Targeting Intracellular Calcium Dysregulation in Hailey–Hailey Disease: A Case‐Based Rationale for Oral Magnesium Chloride Therapy

Hailey–Hailey disease (HHD), or benign familial chronic pemphigus, is a rare autosomal-dominant genodermatosis caused by mutations in the ATP2C1 gene, which encodes the calcium/manganese (Ca2+/Mn2+) ATPase hSPCA1 that regulates Ca2+ homeostasis in the Golgi apparatus. Mutations in this gene disrupt desmosome formation and keratinocyte adhesion, leading to epidermal acantholysis and recurrent vesicopustular and erosive lesions in intertriginous areas. HHD follows a chronic relapsing course, with flares triggered by heat, friction, or infections, markedly impairing quality of life. Therapeutic management is challenging, and standardized treatment guidelines are lacking [1]. Emerging evidence suggests a potential role for oral magnesium chloride (MgCl2) in disease control [2]. In this context, we report the case of a 60-year-old man with a 20-year history of recurrent erythematous eruptions on the presternal region and inguinal folds, exacerbated by sweating (Figure 1A). He reported partial and transient responses to topical corticosteroids, antibiotics, and antifungals. He was initially treated as having severe seborrheic dermatitis with systemic antifungal and topical antimicrobial agents, but he developed new fissuring and yellowish serous exudation in the inguinal folds despite reduced erythema. The family history—his son had similar lesions—together with the chronic course and clinical features prompted suspicion of HHD. Punch biopsy showed suprabasal acantholysis with widespread intraepidermal clefting and the characteristic “dilapidated brick wall” pattern. Direct immunofluorescence was negative for IgG, IgA, IgM, and C3, confirming HHD and excluding autoimmune blistering disorders. Because the patient was reluctant to pursue systemic therapy, oral MgCl2 300 mg/day was started. By 4 weeks, the lesions had cleared (Figure 1B), and after 12 months of continuous therapy, he reported only occasional, mild flares controlled with topical steroids. No other systemic treatments were given; serum Mg2+ was not measured, and renal function was normal. To date, four publications with follow-up data report five histologically confirmed HHD patients (three women, two men; mean age 52.6 years) treated with oral MgCl2. In three patients, magnesium chloride hexahydrate (MgCl2·6H2O, 33 g/L solution, 70 mL/day ≈276 mg elemental Mg2+) produced clinical improvement within 1–2 weeks and near-complete remission by 4 weeks; two of these also received topical corticosteroids or clotrimazole–fusidic acid [2, 3]. In two additional cases, adding oral MgCl2 (≈286–300 mg/day) to ongoing naltrexone yielded benefits not achieved with naltrexone alone, including faster response and sustained clearance [4, 5]. In all reported cases, no significant adverse effects were noted aside from the unpleasant taste of the magnesium solution. Numerous topical, systemic, and procedural therapies for HHD have been explored—including corticosteroids, calcineurin inhibitors, antimicrobials, immunosuppressants, retinoids, biologics, Janus kinase (JAK) inhibitors, laser, dermabrasion, botulinum toxin, and phototherapy—but none are curative, and relapses are frequent [1]. HHD arises from ATP2C1 mutations encoding hSPCA1, a Golgi Ca2+/Mn2+-ATPase; its dysfunction lowers Golgi Ca2+ uptake, disrupts junctional protein synthesis and desmosome assembly, and causes keratinocyte detachment and acantholysis. Rather than correcting the genetic defect, MgCl2 may exert beneficial effects by modulating intracellular Ca2+ availability in HHD: in vitro data indicate that MgCl2 reduces cellular Ca2+ efflux without affecting Golgi filling, a finding consistent with inhibition of plasma-membrane Ca2+-ATPases by elevated intracellular Mg2+, thereby increasing intracellular Ca2+ availability to support desmosome formation [2]. Case reports document rapid clinical responses (often within 1–4 weeks), good tolerability aside from the taste, and low cost. MgCl2 appears safe and potentially effective for prolonged use, either as monotherapy or adjunctive therapy, but it is not a proven disease-modifying treatment for HHD, and evidence remains limited to case reports. Caution is advised in patients with renal impairment. Larger studies with defined dosing, therapy duration, and patient selection are needed. MgCl2 may also merit investigation in other acantholytic dermatoses, such as Darier and Grover diseases [4]. The authors have nothing to report. The research conforms to the ethical standards described by the Declaration of Helsinki. Informed consent has been obtained to publish patients' photographs and data. The authors declare no conflicts of interest. The data that support the findings of this study are available upon request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.