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Purpose: To evaluate the incidence, clinical features, diagnostic challenges, management and prognosis of cutaneous squamous cell carcinoma of the eyelid (ecSCC) in southern Finland, northern Europe, latitude 62° N. Methods: Patients were identified from the Finnish Cancer Registry and the Helsinki University Hospital databases during a 25‐year period (1998–2022). Age, sex, location, clinical and histopathological diagnosis, treatment and outcome were retrieved. Results: Cutaneous squamous cell carcinoma of the eyelid (ecSCC) was diagnosed in 58 patients. The mean age‐standardized incidence was 1.03 per 100 000. Median age at the time of histopathological diagnosis was 79 (range 55–93) years; sex ratio was 0.52. Clinical diagnosis in the referral was ecSCC in only three patients. The most frequent misdiagnosis (38%) was basal cell carcinoma (BCC). One or more of the known risk factors (smoking, history of extensive sun exposure, systemic immunosuppression and previous in situ cSCC/cSCC) were documented in 71% of the patients. More than one third (38%) of the patients developed in situ SCC elsewhere on the skin; one third (31%) of the patients had invasive cSCC elsewhere. During the median follow‐up time of 24 months, three patients experienced local recurrence, four patients developed metastatic disease (median 19 months) and two patients died of metastatic ecSCC. Conclusion: The estimated incidence of ecSCC in Finland (predominantly white Caucasian) was higher than in a previous study from Europe. Clinical diagnosis of ecSCC is difficult and often misdiagnosed as BCC. Immunosuppression as a risk factor should noticed. Recurrences of ecSCC, which may be lethal, were infrequent. [ABSTRACT FROM AUTHOR]

Purpose: To identify germline variants in myocilin (MYOC) and other known monogenic glaucoma genes in Finnish patients with juvenile open‐angle glaucoma (JOAG). Methods: Finnish patients with JOAG treated between 2010 and 2018 at the Department of Ophthalmology, Helsinki University Hospital, Finland, were enrolled. We sequenced all exonic regions and flanking splice sites of MYOC for five patients and one healthy relative using Sanger sequencing. In 48 patients, we performed exome sequencing to identify variants also in 28 other glaucoma‐related genes. Results: Fifty‐three individuals with JOAG from 50 pedigrees, and one healthy relative, participated. The mean age at diagnosis was 30.8 years [SD 7.6; range 11 to 39]. Five probands had probably pathogenic variants in MYOC: c.1102C>T p.(Gln368Ter), c.1109C>T p.(Pro370Leu), c.1130C>T p.(Thr377Met), c.1132G>A p.(Asp378Asn) and c.1456C>T p.(Leu486Phe). Four of these patients had a family history of dominantly inherited JOAG. The frequency of MYOC variants was 10% (5 of 50 families). One patient and his mother with JOAG had a novel loss‐of‐function variant in the FOXC1 gene, c.366G>A p.(Trp122Ter). A patient with sporadic JOAG had a homozygous likely pathogenic variant in the LTBP2 gene, c.3938G>A p.(Cys1313Tyr). The genetic variants explained 14% (7 out of 50 families; 95% CI, 6%–23%) of JOAG in our cohort. Conclusions: The frequency of pathogenic variants in previously known glaucoma‐associated genes is low in Finnish patients with JOAG. Because of the distinct genetic background of Finns, it might be possible to identify novel glaucoma genes through our JOAG series in the future. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the clinical features, diagnostic challenges, management, and prognosis of sebaceous carcinoma (SC) of the eyelids and periocular region in a Nordic country. Methods: Patients were identified from the Finnish Cancer Registry and the Helsinki University Hospital databases during the 21‐year period 1998–2018. Age, sex, location, clinical and histopathologic diagnosis, treatment and outcome were registered. Results: Sebaceous carcinoma (SC) was diagnosed in 32 patients. The incidence was 0.6 per million. Median age at the time of histopathologic diagnosis was 74 years, and 72% of patients were women. Diagnostic delay was often long, median 12 months. The most common cause for delay was misdiagnosis (72%): a chalazion in 34% and a benign tumour in 22%. The most common location was the upper eyelid (53%) and tumour type a solitary nodule (94%). The SC was not correctly diagnosed in 12 (40%) of 30 preoperative biopsies. The treatment for 31 (97%) patients was complete surgical removal with reconstruction. Conjunctival intraepithelial growth was found in 50%. The leading postoperative problem was ocular irritation (30%). During a median follow‐up of 58 months, two patients (6%) experienced a local recurrence and one patient died from metastatic SC. Conclusions: The estimated incidence of SC in Finland was somewhat higher than in other Western countries. The diagnosis was often markedly delayed. Especially differentiation from chalazion continues to be essential. To improve outcomes, it is essential to inform the pathologist about the possibility of SC in eyelid biopsies and specimens and ideally submit them to an ophthalmic pathology service. [ABSTRACT FROM AUTHOR]

In the article, the authors present their study on the population-based overall survival (OS) of patients with metastatic uveal melanoma (UM) that were managed with best supportive care (BSC). The subjects of their study are patients at the Helsinki University Hospital's Department of Ophthalmology in Finland. Also mentioned are the methods used like the Kaplan-Meier product-limit method and the Cox proportional hazards regression.

Background: Hereditary gelsolin (AGel) amyloidosis is an autosomal dominantly inherited systemic amyloidosis that manifests with the characteristic triad of progressive ophthalmological, neurological and dermatological signs and symptoms. The National Finnish Gelsolin Amyloidosis Registry (FIN-GAR) was founded in 2013 to collect clinical data on patients with AGel amyloidosis, including altogether approximately one third of the Finnish patients. We aim to deepen knowledge on the disease burden and life span of the patients using data from the updated FIN-GAR registry. We sent an updated questionnaire concerning the symptoms and signs, symptomatic treatments and subjective perception on disease progression to 240 members of the Finnish Amyloidosis Association (SAMY). We analyzed the lifespan of 478 patients using the relative survival (RS) framework.Results: The updated FIN-GAR registry includes 261 patients. Symptoms and signs corresponding to the classical triad of ophthalmological (dry eyes in 93%; corneal lattice amyloidosis in 89%), neurological (numbness, tingling and other paresthesias in 75%; facial paresis in 67%), and dermatological (drooping eyelids in 86%; cutis laxa in 84%) manifestations were highly prevalent. Cardiac arrhythmias were reported by 15% of the patients and 5% had a cardiac pacemaker installed. Proteinuria was reported by 13% and renal failure by 5% of the patients. A total of 65% of the patients had undergone a skin or soft tissue surgery, 26% carpal tunnel surgery and 24% at least unilateral cataract surgery. As regards life span, relative survival estimates exceeded 1 for males and females until the age group of 70-74 years, for which it was 0.96.Conclusions: AGel amyloidosis causes a wide variety of ophthalmological, neurological, cutaneous, and oral symptoms that together with repeated surgeries cause a clinically significant disease burden. Severe renal and cardiac manifestations are rare as compared to other systemic amyloidoses, explaining in part the finding that AGel amyloidosis does not shorten the life span of the patients at least for the first 75 years. [ABSTRACT FROM AUTHOR]

Purpose: To report genetic findings in patients with suspected inherited retinal disorders (IRD) in a large Finnish cohort. Methods: The study was conducted retrospectively on IRD‐patients treated at the Department of Ophthalmology, Helsinki University Hospital between January 1, 2012, and December 31, 2020. Eligibility criteria were met by 786 patients. Clinical diagnosis, genetic testing method and result, relevant family history, and mode of inheritance were drawn from the electronic health registries. Results: Of the 638 patients who underwent genetic testing, 79% received a genetic diagnosis. The genetic findings corresponded to autosomal recessive (AR) inheritance in 242 patients, X‐linked in 158, and autosomal dominant (AD) in 94, whereas pathogenic variants in mitochondrial genes were found in 22 patients. The most common genetic diagnosis was a pathogenic variant in RS1 causing X‐linked retinoschisis (n = 86, 17% of all patients with a positive genetic finding). Of retinitis pigmentosa ‐associated genes, causative variants were most commonly found in CERKL (n = 43, 8.5%), RPGR (n = 31, 6.1%), and EYS (n = 25, 5.0%). CERKL variant c.375C > G, p.(Cys125Trp) and EYS variant c.1155 T > A, p.(Cys385Ter), both with known founder effects in the Finnish population, were frequently discovered (n = 69 and 53, respectively). Variants in the ABCA4 gene explained IRD in 24 patients. Pathogenic variants were also found in CHM (n = 26), OPA1 (n = 16), and CLRN1 (n = 16). Conclusions: The genetic causes of IRDs in Finland differ from other countries because of its isolated population history. Compared to similar studies in other countries, the percentage of patients with a positive genetic finding was higher (79%), which can partly be explained by the enriched founder mutations in the population. About 20% of the patients still lack a genetic diagnosis. These patients might have causative variants that are difficult to detect with current testing methods (such as complex structural variants) or the variants are in genes not yet associated with IRD. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is a rare yet aggressive eye cancer causing over 50% mortality from metastasis. Familial UM, amounting to 1%-6% of patients in Finland and the United States, mostly lack identified genetic cause, while 8% show associations with other cancer syndromes. We searched novel genetic associations for predisposition to UM, additional to already studied BAP1 and MBD4, by using targeted amplicon sequencing of 19 genes associated with UM, BAP1, or renal cell carcinoma in 270 consecutively enrolled Finnish patients with UM. Key UM drivers GNAQ, GNA11, CYSLTR2, PLCB4, EIF1AX, and SF3B1 lacked pathogenic germline variants. One patient carried the pathogenic BRCA1 variant c.3626del p.(Leu1209*), and one harbored a novel truncating MET variant c.252C > G p.(Tyr84*), classified as likely pathogenic. FLCN and BRCA2, previously identified with pathogenic variants in patients with UM, did not have such variants in our cohort. Two patients were heterozygous for a pathogenic recessive BLM variant c.2824-2A > T. None of the carriers of identified variants had familial UM. We identified BRCA1 and MET as genes with pathogenic germline variants in Finnish UM patients, each with a frequency of 0.4% (95% confidence interval, 0-2)., (© 2024 The Author(s). Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)

Purpose: To describe four Finnish families with epithelial recurrent erosion dystrophy (ERED) caused by the pathogenic variant c.3156C>T in collagen type XVII alpha 1 chain gene (COL17A1)., Methods: Eleven affected and two unaffected individuals underwent clinical ophthalmological examination, anterior segment photography, and corneal topography. Two of them underwent phototherapeutic keratectomy (PTK). Genetic analysis included both next-generation and Sanger sequencing. Specimens from the manual keratectomy of one patient were available for ophthalmic pathologic examination, including immunohistochemistry., Results: The common splice-site altering synonymous variant c.3156C > T, p.(Gly1052=) in COL17A1 was confirmed in 15 individuals with ERED from the four families. Subepithelial corneal scarring grades varied and increased with age, leading to decreased best-corrected visual acuity. PTK improved vision in 58- and 67-year-old individuals without reactivating the disease. The keratectomy specimens showed an uneven epithelium and a spectrum of basement membrane abnormalities, including breaks, fragmentation, multiplication and entrapment within the subepithelial scar, reflecting recurrent erosions. The stromal cells consisted of varying proportions of bland and activated fibroblasts and myofibroblasts, reflecting different ages of scars. The family with the largest number of known affected generations originated from Southern Sweden., Conclusion: The phenotype in the Finnish ERED families is consistent with earlier reports of the c.3156C > T variant, although the severity has varied between reports. The phenotype may be modulated by other genes. This study suggests a likely founder effect of the variant in both Finnish and Swedish populations due to their shared population histories. If vision is compromised, PTK can be considered especially in older patients., (© 2023 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: The purpose of this study was to analyze trends in number, age-adjusted frequency, and type of keratoplasty in a major tertiary referral center, relative to patient and graft characteristics., Methods: A retrospective registry study of 1574 patients who in 1995 to 2015 underwent keratoplasty in the Helsinki University Eye Hospital (HUEH). Graft type and sequence, patient characteristics, and date of surgery were recorded. Main outcome measures were annual number, type, and age-adjusted frequency of keratoplasty; patient and graft characteristics; graft procurement; and national population-adjusted frequency of keratoplasty., Results: In HUEH, from 1995 to 2015, a total of 2191 keratoplasties were performed with 48% of the grafts procured intramurally; 76% were primary and 24% regrafts. The age-adjusted frequency of primary penetrating keratoplasty decreased by 52% from 0.96 to 0.46 per 100,000. The corresponding frequency of primary Descemet stripping automated endothelial keratoplasty increased by 367% from 0.3 to 1.4 after 2006, finally accounting for 68% of primary grafts. Men underwent primary penetrating keratoplasty (median 48 vs. 67 yrs, P = 0.0001) and anterior lamellar keratoplasty (median 37 vs. 46 yrs, P = 0.0015) at a younger age than women. Interval to the first regraft was comparable between sexes (median 2.2 vs. 1.9 yrs, respectively, P = 0.17). The national median population-adjusted frequency of keratoplasties was 3.2 per 100,000 from 2009 to 2015, and HUEH accounted for a median of 69% of them., Conclusions: The increased frequency of keratoplasty in HUEH resulted from rapid adoption of Descemet stripping automated endothelial keratoplasty after 2006 and was facilitated by centralizing graft procurement to HUEH and the National Cell and Tissue Center Regea., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: We describe the phenotype of a variant lattice corneal dystrophy (LCD) potentially caused by a novel variant c.1772C>T p.(Ser591Phe) in exon 13 of the transforming growth factor beta-induced (TGFBI) gene., Case Report: The proband, a 71-year-old woman referred because of bilateral LCD, first seen at the age of 65 years, with recent progressive symptoms, underwent a clinical ophthalmological examination, anterior segment optical coherence tomography and confocal microscopy. Additionally, three siblings and three children were examined. The identified TGFBI variant was screened in six family members using Sanger sequencing. A corneal dystrophy gene screen was performed for the proband. Translucent subepithelial irregularities and central to midperipheral stubby branching corneal stromal lattice lines, asymmetric between the right and the left eye, were visible and resulted in mild deterioration of vision in one eye. Genetic testing revealed a novel variant c.1772C>T in TGFBI , leading to the amino acid change p.(Ser591Phe). One daughter carried the same variant but had only thick stromal nerve fibres at the age of 49 years. The other family members neither had corneal abnormalities nor carried the variant. No keratoplasty is yet planned for the proband., Conclusions: We classify the novel variant in TGFBI as possibly pathogenic, potentially causing the late-onset, asymmetric variant LCD. Our findings add to the growing number of TGFBI variants associated with a spectrum of phenotypes of variant LCD.

Purpose: To chart clinical findings in individuals with keratitis fugax hereditaria (KFH) and the geographic distribution of their ancestors., Design: A prospective cross-sectional study., Methods: This study took place in a tertiary referral center with a cohort of 84 Finnish patients (55% female) from 25 families with the pathogenic nucleotide-binding domain, leucine-rich repeat (NLR) family pyrin domain containing 3 (NLRP3) variant c.61G>C. Observation procedures and main outcome measures were Sanger sequencing, clinical examination, corneal imaging, and a questionnaire regarding symptoms, quality of life, treatment, and comorbidities., Results: The oldest members in each family were born in Ostrobothnia in Western Finland or in Southwestern Finland with historical ties to Sweden. One carrier was asymptomatic. Most (77%, 46/60) experienced their first attack between age 6 and 20 years. Three-quarters had unilateral attacks 3 to 5 times annually, primarily triggered by cold wind or air, or stress. Eighty percent (48/60) reported ocular pain (median, 7 on scale 1-10), conjunctival injection, photophobia, foreign body sensation, and tearing during attacks. Visual blur occurred in 75% (45/60) and 91% (55/60) during and after the attack, respectively, for a median of 10 days (range, 1 day-2 months). Forty-seven percent (39/60) had corneal oval opacities with irregular tomography patterns and mild to moderate decrease (20/60 or better) in best-corrected visual acuity that improved with scleral contact lenses. Except for headache in 40%, systemic symptoms were absent during the attacks., Conclusions: Symptoms and signs of KFH are restricted to the anterior segment of the eye and vary widely between individuals. We recommend scleral contact lenses as the first-line treatment for reduced vision. Allele frequencies suggest that KFH goes unrecognized in Sweden and populations with Scandinavian heritage., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: To determine the incidence of retinoblastoma (Rb) and subsequent survival in the Finnish population during five decades., Methods: This retrospective observational cohort study comprised all patients with Rb born in Finland during 1964 - 2014 and diagnosed in 2018 (birth cohort analysis) or diagnosed in 1964 - 2014 (standard annual analysis), identified from the Finnish Cancer Registry and the national referral centre. We report age-adjusted incidences and survival according to cause of death., Results: Of children born in 1964 - 2014, 205 developed Rb, whereas 204 Rbs were diagnosed during these years; 196 belonged to both cohorts. Altogether 80 (38%) of the 213 children had heritable Rb and 19 (9%) had familial disease. The sex ratio was 1.34, suggesting male preponderance. Birth cohort analysis showed a median incidence of 6.2 per 100 000 live births (1:16 130) and less variability as compared with standard annual analysis (12.1, 6.5 and 4.4 per million children 0 - 4, 0 - 9 and 0 - 14 years of age, respectively). The incidence of heritable Rb increased with time, reflecting the increase in familial tumours. Five-year mortality rates from Rb were 6.2% and 7.6% for non-heritable and heritable diseases, respectively, and 35-year mortality rates from second malignancies were 0% and 14.3%, respectively. Family history predicted improved survival, whereas the period of diagnosis did not., Conclusion: The incidence of familial Rb has increased, along with improvement in survival in Finland in 1964-2014, whereas the overall incidence of Rb was stable. Long-term risk of dying of second malignancies after heritable Rb was in line with other countries., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Uveal melanoma (UM) is a rare intraocular cancer with the highest incidence in northern latitudes. Metastases develop in approximately 50% of patients, whereafter the median survival is 13 months. Generally, the mutation burden of these tumors is low. Germline variants predisposing to UM have been previously described in BRCA1-associated protein 1 (BAP1). Recently, germline and somatic loss-of-function (LOF) variants in the methyl-CpG-binding domain 4 (MBD4) gene have been found to cause a hypermutated UM, and MBD4 also has been put forward as a gene predisposing to UM. We sequenced for MBD4 germline variants in 440 Finnish patients with UM and identified seven rare exonic missense variants in 16 (3.6%) patients, of which one likely alters MBD4 function. The frequency of likely pathogenic variants in our cohort is 0.23% (1/432; 95% CI, 0.01-1.28). We identified no LOF variants though their frequency in the Finnish population is 0.052%. Thus, our data do not support the suggestion that MBD4 germline variants predispose to UM. Somatic loss of MBD4 might modify the mutational burden in UM and change its response to immune checkpoint inhibitors., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Fireworks-related eye injuries occur all over the world whenever fireworks are available for the public. The two prospective registers from Finland over 20 years and from the Netherlands over 10 years have tracked the effect of regulations, awareness, and safety campaigns. The incidence of fireworks-related injuries in these two countries has been reduced to about one half during the last 10 years through addressing the number of hours allowed for private fireworks, the use of safety glasses, awareness campaigns, and stricter regulations on fireworks available for purchase. Although the total number of injuries has decreased, the average severity of eye injuries in the Netherlands seems to have increased due to higher content of gunpowder in fireworks. Boys and young men are mainly affected as well as bystanders who account for more than half of fireworks-related eye injuries. More work on safety of fireworks is still needed through regulating private consumer use of fireworks, a challenge that lies ahead for ophthalmologic organizations worldwide, including the European Society of Ophthalmology (SOE), the International Council of Ophthalmology (ICO) and national societies. But every eye saved from severe injury is worth the effort.

Fireworks-related eye injuries occur all over the world whenever fireworks are available for the public. The two prospective registers from Finland over 20 years and from the Netherlands over 10 years have tracked the effect of regulations, awareness, and safety campaigns. The incidence of fireworks-related injuries in these two countries has been reduced to about one half during the last 10 years through addressing the number of hours allowed for private fireworks, the use of safety glasses, awareness campaigns, and stricter regulations on fireworks available for purchase. Although the total number of injuries has decreased, the average severity of eye injuries in the Netherlands seems to have increased due to higher content of gunpowder in fireworks. Boys and young men are mainly affected as well as bystanders who account for more than half of fireworks-related eye injuries. More work on safety of fireworks is still needed through regulating private consumer use of fireworks, a challenge that lies ahead for ophthalmologic organizations worldwide, including the European Society of Ophthalmology (SOE), the International Council of Ophthalmology (ICO) and national societies. But every eye saved from severe injury is worth the effort.

Background: To analyse in a population-based setting the clinical features, prognostic factors, and seasonality of patients diagnosed with acute idiopathic optic neuritis (ON)., Methods: Retrospective analysis of ophthalmological records, laboratory parameters, and magnetic resonance imaging (MRI) of patients with symptoms suggestive of ON referred to the Helsinki University Hospital (serving a population of 1.53 million in Southern Finland) were analysed between May 1, 2008 and April 14, 2012., Results: Of the 291 patients with suspected ON, 184 (63%) were diagnosed with ON (mean age 34 years, 76% females). Intravenous methylprednisolone treatment was administered in 131 (71%) patients. First ON was diagnosed in 123 patients (67%), 55 (30%) had a previous diagnosis of multiple sclerosis (MS) and two patients with their first ON were diagnosed with neuromyelitis optica. Evolution of best corrected visual acuity (BCVA) was analysed in 132 (72%) patients, who were reviewed median of 38 days after onset. Median and mean BCVAs in these reviewed patients were 0.4 and 0.2 at the time of diagnosis and 1.0 and 0.5 at the time of the review. Recovery was relatively good in the majority of patients; 82% (n = 108) had reached BCVA of ≥0.5 and 70% (n = 92) and BCVA of ≥0.8 at the time of the review, while thirteen (10%) had poor prognosis, BCVA ≤0.1 at review. Accessory clinical features included optic disc swelling (21%), colour vision impairment (75%), and pain with eye movements (65%). Relative afferent pupillary defect was abnormal in 76% of the patients with their first ON. Baseline visual acuity was most strongly associated with visual outcome at review (P < 0.001, linear regression). Optic disc swelling and the presence of lesions in the optic nerve on MRI had a more modest association with poorer recovery (P = 0.033 and P = 0.049, respectively), while age, sex, previous history of ON, and previous diagnosis of multiple sclerosis were not associated with outcome at review. Incidence of ON showed a clear seasonal pattern; there were two times more cases in April to June versus October to December (P = 0.03), confirming previous results from Sweden., Conclusions: Our data suggest that besides baseline visual acuity, optic disc swelling and lesions in the optic nerve on MRI are associated with poorer prognosis. As in previous studies, we observed that diagnostics of ON is difficult, accessory clinical findings such as pain and RAPD are not always present. Although the diagnosis of ON is clinical, the role of MRI should be considered in differential diagnostics and in defining potential prognostic markers., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Pathogenic germline variants in the BRCA1-associated protein 1 (BAP1) gene cause the BAP1 tumor predisposition syndrome (BAP1-TPDS) with increased risk of several cancers, the most frequent of which is uveal melanoma (UM). Pathogenicity of loss-of-function (LOF) BAP1 variants is clear, as opposed to that of missense and regulatory region variants. We sequenced the coding, promoter, untranslated region (UTR) and intronic regions of BAP1 and analyzed copy number variations (CNVs). In this nationwide study, the cohort comprised UM patients diagnosed between 2010 and 2017. These included 432 of 520 consecutive Finnish UM patients, 16 of whom were familial, and one additional patient from a Finnish-Swedish family. Twenty-one different rare variants were found: seven exonic, seven intronic, four 3' UTR and three promoter. We considered five variants likely to be pathogenic by effect on splicing, nuclear localization or deubiquitination activity. Intron 2 (c.67+1G>T) and exon 14 (c.1780&#95;1781insT) LOF variants were presumed founder mutations, occurring in two and four families, respectively; both abolished nuclear localization in vitro. Intron 2, exons 5 (c.281A>G) and 9 (c.680G>A) missense variants markedly reduced deubiquitinating activity. A deep intronic 25 base pair deletion in intron 1 caused aberrant splicing in vitro. On the basis of functional studies and family cancer history, we classified four exon 13 missense variants as benign. No CNVs were found. The prevalence of pathogenic variants was 9/433 (2%) and 4/16 (25%) in Finnish UM families. Family cancer history and functional assays are indispensable when establishing the pathogenicity of BAP1 variants. Deep intronic variants can cause BAP1-TPDS., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: To estimate the population-based incidence of acute idiopathic optic neuritis (ON) and analyse its differential diagnosis in patients referred with symptoms suggestive of ON., Methods: Patients with suspected ON referred to the Helsinki University Hospital, serving a population of 1.5 million in Southern Finland, were reviewed between 1st May 2008 and 14th April 2012. Brain and optic nerve magnetic resonance imaging (MRI) was performed within 24 hours in 83% of patients., Results: Of 291 referred patients, 184 (63%; 95% confidence interval [CI], 57-69%) were diagnosed with ON whereas 107 (37%) had another condition. The estimated crude incidence of ON in Southern Finland was 3.0 (95% CI 2.8-3.3) per 100,000 (females, 4.6 and males, 1.4). Mean age was 34 years (range 15-61), 76% were female. Two (1%) were diagnosed with neuromyelitis optica. ON as the first demyelinative episode was diagnosed in 108 (59%) patients, and MRI showed demyelinating lesions (MRI+) in 82% (95% CI, 75-89) of them. MRI+ predicted the development of multiple sclerosis (MS): 54% of MRI+ vs. 5% MRI- patients were diagnosed as MS during a mean follow-up of 7.7 years. The most common differential diagnosis was non-arteritic anterior ischemic optic neuropathy (12%). Six (2%) intracranial compressive lesions were found upon MRI scan., Conclusions: More than a third of patients with symptoms suggestive of ON had another condition. Demyelinative lesions on MRI indicated higher risk of developing MS. We recommend the use of MRI to improve the differential diagnostic accuracy of ON and to identify patients with high risk of MS.

Purpose: Germline mutations of the BRCA1-associated protein-1 gene (BAP1) predispose carriers to uveal melanoma. We report the population-based frequency of germline pathogenic variants of BAP1 in Finnish patients with uveal melanoma who live in a high-risk region for this cancer., Design: Cohort study., Participants: In Finland, uveal melanomas are treated centrally in the Ocular Oncology Service, Helsinki University Hospital. We collected clinical data and genomic DNA from 148 of 188 consecutive patients diagnosed from January 2010 through December 2012. Seven of these patients from 6 families had a history of uveal melanoma in 1 relative, and 2 patients from 2 additional families had such a history in 2 relatives., Methods: Sequencing BAP1., Main Outcome Measures: Pathogenic variants in BAP1., Results: We found 2 different pathogenic variants in BAP1 in 3 patients. Two patients had a single nucleotide insertion in exon 14 resulting in a shift of reading frame. Both had a family history of uveal melanoma in at least 1 relative. One patient without a family history of uveal melanoma had a single nucleotide substitution in the conserved splice donor site of intron 2. BAP1 cancer predisposition syndrome-related cancers were present in all 3 families. The overall frequency of BAP1 pathogenic variants was 2.0% (3/148; 95% confidence interval, 0.4-5.8), the frequency among patients 50 years of age or younger was 3.6% (1/28; 95% confidence interval, 0.1-18), and a pathogenic variant was detected in 2 of 8 families with a history of uveal melanoma., Conclusions: The frequency of BAP1 germline pathogenic variants in consecutive Finnish patients with uveal melanoma who come from a high-risk region for the development of this cancer is comparable with reports from other populations., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To compare ocular findings in eyes with primary open-angle glaucoma (POAG) and exfoliation glaucoma (EG) at the time of diagnosis when identical diagnostic criteria for glaucoma were applied., Methods: We conducted a study on records of 519 consecutive, unselected patients with chronic glaucoma filing for cost-free medication from the Finnish National Social Insurance Institute (FSII). Fourteen cases were excluded for having other types of glaucoma. The documents were provided by eye hospitals or by licensed ophthalmologists. The criteria for glaucoma were set by the Parliament of Finland and applied by FSII. A total of 329 patients had POAG and 176 had EG. The main outcome measures were best-corrected visual acuity (BCVA), intraocular pressure (IOP), cup-to-disc ratio of the optic nerve head (C/D), and glaucomatous changes of the visual fields (VF)., Results: As regards sex, the 2 groups were comparable: 66% female with POAG and 68% with EG. The EG patients were older (mean ± SD 74 ± 8.6 years) vs POAG (68 ± 11.4 years). The EG eyes had slightly lower BCVA. The POAG eyes had mean intraocular pressure (IOP) 24 ± 5.4 mm Hg. A total of 12% in this group had highest IOP of less than 18 mm Hg (low-tension glaucoma [LTG]) but there were none of EG. All EG eyes had a mean IOP 28.3 ± 9.3 mm Hg. Among EG patients, 26% had unilateral disease, with a mean IOP of 33.7 ± 8.7 mm Hg, while the opposite eyes had a mean of 19 ± 3 mm Hg. There was not much difference in the C/D ratios of POAG and EG eyes and the VF profiles were similar., Conclusions: At diagnosis, patients with EG were older than those with POAG and had higher mean IOP values. Among patients with POAG, there were 12% with LTG, but none among EG. A total of 26% among EG had unilateral disease with marked IOP asymmetry. The C/D and VF profiles were similar because the patients had been seen early in the disease course. Early recognition and lifelong most effective therapy of EG are strongly advocated.

Purpose: To report vascular comorbidities, arterial hypertension (HT), ischemic heart disease (IHD), and diabetes mellitus (DM) in patients with low-tension glaucoma (LTG) with maximum intraocular pressure (IOP) of 18 mm Hg or less. Uniform criteria for glaucoma and the comorbidities were applied., Methods: We reviewed records of 519 consecutive patients to whom the Finnish National Social Insurance Institution (FSII) had granted cost-free medication for the treatment of glaucoma. The FSII operates national health insurance, which is compulsory for all Finnish citizens. There were 344 patients with primary open-angle glaucoma (POAG) and 155 with exfoliative glaucoma (EG). Twenty cases were discarded for having other types of glaucoma. In the POAG group, there were 38 patients, with a median IOP of 16 mm Hg (range 12-18). We were masked to the systemic comorbidities when the registry provided us data on those to whom FSII had also granted cost-free medication for HT, IHD, or DM according to the uniform national criteria., Results: None of the patients with LTG had exfoliation syndrome. There was a female predominance, 81%, compared to 68% in high-tension POAG. Hypertension had been diagnosed in 34%, which is the same as in high-tension POAG. A total of 24% had IHD, which is the same as in the Finnish population registry. Diabetes mellitus was present in only 5%. In all groups, patients with LTG with systemic comorbidity were markedly older than those without., Conclusions: In patients with LTG with median IOP 16 mm Hg (range 12-18), glaucomatous optic disc cupping and glaucomatous visual field defects probably developed independently of the systemic vascular comorbidity. However, the diagnostic criteria for HT, IHD, and DM used in the current study were based on the severity of stages set in the FSII system.

Purpose: To study mortality among unselected Finnish patients with either primary open-angle glaucoma (POAG) or exfoliative glaucoma (EG) after a minimum follow-up of 7 years after enrollment., Methods: A total of 344 patients with POAG and 155 patients with EG had received free medication for the treatment of glaucoma from the Finnish National Social Insurance Institution (FSII). The FSII operates national health insurance, which is compulsory for all Finnish citizens. To be granted free medication, the patient has to file an application with a certificate from an ophthalmologist. If the predefined criteria for glaucoma specified by the Finnish Parliament are met, full reimbursement for glaucoma medications is granted and the patient is listed in the registry of FSII. We reviewed the records of 519 consecutive patients who had been diagnosed with glaucoma and to whom free medication had been granted between June 2004 and December 2005. Patients with acute glaucoma or secondary glaucoma were excluded. Those with open angles were classified into POAG or EG. The quality of the ophthalmologists' records was high. The Finnish Population Registry, a governmental institute, provided information on those patients who had died before January 2013., Results: At enrollment, the groups with POAG and EG were comparable as regards sex: 66% female with POAG and 68% with EG. The patients with POAG were younger (median 68 years) than those with EG (median 74 years). By January 2013, 59 patients with POAG and 48 with EG had died. At death, the patients with POAG were younger (median 81.8 years) than those with EG (87.9 years). In both groups, the women lived longer than the men, but among patients with POAG, women and men died at a younger age than those with EG., Conclusions: As has been reported previously, life expectancy of patients with EG was longer when compared to those with POAG. Higher death rate among patients with EG is explained by higher median age at baseline.