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Thyroid eye disease (TED) is the most common extrathyroidal manifestation of Graves disease. There has been no effective medication to prevent proptosis in thyroid eye disease until 2020 when the anti–insulin-like growth factor 1 receptor (anti–IGF-1R) antibody, Teprotumumab, was approved by the US Food and Drug Administration, sparking increased interest in immune-based drug development. This study aims to review the newly developed drug therapy as well as conventional treatment for TED. Treatment of TED has traditionally been high-dose steroids and orbital radiotherapy, but recently there has been a paradigm shift in the treatment of TED in the United States with the introduction of the therapeutic agent teprotumumab, which dramatically reduces proptosis. However, concerns remain about the development of hearing impairment as a potentially fatal complication and long-term safety. Recently, several clinical trials are underway to assess the efficacy and safety of novel drugs targeting mammalian target of rapamycin complex 1, interleukin-6, fragment crystallizable receptor, and IGF-1R in treating TED. With the explosive increase in interest from academia and pharmaceutical companies in TED, there is anticipation for the development of drugs that are equivalent or superior to teprotumumab while being safer.

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Purpose@#Orbital fibroblasts play key roles in the pathogenesis of Graves’ orbitopathy (GO), and previous findings have shown that endoplasmic reticulum (ER) stress and autophagy also contribute to GO. In this study, we investigated the presently unclear roles of inositol-requiring enzyme 1 (IRE1) and related autophagy processes in the pro-fibrotic mechanism of GO. @*Materials and Methods@#Orbital adipose/connective tissues were obtained from eight GO patients and six normal individuals during surgery. GO fibroblasts were transfected with IRE1 small-interfering RNA and treated with bafilomycin A1 (Baf-A1) to evaluate the inhibitory effects of ER stress and autophagy, and protein-expression levels were analyzed through western blotting after stimulation with transforming growth factor (TGF)-β. @*Results@#TGF-β stimulation upregulated IRE1 in GO orbital fibroblasts, whereas silencing IRE1 suppressed fibrosis and autophagy responses. Similarly, Baf-A1, an inhibitor of late-phase autophagy, decreased the expression of pro-fibrotic proteins. @*Conclusion@#IRE1 mediates autophagy and the pro-fibrotic mechanism of GO, which provides a more comprehensive interpretation of GO pathogenesis and suggests potential therapeutic targets.

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Background@#Phospholipase C-γ (PLC-γ) plays a crucial role in immune responses and is related to the pathogenesis of various inflammatory disorders. In this study, we investigated the role of PLC-γ and the therapeutic effect of the PLC-specific inhibitor U73122 using orbital fibroblasts from patients with Graves’ orbitopathy (GO). @*Methods@#The expression of phospholipase C gamma 1 (PLCG1) and phospholipase C gamma 2 (PLCG2) was evaluated using polymerase chain reaction in GO and normal orbital tissues/fibroblasts. The primary cultures of orbital fibroblasts were treated with non-toxic concentrations of U73122 with or without interleukin (IL)-1β to determine its therapeutic efficacy. The proinflammatory cytokine levels and activation of downstream signaling molecules were determined using Western blotting. @*Results@#PLCG1 and PLCG2 mRNA expression was significantly higher in GO orbital tissues than in controls (P<0.05). PLCG1 and PLCG2 mRNA expression was significantly increased (P<0.05) in IL-1β, tumor necrosis factor-α, and a cluster of differentiation 40 ligand-stimulated GO fibroblasts. U73122 significantly inhibited the IL-1β-induced expression of proinflammatory molecules, including IL-6, IL-8, monocyte chemoattractant protein-1, cyclooxygenase-2, and intercellular adhesion molecule-1 (ICAM-1), and phosphorylated protein kinase B (p-Akt) and p38 (p-p38) kinase in GO fibroblasts, whereas it inhibited IL-6, IL-8, and ICAM-1, and p-Akt and c-Jun N-terminal kinase (p-JNK) in normal fibroblasts (P<0.05). @*Conclusion@#PLC-γ-inhibiting U73122 suppressed the production of proinflammatory cytokines and the phosphorylation of Akt and p38 kinase in GO fibroblasts. This study indicates the implications of PLC-γ in GO pathogenesis and its potential as a therapeutic target for GO.

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Purpose@#To compare serum selenium levels in Graves patients and non-Graves control participants and to evaluate associations between serum selenium levels and clinical features of Graves orbitopathy (GO). @*Methods@#We conducted a single-center, retrospective case-control study among 33 patients with Graves disease without GO (GD), 31 patients with diagnosed GO, and 27 unaffected healthy participants enrolled between 2013 and 2020 at Severance Hospital. We compared serum selenium concentrations between the GD, GO, and healthy control groups, and analyzed associations between serum selenium and GO patients’ clinical activity scores, severity (assessed through modified NOSPECS scores), and other clinical features using multivariate linear regression analysis. @*Results@#Mean serum selenium levels were 109.30 ± 16.39, 111.39 ± 14.04, and 126.09 ± 21.09 ng/mL in GO patients, GD patients, and healthy control participants, respectively. Mean serum selenium levels in Graves patients with and without orbitopathy were significantly lower than those in the healthy control group (p < 0.05), and mean selenium levels were slightly lower in GO than those in GD patients (p = 0.594). Serum selenium levels were significantly lower in GO patients with eyelid retraction than in patients without retraction (p = 0.038). However, serum selenium levels were not associated with clinical activity scores and modified NOSPECS scores (p = 0.241 and 0.801, respectively). @*Conclusions@#Serum selenium levels were significantly lower in Graves patients with or without GO, compared to non-Graves control participants. Selenium levels were not associated with clinical activity scores or NOSPECS scores, though we observed an association with eyelid retraction.

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Purpose@#We sought to evaluate the safety and effectiveness of patient-specific ocular prostheses produced by three-dimensional (3D) printing and the sublimation technique. A comparison with prostheses produced using manual manufacturing methods was then performed. @*Methods@#To confirm the biological and physiochemical safety, cytotoxicity, systemic acute toxicity, intradermal reaction, and skin sensitization tests were conducted according to the International Organization for Standardization guidelines. The compressive strength of the prostheses was also tested. Further, a case series of three patients who wore the 3D printed prostheses for more than eight hours daily for 4 weeks was executed. Self-assessments by these individuals using a questionnaire and safety evaluations focusing on the occurrence of conjunctival inflammation or allergic reactions according to the Cornea and Contact Lens Research Unit criteria by slit-lamp examination and similarity assessment were completed. @*Results@#The 3D printed ocular prostheses met the necessary qualifications per the biological and physiochemical safety tests, showing the absence of cytotoxicity, acute systemic toxicity, intradermal reactivity, and skin-sensitizing potency. Also, there was no difference in strength test results between previous ocular prostheses and the 3D printed ones. Self-assessment by the patients yielded satisfactory results, with no significant difference in the level of satisfaction reported for the 3D printed and previous handmade ocular prostheses. The 3D printed prosthesis did not trigger any side effects in the conjunctival sac and showed similar objective findings with respect to the color of the iris, sclera, and vessel patterns. @*Conclusions@#Our study confirms the biologic and physiochemical safety of 3D-printed ocular prostheses created using computer-aided design technology and a sublimation technique. The patients’ questionnaires and the judgment of the ophthalmologists/ocularists showed that the 3D printed ocular prosthesis was acceptable in function and appearance through a case series report.

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PURPOSE: To evaluate the efficacy and safety of BOTULAX® in subjects with essential blepharospasm.METHODS: In this study, a total of 250 subjects with essential blepharospasm were enrolled at 15 investigational sites and a total of 220 subjects completed the study. The efficacy and safety were evaluated at weeks 4 and 16 after treatment compared with baseline. In total, 240 subjects were enrolled, treated with the investigational product, and evaluable for the primary efficacy assessment at week 4 after treatment; these subjects were included in the intention-to-treat (ITT) population. With the ITT set as the main efficacy set, efficacy assessment included Jankovic rating scale (JRS), functional disability score, investigator evaluation of global response and quality of life. Safety assessment including the incidence of adverse events was also performed.RESULTS: In terms of the primary efficacy endpoint (i.e., change in JRS total score at week 4 after treatment from baseline [ITT set]), mean change indicated a statistically significant reduction (p < 0.0001) and demonstrated the non-inferiority of the test drug to similar drugs. In terms of the secondary efficacy endpoints, mean change in JRS total score at week 16 after treatment and mean change in functional disability score at weeks 4 and 16 after treatment both exhibited a statistically significant reduction compared with baseline (p < 0.0001 for all). Among the 249 subjects treated with the investigational product in this study, 44 (17.67%) experienced 76 treatment emergent adverse events but no serious adverse events were observed.CONCLUSIONS: Based on the study results, BOTULAX® is considered to be an effective and safe treatment for essential blepharospasm.

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Purpose@#A case of a huge ethmoid sinus and orbital cyst causing ocular deviation initially diagnosed as a mucocele-like cyst and after orbitotomy eventually discovered to be a naso-orbital encephalocele is described.Case summary: A 5-year-old male with no previous medical history presented with a palpable mass in the medial canthus area with left exodeviation of the left eye. His best-corrected visual acuity was 20/25 in the right eye and 6/12 in the left eye with limitation of motion of -4 at adduction in the left eye. Brain magnetic resonance imaging scans revealed a 3.0 × 2.5 × 2.5 cm-sized cystic mass suspected as a mucocele or nasolacrimal duct cyst invading the orbital space. The cyst was removed using a Lynch and caruncle incision, and intracystic fluid was aspirated. During the excision, a small defect of the skull base was detected with cerebrospinal fluid (CSF) leakage and leaking point of dura was sealed. His pathologic result was disorganized glial and fibrous tissue, consistent with encephalocele. Three days later, CSF leakage recurred. On postoperative day 8, duroplasty was performed. A one month later, his best-corrected visual acuity was 6/12 in the left eye with orthotropic eye position. Limitation of motion was improved to -1 at adduction with enophthalmos. No other complications were detected. @*Conclusions@#Congenital naso-orbital encephalocele invading the orbit is rare. However, a cystic mass in the sinuses involving the orbit should be considered, rendering thorough physical and radiologic examinations including computed tomography scans necessary to look for bone defects.

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Purpose@#Chemokines are involved in the pathogenesis of various autoimmune diseases, including Graves’ orbitopathy (GO), but comprehensive analyses of the dynamics of these cytokines and their receptors in such diseases remain lacking. In this study, we investigated the expressions of chemokines and their receptors during adipogenesis and inflammation in primary cultured orbital fibroblasts from patients with GO. @*Methods@#The messenger RNA (mRNA) expression levels of chemokines were compared between GO (n = 6) and non-GO (n = 5) orbital tissues by real-time polymerase chain reaction. After adipogenesis was induced in primary cultured orbital fibroblasts from patients with GO (n =5) and following stimulation with interleukin (IL)-1β and tumor necrosis factor (TNF)-α, the mRNA expression levels of chemokines and their receptors were analyzed. @*Results@#Chemokines were significantly downregulated in GO orbital tissues compared to non-GO orbital tissues (p < 0.05). Adipogenesis resulted in a strong increase in mRNA expression levels of chemokines and their receptors at an early stage (day 1); however, expression levels started to decrease thereafter and, eventually, decreased to below basal levels at the end of adipogenesis (day 10). Following stimulation with IL-1β and TNF-α, the mRNA expression levels of chemokines and their receptors increased, showing different responses to various proinflammatory cytokines. @*Conclusions@#Chemokines were strongly upregulated in the early phase of adipogenesis before decreasing continuously until the end of adipogenesis. Also, overt mature GO tissues showed reduced mRNA expression of chemokines compared to controls, which might indicate the existence of a shorter window for effective medical inflammatory treatment. The heightened levels of chemokines and their receptors observed after stimulation with IL-1β and TNF-α suggest a crucial role of proinflammatory cytokines in the pathogenesis of GO and, further, support the idea that chemokines could be used as biomarkers of GO activity.

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PURPOSE: To describe cases of exposed hydroxyapatite (HA) implants wrapped with the synthetic dura substitute Neuro-Patch treated via simple Neuro-Patch removal. METHODS: The medical records of seven patients who experienced exposure of their HA implant were reviewed. All patients had been enucleated and implanted with HA wrapped with Neuro-Patch. For treatment, Neuro-Patch was removed to the greatest extent possible. After applying local anesthesia with lidocaine, blunt dissection was performed to separate the conjunctiva and Neuro-Patch via the site of exposure. Pressure was applied to the remaining Neuro-Patch with forceps and removed with scissors. RESULTS: Neuro-Patch was visible at the area of exposure in all patients. No surgery beyond initial Neuro-Patch removal was necessary in six of the seven patients. In five cases, the exposed area began to heal rapidly after Neuro-patch removal without primary closure of the defect. In one case, the Neuro-Patch material and all necrotic tissue was removed aggressively due to inflammation around the orbital implant. Lastly, an infection was noted in one case, prompting complete removal of the Neuro-Patch–wrapped HA implant. CONCLUSIONS: Wrapping material may hinder implant vascularization. Exposure of HA in wrapped implants can be successfully treated by a simple removal procedure if detected and managed early.

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PURPOSE: We sought to investigate the effects of Graves' orbitopathy (GO) and orbital decompression on lamina cribrosa depth (LCD) using spectral-domain optical coherence tomography. METHODS: Forty eyes that underwent orbital decompression to relieve compressive optic neuropathy or correct disfiguring exophthalmos in the context of GO were included. Subjects were imaged with spectral-domain optical coherence tomography before surgery and at 1 and 3 months after surgery, at which the examiner measured the LCD (distance from the anterior surface of the lamina cribrosa to the Bruch membrane opening line) and peripapillary retinal nerve fiber layer thickness. Subjects were divided into two groups—a muscle-dominant group composed of patients who had extraocular muscle enlargement on preoperative orbital computed tomography scan and a fat-dominant group composed of patients who did not show extraocular muscle enlargement on preoperative orbital computed tomography scan—and subgroup analysis was performed. Preoperative and postoperative intraocular pressure, exophthalmos, LCD, and retinal nerve fiber layer thickness were evaluated. RESULTS: At baseline, LCD was remarkably shallower in the muscle-dominant group than in the fat-dominant group (95% confidence interval, p = 0.007). In the muscle-dominant group, LCD showed no definite change after surgery. However, the fat-dominant group showed temporary posterior displacement of the lamina cribrosa at 1-month postoperation that was reversed to baseline at 3 months postoperation (95% confidence interval, p < 0.01). CONCLUSIONS: The lamina cribrosa was anteriorly displaced preoperatively, and its position was nearly unchanged after the surgery, especially in association with extraocular muscle enlargement. An enlarged extraocular muscle could reduce the pressure-relieving effect of orbital decompression around the scleral canal in patients with GO.

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PURPOSE: Uveal melanoma has a very poor prognosis despite successful local primary tumor treatment. In this study, we investigated prognostic factors that more accurately reflected the likelihood of recurrence and survival and delineated a prognostic model that could effectively identify different risk groups based on initial clinical parameters. MATERIALS AND METHODS: Prognostic factors associated with distant recurrence, recurrence-free survival (RFS), progression-free survival, and overall survival from distant recurrence to death (OS2) were analyzed in 226 patients with stage I-III uveal melanoma who underwent primary local therapy. RESULTS: Forty-nine patients (21.7%) had distant recurrences, which occurred most frequently in the liver (87.7%). In a multivariate analysis, local radiotherapy improved RFS among patients with multiple recurrence risk factors relative to excision (not reached vs. 19.0 months, p=0.004). Patients with BRCA1-associated protein-1 (BAP1)–negative primary tumors showed a longer RFS duration after primary treatments, while those with BAP1-negative metastatic tissues had a shorter OS2 compared to those with BAP1-positive tumors, both not statistically insignificance (RFS: not reached vs. 82.0 months, p=0.258; OS2: 15.7 vs. 24.4 months, p=0.216). Male sex (hazard ratio [HR], 3.79; p=0.012), a short RFS (HR, 4.89; p=0.014), and a largest metastatic tumor linear diameter ≥ 45 mm (HR, 5.48; p=0.017) were found to correlate with worse post-recurrence survival. CONCLUSION: Risk factors could be used to classify uveal melanoma cases and subsequently direct individual treatment strategies. Furthermore, metastasectomy appears to contribute to improved survival outcomes.

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PURPOSE: To investigate the clinical characteristics of idiopathic orbital inflammatory disease (IOI) with paranasal sinusitis. METHODS: This study is a retrospective, comparative case series of patients who were diagnosed with IOI between January 2009 and December 2016. This study included patients with available medical and radiologic data at diagnosis and who participated in follow-up for more than 12 months after treatment. The patients were divided into two groups according to accompaniment of paranasal sinusitis and were compared. RESULTS: Among 101 patients with IOI, 13 (12.9%) were identified to have paranasal sinusitis. The incidence of pain was higher in patients with sinusitis (69.2%) than in patients without sinusitis (25.0%, p = 0.003). More patients with paranasal sinusitis experienced recurrence after systemic steroid therapy (69.2%) than in the other group (34.1%, p = 0.033). Additional immunosuppressants and/or radiation therapy were needed only in 9.1% patients without sinusitis but in 38.5% patients with sinusitis (p = 0.039). CONCLUSIONS: IOI patients with sinusitis showed a significantly higher recurrence rate. More careful follow-up of patients during steroid tapering and treatment of sinusitis might be helpful to prevent recurrence of IOI.

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PURPOSE: To report the patient characteristics and treatment outcomes in 12 cases of orbital lymphangioma. METHODS: In this study, orbital lymphangioma was diagnosed based on clinical, radiologic (computed tomography, magnetic resonance imaging), and histologic findings when possible. Patients whose vision was not compromised by orbital lymphangioma, or that did not have increased intraocular pressure (IOP), received oral corticosteroids. Orbital lymphangioma that affected vision or increased IOP was treated by surgery, which included aspiration of blood or partial resection with or without injection of a sclerosant. RESULTS: Four patients without compromised vision responded well to oral corticosteroids. Eight patients with compromised vision underwent some form of surgery. Bleeding recurred in three patients after aspiration of blood and in two after partial resection and intralesional injection of a sclerosant. Overall, five patients were treated successfully by aspiration of blood, intralesional injection of a sclerosant, and application of continuous negative pressure by appropriate drainage. Partial resection was successful in two patients with organized hematoma. CONCLUSIONS: Orbital lymphangioma that does not compromise vision can be treated medically using oral corticosteroids. Patients with threatened vision or elevated IOP due to acute hemorrhage should be treated by aspiration of blood, intralesional injection of a sclerosant, and application of continuous negative pressure. Partial resection may be effective only in patients with organized hematoma.

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BACKGROUND/OBJECTIVES: The doubly labeled water (DLW) method is considered the gold standard for the measurement of total energy expenditure (TEE), which serves to estimate energy requirements. This study evaluated the accuracy of predictive dietary reference intake (DRI) equations for determining the estimated energy requirements (EER) of Korean adults by using the DLW as a reference method. SUBJECTS/METHODS: Seventy-one participants (35 men and 36 women) aged between 20 and 49 years were included in the study. The subjects' EER, calculated by using the DRI equation (EER(DRI)), was compared with their TEE measured by the DLW method (TEE(DLW)). RESULTS: The DRI equations for EER underestimated TEE by -36.3 kcal/day (-1.3%) in men and -104.5 kcal/day (-4.9%) in women. The percentages of accurate predictions among subjects were 77.1% in men and 62.9% in women. There was a strong linear correlation between EER(DRI) and TEE(DLW) (r=0.783, P<0.001 in men and r=0.810, P<0.001 in women). CONCLUSIONS: The present study supports the use of DRI prediction equations to determine EER in Korean adults. More studies are needed to confirm our results and to assess the validity of these equations in other population groups, including children, adolescents, and older adults.

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A 3-year-old girl presented with congenital orbital fibrosis. We performed molecular genetic analysis by whole exome and mitochondrial genome sequencing. No pathologic mutation was identified in the present case. To our best knowledge, this study presents the first report on the findings of mutational analysis of a patient with congenital orbital fibrosis.

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PURPOSE: To report a case where bilateral malignant retrobulbar lymphoma was diagnosed after repetitive intraocular lens dislocation to the anterior chamber. CASE SUMMARY: An 85-year-old male with a history of stroke who had undergone cataract surgery 10 years ago at another hospital presented with repeated intraocular lens (IOL) dislocations of both eyes into the anterior chamber. He had previously undergone IOL scleral fixation once in his left eye and twice in his right eye, but IOL dislocation was still repeatedly occurring. The best-corrected visual acuity was 0.4 in both eyes. Hertel exophthalmetry was 20 mm in his right eye and 18 mm in his left eye. Painless limitation of motion at supraduction was observed in the right eye. Funduscopy showed newly appeared choroidal folding in the right eye, so orbital computed tomography (CT) with contrast was performed. The CT scans showed bilateral homogenously enhancing retrobulbar masses. Biopsy of the masses showed a MALToma. After radiation therapy, the choroidal folds resolved and exophthalmetry improved to 10 mm in both eyes. No additional IOL dislocation occurred. During 2.5 years of follow-up, there was no evidence of recurrence or distant metastasis of the MALToma. CONCLUSIONS: Orbital lymphomas can cause lid edema, exophthalmos, strabismus, and diplopia, and can be diagnosed with imaging modalities such as CT. Final diagnosis involves biopsy and radiation therapy or chemotherapy. If IOL dislocation occurs repeatedly, it may result from an increase in retrobulbar pressure, and concurrent choroidal folding using funduscopy is strongly recommended for imaging to check for the presence of retrobulbar masses.

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PURPOSE: To analyze the treatment and prognosis of patients from our tertiary medical center with ocular and orbital involvement of granulomatosis with polyangiitis. METHODS: A retrospective analysis of the medical records of patients diagnosed with granulomatosis with polyangiitis that visited our single tertiary referral center from July 2008 to September 2014 was performed. RESULTS: A total of 51 patients diagnosed with granulomatosis with polyangiitis visited our center, and 21 of those patients had received an ophthalmologic examination. Of these, 9 patients (4 males, 5 females) had symptoms of the eye and orbit, and the clinical presentations were as follows: episcleritis, scleritis, marginal keratitis, orbital inflammation, orbital abscess, retinal vasculitis, and nasolacrimal duct obstruction. The patients each received treatments according to clinical presentation with topical, oral, or intravenous steroids or immunomodulatory agents such as cyclophosphamide. Nasolacrimal duct obstruction was treated with surgery in some cases. After an average follow-up period of 58 ± 30 months, all patients showed clinical improvement of their ocular and orbital involvement of granulomatosis with polyangiitis. CONCLUSIONS: Granulomatosis with polyangiitis is a relatively rare disease that sometimes has ocular or orbital involvement and can lead to blindness. Therefore, when ocular symptoms and signs present without a definitive cause, granulomatosis with polyangiitis must be ruled out, and appropriate treatment is needed. However, there are few published reports on the clinical presentation and prognosis of ocular and orbital involvement of granulomatosis with polyangiitis in Asians. This study showed that the incidence of ocular and orbital involvement in granulomatosis with polyangiitis was lower than previous reports.

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PURPOSE: To analyze the treatment and prognosis of patients from our tertiary medical center with ocular and orbital involvement of granulomatosis with polyangiitis. METHODS: A retrospective analysis of the medical records of patients diagnosed with granulomatosis with polyangiitis that visited our single tertiary referral center from July 2008 to September 2014 was performed. RESULTS: A total of 51 patients diagnosed with granulomatosis with polyangiitis visited our center, and 21 of those patients had received an ophthalmologic examination. Of these, 9 patients (4 males, 5 females) had symptoms of the eye and orbit, and the clinical presentations were as follows: episcleritis, scleritis, marginal keratitis, orbital inflammation, orbital abscess, retinal vasculitis, and nasolacrimal duct obstruction. The patients each received treatments according to clinical presentation with topical, oral, or intravenous steroids or immunomodulatory agents such as cyclophosphamide. Nasolacrimal duct obstruction was treated with surgery in some cases. After an average follow-up period of 58 ± 30 months, all patients showed clinical improvement of their ocular and orbital involvement of granulomatosis with polyangiitis. CONCLUSIONS: Granulomatosis with polyangiitis is a relatively rare disease that sometimes has ocular or orbital involvement and can lead to blindness. Therefore, when ocular symptoms and signs present without a definitive cause, granulomatosis with polyangiitis must be ruled out, and appropriate treatment is needed. However, there are few published reports on the clinical presentation and prognosis of ocular and orbital involvement of granulomatosis with polyangiitis in Asians. This study showed that the incidence of ocular and orbital involvement in granulomatosis with polyangiitis was lower than previous reports.

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No abstract available.

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PURPOSE: This study was conducted to identify and to functionally characterize genetic variants in ST3GAL5 and ST8SIA1 in Korean patients with thyroid-associated ophthalmopathy (TAO). MATERIALS AND METHODS: Genetic analyses were conducted using DNA samples from TAO patients (n=50) and healthy subjects (n=48) to identify TAO-specific genetic variants of ST3GAL5 or ST8SIA1. The effect of each genetic variant on the transcription or expression of these genes was examined. Additionally, correlations between functional haplotypes of ST3GAL5 or ST8SIA1 and clinical characteristics of the patients were investigated. RESULTS: Six promoter variants and one nonsynonymous variant of ST3GAL5 were identified, and four major promoter haplotypes were assembled. Additionally, three promoter variants and two major haplotypes of ST8SIA1 were identified. All ST3GAL5 and ST8SIA1 variants identified in TAO patients were also found in healthy controls. Promoter activity was significantly decreased in three promoter haplotypes of ST3GAL5 and increased in one promoter haplotype of ST8SIA1. Transcription factors activating protein-1, NKX3.1, and specificity protein 1 were revealed as having roles in transcriptional regulation of these haplotypes. The nonsynonymous variant of ST3GAL5, H104R, did not alter the expression of ST3GAL5. While no differences in clinical characteristics were detected in patients possessing the functional promoter haplotypes of ST3GAL5, exophthalmic values were significantly lower in patients with the ST8SIA1 haplotype, which showed a significant increase in promoter activity. CONCLUSION: These results from genotype-phenotype analysis might suggest a possible link between the ST8SIA1 functional promoter haplotype and the clinical severity of TAO. However, further studies with larger sample sizes are warranted.

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