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Ophthalmic Manifestations of Congenital Protein C Deficiency: a Case Report and Mini Review Fariba Ghassemi1,2,3*, Fatemeh Abdi4,1 and Mandana Esfahani1

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Ophthalmic Manifestations of Congenital Protein C Deficiency: a Case Report and Mini Review Fariba Ghassemi1,2,3*, Fatemeh Abdi4,1 and Mandana Esfahani1 Ghassemi et al. BMC Ophthalmology (2020) 20:282 https://doi.org/10.1186/s12886-020-01424-x CASE REPORT Open Access Ophthalmic manifestations of congenital protein C deficiency: a case report and mini review Fariba Ghassemi1,2,3*, Fatemeh Abdi4,1 and Mandana Esfahani1 Abstract Background: Homozygous protein C (PC) deficiency is a potentially fatal disease with ocular blinding presentation or sequela. Case presentation: A 5 month-old boy was presented for evaluation of leukocoria. He had a history of frequent bruises and PC deficiency, treated with warfarin. His intraocular pressure was normal. In the left eye leukoma with anterior segment dysgenesis, shallow anterior chamber, and cataract were observed. Fundus was not visible. B-scan revealed a closed funnel retinal detachment. His right eye had a normal anterior segment and a thin retina with anomalous retinal vascular branching at equator and peripheral retina. A fibrovascular tuft on the optic nerve head with induced traction on superior arcade was visible. Total loss of a and b wave of both were appreciated in electroretinography (ERG). Fluorescein angiography (FA) showed very severe leakage at the junction of the vascularized and non-vascularized retina and optic nerve head. Favorable outcome was achieved with lasering of avascular retina in the right eye. Conclusion: The potential for protein C deficiency should be assessed in all infants with leukocoria, anterior segment dysgenesis, retinal detachment and retinal dysplasia. Early diagnosis could save the child’s life and vision. Keywords: Protein C deficiency, Congenital, Ophthalmic manifestations, Retinal detachment, Retinal dysplasia Background 70–140%) and do present within the first few days of life Protein C (PC), first described by Stenflo in 1976, is a [2]. Heterozygotes have about 50% levels of PC and usu- vitamin K dependent anticoagulant enzyme that inacti- ally remain asymptomatic until adolescence or adult- vates the plasma factors Va and VIIIa by limited prote- hood. Neonatal PC deficiency may also be acquired and olysis, thereby inhibiting the conversion of factor X to transient, especially in preterm ill infants [3] with subse- factor Xa and of prothrombin to thrombin [1]. Heredi- quent thrombosis being as severe as in the homozygous tary (congenital) PC deficiency is a rare autosomal dis- condition. Herein, we present a case of congenital PC order that predisposes to potentially blinding and fatal deficiency with asymmetric ophthalmic manifestations. thromboembolic attacks [2]. Homozygotes have very low Fluorescein angiography (FA) and electroretinography or undetectable PC activity (usually less than 1%, normal (ERG) have been performed. The better eye was treated with indirect laser and the vision was saved. * Correspondence: [email protected] 1Eye research center, Farabi Eye Hospital, Tehran University of Medical Sciences, Qazvin Square, Tehran, IR, Iran Case presentation 2 Retina & Vitreous Service, Farabi Eye Hospital, Tehran University of Medical The patient was a full term Iranian male that was deliv- Sciences, Tehran, IR, Iran Full list of author information is available at the end of the article ered with normal labor and was the first child of first © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Ghassemi et al. BMC Ophthalmology (2020) 20:282 Page 2 of 6 cousin parents. He was presented on his third day of life posterior synechia, dilated iris radial vessels, flat anterior with a purpura area on his buttocks and abdomen. chamber and mature membranous cataract. The right Very low protein C activity (less than 8%) was con- eye had a normal anterior segment, on a fundoscopy, a firmed in the laboratory investigations and the patient thin retina with anomalous retinal vascular branching was treated with fresh frozen plasma (FFP) and anti- and fading arterioles and venules was observed at equa- coagulant therapy (warfarin). tor and thereafter. (Fig. 1, a-h) There was a fibrovascular Both parents had low level of PC activity (52% in tuft on the optic nerve head with an induced traction on father and 60% in mother.). Liver and renal function superior arcade. At the B-scan, the left eye had a closed tests were normal and no organomegaly or lymphaden- funnel shaped retinal detachment. Electroretinography opathy was observed. After 5 months, in his first oph- (ERG) elucidated complete loss of a and b wave of both thalmic examination, leukocoria was detected and eyes. Fluorescein angiography (FA) has shown very se- evaluated. The child was on warfarin therapy with no vere leakage at the vascularized and non-vascularized more hypercoagulability state. The examination under borders of the fundus and at the optic nerve head of the anesthesia was conducted at Farabi Hospital for further right eye. Severe patchy and stippled abnormal skin assessment. fluorescence (on the face, thorax, back, buttocks, and Both eyes had normal intraocular pressure (IOP). He limbs) was observed at the time of FA. (Fig. 1, d-h) In- had eye-to-eye contact in the right eye but he couldn’t direct laser has been applied to the avascular areas. fix and follow in left eyes. The skipped areas were lasered during consecutive His right eye had a normal anterior segment with monthly follow-up visits and the neovascularizations round and reactive pupil. He had a central corneal were gone. The patient was followed-up for a total of 28 leukoma on his left eye with a distorted pupil, total months with a favorable outcome, as no new ocular or Fig. 1 Ocular findings of a patient with homozygous congenital protein C deficiency. a In the right eye thin dysplastic retina and peripheral avascularization with a fibrovascular band from optic disc to superior arcade is visible (arrow). b In the left eye leukoma and irregular pupil with posterior synechia and dilated iris vessels and cataract is visible. c Total funnel shaped retinal detachment of left eye is visible in B-scan (arrow). d and e Splinter and patchy abnormal fluorescences of the skin at the time of fluorescein angiography are shown (arrow). f-h Fluorescein angiography with early leakage (arrow) from mid-peripheral vessels all over the retina and later leakage around the optic nerve head due to the tractional effect of fibrovascular band. The leakage increases during less than 1 min with severe vitreous fluorescence Ghassemi et al. BMC Ophthalmology (2020) 20:282 Page 3 of 6 Table 1 Review of the reported ocular problems in Congenital Protein C deficiency Report Reported Involved Anterior segment Posterior segment involvement Global involvement cases eye involvement Estelles A 1 OU Bilateral vitreous hemorrhage and et al [1984] intravitreal mass [6] Marciniak E 1 OU Corneal opacity Case1: Case 1: Vitreous opacity in one eye Microphthalmia et al. [1985] Corneal opacity, pupil not Case 2: total retinal detachment with [7] visible in one eye retinal new and old hemorrhages Case2: Bilateral cataract, Rappaport 1 OU Hyperplastic vitreous bilaterally ES et al. [1987] [8] Pulido JS 1 OU Prominent iris vessels, Bilateral vitreal hemorrhage, and funnel- [1987] [9] shallow anterior chamber, shaped retinal detachment in both eyes synechia, cataract, retrolental membrane Auletta MJ 1 OU Raised intraocular pressure, Bilateral retinal detachment Bilateral leukocoria and flattened anterior chambers, Headington iris atrophy, lens adhesions JT [1988] [10] Hartman KR 1 OU Vitreal eye hemorrhages and Intraparenchymal brain infarction [1989] [11] Hermsen 1 OU Vascularized lens, non- Funnel-shaped retrolental mass, normal Bilateral PHPV, microphthalmos VM et al existent anterior chambers retina and optic nerve [1990] [12] Soria JM 1 Persistence of primary vitreous Microphthalmia, irregular globe et al. [1985] [13] Cassels- 2 OU Case 1: Posterior Case 1: subconjunctival hemorrhage, a Case 1: Brown A embryotoxon, shallow right sided retinal arterial occlusion and Strabismus, nystagmus, leukocoria et al. [1994] anterior chambers, ectropion bilateral florid retinal hemorrhages with Case 2: early birth 25 wk., end up to [14] uvea, posterior synechia swollen hemorrhagic optic discs death at 23 days of life because of Case 2: marked periorbital secondary to retinal venous occlusions, some subarachnoid hemorrhage and edema and hemorrhagic vitreous hemorrhages retinal with worsening lung function conjunctival chemosis detachment in one eye Case 2: hazy media, minor bilateral vitreous hemorrhages, and minor right sided retinal hemorrhage Acheson JF 4 OD Bilateral recurrent ischemic optic Association with Protein S deficiency, et al. [1994] neuropathy antithrombin III [15] Dreyfus M 9OU Unilateral or bilateral blindness 6/9 et al. [1995] cases bilateral PHPV [16] Hattenbach 2 OU Case 1. Shallow anterior Case 1. Left retrolental opacities, funnel Case 1. Strabismus, microphthalmos LO et al. chamber retinal detachment, vitreous Case 2. Microphthalmos [1999] [5] Case 2. Shallow anterior hemorrhage chamber, posterior synechia Case 2. Right vitreous hemorrhage, funnel retinal detachment Ergenekon 1 OS Eye ultrasound revealed an10x7 mm Leukocoria E et al. hyperechogenic structure underneath. [2000] [17] Retina of the left eye consistent with subretinal hemorrhage Churchill AJ 2 OU Case2.
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