How To Diagnose And Manage Hereditary Palmoplantar Keratodermas

While palmoplantar keratodermas in the lower extremity are rare, they are frequently misdiagnosed and challenging to treat. Accordingly, this author reviews essential keys to diagnosing hereditary palmoplantar keratodermas and pertinent considerations for appropriate treatment.

A palmoplantar keratoderma is defined as a persistent thickening of the epidermis of palms and soles, which includes genetic and acquired types. This is a broad category that may physicians often misunderstand, misdiagnose and mistreat.

You may recall learning in podiatry school the disease states of mal de Meleda and Unna-Thost, which are both hereditary palmoplantar keratodermas. In contrast to the hereditary palmoplantar keratoderma, acquired palmoplantar keratodermas are caused by inflammatory skin issues such as psoriasis, eczema, medications or internal malignancy. For this article, let us take a closer look at the hereditary types and their key characteristics.   

Palmoplantar keratodermas are rare. However, if you have a patient present with a suspected palmoplantar keratoderma, the key clinical characteristics to remember are: age of onset, hyperkeratosis severity and location, presence of hyperhidrosis and erythematous border, concomitant fungal infections and other systemic manifestations in order to assist in making the diagnosis. One can diagnose the various hereditary palmoplantar keratodermas based on clinical history and physical features combined with histopathological findings. In addition to a thorough clinical exam and skin biopsy, molecular analysis is the gold standard to confirm the diagnosis of palmoplantar keratodermas.  

There is currently no specific and/or curative therapy for hereditary palmoplantar keratodermas. Topical treatments offer brief to no symptomatic relief depending on the clinical presentation. For most of these patients, systemic retinoids will yield some improvement after topical therapy has failed.  

A Closer Look At The Types Of Hereditary Palmoplantar Keratodermas

We can classify hereditary palmoplantar keratodermas as isolated, complex or syndromic. Isolated palmoplantar keratodermas are the most common and primarily involve the palms and soles. Due to the sheer breadth of this topic, I will be focusing on the isolated varieties.

We can further distill all palmoplantar keratodermas into diffuse, focal, striate (palms) and punctate forms. Diffuse palmoplantar keratodermas, which are the most common, will involve the entire palm or sole with or without a strict demarcation. Focal palmoplantar keratodermas have painful calluses, often at the heels, whereas the punctate palmoplantar keratodermas have small punctate keratosis that can be pitted in nature or project extra-dermally. Podiatric clinicians may misdiagnose these keratodermas as “porokeratoses.”

In order to begin diagnosing this hereditary skin condition, the clinician should:

• ascertain the age of onset of the lesions
• assess the clinical appearance (such as a diffuse callus or punctate lesion)
• determine the distribution (weightbearing lesions, covering the entire plantar surface, and/or palms involved)
• determine the level of hyperkeratosis present
• ask if anyone else in the family has the condition
• gauge if there are any extra-palmoplantar manifestations (other areas involved, dental/oral issues, hearing loss), and
• review the histopathological findings

In recent years, gene sequencing has shown the mutations in one or more of the genes involved in these disorders.¹ The genes involved seem to be related to managing cellular adhesion, cell-cell communication and keratin cytoskeleton stability. Even with these advances, one cannot list a solid clinical symptom to gene mutation pattern but it may be possible to note a mixed gene mutation pattern with probable skin manifestations.  

Differentiating Diffuse Palmoplantar Keratodermas

Diffuse palmoplantar keratodermas, a type of isolated hereditary palmoplantar keratoderma, are either autosomal dominant or recessive entities that have a broad range of gene mutations possible. Let’s focus on the keratin 1 (KRT1) and keratin 9 (KRT9) mutations and their skin manifestations, which are the most common forms of hereditary palmoplantar keratodermas. Keratin 1 encodes for the protein keratin 1, which is expressed in keratinocytes.² Keratin 1 couples with keratin 9 to create filament networks that help to resist the everyday friction and other external stresses the skin experiences.

Therefore, keratin 1 and 9 are especially important to the plantar skin. Mutations in the KRT1 gene may cause ichthyosis across the entire body surface while mutations in the KRT9 gene cause manifestations that are usually limited to the feet and hands.  

We often learn of the entity known as Unna-Thost palmoplantar keratoderma in podiatry school. It is due to a KRT9 mutation and is an autosomal dominant condition. The age of onset is after birth to early childhood and the condition presents as yellow hyperkeratotic plaques involving the entire palm and plantar foot. There is a sharp demarcation and an erythematous halo surrounding the demarcation. These patients will have hyperhidrosis and often have superficial fungal infections and fissures.

Trichophyton rubrum is the most common dermatophyte involved in these cases.³ The podiatric physician should not confuse this with plaque psoriasis, which has red plaques with a silvery or micaceous scale. If the clinician is in doubt, biopsying the lesion and sending the specimen for histopathology will yield the following characteristics: “perinuclear vacuolization and granular degeneration of keratinocytes in the spinous and granular layer.”1 It is rare to see pseudoainhum (annular constriction of the digits from a secondary cause) in Thost-Unna palmoplantar keratoderma but hyperkeratosis of the knuckle pads and clubbed digits is commonly visible.  

Another type of an isolated, diffuse palmoplantar keratoderma is the mal de Meleda type. This is an autosomal recessive disease that involves secreted Ly6/uPAR-related protein-1 (SLURP1) mutations that are present in skin cells, bind to receptors and seem to play a role in skin development.⁴ Researchers first described mal de Meleda in patients from the island of Meleda (now Mljet) off the coast of Croatia.¹

The skin condition is present after birth and clinically appears as a glove and socks distribution of waxy, yellow, well-demarcated hyperkeratosis with an erythematous halo. One can also describe this as transgrediens (contiguously extending beyond the palms and soles). Hyperkeratotic lesions can be present on the elbows, knees and knuckle pads in patients with mal de Meleda. Pseudoainhum is rare but hyperhidrosis maceration and nail dystrophy are common. In addition to the feet and hands being involved, perioral erythema and angular cheilitis may also be present. Histologically, an increased stratum lucidum may be present.  

The next type of palmoplantar keratoderma that is relevant to podiatric practitioners is the focal palmoplantar keratoderma spectrum. This is an autosomal dominant condition and is present in childhood. It is related to the mutations of the KRT6c and KRT16 genes that encode keratin 6c and keratin 16 respectively. These proteins create a network of filaments to give structure, strength and resiliency to the skin cells.⁵ Focal palmoplantar keratodermas create hyperkeratotic patches on the weightbearing surfaces of the feet with or without palm involvement. Contrary to the typical presentation, those with jobs that create a high amount of friction on the feet will develop more of a diffuse pattern. Pseudoainhum is not visible but hyperhidrosis, plantar vesicles and bulla, and hypertrophy of the fifth toenail may be visible. Oral and orogenital lesions can also be present. Histologically, hyperkeratosis, acanthosis and hypergranulosis may arise.   

Lastly, the punctate palmoplantar keratodermas are autosomal dominant, rare and manifest from late childhood to adulthood.¹ These present commonly as hyperkeratotic papules/keratosis that may have central indentation or pits with plugs. In type 1A (Buschke-Fischer-Brauer type), the papules will worsen upon exposure to water. Type 1A is rarely associated with malignancies. Punctate palmoplantar keratodermas manifest as symmetrical lesions on the palms but may coalesce on the feet. So far, researchers have identified mutations in genes AAGAB and COL14A1 as the source.¹ Type II is commonly known as porokeratosis punctata palmaris et plantaris and presents as multiple keratotic lesions on the hands and feet. Cornoid lamellae, which is a defining feature of a true porokeratosis, is present histologically, but authors have not identified a gene mutation.  

True Porokeratoses And Porokeratosis Plantaris Discreta: What You Should Know

True porokeratoses are disorders of keratinization and have a defining histologic feature: the cornoid lamellae. The definition of the cornoid lamellae is columns of parakeratosis (retention of nuclei in keratinocytes within the stratum corneum) “resting on a depression where the granular layer is reduced or absent.”¹ There are several types of true porokeratoses: porokeratosis of Mibelli, disseminated superficial porokeratosis, porokeratosis palmaris et plantaris disseminata, and the linear and punctate types.⁶ Researchers have reported that most of these variants are potentially developing squamous cell carcinoma and one should treat them prophylactically.⁷  

Steinberg and Taub defined the term porokeratosis plantaris discreta in 1970, contending it had similar features to porokeratosis of Mibelli.^8,9 Yanklowitz and Harkless refuted this, showing that porokeratosis plantaris discreta did not have histologic features similar to a true porokeratosis and stated that the term porokeratosis plantaris discreta “should be discontinued.”¹⁰

I agree with Yanklowitz and Harkless. I encourage our profession to 1) discontinue calling every plantar hyperkeratotic punctate lesion a porokeratosis; 2) get a biopsy to prove if it is a true porokeratosis or not, and then treat accordingly; and 3) adopt the term plantar keratosis or punctate keratosis to describe these isolated plantar lesions we often encounter and can’t relate to a specific biomechanical cause. Continuing to call a lesion a porokeratosis without any histological basis causes confusion when communicating to other professions and one should see “porokeratosis” as a historical term, not a current one.  

Pertinent Diagnostic And Treatment Considerations

As I stated earlier, it is important for the clinician to obtain a history and clinically investigate other areas that might be affected beyond the soles and palms. It is impossible to discuss all of the possible variations and subtypes of hereditary palmoplantar keratodermas. However, keep in mind the age of onset (childhood); the quality, type and distribution of hyperkeratosis present; the presence of hyperhidrosis or other nail dystrophies present; history of squamous cell carcinoma; extracutaneous manifestations of deafness; oral/ocular involvement; and other systemic manifestations. Considering these factors should lead you to have a hereditary palmoplantar keratoderma in your differential diagnosis. Taking a biopsy of a lesion followed by molecular identification of the gene mutation is imperative in filtering the diagnosis.  

Hereditary palmoplantar keratodermas are not life-threatening but do reduce quality of life for many.¹¹ Limited acral functionality and pain besides the hyperkeratotic lesions are frequent complaints. Topical therapies only relieve the symptoms, if at all, but do not treat the underlying issues. In my practice, I have prescribed everything from topical antifungals for dermatophyte infections to aluminum chloride to reduce the hyperhidrosis to emollients. Topical urea and salicylic acids may or may not improve the thickness of the skin. One should manage the skin infections that may occur from the fissures present with topical or oral antibiotics depending on the presentation. Iontophoresis and injections of botulinum toxin may assist those with hyperhidrosis or those who have lesions that worsen upon water exposure.¹¹ Patients can wear custom footwear for pain relief along with analgesics and topical anesthetics.¹¹

Taking these patients to the operating room to debride the hyperkeratosis or performing this task in office will not yield the outcome you or the patient are seeking as palmoplantar keratodermas are genetically based and the hyperkeratosis  will appear again. Debridement would only be palliative in nature but in some cases will briefly improve quality of life. It is important to discuss this expectation with the patient as well as foot hygiene and care.  

What I have struggled with in my practice is dispensing oral acitretin (Soriatane, Stiefel), a systemic retinoid, to the appropriate patient. Never prescribe this medication for women of childbearing age without a lengthy discussion and contraception initiation as women must avoid pregnancy while on this medication. Acitretin may also cause skin dryness, premature epiphyseal closure and tendon calcifications. Monitor these patients with frequent lab work and radiographs. Acitretin may improve some of the symptoms these patients have but as always, one must weigh treatment initiation against the risks and benefits of therapy. If you don’t feel confident in handling the side effects and monitoring of acitretin therapy, refer the patient to a dermatologist who will be more accustomed to its use as dermatologists frequently prescribe the medication for psoriasis.

In Conclusion

Overall, palmoplantar keratodermas are rare entities that require a thorough clinical history, workup and discussion of treatment options with little chance of topical agents meeting patient expectations. Palliative care and shoe gear modifications may offer some temporary relief, but it is best to work with a dermatologist to manage these patients on systemic therapies.

Dr. Vlahovic is a Clinical Associate Professor in the Department of Podiatric Medicine at the Temple University School of Podiatric Medicine.

References
1.    Guerra L, Castori M, Didona B, Castiglia D, Zambruno G. Hereditary palmoplantar keratodermas. Part I. Non-syndromic palmoplantar keratodermas: classification, clinical and genetic features. J Eur Acad Dermatol Venereol. 2018; epub Feb 28.
2.    U.S. National Library of Medicine. KRT1 gene. Available at https://ghr.nlm.nih.gov/gene/KRT1 .
3.    Maruyama R, Katoh T, Nishioka K. A case of Unna-Thost disease accompanied by Epidermophyton floccosum infection. J Dermatol. 1999;26(1):63-66.
4.    U.S. National Library of Medicine. SLURP1 gene. Available at https://ghr.nlm.nih.gov/gene/SLURP1 .
5.    U.S. National Library of Medicine. KRT6 gene. Available at https://ghr.nlm.nih.gov/gene/KRT6C .
6.    Prak AH. Porokeratosis. Medscape. Available at https://emedicine.medscape.com/article/1059123-overview . Published Aug. 7, 2017.
7.    Kanitakis J. Porokeratoses: an update of clinical, aetiopathogenic and therapeutic features. Eur J Dermatol. 2014;24(5):533-44.
8.    Taub J, Steinberg MD. Porokeratosis plantaris discreta, a previously unrecognized dermatopathological entity. Int J Dermatol. 1970; 9(2):83–90.
9.    Lemont H. What’s your diagnosis? Porokeratosis plantaris discreta (Steinberg’s lesion). J Am Podiatr Med Assoc. 2008; 98(4):337–8.
10.    Yanklowitz B, Harkless L. Porokeratosis plantaris discreta. A misnomer. J Am Podiatr Med Assoc. 1990; 80(7):381-384.
11.    Guerra L, Castori M, Didona B, Castiglia D, Zambruno G. Hereditary palmoplantar keratodermas. Part II: syndromic palmoplantar keratodermas - Diagnostic algorithm and principles of therapy. J Eur Acad Dermatol Venereol. 2018; epub Feb 3.