Ocular Symptoms of Ichthyosis

Key points at a glance

• Ichthyosis is a group of hereditary skin disorders with abnormal keratinization and desquamation, affecting the eyelids, cornea, and tear film.
• In lamellar ichthyosis, up to 50% develop ectropion, with high risk of exposure keratopathy.
• X-linked ichthyosis is characterized by corneal stromal opacities and fleck corneal dystrophy due to cholesterol sulfate accumulation.
• Evaporative dry eye due to meibomian gland dysfunction (MGD) is a common issue.
• Early intervention through collaboration between dermatologists and ophthalmologists is essential for maintaining vision.

1. Ocular symptoms of ichthyosis

Ichthyosis is a group of hereditary skin disorders characterized by dry, thickened skin with scales. It results from mutations in genes involved in skin barrier function, leading to defects in keratinization and desquamation (natural skin shedding).

The main types and their prevalence are as follows.

Type	Prevalence	Inheritance
Ichthyosis vulgaris	1/250	Autosomal dominant
X-linked ichthyosis	1/2,000 to 1/6,000 males	X-linked recessive
Lamellar ichthyosis	1/100,000 to 1/300,000	Autosomal recessive
Harlequin ichthyosis	1/1,000,000	Autosomal recessive

Ichthyosis is primarily a skin disease, but it can also cause various ocular complications. Ocular symptoms are mainly related to abnormalities of the eyelids and tear film, which can lead to exposure keratopathy. In particular, lamellar ichthyosis and congenital ichthyosiform erythroderma cause hardening and loss of flexibility of the skin around the eyelids, resulting in a high incidence of ectropion and lagophthalmos¹⁾.

In X-linked ichthyosis (XLI), accumulation of cholesterol sulfate due to steroid sulfatase deficiency leads to characteristic corneal findings (macular corneal dystrophy and stromal opacities)^2,4). Thus, the ocular impact varies greatly depending on the type of ichthyosis.

Q Does ichthyosis always affect the eyes?

A

The impact on the eyes varies greatly depending on the type of ichthyosis. In the most common type, ichthyosis vulgaris, eye involvement is often mild, usually limited to punctate keratitis. In contrast, lamellar ichthyosis causes ectropion in up to 50% of cases, increasing the risk of exposure keratopathy. X-linked ichthyosis shows characteristic corneal changes. Regular eye examinations are recommended for all types.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

• Dryness and foreign body sensation in the eyes
• Burning or stinging sensation
• Photophobia (light sensitivity)
• Blurred vision (hazy vision)
• Redness
• Excessive tearing
• Difficulty opening eyes in the morning (especially in XLI)

Clinical Findings

Eyelid Abnormalities

Ectropion: The lower eyelid turns outward, exposing the conjunctiva and cornea. It occurs in up to 50% of lamellar ichthyosis cases, and almost all cases with TGM1 mutations are associated with eyelid margin abnormalities^3,6)

Lagophthalmos: Incomplete eyelid closure. Caused by hardening of the skin around the eyelids.

Blepharitis: Chronic inflammation of the eyelid margins. Caused by accumulation of scales.

Trichiasis: Eyelashes turn toward the cornea, damaging the ocular surface.

Corneal and Tear Film Abnormalities

Exposure keratopathy: Corneal epithelial damage secondary to ectropion and lagophthalmos. High risk of dryness and ulceration.

Cornea farinata: Characteristic of X-linked ichthyosis. Presents with fine, dust-like stromal opacities.

Corneal stromal deposits: Punctate deposits due to accumulation of cholesterol sulfate. Seen in XLI.

Meibomian gland dysfunction (MGD): Reduction of the tear lipid layer leads to evaporative dry eye.

Ocular Findings by Ichthyosis Type

Type	Eyelid Findings	Corneal Findings
Ichthyosis vulgaris	No significant changes	Punctate superficial keratitis
X-linked ichthyosis	No significant changes	Stromal opacity, cornea farinata
Lamellar	Ectropion	Corneal scarring
Harlequin	Ectropion	Corneal scarring

In X-linked ichthyosis, slit-lamp microscopy may reveal prominent corneal nerves. This is a characteristic finding associated with steroid sulfatase deficiency, and at high magnification, punctate stromal deposits due to cholesterol sulfate accumulation can also be observed ⁴⁾. Cornea farinata is usually asymptomatic and does not affect vision, but it is important as a finding suggesting the presence of a metabolic disorder. In a study of 38 cases by Costagliola et al., the incidence of corneal opacity in XLI patients was approximately 23.7%, similar to that in carrier mothers (24.3%), indicating that the presence or absence of opacity alone cannot confirm the diagnosis of XLI ²⁾.

Regarding the application of advanced imaging techniques such as optical coherence tomography angiography (OCTA), reports specific to ichthyosis are currently limited.

Q What are the characteristic ocular findings in X-linked ichthyosis?

A

In X-linked ichthyosis (XLI), deficiency of the steroid sulfatase enzyme leads to accumulation of cholesterol sulfate in the corneal stroma. This results in prominent corneal nerves, punctate stromal deposits, and a fine dust-like stromal opacity called cornea farinata observed on slit-lamp microscopy. Cornea farinata is usually asymptomatic and does not affect vision, but it is an important clue for diagnosing the underlying disease.

3. Causes and Risk Factors

Genetic Causes

Each type of ichthyosis involves specific genetic mutations.

Ichthyosis vulgaris: Mutations in the filaggrin gene (FLG). It causes skin barrier dysfunction. Autosomal dominant inheritance, and it is the most common type.

X-linked ichthyosis: Mutations in the steroid sulfatase gene (STS). Impaired degradation of cholesterol sulfate leads to accumulation in the skin and cornea. It occurs only in males.

Lamellar ichthyosis: Multiple gene mutations involved in lipid metabolism. TGM1 (transglutaminase 1) is the most common. Autosomal recessive inheritance.

Harlequin ichthyosis: Mutation in the ABCA12 gene. The most severe type, presenting with abnormal lamellar granules and severe hyperkeratosis.

Factors that worsen ocular complications

• Environmental stress: Dry environment, wind, strong ultraviolet light
• Dehydration: Worsens dryness of skin and ocular surface
• Atopic predisposition: Ichthyosis vulgaris is often associated with atopic diseases
• Association with keratoconus: Ichthyosis has been reported as a condition associated with keratoconus

Prevention and daily care

To reduce ocular complications caused by ichthyosis, please keep the following care in mind.

• Regular moisturizing: Apply moisturizer to the skin around the eyes as well to maintain flexibility.
• Use of artificial tears: Frequently instill preservative-free artificial tears during the day.
• Eye protection during sleep: Apply eye ointment or use moisture goggles to prevent corneal dryness at night.
• Warm compresses and eyelid hygiene: Perform warm compresses and eyelid cleaning to prevent meibomian gland blockage.
• Regular eye examinations: Have eye exams 1–2 times a year even if you have no symptoms.

4. Diagnosis and examination methods

Skin Diagnosis

The diagnosis of ichthyosis is based on clinical evaluation. The type is estimated from the characteristic scaly skin appearance and distribution pattern over large areas of the body. Genetic testing is useful for a definitive diagnosis, and identification of specific gene mutations can confirm the type. Histopathological examination reveals findings characteristic of each type, such as orthokeratotic hyperkeratosis, changes in the granular layer, and accumulation of cholesterol sulfate.

Ophthalmic Examination

The following ophthalmic examinations are recommended for patients with ichthyosis:

• Slit-lamp microscopy: Evaluation of eyelid structure, conjunctival inflammation, and confirmation of corneal erosion, ulcer, and opacity
• Tear film evaluation: Assessment of dry eye using tear break-up time (TBUT) and Schirmer test
• Meibomian gland evaluation: Detection of MGD by meibography
• Fluorescein staining: Detection of punctate keratitis and corneal erosion

In X-linked ichthyosis, prominent corneal nerves and punctate stromal deposits are characteristic slit-lamp findings.

Differential Diagnosis

Ocular symptoms of ichthyosis must be differentiated from the following diseases:

• Stevens-Johnson syndrome (SJS): Differentiated by history of systemic fever and rash
• Ocular pemphigoid: Differentiated by conjunctival scarring and progressive symblepharon
• Atopic keratoconjunctivitis: Presence of papillary findings and corneal shield ulcer
• Sjögren’s syndrome: Decreased salivary and lacrimal gland function, autoantibodies
• Infectious conjunctivitis/keratitis: characteristics of eye discharge, culture tests

5. Standard Treatment

Conservative Treatment

Artificial tears: Frequent instillation of preservative-free preparations. For evaporative dry eye, lipid-containing formulations are effective.

Eye ointment: Applied before bedtime to prevent corneal dryness at night.

Warm compresses and eyelid hygiene: For MGD, warm compresses melt meibomian gland lipids, followed by eyelid margin cleaning.

Moisture goggles: Reduce evaporation and maintain ocular surface moisture.

Pharmacological Treatment

Steroid eye drops: Short-term use for severe inflammation. Long-term use requires caution regarding increased intraocular pressure and cataract risk.

Antibiotics: Topical or oral antibiotics (e.g., tetracyclines) are used during exacerbations of blepharitis.

Cyclosporine eye drops: Used for chronic ocular surface inflammation.

Surgical Treatment

Correction of ectropion: Indicated when conservative treatment is insufficient. Procedures such as lateral tarsal strip restore normal eyelid position and resolve corneal exposure.

Treatment of trichiasis: Regular epilation of misdirected lashes. For recurrent cases, consider permanent removal by electrolysis or cryotherapy.

Punctal plugs: When tear volume is insufficient, punctal occlusion reduces tear drainage.

Points to note

Ophthalmic surgery (such as cataract surgery) in patients with ichthyosis carries a risk of inducing ocular surface inflammation postoperatively, leading to rapid progression of keratinization and adhesions. When performing surgery, sufficient anti-inflammatory treatment with steroids or immunosuppressants should be administered preoperatively, and strict postoperative follow-up is necessary.

Q When is surgery considered for ectropion in ichthyosis?

A

Surgical correction is considered when symptoms due to corneal exposure (dryness, redness, pain, corneal erosion/ulcer, etc.) cannot be controlled with adequate conservative treatment such as artificial tears, eye ointments, and moisture goggles. In particular, early surgical intervention is recommended when corneal ulcers recur or when visual acuity decline progresses. Regular ophthalmologic follow-up after surgery is essential.

6. Pathophysiology and detailed pathogenesis

Skin barrier dysfunction and eyelid deformity

The basic pathology of ichthyosis is skin barrier dysfunction. Genetic mutations impair the keratinization process, leading to the formation of abnormal stratum corneum. Normal desquamation is inhibited, resulting in accumulation of scales and hardening of the skin.

When the skin around the eyelids is affected by this process, elasticity is lost and ectropion occurs. In lamellar ichthyosis and harlequin ichthyosis, hyperkeratosis is particularly severe, so ectropion may appear immediately after birth ^3,5). Ectropion causes exposure of the conjunctiva and cornea, leading to chronic dryness and corneal epithelial damage (exposure keratopathy), which can progress to corneal ulceration or perforation if left untreated ^1,5).

Corneal changes in X-linked ichthyosis

In X-linked ichthyosis, steroid sulfatase (STS) enzyme is deficient. This enzyme converts cholesterol sulfate to free cholesterol. Due to the enzyme deficiency, cholesterol sulfate accumulates not only in the skin but also in the cornea.

Accumulation of cholesterol sulfate in the cornea leads to the following findings:

• Punctate deposits in the corneal stroma: Fine deposits distributed from Bowman’s layer to the deep stroma
• Corneal verticillata: Fine dust-like opacities on the anterior surface of Descemet’s membrane. Usually asymptomatic.
• Prominent corneal nerves: Deposits along nerve fibers make corneal nerves more visible on slit-lamp examination.

These changes reflect metabolic abnormalities and usually do not affect vision. However, they are important clues for the diagnosis of XLI. Macsai et al. reported cases in which thickening of the epithelial basement membrane and abnormal protein deposition in Bowman’s layer were confirmed pathologically ⁴⁾.

Mechanism of Meibomian Gland Dysfunction

In ichthyosis, abnormal keratinization of the entire skin also affects the meibomian glands. The openings of the meibomian glands become obstructed by keratinous material, impairing lipid secretion. A decrease in the lipid layer of the tear film leads to increased tear evaporation, resulting in evaporative dry eye. This is a common problem regardless of the type of ichthyosis.

7. Latest Research and Future Perspectives

Association with Keratoconus

Ichthyosis has been reported as a condition associated with keratoconus. Keratoconus is a corneal thinning caused by degradation of corneal collagen, and changes in enzyme activity and oxidative stress have been proposed as causative factors. Abnormalities in corneal structure in ichthyosis may contribute to this disease susceptibility, but the detailed mechanism remains a subject for future research.

Potential for Gene Therapy and Molecular Targeted Therapy

For types of ichthyosis in which the causative gene has been identified, the development of gene therapy and molecular targeted therapy is expected in the future. If fundamental improvement of skin barrier function is achieved, it may also lead to prevention of ocular complications.

Future Challenges

Large-scale studies specifically focusing on ocular complications of ichthyosis are still limited. Accumulation of data on the exact prevalence of ocular complications in each type, optimal intervals for ophthalmic screening, and long-term prognosis is needed.

Disclaimer

The content of this article is intended for informational purposes for healthcare professionals and does not recommend specific diagnosis or treatment. In actual clinical practice, the attending physician should make appropriate decisions based on the latest clinical guidelines and the individual patient’s condition.

8. References

1. Al-Amry MA. Ocular manifestation of Ichthyosis. Saudi J Ophthalmol. 2016;30(1):39-43. PMID: 26949357. PMCID: PMC4759502.

2. Costagliola C, Fabbrocini G, Illiano GM, Scibelli G, Delfino M. Ocular findings in X-linked ichthyosis: a survey on 38 cases. Ophthalmologica. 1991;202(3):152-155. PMID: 1923309.

3. Singh AJ, Atkinson PL. Ocular manifestations of congenital lamellar ichthyosis. Eur J Ophthalmol. 2005;15(1):118-122. PMID: 15751249.

4. Macsai MS, Doshi H. Clinical pathologic correlation of superficial corneal opacities in X-linked ichthyosis. Am J Ophthalmol. 1994;118(4):477-484. PMID: 7943126.

5. Yeoh BJ, Nanthini S. Ophthalmic Review on Neonatal Harlequin Ichthyosis. Cureus. 2023;15(8):e44320. PMID: 37779732. PMCID: PMC10538354.

6. Macriz-Romero N, Vera-Duarte GR, Guerrero-Becerril J, Chacón-Camacho OF, Astiazarán MC, Zenteno JC, Graue-Hernandez EO. Ophthalmic findings in patients with autosomal recessive lamellar ichthyosis due to TGM1 mutations in an isolated population. Int Ophthalmol. 2023;43(10):3659-3665. PMID: 37542530.