DISEASE CARD

Disease group Keratinization disorder
DISEASE NAME HAILEY-HAILEY DISEASE
Synonymous Familial benign chronic pemphigus, HHD
Estimated prevalence -
OMIM 169600
Inheritance Autosomal dominant
Gene (s) ATP2C1 (604384)

Definition

Hailey-Hailey disease (HHD) is a rare genetic blistering disorder first described by the Hailey brothers in 1939. The disease manifests in adulthood and is characterized by painful erosions and fissures in flexures. Histological examination of skin lesions shows widespread acantholysis of the epidermis. The disease is caused by mutations in ATP2C1 encoding a Ca2+ and Mn2+ pump of the Golgi apparatus.

Clinical Description

Onset of the disease is usually after the third or forth decade. HHD is characterized by vesicular lesions, painful erosions and scaly erythematous plaques which occur at sites of friction and flexures (neck, axillae, submammary region, groins and the perineum). Painful fissures (“rhagades”) in flexures are common and very suggestive of the disease. The lesions are often itchy. Mucosal involvement is rare, but oral, esophageal and vulvar involvement is possible. Longitudinal white lines on the fingernails can be seen and are helpful in diagnosing the disease. Penetrance in adults is complete, but expressivity is variable between and within affected families. Mild forms may be limited to nail changes or mild lesions resembling eczema, while severe forms display widespread flexural disease, with hypertrophic and malodorous plaques and painful fissures. This can cause considerable pain and distress and can limit patient mobility. There are no extracutaneous manifestations. Lesions are frequently induced or exacerbated by UV exposure, sweating, friction and skin infection. The disease has a chronic fluctuating course, and patients undergo recurrent exacerbations and remissions which can last months to years. The disease can severely affect the quality of life. The development of squamous cell carcinomas has been rarely reported at HHD skin lesions.

Pathogenesis

The gene for HHD was identified in 2000 as being ATP2C1, encoding the related human secretory pathway Ca2+/Mn2+ ATPase (hSPCA1) on chromosomal region 3q21-24. SPCA1 transports Ca2+ and Mn2+ ions from the cytosol to the Golgi lumen, and therefore plays a major role in the cytosolic and intra-Golgi Ca2+ and Mn2+ homeostasis.
More than 80 pathogenic ATP2C1 mutations have been reported to date. Mutations do not cluster but are scattered across the ATP2C1 gene and show substantial allelic heterogeneity. Of these mutations, 20% are nonsense mutations and 30% are frameshift mutations, indicating that at least 50% of ATP2C1 mutations reported so far lead to premature termination codons (PTC). These mutations predict loss of expression or marked reduction of mutated ATP2C1 via nonsense-mediated mRNA decay, further supporting the possibility that haploinsufficiency of ATP2C1 is a prevalent mechanism for the dominant inheritance of HHD. Nineteen percent of the mutations affect splice sites, but their effects on splicing remains to be determined. Twenty-eight percent of the mutations are missense mutations, while the remaining three percent are in-frame mutations. These mutations lead to amino acid changes in highly conserved critical functional domains of the Golgi Ca2+ pumps from different species (rat, yeast), and between SERCA and PMCA pumps. Some of these mutations occur at amino acid residues which by site directed mutagenesis have been shown to abrogate SERCA1 function.

Comparison between genotype and phenotype, however, fails to detect any clear correlation between the nature of the mutation and the clinical features of HHD (age of onset, severity, progression). Extensive inter-familial and intra-familial variation in clinical features has also been noted, as well as between families sharing the same mutation. In view of the ubiquitous expression of ATP2C1, it is not clear why defects in ATP2C1 result in a disease restricted to the skin, and why it is limited to certain areas of the skin. The mechanism by which mutant ATP2C1 cause acantholysis is also unknown. HHD keratinocytes in culture display elevated resting cytosolic Ca2+, abnormally low Golgi Ca2+ levels, and impaired regulation of excess cytosolic Ca2+ in vitro. Abnormal Ca2+ signaling in HHD keratinocytes correlates with decreased protein levels of ATP2C1. In vivo, clinically normal HHD epidermis contains lower Ca2+ stores and displays an abnormal Ca2+ gradient. Elevated cytosolic Ca2+ could influence gene expression or alter post-translational modification of target proteins (activation of protein kinase C). Alternatively, low Ca2+ or Mn2+ concentrations in the Golgi lumen could impair post-translational modifications (proteolytic processing, glycosylation, trafficking or sorting) of membrane (associated) proteins important in epidermal cell-to-cell adhesion, such as desmosomal components. This may impair desmosome formation and/or stability, leading to the acantholysis characteristic of HHD.

Diagnosis

Histopathology of skin lesions shows widespread loss of cohesion between suprabasal keratinocytes (acantholysis) giving the appearance of a “dilapidated brick wall”. Vesicle formation or epidermal clefting is possible. Dyskeratosis, when present, is mild. There is a considerable clinical and histological overlap with Darier disease, although acantholysis is more widespread in HHD, while dyskeratosis is a predominant feature of Darier disease. Because lesions can considerably vary, the disease can be misdiagnosed as eczema, bacterial or fungal or viral infection, pemphigus.

Treatment

HHD is a difficult disease to treat, and various therapeutic modalities must be considered. Topical corticosteroids associated with antibacterial agents can result in transient improvement. More widespread flares may require systemic antibiotics (erythromycin and tetracyclines). Bacterial culture and sensitivity are useful for appropriate antibiotics. In patients with refractory disease, the response to dapsone, systemic corticosteroids, retinoids (acitretin or isotretinoin), immunomodulators (methotrexate, thalidomide, cyclosporine) is usually poor.

Treatment with systemic or topical calcipotriol was reported to be efficient. More recently, topical application of tacrolimus was also found to be effective. Surgery could remain an option in the absence of response to these treatments. Advice about diet and activity may also be useful. To help minimize friction, patient weight should be maintained at appropriate levels, and comfortable clothing should be recommended to prevent heat, moisure and friction