Hyperkeratosis Lenticularis Perstans (Flegel Disease) 

Updated: Jan 31, 2017
Author: Daniel Roling, MD; Chief Editor: William D James, MD 

Overview

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.[1] 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; some investigators have implicated UV light. However, in one case report, evidence of Borrelia infection (Borrelia burgdorferi and Borrelia garinii) was found using DNA sequencing in fresh tissue and blood from a patient with hyperkeratosis lenticularis perstans, without clinical evidence of Lyme borreliosis.[2] 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 hyperkeratosis lenticularis perstans lesions. Some authors have suggested that a cell-mediated cytotoxicity against epithelial cells may be involved in the pathogenesis of hyperkeratosis lenticularis perstans.

Epidemiology

Frequency

United States

No data exist on incidence or prevalence of this disease. Hyperkeratosis lenticularis perstans (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.[3]

International

Most cases have been reported in Europe. International incidence is similar to that seen in the United States.

Race

Hyperkeratosis lenticularis perstans does not have a race predilection, although it has mostly been reported in the white population.

Sex

No sex predilection is apparent.

Age

Hyperkeratosis lenticularis perstans reportedly occurs most commonly in mid-to-older age groups; however, reports exist of hyperkeratosis lenticularis perstans occurring in patients as young as 13 years.

Prognosis

Except for the possibility that lesions may progress slowly and involve more proximal sites, prognosis for hyperkeratosis lenticularis perstans (Flegel disease) is excellent. No mortality has been reported.

 

Presentation

History

Small keratotic papules typically begin to develop symmetrically on the lower extremities (see the images below).

Clinical photograph of the upper thigh showing num Clinical photograph of the upper thigh showing numerous red-brown papules with sparing of the inguinal crease.
A higher-powered view of the patient seen in the p A higher-powered view of the patient seen in the previous image. Photograph of the upper thigh demonstrates 1- to 4-mm, noncoalescing keratotic papules.

Papules spread proximally at a slow rate. Hyperkeratosis lenticularis perstans usually is an asymptomatic condition.

Physical Examination

Small, red-brown, hyperkeratotic, 1-5 mm papules on the lower extremities are the most frequent and characteristic presentation of hyperkeratosis lenticularis perstans.[4, 5] Involvement of the eyes, ear pinnae, arms, axillae, 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.[6, 7]

Dermatoscopic findings suggest a brown, structureless center with peripheral scaly, white areas enhanced by polarized light.[8]

Removal of the scale reveals a bright-red base, often with pinpoint bleeding. A localized unilateral variant has been reported.[9, 10] The trunk tends to be spared; absence of axial lesions is characteristic.

Causes

To date, the causes of hyperkeratosis lenticularis perstans (Flegel disease) are unknown. Some authors suggest that exposure to the sun may be involved.

 

DDx

Diagnostic Considerations

Consider disseminated superficial actinic porokeratosis (DSAP). 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.

Numerous reports exist in the literature that associate hyperkeratosis lenticularis perstans (Flegel disease) with an endocrinopathy. At a minimum, 4 reports were associated with adult-onset diabetes and 2 with hyperthyroidism.

A relationship between hyperkeratosis lenticularis perstans (Flegel disease) 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 hyperkeratosis lenticularis perstans (Flegel disease) lineage. A possible association between cancers of the digestive system and hyperkeratosis lenticularis perstans (Flegel disease) also has been implied.

The association of hyperkeratosis lenticularis perstans (Flegel disease) with endocrinopathies, skin, and GI neoplasms is weak at best. Certain factors (including rarity of hyperkeratosis lenticularis perstans (Flegel disease) and high prevalence of associated diseases) suggest a reporting bias.

Differential Diagnoses

 

Workup

Other Tests

Since several reports have associated hyperkeratosis lenticularis perstans (Flegel disease) 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 hyperkeratosis lenticularis perstans (Flegel disease). 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. A lymphoid infiltrate with occasional histiocytes in a bandlike pattern in the papillary dermis typically is seen. See the images below.

Hematoxylin and eosin-stained section, low magnifi 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.
Hematoxylin and eosin-stained section, medium magn Hematoxylin and eosin-stained section, medium magnification. The lateral edge of the lesion demonstrates abrupt hyperkeratosis and a combination of epidermal atrophy and acanthosis.
Hematoxylin and eosin-stained section, high magnif 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.

Some evidence has indicated that older lesions may show some histologic differences compared with newer ones.[11] 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.[12]

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.

 

Treatment

Medical Care

A variety of topical agents have been used to treat this disease, but none is universally effective.

Reports on the effectiveness of tacalcitol and calcipotriol conflict with another report stating they are not effective,[13] and yet another report saying calcipotriol is effective.[14]

Topical 5% fluorouracil and a synthetic vitamin D-3 derivative have been used together with effective results.[14]

The most consistently successful therapies have been the topical application of 5% fluorouracil cream (over several months), local excision, and dermabrasion (see Surgical Care).[15, 16]

In 1986, Gabrielsen reported that hyperkeratosis lenticularis perstans (Flegel disease) was effectively treated with etretinate. Initially, treatment aggravated the condition; however, after 10 weeks of treatment, the papules of hyperkeratosis lenticularis perstans (Flegel disease) nearly all resolved.[17]

Oral retinoids have been successful with continuous therapy. However, short-coarse oral retinoid therapy has also shown success in one case.[7] Patients tend to relapse when therapy is discontinued.

Tretinoin, emollients, psoralen with ultraviolet A (PUVA), and keratolytics have shown varying, but mostly unrewarding, results, even in combination.[18, 19, 20] Topical steroids have similarly shown mixed results, although betamethasone dipropionate showed a response in a 2008 case study.[21]

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.

 

Medication

Medication Summary

These medications have proven the most efficacious for the treatment of hyperkeratosis lenticularis perstans (Flegel disease).

Topical cytotoxic agents

Class Summary

Inhibit cell growth and proliferation.

Fluorouracil topical (Efudex, Fluoroplex)

Fluorouracil has been in clinical use since the 1960s. Systemic absorption is limited to approximately 6% of the applied dose and is selectively higher in abnormal skin. Fluorouracil interferes with pyrimidine metabolism by inhibiting thymidylate synthetase, thus inhibiting DNA synthesis.

It is available as 5% (Efudex) or 1% (Fluoroplex) cream, 2% or 5% solution (both Efudex), or 1% solution (Fluoroplex).

If applied with the fingers, wash hands immediately after application.

Fluorouracil is FDA approved for the treatment of actinic keratosis and superficial basal cell carcinomas.

Vitamins

Class Summary

Essential for normal DNA synthesis.

Calcipotriene (Dovonex)

Calcipotriene is 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.