ROSAH syndrome was recently identified as an autosomal dominant systemic disorder due to mutations in ALPK1. It was characterized by retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache. We collected and summarized the clinical data of two patients with juvenile onset splenomegaly and oculopathy. Whole exome sequencing (WES) was adapted for genetic analysis. Mutations in ALPK1 were confirmed by Sanger sequencing. Besides juvenile oculopathy and splenomegaly, both patients had intermittent fever and anhidrosis. Patient 2 also experienced recurrent upper respiratory infections in her infancy and developed dental and nail problems in childhood. Elevated TNF-α was their prominent laboratory features. Both patients were found to have a previously reported mutation, c.710C>T, p. T237M (NM_001102406) in ALPK1. Anti-TNF treatment of adalimumab was applied to patient 1, after which her optic disc edema in the left eye continued and the visual acuity deteriorated further. Patient 1 underwent elective splenectomy due to concern for spontaneous rupture of the spleen. Up to date, 18 patients of ROSAH syndrome have been reported. The clinical manifestations were relatively homogeneous, prominently presenting with juvenile onset oculopathy and splenomegaly. As it mainly involves ocular fundus, severe oculopathy deeply affects the quality of life and prognosis of ROSAH patients. Now little has been known about its treatment. As a newly recognized inherited systemic disorder, ROSAH syndrome needs to be paid more attention to, especially for those with juvenile onset splenomegaly and oculopathy.
This is a preview of subscription content, log in to check access.
Buy single article
Instant unlimited access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Picard C, Bobby Gaspar H, Al-Herz W, et al. International Union of Immunological Societies: 2017 primary immunodeficiency diseases committee report on inborn errors of immunity. J Clin Immunol. 2018;38(1):96–128.
Zhou Q, Wang H, Schwartz DM, et al. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat Genet. 2016;48(1):67–73.
Damgaard RB, Walker JA, Marco-Casanova P, et al. The deubiquitinase OTULIN is an essential negative regulator of inflammation and autoimmunity. Cell. 2016;166(5):1215–30.e20.
Zhou Q, Yu X, Demirkaya E, et al. Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease. Proc Natl Acad Sci U S A. 2016;113(36):10127–32.
Aksentijevich I, Zhou Q. NF-kappaB pathway in autoinflammatory diseases: dysregulation of protein modifications by ubiquitin defines a new category of autoinflammatory diseases. Front Immunol. 2017;8:399.
Zhou P, She Y, Dong N, Li P, He H, Borio A, et al. Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose. Nature. 2018;561(7721):122–6.
Ryzhakov G, West NR, Franchini F, et al. Alpha kinase 1 controls intestinal inflammation by suppressing the IL-12/Th1 axis. Nat Commun. 2018;9(1):3797.
Kuo TM, Yeh KT, Hsu HT, Chiang SL, Chang JG, Huang CM, et al. ALPK1 affects testosterone mediated regulation of proinflammatory cytokines production. J Steroid Biochem Mol Biol. 2015;154:150–8.
Lee CP, Chiang SL, Ko AM, et al. ALPK1 phosphorylates myosin IIA modulating TNF-alpha trafficking in gout flares. Sci Rep. 2016;6:25740.
Williams LB, Javed A, Sabri A, et al. ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder. Genet Med. 2019.
Wang W, Zhou Y, Zhong L, Wang L, Tang X, Ma M, et al. RAS-associated autoimmune leukoproliferative disease (RALD) manifested with early-onset SLE-like syndrome: a case series of RALD in Chinese children. Pediatr Rheumatol Online J. 2019;17(1):55.
Sangiorgi E, Azzara A, Molinario C, et al. Rare missense variants in the ALPK1 gene may predispose to periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome. Eur J Hum Genet. 2019.
Levy-Clarke G, Jabs DA, Read RW, et al. Expert panel recommendations for the use of anti-tumor necrosis factor biologic agents in patients with ocular inflammatory disorders. Ophthalmology. 2014;121(3):785–96.e3.
Ramanan AV, Dick AD, Jones AP, et al. A phase II trial protocol of Tocilizumab in anti-TNF refractory patients with JIA-associated uveitis (the APTITUDE trial). BMC Rheumatol. 2018;2:4.
Simonini G, Cimaz R, Jones GT, Macfarlane GJ. Non-anti-TNF biologic modifier drugs in non-infectious refractory chronic uveitis: the current evidence from a systematic review. Semin Arthritis Rheum. 2015;45(2):238–50.
Conflict of Interest
The authors declare that they have no conflict of interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Zhong, L., Wang, J., Wang, W. et al. Juvenile Onset Splenomegaly and Oculopathy Due to Germline Mutation in ALPK1. J Clin Immunol (2020) doi:10.1007/s10875-020-00741-6
- NF-κB pathway
- autoinflammatory diseases