RECURRENT FEVER SYNDROME/ AUTOINFLAMMATORY DISEASE (HLH & MAS)

Recurrent Fever Syndrome (RFS) is a subtype of the Autoinflammatory Diseases (AD). RF is For More Information characterized as the occurrence of episodic fevers that do not have an infectious cause. Hereditary Periodic Fever Onset can range from infancy to adulthood presenting with cyclical or random attacks of Syndromes: fevers (above 39 degrees Celsius) and localized inflammation lasting days to months. RFS is http:// a genetically heterogeneous condition and can be associated with a range of clinical features emedicine.medscape.com/ including: rash, edema, arthritis, skin lesions, pulmonary complications gastrointestinal article/952254 -overview irritation and hematological abnormalities. Hemophagocytic GENETICS Hemophagocytic Lymphohistiocytosis (HLH) is a disorder related to the accumulation of Lymphohistiocytosis (HLH): lymphocytes and macrophages often with hemophagocytosis involving the spleen, lymph http://www.ncbi.nlm.nih.gov/ nodes, bone marrow, liver and cerebral spinal fluid. Diagnostic criteria for HLH based on the books/NBK1444/ recommendations of the Histiocyte Society include having at least five out of the following eight symptoms: Fever, splenomegaly, Cytopenias, hypertriglyceridemia, Macrophage Activation hemophagocytosis, low natural killer cell function, hyperferratinemia and high levels of Syndrome (MAS): http:// soluble IL-2r. Macrophage activation syndrome (MAS) is a form of HLH associated with emedicine.medscape.com/ article/1380671-overview juvenile idiopathic arthritis (JIA) and other rheumatologic conditions. MAS is characterized by, but not limited to, high fevers, hepatosplenomegaly, lymphadenopathy and hematological SickKids Genomic anomalies. Diagnostics Laboratory: www.sickkids.ca/genome- GENETICS OF TEST METHODS diagnostics

RFS, HLH & MAS Complete sequencing of the coding To locate a genetics center region and flanking intron/exon near you: boundaries of the genes listed below. The genetics of Autoinflammatory Disease, Canadian Association of including RFS and HLH & MAS are complex; This is done via NGS of the targeted gene panels. Testing can be requested Genetic Counsellors (CAGC): autosomal dominant, autosomal recessive and www.cagc-accg.ca X-linked modes of inheritance have been for one or both panels based on clinical described. The targeted Next-Generation features and the suspected mode of National Society of Genetic Sequencing (NGS) panels at our laboratory inheritance. Please refer to our “A Counselors (NSGC): include genes associated with all three Guide to Next-Generation Sequencing” www.nsgc.org modes of inheritance. information sheet available on our website, for further details.

INTERPRETATION OF WHO SHOULD BE TESTED? 1. Current molecular testing TEST RESULTS may not detect all possible muta- tions for this disease. A negative  Individuals clinically suspected of being Genetic testing may reveal one or more test does not rule out the possibil- affected with RFS and HLH & MAS . variants in the Autoinflammatory ity of RFS , MAS or HLH. disease /HLH genes, which should be 2. The clinical course or  The relatives of a proband with identified interpreted in the context of the pathogenic variants in an RFS and HLH & severity of symptoms cannot be suspected inheritance pattern, clinical predicted by molecular analysis. MAS -associated gene findings, family history and other experimental data. 3. Test results should be  Pregnancies at increased risk due to a interpreted in the context of clini- family history of RFS and HLH & MAS. Please refer to our “A Guide to cal findings, family history and Interpreting Sequence Variations” other laboratory data. information sheet available on our 4. This test was developed and website, for further details. its performance characteristics validated by the Molecular Ge- netics Laboratory at the Hospital for Sick Children. It has not been GENES ASSOCIATED WITH AD, MAS, RFS & HLH cleared or approved by the U.S. Food and Drug Administra- See table on page 2 tion. The FDA has determined that such clearance or approval is not necessary. This test is used for clinical purposes. OMG1620AV_02

NGS PANEL 1: RECURRENT FEVER Gene name Disease LPIN2 Majeed Syndrome CECR1 Polyarteritis nodosa, Cat Eye Syndrome Autosomal Recessive PSMB8 CANDLE syndrome IL1RN Deficiency of Interleukin-1 receptor antagonist Autoinflammatory IL36RN Deficiency of Interleukin-36 receptor antagonist Disease Genes RAB27A Griscelli disease, type 2 Pyogenic sterile arthritis, pyoderma gangrenosum, and acne PSTPIP1 (PAPA) syndrome CARD14-mediated pustular psoriasis, Autosomal CARD14 Dominant Pityricisis Rubra Pilaris (PRP) TMEM173 Sting-Associated Vasculopathy, Infantile-Onset NOD2 Blau syndrome MVK Hyper IgD Syndrome Autosomal MEFV Familial Mediterranean Fever syndrome Tumour necrosis factor receptor associated periodic TNFRSF1A Recurrent Fever syndrome (TARPS) Syndrome (RFS) Cryopyrin Associated Periodic Syndromes (CAPS), NLRP3 Genes Autosomal Muckler-Wells syndome Dominant ELANE Cyclic Neutropenia, Severe Congenital Neutropenia NLRP12 Familial Cold Autoinflammatory syndrome 2 NLRC4 Autoinflammation with infantile enterocolitis

NGS PANEL 2: HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

Autosomal NLRC4 Autoinflammation with infantile enterocolitis Dominant AP3B1 Hermansky-Pudlak syndrome Type 2 BLOC1S6 Hermansky-Pudlak syndrome Type 9 CD27 CD27 deficiency ITK Lymphoproliferative syndrome type 1 Autosomal LYST Chediak-Higashi syndrome Recessive PRF1 Familial hemophagocytic lypmphohistiocytosis 2* UNC13D Familial hemophagocytic lymphohistiocytosis 3* STX11 Familial hemophagocytic lypmphohistiocytosis 4* STXBP2 Familial hemophagocytic lypmphohistiocytosis 5* RAB27A Griscelli disease, type 2 SH2D1A Lymphoproliferative syndrome type 1 or Duncan disease X-linked SLC7A7 Lysinuric protein intolerance XIAP Lymphoproliferative syndrome type 2

*MAS has been associated with the four Familial hemophagocytic lypmphohistiocytosis genes listed above. OMG1620AV_02