PRPS1-associated retinopathy: a diagnostic odyssey.

PURPOSE: This study describes how the diagnosis of Usher syndrome was revised to PRPS1-associated retinopathy and Charcot-Marie-Tooth disease type 5. CASE REPORT: A 38-year-old female with bilaterally subnormal vision and non-congenital hearing loss was initially diagnosed with Usher syndrome, based on finding variants in three genes (MYO7A, USH2A, and PCDH15), was re-evaluated at the inherited retinal disorders clinic. She had asymmetric retinopathy and right macular pseudocoloboma. She was also found to have myopathic facies, poor grip strength and atrophy of the calf muscles. Whole exome sequencing including variants in PRPS1 showed a variant (NM_002764.4:c.287 G > A; p.Arg96Gln), which was not detected by targeted Sanger sequencing of the DNA from her mother and sister. CONCLUSION: The constellation of asymmetric retinopathy and non-congenital hearing impairment should prompt the clinician to search for other diagnoses that may not be covered by an Usher syndrome next generation sequencing panel. Interpretation of genetic testing results should be correlated with a detailed clinical phenotype.

Clinicopathological study of ophthalmic cutaneous and mucocutaneous non-langerhans cell histiocytic lesions.

BACKGROUND: The "C group" of the histiocytic disorders is characterized by non-Langerhans-cell histiocytic lesions in the skin, mucosal surfaces, or both, out of which Juvenile xanthogranuloma (JXG) is the most common typically affecting the skin. The eye is the most common extra-cutaneous site of JXG., we aim at providing our clinical and histopathological experience with this group of diseases including the adult-onset xanthogranuloma (AXG). METHODS: This is a retrospective cohort study of all patients with the tissue diagnosis of ocular and periocular cutaneous and mucocutaneous non-LCH disorders who presented to us over a period of 25 years (January 1993 to December 2018). RESULTS: Twenty patients were diagnosed as "Group C" disease with an age range of 2 months-60.9 years. Eleven patients were females (55%) and nine were males (45%). The involvement was mostly unilateral in 80.9%. All cases fell into the xanthogranuloma family with 11 JXG patients, 8 AXG patients of skin and ocular surface, and one patient with solitary reticulohistiocytoma (SRH). The clinical site of involvement in JXG was primarily in the eyelid in 5 patients (45%), ocular surface lesions in 2 (18%), iris in 2 (18%), choroidal and bilateral orbital lesions in 1 patient each (9%). The group of AXG, presented equally with eyelid lesions in 4/8 and ocular surface lesions in 4/8. The non-Langerhans' histiocytic infiltrate showed supportive immunohistochemical staining properties (reactive to CD68 marker and negative to S-100 and langerin markers). CONCLUSION: Among the rare histiocytic disorders, xanthogranulomatosis is the commonest and has wide clinical manifestations. Accurate diagnosis needs to be supported by typical histopathological findings. JXG was the commonest in our study with relatively older mean age at presentation and frequent eyelid rather than iris involvement. AXG is often confused with xanthelasma when involving the eyelids with corneal limbal involvement is relatively frequent.

Phenotypic and genotypic features of POC1B-associated cone dystrophy.

PURPOSE: Patients with cone dystrophy (CD) can present with virtually normal retinal appearance, which may delay diagnosis. This study describes the inconspicuous clinical features of POC1B-associated CD in two Saudi families. METHODS: This is a retrospective case study. Clinical data analyzed included multimodal retinal imaging and electroretinography of the affected individuals. Genetic analysis was done for all probands. RESULTS: Three affected males from two Saudi families with POC1B-associated CD were included. The ages at presentation ranged from 18 to 34 years. Ophthalmic examination showed decreased Snellen visual acuities (range: 20/100-20/300) and color vision bilaterally. Fundus examination showed only mild vascular attenuation. Macular optical coherence tomography showed reduced reflectivity of the external limiting membrane, ellipsoid, and interdigitation zones. Full-field electroretinography demonstrated undetectable light-adapted responses and normal dark-adapted responses in all patients. Next-generation sequencing showed one proband to be homozygous for a previously unpublished nonsense variant in POC1B (NM_172240):c.672C>G; p(Tyr224*). Whole exome sequencing for the second proband showed a novel homozygous frameshifting variant in POC1B: c.991del; p(Arg331Glufs*13). CONCLUSION: We described two novel variants in POC1B and the associated subtle, yet significant retinal features. POC1B-associated CD is a rare cause of visual loss in patients with relatively normal fundus appearance. Deep phenotyping is necessary in formulating appropriate differential diagnosis.

Epiretinal Membrane and Vitreomacular Traction Associated With Vasoproliferative Tumor in Macular Telangiectasia Type 2: A Case Report.

We report a case of a 62-year-old man who presented with blurred and distorted vision in both eyes. Fundus examination revealed a fibrous band-like membrane emanating from the disc to the foveal center in the right eye, aneurysmal gray parafoveal lesions in both eyes, and an inferotemporal peripheral vascular tumor in the right eye. The presence of an epiretinal membrane with vitreomacular traction in this patient has led to the diagnosis of an incidental peripheral vascular tumor. To our knowledge, there are no reports describing an association between macular telangiectasia type 2 and epiretinal membrane formation with vitreomacular traction due to a vasoproliferative tumor.

Ophthalmic histiocytic lesions (diseases of the L group): A multicenter clinicopathological study of 18 cases and review of literature.

INTRODUCTION: Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are rare histiocytic disorders in the L (Langerhans) group diseases. They range from self-limited benign diseases to lethal disseminated forms. METHODS: This retrospective study was conducted in 3 tertiary hospitals in Saudi Arabia and Brazil. Histopathological records were searched for all patients diagnosed with ocular and periocular histiocytic disorders from January 1993 to December 2018. Histopathological slides and medical files were reviewed for data collection and simple analysis of demographics, clinical manifestations, and management. The relevant literature is reviewed. RESULTS: Twenty-two eyes of 18 patients with biopsy-proven histiocytic disorders in the L group were included. Female-to-male ratio was 1.25:1. Average age at presentation was 14 years (range, 1-54). LCH was diagnosed in 14 eyes, while eight eyes had ECD. All LCH cases were unilateral and confined to the bone as cases of eosinophilic granuloma (EG), while patients with ECD were bilateral. Commonest presentations in EG and ECD were eyelid swelling (85.7%) and periocular xanthomas (75%), respectively. Orbit was involved in 100% of EG cases, with bony erosion in 54.5%. Relevant systemic involvement was found in 100% of ECD and 21% of EG cases. Surgical intervention was needed in 16 of the 22 eyes (72.7%). All EG and 25% of patients with ECD required surgical excision. CONCLUSIONS: Histiocytic disorders are a rare group of diseases, including the L group. Relevant systemic associations require specific and selective therapy. A high clinical index and multidisciplinary collaboration are essential for the proper evaluation and management of these patients.

Ophthalmic histiocytic lesions: a baseline demographic and clinicopathological study of 28 cases from two eye centers.

PURPOSE: Ophthalmic histiocytic lesions comprise a heterogeneous rare group of disorders that are characterized by an abnormal proliferation of histiocytes and may affect all age groups of both sexes. The aim of this study was to highlight the basic demographic, clinical, and histopathological characteristics of this rare group of diseases in ophthalmic practice, which has not been previously studied in this area. Only individual cases have been previously reported. METHODS: This was a retrospective study of all biopsied ocular and periocular histiocytic lesions from two centers, King Khaled Eye Specialist Hospital (KKESH) and King Abdulaziz University Hospital (KAUH) in Riyadh, Saudi Arabia, from January 1993 to December 2018. The histopathological diagnosis was confirmed, and the cases were re-classified by reviewing all histopathological slides. The corresponding demographic and clinical data were analyzed. A relevant literature review was also carried out for comparison of our collected analyzed data to published data and to draw our own conclusions. RESULTS: A total of 34 ocular/periocular histiocytic lesions in 28 patients who were mostly Saudis (92.9%) were included. The male-to-female ratio was 4:3. The median age at presentation was 6.4 years (range: 2.8-35 years). Twenty-two patients had unilateral involvement, and six patients had bilateral lesions. In patients with Langerhans cell histiocytosis (LCH; L group), the most common presenting findings were eyelid swelling (75%), periocular tenderness (37.5%), proptosis/globe displacement (37.5%) eyelid erythema (25%), and orbital pain (12.5%). In patients with Rosai Dorfman disease (RDD; R group), proptosis/globe displacement occurred in all patients and 80% had decreased vision. Patients in the C group (Cutaneous non-LCH histiocytoses) had variable clinical features because of the different locations of the histiocytic lesions, with the majority involving the eyelids (66.7%). Diagnosis was accurately reached clinically in 38.8%, 33.7%, and 46.7% of patients in the L, C, and R groups, respectively. Overall, the clinical diagnosis was in concordance with the histopathologic diagnosis in 14 out of 34 lesions (41.2%). CONCLUSIONS: Histiocytic disease is more likely to be overlooked clinically owing to its rarity. In the C group, juvenile xanthogranuloma (JXG) was the most commonly encountered histiocytic lesion and had a tendency to present at a later age with extremely rare intraocular involvement in contrast to previously published reports. The median age at presentation was higher in group R. All patients in group L had strictly unilateral disease, while RDD (group R) was most commonly bilateral. Future research on genetic aspects, management, and prognosis is necessary.

Ophthalmic Rosai-Dorfman disease: a multi-centre comprehensive study.

BACKGROUND: To provide basic demographic information and clinicopathologic features of ophthalmic Rosai-Dorfman disease (RDD) with a literature review. METHODS: A multi-centre retrospective case series reviewing all patients with histopathologically confirmed ophthalmic RDD at three tertiary eye care centres between January 1993 and December 2018. RESULTS: Eleven eyes of eight patients with histopathologically confirmed ophthalmic RDD were included, with equal numbers of males and females. The median age was 40.25 years (range: 26.6-72.4). Two patients had familial RDD. The orbit was the most commonly involved site (90.9% eyes). One patient (one eye) presented with a scleral nodule, anterior uveitis and cystoid macular oedema. Visual acuity ranged from 20/25 to light perception. Six patients had an extra-nodal ophthalmic disease, and the remaining two had an associated submandibular lymphadenopathy (nodal RDD). CONCLUSIONS: Ophthalmic RDD can be the only manifestation of this systemic disease, with the orbit being the most commonly involved site, exhibiting bone destruction, intracranial and/or sinus involvement and variable degree of visual loss. Ophthalmic familial RDD represent a severe form with a malignant course. Steroid monotherapy may be inadequate to control orbital RDD; thus, combined treatment is usually necessary. A comprehensive approach to assessment and management is recommended.

A novel variant in DOCK6 gene associated with Adams-Oliver syndrome type 2.

BACKGROUND: Adams-Oliver syndrome (AOS) is a rare, inherited multi-systemic malformation syndrome characterized by a combination of aplasia cutis congenita and transverse terminal limb defects along with variable involvement of the central nervous system, eyes, and cardiovascular system. AOS can be inherited as both autosomal-dominant and recessive traits. Pathogenic variants in the DOCK6, ARHGAP31, EOGT, RBPJ, DLL4, and NOTCH1 genes have been associated with AOS. PURPOSE: To report a novel homozygous variant in the DOCK6 gene associated with Adams-Oliver syndrome type 2. MATERIALS AND METHODS: Case report. RESULTS: We report a case of a 4-month-old male who presented with microcephaly, global developmental delay, truncal hypotonia, and limb reduction defects. Ophthalmic examination revealed bilateral nystagmus and retinal detachment with mild cataractous changes in addition to retrolental plaque in the left eye. Next generation sequencing analysis identified a novel homozygous frameshift likely pathogenic variant (c.1269_1285dup (p.Arg429Glnfs*32)) in the DOCK6 gene. The constellation of the clinical findings and the genetic mutation were consistent with a diagnosis of AOS type 2. CONCLUSION: The discovery of this new likely pathogenic variant enriches the genotypic spectrum of DOCK6 gene and contributes to genetic diagnosis and counseling of families with AOS. Neurologic and ocular findings appear to be consistent with AOS type 2 for which multidisciplinary clinical evaluation is crucial.