No longer flailing with Flegel disease

By Warren R. Heymann, MD, FAAD
April 19, 2023
Vol. 5, No. 16

I was a toddler in 1958 when Heinz Flegel described hyperkeratosis lenticularis perstans (HLP) a 50-year-old man with persistent lesions on his dorsal feet and lower extremities. (1) In the ensuing decades, other than the clinical and histologic depictions of Flegel disease (FD), what do we genuinely understand about the disorder? As my late grandmother Dora would say, “gornisht mit gornisht” (“nothing with nothing,” in Yiddish). Can we do better? Fortunately, perhaps we can.

HLP usually affects people in the second through fifth decades of life, affecting both genders and all races. FD is considered a rare disorder, although its incidence and prevalence are unknown. Familial cases (inherited in an autosomal dominant fashion) and sporadic cases have been reported. HLP is characterized by asymptomatic to mildly pruritic, symmetrical, small erythematous, or brownish hyperkeratotic papules that affect mainly the limbs, especially the dorsal feet and lower legs. Occasionally, HLP may be appreciated at other sites (such as the trunk, upper extremities, palms, soles, and even the oral mucosa). Rare presentations demonstrate unilaterality or Koebnerization. Characteristically, curettage of the hyperkeratotic components of the lesion leads to slight bleeding. (1,2)

Dermoscopic features of HLP are brown-gray structureless areas with scaly white areas at the periphery of the lesion that are enhanced by polarized light. (3,4) These correlate with histological features, which depend on the age of the lesion. Key features include hyperkeratosis (with variable parakeratosis) atop an atrophic epidermis accompanied by an attenuated or absent granular layer; acanthosis may be noted at the periphery. Subjacent to the attenuated epidermis, a lichenoid mononuclear infiltrate is appreciated and vascular dilatation is observed. As lesions age, epidermal atrophy and the inflammatory infiltrate may be absent. (5) Immunohistochemical studies demonstrated CD4 > CD8 positivity. (6) CD30 cells may be observed. (7) Ultrastructural studies revealed that the presence of many normal-appearing membrane-coating granules (Odland bodies) in the keratinocytes of the older lesion whereas these organelles were not found in the keratinocytes of the early lesion. (6)

The differential diagnosis of HLP includes punctate porokeratosis (usually on the palms and soles, demonstrating a cornoid lamella on histology), acrokeratosis verruciformis of Hopf (often associated with Darier disease, displaying hyperkeratosis, papillomatosis, and acanthosis on biopsy), perforating granuloma annulare (presenting as umbilicated, keratotic papules with transepidermal elimination of degenerated collagen histologically), stucco keratoses (usually dorsal feet and ankles with orthokeratosis overlying an acanthotic epidermis microscopically). (8)

The etiology of FD remains a mystery, with the perpetual question of whether this is a disorder of keratinization/epidermal differentiation with secondary inflammation, versus an inflammatory disorder with secondary epidermal changes, or some combination thereof. Although attention has focused on the role of Odland bodies in HLP (given their function in desquamation of the stratum corneum where their absence could lead to a retention hyperkeratosis), inconsistent findings regarding their presence or absence preclude these organelles as being essential to lesional development. Authorities consider FD to be a complex disorder of epidermal differentiation secondary to an inflammatory event, whereby qualitative and/or quantitative changes in Odland bodies occur because of epidermal atrophy and attenuation of the granular layer. (1,6) Jägle et al evaluated 5 patients with FD using next-generation sequencing for mutational analysis. All 5 samples demonstrated rare variants in the SPTLC1 gene — in 4 patients there were small deletions/frameshift variants and in one patient a splicing variant was identified. This aberration in the sphingolipid biosynthesis pathway causes diminished levels of SPTLC1 protein. This deregulation of sphingolipid synthesis could be the springboard for novel therapies for FD. (9)

There is no standard therapy of FD — while there are occasional reports of some benefit, only rarely are they effective in altering the progress of the disease. Emollients, topical steroids, 5-fluorouracil, topical or systemic retinoids, vitamin D synthetics, imiquimod, PUVA, surgical treatments (excision, curettage, cryosurgery, electrosurgery, CO2 laser), and photodynamic therapy have all been utilized. (1,10)

Where do we go from here? We need to understand how the diminution of lesional SPTLC1 affects Odland bodies and results in the FD phenotype. Think of the dividends such studies yielded on the porokeratoses, determining that mutations in the mevalonate pathway are pathogenic, leading to the (at least partial) success of utilizing topical lovastatin/cholesterol for these patients. (11) Even if such studies are not performed, assuming that inflammation plays a key role in the development of HLP in presumably genetically predisposed patients, therapy with topical calcineurin inhibitors, PDE 4 inhibitors, and JAK inhibitors can be attempted; none of these have been reported to the best of my knowledge. Developing agents that enhance sphingolipid synthesis is a tantalizing prospect.

Flegel means “flail” in German. I assume that is the noun, but in the case of FD, I will use the verb. For over 60 years, dermatologists have been flailing about trying to understand and treat this disorder. With the discovery of the pathogenic variants in the SPTLC1 gene, I am optimistic that in short order that situation will change for the better. As Grandma Dora would say, “zayn vunderlekh” (it’s wonderful).

Point to Remember: Flegel disease, also known as hyperkeratosis lenticularis perstans, remains an enigma. Pathogenic variants in the SPTLC1 gene affecting sphingolipid synthesis have been identified, possibly leading to novel therapies for this perplexing disorder.

Our expert’s viewpoint

Gianluca Nazzaro, MD
Adjunct Professor, Dermatology and Venereology
University of Milan
Milan, Italy

Flegel disease (FD) is a rare condition characterized by bilateral red to brown hyperkeratotic papules on the limbs, especially lower extremities. It can be both sporadic or familial and its aetiology is unknown: There is still a debate whether FD is a keratinization defect or an inflammatory condition to a (yet to be determined) initiating factor. The recent discovery of a mutation of the SPTLC1 gene which determines an alteration of the synthesis of sphingolipids could lead us to hypothesize a genetic etiology, even if it is not clear which is the triggering agent which determines the onset of the clinical manifestations in adulthood. Clinically, the papules are usually asymptomatic, or mildly pruritic. They are often incidentally recognized by dermatologists when examining an affected patient for other reasons. Due to the aforementioned factors its prevalence is probably underestimated. In clinical practice and in our experience, FD is most often recognized in women because of an increased aesthetic concern compared to men. Histological examination is mandatory to confirm the diagnosis due to the scarcity of reported patients. There is no standard effective therapy: available treatments include topical containing urea, cryotherapy, laser therapy.

1. Bortoluzzi P, Cusini M, Veraldi S, Nazzaro G. Hyperkeratosis lenticularis perstans (Flegel's disease): our experience and review of the literature. Int J Dermatol. 2021 Jan;60(1):33-38. doi: 10.1111/ijd.14930. Epub 2020 May 13. PMID: 32403156.

2. Didona D, Wolter M, Eming R, Juratli HA. Hyperkeratosis lenticularis perstans: a case report of a rare entity. Int J Dermatol. 2021 Dec;60(12):e511-e512. doi: 10.1111/ijd.15856. Epub 2021 Aug 17. PMID: 34403499.

3. Valdebran M, Terrero D, Xue R. Dermoscopic findings in hyperkeratosis lenticularis perstans. J Am Acad Dermatol. 2016 Dec;75(6):e211-e213. doi: 10.1016/j.jaad.2016.03.016. PMID: 27846965.

4. Errichetti E, Turina M, Pizzolitto S, Stinco G. Dermoscopy of hyperkeratosis lenticularis perstans (Flegel disease). J Dermatol. 2019 Aug;46(8):e298-e299. doi: 10.1111/1346-8138.14825. Epub 2019 Feb 25. PMID: 30802320.

5. Piotrowski MJ, Gunn H, Kirby J, Ali L, Helm K. JAAD Grand Rounds quiz: Red-brown hyperkeratotic papules in a 69-year-old man. J Am Acad Dermatol. 2015 Aug;73(2):346-8. doi: 10.1016/j.jaad.2012.06.036. PMID: 26183990.

6. Ando K, Hattori H, Yamauchi Y. Histopathological differences between early and old lesions of hyperkeratosis Lenticularis Perstans (Flegel's disease). Am J Dermatopathol. 2006 Apr;28(2):122-6. doi: 10.1097/01.dad.0000181544.50959.ae. PMID: 16625073.

7. Sterneberg-Vos H, van Marion AM, Frank J, Poblete-Gutierrez P. Hyperkeratosis lenticularis perstans (Flegel's disease) - successful treatment with topical corticosteroids. Int J Dermatol. 2008 Nov;47 Suppl 1:38-41. doi: 10.1111/j.1365-4632.2008.03958.x. PMID: 18986485.

8. Alniemi DT, Greene L, Bui M. Spiky papules on the dorsal feet. Cutis. 2020 Mar;105(3):123-125. PMID: 32352436.

9. Jägle S, Hsu HH, Juratli HA, Zimmer AD, Prieschl A, Alter S, Wiedenhofer B, Metze D, Emmert S, Fischer J. Pathogenic variants in the SPTLC1 gene cause hyperkeratosis lenticularis perstans. Br J Dermatol. 2023 Jan 23;188(1):94-99. doi: 10.1093/bjd/ljac019. PMID: 36689507.

10. Torabian S, Fung M, Eisen D. Topical 5-aminolevulinic acid–based photodynamic therapy: A novel treatment for refractory Flegel's disease. J Am Acad Dermatol 2008;58(2): AB113.

11. https://www.aad.org/dw/dw-insights-and-inquiries/2019-archive/july/a-metabolic-pathway.

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