Familiar Mediterranean fever (FMF) is the most common inherited autoinflammatory disease.1 It is transmitted in an autosomal recessive manner, and 393 variants have been identified.
A 51-year-old male, ex-smoker, with depressive anxiety disorder, glaucoma, who had undergone a bilateral phakectomy. He reported suffering from episodes of fever 37 °C–38 °C between the age of 16 and 18 years of periodic onset, and lasting a week. He was under treatment with vortioxetine 20 mg/24 h and anafranil 35 mg/24 h.
He consulted for a control analysis, asymptomatic. In a check of previous routine tests, some showed elevated C-reactive protein, up to 128 mg/l (normal 0–5).
Physical examination revealed only a large, flat, brown, pigmented lesion on the front of the legs and feet (Fig. 1a).
Blood count and biochemistry were normal: beta-2-microglobulin 2.43 mg/l (normal .80–2), complement CH50 > 95U/ml (normal 42–95), tumour necrosis factor (TNF-alpha) 13.1 pg/ml (normal 0–12.4). Angiotensin converting enzyme, interleukin 1, interleukin 6, immunoglobulins, complement C3, complement C4, and vascular endothelial growth factor were normal.
Lupus anticoagulant: 1.32 (positive >1.20). Rheumatoid factor, antinuclear antibodies, ENA SSA/RO, ENA SSB/La, ENA SM, ENA Scl-70, anti-cyclic citrullinated peptide antibody, anti-endothelial cell antibody, anti-proteinase antibody 3, and anti-myeloperoxidase antibody were negative.
Axial tomography of the chest and abdomen showed calcified mediastinal and hilar lymph nodes; a right axillary adenopathy of 10 mm in diameter; bilateral axillary lymph nodes of subcentimetric size, mesenteric, retroperitoneal para-aortic, and bilateral iliac nodes, some of which were calcified; spleen with multiple millimetric calcifications; punctate lithiasis in the middle collecting system of the right kidney and the lower collecting system of the left kidney; a blast lesion was also observed in the right iliac bone.
Skin biopsy of the lesion on the anterior leg showed a hyperpigmented basal layer with atrophy of epidermal papillae; both the papillary and reticular dermis had moderate fibrosis, together with a perivascular lymphocytic inflammatory infiltrate; the subcutaneous adipose tissue at the lobular level had dystrophic, adipocytic, and steatonecrosis changes; the septa were moderately thickened by fibrosis; histiocytes and multinucleated giant cells, both with xanthosis changes, were observed in relation to the areas of lipodystrophy/steatonecrosis, all compatible with lobular panniculitis plus lipophagic histiocytic necrosis (Fig. 1b). Congo red staining of skin, rectal, and subcutaneous fat biopsies was negative.
The autoinflammatory disease study detected the heterozygous variant p.(Tyr135His) in the MEFV (Mediterranean fever) gene; this missense-type change predicts the substitution of an amino acid tyrosine for histidine at position 135 of the protein.
FMF is suspected in short, recurrent febrile episodes with asymptomatic intervals, usually occurring before the age of 20 years; erysipeloid lesions on the legs and dorsum of the feet2 may occur, although rare, and lymphadenopathy may also be observed.3 Elevations of acute phase reactants are often present during outbreaks.4 Routine testing showed elevations in CRP, beta-2-microglobulin, and complement CH50, revealing an inflammatory state.
The variant p.(Tyr135His) is not described in clinical databases, nor the scientific literature consulted at the time of writing. It does appear in the dbSNP (database of Single Nucleotide Polymorphisms) database (rs145078602), but not in the population frequency database gnomAD (The Genome Aggregation Database). The bioinformatics predictor CADD (Combined Annotation Dependent Depletion) estimates that the change would have a tolerated effect (<10).
FundingNo funding or grant was received for this article.
