This study aims to report a sporadic case of acrokeratosis verruciformis of Hopf (or acrokeratosis verruciformis (AKV)) with an unusual clinical presentation, highlighting its diagnostic challenges and key distinguishing features. A 54-year-old female patient with no relevant medical history presented with multiple skin-colored, flat-topped, hyperkeratotic papules on the dorsal aspects of the hands since childhood, and onychopathy for 12 years. Nail changes included thickening of the nail plate and subungual hemorrhages. She presented a soft, warty pink-colored plaque in the right inguinal region. Dermoscopy of the dorsum of the hand showed a white network and papules with a central homogeneous area and a peripheral cobblestone appearance. A biopsy was performed and showed hyperorthokeratosis and epidermal hyperplasia with focal papillomatosis. Treatment was started with keratolytics. The patient has been under follow-up by our department for three months with partial improvement of the lesions.  AKV, a rare genodermatosis, presents a diagnostic challenge due to its subtle onset, relying primarily on clinical presentation and histopathological characteristics. Genetic studies can aid in identifying underlying mutations, with Darier's disease being the main differential diagnosis. Management typically involves keratolytic agents and retinoids, though superficial ablation is considered first-line treatment.  AKV should be suspected in patients presenting with numerous flat, skin-colored, polygonal papules on acral areas and long-standing onychopathy. This case emphasizes the critical role of comprehensive clinical assessment and histopathological study for accurate diagnosis, especially given its unusual manifestations.

Darier's disease and Acrokeratosis Verruciformis of Hopf can exhibit overlapping clinical features due to mutations in the same ATP2A2 gene. Recognizing this genetic and phenotypic overlap is crucial for accurate diagnosis, genetic counseling, and treatment, especially in mixed presentations of these rare genodermatoses.

Acrokeratosis verruciformis of Hopf (AVH) is a rare dermatological disorder associated with keratotic lesions primarily on the dorsal surfaces of the hands and feet, caused by a missense mutation in the ATP2A2 gene. Here, we report the case of a 24-year-old woman presenting with multiple wart-like lesions on the hands, feet, and neck over four years. A V-shaped notch on the nails indicated nail dystrophy. The patient had no family history of similar symptoms and an unremarkable medical history. The histopathological examination of a skin biopsy revealed marked hyperkeratosis, acanthosis, papillomatosis, and church spire-like epidermal elevations, confirming the diagnosis of AVH. AVH poses diagnostic challenges due to its similarity to other conditions, such as seborrheic keratosis, lichen planus, and Darier disease. Despite resource limitations precluding genetic testing, thorough clinical and histopathological evaluations were crucial for accurate diagnosis. This case underscores the importance of awareness and documentation of AVH, particularly in nonfamilial cases, to facilitate early recognition and management. Increased vigilance among dermatologists is essential to prevent misdiagnosis and to manage this rare condition effectively.

Darier disease (DD) is a rare genetic skin disorder caused by heterozygous variants in the ATP2A2 gene. Clinical manifestations include recurrent hyperkeratotic papules and plaques that occur mainly in seborrheic areas. Although some of the lesions wax and wane in response to environmental factors, others are severe and respond poorly to therapy. To investigate the molecular mechanism underlying the persistency of skin lesions in DD. In this case series, DNA was extracted from unaffected skin, transient and persistent lesional skin, and blood from 9 patients with DD. Genetic analysis was used using paired-whole exome sequencing of affected skin and blood or by deep sequencing of ATP2A2 of affected skin. Chromosomal microarray analysis was used to reveal copy number variants and loss of heterozygosity. All variants were validated by Sanger sequencing or restriction fragment length polymorphism. Paired whole-exome sequencing and deep sequencing of ATP2A2 gene from blood and skin samples isolated from persistent, transient lesions and unaffected skin in patients with DD. Germline and somatic genomic characteristics of persistent and transient cutaneous lesions in DD. Of 9 patients with DD, all had heterozygous pathogenic germline variants in the ATP2A2 gene, 6 were female. Participant age ranged from 40 to 69 years on enrollment. All 11 persistent skin lesions were associated with second-hit somatic variants in the ATP2A2 gene. The somatic variants were classified as highly deleterious via combined annotation-dependent depletion (CADD) scores or affect splicing, and 3 of them had been previously described in patients with DD and acrokeratosis verruciformis of Hopf. Second-hit variants in the ATP2A2 gene were not identified in the transient lesions (n = 2) or the normal skin (n = 2). In this study, persistent DD lesions were associated with the presence of second-hit somatic variants in the ATP2A2 gene. Identification of these second-hit variants offers valuable insight into the underlying mechanisms that contribute to the lasting nature of persistent DD lesions.

Acrokeratosis verruciformis of Hopf (AKVH) is a rare genetic skin condition associated with an ATP2A2 gene mutation, thus affecting keratinization. Classically, AKVH appears in childhood over acral sites as symmetrical, flat, verruca plana-like lesions with an autosomal dominant inheritance, while sporadic cases affect atypical sites in adulthood. As this entity can closely mimic other verrucous skin conditions, identifying characteristic histopathological changes is essential to make a diagnosis in the absence of genetic studies, especially in resource-poor countries. This is the first reported case of AKVH from North-East India clinically mimicking extensive verruca vulgaris in an adult with a possible sporadic occurrence. AKVH is usually difficult to treat and superficial ablation is the treatment of choice. However, this case highlights the role of cryotherapy with acitretin in the management of AKVH with a rapid response.