Periodic Fever Syndrome
Disease synonyms
Hereditary Periodic Fever Syndrome
Inheritance pattern
Autosomal recessive, autosomal dominant
Clinical features
Periodic fever syndrome is a group of diseases characterized by episodes of fever with healthy intervals between febrile episodes. The main inherited periodic fever syndromes are:
- Familial Mediterranean fever (FMF) caused by pathogenic variants in MEFV
- Periodic fever, familial caused by pathogenic variants in TNFRSF1A
- Muckle-Wells syndrome caused by pathogenic variants in NLRP3
- Cyclic neutropenia caused by pathogenic variants in ELANE
- Majeed syndrome caused by pathogenic variants in LPIN2
- Hyper-IgD syndrome caused by pathogenic variants in MVK
- Pyogenic sterile arthritis caused by pathogenic variants in PSTPIP1.
Familial Mediterranean fever (FMF) is the most common hereditary periodic fever syndrome in the Mediterranean region. It is an autosomal recessive disorder resulting from pathogenic variants in the MEFV gene (Mediterranean fever) located in chromosome 16. This disease predominantly affects people of Mediterranean and Middle Eastern descent, typically Sephardic Jews, Turks, Arabs, and Armenians. FMF episodes start before the age of 20 years in approximately 90% of the patients 1. In more than half the disease appears before the age of 10 years.
Familial Mediterranean fever (FMF) is divided into two phenotypes (types 1 and 2) 2:
- FMF type 1 is characterized by recurrent short episodes of inflammation and serositis including fever, peritonitis, synovitis, pleuritis, pericarditis, and meningitis. The symptoms vary among affected individuals, sometimes even among members of the same family. Amyloidosis, which can lead to renal failure, is the most severe complication of untreated FMF type 1.
- FMF type 2 is characterized by amyloidosis as the first clinical manifestation of disease in an otherwise asymptomatic individual.
Common manifestations of FMF include the following 2:
- Recurrent fever during early childhood
- Abdominal attacks, experienced by 90% of individuals, start with the sudden onset of fever and pain affecting the entire abdomen
- Articular attacks, experienced by about 75% of individuals with FMF. The fever is very high in the first 24 hours. The most commonly involved joints are hip or knee joints, but it may occur in the ankle, shoulder, or sternoclavicular joint.
- Pre-attack symptoms are experienced by about 50% of persons with FMF
- Pleural attacks, experienced by about 45% of those with FMF, are the sudden onset of an acute, febrile, unilateral pleuritis
- Pericarditis is rare and is characterized by retrosternal pain
- Amyloidosis type AA is common in untreated individuals, especially in Jews of North African origin. It presents with persistent, heavy proteinuria leading to nephrotic syndrome and progressive nephropathy leading to end-stage renal disease.
Less common manifestations of FMF include the following 2:
- Protracted febrile myalgia
- Erysipelas-like erythema
- Vasculitides
- Recurrent urticaria
- Aseptic meningitis
- Reduced fertility
- Decreased atopy
- Chronic ascites
- Psychological features including depression and anxiety.
Identification of biallelic MEFV pathogenic variants on molecular testing confirms the diagnosis if clinical features are inconclusive. To date, more than 200 MEFV sequence variants have been identified, only some of which are regarded as having an associated phenotype and resulting in disease-related symptoms 3.
Targeted analysis for MEFV pathogenic variants can be performed first in individuals of Armenian, Turkish, Arab, North African Jewish, Iraqi Jewish, or Ashkenazi Jewish ancestry. Targeted analysis may include 2, 4:
Exon 3
- c.1105C>T (p.Pro369Ser)
- c.1223G>A (p.Arg408Gln)
Exon 10
- c.1730C>A (p.Thr577Asn)17
- c.1958G>A (p.Arg653His)
- c.2040G>C (p.Met680Ile)
- c.2064C>G (p.Tyr688Ter)
- c.2076_2078del (p.Ile692del)
- c.2080A>G (p.Met694Val)
- c.2082G>A (p.Met694Ile)
- c.2084A>G (p.Lys695Arg)
- c.2177T>C (p.Val726Ala)
- c.2230G>T (p.Ala744Ser)
- c.2282G>A (p.Arg761His)
- c.2081_2083delTGA (p.Met694del)
Intra- and interfamilial clinical differences independent of MEFV genotype suggest genetic and/or environmental modifiers, including the following 2:
- Gender, serum amyloid A concentration, and genes involved in predisposition to arthritis
- Major histocompatibility complex class I chain-related gene A (MICA) potential modifiers including the following:
- The A5 allele had a protective effect against amyloidosis in some p.Met694Val homozygotes
- The A9 allele exacerbated the age of onset in p.Met694Val homozygotes
- The A4 allele dramatically reduced the frequency of attacks
- SAA1-13T genotype on the development of amyloidosis.
In addition to FMF, an increased frequency of MEFV pathogenic variants have been reported in individuals with the following diseases:
- Behçet disease 8
- Ulcerative colitis, especially with episodic arthritis 9
- Systemic-onset juvenile idiopathic arthritis 10
- Juvenile idiopathic arthritis 11
- Rheumatoid arthritis (RA) 12
The following diseases have been reported to occur more commonly in individuals with familial Mediterranean fever:
- Inflammatory bowel disease 13 including Crohn disease, which is more common, presents earlier in individuals with FMF, and is more often complicated by amyloidosis 14
- Juvenile idiopathic arthritis; one individual with FMF and juvenile idiopathic arthritis with osteoporosis was successfully treated with etanercept 15
- Systemic lupus erythematosus (SLE) 16
In addition to familial Mediterranean periodic fever, several other genes have been linked with hereditary periodic syndromes (see table).
Gene | OMIM (Gene) | Associated diseases (OMIM) | Inheritance |
---|---|---|---|
ACTB | 102630 | Baraitser-Winter syndrome 1; Dystonia, juvenile-onset | AD |
ADA | 608958 | Adenosine deaminase deficiency | AR |
ADAR | 146920 | Dyschromatosis symmetrica hereditaria; Aicardi-Goutieres syndrome type 6 | AD, AR |
AICDA | 605257 | Immunodeficiency with hyper-IgM, type 2 | AR |
AIRE | 607358 | Autoimmune polyendocrinopathy syndrome type I with or without reversible metaphyseal dysplasia | AD, AR |
AK2 | 103020 | Reticular dysgenesis | AR |
AP3B1 | 603401 | Hermansky-Pudlak syndrome type 2 | AR |
ARMC4 | 615408 | primary ciliary dyskinesia, 23 | AR |
ATM | 607585 | familial breast-ovarian cancer type 2; ataxia-telangiectasia | AD, AR |
BLM | 604610 | Bloom syndrome | AR |
BLNK | 604515 | Agammaglobulinemia 4 | AR |
BLOC1S3 | 609762 | Hermansky-Pudlak syndrome 8 | AR |
BTK | 300300 | X-linked agammaglobulinemia | XLR |
C3 | 120700 | atypical hemolytic uremic syndrome 5; C3 deficiency | AD, AR |
CARD11 | 607210 | Immunodeficiency 11B with atopic dermatitis | AD, AR |
CASP10 | 601762 | Autoimmune lymphoproliferative syndrome, type II; Lymphoma, non-Hodgkin; Gastric Cancer | AD |
CASP8 | 601763 | familial breast-ovarian cancer type 2; Hepatocellular Carcinoma; Lung Cancer | AD, AR |
CCDC103 | 614677 | Ciliary dyskinesia, primary, 17 | AR |
CCDC114 | 615038 | Ciliary dyskinesia, primary, 20 | AR |
CCDC151 | 615956 | primary Ciliary dyskinesia type 30 | AR |
CCDC39 | 613798 | Ciliary dyskinesia, primary, 14 | |
CCDC40 | 613799 | Ciliary dyskinesia, primary, 15 | |
CCDC65 | 611088 | Ciliary dyskinesia, primary, 27 | AR |
CCNO | 607752 | primary ciliary dyskinesia type 29 | AR |
CD19 | 107265 | Immunodeficiency, common variable, 3 | AR |
CD247 | 186780 | Immunodeficiency-25 | AR |
CD3D | 186790 | Immunodeficiency 19 | AR |
CD3E | 186830 | Immunodeficiency 18 | AR |
CD3G | 186740 | AR | |
CD40 | 109535 | Immunodeficiency with hyper-IgM, type 3 | AR |
CD40LG | 300386 | Immunodeficiency With Hyper-Igm, Type 1 | XLR |
CD46 | 120920 | atypical hemolytic uremic syndrome 2 | AD, AR |
CD59 | 107271 | Hemolytic anemia, CD59-mediated, with or without immune-mediated polyneuropathy | AR |
CD79A | 112205 | Agammaglobulinemia 3 | AR |
CD79B | 147245 | Agammaglobulinemia 6 | AR |
CD81 | 186845 | Immunodeficiency, common variable, 6 | AR |
CFAP298 | 615494 | primary ciliary dyskinesia type 26 | AR |
CFH | 134370 | atypical hemolytic uremic syndrome 1; Complement factor H deficiency | AD, AR |
CFI | 217030 | Complement factor I deficiency; atypical hemolytic uremic syndrome 3 | AD, AR |
CFTR | 602421 | hereditary pancreatitis; Bronchiectasis with or without elevated sweat chloride type 1; cystic fibrosis; congenital bilateral absence of vas deferens | AD, AR |
CHD7 | 608892 | CHARGE syndrome; hypogonadotropic hypogonadism-5 with or without anosmia | AD |
CLCN7 | 602727 | Osteopetrosis, autosomal dominant 2; Osteopetrosis, autosomal recessive 4 | AD, AR |
CLPB | 616254 | 3-methylglutaconic aciduria type VII with cataracts, neurologic involvement and neutropenia | AR |
CORO1A | 605000 | AR | |
CR2 | 120650 | Systemic Lupus Erythematosus, Susceptibility To, 9; Immunodeficiency, common variable, 7 | AR |
CSF2RB | 138981 | Surfactant metabolism dysfunction, pulmonary, 5 | AR |
CSF3R | 138971 | Neutropenia, severe congenital, 7, autosomal recessive | AR |
CTC1 | 613129 | Cerebroretinal microangiopathy with calcifications and cysts | AR |
CTLA4 | 123890 | systemic lupus erythematosus; Autoimmune lymphoproliferative syndrome, type V | AD |
CTPS1 | 123860 | AR | |
CTSC | 602365 | Papillon-Lefevre syndrome | AR |
CXCR4 | 162643 | WHIM syndrome | AD |
CYBA | 608508 | Chronic granulomatous disease, autosomal, due to deficiency of CYBA | AR |
CYBB | 300481 | chronic granulomatous disease | XLR |
DCLRE1C | 605988 | severe combined immunodeficiency, Athabascan type; Omenn syndrome | AR |
DGKE | 601440 | Nephrotic syndrome, type 7 | AR |
DKC1 | 300126 | X-linked dyskeratosis congenita | XLR |
DNAAF1 | 613190 | Ciliary dyskinesia, primary, 13 | AR |
DNAAF2 | 612517 | Ciliary dyskinesia, primary, 10 | |
DNAAF3 | 614566 | Ciliary dyskinesia, primary, 2 | AR |
DNAAF4 | 608706 | Ciliary dyskinesia, primary, 25 | AD, AR |
DNAAF5 | 614864 | Ciliary dyskinesia, primary, 18 | AR |
DNAH11 | 603339 | primary ciliary dyskinesia type 7, with or without situs inversus | AR |
DNAH5 | 603335 | primary ciliary dyskinesia type 3, with or without situs inversus | |
DNAI1 | 604366 | primary ciliary dyskinesia type 1, with or without situs inversus | AR |
DNAI2 | 605483 | primary ciliary dyskinesia type 9, with or without situs inversus | |
DNAL1 | 610062 | Ciliary dyskinesia, primary, 16 | AR |
DOCK8 | 611432 | Hyper-IgE recurrent infection syndrome, autosomal recessive | AR |
DRC1 | 615288 | primary ciliary dyskinesia, 21 | AR |
DTNBP1 | 607145 | Hermansky-Pudlak syndrome 7 | AR |
ELANE | 130130 | Neutropenia, cyclic; Neutropenia, severe congenital 1, autosomal dominant | AD |
FADD | 602457 | recurrent infections with encephalopathy, hepatic dysfunction and cardiovasuclar malformations | AR |
FAS | 134637 | Autoimmune lymphoproliferative syndrome | AD |
FASLG | 134638 | Lung Cancer; Autoimmune lymphoproliferative syndrome | AD |
FGA | 134820 | Amyloidosis, familial visceral; Afibrinogenemia, congenital; Dysfibrinogenemia, congenital | AD, AR |
FGB | 134830 | Afibrinogenemia, congenital; Dysfibrinogenemia, congenital | AR |
FGG | 134850 | Afibrinogenemia, congenital; Dysfibrinogenemia, congenital | AR |
FOXN1 | 600838 | T-cell immunodeficiency, congenital alopecia, and nail dystrophy | AR |
FOXP3 | 300292 | Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked | XLR |
G6PC3 | 611045 | Neutropenia, severe congenital 4, autosomal recessive | AR |
G6PD | 305900 | glucose-6-phosphate dehydrogenase deficiency; resistance to malaria | XLD |
GFI1 | 600871 | Neutropenia, severe congenital 2, autosomal dominant | AD |
HAX1 | 605998 | autosomal recessive severe congenital neutropenia type 3 | AR |
HPS1 | 604982 | Hermansky-Pudlak syndrome type 1 | AR |
HPS3 | 606118 | Hermansky-Pudlak syndrome type 3 | AR |
HPS4 | 606682 | Hermansky-Pudlak syndrome type 4 | AR |
HPS5 | 607521 | Hermansky-Pudlak syndrome type 5 | AR |
HPS6 | 607522 | Hermansky-Pudlak syndrome type 6 | AR |
HYDIN | 610812 | primary ciliary dyskinesia type 5 | AR |
ICOS | 604558 | Immunodeficiency, common variable, 1 | AR |
IFIH1 | 606951 | Singleton-Merten syndrome type 1; Aicardi-Goutieres syndrome 7 | AD |
IFNGR1 | 107470 | immunodeficiency-27A; Mycobacterium Tuberculosis, Susceptibility To; immunodeficiency-27B | AD, AR |
IFNGR2 | 147569 | immunodeficiency-28 | AR |
IGLL1 | 146770 | Agammaglobulinemia 2 | AR |
IKBKB | 603258 | AD, AR | |
IKBKG | 300248 | Incontinentia pigmenti, type II | XLD, XLR |
IKZF1 | 603023 | AD | |
IL12B | 161561 | Immunodeficiency 29, mycobacteriosis | AR |
IL12RB1 | 601604 | Immunodeficiency 30 | AR |
IL12RB2 | 601642 | ||
IL1RN | 147679 | Gastric Cancer, Hereditary Diffuse; Microvascular complications of diabetes, susceptibility to, 4; Osteomyelitis, sterile multifocal, with periostitis and pustulosis | AD, AR |
IL21R | 605383 | Immunodeficiency type 56 | AD, AR |
IL2RA | 147730 | Diabetes mellitus, insulin-dependent, 10; Immunodeficiency 41 with lymphoproliferation and autoimmunity | AR |
IL2RG | 308380 | Severe X-linked combined immunodeficiency; moderate X-linked combined immunodeficiency | XLR |
IL7R | 146661 | Severe combined imunodeficiency, autosomal recessive, T-cell negative, B-cell positive, NK-cell positive | AR |
IRF8 | 601565 | Immunodeficiency 32A, mycobacteriosis, autosomal dominant | AD, AR |
ISG15 | 147571 | Immunodeficiency 38 | AR |
ITK | 186973 | Lymphoproliferative syndrome 1 | AR |
JAGN1 | 616012 | Neutropenia, severe congenital, 6, autosomal recessive | AR |
JAK3 | 600173 | Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, NK cell-negative | AR |
KRAS | 190070 | Arteriovenous malformations of the brain; Bladder Cancer; familial breast-ovarian cancer type 2; Gastric Cancer, Hereditary Diffuse; Schimmelpenning-Feuerstein-Mims Syndrome; Lung Cancer; Pancreatic Cancer; acute myeloid leukemia; Noonan syndrome 3; Autoimmune lymphoproliferative syndrome type IV; Cardiofaciocutaneous syndrome 2 | AD |
LAMTOR2 | 610389 | AR | |
LIG4 | 601837 | LIG4 syndrome | AR |
LPIN2 | 605519 | Majeed syndrome | |
LRBA | 606453 | Immunodeficiency, common variable, 8, with autoimmunity | AR |
LRRC6 | 614930 | Ciliary dyskinesia, primary, 19 | AR |
LRRC8A | 608360 | Agammaglobulinemia 5 | AD |
LYST | 606897 | Chediak-Higashi syndrome | AR |
MAGT1 | 300715 | Immunodeficiency, X-Linked, With Magnesium Defect, Epstein-Barr Virus Infection, And Neoplasia | XLR |
MALT1 | 604860 | Immunodeficiency 12 | AR |
MCM4 | 602638 | Natural killer cell and glucocorticoid deficiency with DNA repair defect | AR |
MEFV | 608107 | autosomal dominant familial Mediterranean fever; autosomal recessive familial Mediterranean fever | AD, AR |
MOGS | 601336 | congenital disorder of glycosylation type 2b | AR |
MS4A1 | 112210 | Immunodeficiency, common variable, 5 | AR |
MVK | 251170 | Porokeratosis 3, Disseminated Superficial Actinic Type; Hyper-IgD syndrome; Mevalonic aciduria | AD, AR |
NBN | 602667 | Nijmegen breakage syndrome; Aplastic Anemia; Acute lymphoblastic leukemia | AR |
NCF1 | 608512 | Chronic granulomatous disease due to deficiency of NCF-1 | AR |
NCF2 | 608515 | Chronic granulomatous disease due to deficiency of NCF-2 | AR |
NCF4 | 601488 | Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type III | AR |
NFKB2 | 164012 | Common variable Immunodeficiency type 10 | AD |
NFKBIA | 164008 | Ectodermal dysplasia, anhidrotic, with T-cell immunodeficiency | AD |
NHEJ1 | 611290 | Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation | |
NHP2 | 606470 | Dyskeratosis Congenita, Autosomal Recessive, 2 | AR |
NLRC4 | 606831 | Autoinflammation with infantile enterocolitis | AD |
NLRP12 | 609648 | Familial cold autoinflammatory syndrome 2 | AD |
NLRP3 | 606416 | Familial Cold Autoinflammatory Syndrome 1; Muckle-Wells syndrome; CINCA syndrome | AD |
NME8 | 607421 | Ciliary dyskinesia, primary, 6 | AR |
NOD2 | 605956 | Blau syndrome; Inflammatory Bowel Disease 1 | AD |
NOP10 | 606471 | Dyskeratosis Congenita, Autosomal Recessive, 1 | AR |
NRAS | 164790 | colorectal cancer; Melanocytic nevus syndrome, congenital, somatic; Nevus, Epidermal; Schimmelpenning-Feuerstein-Mims Syndrome; Thyroid Carcinoma, Follicular; Neurocutaneous melanosis, somatic; Noonan syndrome 6; Autoimmune lymphoproliferative syndrome type IV | AD |
OFD1 | 300170 | Simpson-Golabi-Behmel syndrome type 2; Retinitis pigmentosa 23; Joubert syndrome 10; oral-facial-digital syndrome 1 | XLD, XLR |
PARN | 604212 | Dyskeratosis congenita, autosomal recessive 6; telomere-related pulmonary fibrosis and/or bone marrow failure type 4 | AD, AR |
PEPD | 613230 | Prolidase deficiency | AR |
PIK3CD | 602839 | Immunodeficiency 14 | AD |
PIK3R1 | 171833 | SHORT syndrome; Immunodeficiency 36 | AD, AR |
PLCG2 | 600220 | Familial cold autoinflammatory syndrome 3 | AD |
PNP | 164050 | Purine nucleoside phosphorylase deficiency | AR |
POLE | 174762 | Colorectal cancer, susceptibility to, 12; FILS syndrome | AD, AR |
PRF1 | 170280 | familial hemophagocytic lymphohistiocytosis 2; Lymphoma, non-Hodgkin; Aplastic Anemia | AR |
PRKCD | 176977 | Autoimmune lymphoproliferative syndrome, type III | AR |
PSTPIP1 | 606347 | Pyogenic sterile arthritis, pyoderma gangrenosum, and acne | AD |
PTPRC | 151460 | Severe combined imunodeficiency, autosomal recessive, T-cell negative, B-cell positive, NK-cell positive; Hepatitis C Virus, Susceptibility To | AR |
RAB27A | 603868 | Griscelli syndrome, type 2 | AR |
RAC2 | 602049 | Neutrophil immunodeficiency syndrome | |
RAG1 | 179615 | Combined cellular and humoral immune defects with granulomas; t cell-negative, b cell-negative, nk cell-positive autosomal recessive severe combined immunodeficiency; Omenn syndrome; Alpha/beta t-cell lymphopenia with gamma/delta t-cell expansion, severe cytomegalovirus infection and autoimmunity | AR |
RAG2 | 179616 | Combined cellular and humoral immune defects with granulomas; t cell-negative, b cell-negative, nk cell-positive autosomal recessive severe combined immunodeficiency; Omenn syndrome | AR |
RANBP2 | 601181 | acute infection-induced encephalopathy-3 | AD |
RBCK1 | 610924 | Polyglucosan body myopathy 1 with or without immunodeficiency | AR |
RFX5 | 601863 | MHC class II deficiency, complementation group B | AR |
RNASEH2A | 606034 | Aicardi-Goutieres syndrome type 4 | AR |
RNASEH2B | 610326 | Aicardi-Goutieres syndrome type 2 | AR |
RNASEH2C | 610330 | Aicardi-Goutieres syndrome 3 | AR |
RORC | 602943 | AR | |
RSPH1 | 609314 | primary ciliary dyskinesia, 24 | AR |
RSPH4A | 612647 | Ciliary dyskinesia, primary, 11 | |
RSPH9 | 612648 | Ciliary dyskinesia, primary, 12 | |
RTEL1 | 608833 | dyskeratosis congenita; that telomere-related pulmonary fibrosis and/or bone marrow failure type 3 | AD, AR |
SAMD9 | 610456 | normophosphatemic familial tumoral calcinosis; MIRAGE syndrome | AD, AR |
SAMHD1 | 606754 | Aicardi-Goutieres syndrome type 5; Chilblain lupus type 2 | AD, AR |
SBDS | 607444 | Shwachman-Bodian-Diamond syndrome; Aplastic Anemia | AR |
SERPING1 | 606860 | hereditary angioedema type 1 | AD, AR |
SH2D1A | 300490 | Lymphoproliferative Syndrome, X-Linked, 1 | XLR |
SLC35C1 | 605881 | Congenital disorder of glycosylation, type IIc | AR |
SLC7A7 | 603593 | Lysinuric protein intolerance | AR |
SPAG1 | 603395 | Primary Ciliary dyskinesia type 28 | AR |
SPINK5 | 605010 | Netherton syndrome | AR |
SRP72 | 602122 | Bone marrow failure, familial | AD |
STAT1 | 600555 | Autosomal recessive Immunodeficiency 31B, mycobacterial and viral infections; Immunodeficiency 31C, autosomal dominant | AD, AR |
STAT3 | 102582 | Hyper-IgE recurrent infection syndrome; infantile-onset multisystem autoimmune disease, 1 | AD |
STAT5B | 604260 | Growth hormone insensitivity with immunodeficiency | |
STIM1 | 605921 | Myopathy, tubular aggregate, 1; Immunodeficiency 10 | AD, AR |
STING1 | 612374 | STING-associated vasculopathy, infantile-onset | AD |
STX11 | 605014 | Hemophagocytic lymphohistiocytosis, familial, 4 | AR |
STXBP2 | 601717 | Hemophagocytic lymphohistiocytosis, familial, 5 | |
TAZ | 300394 | Barth syndrome | XLR |
TBX1 | 602054 | Tetralogy of Fallot; DiGeorge syndrome; Velocardiofacial syndrome; Conotruncal Heart Malformations | AD |
TCN2 | 613441 | Transcobalamin II deficiency | AR |
TERT | 187270 | acute myeloid leukemia; Dyskeratosis congenita 4; Bone marrow failure, telomere-related, 1 | AD, AR |
THBD | 188040 | atypical hemolytic uremic syndrome 6 | AD |
TICAM1 | 607601 | AD, AR | |
TINF2 | 604319 | Revesz syndrome; Dyskeratosis congenita, autosomal dominant 3 | AD |
TLR3 | 603029 | Human Immunodeficiency Virus Type 1, Susceptibility To; Herpes simplex encephalitis, susceptibility to, 2 | AD, AR |
TNFRSF13B | 604907 | Immunodeficiency, common variable, 2; Immunoglobulin a deficiency 2 | AD, AR |
TNFRSF13C | 606269 | Immunodeficiency, common variable, 4 | AR |
TNFRSF1A | 191190 | Periodic fever, familial | AD |
TREX1 | 606609 | systemic lupus erythematosus; retinal vasculopathy with cerebral leukodystrophy; Aicardi-Goutieres syndrome type 1; chilblain lupus type 1 | AD, AR |
TRNT1 | 612907 | Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay | AR |
TTC7A | 609332 | Gastrointestinal defects and immunodeficiency syndrome | AR |
TYK2 | 176941 | Tyrosine kinase 2 deficiency | AR |
UNC13D | 608897 | familial hemophagocytic lymphohistiocytosis 3 | AR |
UNG | 191525 | Immunodeficiency with hyper IgM, type 5 | AR |
VPS13B | 607817 | Cohen syndrome | AR |
VPS45 | 610035 | Severe congenital neutropenia type 5 | AR |
WAS | 300392 | Neutropenia, severe congenital, X-linked; Wiskott-Aldrich syndrome; Thrombocytopenia 1 | XLR |
WRAP53 | 612661 | Autosomal recessive dyskeratosis congenita type 3 | AR |
XIAP | 300079 | X-linked lymphoproliferative disease 2 | XLR |
ZAP70 | 176947 | Selective T-cell defect | AR |
ZMYND10 | 607070 | primary ciliary dyskinesia, 22 | AR |
FMF cannot be cured, but it can be well controlled by a life-long use of colchicine. Colchicine prevents the inflammatory attacks and the deposition of amyloid. Symptomatic individuals with a heterozygous MEFV pathogenic variant may benefit from a trial of colchicine. Further treatment of an acute episode of hereditary periodic fever syndromes is mainly supportive, including administration of intravenous saline for hydration and use of nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol, or dipyrone for pain relief; treatment of febrile and inflammatory episodes with NSAIDs; routine treatment of end-stage renal disease, including renal transplantation.
CENTOGENE offers sequencing and deletion/duplication analysis of genes in the Periodic fever syndrome panel (ELANE, LPIN2, MEFV, MVK, NLRP3, PSTPIP1, TNFRSF1A).
Differential diagnosis
The differential diagnosis of periodic fever syndrome includes the following diseases - depending on the major presenting symptoms:
- Familial Hibernian fever
- Hyperimmunoglobulin D and periodic fever syndrome
- Acute Rheumatic Fever
- Systemic Lupus Erythematosus (SLE)
- Appendicitis
- Nephrolithiasis
- Pleurodynia.
Testing strategy
CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.
To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for periodic fever syndrome using NGS Panel Genomic targeted towards this specific phenotype:
Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Periodic fever syndrome panel. Copy Number Variants analysis derived from NGS data is also included.
Step 2: If no clinically relevant variant is identified after analysis of the periodic fever syndrome panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.
Referral reasons
The following individuals are candidates for periodic fever syndrome gene testing:
- Individuals with a family history of periodic fever syndrome and presentation of the most common symptoms, including visual and hearing abnormalities
- Individuals without a positive family history, but with symptoms resembling periodic fever syndrome
- Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).
Test utility
Sequencing, deletion/duplication of periodic fever syndrome related genes should be performed in all individuals suspected of having periodic fever syndrome. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of pathogenic variants, due to the overlap in many clinical features caused by those particular genes.
Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of periodic fever syndrome, identify at-risk family members, provide information about reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.