Acrokeratoelastoidosis

Etiology

Genetic Factors

Although there are reports of sporadic cases, acrokeratoelastoidosis is considered to be a genodermatoses with autosomal dominant being the primary mode of inheritance (although anecdotal reports exist of an autosomal recessive mode). As per the classification of palmoplantar keratodermas (PPK), inherited acrokeratoelastoidosis is considered to be a type of inherited punctate palmoplantar keratoderma (PPKP), specifically Type 3 PPKP.[5][6] OMIM recognizes three distinct types of inherited punctate PPK. These are; PPKP1 (also known as the Buschke-Fischer-Brauer type, OMIM #148600), mapped to 15q22; PPKP2 (porokeratotic type, OMIM #175860), not yet mapped; and PPKP3 (acrokeratoelastoidosis, OMIM #101850), where preliminary linkage suggests a possible locus on 2p25-p12.[5] Thus, chromosome 2 seems the most probable locus involved in inherited AKE.[7] It is important to mention that the AAGAB gene, implicated in type I PPK, is not involved in AKE.[6] In PPKP1, AAGAB gene associated reduced expression of the cytosolic p34 protein has been implicated, which results in increased epidermal cell proliferation.[5][8] The possibility of a similar gene-protein complex involved in the pathogenesis of acrokeratoelastoidosis cannot be discounted and merits further exploration.

Acquired Factors

The exact pathogenesis remains unclear. Although a history of chronic trauma and excessive sun-exposure has been reported in few cases[2][3][4][9][10]; there is no establishment of a direct causal relationship.  

It is important to note that although the clinical presentation is predominated by lesions generally localized to the acral parts; some workers have reported that elastorrhexis (fragmentation of dermal elastic fibers). The histopathological hallmark of the condition seen in acral papules also involves apparently normal-appearing skin in some patients suggesting that AKE may represent a disorder with a generalized defect of elastic tissue.[11] Presumptively, factors like chronic or repeated bouts of unnoticed trauma (which are much more common over the acral parts of the body) may result in the predominance of clinical expression of the disorder over the palms and soles.

The anecdotal report of AKE-like lesions in patients with scleroderma has its basis in the abnormal connective tissue metabolism of scleroderma.[12][13] Other anecdotal observations of unclear etiological association include hyperhidrosis and aquagenic PPK.[10][14][15]

Epidemiology

The disease is not congenital; instead, its typical onset occurs in childhood or adolescence. As mentioned before, evaluation of the limited number of total reported cases does not suggest a predilection for any gender or ethnicity. Owing to the rarity of the condition, the exact incidence of the disorder remains unknown.

Most cases of AKEs that have been reported so far had their onset before the second and third decades of life. The youngest age reported for a patient of AKE was 3 years.[9]

Although bilateral involvement is characteristic of acrokeratoelastoidosis, there are reports of a few cases with unilateral involvemen.[2][16] There have been suggestions that the unilateral variant of AKE arises from genetic mosaicism. 

Although some investigators have reported an increase in the number of papules over time,[10] a general consensus to that observation remains elusive.

Pathophysiology

In familial cases that constitute the majority of the reports to date implicate a genetic abnormality involving chromosome 2. A hypothesis of altered expression of a gene-protein complex akin to p34 involvement in PPKP1 has been previously mentioned (vide supra). In sporadic cases, factors like excessive sun-exposure and chronic trauma may serve as possible triggering factors.

Elastorrhexis is the histo-pathophysiological hallmark of the disorder. Exaggerated production and accumulation of filaggrin in the form of a dense band over stratum granulosum, before getting incorporated into the protein matrix of mature epidermal keratin has been postulated to result in the formation of the characteristic keratotic papules.[17] Presence of abnormal dense granules in dermal fibroblasts of lesional skin hints at the possibility of acrokeratoelastoidosis representing the outcome of abnormal secretion of elastic fibers rather than that of fiber degradation as its name suggests.[17]

Histopathology

The most common findings on histopathology [Figure 1 (D)] are hyperkeratosis, hypergranulosis, mild acanthosis, collagen homogenization and alterations in the elastic fibers of the dermis, which are fewer and fragmented (elastorrhexis).[3] Hyperkeratosis sometimes causes depression in the underlying epithelial planes, forming a concavity.[3] One observes areas of collagen homogenization in the superficial dermis with thin elastic and reduced and fragmented fibers.

It is noteworthy that elastorrhexis involving the dermis down to the reticular dermis level is a unique and archetypical pathological feature of acrokeratoelastoidosis, which also differentiates it from acral focal hyperkeratosis, a very close clinical differential. In the latter, histological alterations are limited to the epidermis in the form of epidermal hyperkeratosis with elastorrhexis of the reticular dermis typically absent.[18]

Electron microscopy shows disaggregation of elastic fibers with microfibrillar fragmentation.[18]

Special stains for elastin (and collagen) such as VVG, Weigert, and oOrcein demonstrate the changes in elastic fibers (elastorrhexis) better [Figure 1(E)] than the routine hematoxylin-eosin stain.[3]

History and Physical

Acrokeratoelastoidosis typically presents in children and adolescents, usually before the 2nd and 3rd decades of life, although reports do exist of onset in adulthood.[19] Clinically, AKE presents with clusters of multiple asymptomatic, small, round-to-oval, skin-colored/translucent or yellowish firm papules located over the lateral and/or medial margins of hands and/or feet. Papules have a keratotic rough surface and may show a crateriform to umbilicated appearance [Figure 1(A)]. Papular acrokeratosis, a synonym for acrokeratoelastoidosis stems from such characteristic morphology and location of lesions. Involvement of the dorsa of hands/feet is characteristic [Figure 1(B)], qualifying the lesion as 'inverse' papular acrokeratosis.[18][20] Other areas reported to have occasional involvement include - the posteromedial border of the feet and the pre-tibial region.[20] The lesions are typically distributed in a bilateral and symmetrical pattern, although unilateral involvement has been reported.[2][16][21] The papules may coalesce to form plaques.

Typically, except for cosmetic disfigurement, the lesions are asymptomatic in most of the cases. Mild itching, hyperhidrosis, and aquagenic palmoplantar keratoderma constitute uncommon presentations/associations.[3][15] A family history of similar lesions is commonly positive since the majority of cases show an autosomal dominant mode of inheritance. The clinician should inquire about a history of chronic or repeated trauma to palms and soles or excessive sun exposure. Trauma, handwashing, clothes, and irritation from ill-fitting footwear may increase the dimensions of acrokeratoelastoidosis. 

In most cases, the lesions stabilize after a few weeks to months of onset although there are anecdotal reports of rapid progression of lesions during pregnancy.[10]

Evaluation

Dermoscopy

Polarized videodermoscopic evaluation of the affected areas of the thumbs and index fingers shows focal clusters of pale-to-yellowish colored papules with slight umbilication in a few of them, interspersed with pale yellow-colored structureless areas [Figure 1 (C)].

Histopathology

The gold-standard technique of diagnosis of acrokeratoelastoidosis remains histopathology. Apart from various epidermal alterations (vide infra), the presence of a reduced number of thick and fragmented elastic fibers in the dermis ('elastorrhexis') is the diagnostic hallmark; the latter feature is observed even on a routine hematoxylin-eosin (H & E) section [Figure 1 (D)].but better appreciated with special stains for elastin such as Verhoeff’s-Van Gieson (VVG) [Figure 1 (E)], Weigert and Orcein.

Ultrasonography: Doppler Study

In a recent study, the use of Doppler ultrasound (USG) examination was reported to be a useful non-invasive adjuvant investigation for confirmation of diagnosis and benignancy of the condition (lack of protrusions of fat lobules) and ruling out the presence of piezogenic pedal papules and granulomas.[22] In acrokeratoelastoidosis, doppler USG demonstrates several focal solid hypoechoic and hypovascular areas with thickening of the epidermis and upper dermis.[22]

Treatment / Management

Since the condition is asymptomatic and benign, treatment should focus on patients who are cosmetically concerned. To date, various forms of treatments - topical, oral and surgical/physical have been attempted to improve upon the appearance of AKE-affected acral parts of the patients, but the outcome has been modest to poor. The various treatment modalities tried [3][10][22][10][23][24]:(B3)

1. Topical - emollients and keratolytic agents including salicylic acid, urea, sulfur, coal tar, and tretinoin, as well as topical corticosteroids
2. Oral - corticosteroids, antibiotics, dapsone, methotrexate, isotretinoin, acitretin
3. Physical/surgical - cryotherapy with liquid nitrogen, and surgery with laser erbium: yttrium-aluminum-garnet (Er: YAG)

Treatment with oral retinoids, especially acitretin has been suggested as the most effective; however, relapse post-cessation is inevitable[10](B3)

Summarily, even in patients with acrokeratoelastoidosis  offered treatment for cosmetic improvement, three factors merit consideration and require explanation to the patient before commencing treatment:

1. Modest response to be expected
2. If using topicals - indefinite use may be necessary to maintain any improvement
3. If planning oral/systemic therapy - the possibility of an almost inevitable relapse on stoppage of the drug, and the adverse effects of the drug(s)

Differential Diagnosis

Differential diagnosis includes conditions considered as members of the family of marginal and acral keratodermas, and other distinctive disorders involving the acral parts with similar appearing lesions. It is important to know that involvement of the borders or palmoplantar transition areas typifies 'marginal keratodermas'; involvement of the dorsum of the hands and feet qualifies the marginal keratoderma to be called 'inverse.'[18]  Some of the important differentials include[3][10][25][22]:

1. Focal acral hyperkeratosis - differentiable on histopathology due to changes limited to the epidermis, with the absence of elastorrhexis
2. Keratoelastoidosis marginalis (also known as Ramos and Silva marginal keratoderma) - associated with intense sun exposure and shows prominent actinic damage
3. Other acral keratoderma variants - hereditary papulotranslucent acrokeratoderma, acrokeratoderma hereditarium punctatum, punctate palmoplantar keratoderma
4. Miscellaneous conditions - acrokeratosis verruciformis of Hopf, degenerative collagenous plaques (of the hands), digital papular calcinosis, verruca plana, primary cutaneous amyloidosis, and mosaic acral keratosis

Prognosis

It is important to reiterate that many forms of PPK, including certain types of PPKP, are harbingers or cutaneous markers of serious underlying morbidity. However, AKE is a benign form of PPKP, with no associated medical condition. Discounting the fact of poor response to treatments and indefinite persistence of lesions, the overall prognosis of the condition is excellent. 

Complications

There are no known or reported complications of acrokeratoelastoidosis.