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Journal Articles Clinical Genetics Year : 2022

ROSAH syndrome mimicking chronic uveitis

ROSAH syndrome et pseudo-uvéite


Purpose: To suggest a unique missense variant candidate based on long term ophthalmological changes and associated systemic signs described in unrelated families affected by an autosomal dominant multi-systemic disorder including Retinal dystrophy, Optic nerve edema, Splenomegaly, Anhidrosis and migraine Headaches, called ROSAH syndrome, related to a unique missense variant in ALPK1 gene. Design: Observational longitudinal followup study of unrelated families... Methods: Clinical analysis of ophthalmological and systemic examinations was performed followed by genetic analysis including targeted Next Generation Sequencing (NGS), and Whole-Genome Sequencing (WGS). Results: The ophthalmological phenotype showed extensive optic nerve swelling -associated with early macular oedema and vascular leakage. Main associated systemic manifestations were recurrent fever, splenomegaly, anhidrosis, mild cytopenia, anicocytosis and hypersegmented polynuclear cells. WGS, shortened in the second family by the gene candidate suggestion, revealed in all patients the heterozygous missense variant c.710C>T; p.(Thr237Met) in ALPK1. Conclusions: The main morbidity in ROSAH syndrome appeared ophthalmological. Comprehensive retinal phenotype changes and detailed systemic and family history aided by the advancement in genetic testing may allow an early diagnosis of ROSAH syndrome. Multidisplinary team discussion could help in the adaptation of systemic immunosuppressive treatment levels. The unique missense variant may be further suggested as a target of gene correction therapy. Introduction Retinal dystrophies (RD) are a group of inherited degenerative disorders characterized by a progressive damage of photoreceptor cells and retinal pigmentary epithelium (RPE).1 Despite the good performances of Next Generation Sequencing (NGS) of targeted RD genes (PMID 30718709), the use of Whole-Exome Sequencing (WES) and Whole-Genome Sequencing (WGS) combined with clinical analysis has improved the diagnosis of rare syndromic retinal dystrophies. WGS lead to the recent identification of ALPK1 gene as the cause of the ocular systemic disorder called ROSAH syndrome, due to its clinical features including familial autosomal dominant Retinal dystrophy, Optic nerve edema, Splenomegaly, Anhidrosis and migraine Headaches syndrome.2,3 We report the ophthalmological changes, systemic features and genetic analysis in patients from 2 unrelated families treated as bilateral chronic posterior uveitis. 2,5 Material and Methods This longitudinal observational follow-up study included 5 patients from 2 unrelated families. A full clinical and ophthalmological workup including autoimmune, infectious, storage disease and genetic studies, has been performed. Detailed ophthalmological tests are displayed in supplementary documents. Ethics and consents The current study was approved on November 10th of 2021 by an institutional review board in Montpellier University Hospital (IRB ID:202100959) . The study was conducted in compliance with good clinical practice and followed the tenets of the Declaration of Helsinki. Informed written consents were obtained in accordance with the French bio-ethics law n°2011-814, decree 2013-527, from patients and from the parents of minors. Written photo consent has been obtained from each involved patient. Molecular Analysis Genetic analysis used different NGS panels including main genes known to be associated with autosomal dominant inherited Retinal dystrophies and were unsuccessfull to identify the causal pathogenic variant. With recent knowledge of novel syndromes from Chronic infantile neurological cutaneous articular (CINCA) to ROSAH syndromes, - WGS were required to identify the pathogenic variant previously reported in Rosah syndrome. Sanger sequencing was used to confirm the results obtained from WGS. High-quality genomic DNA samples were randomly fragmented by Covaris Technology. Detailed methods are shown in supplementary document.
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Dates and versions

hal-04057824 , version 1 (04-04-2023)



Christine Fardeau, Munirah Alafaleq, Claire‐marie Dhaenens, Hélène Dollfus, Isabelle Koné‐paut, et al.. ROSAH syndrome mimicking chronic uveitis. Clinical Genetics, 2022, 103, pp.453 - 458. ⟨10.1111/cge.14286⟩. ⟨hal-04057824⟩
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