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  3. NGS Panel – Genetic Testing for Periodic Fever Syndrome

Periodic Fever Syndrome

September 29, 2017

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 CentoMD® exclusive variant numbers (++)
ACTB 102630 Baraitser-Winter syndrome 1; Dystonia, juvenile-onset AD 11
ADA 608958 Adenosine deaminase deficiency AR 6
ADAR 146920 Dyschromatosis symmetrica hereditaria; Aicardi-Goutieres syndrome type 6 AD, AR 17
AICDA 605257 Immunodeficiency with hyper-IgM, type 2 AR 0
AIRE 607358 Autoimmune polyendocrinopathy syndrome type I with or without reversible metaphyseal dysplasia AD, AR 1
AK2 103020 Reticular dysgenesis AR 0
AP3B1 603401 Hermansky-Pudlak syndrome type 2 AR 18
ARMC4 615408 primary ciliary dyskinesia, 23 AR 2
ATM 607585 familial breast-ovarian cancer type 2; ataxia-telangiectasia AD, AR 82
BLM 604610 Bloom syndrome AR 9
BLNK 604515 Agammaglobulinemia 4 AR 0
BLOC1S3 609762 Hermansky-Pudlak syndrome 8 AR 3
BTK 300300 X-linked agammaglobulinemia XLR 5
C3 120700 atypical hemolytic uremic syndrome 5; C3 deficiency AD, AR 81
CARD11 607210 Immunodeficiency 11B with atopic dermatitis AD, AR 2
CASP10 601762 Autoimmune lymphoproliferative syndrome, type II; Lymphoma, non-Hodgkin; Gastric Cancer AD 4
CASP8 601763 familial breast-ovarian cancer type 2; Hepatocellular Carcinoma; Lung Cancer AD, AR 0
CCDC103 614677 Ciliary dyskinesia, primary, 17 AR 3
CCDC114 615038 Ciliary dyskinesia, primary, 20 AR 7
CCDC151 615956 primary Ciliary dyskinesia type 30 AR 0
CCDC39 613798 Ciliary dyskinesia, primary, 14 8
CCDC40 613799 Ciliary dyskinesia, primary, 15 27
CCDC65 611088 Ciliary dyskinesia, primary, 27 AR 1
CCNO 607752 primary ciliary dyskinesia type 29 AR 3
CD19 107265 Immunodeficiency, common variable, 3 AR 0
CD247 186780 Immunodeficiency-25 AR 0
CD3D 186790 Immunodeficiency 19 AR 0
CD3E 186830 Immunodeficiency 18 AR 1
CD3G 186740 AR 0
CD40 109535 Immunodeficiency with hyper-IgM, type 3 AR 1
CD40LG 300386 Immunodeficiency With Hyper-Igm, Type 1 XLR 4
CD46 120920 atypical hemolytic uremic syndrome 2 AD, AR 23
CD59 107271 Hemolytic anemia, CD59-mediated, with or without immune-mediated polyneuropathy AR 1
CD79A 112205 Agammaglobulinemia 3 AR 0
CD79B 147245 Agammaglobulinemia 6 AR 0
CD81 186845 Immunodeficiency, common variable, 6 AR 0
CFAP298 615494 primary ciliary dyskinesia type 26 AR 1
CFH 134370 atypical hemolytic uremic syndrome 1; Complement factor H deficiency AD, AR 56
CFI 217030 Complement factor I deficiency; atypical hemolytic uremic syndrome 3 AD, AR 34
CFTR 602421 hereditary pancreatitis; Bronchiectasis with or without elevated sweat chloride type 1; cystic fibrosis; congenital bilateral absence of vas deferens AD, AR 113
CHD7 608892 CHARGE syndrome; hypogonadotropic hypogonadism-5 with or without anosmia AD 103
CLCN7 602727 Osteopetrosis, autosomal dominant 2; Osteopetrosis, autosomal recessive 4 AD, AR 25
CLPB 616254 3-methylglutaconic aciduria type VII with cataracts, neurologic involvement and neutropenia AR 2
CORO1A 605000 AR 0
CR2 120650 Systemic Lupus Erythematosus, Susceptibility To, 9; Immunodeficiency, common variable, 7 AR 0
CSF2RB 138981 Surfactant metabolism dysfunction, pulmonary, 5 AR 19
CSF3R 138971 Neutropenia, severe congenital, 7, autosomal recessive AR 1
CTC1 613129 Cerebroretinal microangiopathy with calcifications and cysts AR 3
CTLA4 123890 systemic lupus erythematosus; Autoimmune lymphoproliferative syndrome, type V AD 2
CTPS1 123860 AR 0
CTSC 602365 Papillon-Lefevre syndrome AR 8
CXCR4 162643 WHIM syndrome AD 4
CYBA 608508 Chronic granulomatous disease, autosomal, due to deficiency of CYBA AR 1
CYBB 300481 chronic granulomatous disease XLR 3
DCLRE1C 605988 severe combined immunodeficiency, Athabascan type; Omenn syndrome AR 6
DGKE 601440 Nephrotic syndrome, type 7 AR 27
DKC1 300126 X-linked dyskeratosis congenita XLR 3
DNAAF1 613190 Ciliary dyskinesia, primary, 13 AR 9
DNAAF2 612517 Ciliary dyskinesia, primary, 10 6
DNAAF3 614566 Ciliary dyskinesia, primary, 2 AR 2
DNAAF4 608706 Ciliary dyskinesia, primary, 25 AD, AR 0
DNAAF5 614864 Ciliary dyskinesia, primary, 18 AR 12
DNAH11 603339 primary ciliary dyskinesia type 7, with or without situs inversus AR 56
DNAH5 603335 primary ciliary dyskinesia type 3, with or without situs inversus 38
DNAI1 604366 primary ciliary dyskinesia type 1, with or without situs inversus AR 4
DNAI2 605483 primary ciliary dyskinesia type 9, with or without situs inversus 5
DNAL1 610062 Ciliary dyskinesia, primary, 16 AR 2
DOCK8 611432 Hyper-IgE recurrent infection syndrome, autosomal recessive AR 27
DRC1 615288 primary ciliary dyskinesia, 21 AR 2
DTNBP1 607145 Hermansky-Pudlak syndrome 7 AR 6
ELANE 130130 Neutropenia, cyclic; Neutropenia, severe congenital 1, autosomal dominant AD 3
FADD 602457 recurrent infections with encephalopathy, hepatic dysfunction and cardiovasuclar malformations AR 1
FAS 134637 Autoimmune lymphoproliferative syndrome AD 4
FASLG 134638 Lung Cancer; Autoimmune lymphoproliferative syndrome AD 1
FGA 134820 Amyloidosis, familial visceral; Afibrinogenemia, congenital; Dysfibrinogenemia, congenital AD, AR 4
FGB 134830 Afibrinogenemia, congenital; Dysfibrinogenemia, congenital AR 1
FGG 134850 Afibrinogenemia, congenital; Dysfibrinogenemia, congenital AR 2
FOXN1 600838 T-cell immunodeficiency, congenital alopecia, and nail dystrophy AR 1
FOXP3 300292 Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked XLR 5
G6PC3 611045 Neutropenia, severe congenital 4, autosomal recessive AR 3
G6PD 305900 glucose-6-phosphate dehydrogenase deficiency; resistance to malaria XLD 10
GFI1 600871 Neutropenia, severe congenital 2, autosomal dominant AD 0
HAX1 605998 autosomal recessive severe congenital neutropenia type 3 AR 1
HPS1 604982 Hermansky-Pudlak syndrome type 1 AR 14
HPS3 606118 Hermansky-Pudlak syndrome type 3 AR 12
HPS4 606682 Hermansky-Pudlak syndrome type 4 AR 6
HPS5 607521 Hermansky-Pudlak syndrome type 5 AR 7
HPS6 607522 Hermansky-Pudlak syndrome type 6 AR 4
HYDIN 610812 primary ciliary dyskinesia type 5 AR 131
ICOS 604558 Immunodeficiency, common variable, 1 AR 2
IFIH1 606951 Singleton-Merten syndrome type 1; Aicardi-Goutieres syndrome 7 AD 28
IFNGR1 107470 immunodeficiency-27A; Mycobacterium Tuberculosis, Susceptibility To; immunodeficiency-27B AD, AR 1
IFNGR2 147569 immunodeficiency-28 AR 1
IGLL1 146770 Agammaglobulinemia 2 AR 0
IKBKB 603258 AD, AR 0
IKBKG 300248 Incontinentia pigmenti, type II XLD, XLR 7
IKZF1 603023 AD 0
IL12B 161561 Immunodeficiency 29, mycobacteriosis AR 0
IL12RB1 601604 Immunodeficiency 30 AR 3
IL12RB2 601642 3
IL1RN 147679 Gastric Cancer, Hereditary Diffuse; Microvascular complications of diabetes, susceptibility to, 4; Osteomyelitis, sterile multifocal, with periostitis and pustulosis AD, AR 9
IL21R 605383 Immunodeficiency type 56 AD, AR 1
IL2RA 147730 Diabetes mellitus, insulin-dependent, 10; Immunodeficiency 41 with lymphoproliferation and autoimmunity AR 2
IL2RG 308380 Severe X-linked combined immunodeficiency; moderate X-linked combined immunodeficiency XLR 7
IL7R 146661 Severe combined imunodeficiency, autosomal recessive, T-cell negative, B-cell positive, NK-cell positive AR 2
IRF8 601565 Immunodeficiency 32A, mycobacteriosis, autosomal dominant AD, AR 0
ISG15 147571 Immunodeficiency 38 AR 6
ITK 186973 Lymphoproliferative syndrome 1 AR 0
JAGN1 616012 Neutropenia, severe congenital, 6, autosomal recessive AR 2
JAK3 600173 Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, NK cell-negative AR 6
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 9
LAMTOR2 610389 AR 0
LIG4 601837 LIG4 syndrome AR 3
LPIN2 605519 Majeed syndrome 3
LRBA 606453 Immunodeficiency, common variable, 8, with autoimmunity AR 12
LRRC6 614930 Ciliary dyskinesia, primary, 19 AR 2
LRRC8A 608360 Agammaglobulinemia 5 AD 1
LYST 606897 Chediak-Higashi syndrome AR 30
MAGT1 300715 Immunodeficiency, X-Linked, With Magnesium Defect, Epstein-Barr Virus Infection, And Neoplasia XLR 2
MALT1 604860 Immunodeficiency 12 AR 2
MCM4 602638 Natural killer cell and glucocorticoid deficiency with DNA repair defect AR 0
MEFV 608107 autosomal dominant familial Mediterranean fever; autosomal recessive familial Mediterranean fever AD, AR 12
MOGS 601336 congenital disorder of glycosylation type 2b AR 5
MS4A1 112210 Immunodeficiency, common variable, 5 AR 0
MVK 251170 Porokeratosis 3, Disseminated Superficial Actinic Type; Hyper-IgD syndrome; Mevalonic aciduria AD, AR 4
NBN 602667 Nijmegen breakage syndrome; Aplastic Anemia; Acute lymphoblastic leukemia AR 11
NCF1 608512 Chronic granulomatous disease due to deficiency of NCF-1 AR 8
NCF2 608515 Chronic granulomatous disease due to deficiency of NCF-2 AR 0
NCF4 601488 Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type III AR 0
NFKB2 164012 Common variable Immunodeficiency type 10 AD 1
NFKBIA 164008 Ectodermal dysplasia, anhidrotic, with T-cell immunodeficiency AD 0
NHEJ1 611290 Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation 9
NHP2 606470 Dyskeratosis Congenita, Autosomal Recessive, 2 AR 0
NLRC4 606831 Autoinflammation with infantile enterocolitis AD 1
NLRP12 609648 Familial cold autoinflammatory syndrome 2 AD 5
NLRP3 606416 Familial Cold Autoinflammatory Syndrome 1; Muckle-Wells syndrome; CINCA syndrome AD 8
NME8 607421 Ciliary dyskinesia, primary, 6 AR 10
NOD2 605956 Blau syndrome; Inflammatory Bowel Disease 1 AD 3
NOP10 606471 Dyskeratosis Congenita, Autosomal Recessive, 1 AR 0
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 5
OFD1 300170 Simpson-Golabi-Behmel syndrome type 2; Retinitis pigmentosa 23; Joubert syndrome 10; oral-facial-digital syndrome 1 XLD, XLR 22
PARN 604212 Dyskeratosis congenita, autosomal recessive 6; telomere-related pulmonary fibrosis and/or bone marrow failure type 4 AD, AR 3
PEPD 613230 Prolidase deficiency AR 5
PIK3CD 602839 Immunodeficiency 14 AD 4
PIK3R1 171833 SHORT syndrome; Immunodeficiency 36 AD, AR 3
PLCG2 600220 Familial cold autoinflammatory syndrome 3 AD 4
PNP 164050 Purine nucleoside phosphorylase deficiency AR 0
POLE 174762 Colorectal cancer, susceptibility to, 12; FILS syndrome AD, AR 9
PRF1 170280 familial hemophagocytic lymphohistiocytosis 2; Lymphoma, non-Hodgkin; Aplastic Anemia AR 17
PRKCD 176977 Autoimmune lymphoproliferative syndrome, type III AR 2
PSTPIP1 606347 Pyogenic sterile arthritis, pyoderma gangrenosum, and acne AD 7
PTPRC 151460 Severe combined imunodeficiency, autosomal recessive, T-cell negative, B-cell positive, NK-cell positive; Hepatitis C Virus, Susceptibility To AR 0
RAB27A 603868 Griscelli syndrome, type 2 AR 6
RAC2 602049 Neutrophil immunodeficiency syndrome 0
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 6
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 3
RANBP2 601181 acute infection-induced encephalopathy-3 AD 22
RBCK1 610924 Polyglucosan body myopathy 1 with or without immunodeficiency AR 7
RFX5 601863 MHC class II deficiency, complementation group B AR 2
RNASEH2A 606034 Aicardi-Goutieres syndrome type 4 AR 14
RNASEH2B 610326 Aicardi-Goutieres syndrome type 2 AR 23
RNASEH2C 610330 Aicardi-Goutieres syndrome 3 AR 6
RORC 602943 AR 0
RSPH1 609314 primary ciliary dyskinesia, 24 AR 0
RSPH4A 612647 Ciliary dyskinesia, primary, 11 5
RSPH9 612648 Ciliary dyskinesia, primary, 12 2
RTEL1 608833 dyskeratosis congenita; that telomere-related pulmonary fibrosis and/or bone marrow failure type 3 AD, AR 8
SAMD9 610456 normophosphatemic familial tumoral calcinosis; MIRAGE syndrome AD, AR 4
SAMHD1 606754 Aicardi-Goutieres syndrome type 5; Chilblain lupus type 2 AD, AR 26
SBDS 607444 Shwachman-Bodian-Diamond syndrome; Aplastic Anemia AR 11
SERPING1 606860 hereditary angioedema type 1 AD, AR 31
SH2D1A 300490 Lymphoproliferative Syndrome, X-Linked, 1 XLR 3
SLC35C1 605881 Congenital disorder of glycosylation, type IIc AR 1
SLC7A7 603593 Lysinuric protein intolerance AR 11
SPAG1 603395 Primary Ciliary dyskinesia type 28 AR 0
SPINK5 605010 Netherton syndrome AR 17
SRP72 602122 Bone marrow failure, familial AD 1
STAT1 600555 Autosomal recessive Immunodeficiency 31B, mycobacterial and viral infections; Immunodeficiency 31C, autosomal dominant AD, AR 6
STAT3 102582 Hyper-IgE recurrent infection syndrome; infantile-onset multisystem autoimmune disease, 1 AD 5
STAT5B 604260 Growth hormone insensitivity with immunodeficiency 0
STIM1 605921 Myopathy, tubular aggregate, 1; Immunodeficiency 10 AD, AR 1
STING1 612374 STING-associated vasculopathy, infantile-onset AD 2
STX11 605014 Hemophagocytic lymphohistiocytosis, familial, 4 AR 2
STXBP2 601717 Hemophagocytic lymphohistiocytosis, familial, 5 9
TAZ 300394 Barth syndrome XLR 6
TBX1 602054 Tetralogy of Fallot; DiGeorge syndrome; Velocardiofacial syndrome; Conotruncal Heart Malformations AD 11
TCN2 613441 Transcobalamin II deficiency AR 11
TERT 187270 acute myeloid leukemia; Dyskeratosis congenita 4; Bone marrow failure, telomere-related, 1 AD, AR 5
THBD 188040 atypical hemolytic uremic syndrome 6 AD 11
TICAM1 607601 AD, AR 0
TINF2 604319 Revesz syndrome; Dyskeratosis congenita, autosomal dominant 3 AD 2
TLR3 603029 Human Immunodeficiency Virus Type 1, Susceptibility To; Herpes simplex encephalitis, susceptibility to, 2 AD, AR 3
TNFRSF13B 604907 Immunodeficiency, common variable, 2; Immunoglobulin a deficiency 2 AD, AR 4
TNFRSF13C 606269 Immunodeficiency, common variable, 4 AR 0
TNFRSF1A 191190 Periodic fever, familial AD 7
TREX1 606609 systemic lupus erythematosus; retinal vasculopathy with cerebral leukodystrophy; Aicardi-Goutieres syndrome type 1; chilblain lupus type 1 AD, AR 12
TRNT1 612907 Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay AR 0
TTC7A 609332 Gastrointestinal defects and immunodeficiency syndrome AR 10
TYK2 176941 Tyrosine kinase 2 deficiency AR 0
UNC13D 608897 familial hemophagocytic lymphohistiocytosis 3 AR 16
UNG 191525 Immunodeficiency with hyper IgM, type 5 AR 1
VPS13B 607817 Cohen syndrome AR 28
VPS45 610035 Severe congenital neutropenia type 5 AR 1
WAS 300392 Neutropenia, severe congenital, X-linked; Wiskott-Aldrich syndrome; Thrombocytopenia 1 XLR 4
WRAP53 612661 Autosomal recessive dyskeratosis congenita type 3 AR 1
XIAP 300079 X-linked lymphoproliferative disease 2 XLR 6
ZAP70 176947 Selective T-cell defect AR 0
ZMYND10 607070 primary ciliary dyskinesia, 22 AR 1

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.