromia by itself. Treatment is directed at the underlying cause, including underlying eye diseases. If the heterochromia is associated with other signs of Horner syndrome such as miosis and partial ptosis, the most common cause is congenital Horner syndrome which does not require any treatment. On the other hand, congenital or early childhood onset Horner syndrome may result from an underlying tumor of the sympathetic chain, especially neuroblastoma which will need urgent workup, diagnosis, and treatment.[21] Heterochromia caused by an acquired Horner syndrome, especially in adults, signifies a chronic and longstanding illness. The underlying cause is very unlikely to be a malignancy.

Differential Diagnosis

Heterochromia is a clinical sign. The differential diagnosis will include all the causes listed above. The most important differential diagnoses to consider are:

• Benign isolated heterochromia
• Congenital Horner syndrome[16]
• Horner syndrome with onset before age of two
• Acquired longstanding Horner syndrome
• Heterochromia as part of other congenital syndromes
• Local iris and eye diseases including Fuchs heterochromic iridocyclitis and melanoma[17]

Prognosis

The prognosis of heterochromia depends on the underlying cause. In infants and children, it is important to rule out underlying neoplasia of the sympathetic chain, especially neuroblastoma which carries a poor prognosis when diagnosed and treated late.[22] Fuchs heterochromic iridocyclitis may threaten vision due to complications of glaucoma. An iris melanoma may be malignant. The most common cause is benign heterochromia with no clinical significance. The other significant group of causes is congenital Horner syndrome which usually has a good prognosis.[16]

Complications

Heterochromia is a clinical sign, and there is no health complication due to this sign per se.