Familial Benign Pemphigus (Hailey-Hailey Disease)

Updated: Jul 07, 2022
  • Author: Thomas N Helm, MD; Chief Editor: Dirk M Elston, MD  more...
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Familial benign pemphigus (Hailey-Hailey disease) originally was described by the Hailey brothers in 1939. [1] Familial benign pemphigus is a chronic autosomal dominant disorder with incomplete penetrance. Approximately two thirds of patients with familial benign pemphigus have a family history of the disorder. A history of multiple relapses and remissions is characteristic. Decreased numbers of desmosomes have been implicated in the pathogenesis of benign familial pemphigus. Therapeutic options are limited.

Medscape Drugs & Diseases articles on pemphigus include Pemphigus Erythematosus, Pemphigus Foliaceus, Pemphigus Herpetiformis, and Pemphigus Vulgaris.



Keratinocytes are held together through desmosomes and adherens junctions. These junctions consist of calcium-binding transmembrane glycoproteins, which contribute to cellular adhesion. Many hypotheses exist concerning the pathogenesis of familial benign pemphigus, but the cause remains uncertain. An overall defect in keratinocyte adhesion appears to be secondary to a primary defect in a calcium pump protein, ATP2C1.

ATP2C1 encodes the secretory pathway Ca2+/Mn2 ATPase (hSPCA1). Mutant proteins in familial benign pemphigus create a loss of sensitivity to Ca2+ and Mn2+ ion binding and transport. Low levels of Ca2+ within Golgi bodies impair protein processing. Gene expression may be affected in benign familial pemphigus, as may phosphorylation of adhesion molecules. Localized postzygotic mutation has caused segmental manifestations of familial benign pemphigus. [2, 3]

A 2009 study has shown that the calcium content of basal keratinocytes is lower than in normal skin and that transition of keratin 14 to 10 is abnormal. [4] . Study of familial and sporadic cases of familial benign pemphigus in the Chinese population has revealed a number of mutations scattered throughout the ATP2C1 gene. [5] At least 81 different mutations have been identified to date.



Hailey-Hailey disease, or familial benign pemphigus, is hypothesized to result from a genetic defect in a calcium pump protein. The pump mutation is in ATP2C1, a gene localized on chromosome 3. [6] This gene defect is similar to the genetic defect in Darier disease, which also is a calcium pump defect, ATP2A2. The gene ATP2C1 encodes the human secretory pathway Ca++ -ATPase hSPCA1, which is dysfunctional and causes abnormal calcium release from the Golgi apparatus and endoplasmic reticulum. Acantholytic dermatosis of the crural folds may be a variant of Hailey-Hailey disease (familial benign pemphigus) and is also associated with ATP2C1 mutation. [7]

Pathways involved in PI3K-Akt signaling may play a role in the altered focal adhesion and extracellular matrix (ECM)‒receptor interactions noted in Hailey-Hailey disease. [8] Changes in protein digestion and absorption may impact microfibril-associated glycoprotein 4 and plakophilin. [8]

In addition to the primary gene defect in Hailey-Hailey disease (familial benign pemphigus), contributing factors are known that exacerbate the disease. These include heat, friction, and infection, resulting in separation of keratinocytes, especially in the intertriginous areas. Through ultrastructural studies of familial benign pemphigus lesions, characteristic changes in keratinocyte morphology have been described, including retracted tonofilaments, elongated membrane microvilli, and reduced numbers of desmosomes.




No precise data are available on the incidence of familial benign pemphigus.


Both sexes are affected equally by familial benign pemphigus.


Familial benign pemphigus often manifests in the late teenage years or in adulthood (30s and 40s).



Familial benign pemphigus causes discomfort but is not life threatening. Benign familial pemphigus lesions often begin during the teenage years and manifest as itchy and malodorous plaques. Patients with familial benign pemphigus live long and productive lives. The skin disorder is more of a nuisance than a serious health threat. New treatment options are under study and offer hope for better treatments in the future.


Patient Education

Patients with familial benign pemphigus must be instructed to recognize flares in the disease promptly and to seek treatment for secondary infection before it becomes severe.