Hailey-Hailey Disease with Lichenoid Lesions Around the Anus: A Case Report

0
0
0

Hailey-Hailey Disease with Lichenoid Lesions Around the Anus: A Case Report and Review of a Novel ATP2C1 Mutation

Hailey-Hailey disease (HHD), also known as familial benign chronic pemphigus, is a rare autosomal dominant genodermatosis characterized by recurrent blistering and erosions primarily affecting intertriginous regions. The disease arises from mutations in the ATP2C1 gene located on chromosome 3q21-2, which encodes a calcium/manganese transporter ATPase critical for maintaining intracellular calcium homeostasis in keratinocytes. Dysregulation of calcium signaling disrupts cell adhesion mechanisms, leading to suprabasal acantholysis and the formation of painful, malodorous lesions. While HHD typically manifests in areas prone to friction, such as the neck, axillae, and groin, this case highlights an unusual presentation of perianal lichenoid lesions with a novel ATP2C1 mutation, emphasizing the diagnostic and therapeutic challenges in atypical presentations.

Clinical Presentation and Diagnostic Challenges

A 51-year-old woman initially presented with widespread blisters and erythema on the chest, axillae, and waist, consistent with pemphigus vulgaris (PV). She responded well to systemic corticosteroids, with resolution of these lesions. However, seven months later, she developed persistent perianal lesions characterized by clustered white or skin-colored papules (0.1–0.5 cm in diameter) and lichenoid plaques in the gluteal sulcus [Figure 1B]. These lesions were refractory to corticosteroid therapy, prompting reevaluation. The patient reported mild chronic diarrhea, likely contributing to localized friction and moisture, which exacerbated the condition.

Histopathological examination of a perianal biopsy revealed hyperkeratosis, parakeratosis, and extensive acantholysis within the epidermis [Figure 1C]. Dyskeratotic features, including “grains” (flattened, elongated keratinocytes) and “corps ronds” (rounded, eosinophilic cells with pyknotic nuclei), were observed [Figure 1D]. Direct immunofluorescence was negative for intercellular IgG or complement deposition, ruling out pemphigus. Genetic testing identified a heterozygous nonsense mutation in ATP2C1 (c.1504C>T, p.Arg502Ter) on exon 16 [Figure 1E], confirming HHD. This mutation introduces a premature stop codon, truncating the ATPase protein and impairing its calcium-transport function.

Novel Mutation and Pathogenetic Insights

The ATP2C1 c.1504C>T mutation represents a novel pathogenic variant in HHD. Previous studies have linked ATP2C1 loss-of-function mutations to defective Golgi calcium storage, leading to endoplasmic reticulum stress and impaired keratinocyte adhesion. The p.Arg502Ter mutation likely abolishes the ATPase’s catalytic domain, exacerbating calcium dysregulation. This case underscores the allelic heterogeneity of HHD and expands the mutational spectrum associated with the disease.

Notably, the perianal lesions exhibited features of papular acantholytic dyskeratosis (PAD), a rare entity histologically indistinguishable from HHD. Recent evidence suggests PAD may represent a localized or forme fruste of HHD, supported by shared ATP2C1 mutations. However, the relationship remains contentious, as PAD lesions often lack a family history or generalized involvement. In this patient, the coexistence of prior PV-like lesions and the novel mutation strengthens the hypothesis that PAD and HHD exist on a phenotypic continuum.

Differential Diagnosis and Pitfalls

The perianal localization posed significant diagnostic challenges. Lichenoid papules and plaques raised suspicion for extramammary Paget disease, bowenoid papulosis, or infectious etiologies (e.g., candidiasis, herpes simplex). Histopathological exclusion of Paget cells, viral cytopathic changes, or fungal hyphae was critical. Darier disease and Grover disease were also considered but dismissed due to the absence of alternating orthokeratosis/parakeratosis (“church-spire” hyperkeratosis) or transient acantholytic dyskeratosis, respectively.

The initial misdiagnosis of PV highlights the importance of clinicopathological correlation. Unlike PV, HHD lacks intercellular IgG autoantibodies and demonstrates acantholysis primarily in the suprabasal layers. The transient response of PV-like lesions to corticosteroids further complicated the diagnosis, underscoring the need for genetic testing in refractory or atypical cases.

Therapeutic Strategies and Outcomes

Management of perianal HHD is notoriously challenging due to anatomical susceptibility to moisture, friction, and recurrent trauma. The patient’s chronic diarrhea likely perpetuated inflammation, necessitating multidisciplinary intervention. Topical 0.1% tacrolimus ointment, applied twice daily, induced complete resolution of lesions within two months [Figure 1F], with sustained remission over one year. Tacrolimus, a calcineurin inhibitor, modulates T-cell activation and suppresses proinflammatory cytokines without the atrophogenic effects of corticosteroids. Its efficacy in this case aligns with reports of successful use in intertriginous HHD.

For refractory cases, surgical modalities such as CO₂ laser ablation, dermabrasion, or argon plasma coagulation may be warranted. These interventions aim to destroy acantholytic epidermis and promote re-epithelialization. However, the risk of scarring and recurrence limits their utility. This case reinforces tacrolimus as a first-line therapy for localized, chronic HHD, particularly in sensitive areas.

Implications for Clinical Practice

This report illustrates several key points:

  1. Genetic testing is indispensable in diagnosing HHD, especially when lesions are localized or mimic other acantholytic disorders.
  2. Environmental triggers (e.g., friction, humidity) profoundly influence disease expression. Addressing underlying factors, such as diarrhea, is crucial for long-term control.
  3. PAD and HHD may share a genetic basis, necessitating reevaluation of their classification.
  4. Topical tacrolimus offers a safe and effective alternative to corticosteroids or invasive procedures in perianal HHD.

Conclusion

The identification of a novel ATP2C1 mutation in this patient expands the genetic landscape of HHD and reinforces the role of calcium dysregulation in its pathogenesis. The case also demonstrates the therapeutic potential of tacrolimus in managing refractory perianal lesions, providing a valuable addition to the limited armamentarium for this debilitating condition. Clinicians should maintain a high index of suspicion for HHD in cases of persistent intertriginous or anogenital lichenoid eruptions, particularly when conventional therapies fail.

doi.org/10.1097/CM9.0000000000000097

Was this helpful?

0 / 0