Signal Peptide Variants in Inherited Retinal Diseases: A Multi-Institutional Case Series.

Signal peptide (SP) mutations are an infrequent cause of inherited retinal diseases (IRDs). We report the genes currently associated with an IRD that possess an SP sequence and assess the prevalence of these variants in a multi-institutional retrospective review of clinical genetic testing records. The online databases, RetNet and UniProt, were used to determine which IRD genes possess a SP. A multicenter retrospective review was performed to retrieve cases of patients with a confirmed diagnosis of an IRD and a concurrent SP variant. In silico evaluations were performed with MutPred, MutationTaster, and the signal peptide prediction tool, SignalP 6.0. SignalP 6.0 was further used to determine the locations of the three SP regions in each gene: the N-terminal region, hydrophobic core, and C-terminal region. Fifty-six (56) genes currently associated with an IRD possess a SP sequence. Based on the records review, a total of 505 variants were present in the 56 SP-possessing genes. Six (1.18%) of these variants were within the SP sequence and likely associated with the patients' disease based on in silico predictions and clinical correlation. These six SP variants were in the CRB1 (early-onset retinal dystrophy), NDP (familial exudative vitreoretinopathy) (FEVR), FZD4 (FEVR), EYS (retinitis pigmentosa), and RS1 (X-linked juvenile retinoschisis) genes. It is important to be aware of SP mutations as an exceedingly rare cause of IRDs. Future studies will help refine our understanding of their role in each disease process and assess therapeutic approaches.

Bleeding assessment in female patients with the Hermansky-Pudlak syndrome-A case series.

INTRODUCTION: The Hermansky-Pudlak syndrome (HPS) is an autosomal recessive rare disorder characterized by oculocutaneous albinism, bleeding diathesis, chronic granulomatous colitis and/or pulmonary fibrosis. HPS is the most common single-gene disorder in Puerto Rico with a prevalence of 1:1,800 in the Northwest of the island. Risk of menorrhagia and post-partum hemorrhage (PPH) in cases of women with HPS have been described in the medical literature, but data regarding comprehensive description of bleeding diathesis remains lacking. For this reason, we aim to identify bleeding events using the International Society on Thrombosis and Hemostasis Bleeding Assessment Tool (ISTH-BAT), a standardized quantitative tool that translates the range of severity of bleeding symptoms into a cumulative bleeding score (BS). OBJECTIVE: To use the ISTH-BAT in HPS in order to describe bleeding symptoms and allow for comparison with other inherited bleeding disorders. METHODS: Puerto Rican females and adult participants with HPS based on genetic linkage were enrolled. The ISTH-BAT was administered and results were identified using descriptive statistical analysis. RESULTS: Questionnaire answers of twelve women with HPS-1 and HPS-3 were evaluated. Participants' mean BS was HPS-1 (11.4) and HPS-3 (8.0) Participants with HPS-1 and HPS-3 reported abnormal bleeding events that presented during dental extractions, menorrhagia, surgical interventions, gastrointestinal, oral cavity and post-partum. Patients with history of pulmonary fibrosis (PF) showed a higher mean bleeding score than those who had no history of PF. CONCLUSIONS: Female patients with HPS type 1 and 3 experienced abnormal bleeding events according to the ISTH-BAT bleeding score. Bleeding medications were inconsistently used and varied independently from healthcare professionals. The benefits of this study were to understand the history of bleeding complications in patients with HPS type 1 and 3 using an international validated system. The results of this study will help design strategies to improve the care we provide to this population.

Ocular Symptoms and Signs of Chikungunya Fever in Puerto Rico.

OBJECTIVE: To determine what ocular symptoms and signs are most common and if there are any associations with comorbid conditions in patients with Chikungunya fever. METHODS: A retrospective data review and analysis of the ocular symptomatology of 139 patients with Chikungunya fever who visited a local emergency room from August through September 2014. Frequencies were calculated, and Pearson's chisquare test employed. All the patients were confirmed as having Chikungunya with IgM (ELISA) before admittance into the study. RESULTS: Of the 139 patients, 42 (30.2%) had red eyes, 27 (19.4%) had conjunctivitis, and 13 (9.4%) had symptoms related to anterior uveitis, such as unilateral red eye, ciliary flush, or irregular pupil(s). Patients with a history of diabetes, hypertension, or cancer were more likely to have both red eyes (p = 0.033) and the symptomatology of anterior uveitis (p = 0.006), while patients with nausea or vomiting were more likely to have red eyes only (p = 0.001). CONCLUSIONS AND RELEVANCE: Red eyes, conjunctivitis, and anterior uveitis occur frequently in patients with Chikungunya fever. Systemic diseases, such as diabetes, hypertension, and cancer, may increase the risk of such ocular manifestations. Routine ophthalmic evaluation is warranted in patients with these medical conditions. The relevance of this study lies in the fact that this disease remains an important public health issue, since such ocular sequelae as may be present can range from mild to severe, either as an acute or a delayed manifestation.

Klinefelter Syndrome (49, XXXXY/48, XXXY) associated with narrow angle glaucoma: A case report.

INTRODUCTION: Previous studies have described Klinefelter syndrome as a genetic disorder characterized by at least one extra X chromosome and at least 47 chromosomes. It is the most common sex chromosome aneuploidy among men. Patients may present with large height, gynecomastia, low testosterone levels, infertility, hypogonadism and diseases usually more common in females such as osteoporosis, breast cancer and auto-immune disorders. Other rare ophthalmic associations have been described, such as diffuse choroidal atrophy, microphtalmia, cataracts, juvenile glaucoma, choroid colobomas and goniodysgenesis. OBJECTIVES: To report on the ocular findings in a Puerto Rican patient with Klinefelter syndrome (XXXXY/XXXY). PATIENTS AND METHODS: A patient with Klinefelter syndrome with revious history of elevated intraocular pressure underwent a comprehensive ocular examination, Humphrey visual fields and Stratus optical coherence tomography (OCT) tests. Patient had inreased intraocular pressure, visual field loss and OCT findings compatible with glaucoma. After laser YAG laser iridotomies, high IOP persisted. Brimonidine 0.2 % drops three times a day drops were prescribed to lower IOP. CONCLUSIONS: A patient with Klinefelter syndrome had poor visual acuity, high intraocular pressure, visual fields and OCT results, all compatible with angle closure glaucoma as part of the syndrome.

Germline retinoblastoma without inherited gene mutation: a case report.

Retinoblastoma is the most common primary ocular malignancy in childhood and can occur as a germline or somatic mutation. Recent studies have suggested a higher incidence of retinoblastoma in Hispanic children as compared to non-Hispanic white children of the same ages. We report the ocular findings of a 20 years old Hispanic male with a history of bilateral retinoblastoma. Although screening is currently performed with the red reflex test, analysis of current literature suggests the need to reassess screening recommendations for retinoblastoma.

GRANULOMATOSIS WITH POLYANGIITIS IN PUERTO RICO: CASE REPORTS.

Wegener's Granulomatosis or Granulomatosis with Polyangiitis (WG/GPA) is one of the antineutrophil cytoplasmic antibody associated vasculitis. Ocular manifestations the first presenting signs in patients with WG/GPA. We report on two patients diagnosed with WG/GPA and discuss their pertinent clinical findings. Our case report reviews the most common clinical manifestations and ophthalmic associations to compare them with the physical findings of two Hispanic patients. Further, to our knowledge this is the first report of ocular findings in patients with WG/GPA in two Puerto Rican patients.

Unilateral Cataract and Retinitis Pigmentosa in a Patient With Polyneuropathy, Hearing Loss, Ataxia, Retinitis Pigmentosa, and Cataract (PHARC) Syndrome: A Case Report.

Patients with mutations in the α/ß-hydrolase (ABHD) 12 gene develop ocular complications including cataracts and retinitis pigmentosa (RP), as part of the polyneuropathy, hearing loss, ataxia, RP, and cataract (PHARC) syndrome. A chart review on a patient with a heterozygous mutation on the ABHD12 gene underwent a comprehensive ophthalmic evaluation. Visual acuity was 0 and 1.3 (logMAR) on the right eye (OD) and left eye (OS), respectively. There was pseudophakia in the OS. Fundus examination in OD was normal and pale optic nerve, attenuated vessels, cystoid macular edema, and mid-peripheral bony spicules were found in OS. Visual field test showed a ring scotoma in the OS. Macular optical coherence tomography (OCT) and fundus autofluorescence were compatible with cystoid macular edema of the OS. The electroretinogram (ERG) of left eye was flat. Patient's systemic findings included: polyneuropathy and hearing loss. Unilateral presentation of cataract and RP in a patient with a heterozygous pathogenic mutation on the ABHD12 gene is rare. This could be due to mosaicism. Retinal follow-up is warranted in this patient since manifestations may occur later in the contralateral eye. A heterozygous pathogenic mutation on the ABHD12 gene may lead to partial ocular and systemic manifestations of the PHARC syndrome.

Open-Angle and Steroid-Induced Glaucoma in Patients With Retinitis Pigmentosa: A Dangerous Liaison.

Previous studies have reported that patients with retinitis pigmentosa (RP) may develop open-angle and angle-closure glaucoma. We conducted a chart review of patients with RP. Two siblings with RP associated with a mutation in the PDE6B gene (c. 1540del, p.Leu514Trpfs*61) developed cystoid macular edema (CME) as part of the disease. For this reason, they both underwent intravitreal steroid injections. Both brothers developed steroid-induced glaucoma (SIG). Despite undergoing maximal medical therapy, they underwent seton implants to control their intraocular pressure. A third female patient with RP due to a mutation in the RPGR gene underwent cataract surgery. Topical steroids were prescribed and developed SIG. Increased intraocular pressure remains a complication of topical, injected, and systemic steroids. However, steroids may be needed to treat post-operatively and patients with CME. This case series unveils a complex association between RP and key comorbidities in these patients, with a focus on cataracts, glaucoma, and macular edema. Cataract surgery in patients with RP shows a link to the emergence of glaucoma, particularly in those with RPGR and PDE6B gene mutations, revealing a novel association with PDE6B mutations not previously documented. Furthermore, the paper explores a unique parallel with Schwartz-Matsuo syndrome, suggesting that patients with RP undergoing cataract surgery may develop increased intraocular pressure due to an outflow disturbance akin to Schwartz syndrome. This novel perspective deepens our understanding of the pathophysiological mechanisms governing intraocular pressure dynamics in patients with RP. To our knowledge, this is the first report of steroid-induced glaucoma in patients with RP due to mutations in the PDE6B gene. Intraocular pressure evaluation remains of utmost importance in the follow-up of patients with the disease.

A Novel Variant in the FBN1 Gene Causing Marfan Syndrome: A Case Report.

Our purpose is to report a patient with a novel variant in the fibrillin-1 (FBN1) gene causing the Marfan syndrome (MFS). The 29-year-old female patient with musculoskeletal, cardiovascular, and ocular findings compatible with the MFS had a novel pathogenic mutation on the FBN1 gene. We report on a patient whose clinical findings are compatible with the MFS. This patient's variant on the FBN1 gene leading to the syndrome has not been previously described. Additional investigations are needed to determine whether this variant contributes to the development of camptodactyly in patients with the syndrome.

Uncovering an Unusual FBN1 Gene Mutation Responsible for Marfan Syndrome: A Case Study.

Patients with Marfan syndrome have a constellation of clinical features and a heterogeneous phenotype. The purpose of this study is to report a 47-year-old male patient with an unusual variant in the FBN1 gene causing Marfan syndrome. The patient with musculoskeletal, cardiovascular, and ocular findings compatible with Marfan syndrome had an unusual pathogenic mutation on the FBN1 gene. The patient was examined by at least one of the authors (NJI). The patient's clinical findings were compatible with Marfan syndrome. Our patient had a unique mutation in the FBN1 gene (c.8054A>G p.His2685Arg) located on exon 65. Next-generation sequencing was done using the Invitae panel. This variant was categorized as one of uncertain significance. This patient's variant on the FBN1 gene leading to the syndrome has scant data associated with it and this is the first time it is reported from Puerto Rico.

Ocular findings in patients with oculocutaneous albinism type ia with G47D tyrosinase gene mutation in Puerto Rico: a case report.

UNLABELLED: Previous studies have suggested that the G47D mutation leads patients to develop Oculocutaneous albinism (OCA) type IA. This mutation has been described in the Canary Islands. Historically, there has been a migration from the Canary Islands to some regions of Puerto Rico. OBJECTIVE: To report on the ocular findings of two Puerto Rican patients with OCA IA due to the G47D Tyrosinase gene mutation. PATIENT AND FINDINGS: Two unrelated patients with OCA underwent a comprehensive eye examination and were referred for genetic analysis. Patients had almost total iris transillumination, clear lenses, foveal hypoplasia with transparent maculae, and albinotic mid peripheries. Both patients had nystagmus, and only one patient had strabismus. CONCLUSIONS: Patients with the G47D muta- tion leading to OCA IA have poor visual acuities and poorly pigmented phenotypic ophthalmic findings. Further studies comparing ocular findings in patients th several mutations leading to OCA IA are warranted. To our knowledge this is the first report on ocular findings in Puerto Rican patients with OCA type IA with the rare G47D mutation.

Musculoskeletal Manifestations in Patients With Bardet-Biedl Syndrome: A Report of Two Cases.

We report two patients with musculoskeletal manifestations as part of the Bardet-Biedl syndrome. The first patient (case 1) was born with polydactyly and later diagnosed with coxa vara. He had homozygous pathogenic mutation in the BBS1 gene of the variant c.1645G>T (p.Glu459*). The second patient (case 2) had nyctalopia and progressive vision worsening had osteoarthritis symptoms. He had a heterozygous mutation in the BBS1 gene of the variant c.1169T>G (p.Met390Arg). Although polydactyly is the most prevalent musculoskeletal association in patients with the syndrome, co-management of the musculoskeletal manifestations remains of utmost importance in patients with the syndrome.

A New Variant in the PRPF6 Gene Leading to Retinitis Pigmentosa: A Case Report.

We report on a case of a 34-year-old Hispanic female patient with a medical history of diabetes mellitus, thyroid disease, and cataract surgery in the right eye, who was evaluated due to progressive vision loss in both eyes. The patient had waxy pallor of the optic disc, vessel attenuation, retinal pigment epithelium (RPE) degeneration, and bony spicules OU. These findings are compatible with a diagnosis of retinitis pigmentosa (RP). Gene sequencing and deletion/duplication analysis were performed. The patient was positive for a heterozygous mutation in the PRPF6 gene with the variant c.2228C>T (p.Thr743Ile). This PRPF6 variant was reported as a variant of unknown significance. The Combined Annotation Dependent Depletion (CADD) score of this PRPF6 variant is 23.5, which strengthens the idea that it could potentially be associated with RP. To our knowledge, this is the first case reported on an RP patient with the PRPF6 variant c.2228C>T (p.Thr743Ile). Our case suggests that this PRPF6 variant may be associated with bilateral RP. Further molecular studies are warranted to better understand the molecular changes in the PRPF6 gene leading to RP.

Adult Refsum Disease in Puerto Rico: A Case Report.

Patients with adult Refsum Disease (ARD) have retinitis pigmentosa and thus nyctalopia, anosmia, sensorineural deafness, polyneuropathy, and ataxia. Upon physical examination, patients with ARD have congenital short metacarpals, metatarsals, and cardiac arrhythmias. Manifestations due to the lack of phytanoyl-CoA hydroxylase in peroxisomes needed for alpha-oxidation of phytanic acid lead patients to accumulate phytanic acid in their body tissues. To our knowledge, no consensus for clinical diagnostic criteria for patients with ARD has been published. Our patient had nyctalopia, retinal findings, and visual field results compatible with retinitis pigmentosa. Additionally, the patient had decreased macular thickness and volume in both eyes, the findings being worse in the left eye. The patient had undergone hand surgery due to chronic pain in both hands, as well as his fourth and fifth metatarsal bones were shortened. Interestingly, audiology evaluation showed mild hearing loss in the right ear and mild to moderate hearing loss in the left ear. Inheritance patterns in patients with ARD have been described. Physical examination, phytanic acid evaluation, and genetic studies may all help reach an ARD diagnosis. This is the first report of adult Refsum disease in Puerto Rico.

Retinitis Pigmentosa Sine Pigmento in a Carrier of Usher Syndrome.

We report a carrier of Usher syndrome type I with retinitis pigmentosa sine pigmento. A 71-year-old male was referred for further evaluation of severe, progressive, painless vision loss in both eyes over the course of four years. He had bilateral sensorineural hearing loss. Upon a comprehensive examination, his best-corrected visual acuity was 20/100 in the right eye and 20/40 in the left eye. He had an unremarkable anterior segment examination and normal intraocular pressures in both eyes. Upon fundus examination, the patient had pale discs, optic disc cupping, and multiple scattered drusen in the macula and at the midperiphery of both eyes. Optical coherence tomography showed retinal nerve fiber layer thinning in all quadrants. The visual field was severely constricted in both eyes. A comprehensive workup for infectious and inflammatory causes, as well as a brain MRI, was unremarkable. Sequencing analysis showed that he carried a heterozygous pathogenic mutation, USH1C c.672C>A (p.Cys224*) variant. Usher syndrome is a rare genetic disease characterized by hearing loss and retinitis pigmentosa. Our case suggests that patients and carriers of Usher syndrome may have a phenotype compatible with retinitis pigmentosa sine pigmento.

Pseudodominant Inheritance of Retinitis Pigmentosa Due to Mutations in the Phosphodiesterase 6B Gene: A Case Report.

Mutations in the phosphodiesterase 6B (PDE6B) gene are a rare cause of autosomal recessive retinitis pigmentosa (arRP). We report on a non-consanguineous family with a pseudodominant inheritance of RP due to PDE6B mutations. We conducted a chart review of four members of a Puerto Rican family who underwent a comprehensive ophthalmic evaluation by at least one of the authors. The mutational screening was done using a genotyping microarray provided by Invitae Corporation, using next-generation sequencing (NGS) technology. Genomic DNA obtained from saliva samples is enriched for targeted regions using a hybridization-based protocol and sequenced using Illumina technology. A descriptive analysis was done. Patient 1A had a normal ophthalmic examination and a heterozygous pathogenic variant in the PDE6B gene c.1540del PLeu514Trpfs*61. Patients 1B, 2A, and 2B had mid-peripheral retinitis pigmentosa, concentric visual field ring scotomata in both eyes (OU), extinguished electroretinogram (ERG), and homozygous pathogenic variants in the PDE6B gene c.1540del PLeu514Trpfs*61. Even though mutations in the PDE6B gene usually lead to arRP, they may be inherited in a pseudodominant pattern in geographically isolated populations. Genotyping studies in patients with RP are warranted to classify inheritance mode correctly.

Neuroophthalmology meets oncology: a case report.

Breast cancer is the second most common type of cancer worldwide and metastasis occurs in approximately 10% of the patents. A 69-year-old woman with past medical history of breast cancer came to her outpatient ophthalmologic clinic for follow-up evaluation of glaucoma. Upon evaluation the patient complained of ataxia, tinnitus, and headaches. Her visual field analysis showed a left homonymous hemianopsia. An MRI was ordered showing an intra-parenchymal lesion in the right cerebellar hemisphere. The visual signs were not compatible with the lesion on the cerebellum, but the MRI evidenced no other lesions in the optic tract. Our case report reminds physicians the importance and sensitivity of radiologic studies, the evaluation of neurologic symptoms in patients with history of breast cancer making co-management of these patients of utmost importance.

Open-angle glaucoma in patients with diabetic retinopathy at the Puerto Rico Medical Center.

BACKGROUND: The association of open-angle glaucoma (OAG) with diabetes mellitus remains controversial. We report on the frequency of open-angle glaucoma in patients having diabetic retinopathy in a population of the Puerto Rico Medical Center. MATERIAL AND METHODS: A cross-sectional study of 1,442 patients was done. Only the chart of patients 40 years-of-age and older, with a diagnosis of diabetic retinopathy and/or open-angle glaucoma were included. Descriptive analysis was done. Unadjusted and gender-adjusted logistic regression analyses were used to estimate risk of developing open-angle glaucoma in patients with diabetic retinopathy for each subsequent decade. RESULTS: 1,040 patients were diagnosed with diabetic retinopathy from July 1, 2004 to June 30, 2009. Also, 402 patients were diagnosed with open-angle glaucoma from July 1, 2007 to June 30, 2009. Of the 1,040 patients with diabetic retinopathy, 64 patients (6.15%) also had OAG. According to our gender-adjusted logistic regression analysis the estimated risk of developing open-angle glaucoma for patients 40 years-of-age with diabetic retinopathy increased for each subsequent decade until the seventh decade, odds ratio = 5.07 (95% confidence interval: 1.62-15.86). Thereafter, it decreased, odds ratio = 2.07 (95% confidence interval: 0.36-11.82). CONCLUSIONS: Our findings suggest that Puerto Rico patients between 40 to 79 years of age with diabetic retinopathy have an increased risk of developing open-angle glaucoma with each subsequent decade. Screening for open-angle glaucoma in patients with diabetic retinopathy is of utmost importance in the aging Puerto Rico population to prevent blindness.

A patient with the Weaver syndrome in Puerto Rico: a case report.

We report a 4 year-old boy with clinical features consistent with the Weaver syndrome. In addition to the typical findings, our patient had tarsal epicanthus, intermittent exotropia, hyperopia, and astigmatism. The deletion of the subtelomeric region of 18q has not been previously described in patients with the syndrome. Comparing clinical findings between patients with the de Grouchy and the Weaver syndrome suggest that both entities may be a spectrum of the same disease.

Determining the Incidence of Retinoblastoma and Survival Rate of Retinoblastoma Patients in Puerto Rico using the Cancer Registry of Puerto Rico (1985-2012).

OBJECTIVE: To determine the incidence of retinoblastoma (Rb) and the survival rate of patients with Rb in Puerto Rico. METHODS: This was a retrospective review of data from the Puerto Rico Central Cancer Registry (1985 - 2012). RESULTS: There were a total of 57 patients with Rb, with an overall incidence of 3.6 per 100,000 live births. By birth cohort, the incidence was 1 of every 29,393 live births. The mortality rate was 14.04% at 5 years. The incidence and the survival rate did not change over the 2 time periods that were compared: 1985 through 1998 and 1999 through 2012. CONCLUSION: The incidences of Rb are similar in Puerto Rico and the continental United States. However, our data indicate that the survival rate is lower in the former than it is in the latter. The incidence and the survival rate remained stable over the time studied.