Periodic Fever Syndrome

Hereditary Periodic Fever Syndrome

Autosomal recessive, autosomal dominant

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).

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).

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.

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.

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).

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.