Dematiaceous fungi cause phaeohyphomycosis, which can present with mucocutaneous or disseminated systemic infection. Here, we report a rare case involving the skin, mucosa, eyes, lymph nodes, and hepatobiliary system associated with a novel mutation in the CARD 9 gene. A 30-year-old man presented with slowly progressive, multiple, umbilicated papules and a crusted plaque over the face with nasal and buccal mucosal involvement for 15 years with significant cervical lymphadenopathy (Figure 1a,b). It began as a papule near the left lip following a penetrative road traffic injury and gradually enlarged. It was associated with decreased vision in the right eye and an episode of acute abdominal pain and jaundice a year back. Magnetic resonance imaging (MRI) with MR cholangiopancreatography revealed thickening of intrahepatic and extrahepatic bile ducts with contrast enhancement, multifocal partial strictures of bile ducts and proximal dilation extending up to the periampullary region. His symptoms were relieved by an endoscopic biliary stenting but required replacement in 6 months. Biopsy from the periampullary region, skin and cervical lymph node showed granulomatous inflammation with fungal hyphae and spores (Figure 2a) and a diagnosis of disseminated fungal infection was made. Tissue culture grew olivaceous black colonies with a slimy center due to yeast-like growth, with floccose margins. Microscopy showed abundant yeast cells and erect brown cylindrical conidiophores consistent with Exophiala spinifera (Figure 2b). Contrast-enhanced computed tomography of the head, neck, chest, and abdomen revealed multiple necrotic cervical and left axillary lymph nodes and liver lesions similar to previous imaging (Figure 2c). Fundus examination and optical coherence tomography revealed fungal endophthalmitis of the right eye with a visual acuity of 6/60, amounting to a significant reduction in vision. An immunodeficiency state was suspected owing to the extensive and invasive involvement. Human immunodeficiency virus (HIV) serology, immunoglobulin levels, CD4 counts, T-cell and B-cell function, and dihydrorhodamine assay were normal. Whole exome sequencing revealed a novel homozygous missense mutation in exon 3 of the CARD 9 gene (chr9;g.136371350G>A; Depth:169×), leading to substitution of leucine for proline at codon 99. Based on clinical and laboratory evaluation, a diagnosis of disseminated phaeohyphomycosis in the background of CARD 9 mutation was made. Before visiting us, the patient was treated with oral voriconazole 400 mg/day for 5 months, followed by itraconazole 400 mg/day and terbinafine 500 mg/day for 2 months with minimal response. Owing to an inadequate therapeutic response to the conventional dosing regimen, he was restarted on itraconazole at 800 mg/day and terbinafine 500 mg/day with close monitoring of liver and renal function. Serum itraconazole levels were within the therapeutic range. Over 6 months, there was marked flattening of cutaneous lesions and clearance of mucosal plaques. At 1-year follow-up, the skin lesions and lymphadenopathy continued to regress (Figure 1c,d). For the right eye endophthalmitis, three intralesional voriconazole injections (100 μg/0.1 mL) were administered, after which no further progression occurred, although visual acuity remained unchanged. Despite the absence of abdominal symptoms, repeat contrast-enhanced computed tomography (CECT) showed only mild improvement in hepatobiliary findings; hence, the same antifungal regimen has been continued at the same dosage for one year after initiation of therapy. Phaeohyphomycosis can present as subcutaneous nodules, papules, verrucous plaques, non-healing ulcers, and sinuses, mostly over trauma-prone sites and may also involve internal organs. The melanin in the cell wall of dematiaceous fungi acts as their key virulence factor 1. Common cutaneous pathogens include Exophiala jeanselmei and Exophiala dermatitidis 2, while Scedosporium prolificans and Bipolaris spicifera cause systemic infection 2. Systemic infections are reported with primary immunodeficiency disorders such as CARD 9 and Dectin-1 mutations 3, 4. CARD 9 encodes a protein that relays fungus-sensing signals via receptors like Dectin-1 and promotes neutrophil recruitment and IL-17 production 4. These patients show an anergy to fungal pathogens even though their defense against other pathogens remains intact 4. Itraconazole, voriconazole, posaconazole with or without terbinafine have been found beneficial in various case reports, and surgical excision should be done whenever feasible 5. Because our patient did not respond to conventional itraconazole dosing, escalation to 800 mg/day with terbinafine led to significant improvement in skin lesions and prevented worsening of lesions in the liver and eye. Despite this, deciding the endpoint of treatment is challenging, and thus, counseling of the patient regarding the prolonged disease course is also an important part of the management. The authors have nothing to report. The study was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The patient has given his written informed consent to the publication of his case and images. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Najeeb et al. (Wed,) studied this question.