Alternative titles; symbols
SNOMEDCT: 84625002; ICD10CM: L98.2; ORPHA: 3243;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p13.3 | Neutrophilic dermatosis, acute febrile | 608068 | Autosomal dominant | 3 | MEFV | 608107 |
A number sign (#) is used with this entry because of evidence that acute febrile neutrophilic dermatosis (AFND), also referred to as pyrin-associated autoinflammatory disease (PAAND), is caused by heterozygous mutation in the MEFV gene (608107) on chromosome 16p13.
Heterozygous mutation in the MEFV gene can also cause autosomal dominant familial Mediterranean fever (FMF; 134610), which shows some overlapping features.
Acute febrile neutrophilic dermatosis (AFND) is an autosomal dominant autoinflammatory disorder characterized by onset of recurrent fever and dermatologic abnormalities in childhood. Laboratory studies show elevated acute-phase reactants and activation of the inflammatory response, particularly IL1B (147720). Additional more variable features may include myalgia and arthralgia (summary by Masters et al., 2016).
Masters et al. (2016) reported a 3-generation Belgian family in which 12 individuals had a childhood-onset autoinflammatory disease. The patients had neutrophilic dermatosis, recurrent episodes of fever lasting weeks, arthralgias, and myalgias. The neutrophilic dermatosis comprised a spectrum of clinical manifestations, including severe acne, sterile skin abscesses, pyoderma gangrenosum, and neutrophilic small-vessel vasculitis. Pathologic examination of affected skin showed a dense, predominantly neutrophilic, vascular, perivascular, and interstitial infiltrate. Serum cytokine analysis revealed elevated inflammatory mediators and acute-phase reactants, such as IL1B, IL6 (147620), and TNFA (191160), as well as cytokines induced by inflammation, such as IL1RA (147810). One patient presented with dilated cardiomyopathy at 13 years of age, which evolved into chronic cardiac decompensation necessitating cardiac transplantation at age 20. Skeletal muscle biopsy from this patient showed inflammatory infiltrates, mainly macrophages.
Masters et al. (2016) also reported a French woman and a British man with AFND. They had neutrophilic dermatosis, recurrent fever, arthralgia, myalgia, and elevated acute-phase reactants. The mother of the British man was also affected, but she did not manifest neutrophilic dermatosis: she had only recurrent fevers, arthralgia, myalgia, and acute-phase reactants. This suggested either clinical variability or incomplete penetrance of some features.
Moghaddas et al. (2017) reported 3 members of a Spanish family with neutrophilic dermatosis. The proband had onset of recurrent fevers, severe pustular acne, hidradenitis suppurativa, pyoderma gangrenosum, and arthralgia in the first decade of life. Laboratory studies showed increased C-reactive protein, increased erythrocyte sedimentation rate, and increased neutrophil count. Treatment with corticosteroids and adalimumab and infliximab (TNFA antagonists) was not completely effective. The proband's mother and brother were similarly affected, with variable expressivity.
Sweet Syndrome
Sweet (1964) described 8 patients, all women, with an acute dermatosis characterized by fever, neutrophilia, painful erythematous plaques, a dense dermal infiltrate of mature neutrophils, and rapid response to corticosteroids. In 7 of the patients the condition was preceded by an illness, usually infective. Large, tender, raised dark red plaques occurred most commonly on the face, neck, arms, and legs. Pustules, when present, were sterile. No evidence of infection was found.
Uncommon systemic manifestations of Sweet syndrome involve sterile neutrophilic infiltration in organs other than skin, such as lungs, bones, joints, central nervous system, liver, gastrointestinal tract, lymph nodes, spleen, cardiovascular system, and eyes (von den Driesch, 1994; Vignon-Pennamen and Wallach, 1995).
Von den Driesch (1994) stated that Sweet syndrome can be subdivided into 4 broad groups: classic/idiopathic, parainflammatory, paraneoplastic, and pregnancy-associated. Parsapour et al. (2003) delineated 2 forms of Sweet syndrome, idiopathic and associated with malignancy. The malignancy-associated form is less common, accounting for 20% of cases, and gender-independent. Malignancies associated with Sweet syndrome are usually hemoproliferative disorders or solid tumors. They stated that although Sweet syndrome is seen most commonly in the middle-aged female population, pediatric cases account for about 8% of reported cases and are generally gender-nonspecific.
Su and Liu (1986) proposed 2 major and 4 minor criteria for diagnosis of Sweet syndrome. They suggested fulfillment of both of the major criteria (abrupt onset of tender or painful erythematous or violaceous plaques or nodules; predominantly neutrophilic infiltration in the dermis without leukocytoclastic vasculitis) and 2 of the minor criteria (onset preceded by fever or infections; condition accompanied by fever, arthralgia, conjunctivitis, or underlying malignancy; leukocytosis; good response to systemic steroids but not to antibiotics) as indicative of a definite diagnosis. Von den Driesch (1994) presented a revised version of the minor criteria to include onset preceded by vaccination or associated with inflammatory diseases such as chronic autoimmune disorders, or associated with hemoproliferative disorders, solid malignant tumors, or pregnancy; they also suggested laboratory values during onset.
Differential Diagnosis
Behcet disease (109650) and Sweet syndrome have overlapping symptoms, including eye lesions, oral aphthae, genital ulcers, and skin lesions (Mizoguchi et al., 1987). The incidence of Behcet disease is very high in Japan (1 per 15,000 people); although no cases of Sweet syndrome with Behcet syndrome had been reported outside Japan, several Japanese patients with Behcet disease also had features of Sweet syndrome. Mizoguchi et al. (1987) reported a case of Sweet syndrome associated with Behcet disease and discussed the relationship between the 2 disorders. They came to the conclusion that Sweet syndrome may be associated with several underlying disorders, of which Behcet disease is one.
Von den Driesch (1994) stated that oral administration of corticosteroids represents the standard treatment for Sweet syndrome; potassium iodide is as effective, but may cause severe vasculitis. Because recurrence is common, the long-term use and subsequent effects of corticosteroid therapy become major obstacles in the pediatric population (Parsapour et al., 2003).
Masters et al. (2016) reported successful treatment of 1 AFND patient with anakinra, which blocks IL1RA.
The transmission pattern of AFND in the families reported by Masters et al. (2016) was consistent with autosomal dominant inheritance. There was evidence of incomplete penetrance and variable expressivity.
Parsapour et al. (2003) performed a comprehensive review of the literature on pediatric Sweet syndrome and reported 2 Caucasian male sibs with idiopathic neonatal Sweet syndrome, providing further evidence for a genetic component.
In 12 affected members of a large 3-generation Belgian family with AFND, Masters et al. (2016) identified a heterozygous missense mutation in exon 2 of the MEFV gene (S242R; 608107.0021). The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The same heterozygous S242R mutation was subsequently identified in 2 additional pedigrees with an overlapping phenotype. In vitro functional expression studies in HEK293 cells showed that the mutation enhanced the formation of ASC (PYCARD; 606838) specks compared to controls. Downstream of ASC, the S242R mutation resulted in activation of CASP1 (147678), as well as increased secretion of IL1B compared to wildtype. Further studies showed that the mutation impaired phosphorylation of residue S242, which resulted in removal of inhibitory 14-3-3 proteins (see, e.g., 609009 and 605066) and constitutive activation of pyrin. Masters et al. (2016) noted that the molecular mechanism resulting from the S242R mutation differed from that of FMF-associated mutations M694V, M680I, and V726A, which had no appreciable effect on 14-3-3 binding.
In 3 affected members of a Spanish family with AFND, Moghaddas et al. (2017) identified a heterozygous missense mutation in exon 2 of the MEFV gene (E244K; 608107.0022). The mutation, which was found by direct sequencing of the MEFV gene, was not found in the 1000 Genomes Project, ExAC, or Exome Variant Server databases, or in 250 healthy Spanish controls. Patient-derived monocytes and transfected with the mutation showed augmented ASC speck formation both at baseline and upon LPS exposure, increased CASP1 activity, increased IL1B and IL18, and increased inflammatory cell death compared to controls, consistent with activation of the inflammasome. These findings were associated with reduced phosphorylation of the MEFV 14-3-3 binding motif and reduced 14-3-3 binding compared to controls, ultimately resulting in inappropriate activation of MEFV.
Kiyota et al. (2020) reported a 45-year-old Japanese man with a systemic autoinflammatory disorder with intermittent fever and amyloidosis (FMF; 249100) who also had pustular dermatosis with neutrophilic aggregates since childhood. The authors noted that he had abdominal symptoms, rather than classic serositis, and that the skin problems had been the main symptom since childhood, suggesting a phenotype that overlapped with AFND. Genetic analysis identified compound heterozygous missense variants in the MEFV gene (S242R, 608107.0021 and E148Q, 608107.0005). His unaffected mother was heterozygous for the S242R mutation, indicating incomplete penetrance of AFND. Functional studies of the variants were not performed, but the authors suggested that the E148Q polymorphism may act as a disease modifier. Treatment with corticosteroids and colchicine were ineffective, but his abdominal symptoms responded well to the IL6R (147880) antibody tocilizumab; the skin rash did not change with treatment.
Mizoguchi et al. (1988) reported a Japanese patient with Sweet syndrome with symptoms similar to those of Behcet disease and performed HLA typing on 28 patients with Sweet syndrome and 49 patients with Behcet disease. They found that the frequency of HLA-Bw54 was significantly higher in patients with Sweet syndrome than in controls, while there was no significant difference in the incidence of HLA-Bw54 between patients with Behcet disease and controls. No differences in HLA antigen frequencies were seen in patients with Sweet syndrome without Behcet disease symptoms and controls. The frequency of HLA-Bw54 is higher in Japanese (17.9%) compared with white (0.6%) or black (0%) populations and suggests a genetic predisposition among Japanese for Sweet syndrome.
Sweet (1964) referred to the disorder as acute febrile neutrophilic dermatosis and noted that it had in his department been referred to as Gomm-Button disease, in eponymous honor of the first 2 patients. Whittle et al. (1968) and Crow et al. (1969) were the first to use the designation 'Sweet syndrome' in their case descriptions.
Crow, K. D., Kerdel-Vegas, F., Rook, A. Acute febrile neutrophilic dermatosis: Sweet's syndrome. Dermatologica 139: 123-134, 1969. [PubMed: 5810898] [Full Text: https://doi.org/10.1159/000253902]
Kiyota, M., Oya, M., Ayano, M., Niiro, H., Iwasaki, T., Fujiwara, M., Oda, Y., Fujimoto, K., Ida, H. First case of pyrin-associated autoinflammation with neutrophilic dermatosis complicated by amyloidosis. (Letter) Rheumatology (Oxford) 59: e41-e43, 2020. [PubMed: 31998953] [Full Text: https://doi.org/10.1093/rheumatology/keaa005]
Masters, S. L., Lagou, V., Jeru, I., Baker, P. J., Van Eyck, L., Parry D A., Lawless, D., De Nardo, D., Grcia-Perez, J. E., Dagley L. F., Holley, C. L., Dooley, J., and 20 others. Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation. Sci. Transl. Med. 8: 332ra45, 2016. Note: Electronic Article. [PubMed: 27030597] [Full Text: https://doi.org/10.1126/scitranslmed.aaf1471]
Mizoguchi, M., Chikakane, K., Goh, K., Asahina, Y., Masuda, K. Acute febrile neutrophilic dermatosis (Sweet's syndrome) in Behcet's disease. Brit. J. Derm. 116: 727-734, 1987. [PubMed: 3593637] [Full Text: https://doi.org/10.1111/j.1365-2133.1987.tb05908.x]
Mizoguchi, M., Matsuki, K., Mochizuki, M., Watanabe, R., Ogawa, K., Harada, S., Hino, H., Amagai, M., Juji, T. Human leukocyte antigen in Sweet's syndrome and its relationship to Behcet's disease. Arch. Derm. 124: 1069-1073, 1988. [PubMed: 3389850]
Moghaddas, F., Llamas, R., De Nardo, D., Martinez-Banaclocha, H., Martinez-Garcia, J. J. Mesa-del-Castillo, P., Baker, P. J., Gargallo, V., Mensa-Vilaro, A., Canna, S., Wicks, I. P., Pelegrin, P., Arostegui, J. I., Masters, S. L. A novel pyrin-associated autoinflammation with neutrophilic dermatosis mutation further defines 14-3-3 binding of pyrin and distinction to familial Mediterranean fever. Ann. Rheum. Dis. 76: 2085-2094, 2017. [PubMed: 28835462] [Full Text: https://doi.org/10.1136/annrheumdis-2017-211473]
Parsapour, K., Reep, M. D., Gohar, K., Shah, V., Church, A., Shwayder, T. A. Familial Sweet's syndrome in 2 brothers, both seen in the first 2 weeks of life. J. Am. Acad. Derm. 49: 132-138, 2003. [PubMed: 12833027] [Full Text: https://doi.org/10.1067/mjd.2003.328]
Su, W. P. D., Liu, H.-N. H. Diagnostic criteria for Sweet's syndrome. Cutis 37: 167-174, 1986. [PubMed: 3514153]
Sweet, R. D. An acute febrile neutrophilic dermatosis. Brit. J. Derm. 76: 349-356, 1964. [PubMed: 14201182] [Full Text: https://doi.org/10.1111/j.1365-2133.1964.tb14541.x]
Vignon-Pennamen, M. D., Wallach, D. Neutrophilic disease: a review of extra-cutaneous neutrophilic manifestations. Europ. J. Derm. 5: 449-455, 1995.
von den Driesch, P. Sweet's syndrome (acute febrile neutrophilic dermatosis). J. Am. Acad. Derm. 31: 535-556, 1994. [PubMed: 8089280] [Full Text: https://doi.org/10.1016/s0190-9622(94)70215-2]
Whittle, C. H., Beck, G. A., Champion, R. H. Recurrent neutrophilic dermatitis of the face: a variant of Sweet's syndrome. Brit. J. Derm. 80: 806-810, 1968. [PubMed: 5706799] [Full Text: https://doi.org/10.1111/j.1365-2133.1968.tb11950.x]