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 flexural areas. 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 fourth decade. HHD is characterized by vesicular lesions, painful erosions and scaly erythematous, itchy plaques, which occur usually symmetrically at sites of friction and flexures (e.g. neck, axillae, submammary region, umbilicus, groins and the perineum). The lesions often result in malodorous vegetations and tend to spread peripherally forming annular shapes. Painful fissures (“rhagades”) in flexures are common and highly suggestive of the disease. Secondary infections are common. Wound healing is impaired and results in postinflammatory hyperpigmentation or scarring.

Mucosal involvement is rare, but oral, esophageal and vulvar involvement has been reported. Longitudinal white lines on the fingernails (longitudinal leukonychia) are occasionally present and of diagnostic value. 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 limit patient mobility. There are no extracutaneous manifestations.

The development of squamous cell carcinomas has been rarely reported at HHD skin lesions. Lesions are frequently induced or exacerbated by UV exposure, sweating, friction and microbial colonization. The disease has a chronic fluctuating course, and patients undergo recurrent exacerbations and remissions which can last months to years. Flares usually become less frequent with age. The disease severely affects the quality of life, due to burdensome symptoms like pain, pruritus and predilection for cutaneous infections. 2-5

 

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 3q21-24.6, 7 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.
Up-to-date known mutations do not cluster but are scattered across the ATP2C1 gene and show substantial allelic heterogeneity. A broad inter-familial and intra-familial variation in clinical features has been noted. 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. 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. 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.2, 8

Penetrance in adults is complete, but expressivity is variable between and within affected families.

 

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 is sparse or missing. 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. Dermoscopic features include irregular pink and white areas separated by pink furrows along with polymorphous vessels.9, 10 Diagnosis can be confirmed by molecular analysis of the ATP2C1 gene.

Apart from Darier disease, further differential diagnosis include eczema, bacterial, fungal and viral infections as well as pemphigus.11

 

Treatment

Up-to-date, various therapeutic modalities failed to provide long-term relief for the majority of patients. Topical corticosteroids combined with antibacterial agents may induce transient improvement, similar to topical calcipotriol and tacrolimus. More widespread flares may require systemic antibiotics (erythromycin and tetracyclines). Bacterial culture and sensitivity are useful for choosing the appropriate antibiotics. In patients with refractory disease, dapsone, systemic corticosteroids, retinoids (acitretin or isotretinoin), naltrexone, immunomodulators (methotrexate, thalidomide, cyclosporine), afamelanotide and glycopyrrolate have been tried as well as photodynamic therapy and electron beam radiotherapy. The response in general is rather poor to those treatment options. Surgery or laser ablation could remain an option in the absence of response to these treatments, although carrying the risk of postoperative complications. Botulinic toxin seems to be an effective treatment option for some patients as well and should be the first choice when more conservative therapies have failed. Advices about diet, activity, comfortable clothing and weight management, to minimize friction, may be useful. The effect of sun exposure varies between patients – some report improvement, others worsening of skin symptoms. 12-16

 

References

1. Hailey H, Hailey H. Familial benign chronic pemphigus. Archives of Dermatology and Syphilology. 1939;39(4):679-685.

2. Deng H, Xiao H. The role of the ATP2C1 gene in Hailey–Hailey disease. Cellular and Molecular Life Sciences. 2017;74(20):3687-3696.

3. Burge SM. Hailey–Hailey disease: the clinical features, response to treatment and prognosis. British Journal of Dermatology. 1992;126(3):275-282.

4. Holst VA, Fair KP, Wilson BB, Patterson JW. Squamous cell carcinoma arising in Hailey-Hailey disease. J Am Acad Dermatol. 2000;43(2):368-371.

5. Gisondi P, Sampogna F, Annessi G, Girolomoni G, Abeni D. Severe impairment of quality of life in Hailey-Hailey disease. Acta Derm Venereol. 2005;85(2):132-135.

6. Hu Z, Bonifas JM, Beech J, et al. Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nat Genet. 2000;24(1):61-65.

7. Sudbrak R, Brown J, Dobson-Stone C, et al. Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca(2+) pump. Hum Mol Genet. 2000;9(7):1131-1140.

8. Yang L, Zhang Q, Zhang S. Generalized Hailey-Hailey disease: Novel splice-site mutations of ATP2C1 gene in Chinese population and a literature review. 2020:e1580.

9. Kelati A, Argenziano G, Mernissi FZ. Dermoscopic presentation of Hailey-Hailey. J Am Acad Dermatol. 2017;76:S31-33.

10. Oliveira A, Arzberger E, Pimentel B, de Sousa V, Leal‐Filipe P. Dermoscopic and reflectance confocal microscopic presentation of Hailey‐Hailey disease: A case series. Skin Research and Technology. 2018;24(1):85-92.

11. See SHC, Peternel S. Distinguishing histopathologic features of acantholytic dermatoses and the pattern of acantholytic hypergranulosis. 2019;46(1):6-15.

12. Dreyfus I, Maza A, Rodriguez L, et al. Botulinum toxin injections as an effective treatment for patients with intertriginous Hailey-Hailey or Darier disease: an open-label 6-month pilot interventional study. Orphanet J Rare Dis. 2021;16(1):93.

13. Rubegni P, Poggiali S, Sbano P, Risulo M, Fimiani M. A case of Darier's disease successfully treated with topical tacrolimus. J Eur Acad Dermatol Venereol. 2006;20(1):84-87.

14. Tchernev G, Cardoso JC. Familial benign chronic pemphigus (Hailey-Hailey Disease): use of topical immunomodulators as a modern treatment option. Rev Med Chil. 2011;139(5):633-637.

15. Farahnik B, Blattner CM, Mortazie MB, Perry BM, Lear W, Elston DM. Interventional treatments for Hailey-Hailey disease. J Am Acad Dermatol. 2017;76(3):551-558.e553.

16. Alsahli M, Debu A, Girard C, et al. Is photodynamic therapy a relevant therapeutic option in refractory benign familial pemphigus (Hailey–Hailey disease)? A series of eight patients. Journal of Dermatological Treatment. 2017;28(7):678-682.