Introduction

First described in 1939 by its namesake, Hailey-Hailey Disease (HHD) is a rare hereditary disorder, otherwise known as benign familial pemphigus.¹ The disease typically manifests in the form of recurrent blisters, erosions, and plaques in areas where skin may be subject to friction, such as the neck, groin, and armpits.² Although HHD is uncommon, with an estimated prevalence of only 1 out of 50,000 people, the discomfort caused by this disease and its chronic nature tends to have a grave impact on patients' quality of life.³ 

To understand how HHD works and develops, it is important to understand its pathophysiology - the cellular and molecular mechanisms that lead to the physical characteristics observed. It is this understanding that allows accurate diagnosis and tailored treatment methods.  

Genetic basis of hailey-hailey disease

HHD is caused by mutations in the ATP2C1 gene, which is located on chromosome 3. This gene encodes a protein known as SPCA1, a calcium transporter that plays a crucial role in regulating calcium levels within skin cells, otherwise known as keratinocytes.⁴ Maintaining the balance of calcium levels in cells is important to maintain the function of many cellular processes, including cellular adhesion and cell signalling.⁵ 

This disease has an autosomal dominant inheritance pattern.¹ This means that only one mutated copy of the affected ATP2C1 gene needs to be inherited from an affected parent in order to develop HHD. However, some cases of the disease have also developed from spontaneous mutations with no family history of HHD.⁶ 

Mutations in ATP2C1 result in the dysregulation of calcium levels within the keratinocytes. This disrupts cellular processes that are crucial for maintaining the integrity of the skin epidermis, including growth and differentiation of the keratinocytes and maintenance of intercellular junctions (channels between adjacent cells which allow for the transportation of ions) responsible for holding keratinocytes together.^7,8 This results in the observed characteristics of HHD - skin fragility and blistering as a result of loss of cellular adhesion. The loss of cellular adhesion is known as acantholysis. 

Calcium homeostasis and role in dysfunction

Calcium homeostasis is a state of balance maintained by living organisms within their bodies and is essential for the proper functioning of the body, particularly the skin epidermis. 

Calcium ions play a key role in the regulation of cell-cell interactions in maintaining the skin barrier as well as the differentiation and adhesion of keratinocytes.⁹ In addition, these ions have also been found to be involved in the assembly and maintaining stability of adherens junctions and desmosomes, which are specialised proteins that help anchor keratinocytes together.¹⁰ In this way, these junctions are responsible for maintaining the integrity of the skin tissue. 

In healthy skin, the protein SPCA1 functions as a pump, moving calcium ions from the cytoplasm of keratinocytes into the Golgi apparatus, which is where the ions are typically stored. The storage and intracellular homeostasis of calcium ions is key for many cellular processes. 

In HHD, mutations result in the loss of function of the protein SPCA1. This loss of SPCA1 function results in a disruption of calcium levels within cells, causing calcium ions to accumulate in the cytoplasm over time and depletion of calcium ions in the Golgi apparatus. Due to this, the normal trafficking and processing of proteins required for keratinocyte adhesion is interrupted. 

Some downstream effects of this calcium imbalance that compromise skin integrity include:^1,6,10,14,15 

• Impaired protein processing and trafficking: Calcium is essential for the proper formation and trafficking of proteins involved with cell-cell adhesion and communication. When calcium ion  levels are dysregulated; these proteins are unable to go to and function where they’re needed at the cell surface
• Dysfunction of desmosomes: Responsible for maintaining cell-cell adhesion, desmosomes require calcium ions for proper formation and function. Dysregulation of calcium ion levels in cells causes the formation of defective desmosomes

The result of these cellular dysfunctions is the loss of adhesion between keratinocytes, known as acantholysis. The skin loses its integrity and becomes fragile, and even mild trauma and friction cause the formation of blisters and erosions on the skin. 

The role of environmental and triggering factors

While genetic mutations are at the core of HHD and are the main cause of the disease, environmental factors also play a role in triggering and worsening the symptoms. 

Friction 

Constant friction, like friction of skin against skin, or against clothing,  can cause blisters and erosion of existing blisters due to the fragility of the skin. This is especially a problem in areas where the skin folds, such as the armpits and groin, as friction is constant in those areas even with the tiniest movement.  

Secondary infection 

Damaged skin is more susceptible to bacterial and fungal infections, as the now compromised skin barrier offers an opening for these pathogens to enter the body. 

Infections caused by Staphylococcus aureus appear to be most common among patients of HHD. 

Heat and humidity 

Heat and humidity exacerbate sweating, which keeps the skin moist. If moist for prolonged periods of time, the skin becomes more fragile and is more prone to irritation and inflammation. 

Trauma 

Trauma, such as scratching or rubbing can worsen the condition, leading to further loss of skin integrity and causing symptoms to flare up. 

Emotional stress 

It is believed that emotional stress either exacerbates the body’s inflammatory response or leads to behaviours that worsen the symptoms of HHD, such as sweating and scratching.^1,6 

Symptoms of hailey-hailey disease

As with many illnesses, being able to recognise what HHD looks like on the surface is an important part of timely diagnosis. These symptoms occur as a direct result of acantholysis and the breakdown of the integrity of the skin, as previously described. 

The primary symptoms of this disease are blisters and erosions, particularly in regions prone to friction, heat, humidity, minor trauma, and secondary infection. This includes the armpits, groin, neck, under the breasts, buttocks, inner thighs, and lower abdomen. In some patients, blisters and erosions have also been found on the back. 

Common symptoms of HHD include:^1,6,11,12,13

• Blisters/plaques and erosions: painful lesions form on the skin in high-risk regions described above and these blisters are fragile and rupture easily, leading to erosions and crusting around the blister 
• Fissures: In severe cases, deep fissures may develop in the skin. (Fissures refer to tearing in the skin, which may cause pain and bleeding) 
• Itching (pruritus) and pain: Itching and burning sensations are common and have been described by many HHD patients and pain is typically associated with fissures or infectious lesions 
• Longitudinal white bands on nails
• Recurrent nature of the blisters: A major aspect of HHD is the pattern of recurrence and remission, with symptoms flaring up and semi-healing consistently 

Although these symptoms are not prone to causing any systemic complications involving other organs, the chronic nature of this disease and its painful symptoms have significant impacts on patients’ quality of life 

Summary

Hailey-Hailey disease (HHD) is a complex genetic disorder that occurs as a result of mutations in the ATP2C1 gene, which disrupts calcium homeostasis in skin cells, known as keratinocytes. This leads to the loss of adhesion between keratinocytes, ultimately resulting in the characteristic recurrent blistering and skin fragility. 

Although environmental factors, such as humidity and friction, are known to exacerbate the symptoms of HHD, it is our understanding of the molecular and genetic basis of the disease that has brought us more effective diagnosis and treatment methods, allowing patients to manage the recurring flare-ups of the disease and improve their quality of life. Although there is yet to be a cure, continued research holds incredible promise for the development of better and more effective treatments for Hailey-Hailey disease.