Non-syndromic inherited retinal diseases in Poland: Genes, mutations, and phenotypes.

Purpose: Inherited retinal diseases (IRDs), encompassing many clinical entities affecting the retina, are classified as rare disorders. Their extreme heterogeneity made molecular screening in the era before next-generation sequencing (NGS) expensive and time-consuming. Since then, many NGS studies of IRD molecular background have been conducted in Western populations; however, knowledge of the IRD mutational spectrum in Poland is still limited. Until now, there has been almost no comprehensive analysis of this particular population regarding the molecular basis and inheritance of IRDs. Therefore, the purpose of this study was to gain knowledge about the type and prevalence of causative variants in the Polish population. Methods: We recruited 190 Polish families with non-syndromic IRDs, including Stargardt disease (STGD), retinitis pigmentosa (RP), cone- and cone-rod dystrophy (CD/CRD), achromatopsia, and congenital stationary night blindness. A pool of molecular inversion probes was used, which targeted 108 genes associated with non-syndromic IRDs known in 2013. We applied filtering for known variants occurring with an allele frequency >0.5% in public and in-house databases, with the exception of variants in ABCA4, when the frequency filter was set to 3.0%. Hypomorphic p.(Asn1868Ile) was added manually. In the case of novel missense or splicing variants, we used in silico prediction software to assess mutation causality. Results: We detected causative mutations in 115 of the 190 families with non-syndromic IRD (60.2%). Fifty-nine individuals with STGD, RP, and CD/CRD carried causal variants in ABCA4. Novel single nucleotide variants were found in ABCA4, CEP290, EYS, MAK, and CNGA3. The complex allele c.[1622T>C;3113C>T], p.[Leu541Pro;Ala1038Val] was found in 33 individuals with ABCA4-associated disorders, which makes it the most prevalent allele in the Polish population (17% of all solved cases). Diagnosis was reevaluated in 16 cases. Conclusions: Previously, there were no comprehensive reports of IRDs in the Polish population. This study is the first to indicate that the most common IRDs in Poland are ABCA4-associated diseases, regardless of the phenotype. In Polish patients with RP, the second most prevalent causal gene was RHO and the third RPGR, while there were not as many mutations in EYS as in Western populations. The number of initial erroneous diagnoses may be the result of limited access to diagnostics with advanced tools, such as electroretinography; however, it is necessary to raise awareness among Polish ophthalmologists of rare IRDs. Additionally, it must be emphasized that in some cases genetic analysis of the patient is necessary to achieve an accurate diagnosis.

Intrafamilial phenotypic variability in a Polish family with Sensenbrenner syndrome and biallelic WDR35 mutations.

Sensenbrenner syndrome (cranioectodermal dysplasia, CED) is a very rare autosomal recessive ciliopathy. Cranioectodermal dysplasia is characterized by craniofacial, skeletal, and ectodermal abnormalities. About 50 patients have been described to date. Sensenbrenner syndrome belongs to a group of ciliary chondrodysplasias and is a genetically heterogeneous disorder. Mutations in five genes: IFT122, WDR35, IFT43, WDR19, and IFT52 have been associated with CED. All known genes encode proteins that are part of the intraflagellar transport complex, which plays an important role in the assembly and maintenance of cilia. Here, we report a family with two children affected by Sensenbrenner syndrome, a 9-year-old girl and her older sister who died in infancy due to respiratory, liver, and renal insufficiency. Dysmorphic features included short stature with rhizomelic shortening of limbs, short fingers, preaxial polydactyly of left hand, narrow chest, craniosynostosis, dolichocephaly, high anterior hairline, epicanthal folds and telecanthus, depressed nasal bridge, low-set ears, and additional ectodermal abnormalities. The patient presented with chronic tubulointerstitial renal disease. She had abnormal echogenicity on renal ultrasound, reduced glomerular filtration, albuminuria and tubular proteinuria, hypocalciuria and hypocitraturia, accompanied by pre-hypertensive state. This pattern of renal abnormality was regarded as nephronophthisis. Psychomotor development was apparently normal. Molecular analysis in one of the affected individuals identified compound heterozygosity for a nonsense (c.1922T>G, p.(Leu641*)) and missense (c.2522A>T, p.(Asp841Val)) variants in WDR35. We present a detailed clinical descriptions of two female siblings showing an intrafamilial phenotypic variability of the disease, and illustrating the potential lethality of CED.

[Ocular findings in Nijmegen breakage syndrome]. / Objawy okulistyczne w przebiegu zespolu Nijmegen.

UNLABELLED: Nijmegen Breakage Syndrome (NBS) is a genomic instability disease caused by inherited mutations in the NBN/NBS1 gene. The clinical symptoms of NBS are: primary microcephaly, characteristic facial appearance, recurring respiratory tract infections caused by immune deficiency and extremely high risk of cancer development at early age. PURPOSE: The aim of the study was to assess the vision organ in patients with NBS. MATERIAL AND METHODS: Ophthalmological examination of 10 NBS patients was performed. The visual acuity, refractive errors, anterior and posterior segment of the eye ball test, tonometry and biometry were assessed. RESULTS: Serious pathology of the sight organ in the study group were found, including upward slanting of the palpebral fissures, reduced visual acuity, small eyes, small cornea diameter, lens opacity, refractive errors. CONCLUSIONS: The patients with Nijmegen breakage syndrome have significant sight organ abnormalities. These pathologies require long-term ophthalmologic care.

Severe neonatal spondylometaphyseal dysplasia in two siblings.

We report on two siblings with a severe neonatal form of spondylometaphyseal dysplasia (SMD). Similar cases have been reported in four publications. Analysis of pedigree data from the original and present families suggests an autosomal recessive mode of inheritance, although parental gonadal mosaicism is also possible. The similarities in the phenotype between our patients and spondyloepimetaphyseal dysplasia congenita (SEMDC) and spondyloepimetaphyseal dysplasia Strudwick (SEMDS) type, indicated that these patients could have a defect in the COL2A1 gene. Molecular analysis of genomic DNA of these patients excluded this gene. Another potential candidate gene PTHR1, was also analyzed in the selected regions and no mutation was found. This gene is probably causative in the Jansen type of SMD, which shares some phenotypic features with the siblings whom we documented. Our results indicate that a new candidate gene for the reported form of SMD should be sought.

Orbital tumor as an initial manifestation of Wegener's granulomatosis in children: a series of four cases.

BACKGROUND: Wegener's granulomatosis (WG) is a rare idiopathic disease in which small and medium-sized arteries are affected by necrotizing granulomatous inflammation. It is associated with a triad of pulmonary (cavitating granulomatous lesions with hemoptysis, cough, and dyspnea), renal (glomerulonephritis with hematuria, proteinuria), and head (otitis media, recurrent sinusitis, eye or orbital involvement) manifestations. CASE REPORT: Four children aged 7-11 years diagnosed with WG between 1995-2008 initially presented with unilateral proptosis and ptosis due to orbital tumor. CT or MRI, orbital lesion biopsy, and laboratory tests (ERS, CRP, ANCA) were part of the diagnostic workup. The diagnoses were based on correlation between clinical presentation and diagnostic findings. All four patients had orbital lesions on contrast-enhanced CT and MRI. Two had lesions of the temporal pyramid. Orbital tumor biopsies showed granulomatous lesions in two patients, necrotizing vasculitis with leukocytoclasia in three, and an orbital pseudotumor in one. ESR and CRP were positive in all. ANCA positivity was variable (c-ANCA did not allow WG diagnosis or there were atypical ANCAs). All had blood and protein in the urine, but only one had advanced renal involvement. All were treated with oral steroid and immunosuppression; remission was successful. CONCLUSIONS: WG is often more difficult to diagnose in children than in adults due to frequent absence of its signature features. The absence of the classic triad and atypical laboratory or biopsy findings do not exclude a diagnosis of WG. Orbital demonstration helps achieve early diagnosis and treatment of this potentially fatal rheumatologic disease.

Genetic Spectrum of ABCA4-Associated Retinal Degeneration in Poland.

Mutations in retina-specific ATP-binding cassette transporter 4 (ABCA4) are responsible for over 95% of cases of Stargardt disease (STGD), as well as a minor proportion of retinitis pigmentosa (RP) and cone-rod dystrophy cases (CRD). Since the knowledge of the genetic causes of inherited retinal diseases (IRDs) in Poland is still scarce, the purpose of this study was to identify pathogenic ABCA4 variants in a subgroup of Polish IRD patients. We recruited 67 families with IRDs as a part of a larger study. The patients were screened with next generation sequencing using a molecular inversion probes (MIPs)-based technique targeting 108 genes involved in the pathogenesis of IRDs. All identified mutations were validated and their familial segregation was tested using Sanger sequencing. In the case of the most frequent complex allele, consisting of two variants in exon 12 and 21, familial segregation was tested using restriction fragment length polymorphism (RFLP). The most prevalent variant, a complex change c.[1622T>C;3113C>T], p.[Leu541Pro;Ala1038Val], was found in this cohort in 54% of all solved ABCA4-associated disorder cases, which is the highest frequency reported thus far. Additionally, we identified nine families displaying a pseudo-dominant mode of inheritance, indicating a high frequency of pathogenic variants within this population.

[Evaluation of the results of treatment orbital rhabdomyosarcoma in children]. / Ocena wyników leczenia miesaka miesni prazkowanych oczodolu u dzieci.

PURPOSE: To estimate the state of the vision organ in the children treated for orbital rhabdomyosarcoma. Rhabdomyosarcoma (RMS) is the most common primary malignant orbital tumor in children. RMS usually manifest clinically as rapidly progressive exophthalmus and displacement of the globe. The diagnosis is based on biopsy, CT and MR images. The treatment includes radiation, chemotherapy, and surgery. MATERIAL AND METHODS: The retrospective review of data of 14 children between 0 and 11 years old with rhabdomyosarcmoa of orbit. After a biopsy, with precedent CT or MRI, all patients were treated with chemotherapy including or not including radiotherapy. RESULTS: 3 children died, orbital exentaration was necessary because of tumor recurrence in 3 cases, 8 children remained healthy (without recurrent disease). CONCLUSIONS: Fast diagnosis using CT, MRI and the result of biopsy, have a positive influence on the effect of neoplastic treatment and prognosis.

Optical Coherence Tomography and Optical Coherence Tomography Angiography in Monitoring Coats' Disease.

Purpose. The aim of this study was to evaluate the usefulness of optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) in monitoring pediatric patients with Coats' disease. Material and Methods. This retrospective study included 9 Caucasian patients receiving treatment for Coats' disease at the Children's Memorial Health Institute Ophthalmology Department between December 2014 and May 2016. The course of the disease was monitored with OCTA in combination with OCT and fluorescein angiography (FA). Results. OCT B-scans obtained in all patients correlated with FA findings. Reliable OCTA images were obtained in 8 patients. In one patient, numerous artifacts due to poor visual acuity and retinal detachment confounded the interpretation of findings. Conclusions. OCTA and OCT, in combination with FA, are useful in Coats' disease diagnostics and treatment monitoring. As noninvasive methods, OCT and OCTA may be performed more often than FA, which enable precise monitoring of the disease and making decisions as to its further treatment.

[Childhood glaucoma associated with Sturge-Weber syndrome --the efficacy of cyclofotocoagulation and other therapeutic methods]. / Jaskra w zespole Sturge-Webera u dzieci --skutecznosc cyklofotokoagulacji oraz tradycyjnych metod terapeutycznych.

PURPOSE: Sturge-Weber syndrome is a rare congenital neurooculocutaneous disorder. Ocular involvement can include glaucoma and vascular malformations of the conjunctiva, episclera, choroid and retina. MATERIAL AND METHODS: 16 children (16 eyes) with Sturge-Weber syndrome associated with glaucoma (mean age--34 month, mean follow up 8.87 years) treated in our institution, were reviewed. In retrospective analysis were assessed: IOP and postoperative complications after diode laser cyklophotocoagulation (16 eyes), after trabeculectomy (6 eyes) and trabeculectomy with MMC (3 eyes). RESULTS: In ten eyes (62.5%) good result (IOP 6-22 mmHg) post cyclophotokoagulation--(3x) was recorded, as well as in 3 eyes (50%) post trabeculectomy and in 3 eyes (100%) post trabeculectomy with MMC 0.2/4 min. No postoperative complications occured in cyclophotocoagulation group. Complications after trabeculectomy were the following: 3 cases of hypotony, 4 cases with shallow anterior chamber and 5 with choroidal effusions. CONCLUSIONS: Diode laser cyclophotocoagulation combined with topical medication is an effective and safe treatment of glaucoma in children with Sturge-Weber syndrome.

[Ocular albinism in pediatric patients with nystagmus]. / Albinizm oczny u dzieci z oczoplasem.

PURPOSE: Presentation of diagnostic methods and results obtained in childre with nystagmus, with suspicion of ocular albinism. MATERIAL AND METHODS: Records of 9 children (range 0.2 to 5.5 years) are presented. In all cases family history, ophthalmic examination and visual evoked potentials were analyzed. RESULTS: Clinical signs of ocular albinism were found in all patients. 2 children had cutaneous albinism, VEP records of 7 children indicated abnormalities typical for albinism, clinical signs of gene carrying were found in 7 mothers. CONCLUSIONS: Clinical signs enable us to diagnose ocular albinism with relatively high probability, nevertheless characteristic VEP records confirm diagnosis in clinically difficult cases.

No Evidence for Association of SCO2 Heterozygosity with High-Grade Myopia or Other Diseases with Possible Mitochondrial Dysfunction.

SCO2 mutations cause recessively inherited cytochrome c oxidase deficiency. Recently Tran-Viet et al. proposed that heterozygosity for pathogenic SCO2 variants, including the common E140K variant, causes high-grade myopia. To investigate the association of SCO2 mutations with myopia, ophthalmic examinations were performed on 35 E140K carriers, one homozygous infant, and on a mouse model of Sco2 deficiency. Additionally, a screen for other putative effects of SCO2 heterozygosity was carried out by comparing the prevalence of the common E140K variant in a population of patients with undiagnosed diseases compatible with SCO2-related pathogenesis to that in a general population sample. High-grade myopia was not identified in any of the studied individuals. Of the carriers, 17 were emmetropic, and 18 possessed refractive errors. Additionally, no significant axial elongation indicative of high-grade myopia was found in mice carrying E129K (corresponding to E140K in humans) knock-in mutations. The prevalence of E140K carriers in the symptomatic cohort was evaluated as 1:103 (CI: 0.44-2.09) and did not differ significantly from the population prevalence (1:147, CI: 0.45-1.04).Our study demonstrates that heterozygosity for pathogenic SCO2 variants is not associated with high-grade myopia in either human patients or in mice.

[Congenital stationary night blindness]. / Wrodzona niepostepujaca slepota nocna.

Authors present diagnostic procedures and dinical features of the congenital stationary night blindness (CSNB) in 19 patients. Effective therapy of the concomitant ophthalmological pathologies usually improves patient's vision ability.

Efficacy and safety of azithromycin 1.5% eye drops in paediatric population with purulent bacterial conjunctivitis.

OBJECTIVE: To determine the efficacy and safety of azithromycin 1.5% eye drops in a paediatric population with purulent bacterial conjunctivitis. PATIENTS AND METHODS: This was a multicentre, international, randomised, investigator-masked study in 286 children with purulent discharge and bulbar conjunctival injection. Patients received either azithromycin 1.5% eye drops (twice daily for 3 days) or tobramycin 0.3% eye drops (every 2 h for 2 days, then four times daily for 5 days). Clinical signs were evaluated on day (D) 0, 3 and 7, and cultures on D0 and D7. The primary variable was the clinical cure (absence of bulbar conjunctival injection and discharge) on D3 in the worse eye for patients with positive cultures on D0. RESULTS: 286 patients (mean age 3.2 years; range 1 day-17 years) were included; 203 had positive cultures on D0. Azithromycin was superior to tobramycin in clinical cure rate on D3 (47.1% vs 28.7%, p=0.013) and was non-inferior to tobramycin on D7 (89.2% vs 78.2%, respectively). Azithromycin treatment eradicated causative pathogens, including resistant species, with a similar resolution rate to tobramycin (89.8% vs 87.2%, respectively). These results were confirmed in a subgroup of patients younger than 24 months old. CONCLUSIONS: Azithromycin 1.5% eye drops provided a more rapid clinical cure than tobramycin 0.3% eye drops in the treatment of purulent bacterial conjunctivitis in children, with a more convenient twice-a-day dosing regimen.