A rare severe tuberculosis cutis orificialis in a patient with compound heterozygous mutations in the PRF1 gene

A 25-year-old man complained of multiple painful ulcerated nodules on his cheek and tongue for half a year. He received intermittent oral antibiotic treatment for over 2 months, but the lesions aggravated. He was ever pathologically diagnosed with intestinal tuberculosis after biopsy of necrotic bowel tissue 2 years ago, and was treated with triple anti-tuberculosis therapy (isoniazid, rifampicin and pyrazinamide) for 1 year. The symptoms of abdominal pain, diarrhoea and hematochezia disappeared after treatment. However, multiple red papules occurred periorally and gradually grew into nodules since discontinued therapy. Meanwhile, the enlarged nodules on his tongue obstructed his eating. A physical examination showed multiple ulcerated coalescent nodules on his face. The swollen tongue was also involved in subcutaneous nodules (Figure 1a). The routine blood test showed normal neutrophil and red blood cells counts, but low lymphocyte counts (0.63 × 109/L) were detected. Considering possible severe infection, immunity was evaluated. The results revealed low proportion of CD19+ cells (6.3%, 16%–28%) and NK cells (1.3%, 9.37%–39.50%). Serum biochemical indicators were within normal limits. Routine bacterial cultures, T-Spot®.TB, HIV and PPD tests were negative. Skin biopsy from ulcerated nodule on his face showed dense infiltration of epithelioid histocytes throughout the dermis to subcutaneous, in which no obvious caseous necrotic granuloma was found from H&E-staining (Figure 2a). Immunohistochemical staining of CD68 showed that the most infiltrating cells were histiocytes. The fungal stains were negative. However, a few acid-fast bacilli were found on Ziehl-Neelsen staining (Figure 2b). PCR analysis confirmed that the bacilli were bovine Mycobacterium tuberculosis. The whole blood genome sequencing of the patient revealed two heterozygous missense mutations in the PRF1 gene[c.139G>T(p.Gly47Cys), c.503G>A(p.Ser168Asn)]. Genetic testing of the family confirmed that the patient's father carried the c.139G>T mutation, the mother carried the c. 503G>A mutation, and the brother carried the c.503G>A mutation. Except the proband, none of his parents and brother suffered from similar conditions. The patient was eventually diagnosed as TCO and prescribed with oral anti-tuberculosis treatment, including rifampicin (0.6 QD), pyrazinamide (0.5 TID), ethambutol (0.75 QD) and moxifloxacin (0.4 QD). Since intolerable adverse reactions such as nausea and decreased appetite occurred during colon tuberculosis therapy, isoniazid was replaced by moxifloxacin. After 1 month of treatment, the nodules and neck lymph nodes were reduced and the ulceration were healed. After 6 months treatment, the cutaneous nodules on his tongue and face subsided and scars left. The patient stopped medication and was followed up for 2 years. No skin lesion recurred (Figure 1b), but he developed pulmonary TB and was transferred to a specialized hospital for further tuberculosis treatment. The TCO often occurs in patients with immunosuppression or immunodeficiency.1-8 PRF1, encoding perforin, plays an important role in cytotoxic lymphocytes and natural killer (NK) cells. In vitro, NK cells destroy both M. tuberculosis and M. kansasii cell wall integrity by secreting perforin and granzymes directly.9 In this case, the patients with a heterozygous mutation in the PRF1 gene had remarkably decreased NK cell in peripheral blood. We hypothesize that the PRF1 mutation accounts for the low NK cell count and perforin dysfunction, which could reduce host immunity against the pathogen. So far, this is the first case report that a heterozygous mutation in the PRF1 gene resulted in highly susceptibility to TB infection and relapse of disease. When the patient discontinued the anti-tuberculosis drug therapy after the skin improved, pulmonary TB relapsed. Recommended multi-drug combination therapy for TB patients with immunosuppression or immunodeficiency should be 12–14 months.10 None. The datasets generated during and/or analysed during the current study are publicly available.