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CASE REPORT

Keratitis Associated With Multiple Endocrine Deficiency

Mehrdad Mohammadpour, MD* and Mohammad-Ali Javadi, MD†

Purpose: To report an 8-year-old girl with bilateral progressive

visual loss and photophobia secondary to stem cell deficiency as a

result of multiple endocrine deficiency.

Methods: A case report and review of medical literature.

Results: The patient suffered from severe photophobia and de-

creased visual acuity since May 2000. Despite multiple outpatient

visits, no definite cause was found, and conservative treatments failed.

On slit-lamp examination severe meibomian gland dysfunction, loss

of eyelashes, decreased tear meniscus, diffuse corneal vascularization,

and delayed punctate fluorescein staining of corneal epithelium were

detected. She had also episodes of hypotension, oral candidiasis, and

seizures. Her systemic work up revealed multiple endocrine defi-

ciency (Addison disease and hypoparathyroidism). Hormone replace-

ment therapy with fludrocortisone and oral calcium accompanied by

punctual occlusion led to significant clinical recovery.

Conclusion: In a pediatric patient with diffuse corneal vascular-

ization and no definite cause, systemic workup should be done to rule

out multiple endocrine deficiencies. Treatment consists of hormone

replacement therapy and management of the dry eye.

Key Words: multiple endocrine deficiency, stem cell deficiency, dry

eye, Addison disease, hypoparathyroidism

(Cornea 0000;00:000–000)

Corneal vascularization has a diverse etiology includinglongstanding ocular surface inflammation or infection,

stem cell deficiency, and immune-mediated disorders. Nor-mally, the limbal stem cells of the cornea inhibit conjunctivalvessels from invading the cornea. Any pathologic conditionthat alters this natural barrier may eventually lead to somedegree of corneal vascularization and subsequent haziness thatlimits the visual acuity.1

Multiple endocrine deficiency (MED), recently renamedautoimmune polyendocrinopathy, is an immune-mediated dis-order that involves multiple organs including parathyroid and

adrenal glands and ectodermal tissues (nails, skin, enamels)and may also cause keratitis.2

Photophobia is an alarming sign in children that may beseen in a various and heterogeneous ocular pathologies such asuveitis associated with systemic diseases (eg, juvenile rheu-matoid arthritis), uveitis with no definite background disease(intermediate uveitis), retinal diseases, and pathologies of thecornea and ocular surface.1–3 We report a case with bilateralcorneal vascularization and dry eye caused by stem cell defi-ciency as a sign of MED.

REPORT OF THE CASEAn 8-year-old white girl was referred to our care in May

2000. She had received medical care elsewhere for somemonths for photophobia and decreased vision, and conserva-tive management with lubricants and artificial tears were pre-scribed for her, but no significant recovery happened. She hadmultiple episodes of seizures and oral candidiasis. Her generalexams revealed nail dystrophy (F F1ig. 1).

On her first ocular examination, her visual acuity was20/40 in her both eyes. Her eyes were injected, and the patientcouldn’t open them completely secondary to severe photo-phobia. On slit-lamp examination, severe meibomian glanddysfunction and decreased tear meniscus were detected.

Corneal vascularization that was more prominent insuperior part of cornea (F F2ig. 2), and punctal epithelial erosionswere seen in her both eyes. Delayed diffuse punctate fluo-rescein staining of the corneal epithelium was also noticed.Other ocular examinations including anterior chamber, iris,lens, vitreous, retina, and intraocular pressure were unremark-able. Corneal impression cytology revealed goblet cells on thecorneal surface epithelium (F F3ig. 3). She also had episodes ofhypotension and seizures caused by an imbalance of serumelectrolytes. Her systemic workup revealed low levels of adrenalhormones [cortisone 3 mg/dL (normal range 5–23 mg/dL)]and disturbance in serum electrolytes (low sodium and cal-cium and high potassium levels). Serum parathormone (PTH)level was 4 pg/mL (normal range 9–65 pg/mL). Ourimpression was of a multiple endocrine deficiency (Addisondisease and hypoparathyroidism), which caused stem cell de-ficiency by altering the stroma of the limbus (stem cell niche)and caused dry eyes, corneal vascularization, and haziness,which resulted in visual loss and photophobia.

The patient received replacement hormone therapy withfludrocortisone acetate (a synthetic steroid with potent min-eralocorticoid and high glucocorticoid activity) and elementalcalcium, and the puncti were occluded by cauterization. After1 year significant clinical improvement occurred (F F4ig. 4).

Received for publication Nov 17, 2004; revision received Mar 9, 2005;accepted Mar 19, 2005.

From the *Ophthalmic Research Center, Labbafinejad Medical Center,Shaheed Beheshti University of Medical Sciences, Tehran, Iran; and†Department of Ophthalmology, Labbafinejad Medical Center, ShaheedBeheshti University of Medical Sciences, Tehran, Iran.

Neither of the authors has any financial interest in this article.Reprints: Dr Mehrdad Mohammadpour, Ophthalmic Research Center,

Labbafinejad Medical Center, Shaheed Beheshti University of MedicalSciences, Tehran, Iran.

Copyright � 2005 by Lippincott Williams & Wilkins

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DISCUSSIONCorneal diseases that are caused by stem cell deficiency

are categorized into 2 main groups. The first group consists ofconditions in which the stem cells are destroyed by variouscauses such as chemical or thermal injuries, Stevens- Johnsonsyndrome (SJS), toxic epidermal necrosis (TEN), multipleocular surgeries or cryotherapy of the limbal area, use of anti-metabolites such as 5-fluorouracil (5-FU), contact lens–inducedkeratopathy, and severe microbial infections. The second groupconsists of diseases that cause severe impairment of limbalstroma, where stem cells develop and proliferate and dif-ferentiate into epithelial cells. These diseases may be ocular,such as aniridia, neurotrophic keratopathy, pterygium, andpseudopterygium; or may have systemic or exogenous etiolo-gies such as irradiation-induced keratopathy, chronic limbalinjury or inflammation, keratitis associated with multiple en-docrine deficiency (MED), and idiopathic dysfunction.4–17

Keratitis associated with MED was first reported byGass8 in 1962. He reported a syndrome of keratoconjuncti-vitis, superficial moniliasis, idiopathic hypoparathyroidism,and Addison disease. Afterward, Wagman et al9 reported a se-ries of 14 patients with an autosomal recessive syndrome char-acterized by hypoparathyroidism, Addison disease, chronicmucocutaneous candidiasis, and immune disorders. Four of themhad a self-limited bilateral keratitis in which the age of onsetranged from 2 to 9 years. Keratitis preceded the onset of anyendocrinopathy in 2 of 4 patients and was among the first signs

of the syndrome. Our case differs from theirs in that thekeratitis was not self-limiting and led to significant dry eye andcorneal vascularization that decreased her vision. She hadalso nail dystrophy, which altogether makes the diagnosis of

FIGURE 2. Superficial corneal vascularization and cornealhaziness (mostly in superior part of the cornea) caused by stemcell deficiency: A, right eye; B, left eye.

FIGURE 3. Impression cytologyshowing goblet cells on the cornealepithelium.

FIGURE 1. Nail dystrophy of all fingers of her both hands.

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Figs. 1–3 live 4/C

‘‘APECED’’ syndrome2 (autoimmune polyendocrinopathy/can-didiasis/ectodermal dystrophy) and is a subgroup of MED.

Interestingly, the keratitis is usually the first manifesta-tion of disease. It may lead to vascularization and scarring ofthe anterior corneal stroma. The corneal involvement usuallystarts from the superior part of cornea, and the corneal epi-thelium becomes irregular and forms a whorl- like pattern.10

The cause of the corneal vascularization is not well rec-ognized, but it seems that deficiency of limbal stem cells—anatural barrier that prevents conjunctival tissue migration to thecorneal surface and maintains the corneal avascular nature—isthe main reason.4–7

On impression cytology,11 migratory goblet cells arefound on the corneal surface. Histopathologic findings of the

limbal area consist of destroyed stem cells, limbal inflam-mation, and progression of conjunctival goblet cells on thecorneal surface.11–14 The treatment of keratitis associated withMED is conservative and supportive and includes hormonereplacement therapy and management of dry eye by lubricants,artificial tears, or punctal occlusion.8,9

In conclusion, in any child with diffuse corneal vascu-larization accompanied by dry eye and meibomian gland dys-function without any definite etiology, systemic workup forendocrine deficiency can be helpful, and hormone replacementtherapy together with measures that improve dry eye statusmay restore the vision and relieve the symptoms.

REFERENCES1. American Academy of Ophthalmology. Basic and Clinical Science

Course: External Disease and Cornea. San Francisco: AAO, 2002–2003.2. Behrman RE, Kliegman RM, Jenson HB. Nelson Textbook of Pediatrics,

17th ed. Philadelphia: WB Saunders, 2004.3. American Academy of Ophthalmology. Basic and Clinical Science

Course: Intraocular Inflammation and Uveitis. San Francisco: AAO,2002–2003.

4. Tseng SCG. Regulation and clinical implications of corneal epithelialstem cells. Mol Biol Rep. 1996;23:47–58.

5. Kruse FE, Chen JJY, Tsai RJF, et al. Conjunctival transdifferentiation isdue to the incomplete removal of limbal basal epithelium. InvestOphthalmol Vis Sci. 1990;31:1903–1913.

6. Chen JJY, Tseng SCG. Corneal epithelial wound healing in partial limbaldeficiency. Invest Ophthalmol Vis Sci. 1990;31:1301–1314.

7. Chen JJY, Tseng SCG. Abnormal corneal epithelial wound healing inpartial thickness removal of limbal epithelium. Invest Ophthalmol Vis Sci.1991;32:2219–2233.

8. Gass JD. The syndrome of keratoconjunctivitis, superficial moniliasis,idiopathic hypoparathyroidism, and Addison’s disease. Am J Ophthalmol.1962;54:660–674.

9. Wagman RD, Kazdan JJ, Kooh SW, et al. Keratitis associated with multipleendocrine deficiency, autoimmune disease, and candidiasis syndrome.Am J Ophthalmol. 1987;103:569–575.

10. Hung AJW, Tseng SCG. Corneal epithelial wound healing in the absenceof limbal epithelium. Invest Ophthalmol Vis Sci. 1991;32:96–105.

11. Puangsricharern V, Tseng SCG. Cytologic evidence of corneal diseasewith limbal stem cell deficiency. Ophthalmology. 1995;102:1476–1485.

12. Huang AJW, Tseng SCG, Kenyon KR. Alteration of epithelial paracellularpermeability during corneal epithelial wound healing. Invest OphthalmolVis Sci. 1990;31:429–435.

13. Kinoshita S. New approaches to human ocular surface epithelium: frombasic understanding to clinical application. In: Kinoshita S, Ohashi Y, eds.First Annual Meeting of the Kyoto Cornea Club. Amsterdam/New York:Kugler Publications, 1995, pp 33–41.

14. Kinoshita S, Yokoi N, Komuro A. Barrier function of ocular surfaceepithelium. In: Lass JH. Advances in Corneal Research. New York:Plenum Press, 1997, pp 47–55.

15. Schwartz GS, Holand EJ. Iatrogenic limbal stem cell deficiency. Cornea.1998;7:33–32. AU1

16. Funjishima H, Shimazaki J, Tsubota K. Temporary corneal stem celldysfunction after radiation therapy. Br J Ophthalmol. 1996;80:911–914.

17. Tseng SCG, Li D-Q. Comparison of protein kinas subtype expressionbetween normal and aniridic human ocular surface: implications forlimbal stem cell dysfunction in aniridia. Cornea. 1996;15:168–178.

FIGURE 4. Decreased corneal vascularization after treatment:A, right eye; B, left eye.

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Fig. 4 live 4/C