Granular C3 dermatosis: A novel entity

Dear Editor,

A 54-year-old woman presented in dermatology OPD with a two-year history of multiple, intensely pruritic, spontaneous fluid-filled lesions on the extensors of both legs and flexors of both arms. Initially, her trunk, palms, and soles were spared. Between 2022 and 2024, she was treated with the clinical possibilities of bullous pemphigoid (BP), prurigo simplex, and pityriasis lichenoides chronica, with topical steroids, antihistamines, doxycycline, nicotinamide, and immunosuppressants (oral steroids, cyclosporine, and methotrexate) with unsatisfactory response. She had discontinued all medications for 5 to 6 months before visiting us. At the time of presentation, a few vesicles and multiple excoriations were noted on the both limbs, lower back and abdomen [Figures 1a-1c] with sparing of oral mucosa. She had no history of celiac disease, gluten sensitivity, or atopy. She was a known case of type 2 diabetes and hypertension for 10 years on treatment with metformin, telmisartan and amlodipine.

Close

Figure 1a-c:

Multiple excoriations, papules, and hyperpigmented macules present on a) both legs, b) arms and c) lower back.

Export to PPT

Pemphigus profile by IgG ELISA (for BP 180, BP 230, desmoglein 1 & 3, envoplakin, and collagen type IV), serum IgA endosomal antibody (IFA), and tissue & epidermal transglutaminase IgA (IgA tTg & TG3; titre 1:10) were negative, ruling out pemphigus group of disorders and dermatitis herpetiformis (DH). Serum IgE levels were 9 IU/mL (bio reference interval <160 IU/mL). Serum anti-thyroglobulin antibody (anti-TG) levels were elevated to 203.2 IU/mL.

A skin biopsy from a vesicle on the right forearm was done for histopathology and direct immunofluorescence (DIF) which revealed basket-weave orthokeratotic hyperkeratosis over an acanthotic epidermis along with hypergranulosis. A subepidermal to lateral intraepidermal (partially re-epithelised) cleft/vesicle with sparse inflammatory infiltrate containing lymphocytes, neutrophils, and eosinophils was seen with fibrin deposition at the edges of the cleft and adjacent epidermis [Figures 2a and b]. The DIF demonstrated a weak C3 granular band along the dermo-epidermal junction (DEJ) without IgG, IgM, and IgA deposits [Figure 2c]. Histopathology was compatible with prurigo. While C3 deposits along the DEJ can be seen non-specifically in various inflammatory dermatoses, including prurigo, exclusive granular C3 deposition may indicate a distinct bullous disorder known as granular C3 dermatosis (GCD) [Table 1].^1-3 After ruling out G6PD deficiency, the patient was treated with dapsone 100 mg daily along with antihistamines, topical mometasone furoate, and tacrolimus. She reported improvement in pruritus and lesions till 2 months of treatment, after which she was lost to follow up.

Close

Figure 2a-b:

Subepidermal to lateral intraepidermal (partially re-epithelised) cleft/vesicle with sparse inflammatory infiltrate containing lymphocytes, neutrophils, and eosinophils (black arrows). Basket weave orthokeratotichyperkeratosis (red arrows) over an acanthotic epidermis showing hypergranulosis (green arrow) (Haematoxylin & eosin, 40× and 100x).

Export to PPT

Close

Figure 2c:

Weak C3 granular band along the dermo-epidermal junction without IgG, IgM, and IgA deposits (200x).

Export to PPT

First described in Japan by Hashimoto et al. in 2016, the term ‘granular C3 dermatosis’ was proposed for exclusive granular C3 deposition along the DEJ.¹ Since then, few reports have been published with similar findings^2-5 [Table 2].

This condition presents with clinical features resembling DH with the absence of other diagnostic criteria (granular deposition of C3 and C5-C9 without other complement components, histopathological features of subepidermal blister and lymphocytic, eosinophilic, and neutrophilic infiltrate in various combinations, and slightly reduced expression of C3 in epidermis).^1,5 The lesions are annular or nummular erythematous patches, with or without vesicles and eczematisation, or BP-like tense bullae, and prurigo-like itchy papules.¹ Our patient had increased serum anti-TG antibody, as reported by Hashimoto et al.¹ in their study as well, but its significance remains unknown.

Hashimoto et al. found a benign disease course with a promising response to oral dapsone and topical steroids, though a relapse was observed on discontinuation.¹ Oral steroids, nicotinamide, and minocycline have shown a reasonable response in previously reported cases.^1,4 Our patient had previously received these medications without a satisfactory response, hence was treated with dapsone.

The true mechanism of C3 deposition remains unknown till the pathogenic role of C3 deposition is elucidated. Lymphocytic infiltration in the upper dermis may have induced C3 deposition similar to the formation of a lupus band in lupus erythematosus and other collagen diseases.⁶ However, this lupus band is induced by sun exposure. The skin lesions in our patient and the 20 patients studied by Hashimoto et al. were not present in sun-exposed sites. A possibility has been proposed that IgG or IgA antibodies were not detected, either because the autoantibodies were too low or because immunoglobulin deposition was masked. Absence of C1q and C4 ruled out activation of complement via classical pathways. Absence of IgA ruled out alternative pathways. Another possibility is that the IgG antibodies disappeared more quickly than C3 deposition.¹

All reported cases so far have been of Asian descent. However, their small number is insufficient to establish any racial or genetic predisposition. The rarity of cases and limited investigations hinder accurate diagnosis, understanding of the disease pathology, and development of effective treatment. Hashimoto et al. reported good clinical response to dapsone, which was also observed in our patient.¹