A novel mutation in a craniofacial pustular pyoderma gangrenosum patient with secondary hemophagocytic lymphohistiocytosis

Dear Editors, Pyoderma gangrenosum (PG) is a rare, severe ulcerative skin disorder with unknown etiology, often associated with underlying conditions in at least half of cases.1-4 Common comorbidities include inflammatory bowel disease, arthritis, and hematological disorders.5-7 Here, we describe a novel mutation in the NFKB1 in a patient with craniofacial pustular pyoderma gangrenosum, who also developed secondary hemophagocytic lymphohistiocytosis (HLH). A 66-year-old man presented with a 20-day history of painful pustules, scabs, and ulcers on the face, neck, and scalp. Physical examination revealed scattered pustules and plaque with crust on the top of the scalp and both temporal regions. A 9 cm x 6 cm plaque in front of the right ear showed extensive purulent secretion and crusting (Figure 1a,b). Complete blood cell count with differential was normal. Tissue cultures for bacteria, fungi, and mycobacteria showed no growth. Except for an elevated antinuclear antibody (ANA), levels of rheumatoid factor (RF) and antineutrophil cytoplasmic antibody (ANCA) were within normal limits. Additionally, the skin biopsy from the right side of the face showed diffuse inflammatory cell infiltration in the dermis and subcutis, predominantly neutrophils and lymphocytes (Figure 1c,d). Pathological changes in the scalp were consistent with a diagnosis of pustular PG. Treatment with oral methylprednisolone 20 mg/BID, Thalidomide 100 mg/BID, and minocycline hydrochloride 100 mg/BID was initiated and progressively reduced, leading to gradual healing of skin lesions. Complete blood cell count with differential remained normal during the period. Two months later, the patient was hospitalized in the hematology department due to high-spiking fevers of 39°C lasting more than 7 days, anemia, significant neutropenia, lymphopenia, and thrombocytopenia. Additional symptoms included low NK cell activity, significantly elevated levels of ferritin (3,002 µg/l) and sCD25 (9,041 pg/ml). No lymphadenopathy or splenomegaly was observed. Bone marrow examination showed no primitive cells or pathological hematopoiesis, and MDS flow cytometry and FISH (MDS) were negative, excluding the presence of myelodysplastic syndrome. Both bone marrow smear and biopsy showed no significant abnormalities, ruling out hematological malignancy. HLH was diagnosed according to HLH-2004 diagnostic guidelines. The patient had no gastrointestinal symptoms; abdominal examination, stool routine, and ultrasound were normal, excluding inflammatory bowel disease. Anti-dsDNA, anti-Sm antibodies, and complement levels were normal, excluding systemic lupus erythematosus. Although the patient had a history of knee and hip pain, no joint tests were conducted, so arthritis could not be excluded. The patient experienced coughing and sputum expectoration. Chest CT examination suggested possible infectious lesions, with fungal infection (e.g., Trichoderma spp.) not excluded. Sputum culture was positive for Pseudomonas aeruginosa and Candida spp. Abdominal and lymph node ultrasounds were normal, with normal tumor markers (AFP, CEA, CA199, T-PSA) and lung tumor markers, excluding malignancies. The patient was treated with mild-dose intravenous immunoglobulin (IVIG) plus corticosteroid. However, the patient abandoned treatment and was voluntarily discharged from the hospital without further consultation, ultimately resulting in a fatal outcome. We speculate that the patient's death may have been caused by a severe pulmonary infection. During treatment, genomic DNA was isolated from the patient's peripheral blood and whole-exome sequencing revealed a novel heterozygous missense mutation in NFKB1: c.2372G>C in exon 21, resulting in the amino acid substitution p.Gly791Ala (Figure 2a,b), which was further confirmed in the lesional tissue. The variant is present in population databases (rs748652265, ExAC 0.03%) but has not been reported in individuals with NFKB1-related conditions. Multiple amino acid sequence alignment showed that Gly791 is highly conserved among different species (Figure 2c). The impact of this mutation on protein structure and function remains to be investigated. The mechanisms explaining the PG and autoinflammation caused by NFKB1 heterozygous mutation require further study. There have been no documented cases of craniofacial PG or the NFKB1 mutation (c.2372G>C) described as a pathogenic variation in PG.8 Due to the lack of sufficient reported cases of PG with secondary hemophagocytic lymphohistiocytosis carrying mutated genes, it is challenging to perform systematic and statistical analysis of the pathogenic potential of the mutation. Collecting such cases is critical for understanding this condition's clinical manifestations and the underlying mechanisms to develop effective treatments. None.