CLINICOPATHOLOGIC REPORTS, CASE REPORTS, AND SMALL CASE SERIES

SECTION EDITOR: W. RICHARD GREEN, MD

In the left , a superonasal biochemical urinalysis revealed no Isolated Ectopia Lentis: was noted in the dilated features of , and the Potential Role of Matrix (Figure, A). The day after he diagnostic criteria for Marfan syn- 2 Metalloproteinases in was first seen in our clinic, he un- drome were not met ; ectopia len- Fibrillin Degradation derwent repair by tis was the only major criterion means of external drainage of sub- present when 2 are needed. The pa- retinal fluid and a scleral buckling tient’s aortic regurgitation was not Isolated ectopia lentis is a rare dis- procedure. The dislocated right lens associated with aortic root dilata- order in which no underlying cause remained in the vitreous cavity. tion; therefore, it did not fulfill a mi- for lens subluxation can be found, By September 1998, the dislo- nor criterion for . and it remains primarily a clinical di- cated right lens was cataractous, and In addition to analysis of the ex- agnosis. Patients with this disorder the patient had abandoned regular tracted left lens, a skin punch bi- may have a variety of ocular com- use of a contact lens. In anticipa- opsy was performed for fibrillin im- plaints, most commonly decreased tion of the possibility of spontane- munoreactivity. The lens was vision due to lens subluxation. ous total subluxation of the left lens, compared with lenses from age- Matrix metalloproteinases removal of the right lens before in- matched and sex-matched normal (MMPs) are proteolytic enzymes im- traocular lens placement was rec- postmortem (n=10) obtained portant in physiologic and patho- ommended. Right vitreolensec- from the Lions Eye Bank (Sydney, logic connective tissue remodel- tomy and placement of a scleral Australia). Enucleated lenses and the ing. Proteolytic activity is stringently fixated posterior chamber intraocu- patient’s lens were processed as pre- controlled by a family of natural an- lar 21 OD lens (CZ70BD; Alcon viously described.3 Eyes with pos- tagonists, the tissue inhibitors of me- Laboratories Inc, Ft Worth, Tex) terior synechiae or posterior sub- talloproteinases (TIMPs). The MMPs were successfully performed. Post- capsular, nuclear, or other forms of and TIMPs are present in the aque- 1 operatively, the best-corrected vi- were excluded. In addi- ous humor in normal eyes and may sual acuity eventually was 20/30 OD. tion, patients with a recent history interact with the lens zonules. In May 2001, the patient sought of trauma, steroid treatment, alco- We describe a patient with lens treatment because of a 5-week his- hol abuse, or premature cataract for- subluxation associated with posi- tory of reduced vision in the left eye. mation were excluded. The 10 sub- tive MMP expression and no demon- There was no history of ocular jects from whom the control eyes strable TIMP immunoreactivity trauma. Ophthalmological examina- were obtained had no previous or within the lens. To our knowledge, tion results revealed total disloca- family history of ophthalmic dis- this is the first report of MMP activ- tion of the left crystalline lens. In Au- ease and had not been receiving any ity, which we postulate leads to iso- gust 2002, a pars plana vitrectomy was medication known to influence cata- lated ectopia lentis. Understanding performed, and the dislocated lens ract formation. the role of these proteases may lead was removed from the eye in toto via Macroscopically, the lenses to novel therapies to reduce the pro- a superior limbal incision. An intra- (n=11) were oriented, retroillumi- gressive nature of lens subluxation ocular lens (CZ70BD; Alcon Labora- nated, and photographed under a mi- affecting the other eye. tories Inc) was located in the ciliary croscope. Slitlamp examination (Fig- Report of a Case. A 60-year-old man sulcus and fixed with polypropylene ure, A) was used to orient the patient’s was examined across 12 years of fol- sutures (Alcon Laboratories Inc) to extracted lens (Figure, B). Three ex- low-up in the Ophthalmology Clinic the . The removed lens (Fig- perienced and masked observers as- at Prince of Wales Hospital (Syd- ure, B) was immediately washed twice sessed all photographs for opacifica- ney, Australia). The patient initially with phosphate-buffered saline and tion. The photographs were scanned was seen at our department in June prepared at room temperature in buff- (OpticPro 4830; Plustek, Taipei, Tai- 1990 with a 2-week history of re- ered saline for analysis. wan, Republic of China) and ana- duced peripheral vision in his right The patient’s general medical lyzed with a Nikon 2.0 (Nikon Corp, eye because of a rhegmatogenous reti- history included mild aortic regur- Tokyo, Japan) in Windows 98 (Mi- nal detachment that was primarily su- gitation, gastroesophageal reflux, hy- crosoft Corp, Redmond, Wash). perotemporal. He had sought treat- pothyroidism after a left thyroid lo- After orientation, the lenses ment elsewhere 9 months previously bectomy, and left-sided deafness that were weighed and placed on a grid because of sudden reduction in vi- began spontaneously in December for dissection into 4 quadrants un- sion; the right crystalline lens was to- 1996. There was no family history der a microscope. Each quadrant of tally dislocated. After the manifesta- of systemic or ocular disease. Find- each lens was weighed individually tion of right retinal detachment, the ings from a thorough systemic ex- before and after a small region from best-corrected visual acuity was amination and investigation by a car- each quadrant of the anterior cap- counting fingers OD and 20/20 OS. diologist and general physician and sule periphery was carefully dis-

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 A B C

D E F

G H I

J K L

M N O

A, Clinically observed dislocation of the lens in the left eye viewed with a slitlamp. B, Macroscopic view of extracted lens (original magnification ϫ5). C, Macroscopic view of a normal age-matched and sex-matched lens (original magnification ϫ5). Immunolocalization of ectopic lens zonule matrix metalloproteinase (MMP)-1 (D, arrow), MMP-3 (E, arrows), and MMP-9 (F, arrow) (original magnification ϫ250). Control lens (D, inset, arrow) negative for MMP-1 (original magnification ϫ125). Lack of ectopic lens zonule staining for tissue inhibitor of metalloproteinase (TIMP)-1 (G, arrow), TIMP-2 (H, arrows), and TIMP-3 (I, arrow) (original magnification ϫ250). Positive fibrillin immunoreactivity in the patient’s lens zonule (G, inset, arrow) and skin biopsy results (H, inset) (original magnification ϫ125). A normal age-matched and sex-matched lens revealed no immunoreactivity for MMP-1 (J, arrow), MMP-3 (K, arrow), or MMP-9 (L, arrow) but positive staining for TIMP-1 (M, arrow), TIMP-2 (N, arrow), and TIMP-3 (O, arrow) (original magnification ϫ250). Control lenses were negative for MMP-1 (J, inset, arrow) and TIMP-1 (M, inset, arrow) (original magnification ϫ125).

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 sected under a microscope and placed in 4% paraformaldehyde to immu- Proteolytic Activity in 11 Lenses* nolocalize zonular proteins MMP-1, MMP-3, and MMP-9 and TIMP-1, Quadrant TIMP-2, and TIMP-3, as previously Antibody Superonasal Inferonasal Inferotemporal Superotemporal 3 described. Lens quadrants were in- Dislocated Lens (n = 1) dividually homogenized, and the su- MMP-1 56 ± 4.2 20 ± 1.4 15 ± 1.3 6 ± 0.3 pernatant was analyzed with enzyme- MMP-3 80 ± 6.3 79 ± 6.4 74 ± 4.4 78 ± 6.4 linked immunosorbent assay in MMP-9 63 ± 5.3 40 ± 3.4 32 ± 2.4 20 ± 2.1 triplicate to quantify MMP-1, MMP-3, TIMP-1 5 ± 0.4 6 ± 0.3 8 ± 0.4 7 ± 0.2 MMP-9, TIMP-1, and TIMP-2. TIMP-2 8 ± 0.5 7 ± 0.3 6 ± 0.2 7 ± 0.6 Normal Lenses (n = 10) Results. The mean±SD time from MMP-1 10 ± 1.0 10 ± 1.1 9 ± 0.7 8 ± 0.3 death to fixation of the control lenses MMP-3 10 ± 0.5 7 ± 0.2 8 ± 0.4 6 ± 0.2 MMP-9 15 ± 1.2 12 ± 0.2 13 ± 0.2 13 ± 0.2 was 5.5±1.4 hours (range, 4-9 TIMP-1 80 ± 6.4 80 ± 8.3 83 ± 6.4 86 ± 7.3 hours). None of the control lenses TIMP-2 86 ± 6.3 81 ± 5.4 83 ± 7.4 84 ± 6.3 was subluxated. There was no sig- nificant difference in the weight of Abbreviations: MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase. each quadrant in all 11 lenses ex- *Data are expressed as the mean ± SD nanograms per gram. amined. All 10 control lenses were normal macroscopically (Figure, C), and the capsules were normal his- the patient’s lens (Figure, G, inset). into the lens from the aqueous hu- tologically at hematoxylin-eosin Sections incubated with isotype con- mor or or quantified the staining. The patient’s left lens mac- trol antibodies demonstrated no re- levels within human lenses. The fibril- roscopically appeared compacted in activity in normal lenses or the pa- lin in some cases of ectopia lentis is the superonasal quadrant and apart tient’s lens (Figure, D, inset, J, inset, abnormal.6 We hypothesize that (1) from nuclear sclerosis appeared oth- and M, inset). Enzyme-linked im- the fibrillin in patients with iso- erwise normal (Figure, B). munosorbent assay analysis (Table) lated ectopia lentis is more prone to None of the normal lens zon- revealed a MMP-1 level 5.6 times degradation by MMPs than is nor- ules (n=10) had MMP-1 (Figure, J), higher in the superonasal quadrant mal fibrillin; (2) there is an abnor- MMP-3 (Figure, K), or MMP-9 (Fig- of the dislocated lens than in nor- mal zonular protein in ectopia len- ure, L) immunoreactivity, and mal lenses and 4.1 times higher than tis that predisposes fibrillin to MMP TIMP-1 (Figure, M), TIMP-2 (Fig- the mean of the other 3 quadrants. degradation, as in Marfan syn- ure, N), and TIMP-3 (Figure, O) In the dislocated lens, there was an drome; or (3) dysregulation of staining was observed in all 10 nor- unequal distribution among quad- MMPs and TIMPs results in the pro- mal lens zonules. Positive staining rants (PϽ.001). Similarly, there were gressive destruction of lens zon- of the zonules immunolocalized only 8.0 times greater MMP-3 and 4.2 ules and subsequent lens subluxa- to the capsular insertion point and times greater MMP-9 levels in the su- tion. These data support existing lens epithelium in all eyes. Enzyme- peronasal quadrant between the dis- study results that show that exces- linked immunosorbent assay analy- located lens and normal lenses and sive proteolysis of the lens zonule re- sis of the normal age-matched and unequal distribution among quad- sults in fibrillin degradation.7 The sex-matched lenses revealed low rants (PϽ.001) in the dislocated presence of excessive MMP-1, MMP-1, MMP-3, and MMP-9 activ- lens. Little TIMP-1 or TIMP-2 was MMP-3, and MMP-9 and low ity levels (Table), and the results found in the dislocated lens, and lev- TIMP-1 and TIMP-2 levels in the su- were not different among quad- els were not significantly different peronasal quadrant in this patient rants. Levels of TIMP-1 and TIMP-2 among quadrants. Skin biopsy re- correlate with the inferotemporal di- activity for the whole lenses were sults revealed normal fibrillin mor- rection of lens displacement ob- more than 11 times higher in nor- phology (Figure, H, inset). served clinically before total sub- mal lenses, as compared with that in luxation. the subluxated lens, and were not Comment. To our knowledge, this is The lens zonule consists of a se- different among quadrants. the first article in which lens- ries of fibers composed of microfi- In contrast, MMP-1 (Figure, D), associated immunoreactivity to MMPs brils 8 to 12 nm in diameter. The MMP-3 (Figure, E), and MMP-9 and TIMPs in isolated ectopia lentis fibrils consist largely of a cysteine- (Figure, F) were localized to the de- is quantified. Authors of previous ar- rich microfibrillar component of the graded lens zonule and lens epithe- ticles have shown that MMPs de- elastin system, fibrillin. In other tis- lium in the superonasal area in the grade fibrillin4 and may play a role in sues, fibrillin provides a template for subluxated lens. No TIMP-1 (Fig- lens subluxation in Marfan syn- elastin deposition.8 Understanding ure, G), TIMP-2 (Figure, H), or drome.3 The MMPs appear to be of the functions of the fibrillin- TIMP-3 (Figure, I) staining was stable for as long as 24 hours post containing microfibrils is still incom- found in the dislocated lens. A fibril- mortem in removed ocular tissue.5 To plete; correspondingly, no compre- lin monoclonal antibody was in- our knowledge, no authors have ex- hensive theory of the pathogenesis of cluded to identify the lens zonule in amined whether MMPs can diffuse lens dislocation has emerged.

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Both fibrillin molecules and aqueous humor of patients and experimental nized, the most common being animals with . Curr Eye Res. 1996;15: fibrillin-rich microfibrils are suscep- 1060-1068. carcinoma arising from a preexist- tible to degradation by serine pro- 2. Pyeritz RE. The Marfan syndrome. Annu Rev ing pleomorphic adenoma.1,2 The teases, and the amino acid substitu- Med. 2000;51:481-510. second type is the metastasizing 3. Sachdev NH, Di Girolamo N, McCluskey PJ, et al. tions found in Marfan syndrome Lens dislocation in Marfan syndrome: potential mixed tumor, which has benign- change the fragmentation pat- role of matrix metalloproteinases in fibrillin deg- appearing epithelial and stromal 4 radation. Arch Ophthalmol. 2002;120:833-835. 1,2 terns. Fibrillin degradation prod- 4. Ashworth JL, Murphy G, Rock MJ, et al. Fibril- components. The true malignant ucts generated by MMP activity pro- lin degradation by matrix metalloproteinases: mixed tumor or carcinosarcoma, an vide conclusive evidence that these implications for connective tissue remodel- exceptionally rare tumor, is the third ling. Biochem J. 1999;340:171-181. enzymes cause specific changes to 5. Kamei M, Hollyfield JG. TIMP-3 in Bruch’s subtype and is composed of malig- assembled microfibrils.4 In Marfan membrane: changes during aging and in age- nant epithelial and malignant mes- syndrome, most of the mutations in related . Invest Ophthal- 2,3 mol Vis Sci. 1999;40:2367-2375. enchymal elements. fibrillin-1 are found within epider- 6. Tsipouras P, Del Mastro R, Sarfarazi M, et al. Less than 5% of all salivary mal growth factor–like motifs and Genetic linkage of the Marfan syndrome, ec- gland neoplasms are seen in pa- topia lentis, and congenital contractural arach- are predicted to disrupt calcium nodactyly to the fibrillin genes on chromo- tients younger than 16 years and binding. These mutations may ren- somes 15 and 5: the International Marfan 13% of these tumors are solid, of der fibrillin-1 more susceptible to Syndrome Collaborative Study. N Engl J Med. which only 23% are malignant.4 The 9 1992;326:905-909. proteolytic cleavage. Patients with 7. Booms P, Tiecke F, Rosenberg T, et al. Differ- most common malignant salivary isolated ectopia lentis may also have ential effect of FBN1 mutations on in vitro pro- gland tumor in children is muco- an increased susceptibility to zonu- teolysis of recombinant fibrillin-1 fragments. Hum Genet. 2000;107:216-224. epidermoid carcinoma, followed by lar degradation. Structural modifi- 8. Robinson PN, Godfrey M. The molecular ge- rhabdomyosarcoma and acinic cell cations in fibrillin-rich microfibrils netics of Marfan syndrome and related micro- carcinoma.4 We herein describe a fibrillopathies. J Med Genet. 2000;37:9-25. occur during aging of the human 9. Reinhardt DP, Ono RN, Sakai LY. Calcium sta- highly unusual patient with a car- 10 ciliary zonule. These age-related bilizes fibrillin-1 against proteolytic degrada- cinosarcoma of the parotid gland changes may account for the in- tion. J Biol Chem. 1997;272:1231-1236. 10. Hanssen E, Franc S, Garrone R. Fibrillin-rich that metastasized to ipsilateral or- creased incidence of ocular disease microfibrils: structural modifications during ag- bit and intraocular structures. in older patients with ectopia len- ing in normal human zonule. J Submicrosc Cy- tis. The hypothesis regarding the role tol Pathol. 1998;30:365-369. Report of a Case. A 10-year-old boy of MMPs in lens subluxation im- was seen at another institution be- plies that an imbalance of lens pro- cause of right orbital and preauricu- teases and their antagonists may be lar masses that evolved gradually Orbital Metastasis and involved in the development of ec- during a period of 6 months Intraocular Invasion of topia lentis. (Figure 1). His medical history in- Malignant Mixed Tumor cluded trabeculectomy for right con- Nitin H. Sachdev, MBChB (Carcinosarcoma) of the genital at the age of 3 Minas T. Coroneo, MD, Parotid Gland in a Child years. His records indicate that there FRANZCO, FRACS was no evidence of an intraocular Denis Wakefield, MD, Malignant mixed tumor of the sali- mass or neovascularization. FRACP, FRCPA vary glands is a rare neoplasm, and Visual acuity in the right eye Michael P. Hennessy, the majority of these tumors arise had remained no light perception MBiomedE, FRANZCO from the parotid gland.1 Histopatho- since then. Magnetic resonance im- Sydney, Australia logically, 3 distinct variants of ma- ages showed a right anterior orbital lignant mixed tumors are recog- and preseptal mass, as well as a large We thank ophthalmologists Malcolm Capon, FRANZCO, and John Downie, FRANZCO; physician Warren Kid- son, FRACP; cardiologist Anthony Freeman, MD; and masked observers Timothy Nolan, MBBS, Jeanie Chui, MBBS, and Jenny Lan, PhD. The authors have no relevant fi- nancial interest in this article. Corresponding author: Michael P. Hennessy, MBiomedE, FRANZCO, Dept of Ophthalmology, Prince of Wales Hospital, University of New South Wales, Randwick, Sydney, Aus- tralia (e-mail: hennessymp@sesahs .nsw.gov.au).

1. Di Girolamo N, Verma MJ, McCluskey PJ, et al. Increased matrix metalloproteinases in the Figure 1. Patient at initial examination, the day after the incisional biopsy was performed.

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