50: Acantholytic Disorders Flashcards
What are the typical age ranges for the first manifestations of Darier Disease?
First manifestations usually appear between ages of 6 and 20 years, with a peak between 11 and 15 years. It may also develop in infants or older adults.
What are some common cutaneous findings associated with Darier Disease?
Common cutaneous findings include:
- Itch, malodor, and pain.
- Exacerbation due to heat, sweating, and sunlight (UVB).
- Discrete, greasy yellowish-brown keratotic papules with a predilection for seborrheic areas.
- Papules coalescing into crusted plaques.
- Foul-smelling hypertrophic disease in the groin.
- Nail changes such as fragility and longitudinal splits.
What are the clinical variants of Darier Disease?
Clinical variants of Darier Disease include:
- Painful erosive DD
- Vesiculobullous DD
- Cornifying DD (grossly hyperkeratotic plaques)
- Nipple hyperkeratosis
- Keratoderma
- Comedonal DD
- Freckled ‘Groveroid’ DD
- Guttate leukoderma with confetti-like hypopigmented macules and papules
- Acrokeratosis verruciformis of Hopf (AKV)
What is the inheritance pattern of Darier Disease?
Darier Disease is inherited in an autosomal dominant manner, affecting both sexes and all ethnic groups. The penetrance is complete, but spontaneous mutations are frequent.
What are the characteristics of Type 1 Mosaicism in Darier Disease?
Type 1 Mosaicism in Darier Disease is characterized by:
- One or more unilateral bands of keratotic papules following Blaschko lines.
- Reflects postzygotic somatic mutation in the ATP2A2 gene early in embryogenesis.
What are the common cutaneous findings associated with Darier Disease, particularly regarding the age of onset and symptoms?
- First manifestations usually appear between ages of 6 and 20 years, with a peak between 11 and 15 years.
- Symptoms include itch, malodor, and pain.
- Exacerbations can occur due to heat, sweating, and sunlight (UVB) exposure.
- Characteristic findings include greasy yellowish-brown keratotic papules that may coalesce into crusted plaques and affect seborrheic areas.
How does the presence of nail changes serve as an indicator for Darier Disease?
- Nail changes such as fragility, painful longitudinal splits, and distinctive red and white longitudinal bands terminating in V-shaped nicks are frequent and highly suggestive of Darier Disease.
- More than 96% of patients may have affected hands, nails, or both, which can be among the first signs of the disease.
What are the clinical variants of Darier Disease and their characteristics?
Clinical Variant | Description |
|——————|————-|
| Painful erosive DD | Characterized by painful erosions. |
| Vesiculobullous DD | Presents with vesicles and bullae. |
| Cornifying DD | Features grossly hyperkeratotic plaques. |
| Nipple hyperkeratosis | Thickening of the skin around the nipples. |
| Keratoderma | Thickened skin on palms and soles. |
| Comedonal DD | Presence of comedones. |
| Groveroid DD | Freckled appearance with specific lesions. |
| Guttate leukoderma | Confetti-like hypopigmented macules and papules. |
| Acrokeratosis verruciformis of Hopf (AKV) | Mimics other forms but has distinct histology.
What are the characteristics of Type 1 and Type 2 Mosaicism in Darier Disease?
Type | Characteristics |
|——|—————–|
| Type 1 Mosaicism | - One or more unilateral bands of keratotic papules following Blaschko lines.
- Reflects post-zygotic somatic mutation in ATP2A2 early in embryogenesis. |
| Type 2 Mosaicism | - Very rare, reported only twice.
- Excessively pronounced unilateral linear band of DD with segmental pattern superimposed on generalized disease.
- Caused by a postzygotic mutation at the ATP2A2 locus.
What are the clinical variants of Darier Disease?
Variants include painful erosive DD, vesicobullous DD, cornifying DD, nipple hyperkeratosis, keratoderma, comedonal DD, freckled ‘Groveroid’ DD, and guttate leukoderma.
A patient presents with greasy yellowish-brown keratotic papules in seborrheic areas and nail fragility. What is the likely diagnosis, and what gene mutation is associated with it?
The likely diagnosis is Darier Disease (DD), and it is associated with mutations in the ATP2A2 gene.
A patient with Darier Disease has nail fragility and V-shaped nicks. What other nail findings might you observe?
Other nail findings include painful longitudinal splits and distinctive red and white longitudinal bands.
What are the noncutaneous findings associated with Darier Disease?
- Oral, esophageal, rectal, and cervical mucosa with white papules
- Corneal abnormalities
- Bone changes, particularly bone cysts
What related physical findings are observed in patients with Darier Disease?
- Neuropsychiatric disease including seizures, bipolar disorder, and schizophrenia
- Lithium, prescribed for bipolar disorder, exacerbates Darier Disease possibly by suppressing levels of epidermal SERCA2.
What complications can arise from Darier Disease?
- Impetiginization and eczematization
- Eczema herpeticum and Herpes zoster virus
- Blockage of salivary glands
- Squamous cell carcinoma has been reported infrequently, sometimes associated with HPV.
What is the genetic basis of Darier Disease?
- The gene for Darier Disease is ATP2A2 located on chromosome region 12q23-24.
- Darier Disease is caused by inactivating ONE ATP2A2 allele.
- ATP2A2 encodes sarco- and endoplasmic reticulum Ca2+ adenosine triphosphatase (ATPase) isoform 2 (SERCA2).
What are the three isoforms of SERCA2 and their expression?
Isoform | Expression |
|———–|———————————————-|
| SERCA2a | Expressed in slow twitch skeletal and cardiac muscle (unaffected in DD) |
| SERCA2b | Ubiquitously expressed, MAJOR ISOFORM in the epidermis |
| SERCA2c | Ubiquitously expressed |
What are the pathophysiological changes in keratinocytes in Darier Disease?
- High concentrations of Ca2+ are required for normal keratinocyte intercellular adhesion and differentiation.
- Breakdown of desmosomes with aggregation of keratin filaments around the cell nucleus is the earliest ultrastructural change.
- Dyskeratotic cells in the epidermis are formed through apoptosis, triggered by the loss of adhesion.
What role do glucosidases play in the maturation of desmosomal proteins in Darier Disease?
- Glucosidases are essential for the proper maturation of essential transmembrane proteins such as desmosomal proteins.
- Miglustat, a glucosidase inhibitor, was shown to restore normal E-cadherin and desmosomal localization, improving intercellular strength of Darier keratinocytes.
What histopathological features are observed in the epidermis of patients with Darier Disease?
- Downgrowths of narrow cords of keratinocytes
- Suprabasal acantholysis with suprabasal cleft (lacunae)
- Dyskeratosis (premature and abnormal keratinization)
- Hyperkeratosis
- Apoptosis results in rounded eosinophilic dyskeratotic cells and flatted parakeratotic cells in the cornified layer.
What are the noncutaneous findings associated with Darier Disease (DD)?
Noncutaneous findings in Darier Disease include:
- Oral, esophageal, rectal, and cervical mucosa with white papules
- Corneal abnormalities
- Bone changes, particularly bone cysts.
How does lithium affect patients with bipolar disorder who also have Darier Disease?
Lithium, prescribed for bipolar disorder, may exacerbate Darier Disease by suppressing levels of epidermal SERCA2, which is crucial for calcium transport in keratinocytes.
What is the genetic basis of Darier Disease?
Darier Disease is caused by inactivating mutations in the ATP2A2 gene located on chromosome region 12q23-24. This gene encodes the sarco- and endoplasmic reticulum Ca2+ ATPase isoform 2 (SERCA2), which is essential for calcium transport in cells.
What are the implications of SERCA2 mutations in the pathogenesis of Darier Disease?
Mutations in SERCA2 lead to impaired calcium transport, resulting in reduced intercellular adhesion and differentiation of keratinocytes. This disruption contributes to the characteristic dyskeratosis and other skin abnormalities seen in Darier Disease.