Papular Acantholytic Dyskeratosis of the Anogenital Area with Novel ATP2C1 Gene Mutations
Papular acantholytic dyskeratosis (PAD) is a rare dermatological condition characterized by the presence of multiple smooth, skin-colored or white papules, typically located in the anogenital area. This condition has been the subject of increasing interest due to its clinical and histopathological similarities to other dermatoses such as Hailey-Hailey disease (HHD) and Darier disease (DD). The identification of novel mutations in the ATP2C1 gene in patients with PAD has provided new insights into the genetic basis of this condition and its relationship with HHD.
The first case of PAD was reported in 1984 in a 23-year-old female with pathological manifestations of focal acantholytic dyskeratosis (FAD). Since then, approximately 30 cases have been reported worldwide, with a predilection for middle-aged women. However, PAD can also occur in men, albeit less frequently, with only six male cases reported to date. The clinical presentation of PAD includes multiple smooth papules with a diameter of 1 to 5 mm, which can coalesce into plaques and may be accompanied by itching or burning sensations. The disease course is chronic, and the lesions are most commonly found in the vulva, perineum, and perianal area, although they can also affect the upper thigh, groin, and vaginal epithelium.
Histopathological examination of PAD lesions reveals hyperkeratosis, parakeratosis, acantholysis with varying degrees of dyskeratosis, and the presence of corps ronds and grains. These features are not unique to PAD and can be observed in other dermatoses such as DD and HHD. However, PAD is distinguished by the absence of immunoglobulin or complement deposition in the skin lesions, which helps to exclude autoimmune bullous diseases.
The genetic basis of PAD has been explored in several studies, with mutations in the ATP2C1 gene being identified as a potential cause. The ATP2C1 gene encodes the human secretory pathway Ca2+-ATPase pump type 1 (hSPCA1), which is localized in the Golgi apparatus of keratinocytes and plays a crucial role in calcium ion transport and storage. Mutations in this gene can disrupt intercellular adhesions, leading to the characteristic acantholysis observed in PAD and HHD.
In this study, two patients with sporadic PAD were investigated for mutations in the ATP2C1 and ATP2A2 genes. Case 1 was a 39-year-old male with itchy eruptions on the perianal area for 5 years. Clinical examination revealed multiple skin-colored, dome-shaped papules and nodules around the anus. Histopathological examination showed extensive suprabasilar and intra-spinous acantholysis with few dyskeratotic cells and incomplete acantholysis in part of the epidermis, giving a “dilapidated brick wall” appearance. Case 2 was a 60-year-old female with itchy lesions on her genital area for 5 years. Histopathological examination of the labia majora papules showed typical acantholytic dyskeratotic cells and acantholysis in the upper stratum spinosum.
Genomic DNA was extracted from the peripheral blood samples of the patients and their parents, and 100 unrelated healthy individuals served as controls. Skin lesion specimens were collected, fixed in 4% formaldehyde solution, dehydrated, embedded in paraffin, and sliced into sections. DNA was extracted using the phenol-chloroform method, and all exons of the ATP2C1 and ATP2A2 genes with intronic flanking sequences were amplified by polymerase chain reaction and sequenced.
In case 1, a heterozygous missense mutation in exon 17 of ATP2C1 was identified (NM_014382.4: c.1468T>C, p.C490R). In case 2, a heterozygous nonsense mutation in exon 25 of ATP2C1 was identified (c.2395C>T, p.R799X). These mutations were not detected in the parents of the two patients, 100 normal controls, or the National Center for Biotechnology Information Single-nucleotide Polymorphism database. The p.C490R mutation is novel and not documented in the Human Gene Mutation Database or PubMed database. No mutations in the ATP2A2 gene were found.
The p.C490R mutation was predicted to be “possibly damaging” by PolyPhen, “deleterious” by PROVEAN, “damaging” by SIFT, “disease causing” by MutationTaster, and “high functional impact” by MutationAssessor. The nonsense mutation p.R799X results in a truncated hSPCA1 protein of 798 amino acids but lacking the last 121 amino acids. The amino acids encoded by the two ATP2C1 mutations (c.1468T>C and c.2395C>T) are located in the cytoplasmic region between transmembrane fragments 4 and 5 and in the lumen region between transmembrane fragments 7 and 8, respectively. It is speculated that structural changes in hSPCA1 occur when these regions are mutated, affecting calcium ion transport and storage functions, and ultimately destroying intercellular adhesions.
The identification of ATP2C1 mutations in these two PAD patients further confirms that mutations in this gene can cause PAD. This study is significant as it may be the first to identify a mutation in ATP2C1 in a male patient with PAD. The similarities between PAD and HHD in terms of clinical pathology and molecular genetics suggest that PAD may not be an independent disease but rather a forme fruste or restricted type of HHD, implicating a common continuous disease spectrum with HHD.
In addition to the cases reported in this study, genetic changes have been described in six other PAD cases. One patient carried a mosaic mutation in ATP2A2, while ATP2C1 mutations were identified in the other cases. There are also reports of PAD transforming into typical HHD after many years and of PAD combined with HHD, further supporting the relationship between these conditions.
The ATP2C1 gene mutations identified in this study are believed to be pathogenic due to their predicted damaging effects on protein function and their conservation in mammals, indicating their importance in maintaining protein activity during evolution. The structural changes in hSPCA1 resulting from these mutations likely disrupt its calcium ion transport and storage functions, leading to the acantholysis and dyskeratosis observed in PAD.
In conclusion, this study provides further evidence that ATP2C1 mutations can cause PAD and supports the hypothesis that PAD may be a forme fruste or restricted type of HHD. The identification of novel mutations in the ATP2C1 gene in these patients contributes to our understanding of the genetic basis of PAD and its relationship with other acantholytic dermatoses. Future research should focus on elucidating the mechanisms by which these mutations lead to the clinical and histopathological features of PAD and exploring potential therapeutic targets for this rare condition.
doi.org/10.1097/CM9.0000000000001443
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