Darier Disease and Hailey-Hailey Disease

Question 1

What is the inheritance pattern of Darier’s disease?

Answer 1

AD, complete penetrance and variable expressivity

Question 2

What is the peak onset for Darier’s disease?

Answer 2

Puberty (70% prior to 20 y/o)

Question 3

What is the mutation in Darier’s disease and what is the protein that is affected?

Answer 3

ATP2A2 –> encodes SERCA2 which is a calcium ATPase of the endoplasmic reticulum

Question 4

Pathogenesis of Darier’s disease?

Answer 4

The mutation in SERCA leads to defective Ca²⁺ in the endoplasmic reticulum which leads to impaired synthesis and folding of cell adhesion proteins leading to keratinocyte acantholysis and apoptosis

• This happens in the skin and not elsewhere we believe because keratinocytes lack the SERCA3 protein that compensates for this defect elsewhere in other tissues

Question 5

What are the general skin findings in Darier’s disease?

Answer 5

Malodorous, warty, crusted, and red-brown papules/plaques in a seborrheic distribution

almost always see keratotic palmar papules/pits; longitudinal red and white alternating nail streaks with distal “v-shaped” notiching, and some have the oral cobblestoning (most commonly on the hard palate)

Question 6

What is segmental Darier’s type I?

Answer 6

Most common form of segmental Darier’s

• Blaschkoid streaks of Darier’s lesions; post-zygotic ATP2A2 lesions

Question 7

What is segmental Darier’s disease type II?

Answer 7

Generalized Darier’s w/ focal areas of severe involvement; heterozygous germline mutation + postzygotic loss of other allele

Question 8

What should you suspect if you see erosions or vesicles in a patient w/ Darier’s disease?

Answer 8

You need to suspect Kaposi’s varicelliform eruption which is a herpes superinfection of lesions –> needs to be treated w/ systemic antiviral like valacyclovir

Question 9

What is the classic histopathology of Darier’s disease?

Answer 9

Papillomatous epidermal hyperplasia w/ epidermal acantholysis and dyskeratosis

Classically see corps ronds (large acantholytic keratinocytes in malpighian layer w/ darkly staining and fragmented nuclei w/ surrounding clear cytoplasm and a bright ring of keratin bundles) and grains (highly eosinophilic oval cells in the stratum corneum w/ eosinophilic cytoplasm made of collapsed keratin bundles and shrunken parakeratoitc nuclear remenants)

Question 10

What is the treatment for Darier’s disease?

Answer 10

Systemic: retinoids are the most effective (effective in ~90%)

Topical: topical steroids are best as monotherapy, can be used w/ topical steroids

Skin care: Daily cleansing w/ antimicrobial washes, keratolytic lotions/creams and abundant use of emollients. Likewise, good sun avoidance (UVB can worsen), light clothes (occlusion worsens), and avoidance of occlusion in warm/humid environments can all help

Question 11

What is the inheritance of Hailey-Hailey disease?

Answer 11

AD, complete penetrance, variable expressivity

Question 12

What is the range of age onset for Hailey-Hailey disease?

Answer 12

Wider than for Darier’s, often teens to 20 y/o but may arise earlier

Question 13

What is the mutation in Hailey-Hailey disease and what protein does it encode for?

Answer 13

ATP2C1 –> encodes hSPCA1, a Ca²⁺ ATPase of the Golgi apparatus which leads to defective Ca²⁺ sequestration into the golgi –> impaired processing of proteins involved in cell-cell adhesion –> acantholysis

Question 14

Pathogenesis of Hailey-Hailey disease?

Answer 14

mutation in ATP2C1 leads to defective hSPCA1, a Ca2+ ATPase of the Golgi apparatus which leads to defective Ca2+ sequestration into the golgi –> impaired processing of proteins involved in cell-cell adhesion –> acantholysis

Question 15

What is the most common distribution of Hailey-Hailey disease?

Answer 15

Intertriginous sites (lateral neck, inframammary, axillae, groin, and perianal

No mucosal involvement This can be helpful for comparing w/ Darier’s which can have the cobblestone-like lesions in the mouth

Question 16

What is the morphology of the lesions in Hailey-Hailey disease?

Answer 16

Subtle, flaccid vesicle on normal or inflamed skin. When these rupture it leads to macerated, eroded plaques often w/ circinate shape

Question 17

Are the lesions in Hailey-Hailey disease susceptible to secondary infection?

Answer 17

Yes! like Darier’s disease, these too can get Kaposi’s varicelliform eruption and other less serious infections

Question 18

What is the typical histology for Hailey-Hailey disease?

Answer 18

Psoriasiform hyperplasia (differentiating from pemphigus) w/ diffuse acantholysis (dilapidated brick wall); fewer dyskeratotic keratinocytes as Darier’s

Question 19

Treatment for Hailey-Hailey disease?

Answer 19

Topical steroids; surgical intervention (CO2 laser ablation) can be effective

Systemic retinoids are not nearly as effective for Hailey-Hailey disease as for Darier’s

Question 20

What are the seasonal effects noted with Darier’s disease?

Answer 20

Often worse in the summer months due to heat, sweating, and also UVB appears to also worsen lesions

Question 21

What seasonal effects are noted with Hailey-Hailey disease?

Answer 21

Like Darier’s can be worsened by the heat/humidity of summer but UV does not appear to have the same effect as in Darier’s

Question 22

What should be considered if you see widespread and severe blistering in Hailey-Hailey disease?

Answer 22

A staphylococcal infection which can potentiate this worsening