-
Annals of the Rheumatic Diseases Oct 2022To test the hypothesis that ROSAH (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache) syndrome, caused by dominant mutation in , is an...
Gain-of-function mutations in cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome.
OBJECTIVES
To test the hypothesis that ROSAH (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache) syndrome, caused by dominant mutation in , is an autoinflammatory disease.
METHODS
This cohort study systematically evaluated 27 patients with ROSAH syndrome for inflammatory features and investigated the effect of mutations on immune signalling. Clinical, immunologic and radiographical examinations were performed, and 10 patients were empirically initiated on anticytokine therapy and monitored. Exome sequencing was used to identify a new pathogenic variant. Cytokine profiling, transcriptomics, immunoblotting and knock-in mice were used to assess the impact of mutations on protein function and immune signalling.
RESULTS
The majority of the cohort carried the p.Thr237Met mutation but we also identified a new ROSAH-associated mutation, p.Tyr254Cys.Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis and AA amyloidosis. However, there was significant phenotypic variation, even within families and some adults lacked functional visual deficits. While anti-TNF and anti-IL-1 therapies suppressed systemic inflammation and improved quality of life, anti-IL-6 (tocilizumab) was the only anticytokine therapy that improved intraocular inflammation (two of two patients).Patients' primary samples and in vitro assays with mutated ALPK1 constructs showed immune activation with increased NF-κB signalling, STAT1 phosphorylation and interferon gene expression signature. Knock-in mice with the T237M mutation exhibited subclinical inflammation.Clinical features not conventionally attributed to inflammation were also common in the cohort and included short dental roots, enamel defects and decreased salivary flow.
CONCLUSION
ROSAH syndrome is an autoinflammatory disease caused by gain-of-function mutations in and some features of disease are amenable to immunomodulatory therapy.
Topics: Amyloidosis; Animals; Cohort Studies; Gain of Function Mutation; Hereditary Autoinflammatory Diseases; Humans; Inflammation; Mice; Mutation; NF-kappa B; Protein Kinases; Quality of Life; Serum Amyloid A Protein; Syndrome; Tumor Necrosis Factor Inhibitors
PubMed: 35868845
DOI: 10.1136/annrheumdis-2022-222629 -
Indian Journal of Dermatology 2019Dermatopathia pigmentosa reticularis is a rare ectodermal dysplasia that presents with a triad of reticulate hyperpigmentation, nonscarring alopecia, and nail dystrophy....
Dermatopathia pigmentosa reticularis is a rare ectodermal dysplasia that presents with a triad of reticulate hyperpigmentation, nonscarring alopecia, and nail dystrophy. We report herein a case of a 23-year-old male presenting with the characteristic triad associated with anhidrosis and palmoplantar keratoderma.
PubMed: 30983613
DOI: 10.4103/ijd.IJD_401_17 -
Ugeskrift For Laeger Apr 2023
Topics: Female; Humans; Child; Autonomic Nervous System Diseases; Hypohidrosis
PubMed: 37114574
DOI: No ID Found -
Eye and Brain 2015Horner syndrome consists of unilateral ptosis, an ipsilateral miotic but normally reactive pupil, and in some cases, ipsilateral facial anhidrosis, all resulting from... (Review)
Review
Horner syndrome consists of unilateral ptosis, an ipsilateral miotic but normally reactive pupil, and in some cases, ipsilateral facial anhidrosis, all resulting from damage to the ipsilateral oculosympathetic pathway. Herein, we review the clinical signs and symptoms that can aid in the diagnosis and localization of a Horner syndrome as well as the causes of the condition. We emphasize that pharmacologic testing can confirm its presence and direct further testing and management.
PubMed: 28539793
DOI: 10.2147/EB.S63633