Acrokeratosis Verruciformis of Hopf Showing P602L Mutation in ATP2A2 and Overlapping Histopathological Features With Darier Disease

Abstract

The relationship between acrokeratosis verruciformis (AKV) of Hopf and Darier disease (DD) has been debated for several decades. Both diseases are now thought to result from mutations in the same gene, that is, the ATP2A2 gene encoding the sarco (endo) plasmic reticulum Ca ATPase2 pump (SERCA2), although their histopathological features are different. We sought to detect possible overlapping histopathological features between AKV and DD. Fourteen members of a family affected by AKV were analyzed for the underlying molecular genetic derangement, and 3 cases were studied histopathologically using multiple step sections. A heterozygous P602L mutation in ATP2A2 was identified as the underlying cause in this family. This mutation and a heterozygous A698V were previously described in AKV. Both mutations were not among the 162 mutations in ATP2A2, which were reported to date in DD. The histopathological study demonstrated in several consecutive step sections of 2 of the 3 studied cases, foci of small suprabasal clefts with acantholytic keratinocytes, some of which were mildly dyskeratotic. These focal features were reminiscent of the basic histopathological characteristics of DD. These shared histopathological features of AKV with DD suggest that AKV and DD are allelic disorders with variable expression of the same disease, although identical mutations in ATP2A2 in AKV and DD were not reported to date.

Acrokeratosis verruciformis of Hopf exhibiting Darier disease-like cytological features

“…The unique finding of AVH is of a church spire, while DD uniquely exhibits suprabasal dyskeratosis with corps ronds and grains in histopathological examination . However, as in our case, histopathological studies on serial sections obtained from AVH lesions have demonstrated certain histopathological features that overlap with those of DD . In our case, the histopathological findings of compact hyperkeratosis, hypergranulosis, slight acanthosis, and circumscribed epidermal elevations resembling church spires were consistent with AVH, but there was also the DD‐like finding of a cleft in the granular layer with several acantholytic keratinocytes.…”

Somatic ATP2A2 mutation in a case of papular acantholytic dyskeratosis: mosaic Darier disease

“…The mutation identified in our patient was previously reported in an Italian patient with germline Darier disease manifesting as acrokeratosis verruciformis with nail changes . There is evidence that acrokeratosis verruciformis and Darier disease are allelic disorders with variable expression of overlapping features . Mutations in the same codon of ATP2A2 have resulted in clinical phenotypes of acrokeratosis verruciformis and Darier disease in separate individuals .…”

“…27 There is evidence that acrokeratosis verruciformis and Darier disease are allelic disorders with variable expression of overlapping features. 28 Mutations in the same codon of ATP2A2 have resulted in clinical phenotypes of acrokeratosis verruciformis and Darier disease in separate individuals. 29 The p.706D>N mutation falls within a domain regulating enzymatic phosphorylation required for calcium conductance and is known to reduce phosphorylation rate and calcium flux.…”

Mendelian Disorders of Cornification Caused by Defects in Intracellular Calcium Pumps: Mutation Update and Database for Variants in ATP2A2 and ATP2C1 Associated with Darier Disease and Hailey-Hailey Disease

“…However, two families and one sporadic patient suffered from AKV rather than generalized DD, caused by mutations p.(Pro602Leu) and p.(Leu590Pro), respectively (see Table 1). These mutations, as well as variant p.(Ala698Val), have been reported in association with the AKV phenotype before [Dhitavat et al, 2003b;Berk et al, 2010;Bergman et al, 2012;Nellen et al, 2015]. All mutations are found in exon 14, encoding the ATPbinding domain of SERCA2.…”