# New Diseases Linked to MEFV Variants or Pyrinopathies

Philippe Mertz, Guilaine Boursier, Véronique Hentgen, Sophie Georgin-Lavialle

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Philippe Mertz, Guilaine Boursier, Véronique Hentgen, Sophie Georgin-Lavialle. New Diseases Linked to MEFV Variants or Pyrinopathies. Journal of Allergy and Clinical Immunology: In Practice, 2025, 13 (3), pp.522-532. 10.1016/j.jaip.2024.12.022. hal-05016123

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# New Diseases Linked to MEFV Variants or Pyrinopathies

<figure><img src="image_2.png" /></figure>

Philippe Mertz, MD<sup>a,b,c,d</sup>, Guilaine Boursier, PhD<sup>b,e</sup>, Véronique Hentgen, MD<sup>c</sup>, and Sophie Georgin-Lavialle, MD, PhD<sup>a,b</sup>

Paris, Le Chesnay, and Montpellier, France

Autoinflammatory diseases (AIDs) are characterized by dysregulation of innate immunity, leading to systemic inflammation. Familial Mediterranean fever (FMF) is the most common AID, associated with variants in exon 10 of *MEFV*. This gene codes for pyrin, a key protein in the inflammasome of the same name, involved in the innate immune response. Since the discovery of FMF, many other pathogenic variants of *MEFV* have been identified. These variants, apart from exon 10, are responsible for a variety of AIDs known as pyrin-associated AIDs or pyrinopathies. Variants in exon 10, 8, 5, and 3 are associated with dominant forms of FMF. Other inflammatory clinical pictures not resembling typical FMF are possible: pyrin-associated autoinflammation with neutrophilic dermatosis is characterized by febrile attacks and severe neutrophilic dermatosis associated with variants in exon 2; pyrin-associated autoinflammation with hypereosinophilia was described among patients displaying severe inflammation and hypereosinophilia-associated variants in exon 2, different from pyrin-associated autoinflammation with neutrophilic dermatosis; and pyrin-associated autoinflammation associated with neuroinflammation manifests with systemic inflammation, serositis, and neuroinflammation associated with variants in exon 9. Somatic forms of FMF have also been described. We present here a review of the literature on the various AIDs associated with pathogenic *MEFV* variants and propose a practical approach to the genetic diagnosis of *MEFV*-associated AIDs. © 2024 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)). (J Allergy Clin Immunol Pract 2025;13:522-32)

**Key words:** Autoinflammatory disease; Familial Mediterranean fever; Inflammasomopathies; Pyrin; MEFV

## INTRODUCTION

Autoinflammatory diseases (AIDs) are disorders of innate immunity associated with systemic inflammation and a range of clinical manifestations.¹ Among the various categories of AIDs, inflammasomopathies are associated with pathogenic variants in genes encoding inflammasomes. Familial Mediterranean fever (FMF) is the most prevalent monogenic AID worldwide² (as high as one in 200 in at-risk populations) and is regarded as the archetypal inflammasomopathy. Familial Mediterranean fever is associated with pathogenic variants in exon 10 of the *Mediterranean Fever (MEFV)* gene, which is located on chromosome 16 (Figure 1, A). *MEFV* encodes the pyrin protein, which is involved in the function of the inflammasome that shares its name. Its inheritance is typically autosomal recessive. The link between pathogenic variants and FMF was first identified in 1997 by a French and international consortium.³,⁴ The field of AIDs has since expanded steadily³,⁵ owing to the development and widespread adoption of high-throughput sequencing (next-generation sequencing [NGS]). New pathogenic variants of *MEFV* have been identified worldwide and associated with a variety of clinical phenotypes. These constitute the spectrum of AIDs associated with *MEFV* variants, also known as pyrinopathies or pyrin-associated AIDs (PAADs), as proposed by Ben Chetrit et al.⁶

This review provides an update on AIDs associated with pathogenic variants in *MEFV* actually called pyrinopathies. Those include new dominant forms (exon 10 delM694 and non-exon 10 T577, H478, and P373), pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND), pyrin-associated autoinflammation with neuroinflammation, and pyrin-associated autoinflammation with hypereosinophilia. A section dedicated to current somatic forms of FMF is also developed. Several patients with undifferentiated systemic AIDs/syndrome of undifferentiated recurrent fever⁷ may present with symptoms similar to FMF but are not included in this work, which focuses on describing published patients with pathogenic

<footnote><sup>a</sup>Department of Internal Medicine, Sorbonne University, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France</footnote>

<footnote><sup>b</sup>Reference Center for Autoinflammatory Diseases and Inflammatory Amyloidosis, Paris, France</footnote>

<footnote><sup>c</sup>Department of Pediatric Rheumatology, Center Hospitalier de Versailles, Le Chesnay, France</footnote>

<footnote><sup>d</sup>Institut Cochin, Université Paris Cité, INSERM, CNRS, Paris, France</footnote>

<footnote><sup>e</sup>Service de Génétique Moléculaire et Cytogénomique, Laboratoire de Référence des Maladies Rares et Autoinflammatoires, IRMB, INSERM, CHU Montpellier, Univ Montpellier, Montpellier, France</footnote>

<footnote>**Conflicts of interest:** The authors declare that they have no relevant conflicts of interest.</footnote>

<footnote>Received for publication October 10, 2024; revised November 26, 2024; accepted for publication December 3, 2024.</footnote>

<footnote>Available online December 24, 2024.</footnote>

<footnote>Corresponding author: Sophie Georgin-Lavialle, MD, PhD, Department of Internal Medicine, Tenon Hospital, Sorbonne University, Assistance Publique-Hôpitaux de Paris, Reference Center for Autoinflammatory Diseases and Inflammatory Amyloidosis, 4 Rue de la Chine, 75020 Paris, France. E-mail: sophie.georgin-lavialle@aphp.fr; Or: Philippe Mertz, MD, Department of Internal Medicine, Tenon Hospital, Sorbonne University, Assistance Publique-Hôpitaux de Paris, Reference Center for Autoinflammatory Diseases and Inflammatory Amyloidosis, 4 Rue de la Chine, 75020 Paris, France. E-mail: philippe.mertz@aphp.fr.</footnote>

<footnote>2213-2198</footnote>

<footnote>© 2024 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)).</footnote>

<footnote>https://doi.org/10.1016/j.jaip.2024.12.022</footnote>
Abbreviations used

ASC- Apoptosis-associated speck-like protein containing a caspase recruitment domain

CRP- C-Reactive protein

FMF- Familial Mediterranean fever

MEFV- Mediterranean Fever gene

NGS- Next-generation sequencing

PAAD- Pyrin-associated autoinflammatory disease

PAAND- Pyrin-associated autoinflammatory disease with neutrophilic dermatosis

PYD- Pyrin domain

mutations in *MEFV*. Similarly, FMF-like disease associated with the presence of a single pathogenic mutation in exon 10 of *MEFV*, sometimes referred to as heterozygous FMF, is not addressed in this review. Both topics should benefit from dedicated research or specific reviews.

## THE PYRIN INFLAMMASOME

The pyrin protein is predominantly expressed by neutrophils and monocytes, but not lymphocytes.⁸ The protein is composed of five functional domains, each of which has an important role in enabling interactions with different regulatory or effector proteins⁹ (Figure 1, A). These domains are arranged in the following order, from N- to C-terminal:

* The N-terminal pyrin domain (PYD) enables polymerization of the pyrin inflammasome via interaction with another PYD present on the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) adaptor protein.

* The protein contains a domain that enables interactions with chaperone protein 14-3-3 when phosphorylated on its serines at positions Ser-208 and Ser-242.

* A B-box domain interacts with regulatory proline-serine-threonine phosphatase interacting protein 1).

* A coiled-coil α domain is termed the central helical scaffold.

* The C-terminal B30.2 domain is an important regulatory domain that interacts with several inflammasome activating or inhibiting ligands.

In its inactive state, the pyrin protein undergoes phosphorylation at residues Ser-208 and Ser-242, resulting in its folding onto itself. This folding is facilitated by an interaction between the C-terminal and N-terminal domains, which depends on a specific residue, E583.¹⁰ This phosphorylated configuration favors pyrin's interaction with the chaperone protein 14-3-3,¹¹⁻¹³ and this folding mechanism effectively masks the PYD of pyrin, which is crucial for its interaction with the ASC adaptor protein and subsequent scaffolding and polymerization of the pyrin inflammasome.¹¹,¹⁴,¹⁵

Pyrin is an indispensable protein in the innate immune response, particularly in the context of bacterial infections. Activation of this protein is regulated by monitoring the inhibition of RhoA GTPase,¹⁶ which is activated when it is bound to GTP and remains inactive when it is bound to GDP. A number of bacterial toxins, including those produced by *Clostridium difficile* toxins A and B, have been demonstrated to inactivate RhoA GTPase.¹⁷ In its active state, RhoA GTPase maintains pyrin in a phosphorylated and therefore inactive state.¹⁸ Inhibition of RhoA GTPase by toxins results in the dephosphorylation of pyrin on residues

Ser-208 and Ser-242 by reducing phosphokinase 1/2 activity. This leads to detachment of chaperone protein 14-3-3 and ends this initial stage.¹¹⁻¹³

The second essential stage entails a conformational alteration in the protein enabling the exposure of its PYD and subsequent inflammasome assembly.¹¹,¹⁴,¹⁵ Proline-serine-threonine phosphatase interacting protein 1, which interacts with pyrin via its B-box domain, is essential for this conformational change, which results in exposure of the PYD.¹⁹⁻²¹ Activation of this B30.2 domain by various ligands, including β2-microglobulin and steroid catabolites such as pregnanolone and etiocholanolone, is a crucial step in this transition.¹⁴,²² Figure 1, B summarizes the two principal stages in the regulation of the pyrin inflammasome.

The architecture of the cell's cytoskeleton has a crucial role in this activation phase, although the exact mechanisms remain partially elucidated. Microtubules, for example, have been demonstrated to be essential, as evidenced by the inhibition of pyroptosis mediated by the pyrin inflammasome (see subsequent discussion) in the presence of microtubule-affecting substances such as paclitaxel or colchicine.¹¹,²³

Once the PYD is exposed, it is able to associate with the ASC adaptor protein, initiating polymerization of the pyrin inflammasome. The caspase recruitment domain of ASC facilitates the recruitment of caspase 1, which then self-activates and cleaves proinflammatory cytokines pro-IL-1β and pro-IL-18 into their active forms.¹⁹,²⁴ Caspase 1 also activates gasdermin D, which oligomerizes at the cell membrane to form a pore, releasing IL-1β and IL-18.²⁵ This process, known as pyroptosis, induces proinflammatory cell death (Figure 1, C).

## FAMILIAL MEDITERRANEAN FEVER

Familial Mediterranean fever predominantly affects populations originating from the Mediterranean basin, particularly Turks, Armenians, Sephardic Jews, and Arabs³; however, patients have been described all over the world.

Symptoms of FMF typically manifest during childhood, and 80% of cases occur before age 20. Patients present with acute, stereotyped febrile attacks, with an average duration of 3 days. These attacks are typically accompanied by abdominal pain in 95% of patients and arthralgia in 50% to 75%. It is less common for patients to experience chest pain, pseudo-erysipelas, and lower limb myalgia.²⁶ During a crisis, there is a constant elevation in blood biomarkers of inflammation. Triggering factors include fatigue, physical exertion, psychological stress, and the menstrual cycle.

The reference standard of treatment is colchicine, administered daily over the long term. This is the only treatment that has been shown to reduce the risk of inflammatory AA amyloidosis.²⁷ Up to 5% to 10% of patients are resistant to colchicine²⁸ and require biotherapies targeting IL-1 to control inflammation and symptoms.

Given its recessive mode of transmission, the diagnosis of classical FMF is confirmed by identifying two pathogenic variants typically in exon 10 of *MEFV*. The most frequent and severe variant is M694V.²⁹ A list of variants described in FMF and their score of pathogenicity (class 4 indicates probably pathogenic; and class 5, pathogenic) is available on the Infevers database.³⁰ The consequences of *MEFV* mutations for inflammasome activation are still poorly understood. Magnotti et al³¹ demonstrated that blocking pyrin phosphorylation triggers inflammasome activation
<figure><img src="image_3.png" /><figcaption>FIGURE 1. (A) Structure of *Mediterranean Fever* gene (MEFV) and correspondence to functional domains and activation of the pyrin protein. (B) Regulatory mechanisms of two-step activation of pyrin inflammasome. (C) Pyrin-dependent pyroptosis.</figcaption></figure>

in monocytes from patients with FMF compared with healthy
donors. Expression of the pathogenic p.M694V MEFV allele is
essential for initiating caspase-1- and gasdermin D-mediated
pyroptosis. It may affect the conformational state of pyrin and
influence a physiologic control mechanism, likely related to the
second stage of the process of activation resulting in pyrin
inflammasome activation being regulated only by pyrin (de)
phosphorylation in patients with FMF.

NEW AIDS ASSOCIATED WITH *MEFV* VARIANTS:
SPECTRUM OF PYRINOPATHIES OR PAADS

Figure 2 summarizes the characteristics of these different pyrinopathies and Figure 3 shows the global distribution of geographic origins of published patients with pyrinopathies (excluding FMF). This figure does not show the incidence of the diseases, which may be biased by access to genetic sequencing, but rather the regions where different diseases have been
<table><thead><tr><th>CHARACTERISTICS</th><th>CLASSICAL FMF</th><th>PAAD</th><th>PAAND</th><th>PAANI</th><th>PAAHE</th></tr></thead><tbody><tr><td>Number of reported patients</td><td>> 100.000</td><td>47</td><td>19</td><td>3</td><td>3</td></tr><tr><td>Exon</td><td>10</td><td>8-5-3</td><td>2</td><td>9</td><td>2</td></tr><tr><td>Transmission</td><td>Recessive</td><td>Dominant</td><td>Dominant</td><td>Dominant</td><td>Recessive</td></tr><tr><td>World repartition</td><td>Mediterranean</td><td>Worldwide</td><td>China</td><td>Pakistan</td><td></td></tr></tbody></table><table><thead><tr><th colspan="6">MAIN CLINICAL MANIFESTATIONS</th></tr></thead><tbody><tr><td>Fever</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Chest pain</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Abdominal pain</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Arthralgia/ myalgia</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Others</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Pseudo-erysipela</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Kidney inflammatory AA amyloidosis</td><td>✓</td><td>✓</td><td>✓</td><td></td><td></td></tr><tr><td>Somatic variants</td><td>✓</td><td></td><td></td><td></td><td></td></tr><tr><td>TREATMENT</td><td>Colchicine +/- IL-1 inhibitors</td><td>Colchicine +/- IL-1 inhibitors</td><td>Colchicine +/- TNF or IL-1 inhibitors</td><td>Colchicine</td><td>?</td></tr></tbody></table>

**FIGURE 2.** Main characteristics and differences of pyrinopathies. In Main Clinical Manifestations, color gradients indicate more frequent manifestations (≥50% of patients) for darker colors. *Gray* indicates absence of this manifestation in the disease under consideration. *PAAD*, Pyrin-associated autoinflammatory disease; *PAAHe*, pyrin-associated autoinflammatory disease with hypereosinophilia; *PAAND*, pyrin-associated autoinflammatory disease with neutrophilic dermatosis; *PAANI*, pyrin-associated autoinflammatory disease with neuroinflammation.

genetically diagnosed to facilitate further diagnosis and treatment (known as the regional founding effect).

**Dominant PAAD phenotype associated with M694del exon 10 variant**

In 2017, Rowczenio et al³² conducted a sequencing analysis of exons 1, 2, 3, 5, 8, 9, and 10 of *MEFV* in 3,500 patients referred for suspected FMF to the National Amyloidosis Centre in

England. An M694del variant was identified in 21 patients, all of whom exhibited a phenotype suggestive of FMF. Most patients (90%) experienced febrile abdominal pain, whereas 40% reported chest pain. Two patients exhibited arthralgia that was compatible with FMF, although the specific joints involved were not specified. Two other patients experienced attacks of pseudo-erysipela. Median duration of febrile attacks was 2.5 days (range, 1-6 days; median frequency of 1 attack/mo). Atypical features
<figure><img src="image_4.png" /><figcaption>**FIGURE 3.** Geographic origins of published patients with pyrinopathies (excluding familial Mediterranean fever). *PAAD*, Pyrin-associated autoinflammatory disease; *PAAHe*, pyrin-associated autoinflammatory disease with hypereosinophilia; *PAAND*, pyrin-associated auto-inflammatory disease with neutrophilic dermatosis; *PAANI*, pyrin-associated autoinflammatory disease with neuroinflammation</figcaption></figure>

included late onset, median age of 18 years (range, 6-48 years), and autosomal dominant inheritance. The onset of attacks could be precipitated by menstruation, copious meals, or stress. During inflammatory episodes, C-reactive protein (CRP) was consistently elevated. Three patients exhibited nephrotic syndrome resulting from inflammatory AA amyloidosis, which led to the diagnosis of FMF. All patients demonstrated a favorable response to colchicine, with effective symptom control after the commencement of treatment and negative inflammatory markers even during the inter-critical phase.

## Dominant PAAD phenotypes associated with variants outside exon 10

**Associated with exon 3 variant P373L.** In 2019, Rowczenio et al³³ reported the case of a British man with the diagnosis of systemic juvenile idiopathic arthritis at age 7. Retrospectively, he recalled episodes of fever with severe abdominal and chest pain, small joint arthritis, erythematous rash, and night sweats since early childhood. At age 23, he developed proteinuric renal disease with biopsy-proven AA amyloidosis and required hemodialysis for 4 years before receiving a cadaveric renal transplant at age 32. He had started receiving low-dose colchicine (0.5 mg/d) for presumed post-transplant gout, which improved the symptoms significantly, and he continued the treatment. The transplant function remained stable without proteinuria. Nine years after transplant, he sought a specialist opinion about amyloidosis owing to media interest in novel amyloid treatments. The CRP and serum amyloid A

protein levels were generally normalized, except when he briefly ran out of colchicine, causing them to spike.

Nearly 20 years after the patient's diagnosis, his sister presented at age 47 with nephrotic syndrome. Given the family history, amyloidosis was suspected, confirmed by a 123¹-labeled serum amyloid P component scan showing amyloid in the spleen and kidneys. She reported recurrent severe abdominal and chest pain, swelling of large joints, and red eyes, but denied fevers or night sweats. The baseline CRP and serum amyloid A protein were elevated but normalized with colchicine prophylaxis (1.5 mg/d).

The family history included their father, who died at age 52 of complications after a cadaveric renal transplant and post-humously received the diagnosis of extensive AA amyloidosis, and their mother, who had recurrent abdominal pain and arthritis and died of cancer. Two cousins and three of their children also presented with recurrent abdominal and chest pain from childhood.

Next-generation sequencing analysis of an AIDs genes panel revealed the variant P373L in exon 3 of *MEFV* in the index patient and his sister. No other pathogenic variants were identified. Sanger sequencing confirmed that this variant segregates in the family with a dominant inheritance pattern.

All symptomatic individuals treated with colchicine (1-2 mg/d) experienced complete resolution of inflammatory symptoms.

**Associated with exon 5 variant H478Y.** In 2004, Aldea et al³⁴ described a nonconsanguineous Spanish family in which five patients over three generations presented with an
autoinflammatory phenotype meeting the classification criteria for FMF of Tel HaShomer.³⁵ These patients exhibited a severe autoinflammatory syndrome that was refractory to colchicine treatment. In some cases, the syndrome was complicated by AA amyloidosis with renal involvement. A genetic analysis revealed the presence of a heterozygous H478Y variant in *MEFV*, which segregated exclusively within the affected individuals.

The febrile attacks commenced during childhood and persisted for 3 to 6 days, with an incidence of four to eight episodes per year. Additionally, 80% of patients presented with episodes of arthritis and pseudo-erysipelas as well as abdominal and chest pain, and a history of white laparotomy was documented in this subset of female patients. Migratory inflammatory arthralgia, predominantly affecting the hands and feet, may persist for 3 to 25 days after the cessation of the attack, which is atypical for FMF. The attacks were frequently precipitated by stress, cold, or fatigue, and CRP was consistently elevated during the inflammatory episodes. Two patients developed inflammatory AA amyloidosis, with diagnoses occurring at ages 50 and 48 years, respectively.

All patients were administered colchicine at the maximum tolerated dose, 1 to 2.5 mg/d. This proved ineffective in 80% of patients, with one patient exhibiting partial efficacy. These patients were effectively treated with intravenous infliximab at the initial dose of 5 mg/kg every 2 weeks, then progressively spaced out to a dose every 8 weeks in addition to colchicine treatment.

**Associated with T577x exon 8 variants.** In 2014, Stoffels et al³⁶ identified four pathogenic variants at position T577 of *MEFV* in four distinct families, all of whom presented with a severe autoinflammatory syndrome with autosomal dominant transmission. These cases resembled FMF, but with certain peculiarities.

The initial family (T577N) was nonconsanguineous and hailed from the United Kingdom. The initial patient exhibited symptoms at age of 6, including recurrent episodes of arthritis, pleurisy, peritonitis, and a skin rash. A number of family members exhibited comparable symptoms, and whole-exome sequencing of two symptomatic individuals revealed the T577N variant in exon 8 of *MEFV*. The authors conducted functional studies on peripheral blood mononuclear cells from these patients and observed elevated expression of IL-1β mRNA, which was normalized by colchicine.

The second family (T577S) was of Turkish origin and exhibited a phenotype reminiscent of FMF, with autosomal dominant inheritance and a favorable response to colchicine.

The third family (T577S) resided in the Netherlands but were of French origin and exhibited a T577S variant and the FMF-related T267I variant in exon 2, which has been classified as probably pathogenic based on a recessive inheritance pattern. No details were provided concerning the symptomatology observed.

The fourth and final family (T577A) also resided in the Netherlands and exhibited a severe autoinflammatory phenotype with autosomal dominant inheritance. The index patient, aged 2 years 2 months, presented with recurrent episodes of fever, cutaneous rash, arthritis, conjunctivitis, lymphadenopathy, hepatosplenomegaly, and profound anemia. After 1 month of treatment with anakinra, abnormalities had normalized. The patient's brother and mother exhibited comparable symptoms, albeit less severe in the latter, and were also well controlled by anakinra.

Subsequently, several authors have reported families with an autoinflammatory syndrome with PAAD type presentation associated with the T577N variant.

Nakaseko et al³⁷ reported the T577N variant in a Japanese family with similar symptoms and autosomal dominant transmission in 2019. The father developed proteinuria at age 18, which progressed to chronic renal failure and the need for dialysis at age 51. He declined to undergo further investigations to confirm the probable diagnosis of inflammatory AA amyloidosis.

Subsequently, in 2019, Endo et al³⁸ reported a Japanese family with similar symptoms and autosomal dominant inheritance in seven individuals. The patients had a history of rheumatoid purpura and aseptic osteomyelitis.

In 2020, Elhani et al³⁹ reported two new cases in a family of Caucasian origin with PAAD-like symptoms and good sensitivity to colchicine.

## Dominant PAAND phenotype associated with exon 2 variants S242 and E244

In 2016, Masters et al⁴⁰ described a novel autoinflammatory syndrome with autosomal dominant inheritance in 12 members of a Belgian family. This syndrome, designated PAAND, is characterized by recurrent febrile episodes commencing in childhood and persisting for several weeks. These episodes are accompanied by arthralgias, myalgias/myositis, and severe neutrophilic dermatosis. Dermatologic manifestations include severe acne, aseptic abscesses, pyoderma gangrenosum, and small-vessel neutrophilic vasculitis.

Exome analysis of several trios from the princeps family revealed a heterozygous S242R variant in exon 2 of *MEFV*. This variant impedes the appropriate constitutive phosphorylation of pyrin in position S242, which is essential for its interaction with inhibiting chaperon protein 14-3-3, facilitating pyrin activation and therefore IL-1β maturation. After searching relevant databases, the authors subsequently identified three additional families (from France, Lebanon, and England) presenting with a similar clinical picture and carrying the same variant. The only treatment data available pertain to the English patient, who, despite the failure of corticosteroid therapy and methotrexate, responded well to anakinra (100 mg daily), resulting in clinical remission and the normalization of inflammatory parameters.

In 2017, Moghaddas et al⁴¹ presented a comparable case study involving a Spanish patient with a novel E244K variant in exon 2, which also affected pyrin phosphorylation. The administration of anakinra (100 mg daily) proved to be an ineffective treatment for this patient, who exhibited a favorable response to anti-TNF-α (adalimumab). Gargallo et al⁴² additionally described the efficacy of anti-TNF-α in a Spanish patient who received infliximab 5 mg/kg for 10 years, with secondary loss of efficacy despite the absence of anti-drug antibodies. A trial of anakinra (100 mg daily) proved ineffective. However, good disease control was regained with adalimumab (40 mg/wk). In 2024, Bueno-Molina et al⁴³ reported the case of another Spanish patient with the E244K variant in exon 2. At age 20, the patient had inflammatory and scarring nodulocystic acne. By age 30, he developed multiple pyoderma gangrenosum on the lower limbs, polyarthralgia, and recurrent low-grade fevers lasting around 10 days. Treatment with the anti-TNF-α drug infliximab (5 mg/kg every 6 weeks) initially improved pain and suppuration. However, 2 months after the induction phase, he experienced a loss of therapeutic response owing to inadequate therapeutic blood
levels with no detectable anti-drug antibodies, which led to the discontinuation of infliximab. Anakinra (100 mg/d) and prednisone (0.5 mg/kg per day) were then initiated, resulting in a favorable and sustained clinical response.

In 2020, Kiyota et al⁴⁴ described the first Japanese case of PAAND complicated by inflammatory AA amyloidosis, with digestive and cardiac involvement and no impairment of renal function. The administration of tocilizumab via intravenous route at a dosage of 8 mg/kg, with subsequent doses at 4-week intervals and then at 2-week intervals, resulted in the normalization of inflammatory markers in the patient.

In 2021, Vahidnezhad et al⁴⁵ presented two cases of PAAND in a consanguineous Iranian family, characterized by a homozygous S242G variant. Both children exhibited a favorable response to treatment with colchicine 1 mg/d and prednisolone 2.5 mg/every other day.

In 2021, Van Nieuwenhove et al⁴⁶ initiated an open-label therapeutic trial with three patients with S242R PAAND to assess the efficacy and safety of anakinra 100 mg daily. However, the results were disappointing, with only one complete and two partial efficacies observed. The dermatologic manifestations of the disease do not appear to respond adequately to inhibition of the IL-1 pathway. When biological treatment is required, targeting the TNF-α pathway seems to be a more effective approach. Lenalidomide may also be a potential treatment option for cases of difficult-to-treat mucocutaneous manifestations.⁴⁷

## Dominant pyrin-associated AIDs with neuroinflammation phenotype associated with exon 9 variant E583A

In 2023, Wang et al¹⁰ presented a case of three Chinese monozygotic triplets, aged 5 to 6 years, who had auto-inflammatory symptoms characterized by recurrent abdominal and chest pain. These flares were associated with a biological inflammatory syndrome but did not present with fever. Neuro-inflammation was observed on several occasions, manifesting as seizures or recurrent aseptic meningitis. The patients exhibited elevated levels of IL-1β and IL-18. They responded favorably to treatment with colchicine alone.

## Whole-exome sequencing revealed a de novo E583A variant in exon 9 of the MEFV gene.

Truncation experiments suggested that the E583A variant could lead to instability in binding of the B30.2 domain to the coiled coil, causing a conformational change in pyrin. As a result, it prevents pyrin from self-inhibiting by folding back on itself and keeps it in an unfolded state that favors its activation. As stated by the authors, additional experiments are needed to confirm this hypothesis.

## Recessive pyrin-associated autoinflammation with hypereosinophilia phenotype associated with exon 2 variant S208.

In 2019, Hong et al⁴⁸ presented the case of two Pakistani children from a consanguineous union who exhibited a severe autoinflammatory presentation with onset in the neonatal period. This was accompanied by episodes of recurrent fever, oral aphthosis, arthralgias, digestive inflammation, leukocytoclastic vasculitis, hepatosplenomegaly, polyadenopathies, and staturoponderal growth retardation. Both patients exhibited a pronounced biological inflammatory syndrome accompanied by a notable eosinophil count (82 g/L).

Bone marrow examination revealed significant eosinophilic infiltration comprising 81% of the bone marrow, with no evidence of neoplasia or abnormalities in other cell lineages. Administration of cyclophosphamide, mycophenolate mofetil, methotrexate, azathioprine, and anti-TNF-α was unsuccessful in achieving the desired outcome.

A whole-exome sequencing analysis identified a homozygous S208T variant of MEFV exon 2 inherited from asymptomatic parents. The S208 site corresponds to the second serine required for pyrin phosphorylation, which enables its interaction with the 14-3-3 protein.

Furthermore, the authors identified a third Pakistani child from a consanguineous union with similar symptoms, including hypereosinophilia and aseptic osteitis. This child carried a homozygous S208C variant of the same gene. The mechanism of the hypereosinophilia remains unclear. Table I lists the main findings of the described pyrinopathies.

## Variants reported as pathogenic but currently considered probably benign in the absence of proven pathogenicity: the example of exon 2 variants R202Q and G304R

A number of variants have been documented in the scientific literature as being associated with a range of autoinflammatory presentations. These have been characterized as novel variants responsible for FMF with atypical manifestations. Most of these variants are known and have been classified as benign or probably benign on Infevers.³⁰ Consequently, the autoinflammatory pictures described are more likely to correspond to undifferentiated AIDs⁷ (syndrome of undifferentiated recurrent fever and undifferentiated systemic AID). These pictures correspond to probable monogenic AIDs whose genetic substrate is not yet known. However, they are neither FMF nor atypical FMF.

For example, the article by Han,⁴⁹ published in 2015 in the *New England Journal of Medicine*, reports on two 63-year-old Japanese patients with myelodysplastic syndrome (MDS) associated with inflammatory symptoms marked by fever flares, neutrophilic dermatosis, inflammatory arthralgias, pericarditis, colitis, and neutrophilia. The first patient presented with refractory anemia-type MDS with excess blasts, whereas the second had refractory cytopenic-type MDS with multiple-lineage dysplasia. Both patients exhibited International Prognostic Scoring System scores that indicated a high risk.

MEFV analysis revealed the presence of a heterozygous G304R variant (exon 2) in the first patient and a heterozygous R202Q variant (exon 2) in the second. The authors posit that these variants are insufficient to explain the inflammatory manifestations and hypothesize that MDS acts as a second hit, enabling facilitated activation of the pyrin inflammasome. The administration of colchicine was attempted in the initial patient, but it proved ineffective.

These variants are classified as probably benign and benign, respectively, on Infevers.³⁰ Consequently, they cannot be responsible for the autoinflammatory picture presented by the patients. In retrospect, the most probable hypothesis is that of a potential VEXAS syndrome, which was not known at the time.

This emphasizes the importance of collaborating with reference centers on AIDs, whose expertise in interpreting genetic data is crucial to prevent misdiagnosis. This can have significant implications for prognostic, treatment, and genetic counseling.
<table><caption>TABLE I. Main characteristics of diseases associated with pathogenic *MEFV* mutations (pyrinopathies)</caption><thead><tr><th>Phenotype</th><th>Classic familial Mediterranean fever</th><th>Dominant pyrin-associated autoinflammatory disease</th><th>Pyrin-associated autoinflammatory disease with neuroinflammation</th><th>Dominant pyrin-associated autoinflammatory disease</th><th>5</th><th>3</th><th>2</th><th>Pyrin-associated autoinflammatory disease with neutrophilic dermatosis</th><th>Pyrin-associated autoinflammatory disease with hypereosinophilia</th></tr></thead><tbody><tr><td>Exon MEFV</td><td>10</td><td>10</td><td>9</td><td>8</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Associated variant</td><td></td><td>M694del</td><td>E583A</td><td>T577N</td><td>T577S</td><td>T577A</td><td>H478Y</td><td>S242R<br>E244K</td><td>S208T<br>S208C</td></tr><tr><td>Transmission mode</td><td>Autosomal recessive</td><td>Autosomal dominant</td><td>Autosomal dominant</td><td>Autosomal dominant</td><td>Autosomal dominant?</td><td>Autosomal dominant (can be somatic)</td><td>Autosomal dominant</td><td>Autosomal dominant or recessive</td><td>Autosomal recessive</td></tr><tr><td>Geographic distribution</td><td>Mediterranean region</td><td>England<sup>29</sup></td><td>China<sup>8</sup></td><td>England<sup>35</sup><br>Japan<sup>16,37</sup><br>France<sup>38</sup></td><td>Turkey<sup>35</sup><br>Netherlands<sup>35</sup></td><td>Netherlands<sup>35</sup></td><td>Spain<sup>33</sup></td><td>Belgium<sup>39</sup><br>France<sup>46</sup><br>England<sup>39</sup><br>Lebanon<sup>39</sup><br>Iran<sup>44</sup><br>Spain<sup>40-42</sup><br>Japan<sup>43</sup></td><td>Pakistan<sup>47</sup></td></tr><tr><td>Age at onset of symptoms</td><td>4 y (&lt;20 y in 80% of cases)</td><td>6-48 y</td><td>5-6 y</td><td>3-28 y</td><td>?</td><td>2 y</td><td>9-13 y</td><td>7-?</td><td>Neonatal to 43 y</td><td>9-12 y</td></tr><tr><td>Clinical atypia</td><td>—</td><td>Late age at onset (median, 18 y)</td><td>Neuroinflammation (seizures, aseptic meningitis)</td><td>Longer febrile attacks (from a few days to several weeks)<br>Evanescent cutaneous rash contemporary with febrile episodes</td><td>Longer febrile attacks (at least 1 wk)</td><td>Urticaria<br>Conjunctivitis<br>Polyadenopathy and massive<br>hepatosplenomegaly<br>Profound anemia of undetermined etiology<br>Developmental and<br>psychomotor delay<br>Bipolar aphthosis in mother's childhood<br>Colitis with granulomatous inflammation</td><td>Longer febrile attacks (3-6 d)<br>Topography of joint involvement (hands and feet)<br>Inflammatory arthralgias persist between febrile attacks</td><td>—</td><td>Longer febrile attacks<br>Neutrophilic dermatosis in foreground<br>No serositis<br>Probable inflammatory bowel disease-like digestive damage</td><td>Longer febrile attacks<br>Neutrophilic dermatosis<br>No serositis<br>Probable MICI-like digestive damage<br>Major eosinophilia<br>Aseptic osteitis</td></tr><tr><td>Colchicine sensitivity</td><td>Colchicine resistance in 5% of cases</td><td>Good sensitivity to colchicine</td><td>Good sensitivity to colchicine</td><td>Good sensitivity to colchicine</td><td>Good sensitivity to colchicine</td><td>Colchicine resistance<br>Good sensitivity to anakinra</td><td>Colchicine resistance in four of five patients</td><td>Good sensitivity to colchicine</td><td>Efficacy of colchicine in two homozygous children<sup>44</sup><br>Partial anakinra sensitivity<br>Anti-TNF-α seems to be more interesting<br>Lenalidomide may be effective in resistant dermatologic manifestations</td><td>?</td></tr><tr><td>Risk of amyloidosis</td><td>Yes</td><td>Yes</td><td>?</td><td>Probable (nephrotic syndrome, chronic renal failure on dialysis in one patient but refusal of renal biopsy)</td><td>?</td><td>?</td><td>Yes</td><td>Yes</td><td>Yes</td><td>?</td></tr></tbody></table>

MEFV, Mediterranean Fever gene.
<table><caption>TABLE II. Ongoing challenges and future needs in field of diseases associated with MEFV pathogenic mutations pyrinopathies</caption><thead><tr><th></th><th></th></tr></thead><tbody><tr><td>Diagnostic complexity</td><td>Lack of standardized diagnostic criteria for nonclassical pyrinopathies<br>Difficulty in distinguishing pyrinopathies from other autoinflammatory diseases in absence of genetic sequencing owing to overlapping clinical features<br>Limited availability of Sanger or more advanced genetic testing in some areas<br>Unclear genotype-phenotype correlations, making prognosis and disease classification difficult<br>Occasional late-onset or atypical symptoms that delay diagnosis<br>Non-Mediterranean origin of patients, delaying diagnosis</td></tr><tr><td>Treatment challenges and prognostic uncertainties</td><td>Poor understanding of long-term outcomes and complications, including risks of AA amyloidosis or organ damage<br>Variable response to colchicine in several nonclassical pyrinopathies<br>Limited data on efficacy of biologics (eg, IL-1 or IL-6 inhibitors) in management of pyrinopathies<br>Need for development of collaborative research networks to address research gaps<br>Develop of international networks and consensus guidelines to define classical familial Mediterranean fever without genetic testing of exon 10<br>Mediterranean Fever gene mutations to advance research and harmonize care protocols<br>Encouraging collaboration among clinicians, geneticists, and researchers to accelerate discoveries and improve outcomes</td></tr></tbody></table>

## Somatic variants

**Somatic variant T577A.** In 2024, Terré et al⁵⁰ presented the case study of a 28-year-old Caucasian patient who had experienced recurrent episodes of fever accompanied by abdominal pain, pseudo-erysipelas, and arthromyalgia since age 2 years. The febrile episodes, which lasted 2 to 3 days, were accompanied by elevated inflammatory markers. The patient initially received the diagnosis of spondylarthritis and Crohn's-like disease owing to inflammatory pancolitis observed during digestive endoscopies. However, despite the administration of several treatments, the patient exhibited resistance to these interventions. Subsequently, the patient was referred to a specialist consultation for suspected AID. Genetic testing using high-throughput sequencing revealed a T577A somatic variant with an allelic frequency of 16%. The patient exhibited a favorable response to treatment with colchicine and anakinra 100 mg daily, with effective control of symptoms. The cessation of anakinra and the continuation of colchicine alone proved sufficient to maintain this control once symptoms had abated and inflammatory markers had normalized. Functional tests on the patient's monocytes corroborated the pathogenicity of the variant, demonstrating augmented IL-1β secretion after stimulation with UCN-01, a selective phosphokinase 1/2 inhibitor that activates the pyrin inflammasome.

**Somatic variant R652H.** In 2015, Shinar et al⁵¹ reported the case of a 59-year-old patient of Ashkenazi Jewish origin who received a diagnosis of essential JAK2-associated polycythemia at age 52. Four years after the diagnosis of essential polycythemia, the patient developed secondary myelofibrosis and recurrent febrile episodes lasting 48 hours, accompanied by myalgia and abdominal discomfort. The patient's CRP levels were elevated during the febrile episodes.

After eliminating other potential causes of fever and considering the clinical presentation, the authors conducted Sanger sequencing of MEFV. An R652H variant of undetermined significance was identified in cells carrying the JAK2 variant, which was absent from the patient's other hematopoietic cells. The analysis of old samples revealed the presence of this somatic variant, which was initially undetectable and was restricted to JAK2 variant-carrying cells at the time of polycythemia diagnosis.

Over time, there was a progressive increase in the number of variant-carrying cells, reaching 46% of alleles at the time of somatic FMF diagnosis.

## Administration of colchicine resulted in alleviation of inflammatory episodes

Although the diagnosis of pyrinopathy is not confirmed to our knowledge, this is the first case of acquired MEFV variant restricted to cells carrying a variant responsible for essential myelofibrosis. The MEFV variant may therefore be regarded as a passenger variant in a myeloproliferative syndrome in which JAK2 was the driver variant. Other cases of somatic auto-inflammatory disease linked to transient variants have been documented, notably with NLRC4 and TET2.⁵²

## ONGOING CHALLENGES AND FUTURE NEEDS IN DIAGNOSING AND MANAGING PYRINOPATHIES

Table II lists ongoing challenges and future needs in the field of pyrinopathies. Key diagnostic challenges include the lack of standardized criteria, difficulties in distinguishing pyrinopathies from other AIDs without genetic testing, unclear genotype-phenotype correlations, and delayed diagnosis owing to atypical presentations or non-Mediterranean origin. Treatment challenges include a limited understanding of long-term outcomes, variable response to colchicine, and scarce data on the efficacy of biologics. The table highlights the need for international collaborative research, consensus guidelines, and better integration of clinicians, geneticists, and researchers to advance diagnosis, treatment, and care protocols.

## IN PRACTICE: WHAT GENETIC ANALYSIS SHOULD BE REQUESTED IF PYRINOPATHY IS SUSPECTED?

Given the high prevalence of classical recessive FMF in Mediterranean populations, Sanger sequencing of MEFV exon 10 is often sufficient for diagnosis in typical cases. In familial cases, sequencing of the entire MEFV exon 10 in all symptomatic relatives is recommended, ideally using trio whole-exome sequencing and, if negative, trio whole-genome sequencing. This approach is critical because more than two pathogenic alleles can sometimes mimic pseudodominant inheritance. In typical clinical cases with negative Sanger
sequencing, NGS should be performed to ensure sufficient depth to detect somatic mutations. Although FMF is most common in individuals of Eastern Mediterranean descent, it occurs with lower prevalence in all ethnic groups. In cases of clinical atypia or negative Sanger results, NGS of the entire *MEFV* gene can identify pathogenic variants outside exon 10. Adequate coverage depth is essential for the detection of somatic variants, because Sanger sequencing cannot reliably identify low-level mosaicism.<sup>53,54</sup>

## CONCLUSIONS

Recent studies demonstrate that a variety of clinical presentations are associated with different pathogenic variants of *MEFV*, with a worldwide distribution. The identification of these novel diseases, designated pyrinopathies, and encompassing diverse variants enhances our comprehension of the regulatory processes of pyrin, which is a pivotal component of the innate immune system. It is probable that the spectrum of pyrinopathies, AID associated with pathogenic *MEFV* mutations, will continue to diversify in forthcoming years.

## Acknowledgments

Illustrations were created from www.BioRender.com. The worldwide distribution of pyrinopathies used the www.sciencespo.fr/cartographie/khartis/app/project/new/step1 mapping tool.

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