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Dermatology > PAPULOSQUAMOUS DISEASES
Hyperkeratosis Lenticularis Perstans (Flegel Disease)
Article Last Updated: Feb 14, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Daniel Roling, MD, Assistant Clinical Professor, Department of Dermatology, Hospital of the University of Pennsylvania
Daniel Roling is a member of the following medical societies: American Academy of Dermatology and Pennsylvania Medical Society
Coauthor(s):
Jacqueline M Junkins-Hopkins, MD, Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine
Editors: Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Columbia University; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Private Practice; Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA; Rosalie Elenitsas, MD, Associate Professor of Dermatology, University of Pennsylvania School of Medicine; Director, Penn Cutaneous Pathology Services, Department of Dermatology, University of Pennsylvania Health System; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System
Author and Editor Disclosure
Synonyms and related keywords:
Flegel's disease, HLP, Odland bodies, keratosis, keratotic papules
Background
Flegel originally described hyperkeratosis lenticularis perstans (HLP) in 1958 as red-brown papules with horny scales of irregular outline measuring 1-5 mm in diameter and up to 1 mm in depth. Lesions are located primarily on the dorsal feet and lower legs, with a decreasing likelihood of manifestation proximally. Most cases have been reported in Europe.
Pathophysiology
No instigating factor has been identified clearly; however, some investigators have implicated UV light. Ultrastructurally, a loss or decreased number of membrane-coating granules (also termed Odland bodies) has been reported. Membrane-coating granules are influential in the normal process of desquamation. A decrease, malformation, or absence of these membrane-coating granules may result in decreased desquamation of the stratum corneum, retention hyperkeratosis, and clinically keratotic HLP lesions. Some authors have suggested that a cell-mediated cytotoxicity against epithelial cells may be involved in the pathogenesis of HLP.
Frequency
United States
No data exist on incidence or prevalence of this disease. Flegel disease likely has both a familial and nonfamilial variant, since several reports have postulated both an autosomal dominant and a sporadic mode of inheritance.
International
Most cases have been reported in Europe. International incidence is similar to that seen in the United States.
Race
To date, all reports of HLP have been in white patients.
Sex
No sex predilection is apparent.
Age
HLP reportedly occurs most commonly in mid-to-older age groups; however, reports exist of HLP occurring in patients as young as 13 years.
History
- Small keratotic papules typically begin to develop symmetrically on the lower extremities (see Images 1-2).
- Papules spread proximally at a slow rate.
- HLP usually is an asymptomatic condition.
Physical
- Small, red-brown, hyperkeratotic, 1-5 mm papules on the lower extremities are the most frequent and characteristic presentation of HLP.
- Involvement of the ear pinnae, arms, palms, soles, and the oral mucosa has been reported, although these reports are rare. Involvement of the trunk has been reported but remains an unusual variant.
- Removal of the scale reveals a bright red base, often with pinpoint bleeding.
- A localized unilateral variant has been reported.
- The trunk tends to be spared; absence of axial lesions is characteristic.
Causes
To date, the causes of HLP are unknown. Some authors suggest that exposure to the sun may be involved.
Acrokeratosis Verruciformis of Hopf
Actinic Keratosis
Arsenical Keratosis
Keratosis Follicularis (Darier Disease)
Kyrle Disease
Porokeratosis
Stucco Keratosis
Other Problems to be Considered
Disseminated superficial actinic porokeratosis (DSAP) should be considered. Porokeratoses are progressive, hyperkeratotic, irregular plaques with a characteristic and prominent peripheral keratotic ridge. The superficial disseminated form occurs as a generalized symmetric process confined exclusively to sun-exposed areas. Lesions are small, 1- to 3-mm, keratotic lesions, with a central dell and a peripheral keratotic ridge that may number in the hundreds. DSAP is a relatively common condition occurring in the third and fourth decades, and it slowly progresses over years. Histologically, the peripheral, raised, keratotic ridge translates into a hyperkeratotic invagination in the epidermis termed cornoid lamellae. Cornoid lamellae are abrupt well-defined stacks of parakeratin confined to the periphery of the lesion. The underlying epidermis lacks a granular layer and frequently shows dyskeratosis.
Porokeratosis of Mibelli
Flat warts
Other Tests
- Since several reports have associated HLP with an endocrinopathy, obtain a thorough and complete systems review, as well as social and family histories. Laboratory, radiographic, or surgical tests are not needed, unless indicated by information gleaned from these sources.
Procedures
- Skin biopsy with hematoxylin and eosin staining shows characteristic findings of HLP. Electron microscopy is not essential.
Histologic Findings
A discrete area of hyperkeratosis occurs (with areas of parakeratosis) overlying a thinned stratum malpighii and thinned-to-absent granular layer. Irregular acanthosis and some vascular dilatation are peripheral (see Images 3-4). A lymphoid infiltrate with occasional histiocytes in a bandlike pattern in the papillary dermis typically is seen (see Images 4-5). Recently, some evidence has indicated that older lesions may show some histologic differences compared with newer ones. Older lesions can show absence of epidermal atrophy and may infiltrate the upper dermis. Ultrastructural studies also reveal the presence of many normal-appearing, membrane-coating granules in the keratinocytes of an old lesion, whereas these normal organelles were not found in the keratinocytes of earlier hyperkeratotic skin lesions. Electron microscopy Several authors have reported an absence or decrease in the number of membrane-coating granules, or Odland bodies, within lesional keratinocytes. Although other authors have found Odland bodies to be present, most suggest that the membrane-coating granules may undergo some alterations in number or morphology. Perilesional skin uniformly shows normal keratinocyte differentiation.
Medical Care
A variety of topical agents have been used to treat this disease, but none is universely effective.
- Reports on the effectiveness of tacalcitol and calcipotriol conflict with another report stating they are not effective (Blaheta, 2001) and yet another report saying calcipotriol is effective (Metze, 2000).
- Topical 5% fluorouracil and a synthetic vitamin D-3 derivative have been used together with effective results
- The most consistently successful therapies have been the topical application of 5% fluorouracil cream (over several months), local excision, and dermabrasion (see Surgical Care).
- In 1986, Gabrielsen reported that HLP was effectively treated with etretinate. Initally, treatment aggravated the condition; however, after 10 weeks of treatment, the papules of HLP nearly all resolved.
- Oral retinoids have been successful only with continuous therapy. Patients tend to relapse when therapy is discontinued.
- Tretinoin, topical steroids, emollients, psoralen with ultraviolet A (PUVA), and keratolytics have shown varying, but mostly unrewarding, results, even in combination.
Surgical Care
Dermabrasion is a possible surgical modality. However, a large number of lesions, as well as lesion location, make this an impractical approach. Local excision may be successful, especially if the number of lesions is small. Cryotherapy is an additional possibility.
These medications have proven the most efficacious for the treatment of HLP.
Drug Category: Topical cytotoxic agents
Inhibit cell growth and proliferation.
| Drug Name | Fluorouracil (Efudex, Fluoroplex) |
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| Description | In clinical use since 1960s. Systemic absorption is limited to approximately 6% of applied dose and is selectively higher in abnormal skin. Interferes with pyrimidine metabolism by inhibiting thymidylate synthetase, thus inhibiting DNA synthesis.
Available as 5% (Efudex) or 1% (Fluoroplex) cream, 2% or 5% solution (both Efudex), or 1% solution (Fluoroplex).
If applied with fingers, wash hands immediately after application.
FDA-approved uses are for treatment of actinic keratosis and superficial basal cell carcinomas. |
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| Adult Dose | Apply bid |
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity; potentially serious infections |
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| Interactions | None reported |
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| Pregnancy | X - Contraindicated in pregnancy
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| Precautions | Incidence of inflammatory reactions may occur with occlusive dressings; porous gauze dressing may be applied for cosmetic reasons without increase in reaction; patients should expect inflammatory reaction with crusting; common reactions to application include burning, redness, and pruritus |
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Drug Category: Vitamins
Essential for normal DNA synthesis.
| Drug Name | Calcipotriene (Dovonex) |
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| Description | A synthetic vitamin D-3 derivative that possesses therapeutic properties similar to vitamin D-3, including inhibition of epidermal proliferation, induction of differentiation, and anti-inflammatory effects. |
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| Adult Dose | 0.005% ointment, cream, or solution: Apply qd |
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity; hypercalcemia, vitamin D toxicity |
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| Interactions | None reported |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Hypercalcemia can occur if >100 g/wk used; cutaneous irritation (including redness, dry skin, pruritus) can occur in 20% of patients; use cautiously on face, groin, axillae, or other intertriginous areas |
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Prognosis
- Except for the possibility that lesions may progress slowly and involve more proximal sites, prognosis for HLP is excellent.
- No mortality has been reported.
Medical/Legal Pitfalls
- Failure to distinguish Flegel disease from the less benign conditions that it may simulate. A frequent mimicker is an actinic keratosis, which has a similar histologic pattern to acanthosis and hyperkeratosis but displays keratinocyte atypia. While Flegel disease has no known malignant potential, actinic keratoses have the potential to evolve into more aggressive squamous cell neoplasms. Both conditions can be treated appropriately using various destructive modalities including topical 5-fluorouracil.
Special Concerns
- Numerous reports exist in the literature that associate HLP with an endocrinopathy. At a minimum, 4 reports were associated with adult-onset diabetes and 2 with hyperthyroidism.
- A relationship between HLP and malignancies has been suggested. One report describes epithelial tumors (basal and squamous cell carcinomas) occurring at distant, uninvolved, and nonlesional sites in patients with a familial HLP lineage. A possible association between cancers of the digestive system and HLP also has been implied.
- The association of HLP with endocrinopathies, skin, and GI neoplasms is weak at best. Certain factors (including rarity of HLP and high prevalence of associated diseases) suggest a reporting bias.
| Media file 1:
Clinical photograph of the upper thigh showing numerous red-brown papules with sparing of the inguinal crease. |
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| Media file 2:
A higher-powered view of the patient seen in Image 1. Photograph of the upper thigh demonstrates 1- to 4-mm, noncoalescing keratotic papules. |
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Media type: Photo
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| Media file 3:
Hematoxylin and eosin-stained section, low magnification. Epidermal hyperplasia with rete elongation surmounted by a thickened, compact, hyperkeratotic scale. A bandlike lymphoid infiltrate expands the papillary dermis. |
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Media type: Photo
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| Media file 4:
Hematoxylin and eosin-stained section, medium magnification. The lateral edge of the lesion demonstrates abrupt hyperkeratosis and a combination of epidermal atrophy and acanthosis. |
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Media type: Photo
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| Media file 5:
Hematoxylin and eosin-stained section, high magnification. The section shows mostly orthokeratotic scale, thinning of the epidermis with a diminished granular cell layer, and an infiltrate of lymphocytes in the superficial dermis, which approximate the dermal-epidermal interface. |
 | View Full Size Image | |
Media type: Photo
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Hyperkeratosis Lenticularis Perstans (Flegel Disease) excerpt Article Last Updated: Feb 14, 2007
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