Blue Sclera with and Without Corneal Fragility (Brittle Cornea Syndrome) in a Consanguineous Family Harboring ZNF469 Mutation (P

Home , Keratoglobus, Ptosis (eyelid)

in situ where disc and retinal assessments are essential Ophthalmic examination revealed visual acuity of no and for preoperative evaluation if therapeutic IOL ex- light perception OU. Both eyes were phthisical, had blue change to transparent media is considered. sclera, and were soft to palpation. Moreover, the observed ability of occlusive IOLs to General assessment revealed a well-nourished alert boy transmit infrared light suggests the potential for devel- with normal vital signs and chestnut-colored hair. Height, opment of infrared light–based assessment tools such as weight, and head circumference were age appropriate. Skin Snellen charts for this patient group. was thin, velvety, and without abnormal elasticity. Subcu- taneous veins were easily appreciated. There were scat- Chetan K. Patel, BSc, FRCOphth tered small scars on all extremities and a large one at the Imran H. Yusuf, MBChB (Hons), MRes right elbow where a small surgical incision had been made. Victor Menezo, FRCOphth There was no joint hypermobility (Beighton score 2/9) or Author Affiliations: Oxford Eye Hospital, John Rad- scoliosis. Oral inspection revealed grossly normal denti- cliffe Hospital, Oxford, England. tion and a slightly arched palate. Extremity assessment re- Correspondence: Dr Patel, Oxford Eye Hospital, Ox- vealed bilateral valgus foot (talipes valgus) and hallux val- ford Radcliffe Hospitals National Health Service Trust, gus, which were confirmed by plain-film radiography. West Wing, John Radcliffe Hospital, Headley Way, Head- Skeletal plain-film radiography showed normal bone den- ington, Oxford OX3 9DY, England (ckpatel@btinternet sities without evidence for fractures. Complete blood cell .com). count and electrolyte levels were within normal limits. Financial Disclosure: None reported. Case 2. Sibling 2 is an 8-year-old girl (Figure 2). She had blue sclera since birth. There was a vague history of 1. Hadid OH, Wride NK, Griffiths PG, Strong NP, Clarke MP. Opaque intra- a dislocation in the right forearm following trauma at age ocular lens for intractable diplopia: experience and patients’ expectations and satisfaction. Br J Ophthalmol. 2008;92(7):912-915. 1 year that did not require surgery. She was treated medi- 2. Wong SC, Islam N, Ficker L. Black occlusive IOLs. Ophthalmology. 2007;114 cally for congenital glaucoma until age 5 years, at which (12):2365. time she was diagnosed as having keratoglobus without 3. Choyce DP. Black intraocular lens for leukocoria. J Cataract Refract Surg. 2001; 27(2):179-180. evidence of glaucoma. Cycloplegic refraction at age 4 years 4. Osher RH, Snyder ME. Phakic implantation of a black intraocular lens in a was approximately plano in both eyes and fundus ex- blind eye with leukocoria. J Cataract Refract Surg. 2003;29(4):839-841. amination results were unremarkable. Protective glasses 5. Sandy CJ, Wilson S, Brian Page A, Frazer DG, McGinnity FG, Lee JP. Phaco- emulsification and opaque intraocular lens implantation for the treatment of were stressed but were not used. At age 7 years, she had intractable diplopia. Ophthalmic Surg Lasers. 2000;31(5):429-431. a minor trauma in the left eye that led to Descemet membrane detachment and associated corneal edema, for which she had surgical repositioning of the Descemet membrane via air bubble injection. Ophthalmic examination revealed visual acuity of 20/ Blue Sclera With and Without Corneal 30 OD and 20/400 OS, with no improvement by pinhole. Fragility (Brittle Cornea Syndrome) in a Both eyes had keratoglobus and blue sclera and had grossly Consanguineous Family Harboring ZNF469 normal intraocular pressure by digital palpation. Slitlamp Mutation (p.E1392X) examination revealed thin corneas with keratoglobus and in the left eye corneal haze corresponding to the area of lue sclera with corneal fragility characterizes prior Descemet membrane detachment. At age 6 years, brittle cornea syndrome (BCS) (OMIM #229200), cycloplegic refraction was ϩ0.75−1.50ϫ042 OD and B an underrecognized predominantly ocular dis- −11.00−2.50ϫ090 OS with scissoring of the reflex. Fun- order that is often confused with Ehlers-Danlos syn- dus examination results were within normal limits. drome (EDS).1 Brittle cornea syndrome has recently been General assessment revealed a thin alert girl with nor- associated with recessive mutation in ZNF469, which en- mal vital signs and chestnut-colored hair. Height, weight, codes a classic zinc-finger protein that is likely involved and head circumference were age appropriate; however, she in synthesis and/or organization of corneal collagens.2,3 did have an appearance of frontal bossing and the calvaria In this report, we describe the phenotype/genotype cor- was irregular to palpation. Skin was thin, velvety, without relation for blue sclera with or without BCS in all 3 chil- abnormal elasticity, and without scars. Subcutaneous veins dren of a consanguineous, asymptomatic Syrian couple. were easily appreciated. There was significant joint hyperlaxity (Beighton score 9/9). Oral inspection revealed poor Report of Cases. Case 1. Sibling 1 is a 13-year-old boy dental hygiene and an arched palate. The sternum pro- (Figure 1). He had blue sclera since birth and history truded outward slightly (pectus carinatum). Scoliosis was of hernia repair, the details of which were not available. not present but lumbar lordosis seemed exaggerated. Ex- At age 2 years following minor trauma, he had bilateral tremity assessment revealed bilateral talipes valgus. Skel- corneal rupture and underwent multiple corneal opera- etal plain-film radiography confirmed the irregular cal- tions that led to phthisis. It was suspected that he had varia, exaggerated lumbar lordosis, and bilateral talipes congenital glaucoma. At approximately age 5 years, he valgus; bone densities were normal. Complete blood cell had slightly decreased hearing following recurrent ear in- count and electrolyte levels were within normal limits. fections; this resolved with medical treatment and his hear- Case 3. Sibling 3 is a 4-year-old girl (eFigure 1; http: ing is now considered normal. At age 12 years, he had a //www.archophthalmol.com). This healthy-appearing, right forearm dislocation following a significant fall down alert girl with blue sclera since birth had normal vital signs stairs that required surgical pinning. and chestnut-colored hair. Other than blue sclera, re-

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Figure 1. Sibling 1. A, Blue sclera, phthisical eyes, and small forehead skin scars are seen. Similar skin scars were scattered on the extremities. B, Abnormal skin scarring occurred following small-incision surgery to pin a dislocated forearm. C, Talipes valgus can be appreciated as well as multiple small skin scars. D, Plain-film radiography confirms talipes valgus. R indicates right.

sults from complete ocular examination, directed physi- type VI was known as the ocular subtype of EDS, in fact cal examination, and laboratory investigations were ap- ocular fragility in EDS type VI is less frequent than was propriate for her age. originally thought.1,4 Ehlers-Danlos syndrome type VI can Parents. The father is aged 35 years, and the mother be clinically distinguished from BCS as the former in- is aged 37 years. Both parents were alert, were healthy, cludes symptomatic obvious nonocular signs in chil- and had chestnut-colored hair. They had unremarkable dren, while the latter is characterized by obvious ocular results on ocular examinations and no history of skin dis- disease in children with subtle nonocular findings. Chil- ease, abnormal healing, hyperflexibility, joint disloca- dren with EDS type VI have muscular hypotonia from tions, or spine or extremity deformity. birth, generalized joint laxity, congenital and progres- ZNF469 Analysis. The family had ZNF469 (GenBank sive kyphoscoliosis, radiographically confirmable osteo- NM_001127464.1) analysis performed (eFigure 2).The penia, skin elasticity that is typical for EDS, and a risk of 2 older children (siblings 1 and 2) were homozygous for sudden death from arterial rupture.1,4 In addition, when a novel mutation p.E1392X (c.4174GϾT), while the ocular rupture does occur in EDS type VI, it tends to be youngest child with blue sclera only (sibling 3) and the scleral rather than corneal.1,4 Ehlers-Danlos syndrome type 2 parents were heterozygous for the mutation (primers VI is due to recessive mutation in the gene for lysyl hy- and conditions are available in the eTable). droxylase 1 (PLOD1 [OMIM *153454]). In the current family, the youngest sister had blue sclera Comment. Brittle cornea syndrome has been confused only and was a carrier for the mutation. In the context of with EDS, particularly EDS type VI (OMIM #225400), her older affected siblings, this was phenocopy for the dis- which is also associated with blue sclera.1,4 Although EDS ease. Interestingly, 2 previously described families with BCS

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0.005 mm Color Steps Elevation BFS Elevation BFS 0.005 mm Color Steps 90 90 105 75 7.75 mm/43.6 D 6.84 mm/49.3 D 105 75 Anterior 120 60 120 60 Posterior Float Float 135 45 Diff: 0.019 mm Diff: – 0.010 mm 135 45 Meridian: 103° Meridian: 103° 0.075 150 30 Radius: 0.9 mm Radius: 0.9 mm 150 30 0.075 0.060 0.060 165 165 0.045 15 15 0.045 0.030 Sim K’sAstig: 11.8 D @87 deg 0.030 180 0 Max: 48.0 D @87 deg 180 0 0.015 Min: 36.2 D @177 deg 0.015 0.000 ± 0.000 195 345 3.0 MM Zone: Irreg: 12.6 D 195 345 – 0.015 Mean Pwr 42.1 ± 5.2 D – 0.015 Astig Pwr 12.5 ± 11.5 D – 0.030 210 330 210 330 – 0.030 Steep Axis 92 ± 13 deg – 0.045 – 0.045 225 315 Flat Axis 179 ± 13 deg 225 315 – 0.060 5.0 MM Zone: Irreg: ± 15.7 D – 0.060 300 300 240 Mean Pwr 41.0 ± 7.5 D 240 – 0.075 255 285 255 285 – 0.075 270 Astig Pwr 16.7 ± 13.8 D 270 90 90 N 105 75 ± 105 75 T 57.00 Steep Axis 89 17 deg 900 120 60 Flat Axis 179 ± 16 deg 120 60 54.00 840 135 45 White-to-White [mm]: 12.8 135 45 B 51.00 Pupil Diameter [mm]: 5.1 780 47.3 311 48.00 150 30 Thinnest: 277 um @ (– 2.4, – 0.6) 150 30 720 47.2 45.00 48.6 ACD (Ep): 4.01 mm 660 165 Kappa: 1.45° @ 7.17° 165 42.00 15 15 600 Kappa Intercept: 0.10, – 0.11 39.00 40.6 48.7 540 180 0 180 262 320 307 0 36.00 46.9 34.2 OS 480 33.00 195 195 420 45.7 345 345 30.00 360 v3.12 27.00 210 330 210 335 330 300 Power: 45.51 D Thick: 312 mic 225 315 225 315 Meridian: 103° Meridian: 103° 240 300 Radius: 0.9 mm Radius: 0.9 mm 240 300 Keratometric 255 270 285 255 270 285 Thickness 1.0 D Color Steps Axial Power 0.92 Pachymetry 20 mic Color Steps

D E F

Figure 2. Sibling 2. A, Blue sclera, frontal bossing, and joint hyperlaxity are seen. B, Keratoglobus of the left eye can be appreciated. There is slight corneal haze, present since the repair of a traumatic Descemet membrane detachment. C, An Orbscan of the left cornea before the Descemet membrane detachment reveals corneal thinning and astigmatism. The right cornea (not shown) had comparable thinning without significant ectasia. D, Prominent lumbar lordosis can be appreciated on plain-film radiography. L indicates left. E, Irregularity of the calvaria can be appreciated on plain-film radiography, as can the relatively elongated anterior-posterior distance. F, Subcutaneous veins were prominent throughout the body. The left forearm is shown.

alsoincludedcloserelativeswithbluescleraonly.5,6 Although Author Affiliations: Division of Pediatric Ophthalmol- genetic confirmation was not available for the patients in ogy, King Khaled Eye Specialist Hospital (Dr Khan), these 2 previously described families, their phenotypes and Department of Genetics, King Faisal Specialist Hospi- the fact that they were Jewish of Tunisian ancestry strongly tal and Research Center (Drs Khan, Aldahmesh, support that they truly had BCS.5,6 In the current family, and Alkuraya and Ms Mohamed), and Department of neither parent in this study had blue sclera despite being Pediatrics, King Khalid University Hospital and Col- heterozygous for the mutation, and neither had a history lege of Medicine, King Saud University and Depart- of blue sclera during childhood. One can speculate that het- ment of Anatomy and Cell Biology, College of Medi- erozygous ZNF469 mutation may predispose to childhood cine, Alfaisal University (Dr Alkuraya), Riyadh, Saudi blue sclera without BCS only in certain individuals, depend- Arabia. ing on other genetic and/or environmental conditions. Correspondence: Dr Khan, Division of Pediatric Oph- thalmology, King Khaled Eye Specialist Hospital, PO Box Arif O. Khan, MD 7191, Riyadh 11462, Saudi Arabia (arif.khan@mssm Mohammed A. Aldahmesh, PhD .edu). Jawahir N. Mohamed, BSc Financial Disclosure: None reported. Fowzan S. Alkuraya, MD Funding/Support: This study was supported in part by

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 grant 08-MED497-20 from King Abdulaziz City for Sci- A ence and Technology (Dr Alkuraya). Online-Only Material: The eFigures and eTable are available at http://www.archophthalmol.com.

1. Al-Hussain H, Zeisberger SM, Huber PR, Giunta C, Steinmann B. Brittle cornea syndrome and its delineation from the kyphoscoliotic type of Ehlers- Danlos syndrome (EDS VI): report on 23 patients and review of the literature. Am J Med Genet A. 2004;124A(1):28-34. 2. Abu A, Frydman M, Marek D, et al. Deleterious mutations in the Zinc-Finger 469 gene cause brittle cornea syndrome. Am J Hum Genet. 2008;82(5):1217- 1222. 3. Christensen AE, Knappskog PM, Midtbø M, et al. Brittle cornea syndrome associated with a missense mutation in the zinc-finger 469 gene. Invest Oph- thalmol Vis Sci. 2010;51(1):47-52. 4. Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ; Ehlers- Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Am J Med Genet. 1998;77(1):31-37. 5. Hyams SW, Kar H, Neumann E. Blue sclerae and keratoglobus: ocular signs of a systemic connective tissue disorder. Br J Ophthalmol. 1969;53(1):53- 58. B 6. Stein R, Lazar M, Adam A. Brittle cornea: a familial trait associated with blue Au sclera. Am J Ophthalmol. 1968;66(1):67-69. Au

SURGEON’S CORNER

Au Au O Au Au Histological Evidence of Tissue Reaction to Au Au Gold Weights Used for Mechanical Ptosis 1.00 2.003.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 Kiloelectron Volts old and platinum weights have been im- planted successfully to induce mechanical pto- Figure 1. Evidence of inflammation and analysis of foreign material found in G sis for corneal surface protection, although ocu- case 1. A, Hematoxylin-eosin–stained section from the capsule surrounding lar symptoms of facial paralysis can still persist. Recent the implant showing dense fibrosis with round to polygonal fragments of satisfaction surveys suggest that patients prefer the more dark golden brown material and adjacent foreign body giant cells (arrows) (original magnification ϫ400). B, Trace from scanning electron microscopy expensive platinum linked chain owing to improved con- x-ray microanalysis showing peaks for gold (Au) and oxygen (O). tour and corresponding cosmesis.1 Variations in the surgical approach to pretarsal gold weight implantation have reduced associated rates of with-the-rule corneal astigmatism and extrusion.2 Tissue reaction to gold is un- moved in October 2007 owing to chronic eyelid edema. common. Herein we report 2 cases of nonextruded gold A platinum weight was inserted in August 2008 owing weights removed following treatment of lagophthalmos to residual lagophthalmos. During this procedure, fi- and describe the histological findings. brous tissue was excised from the surgical plane and sent for histological examination. Microscopy revealed frag- Report of Cases. Case 1. A 68-year-old woman under- ments of fibrous tissue with foreign body granuloma- went gold weight insertion in April 2008 owing to ex- tous reaction and dense chronic inflammation associ- posure keratopathy resulting from facial nerve palsy. Fail- ated with dark-staining foreign material. This material ure of this treatment led to the insertion of a heavier weight showed scattered light on epipolarization that, in this con- in May 2009. A fibrous capsule was identified on re- text, was consistent with gold particles3 (Figure 2). moval of the original weight and sent for histological examination. Microscopy revealed a capsule of dense fi- Comment. Gold was originally used for eyelid implanta- brous tissue surrounded by a chronic inflammatory tion owing to its inert nature and mechanical properties. response. The internal surface showed a palisading mac- Such dense material can remain in situ permanently, al- rophage response, areas of collagen necrobiosis, and some though inflammation can occur and type IV hypersensi- refractile crystalline gold-brown foreign material found tivity reactions have been reported in patients allergic to to be consistent with gold using epipolarization light mi- gold.4,5 In both of our cases, a dense inflammatory com- croscopy3 and scanning electron microscopy x-ray mi- ponent was discovered in the fibrous capsule surround- croanalysis (Figure 1). ing the implants. There was also foreign body material iden- Case 2. A 57-year-old woman had a translabyrin- tified as particles of gold. This granulomatous reaction is thine removal of acoustic neuroma in February 2005 with different histologically from the sarcoidal reaction re- primary facial nerve repair. She underwent insertion of ported in granulomatous contact dermatitis due to gold ear- a gold weight to her upper eyelid in March 2006 owing rings and could be responsible for cases of gold weight to residual seventh-nerve palsy. The gold weight was re- extrusion.5,6 Platinum has a higher density, better biocom-

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