Introduction
Acrodermatitis enteropathica (AE) is a rare genetic autosomal recessive disorder caused by intestinal malabsorption of zinc, due to a biallelic mutation in the gene responsible for zinc uptake.[1] AE was first described by Brandt in 1936 and later identified as a distinct entity in 1942 by Danbolt and Closs.[2] The condition usually presents in infancy with a triad of clinical features including dermatitis, alopecia, and gastrointestinal (GI) disturbances. It characteristically has an intermittent yet progressive course; spontaneous bouts of remissions are followed by increasingly severe exacerbations, which left untreated can prove fatal.[2]
In the past, there have been very few studies that reported ocular involvement in AE. These were mostly confined to blepharitis, radial corneal opacities, keratoconjunctivitis, cataract, punctal stenosis, and optic atrophy.[3–5] To the best of our knowledge, this is the first case wherein corneal involvement has been identified as a limbal stem cell deficiency (LSCD) with its classical features.
Case Report
An 18-year-old male presented with a history of photophobia and watering of eyes, more pronounced in the mornings, for 2 years. He was diagnosed with AE at the age of 3 when he presented with alopecia areata and dry, scaly patches in the perioral region, hands, and feet. Born out of a second-degree consanguineous marriage, his elder sibling was reported to have had similar symptoms and had succumbed to the disease as an infant. Hence, a diagnosis of AE was considered and the child was started on zinc and riboflavin supplements. Before this, he had no ocular symptoms.
Currently, apart from ocular symptoms, he also reported a worsening of skin lesions [Figure 1]. There was no history of recurrent fever, impaired wound healing, diarrhea, or weight loss. He had no history of a diminution of vision, ocular pain, discharge, or redness of the eyes. There was no antecedent history of ocular trauma or surgery.
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Figure 1: Scaly erythematous plaques over hands (a) and feet (b)
Ocular examination revealed a best-corrected visual acuity of 20/20 in both eyes. Slit-lamp examination showed the presence of bilateral, symmetrical, subepithelial corneal opacities adjacent to the superior limbus, extending to the visual axis in radiating lines. Fluorescein staining of the cornea demonstrated a whorling pattern superiorly (OS >OD), extending from the limbus to the center of the cornea [Figure 2]. There was a 0.5 mm × 0.5 mm epithelial erosion in both eyes. Schirmer’s 1 test disclosed 30 mm of wetting, tear meniscus height was >0.5 mm, and tear break-up time was 8 s in OU. There was no evidence of corneal vascularization/pannus. The pupils were brisk, the lens was clear, and intraocular pressures and fundus examination were unremarkable. Syringing revealed a patent lacrimal drainage system.
Figure 2: Slit-lamp photographs showing subepithelial opacities (black arrow) in the right (a) and left (c) eyes. Whorling of fluorescein in the right (b) and left (d) eyes with epithelial erosions (red arrowhead)
All the routine blood investigations were within normal limits. His serum zinc level was normal (1.0 μg/mL). GI involvement was ruled out with an upper GI endoscopy. The exacerbation of AE was treated with multivitamins, oral zinc, and iron supplements.
The classical whorling pattern of corneal fluorescein staining along with subepithelial opacities and epithelial erosion in a photophobic eye were strongly suggestive of a partial LSCD. The patient was started on topical Vitamin-A palmitate ointment and lubricants.
At 1-month follow-up, ocular symptoms had resolved and the epithelial erosions in OU had healed. However, the whorled appearance of fluorescein staining persisted.
Discussion
Limbal stem cells (LSCs) are responsible for maintaining the integrity of the corneal epithelium and act as a barrier against the invasion of conjunctival epithelium onto the cornea. LSCD may be primarily due to genetic mutations that lead to destruction or dysfunction of LSC, or secondary to external factors that damage the LSC and its microenvironment.[6]
Patients suffering from LSCD may present with symptoms attributed to poor epithelial wound healing and recurrent corneal erosions (RCEs) such as pain, redness, photophobia, watering, blepharospasm, or decreased vision. An early or mild LSCD may demonstrate a stippling uptake of fluorescein stain. The classical presentation of the moderate stage of LSCD is the “whorl-like epitheliopathy” or vortex pattern of fluorescein stain in a spiral extending from the limbus toward the central cornea. This may be associated with RCE and subepithelial haze or opacities in the affected area. In its advanced stage, LSCD is characterized by superficial vascularization, conjunctivalization, scarring, and persistent epithelial defects.[6]
In 1953, before the advent of zinc therapy in AE, diiodohydroxyquin (DHQ) was discovered to have a beneficial effect and was widely used as empirical therapy. However, due to its numerous side effects, it was discontinued in clinical practice.[7]
Vortex keratopathy due to chloroquine and hydroxychloroquine have been well documented and consist of a spectrum of manifestations from diffuse punctate opacities to radial, whorling lines converging to the central cornea. They occur due to microdeposits of the drug within the epithelium and anterior stroma possibly due to centripetal migration of deposit-laden LSC.[8] DHQ is a halogenated 8-hydroxyquinoline belonging to the same group as the antimalarials and its possibility of producing similar effects in patients on long-term therapy for AE was a matter of debate.[9]
Moynahan discovered the association of AE with low plasma zinc levels and documented rapid improvement of the condition with oral zinc sulfate therapy. Following this discovery in 1974, the administration of oral zinc preparations became the preferred treatment of choice.[9]
Ocular involvement in AE has been documented previously, but whether such features were a direct result of the disease activity or sequelae of DHQ-induced drug toxicity was uncertain. A literature search revealed five cases of AE with similar whorl-like corneal involvement as illustrated [Table 1]. The findings were attributed to DHQ toxicity. However, the last patient did not receive DHQ. We infer that these findings were similar to our patient and were probable manifestations of LSCD.
Table 1: Literature review of corneal involvement in acrodermatitis enteropathica
Our patient never received any drug other than zinc supplements, which completely excludes the possibility of drug toxicity. The classical appearance of the radial corneal opacities and whorled fluorescein staining along with an epithelial erosion seems to point toward a moderate LSCD in our patient. To the best of our knowledge, this is the first case of ocular involvement in AE to be reported as a possible LSCD.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given her consent for images and other clinical information to be reported in the journal. The guardian understands that her names and initials will not be published and due efforts will be made to conceal the patient’s identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
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