Hailey–Hailey disease, also known as benign familial chronic pemphigus, is caused by mutations in a gene called ATP2C1, which encodes a calcium transporter responsible for moving calcium ions into the Golgi apparatus of skin cells. When that pump fails, calcium signaling inside keratinocytes is disrupted, and the molecular glue that holds skin cells together weakens. The result is a process dermatologists call acantholysis: the epidermis literally falls apart, producing recurrent vesicles, blisters, and raw erosions, typically in intertriginous areas where skin folds rub against itself, such as the armpits, groin, and neck. The condition follows an autosomal dominant inheritance pattern, meaning a child of an affected parent has a fifty percent chance of carrying the mutation.

What makes the pediatric form so poorly understood is its sheer rarity. The disease classically appears in the second to fourth decades of life, and textbooks rarely mention early onset. To fill that gap, the Northwestern team conducted a scoping review, searching PubMed and Google Scholar for combinations of the terms Hailey–Hailey disease, familial benign chronic pemphigus, pediatric, and child. They included case reports, case series, and clinical studies, extracting variables such as age, gender, clinical and histopathologic features, anatomic distribution, and treatments. After screening the literature, they identified eight published reports describing a total of nine pediatric patients, a dataset that underscores just how sparse the evidence base remains.

The numbers that emerged from those nine cases are striking. The mean age at symptom onset was 2.6 years, but the median was just six months, meaning most of these children developed their first lesions before they could walk or talk. The mean age at presentation to medical attention was 4.7 years, with a median of 4.5 years. That gap between onset and presentation, and the further delay before a correct diagnosis, illustrates one of the central problems the authors highlight: pediatric Hailey–Hailey disease is so far outside the expected clinical picture that it is often mistaken for more common childhood rashes, including diaper dermatitis, atopic dermatitis, or bacterial and fungal infections.

Clinically, the children in the reviewed reports presented with recurrent vesiculobullous or erosive eruptions accompanied by pruritus, irritation, and pain, mirroring the symptom profile of adult patients. The distribution of lesions varied, with some cases occurring at unusual sites for the disease, a feature that has historically complicated recognition. One of the earliest documented cases, published in 1963, described chronic benign pemphigus in an Indian child, and subsequent reports have described relapsing linear acantholytic dermatosis in young boys and segmental disease affecting the vulva. Together these accounts sketch a condition that, while rare, can appear almost anywhere on a child’s skin and can follow a relapsing course punctuated by flares and partial remissions.

Histopathology provided the diagnostic anchor in these cases. Under the microscope, biopsies from affected children revealed intraepidermal acantholysis with the characteristic dilapidated brick wall appearance, in which the upper layers of the epidermis separate like a crumbling masonry facade. This finding, combined with the clinical history and, in some cases, genetic testing for ATP2C1 mutations, allows clinicians to distinguish Hailey–Hailey disease from its close mimic, Darier disease, which is caused by a mutation in a related calcium transporter gene, ATP2A2. The literature reviewed includes an infant case with a previously unreported ATP2C1 mutation, as well as two sporadic childhood-onset cases involving superimposed mosaicism, a phenomenon in which a second genetic alteration arises in some cells and can modify the disease’s distribution and severity.

Treatment remains the most frustrating aspect of managing these young patients. Because no definitive treatment guidelines exist for the pediatric population, clinicians have borrowed from the adult repertoire, deploying topical corticosteroids, topical antifungals, topical and systemic antibiotics, and topical calcineurin inhibitors with mixed outcomes. The heterogeneity of the reported approaches reflects the absence of controlled trials; with nine patients scattered across decades of case reports, no meaningful comparison of therapies is possible. Some children experienced spontaneous resolution or symptomatic improvement with conservative management alone, a hopeful signal that early-onset disease may occasionally run a milder course, though the reviewed evidence is too limited to predict which patients will fare well.

The report’s authors, who are based at Northwestern University Feinberg School of Medicine in Chicago, emphasize that the fundamental challenge is diagnostic delay. A toddler with recurring erosions in skin folds is far more likely to be treated repeatedly for candidal or bacterial infection before anyone considers a genetic acantholytic disorder. Each misdirected treatment cycle prolongs the child’s pain and irritation and postpones genetic counseling for the family, which matters because an autosomal dominant diagnosis has implications for siblings and future offspring. Raising awareness that Hailey–Hailey disease can begin in infancy, the authors argue, is the first step toward shortening that journey.

The scientific significance of the pediatric cases extends beyond the clinic. Because ATP2C1 governs Golgi calcium handling in keratinocytes, childhood-onset cases offer a natural experiment in how severely, or mildly, impaired calcium transport manifests when it acts on developing skin. The documented cases of superimposed mosaicism, in which children carried the mutation in only a subset of cells, are particularly informative, since they can reveal how the proportion and distribution of affected cells shape the pattern of blistering. Insights from these rare presentations feed into a broader research effort, reflected in recent therapeutic reviews, to develop targeted treatments that restore calcium homeostasis or stabilize keratinocyte adhesion rather than merely suppressing inflammation.

For now, the takeaway from the Northwestern review is a call for vigilance rather than a new therapy. Pediatric Hailey–Hailey disease is a rare acantholytic dermatosis whose features closely resemble adult-onset disease, but whose early appearance invites misdiagnosis and for which no pediatric-specific treatment algorithm exists. By synthesizing eight reports and nine patients into a single reference point, the authors have given dermatologists a clearer baseline: know the median onset of six months, recognize the dilapidated brick wall on biopsy, consider ATP2C1 testing when erosions recur in folds, and counsel families about inheritance. In a field where the entire published pediatric experience fits into a handful of pages, even a short report can meaningfully reshape how the next affected child is diagnosed and treated.

Subject of Research: Pediatric-onset Hailey–Hailey disease, an ATP2C1-related acantholytic skin disorder

Article Title: Pediatric Hailey–Hailey disease: Short report

Article References: Katamanin, O., Riley, J. M., & Flood, K. S. (2026). Pediatric Hailey–Hailey disease: Short report. Archives of Dermatological Research, 318(1), Article 451. https://doi.org/10.1007/s00403-026-04961-5

Image Credits: AI Generated

DOI: 10.1007/s00403-026-04961-5

Keywords: Hailey–Hailey disease, ATP2C1, pediatric dermatology, acantholytic dermatosis, benign familial pemphigus, scoping review, calcium transporter, blistering skin disease, genetic skin disorders, diagnostic delay, intertriginous eruptions, superimposed mosaicism

In groundbreaking research led by the University of Michigan and spearheaded by the laboratory of Pierre Coulombe, Ph.D., new insights have emerged elucidating the role of keratin 16 (K16), a protein central to the pathology of PC and similar dermatoses. This study unravels intricate molecular pathways that connect the dysregulation of K16 to abnormal immune responses within diseased skin, advancing our understanding of PC mechanistically for the first time. The investigation encompasses sophisticated experimental models, including genetically engineered mice and primary skin biopsies obtained from PC patients, uniting clinical and basic science in a synergistic approach.

As Erez Cohen, Ph.D., a key investigator in Coulombe’s lab and the study’s lead author, elaborates, “The skin’s reaction to wounding and stress comprises a precise choreography of molecular signals designed to restore tissue integrity. Our question was what transpires when this response spirals out of control.” This query strikes at the heart of PC and similar inflammatory skin diseases such as psoriasis, where an aberrantly heightened tissue stress response intersects with the immune system’s regulatory networks.

PC shares molecular fingerprints with prevalent conditions like psoriasis and atopic dermatitis (eczema), notably in the upregulation of stress-responsive keratins including K16 and an improperly modulated immune reaction. These keratin proteins, encoded by the mutated genes in PC, are pivotal players in the skin’s adaptive response to environmental and physiological stressors. Yet, prior to this study, the precise functions held by keratins like K16 in the pathogenesis and perpetuation of these disorders remained largely elusive, reflecting a critical gap in dermatological knowledge.

To dissect this complexity, Cohen, Coulombe, and colleagues embarked on a meticulous quest to decode cellular mechanisms governed by K16. Mining patient-derived data revealed a surprising linkage between K16 and the type I interferon (IFN) pathway, a molecular cascade best recognized for its role in antiviral immunity. Type I IFNs act as potent cytokines initiating and amplifying immune defenses, but their hyperactivation can provoke detrimental inflammation. The research team hypothesized that K16 might interface with this pathway, either restraining or exacerbating inflammatory circuits.

Employing a viral mimic—double-stranded RNA molecules that simulate pathogen presence—the researchers modeled immune activation in keratinocytes, the predominant cell type in the skin’s outermost layer. Investigations compared normal keratinocytes with those lacking K16 or harboring mutated K16 variants derived from PC patients. The results were striking: the absence or malfunction of K16 precipitated an exaggerated type I interferon response, magnifying inflammatory signaling beyond typical physiological levels. This finding spotlights K16 not merely as a structural cytoskeletal component but as a critical modulator dampening immune overactivation during stress.

Fundamental to the skin’s ability to heal is the resolution phase following inflammation, wherein activated cells revert to baseline function. This study overturns prior assumptions by demonstrating that K16 functions partly as a molecular “brake,” curbing inflammatory signaling as tissue repair progresses. Loss of this regulatory role, as occurs in PC-associated mutations, fosters persistent inflammation, driving chronic lesions and symptomology. Thus, K16’s dual identity emerges—both a scaffold protein and a key immunomodulatory agent maintaining skin homeostasis.

Excitingly, this mechanistic insight ushers in therapeutic possibilities hitherto unimaginable for PC, a condition currently bereft of effective treatments. The research team leveraged a transgenic mouse model of PC developed in Coulombe’s laboratory, administering topical formulations of ruxolitinib—a FDA-approved Janus kinase (JAK) inhibitor known to suppress type I interferon signaling. Application of ruxolitinib cream attenuated skin lesions and inflammation in the mice, providing compelling preclinical proof-of-concept for a novel targeted therapy that could dramatically improve patient outcomes.

The translational potential extends beyond PC alone, as keratin-associated dysregulation of interferon responses may underpin pathogenesis in multiple keratinopathic and inflammatory skin diseases. Supported by funding from the National Institutes of Health and the National Psoriasis Foundation, this research epitomizes the bench-to-bedside continuum, forging pathways from molecular discovery to clinical intervention. Cohen underscores the importance of foundational science in uncovering therapeutic targets: “Only by unraveling disease mechanisms at the protein and cellular level can we hope to develop precision treatments that truly meet patient needs.”

Pierre Coulombe reflects on the broader impact of studying rare disorders such as pachyonychia congenita, emphasizing their value in illuminating normal tissue biology and disease mechanisms. “Rare diseases often point us toward fundamental biological insights that are broadly relevant but overlooked due to low prevalence,” he states. Highlighting the collaborative nature of this work, Coulombe also praises the Pachyonychia Congenita Project (www.pachyonychia.org), a patient-driven advocacy organization that has been instrumental in facilitating access to critical patient samples and fostering partnerships among patients, clinicians, and scientists.

This pioneering investigation not only clarifies the enigmatic role of keratin 16 in skin inflammation and repair but also delivers hope to those afflicted by rare yet devastating dermatological conditions. By revealing K16 as a linchpin in restraining type I interferon-driven hyperinflammation, it opens new arenas for targeted immune modulation. Future clinical trials of JAK inhibitors and related agents may finally equip clinicians with viable therapies for PC and related keratin-associated skin disorders, transforming patient care and quality of life.

The study, published in Science Translational Medicine, represents a major advance in dermatological research, merging molecular genetics, immunology, and clinical science. Beyond the immediate findings, it exemplifies the power of integrating patient-derived data with sophisticated animal models to dissect complex disease pathways. As investigations continue, the field moves closer to unraveling the full spectrum of keratin functions and their implications for multiple skin pathologies.

With these discoveries, the scientific and medical communities are poised at the cusp of a new era wherein chronic skin diseases, once viewed as untreatable, might be managed or even cured through precise modulation of keratin-mediated immune pathways. The legacy of this work extends beyond pachyonychia congenita, enriching our holistic understanding of tissue stress responses and immune regulation across dermatology and immunology.

Subject of Research: The molecular role of keratin 16 in the regulation of type I interferon responses in stressed and diseased skin, with implications for pachyonychia congenita and related inflammatory skin disorders.

Article Title: Keratin 16 inhibits type I interferon responses in differentiating keratinocytes of stressed and diseased skin

Web References:
Science Translational Medicine DOI Link
Pachyonychia Congenita Project

References:
Cohen Erez et al., “Keratin 16 inhibits type I interferon responses in differentiating keratinocytes of stressed and diseased skin,” Science Translational Medicine, 2024.

Keywords: Pachyonychia congenita, Keratin 16, type I interferon, skin inflammation, psoriasis, atopic dermatitis, JAK inhibitor, ruxolitinib, keratinocyte, immune regulation, tissue stress response, rare genetic diseases