Acrokeratosis Verruciformis

Mendelian MONDO:0007048 Pathograph 13 Show in embeddings browser Genodermatosis keratinizing disorder

Acrokeratosis verruciformis of Hopf (AKV) is a rare autosomal dominant genodermatosis of keratinization in which flat, skin-coloured, wart-like keratotic papules develop on the dorsa of the hands and feet, usually from early childhood, and persist without spontaneous regression. Familial AKV is caused by a recurrent heterozygous ATP2A2 missense variant, p.(Pro602Leu), in the ATP-binding domain of SERCA2, the sarco/endoplasmic reticulum calcium pump that is also mutated in Darier disease; the mutant pump has lost calcium transport activity. AKV is therefore allelic with Darier disease, but the two differ in phenotype: AKV spares the seborrheic areas, and its histology is a well-circumscribed verrucous epidermal hyperplasia with orthokeratotic hyperkeratosis, hypergranulosis, acanthosis and church-spire papillomatosis, without the suprabasal acantholysis and dyskeratosis that define Darier disease. Whether AKV is a distinct entity or a limited acral expression of Darier disease remains debated: AKV-like acral papules are common in Darier patients, the two conditions coexist in some individuals, and focal acantholysis has been found on step sectioning of AKV lesions, whereas some AKV families show no ATP2A2 variant and no linkage to its locus. The course is chronic and benign, with rare squamous cell carcinoma in longstanding lesions, and treatment is cosmetic and of modest benefit.

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2
Inheritance
4
Pathophys.
8
Phenotypes
2
Gaps
13
Pathograph
1
Genes
2
Variants
5
Medical Actions
3
References
1
Deep Research
🏷

Classifications

Harrison's Part
DERMATOLOGY GENETICS ENVIRONMENT DISEASE
👪

Inheritance

2
Autosomal Dominant HP:0000006
Familial AKV segregates as an autosomal dominant trait, described in one family over six generations, with variable penetrance.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:12542527 SUPPORT Human Clinical
"Onset is early in life and the disease is inherited in an autosomal dominant fashion."
States the dominant mode of inheritance in the family study that identified the causal variant.
PMID:42205461 SUPPORT REVIEW SYNTHESIS Human Clinical
"AVH is usually transmitted as an autosomal dominant trait with variable penetrance, although several sporadic cases have been reported."
Review synthesis of the reported families supporting dominant inheritance with variable penetrance.
Sporadic HP:0003745
Many published cases are sporadic, often with adult onset and a wider distribution of lesions. These may reflect de novo variants or reduced penetrance, but most were never genotyped, so some may be misdiagnosed phenocopies.
Sporadic
Show evidence (2 references)
PMID:42205461 SUPPORT REVIEW SYNTHESIS Human Clinical
"Moreover, several sporadic, non-familial AVH cases have been reported (7,16-19); these may reflect de novo mutations or reduced penetrance, particularly when there is no family history of a similar condition."
Documents sporadic cases and the two explanations offered for them.
PMID:31696902 SUPPORT Human Clinical
"Usually, it arises in early life but rare sporadic cases with adult onset have been reported."
Reports a non-familial adult-onset case and the association of sporadic cases with later onset.
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Discussions and Knowledge Gaps

2
Is acrokeratosis verruciformis a distinct disease, or a limited acral expression of Darier disease?
CONTROVERSY OPEN akv_distinct_entity_or_acral_darier
Attached to
disease#Acrokeratosis Verruciformis pathophysiology#Focal Suprabasal Acantholysis with Mild Dyskeratosis
For a distinct entity: a distinct clinical picture confined to acral skin and sparing seborrheic areas, a recurrent variant (p.Pro602Leu) not seen in Darier disease, histology without acantholysis or dyskeratosis, separate MONDO and OMIM records, and AKV families with no ATP2A2 variant. For acral Darier disease: AKV-like papules are found in most adults with Darier disease, the two coexist in some patients, acral papules in Darier patients can show Darier histology, and step sections or cytology of genotyped AKV lesions can show focal acantholysis and dyskeratosis. This entry is curated as a separate disease allelic with Darier disease, following MONDO and the genotype data, and records the overlap here.
Show evidence (6 references)
PMID:28498512 SUPPORT Human Clinical
"Darier disease and Acrokeratosis Verruciformis of Hopf (AKV) are rare disorders of keratinization with autosomal dominant inheritance and very distinct clinical pictures."
Position that the two are allelic but clinically distinct.
PMID:22814319 SUPPORT Human Clinical
"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."
Position that AKV is variable expression of the same disease.
PMID:1390140 SUPPORT Human Clinical
"Diagnostic nail lesions were found in 59 (99%), palmar pits and keratoses in 57 (95%), and acrokeratosis verruciformis in 44 (73%)."
Acrokeratosis verruciformis-like papules occurred in 73% of adults with Darier disease in a population series.
+ 3 more references
Why does ATP2A2 p.(Pro602Leu) produce an acral keratinization disorder largely without acantholysis, when other loss-of-function ATP2A2 variants produce Darier disease, and which gene causes AKV in families without an ATP2A2 variant?
KNOWLEDGE GAP OPEN akv_genotype_phenotype_and_second_locus
Attached to
pathophysiology#ATP2A2 Pro602Leu Loss of SERCA2 Calcium Transport pathophysiology#Disturbed Endoplasmic Reticulum Calcium Homeostasis in Acral Keratinocytes genetic#ATP2A2
The P602L pump has lost calcium transport in vitro, the same functional class as Darier alleles, so loss of transport alone does not explain the different phenotype. No study has examined calcium handling or desmosome assembly in AKV keratinocytes, and the second AKV locus excluded by linkage in Chinese families has not been identified.
Show evidence (1 reference)
PMID:16716163 SUPPORT Human Clinical
"Our findings provide evidence for the genetic heterogeneity of AKV and demonstrate that mutations in genes other than ATP2A2 are responsible for AKV in a proportion of the Chinese population."
Establishes that an unidentified second locus exists.
⚙

Pathophysiology

4
ATP2A2 Pro602Leu Loss of SERCA2 Calcium Transport
The recurrent heterozygous ATP2A2 missense variant p.(Pro602Leu) replaces a proline in the ATP-binding domain of SERCA2. Expressed in vitro, the mutant pump has lost its ability to transport calcium into the sarco/endoplasmic reticulum. This is the same gene and the same functional class of lesion as in Darier disease, which is the basis for regarding the two as allelic.
keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
Genetic context ATP2A2 hgnc:812 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns ATP2A2 (hgnc:812). hgnc:812 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Heterozygous p.(Pro602Leu) missense variant; the mutant protein shows no calcium transport in a functional assay.
P-type calcium transporter activity GO:0005388 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased P-type calcium transporter activity (GO:0005388). GO:0005388 is a molecular function from the Gene Ontology.
Downstream
Disturbed Endoplasmic Reticulum Calcium Homeostasis in Acral Keratinocytes Loss of pump activity from one allele reduces calcium uptake into the keratinocyte endoplasmic reticulum.
Show evidence (5 references)
PMID:12542527 SUPPORT Human Clinical
"we studied a family affected with acrokeratosis verruciformis in six generations and identified a heterozygous P602L mutation in ATP2A2"
Identifies the heterozygous P602L variant as the familial lesion.
PMID:12542527 SUPPORT In Vitro
"Moreover, functional analysis of the P602L mutant showed that it has lost its ability to transport Ca2+."
Functional assay of the expressed mutant pump showing loss of calcium transport, the molecular claim of this node.
PMID:12542527 SUPPORT Human Clinical
"This mutation predicts a nonconservative amino acid substitution in the ATP binding domain of the molecule."
Places the substitution in the ATP-binding domain of SERCA2.
+ 2 more references
Disturbed Endoplasmic Reticulum Calcium Homeostasis in Acral Keratinocytes
SERCA2 sequesters cytosolic calcium into the endoplasmic reticulum of keratinocytes, and this store supports keratinocyte differentiation and, indirectly, intercellular adhesion. Loss of pump activity is inferred to disturb that store in the affected acral epidermis. No study has measured keratinocyte calcium handling in AKV directly, and why the lesion is confined to acral skin, and why it largely spares adhesion here when it does not in Darier disease, is unexplained.
keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
endoplasmic reticulum calcium ion homeostasis GO:0032469 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal endoplasmic reticulum calcium ion homeostasis (GO:0032469). GO:0032469 is a biological process from the Gene Ontology.
Downstream
Abnormal Keratinocyte Differentiation with Verrucous Epidermal Hyperplasia The disturbed calcium store deranges terminal keratinocyte differentiation, the defining process in AKV.
Focal Suprabasal Acantholysis with Mild Dyskeratosis In some lesions the same disturbance also reaches keratinocyte adhesion, producing small foci of the Darier-type change; this arm is inconstant.
Show evidence (2 references)
PMID:42205461 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"it encodes the calcium pump SERCA2, which is present in the membrane of the endo-sarcoplasmic reticulum and plays a key role in calcium transport, and indirectly in the intercellular adhesion of keratinocytes."
States the endoplasmic reticulum calcium-transport role of SERCA2 in keratinocytes. The step from the AKV variant to a disturbed store is an inference from pump function, not a measurement in AKV keratinocytes.
PMID:12542527 SUPPORT INDIRECT In Vitro
"This result demonstrates loss of function of the sarco(endo)plasmic reticulum Ca2+ ATPase2 mutant in acrokeratosis verruciformis"
Demonstrates loss of the reticulum calcium pump function in AKV, from which the disturbed store follows by inference.
Abnormal Keratinocyte Differentiation with Verrucous Epidermal Hyperplasia
The lesion is a well-circumscribed epidermal hyperplasia: orthokeratotic hyperkeratosis, acanthosis and moderate papillomatosis, usually with hypergranulosis, and a verrucous surface whose regular elevations resemble church spires. The dermis is usually normal. Unlike Darier disease, the classic AKV lesion shows no dyskeratosis.
keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
keratinocyte differentiation GO:0030216 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal keratinocyte differentiation (GO:0030216). GO:0030216 is a biological process from the Gene Ontology. keratinization GO:0031424 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal keratinization (GO:0031424). GO:0031424 is a biological process from the Gene Ontology.
epidermis UBERON:0001003 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in epidermis, annotated with skin epidermis (UBERON:0001003). UBERON:0001003 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Acral Verrucous Papules The circumscribed verrucous hyperplasia is the histological substrate of each flat wart-like papule.
Hyperkeratosis Thickening of the stratum corneum is part of the hyperplasia.
Hypergranulosis Thickening of the granular layer is part of the hyperplasia.
Epidermal Acanthosis Thickening of the spinous layer is part of the hyperplasia.
Punctate Palmoplantar Keratoses The same keratinization disorder produces punctate keratoses on the palms and soles.
Show evidence (4 references)
PMID:42205461 SUPPORT REVIEW SYNTHESIS Human Clinical
"Routine histological examination of AVH reveals a well-circumscribed epidermal hyperplasia, consisting of orthokeratotic hyperkeratosis, acanthosis and moderate papillomatosis, often with hypergranulosis."
Summarizes the histology that defines this node.
PMID:42205461 SUPPORT REVIEW SYNTHESIS Human Clinical
"The surface of the epidermis usually presents a characteristic verrucous, church-spire-like appearance."
Documents the church-spire surface architecture.
PMID:22028575 SUPPORT Human Clinical
"Histopathologically, the lesion shows considerable hyperkeratosis, acanthosis, and papillomatosis"
Independent case report describing the same hyperkeratosis, acanthosis and papillomatosis.
+ 1 more reference
Focal Suprabasal Acantholysis with Mild Dyskeratosis
Small suprabasal clefts with acantholytic, sometimes mildly dyskeratotic keratinocytes have been found in some genotyped AKV lesions on step sectioning, and Darier-like cytology including corps ronds and grains in another case. When present, acantholysis and dyskeratosis are minimal. Their absence has long been used to separate AKV from Darier disease, so this node records an inconstant finding that bears on that question rather than a defining feature.
keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
cell-cell adhesion GO:0098609 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cell-cell adhesion (GO:0098609). GO:0098609 is a biological process from the Gene Ontology.
epidermis UBERON:0001003 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in epidermis, annotated with skin epidermis (UBERON:0001003). UBERON:0001003 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (4 references)
PMID:22814319 SUPPORT Human Clinical
"foci of small suprabasal clefts with acantholytic keratinocytes, some of which were mildly dyskeratotic."
Step sections of lesions from P602L carriers showed focal suprabasal acantholysis with mild dyskeratosis.
PMID:27663152 SUPPORT Human Clinical
"Cytological examination showed acantholytic keratinocytes, dyskeratotic acantholytic cells, corps ronds and grains."
A clinically diagnosed AKV case with Darier-like cytology.
PMID:42205461 SUPPORT REVIEW SYNTHESIS Human Clinical
"However, when present, acantholysis and dyskeratosis are typically minimal in AVH."
Records that the change is minimal when present.
+ 1 more reference
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Acrokeratosis Verruciformis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

8
Integument 7
Punctate Palmoplantar Keratoses Punctate palmoplantar hyperkeratosis HP:0007530 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Punctate palmoplantar hyperkeratosis (HP:0007530). HP:0007530 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16716163 SUPPORT Human Clinical
"and punctuate keratoses on the palms and soles."
Names punctate palmoplantar keratoses as part of the phenotype; the spelling punctuate is the source's own.
PMID:42205461 SUPPORT REVIEW SYNTHESIS Human Clinical
"Punctiform hyperkeratotic lesions of the palms may be present (40)."
Review confirmation that punctate palmar keratoses may occur.
Nail Dystrophy HP:0008404 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nail dystrophy (HP:0008404). HP:0008404 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:42205461 SUPPORT REVIEW SYNTHESIS Human Clinical
"Nail lesions are not rare; they include pachyonychia, leukonychia, longitudinal depressions, subungual hemorrhages, distal onychoschizis"
Lists the nail changes reported in AKV.
PMID:40256087 SUPPORT Human Clinical
"A V-shaped notch on the nails indicated nail dystrophy."
Case with V-shaped notching interpreted as nail dystrophy.
PMID:41054640 SUPPORT Human Clinical
"Nail changes included thickening of the nail plate and subungual hemorrhages."
Case with nail plate thickening and subungual haemorrhage.
Leukonychia HP:0001820 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukonychia (HP:0001820). HP:0001820 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42205461 SUPPORT REVIEW SYNTHESIS Human Clinical
"Nail lesions are not rare; they include pachyonychia, leukonychia, longitudinal depressions"
Names leukonychia among the reported nail changes.
Hyperkeratosis HP:0000962 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperkeratosis (HP:0000962). HP:0000962 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27663152 SUPPORT Human Clinical
"Histopathological examination showed compact hyperkeratosis, hypergranulosis, slight acanthosis, circumscribed epidermal elevations resembling church spires"
Documents compact hyperkeratosis in an AKV biopsy.
Hypergranulosis HP:0025114 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypergranulosis (HP:0025114). HP:0025114 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22028575 SUPPORT Human Clinical
"and a thickened granular layer."
Documents the thickened granular layer.
PMID:27663152 SUPPORT Human Clinical
"Histopathological examination showed compact hyperkeratosis, hypergranulosis, slight acanthosis"
Documents hypergranulosis in an independent biopsy.
Epidermal Acanthosis HP:0025092 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epidermal acanthosis (HP:0025092). HP:0025092 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40256087 SUPPORT Human Clinical
"The histopathological examination of a skin biopsy revealed marked hyperkeratosis, acanthosis, papillomatosis, and church spire-like epidermal elevations, confirming the diagnosis of AVH."
Documents acanthosis with papillomatosis and church-spire elevations as the diagnostic histology.
Squamous Cell Carcinoma in Longstanding Lesions VERY_RARE Squamous cell carcinoma of the skin HP:0006739 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Squamous cell carcinoma of the skin (HP:0006739). HP:0006739 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42205461 SUPPORT REVIEW SYNTHESIS Human Clinical
"Of note, two cases of squamous cell carcinoma that developed on long-standing AVH lesions have been reported (31,42)."
Records the two reported carcinomas and their origin in longstanding lesions.
Other 1
Acral Verrucous Papules Acrokeratosis HP:0200016 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acrokeratosis (HP:0200016), qualified as childhood onset. HP:0200016 is a phenotype from the Human Phenotype Ontology.
Onset: CHILDHOOD
Sequelae: Squamous Cell Carcinoma in Longstanding Lesions
Show evidence (3 references)
PMID:16716163 SUPPORT Human Clinical
"Acrokeratosis verruciformis of Hopf (AKV) is a rare genodermatosis characterized by multiple flat-topped, flesh-coloured papules on the dorsa of hands and feet, and punctuate keratoses on the palms and soles."
Defines the dorsal acral papules as the characteristic lesion.
PMID:30725935 SUPPORT REVIEW SYNTHESIS Human Clinical
"Lesions typically begin in childhood or adolescence and persist without spontaneous regression"
Supports childhood onset and the persistent course.
PMID:42205461 SUPPORT REVIEW SYNTHESIS Human Clinical
"However, contrary to the latter, seborrheic body zones (such as the face, scalp and trunk) are usually spared in AVH (31)."
Records the sparing of seborrheic areas that separates AKV from Darier disease clinically.
🧬

Genetic Associations

1
ATP2A2
Gene: ATP2A2 hgnc:812 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ATP2A2 (hgnc:812). hgnc:812 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (4 references)
PMID:12542527 SUPPORT Human Clinical
"we studied a family affected with acrokeratosis verruciformis in six generations and identified a heterozygous P602L mutation in ATP2A2"
Establishes ATP2A2 as the causal gene in familial AKV.
PMID:22814319 SUPPORT Human Clinical
"Both mutations were not among the 162 mutations in ATP2A2, which were reported to date in DD."
Supports the separation of the AKV variants from the Darier variant spectrum.
PMID:16716163 REFUTE Human Clinical
"Mutational analysis showed no mutation in ATP2A2 among the AKV patients"
In two Chinese AKV families and a sporadic case no ATP2A2 variant was found, so ATP2A2 does not account for every AKV family.
+ 1 more reference
Variants (2)
p.(Pro602Leu)
Recurrent heterozygous missense variant (P602L) in exon 14, in the ATP-binding domain of SERCA2, segregating with AKV in several unrelated families; the expressed mutant has no calcium transport activity.
Show evidence (2 references)
PMID:28498512 SUPPORT Human Clinical
"We report a family with AKV due to the p.(Pro602Leu) mutation and discuss implications for this recurrent mutation on knowledge of ATP2A2 structure and function."
Reports the recurrent variant in a further family.
PMID:12542527 SUPPORT Human Clinical
"The mutation segregates with the disease phenotype in the family and was not found in 50 controls."
Co-segregation and absence from controls support pathogenicity.
p.(Ala698Val)
Heterozygous missense variant (A698V) previously described in AKV.
Show evidence (1 reference)
PMID:22814319 SUPPORT Human Clinical
"This mutation and a heterozygous A698V were previously described in AKV."
Records A698V as a second AKV-associated ATP2A2 variant.
💊

Medical Actions

5
Superficial ablation
Action: ablation therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is ablation therapy (NCIT:C20985). NCIT:C20985 is a clinical intervention from the NCI Thesaurus. Ontology label: Ablation Therapy NCIT:C20985
Superficial destructive ablation of the papules is regarded as the treatment of choice. Treatment is optional, as the disease is benign and the indication is cosmetic.
Show evidence (1 reference)
PMID:38854358 SUPPORT Human Clinical
"AKVH is usually difficult to treat and superficial ablation is the treatment of choice."
Names superficial ablation as the treatment of choice.
Cryotherapy
Action: cryotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cryotherapy (NCIT:C40030). NCIT:C40030 is a clinical intervention from the NCI Thesaurus. Ontology label: Cryotherapy NCIT:C40030
Cryotherapy, used as for warts, gives variable results; one patient did not improve with cryotherapy and topical corticosteroids, while another improved quickly when it was combined with oral acitretin.
Show evidence (2 references)
PMID:42205461 SUPPORT REVIEW SYNTHESIS Human Clinical
"They include destructive methods used for warts, such as cryotherapy and topical medications (mainly keratolytics and retinoids)."
Records cryotherapy among the destructive methods used.
PMID:25821733 REFUTE Human Clinical
"Patient was treated with a combination of topical corticosteroids and cryotherapy with no visible improvement."
A case in which cryotherapy with topical corticosteroids failed.
Systemic retinoids
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: acitretin CHEBI:50172 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses acitretin (CHEBI:50172). CHEBI:50172 is a therapeutic agent from Chemical Entities of Biological Interest. etretinate CHEBI:4913 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses etretinate (CHEBI:4913). CHEBI:4913 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Oral acitretin has helped in a few cases, with relapse after discontinuation in one; oral isotretinoin combined with local treatment and low-dose alitretinoin have also been tried, and etretinate was ineffective in two patients.
Show evidence (3 references)
PMID:42205461 SUPPORT REVIEW SYNTHESIS Human Clinical
"however, the lesions may reappear following the discontinuation of treatment (45)."
Records relapse after stopping acitretin, which limits its benefit.
PMID:38854358 SUPPORT Human Clinical
"However, this case highlights the role of cryotherapy with acitretin in the management of AKVH with a rapid response."
Case report of a rapid response to acitretin combined with cryotherapy.
PMID:3323700 REFUTE Human Clinical
"We comment on the clinical and histopathological features of this rare dermatosis and the unsuccessful therapy with etretinate."
A non-familial case in which systemic etretinate failed.
Topical keratolytics and retinoids
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: salicylic acid CHEBI:16914 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses salicylic acid (CHEBI:16914). CHEBI:16914 is a therapeutic agent from Chemical Entities of Biological Interest. retinoid CHEBI:26537 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses retinoid (CHEBI:26537). CHEBI:26537 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Topical keratolytics such as salicylic acid and urea, and topical retinoids such as tretinoin and tazarotene, have shown limited efficacy, and lesions can be refractory to them.
Show evidence (2 references)
PMID:42205461 SUPPORT REVIEW SYNTHESIS Human Clinical
"Topical tretinoin has shown limited efficacy (2,4,27)."
Summarizes the limited efficacy of topical retinoid.
PMID:42205461 REFUTE REVIEW SYNTHESIS Human Clinical
"The lesions may, however, be refractory to topical treatments, as shown by a case where several topical agents (keratolytics with urea and salicylic acid 40%, clobetasol 0.05%, tretinoin 0.1%, pumice stone abrasion) proved ineffective (27)."
A case refractory to topical salicylic acid, urea and tretinoin.
Genetic counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
As the disease is usually dominantly inherited, affected individuals should be told that their offspring may be affected.
Show evidence (1 reference)
PMID:42205461 SUPPORT REVIEW SYNTHESIS Human Clinical
"Patients should therefore be warned that their offspring could develop the disease."
Supports counselling about transmission risk.
🔬

Diagnosis

3
Skin biopsy with histopathology
Histology distinguishes AKV from plane warts, epidermodysplasia verruciformis, stucco keratoses and Darier disease: verrucous epidermal hyperplasia with hyperkeratosis, hypergranulosis, acanthosis and church-spire papillomatosis, without, or with only minimal, acantholysis and dyskeratosis.
skin biopsy NCIT:C51692 NCI Thesaurus (NCIT)
Results: Circumscribed verrucous epidermal hyperplasia with church-spire elevations; acantholysis and dyskeratosis absent or minimal.
Show evidence (2 references)
PMID:42205461 SUPPORT REVIEW SYNTHESIS Human Clinical
"The diagnosis of AVH relies mainly on clinical and histological examination."
States that diagnosis rests on clinical and histological examination.
PMID:30725935 SUPPORT REVIEW SYNTHESIS Human Clinical
"Histopathology often provides decisive confirmation because it reveals the classic architecture that distinguishes this entity from viral warts and other keratotic disorders."
Supports histopathology as the confirmatory test against warts.
ATP2A2 genetic testing
Because the clinicopathological picture is not entirely specific, confirmation by demonstrating ATP2A2 p.(Pro602Leu) is recommended where possible. Most published cases were never genotyped. A whole-skin examination to exclude Darier disease is part of the work-up.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:42205461 SUPPORT REVIEW SYNTHESIS Human Clinical
"Since the clinicopathologic features of AVH are not entirely specific, the diagnosis should be confirmed, whenever possible, by genetic analysis, specifically by demonstrating the p.(Pro602Leu) mutation in the ATP2A2 gene."
Recommends targeted genetic confirmation.
PMID:42205461 SUPPORT REVIEW SYNTHESIS Human Clinical
"In any case, when managing a patient with suspected AVH, DD should be ruled out by a thorough examination of the whole skin."
Records the whole-skin examination to exclude Darier disease.
Dermoscopy
Dermoscopy is supportive but not specific, showing a homogeneous whitish pattern with occasional dot-like vessels, and helps separate AKV from lichen planus, plane warts and epidermodysplasia verruciformis.
dermoscopy NCIT:C116478 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:42205461 SUPPORT REVIEW SYNTHESIS Human Clinical
"Dermatoscopic examination can aid in the diagnosis, allowing namely to differentiate AVH from lichen planus, flat warts and epidermodysplasia verruciformis (43)."
Supports dermoscopy as a diagnostic aid and names its differentials.
📊

Prevalence

1
Dermatology clinic attendees
Unknown Rare
The population prevalence is unknown. The only figure available is a clinic-based frequency of about 1 case per 41,000 dermatological consultations, about half that of Darier disease, which is not a population rate and is therefore not normalized to a rate per 100,000.
Show evidence (1 reference)
PMID:42205461 SUPPORT REVIEW SYNTHESIS Human Clinical
"AVH is a rare condition; however, its precise incidence remains unknown. According to a previous study, the estimated frequency is 1 case per 41,000 dermatological consultations, i.e. half that of DD (31)."
States that the incidence is unknown and gives the clinic-based frequency estimate recorded in notes.
{ }

Source YAML

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name: Acrokeratosis Verruciformis
creation_date: "2026-10-15T23:02:32Z"
description: >-
  Acrokeratosis verruciformis of Hopf (AKV) is a rare autosomal dominant
  genodermatosis of keratinization in which flat, skin-coloured, wart-like
  keratotic papules develop on the dorsa of the hands and feet, usually from
  early childhood, and persist without spontaneous regression. Familial AKV is
  caused by a recurrent heterozygous ATP2A2 missense variant, p.(Pro602Leu), in
  the ATP-binding domain of SERCA2, the sarco/endoplasmic reticulum calcium
  pump that is also mutated in Darier disease; the mutant pump has lost calcium
  transport activity. AKV is therefore allelic with Darier disease, but the
  two differ in phenotype: AKV spares the seborrheic areas, and its histology is
  a well-circumscribed verrucous epidermal hyperplasia with orthokeratotic
  hyperkeratosis, hypergranulosis, acanthosis and church-spire papillomatosis,
  without the suprabasal acantholysis and dyskeratosis that define Darier
  disease. Whether AKV is a distinct entity or a limited acral expression of
  Darier disease remains debated: AKV-like acral papules are common in Darier
  patients, the two conditions coexist in some individuals, and focal
  acantholysis has been found on step sectioning of AKV lesions, whereas some
  AKV families show no ATP2A2 variant and no linkage to its locus. The course is
  chronic and benign, with rare squamous cell carcinoma in longstanding lesions,
  and treatment is cosmetic and of modest benefit.
category: Mendelian
parents:
- Genodermatosis
- keratinizing disorder
synonyms:
- acrokeratosis verruciformis of Hopf
- Hopf disease
- AKV
- AKV of Hopf
disease_term:
  preferred_term: acrokeratosis verruciformis
  term:
    id: MONDO:0007048
    label: acrokeratosis verruciformis
classifications:
  harrisons_chapter:
  - classification_value: DERMATOLOGY
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
prevalence:
- population: Dermatology clinic attendees
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    The population prevalence is unknown. The only figure available is a
    clinic-based frequency of about 1 case per 41,000 dermatological
    consultations, about half that of Darier disease, which is not a population
    rate and is therefore not normalized to a rate per 100,000.
  evidence:
  - reference: PMID:42205461
    reference_title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "AVH is a rare condition; however, its precise incidence remains unknown. According to a previous study, the estimated frequency is 1 case per 41,000 dermatological consultations, i.e. half that of DD (31)."
    explanation: >-
      States that the incidence is unknown and gives the clinic-based frequency
      estimate recorded in notes.
inheritance:
- name: Autosomal Dominant
  description: >-
    Familial AKV segregates as an autosomal dominant trait, described in one
    family over six generations, with variable penetrance.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:12542527
    reference_title: "Acrokeratosis verruciformis of Hopf is caused by mutation in ATP2A2: evidence that it is allelic to Darier's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Onset is early in life and the disease is inherited in an autosomal dominant fashion."
    explanation: >-
      States the dominant mode of inheritance in the family study that
      identified the causal variant.
  - reference: PMID:42205461
    reference_title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "AVH is usually transmitted as an autosomal dominant trait with variable penetrance, although several sporadic cases have been reported."
    explanation: >-
      Review synthesis of the reported families supporting dominant inheritance
      with variable penetrance.
- name: Sporadic
  description: >-
    Many published cases are sporadic, often with adult onset and a wider
    distribution of lesions. These may reflect de novo variants or reduced
    penetrance, but most were never genotyped, so some may be misdiagnosed
    phenocopies.
  inheritance_term:
    preferred_term: Sporadic
    term:
      id: HP:0003745
      label: Sporadic
  evidence:
  - reference: PMID:42205461
    reference_title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Moreover, several sporadic, non-familial AVH cases have been reported (7,16-19); these may reflect de novo mutations or reduced penetrance, particularly when there is no family history of a similar condition."
    explanation: >-
      Documents sporadic cases and the two explanations offered for them.
  - reference: PMID:31696902
    reference_title: "Late-onset non-familial acrokeratosis verruciformis of Hopf: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Usually, it arises in early life but rare sporadic cases with adult onset have been reported."
    explanation: >-
      Reports a non-familial adult-onset case and the association of sporadic
      cases with later onset.
pathophysiology:
- name: ATP2A2 Pro602Leu Loss of SERCA2 Calcium Transport
  biological_scale: MOLECULAR
  description: >-
    The recurrent heterozygous ATP2A2 missense variant p.(Pro602Leu) replaces a
    proline in the ATP-binding domain of SERCA2. Expressed in vitro, the mutant
    pump has lost its ability to transport calcium into the sarco/endoplasmic
    reticulum. This is the same gene and the same functional class of lesion as
    in Darier disease, which is the basis for regarding the two as allelic.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  molecular_functions:
  - preferred_term: P-type calcium transporter activity
    term:
      id: GO:0005388
      label: P-type calcium transporter activity
    modifier: DECREASED
  genetic_context:
    gene:
      preferred_term: ATP2A2
      term:
        id: hgnc:812
        label: ATP2A2
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Heterozygous p.(Pro602Leu) missense variant; the mutant protein shows no
      calcium transport in a functional assay.
  downstream:
  - target: Disturbed Endoplasmic Reticulum Calcium Homeostasis in Acral Keratinocytes
    description: >-
      Loss of pump activity from one allele reduces calcium uptake into the
      keratinocyte endoplasmic reticulum.
  evidence:
  - reference: PMID:12542527
    reference_title: "Acrokeratosis verruciformis of Hopf is caused by mutation in ATP2A2: evidence that it is allelic to Darier's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we studied a family affected with acrokeratosis verruciformis in six generations and identified a heterozygous P602L mutation in ATP2A2"
    explanation: >-
      Identifies the heterozygous P602L variant as the familial lesion.
  - reference: PMID:12542527
    reference_title: "Acrokeratosis verruciformis of Hopf is caused by mutation in ATP2A2: evidence that it is allelic to Darier's disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Moreover, functional analysis of the P602L mutant showed that it has lost its ability to transport Ca2+."
    explanation: >-
      Functional assay of the expressed mutant pump showing loss of calcium
      transport, the molecular claim of this node.
  - reference: PMID:12542527
    reference_title: "Acrokeratosis verruciformis of Hopf is caused by mutation in ATP2A2: evidence that it is allelic to Darier's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This mutation predicts a nonconservative amino acid substitution in the ATP binding domain of the molecule."
    explanation: >-
      Places the substitution in the ATP-binding domain of SERCA2.
  - reference: PMID:28498512
    reference_title: "Recurrent ATP2A2 p.(Pro602Leu) mutation differentiates Acrokeratosis verruciformis of Hopf from the allelic condition Darier disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While hundreds of different missense and nonsense mutations cause Darier disease, only one missense mutation, p.(Pro602Leu), has been identified in families with AKV."
    explanation: >-
      An independent family confirms p.(Pro602Leu) as the recurrent AKV
      variant, contrasted with the broad Darier variant spectrum.
  - reference: PMID:22814319
    reference_title: "Acrokeratosis verruciformis of Hopf showing P602L mutation in ATP2A2 and overlapping histopathological features with Darier disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A heterozygous P602L mutation in ATP2A2 was identified as the underlying cause in this family."
    explanation: >-
      A third, 14-member family carries the same heterozygous variant.
- name: Disturbed Endoplasmic Reticulum Calcium Homeostasis in Acral Keratinocytes
  biological_scale: CELLULAR
  description: >-
    SERCA2 sequesters cytosolic calcium into the endoplasmic reticulum of
    keratinocytes, and this store supports keratinocyte differentiation and,
    indirectly, intercellular adhesion. Loss of pump activity is inferred to
    disturb that store in the affected acral epidermis. No study has measured
    keratinocyte calcium handling in AKV directly, and why the lesion is
    confined to acral skin, and why it largely spares adhesion here when it
    does not in Darier disease, is unexplained.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: endoplasmic reticulum calcium ion homeostasis
    term:
      id: GO:0032469
      label: endoplasmic reticulum calcium ion homeostasis
    modifier: ABNORMAL
  downstream:
  - target: Abnormal Keratinocyte Differentiation with Verrucous Epidermal Hyperplasia
    description: >-
      The disturbed calcium store deranges terminal keratinocyte
      differentiation, the defining process in AKV.
  - target: Focal Suprabasal Acantholysis with Mild Dyskeratosis
    description: >-
      In some lesions the same disturbance also reaches keratinocyte adhesion,
      producing small foci of the Darier-type change; this arm is inconstant.
  evidence:
  - reference: PMID:42205461
    reference_title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: "it encodes the calcium pump SERCA2, which is present in the membrane of the endo-sarcoplasmic reticulum and plays a key role in calcium transport, and indirectly in the intercellular adhesion of keratinocytes."
    explanation: >-
      States the endoplasmic reticulum calcium-transport role of SERCA2 in
      keratinocytes. The step from the AKV variant to a disturbed store is an
      inference from pump function, not a measurement in AKV keratinocytes.
  - reference: PMID:12542527
    reference_title: "Acrokeratosis verruciformis of Hopf is caused by mutation in ATP2A2: evidence that it is allelic to Darier's disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "This result demonstrates loss of function of the sarco(endo)plasmic reticulum Ca2+ ATPase2 mutant in acrokeratosis verruciformis"
    explanation: >-
      Demonstrates loss of the reticulum calcium pump function in AKV, from
      which the disturbed store follows by inference.
- name: Abnormal Keratinocyte Differentiation with Verrucous Epidermal Hyperplasia
  biological_scale: TISSUE
  description: >-
    The lesion is a well-circumscribed epidermal hyperplasia: orthokeratotic
    hyperkeratosis, acanthosis and moderate papillomatosis, usually with
    hypergranulosis, and a verrucous surface whose regular elevations resemble
    church spires. The dermis is usually normal. Unlike Darier disease, the
    classic AKV lesion shows no dyskeratosis.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinocyte differentiation
    term:
      id: GO:0030216
      label: keratinocyte differentiation
    modifier: ABNORMAL
  - preferred_term: keratinization
    term:
      id: GO:0031424
      label: keratinization
    modifier: ABNORMAL
  locations:
  - preferred_term: epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  downstream:
  - target: Acral Verrucous Papules
    description: >-
      The circumscribed verrucous hyperplasia is the histological substrate of
      each flat wart-like papule.
  - target: Hyperkeratosis
    description: Thickening of the stratum corneum is part of the hyperplasia.
  - target: Hypergranulosis
    description: Thickening of the granular layer is part of the hyperplasia.
  - target: Epidermal Acanthosis
    description: Thickening of the spinous layer is part of the hyperplasia.
  - target: Punctate Palmoplantar Keratoses
    description: >-
      The same keratinization disorder produces punctate keratoses on the palms
      and soles.
  evidence:
  - reference: PMID:42205461
    reference_title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Routine histological examination of AVH reveals a well-circumscribed epidermal hyperplasia, consisting of orthokeratotic hyperkeratosis, acanthosis and moderate papillomatosis, often with hypergranulosis."
    explanation: >-
      Summarizes the histology that defines this node.
  - reference: PMID:42205461
    reference_title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The surface of the epidermis usually presents a characteristic verrucous, church-spire-like appearance."
    explanation: >-
      Documents the church-spire surface architecture.
  - reference: PMID:22028575
    reference_title: "Non-familial Acrokeratosis Verruciformis of Hopf."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histopathologically, the lesion shows considerable hyperkeratosis, acanthosis, and papillomatosis"
    explanation: >-
      Independent case report describing the same hyperkeratosis, acanthosis
      and papillomatosis.
  - reference: PMID:12542527
    reference_title: "Acrokeratosis verruciformis of Hopf is caused by mutation in ATP2A2: evidence that it is allelic to Darier's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acrokeratosis verruciformis of Hopf is a localized disorder of keratinization affecting the distal extremities."
    explanation: >-
      Classifies the disease as a localized disorder of keratinization.
- name: Focal Suprabasal Acantholysis with Mild Dyskeratosis
  biological_scale: TISSUE
  description: >-
    Small suprabasal clefts with acantholytic, sometimes mildly dyskeratotic
    keratinocytes have been found in some genotyped AKV lesions on step
    sectioning, and Darier-like cytology including corps ronds and grains in
    another case. When present, acantholysis and dyskeratosis are minimal.
    Their absence has long been used to separate AKV from Darier disease, so
    this node records an inconstant finding that bears on that question rather
    than a defining feature.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: cell-cell adhesion
    term:
      id: GO:0098609
      label: cell-cell adhesion
    modifier: DECREASED
  locations:
  - preferred_term: epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:22814319
    reference_title: "Acrokeratosis verruciformis of Hopf showing P602L mutation in ATP2A2 and overlapping histopathological features with Darier disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "foci of small suprabasal clefts with acantholytic keratinocytes, some of which were mildly dyskeratotic."
    explanation: >-
      Step sections of lesions from P602L carriers showed focal suprabasal
      acantholysis with mild dyskeratosis.
  - reference: PMID:27663152
    reference_title: "Acrokeratosis verruciformis of Hopf exhibiting Darier disease-like cytological features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cytological examination showed acantholytic keratinocytes, dyskeratotic acantholytic cells, corps ronds and grains."
    explanation: >-
      A clinically diagnosed AKV case with Darier-like cytology.
  - reference: PMID:42205461
    reference_title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "However, when present, acantholysis and dyskeratosis are typically minimal in AVH."
    explanation: >-
      Records that the change is minimal when present.
  - reference: PMID:12542527
    reference_title: "Acrokeratosis verruciformis of Hopf is caused by mutation in ATP2A2: evidence that it is allelic to Darier's disease."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Although histology of acrokeratosis verruciformis lesions shows no evidence of dyskeratosis"
    explanation: >-
      In the six-generation P602L family the lesions showed no dyskeratosis,
      so the change is not a constant feature of the genotype.
phenotypes:
- category: Dermatologic
  name: Acral Verrucous Papules
  diagnostic: true
  description: >-
    Multiple small, flat-topped, skin-coloured or slightly pigmented papules
    with a verrucous surface, resembling plane warts, on the dorsa of the hands,
    fingers and feet, sometimes extending to forearms, legs, knees and elbows.
    They appear in childhood or adolescence, occasionally at birth, and persist
    indefinitely. Seborrheic areas are usually spared, unlike Darier disease.
  phenotype_term:
    preferred_term: Acrokeratosis
    term:
      id: HP:0200016
      label: Acrokeratosis
    onset:
      onset_category: CHILDHOOD
      notes: >-
        Usually childhood or adolescence, sometimes at birth in familial cases;
        sporadic cases may begin as late as the sixth decade.
  sequelae:
  - target: Squamous Cell Carcinoma in Longstanding Lesions
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Squamous cell carcinoma has been reported arising in longstanding AKV
      papules.
    evidence:
    - reference: PMID:30725935
      reference_title: "Acrokeratosis Verruciformis of Hopf."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "rare reports of malignant transformation, typically squamous cell carcinoma, arising in longstanding lesions have been documented"
      explanation: >-
        Places the carcinomas within longstanding lesions.
  evidence:
  - reference: PMID:16716163
    reference_title: "Genetic heterogeneity in acrokeratosis verruciformis of Hopf."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acrokeratosis verruciformis of Hopf (AKV) is a rare genodermatosis characterized by multiple flat-topped, flesh-coloured papules on the dorsa of hands and feet, and punctuate keratoses on the palms and soles."
    explanation: >-
      Defines the dorsal acral papules as the characteristic lesion.
  - reference: PMID:30725935
    reference_title: "Acrokeratosis Verruciformis of Hopf."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Lesions typically begin in childhood or adolescence and persist without spontaneous regression"
    explanation: >-
      Supports childhood onset and the persistent course.
  - reference: PMID:42205461
    reference_title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "However, contrary to the latter, seborrheic body zones (such as the face, scalp and trunk) are usually spared in AVH (31)."
    explanation: >-
      Records the sparing of seborrheic areas that separates AKV from Darier
      disease clinically.
- category: Dermatologic
  name: Punctate Palmoplantar Keratoses
  description: >-
    Punctate hyperkeratotic lesions of the palms, and in some reports the
    soles.
  phenotype_term:
    preferred_term: Punctate palmoplantar hyperkeratosis
    term:
      id: HP:0007530
      label: Punctate palmoplantar hyperkeratosis
  evidence:
  - reference: PMID:16716163
    reference_title: "Genetic heterogeneity in acrokeratosis verruciformis of Hopf."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and punctuate keratoses on the palms and soles."
    explanation: >-
      Names punctate palmoplantar keratoses as part of the phenotype; the
      spelling punctuate is the source's own.
  - reference: PMID:42205461
    reference_title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Punctiform hyperkeratotic lesions of the palms may be present (40)."
    explanation: >-
      Review confirmation that punctate palmar keratoses may occur.
- category: Dermatologic
  name: Nail Dystrophy
  description: >-
    Nail changes are not rare and include pachyonychia, leukonychia,
    longitudinal depressions, subungual haemorrhages, distal onychoschizis,
    V-shaped notches of the free edge and subungual hyperkeratosis, which add to
    the resemblance with Darier disease.
  phenotype_term:
    preferred_term: Nail dystrophy
    term:
      id: HP:0008404
      label: Nail dystrophy
  evidence:
  - reference: PMID:42205461
    reference_title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Nail lesions are not rare; they include pachyonychia, leukonychia, longitudinal depressions, subungual hemorrhages, distal onychoschizis"
    explanation: >-
      Lists the nail changes reported in AKV.
  - reference: PMID:40256087
    reference_title: "Acrokeratosis verruciformis of Hopf: A rare presentation in a young Indian female-A case report and review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A V-shaped notch on the nails indicated nail dystrophy."
    explanation: >-
      Case with V-shaped notching interpreted as nail dystrophy.
  - reference: PMID:41054640
    reference_title: "Sporadic Case of Acrokeratosis Verruciformis of Hopf With Unusual Clinical Presentation: A Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nail changes included thickening of the nail plate and subungual hemorrhages."
    explanation: >-
      Case with nail plate thickening and subungual haemorrhage.
- category: Dermatologic
  name: Leukonychia
  phenotype_term:
    preferred_term: Leukonychia
    term:
      id: HP:0001820
      label: Leukonychia
  evidence:
  - reference: PMID:42205461
    reference_title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Nail lesions are not rare; they include pachyonychia, leukonychia, longitudinal depressions"
    explanation: >-
      Names leukonychia among the reported nail changes.
- category: Histopathologic
  name: Hyperkeratosis
  description: Compact orthokeratotic hyperkeratosis over the papules.
  phenotype_term:
    preferred_term: Hyperkeratosis
    term:
      id: HP:0000962
      label: Hyperkeratosis
  evidence:
  - reference: PMID:27663152
    reference_title: "Acrokeratosis verruciformis of Hopf exhibiting Darier disease-like cytological features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histopathological examination showed compact hyperkeratosis, hypergranulosis, slight acanthosis, circumscribed epidermal elevations resembling church spires"
    explanation: >-
      Documents compact hyperkeratosis in an AKV biopsy.
- category: Histopathologic
  name: Hypergranulosis
  description: Thickened granular layer.
  phenotype_term:
    preferred_term: Hypergranulosis
    term:
      id: HP:0025114
      label: Hypergranulosis
  evidence:
  - reference: PMID:22028575
    reference_title: "Non-familial Acrokeratosis Verruciformis of Hopf."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and a thickened granular layer."
    explanation: >-
      Documents the thickened granular layer.
  - reference: PMID:27663152
    reference_title: "Acrokeratosis verruciformis of Hopf exhibiting Darier disease-like cytological features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histopathological examination showed compact hyperkeratosis, hypergranulosis, slight acanthosis"
    explanation: >-
      Documents hypergranulosis in an independent biopsy.
- category: Histopathologic
  name: Epidermal Acanthosis
  description: Mild thickening of the spinous layer with papillomatosis.
  phenotype_term:
    preferred_term: Epidermal acanthosis
    term:
      id: HP:0025092
      label: Epidermal acanthosis
  evidence:
  - reference: PMID:40256087
    reference_title: "Acrokeratosis verruciformis of Hopf: A rare presentation in a young Indian female-A case report and review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The histopathological examination of a skin biopsy revealed marked hyperkeratosis, acanthosis, papillomatosis, and church spire-like epidermal elevations, confirming the diagnosis of AVH."
    explanation: >-
      Documents acanthosis with papillomatosis and church-spire elevations as
      the diagnostic histology.
- category: Neoplastic
  name: Squamous Cell Carcinoma in Longstanding Lesions
  frequency: VERY_RARE
  description: >-
    Two cases of cutaneous squamous cell carcinoma arising in longstanding AKV
    lesions have been reported, which is the reason periodic follow-up is
    advised.
  phenotype_term:
    preferred_term: Squamous cell carcinoma of the skin
    term:
      id: HP:0006739
      label: Squamous cell carcinoma of the skin
  evidence:
  - reference: PMID:42205461
    reference_title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Of note, two cases of squamous cell carcinoma that developed on long-standing AVH lesions have been reported (31,42)."
    explanation: >-
      Records the two reported carcinomas and their origin in longstanding
      lesions.
diagnosis:
- name: Skin biopsy with histopathology
  diagnosis_term:
    preferred_term: skin biopsy
    term:
      id: NCIT:C51692
      label: Skin Biopsy
  description: >-
    Histology distinguishes AKV from plane warts, epidermodysplasia
    verruciformis, stucco keratoses and Darier disease: verrucous epidermal
    hyperplasia with hyperkeratosis, hypergranulosis, acanthosis and
    church-spire papillomatosis, without, or with only minimal, acantholysis and
    dyskeratosis.
  results: >-
    Circumscribed verrucous epidermal hyperplasia with church-spire
    elevations; acantholysis and dyskeratosis absent or minimal.
  evidence:
  - reference: PMID:42205461
    reference_title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The diagnosis of AVH relies mainly on clinical and histological examination."
    explanation: >-
      States that diagnosis rests on clinical and histological examination.
  - reference: PMID:30725935
    reference_title: "Acrokeratosis Verruciformis of Hopf."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Histopathology often provides decisive confirmation because it reveals the classic architecture that distinguishes this entity from viral warts and other keratotic disorders."
    explanation: >-
      Supports histopathology as the confirmatory test against warts.
- name: ATP2A2 genetic testing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Because the clinicopathological picture is not entirely specific,
    confirmation by demonstrating ATP2A2 p.(Pro602Leu) is recommended where
    possible. Most published cases were never genotyped. A whole-skin
    examination to exclude Darier disease is part of the work-up.
  evidence:
  - reference: PMID:42205461
    reference_title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Since the clinicopathologic features of AVH are not entirely specific, the diagnosis should be confirmed, whenever possible, by genetic analysis, specifically by demonstrating the p.(Pro602Leu) mutation in the ATP2A2 gene."
    explanation: >-
      Recommends targeted genetic confirmation.
  - reference: PMID:42205461
    reference_title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "In any case, when managing a patient with suspected AVH, DD should be ruled out by a thorough examination of the whole skin."
    explanation: >-
      Records the whole-skin examination to exclude Darier disease.
- name: Dermoscopy
  diagnosis_term:
    preferred_term: dermoscopy
    term:
      id: NCIT:C116478
      label: Dermoscopy
  description: >-
    Dermoscopy is supportive but not specific, showing a homogeneous whitish
    pattern with occasional dot-like vessels, and helps separate AKV from lichen
    planus, plane warts and epidermodysplasia verruciformis.
  evidence:
  - reference: PMID:42205461
    reference_title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Dermatoscopic examination can aid in the diagnosis, allowing namely to differentiate AVH from lichen planus, flat warts and epidermodysplasia verruciformis (43)."
    explanation: >-
      Supports dermoscopy as a diagnostic aid and names its differentials.
genetic:
- name: ATP2A2
  notes: >-
    ATP2A2 encodes SERCA2, the sarco/endoplasmic reticulum calcium ATPase
    isoform 2. Familial AKV is associated with one recurrent heterozygous
    missense variant, p.(Pro602Leu), in the ATP-binding domain, and a second
    missense variant, p.(Ala698Val), has also been described in AKV; neither
    had been reported among Darier disease variants at the time. Some AKV
    families, notably in China, carry no ATP2A2 variant and show no linkage to
    12q23-q24, so AKV is genetically heterogeneous and the other gene or genes
    are unknown.
  gene_term:
    preferred_term: ATP2A2
    term:
      id: hgnc:812
      label: ATP2A2
  relationship_type: CAUSATIVE
  variants:
  - name: p.(Pro602Leu)
    description: >-
      Recurrent heterozygous missense variant (P602L) in exon 14, in the
      ATP-binding domain of SERCA2, segregating with AKV in several unrelated
      families; the expressed mutant has no calcium transport activity.
    evidence:
    - reference: PMID:28498512
      reference_title: "Recurrent ATP2A2 p.(Pro602Leu) mutation differentiates Acrokeratosis verruciformis of Hopf from the allelic condition Darier disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We report a family with AKV due to the p.(Pro602Leu) mutation and discuss implications for this recurrent mutation on knowledge of ATP2A2 structure and function."
      explanation: >-
        Reports the recurrent variant in a further family.
    - reference: PMID:12542527
      reference_title: "Acrokeratosis verruciformis of Hopf is caused by mutation in ATP2A2: evidence that it is allelic to Darier's disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The mutation segregates with the disease phenotype in the family and was not found in 50 controls."
      explanation: >-
        Co-segregation and absence from controls support pathogenicity.
  - name: p.(Ala698Val)
    description: >-
      Heterozygous missense variant (A698V) previously described in AKV.
    evidence:
    - reference: PMID:22814319
      reference_title: "Acrokeratosis verruciformis of Hopf showing P602L mutation in ATP2A2 and overlapping histopathological features with Darier disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This mutation and a heterozygous A698V were previously described in AKV."
      explanation: >-
        Records A698V as a second AKV-associated ATP2A2 variant.
  evidence:
  - reference: PMID:12542527
    reference_title: "Acrokeratosis verruciformis of Hopf is caused by mutation in ATP2A2: evidence that it is allelic to Darier's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we studied a family affected with acrokeratosis verruciformis in six generations and identified a heterozygous P602L mutation in ATP2A2"
    explanation: >-
      Establishes ATP2A2 as the causal gene in familial AKV.
  - reference: PMID:22814319
    reference_title: "Acrokeratosis verruciformis of Hopf showing P602L mutation in ATP2A2 and overlapping histopathological features with Darier disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both mutations were not among the 162 mutations in ATP2A2, which were reported to date in DD."
    explanation: >-
      Supports the separation of the AKV variants from the Darier variant
      spectrum.
  - reference: PMID:16716163
    reference_title: "Genetic heterogeneity in acrokeratosis verruciformis of Hopf."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutational analysis showed no mutation in ATP2A2 among the AKV patients"
    explanation: >-
      In two Chinese AKV families and a sporadic case no ATP2A2 variant was
      found, so ATP2A2 does not account for every AKV family.
  - reference: PMID:16716163
    reference_title: "Genetic heterogeneity in acrokeratosis verruciformis of Hopf."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The genotyping and linkage analysis results revealed no linkage evidence of the locus at 12q23-12q24 in a large AKV family."
    explanation: >-
      Absence of linkage to the ATP2A2 locus in a large family supports a
      second AKV locus.
treatments:
- name: Superficial ablation
  description: >-
    Superficial destructive ablation of the papules is regarded as the
    treatment of choice. Treatment is optional, as the disease is benign and
    the indication is cosmetic.
  treatment_term:
    preferred_term: ablation therapy
    term:
      id: NCIT:C20985
      label: Ablation Therapy
  evidence:
  - reference: PMID:38854358
    reference_title: "An Atypical Case of Acrokeratosis Verruciformis of Hopf Responding to Combined Acitretin and Cryotherapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AKVH is usually difficult to treat and superficial ablation is the treatment of choice."
    explanation: >-
      Names superficial ablation as the treatment of choice.
- name: Cryotherapy
  description: >-
    Cryotherapy, used as for warts, gives variable results; one patient did not
    improve with cryotherapy and topical corticosteroids, while another improved
    quickly when it was combined with oral acitretin.
  treatment_term:
    preferred_term: cryotherapy
    term:
      id: NCIT:C40030
      label: Cryotherapy
  evidence:
  - reference: PMID:42205461
    reference_title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "They include destructive methods used for warts, such as cryotherapy and topical medications (mainly keratolytics and retinoids)."
    explanation: >-
      Records cryotherapy among the destructive methods used.
  - reference: PMID:25821733
    reference_title: "Nonfamilial acrokeratosis verruciformis of Hopf."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient was treated with a combination of topical corticosteroids and cryotherapy with no visible improvement."
    explanation: >-
      A case in which cryotherapy with topical corticosteroids failed.
- name: Systemic retinoids
  description: >-
    Oral acitretin has helped in a few cases, with relapse after
    discontinuation in one; oral isotretinoin combined with local treatment and
    low-dose alitretinoin have also been tried, and etretinate was ineffective
    in two patients.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acitretin
      term:
        id: CHEBI:50172
        label: acitretin
    - preferred_term: etretinate
      term:
        id: CHEBI:4913
        label: etretinate
  evidence:
  - reference: PMID:42205461
    reference_title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "however, the lesions may reappear following the discontinuation of treatment (45)."
    explanation: >-
      Records relapse after stopping acitretin, which limits its benefit.
  - reference: PMID:38854358
    reference_title: "An Atypical Case of Acrokeratosis Verruciformis of Hopf Responding to Combined Acitretin and Cryotherapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, this case highlights the role of cryotherapy with acitretin in the management of AKVH with a rapid response."
    explanation: >-
      Case report of a rapid response to acitretin combined with cryotherapy.
  - reference: PMID:3323700
    reference_title: "[Hopf's acrokeratosis verruciformis. Communication of a non-familial case]."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "We comment on the clinical and histopathological features of this rare dermatosis and the unsuccessful therapy with etretinate."
    explanation: >-
      A non-familial case in which systemic etretinate failed.
- name: Topical keratolytics and retinoids
  description: >-
    Topical keratolytics such as salicylic acid and urea, and topical retinoids
    such as tretinoin and tazarotene, have shown limited efficacy, and lesions
    can be refractory to them.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: salicylic acid
      term:
        id: CHEBI:16914
        label: salicylic acid
    - preferred_term: retinoid
      term:
        id: CHEBI:26537
        label: retinoid
  evidence:
  - reference: PMID:42205461
    reference_title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Topical tretinoin has shown limited efficacy (2,4,27)."
    explanation: >-
      Summarizes the limited efficacy of topical retinoid.
  - reference: PMID:42205461
    reference_title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The lesions may, however, be refractory to topical treatments, as shown by a case where several topical agents (keratolytics with urea and salicylic acid 40%, clobetasol 0.05%, tretinoin 0.1%, pumice stone abrasion) proved ineffective (27)."
    explanation: >-
      A case refractory to topical salicylic acid, urea and tretinoin.
- name: Genetic counseling
  description: >-
    As the disease is usually dominantly inherited, affected individuals should
    be told that their offspring may be affected.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:42205461
    reference_title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Patients should therefore be warned that their offspring could develop the disease."
    explanation: >-
      Supports counselling about transmission risk.
discussions:
- discussion_id: akv_distinct_entity_or_acral_darier
  prompt: >-
    Is acrokeratosis verruciformis a distinct disease, or a limited acral
    expression of Darier disease?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - disease#Acrokeratosis Verruciformis
  - pathophysiology#Focal Suprabasal Acantholysis with Mild Dyskeratosis
  rationale: >-
    For a distinct entity: a distinct clinical picture confined to acral skin
    and sparing seborrheic areas, a recurrent variant (p.Pro602Leu) not seen in
    Darier disease, histology without acantholysis or dyskeratosis, separate
    MONDO and OMIM records, and AKV families with no ATP2A2 variant. For acral
    Darier disease: AKV-like papules are found in most adults with Darier
    disease, the two coexist in some patients, acral papules in Darier patients
    can show Darier histology, and step sections or cytology of genotyped AKV
    lesions can show focal acantholysis and dyskeratosis. This entry is
    curated as a separate disease allelic with Darier disease, following MONDO
    and the genotype data, and records the overlap here.
  evidence:
  - reference: PMID:28498512
    reference_title: "Recurrent ATP2A2 p.(Pro602Leu) mutation differentiates Acrokeratosis verruciformis of Hopf from the allelic condition Darier disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Darier disease and Acrokeratosis Verruciformis of Hopf (AKV) are rare disorders of keratinization with autosomal dominant inheritance and very distinct clinical pictures."
    explanation: >-
      Position that the two are allelic but clinically distinct.
  - reference: PMID:22814319
    reference_title: "Acrokeratosis verruciformis of Hopf showing P602L mutation in ATP2A2 and overlapping histopathological features with Darier disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: >-
      Position that AKV is variable expression of the same disease.
  - reference: PMID:1390140
    reference_title: "The phenotype of Darier's disease: penetrance and expressivity in adults and children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnostic nail lesions were found in 59 (99%), palmar pits and keratoses in 57 (95%), and acrokeratosis verruciformis in 44 (73%)."
    explanation: >-
      Acrokeratosis verruciformis-like papules occurred in 73% of adults with
      Darier disease in a population series.
  - reference: PMID:9378638
    reference_title: "[Acrokeratosis verruciformis-like changes in Darier disease]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histopathologically, the papules showed the distinctive structures of Darier's disease. Therefore, these lesions are regarded as an abortive form of keratosis follicularis."
    explanation: >-
      Acral verruciform papules in Darier patients showed Darier histology.
  - reference: PMID:15515213
    reference_title: "Coexistence of Darier's disease and acrokeratosis verruciformis of Hopf."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The biopsy taken from the neck showed typical findings for Darier's disease. The biopsy from the dorsa of the left foot revealed the distinctive structures of acrokeratosis verruciformis."
    explanation: >-
      One patient with both histological patterns at different sites.
  - reference: PMID:28426487
    reference_title: "Brief Report: HPV-17 Infection in Darier Disease With Acrokeratosis Verrucosis of Hopf."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although, it has been shown that both diseases are associated with mutations in ATPA2 gene, it is yet to be determined if they are the same disease, or separate but allelic, or interlinked in some other fashion."
    explanation: >-
      States the three positions; ATPA2 is the source's own spelling.
- discussion_id: akv_genotype_phenotype_and_second_locus
  prompt: >-
    Why does ATP2A2 p.(Pro602Leu) produce an acral keratinization disorder
    largely without acantholysis, when other loss-of-function ATP2A2 variants
    produce Darier disease, and which gene causes AKV in families without an
    ATP2A2 variant?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#ATP2A2 Pro602Leu Loss of SERCA2 Calcium Transport
  - pathophysiology#Disturbed Endoplasmic Reticulum Calcium Homeostasis in Acral Keratinocytes
  - genetic#ATP2A2
  rationale: >-
    The P602L pump has lost calcium transport in vitro, the same functional
    class as Darier alleles, so loss of transport alone does not explain the
    different phenotype. No study has examined calcium handling or desmosome
    assembly in AKV keratinocytes, and the second AKV locus excluded by linkage
    in Chinese families has not been identified.
  evidence:
  - reference: PMID:16716163
    reference_title: "Genetic heterogeneity in acrokeratosis verruciformis of Hopf."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings provide evidence for the genetic heterogeneity of AKV and demonstrate that mutations in genes other than ATP2A2 are responsible for AKV in a proportion of the Chinese population."
    explanation: >-
      Establishes that an unidentified second locus exists.
references:
- reference: PMID:42205461
  title: "Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review)."
  findings:
  - statement: "Current review of genetics, clinical and histological features, Darier overlap, and treatment."
- reference: PMID:12542527
  title: "Acrokeratosis verruciformis of Hopf is caused by mutation in ATP2A2: evidence that it is allelic to Darier's disease."
  findings:
  - statement: "Identification of the heterozygous ATP2A2 P602L variant and loss of calcium transport by the mutant pump."
- reference: PMID:30725935
  title: "Acrokeratosis Verruciformis of Hopf."
  tags:
  - StatPearls
  findings:
  - statement: "Point-of-care overview used for orientation on course, histological diagnosis and malignant transformation; not a phenotype baseline."
notes: >-
  No GeneReviews chapter covers acrokeratosis verruciformis; the phenotype
  baseline is the 2026 review PMID:42205461. Acral verruciform papules that
  occur as part of Darier disease belong to the Darier_Disease entry; this entry
  covers isolated AKV. No mechanism module is conformed to: the desmosomal
  adhesion-failure module that Darier disease conforms to requires
  acantholysis, which classic AKV lacks, and the cornification-failure module
  describes barrier failure in the ichthyoses rather than a circumscribed
  verrucous hyperplasia.
📚

References & Deep Research

References

3
PMID:42205461
Acrokeratosis verruciformis of Hopf: Genetic, clinicopathologic and therapeutic features (Review).
1 finding
Current review of genetics, clinical and histological features, Darier overlap, and treatment.
PMID:12542527
Acrokeratosis verruciformis of Hopf is caused by mutation in ATP2A2: evidence that it is allelic to Darier's disease.
1 finding
Identification of the heterozygous ATP2A2 P602L variant and loss of calcium transport by the mutant pump.
PMID:30725935
Acrokeratosis Verruciformis of Hopf.
1 finding
Point-of-care overview used for orientation on course, histological diagnosis and malignant transformation; not a phenotype baseline.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Acrokeratosis Verruciformis · 2026-10-15T23:39:42Z · View source

New entry for acrokeratosis verruciformis of Hopf (MONDO:0007048), replacing the minimal seed and deleting stubs/Acrokeratosis_Verruciformis.yaml. Lump/split decision: curated as a DISEASE allelic with Darier disease, not as a Darier subtype. Grounds: separate MONDO and OMIM (101900) records; a recurrent ATP2A2 p.(Pro602Leu) variant not reported among Darier variants (PMID:28498512, PMID:22814319); acral distribution sparing seborrheic areas and histology without acantholysis or dyskeratosis (PMID:12542527, PMID:42205461); and Chinese AKV families with no ATP2A2 variant and no linkage to 12q23-q24 (PMID:16716163). The counter-evidence (AKV-like papules in 73% of adults with Darier disease, PMID:1390140; Darier histology in such papules, PMID:9378638; coexistence, PMID:15515213; focal acantholysis on step sections of P602L lesions, PMID:22814319; Darier-like cytology, PMID:27663152) is recorded in a CONTROVERSY discussion and a separate, inconstant pathophysiology node with SUPPORT and REFUTE evidence. Darier_Disease.yaml was not edited and still does not mention AKV. Curated: synonyms, parents, Harrison classification, prevalence (UNKNOWN measure, RARE class; the only figure is a clinic-based 1 per 41,000 dermatology consultations, not normalized), autosomal dominant and sporadic inheritance (HP:0000006, HP:0003745), a four-node pathophysiology chain (P602L loss of SERCA2 calcium transport; ER calcium homeostasis in keratinocytes, marked INDIRECT because no study measured it in AKV; abnormal keratinocyte differentiation with verrucous hyperplasia; focal acantholysis with mild dyskeratosis), eight phenotypes with six causally connected (acrokeratosis HP:0200016, punctate palmoplantar hyperkeratosis, hyperkeratosis, hypergranulosis, epidermal acanthosis, and squamous cell carcinoma as a sequela of longstanding papules); nail dystrophy and leukonychia are left unwired because no source gives their mechanism. Genetic block with P602L and A698V variants and REFUTE evidence for genetic heterogeneity; diagnosis (skin biopsy, ATP2A2 testing, dermoscopy); treatments (superficial ablation, cryotherapy, systemic retinoids with acitretin and etretinate, topical keratolytics and retinoids, genetic counseling); a KNOWLEDGE_GAP on why P602L gives an acral non-acantholytic phenotype and on the unidentified second locus. Term bindings reuse the Darier entry's SERCA2/keratinocyte terms (GO:0005388, CL:0000312, GO:0030216, GO:0031424, GO:0098609, UBERON:0001003) where they fit; GO:0032469 and HP:0200016 were looked up in OLS. Deep research: one openscientist report (research/Acrokeratosis_Verruciformis-deep-research-openscientist.md, with .citations.md and an _artifacts dir holding the provider's final_report.html and .pdf). The job was started once; after a container restart the report was retrieved by re-attaching to that original job (aa79c9e3-3df9-47ee-b6b4-a7a78eaef4c7), with no second job submitted. Its reference validation: 19/19 references resolved, 0 off topic, 16/17 quotes found; the unsupported quote attributes a sentence from PMID:31696902 to PMID:28498512, so that attribution was not reused. Term validation: HP:0007531 unresolved (not used) and NCIT:C1516 is Lisofylline, not a keratolytic (not used). Report claims dropped: that P602L is a milder partial loss of function than Darier alleles (contradicted by the functional assay in PMID:12542527 showing loss of calcium transport); that human AKV has no reported skin cancer (two SCC cases are reported in PMID:42205461); the Darier organoid, calcium-pump review and Darier microbiome papers (PMID:41466489, PMID:39207315, PMID:37496039) and the second-hit somatic study (PMID:38536168), because they describe Darier disease and the report itself marks their transfer to AKV as inferred; and the Atp2a2 heterozygous mouse (PMID:11389134), which models tumour predisposition rather than AKV. PMID:3323700 (etretinate failure) was taken from the report. Most evidence came from a separate PubMed search; the 2026 review PMID:42205461 (full text cached) is the phenotype baseline. just preflight-dr could not run: it requires the local MONDO build (/root/.data/oaklib/mondo.db, about 1.3 GB), which is absent and was not downloaded. As a manual Named Entity Confusion check, the report names ATP2A2 37 times, ATP2C1 never, and MONDO:0007048 consistently, matching the MONDO causal gene recorded in the stub. just check-genereviews --online: NO_CHAPTER for GeneReviews; the StatPearls chapter PMID:30725935 is cited and tagged. Validation: just validate, validate-terms, count-verified-snippets (63/63), check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-block-scalar-comments, check-enum-values, check-snippet-length, check-title-snippets, check-folded-hyphens, check-coarse-phenotypes, check-snippet-grading, normalize-cache, check-term-cache-integrity and validate-disorders all passed.

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Acrokeratosis Verruciformis of Hopf — Comprehensive Disease Characterization Report
openscientist-autonomous 12 citations 2026-10-15T23:32:08.531725

Acrokeratosis Verruciformis of Hopf — Comprehensive Disease Characterization Report

Disease: Acrokeratosis Verruciformis of Hopf (AVH / AKV) MONDO ID: MONDO:0007048 · OMIM: #101900 · Category: Mendelian (autosomal dominant genodermatosis) Causal gene: ATP2A2 (SERCA2) · Allelic disorder: Darier disease (OMIM #124200)

Summary

Acrokeratosis verruciformis of Hopf (AVH) is a rare, benign, autosomal dominant disorder of keratinization first described by Gustav Hopf in 1931. It is caused by heterozygous missense variation in ATP2A2, the gene encoding SERCA2 — the sarco/endoplasmic reticulum Ca²⁺-ATPase isoform 2 that pumps calcium into the endoplasmic reticulum (ER) of keratinocytes. The disease is allelic to Darier disease: whereas Darier disease arises from a broad spectrum of mostly loss-of-function ATP2A2 variants, AVH is characteristically associated with a single recurrent missense change, p.(Pro602Leu) (c.1805C>T), which differentiates it genetically and clinically from Darier disease (PMID: 28498512; PMID: 42205461).

Clinically, AVH presents with multiple flat-topped, skin-colored to wart-like (verrucous) hyperkeratotic papules distributed symmetrically on the dorsal surfaces of the hands and feet, frequently accompanied by nail changes (V-shaped notch, longitudinal striations, nail-plate thickening, subungual hemorrhages). Histopathology is distinctive and diagnostic: marked hyperkeratosis, acanthosis, papillomatosis, and "church-spire"-like epidermal elevations without the acantholysis and dyskeratosis that characterize Darier disease (PMID: 40256087; PMID: 31696902). The mechanistic thread connecting genotype to phenotype runs from reduced SERCA2 pump activity → dysregulated ER/intracellular calcium → impaired desmosomal/keratinocyte adhesion and disordered epidermal differentiation → the acral hyperkeratotic papules (PMID: 41466489; PMID: 39207315).

AVH follows a chronic, lifelong but benign course with normal life expectancy; morbidity is essentially cosmetic/psychosocial plus nail dystrophy. There is no curative therapy — management combines keratolytics, topical/systemic retinoids, and destructive/ablative methods (cryotherapy, laser), with superficial ablation considered first-line; responses are variable and lesions recur (PMID: 41054640; PMID: 38854358). Notably, although SERCA2-haploinsufficient Atp2a2(+/−) mice develop squamous cell tumors, an increased skin-cancer risk is not established in human AVH (PMID: 11389134). This report synthesizes 11 confirmed findings across 19 reviewed papers into a full characterization spanning the 15 requested domains.

1. Disease Information

Overview. Acrokeratosis verruciformis of Hopf is a rare heritable autosomal dominant genodermatosis and disorder of keratinization, first described in 1931 by Hopf (PMID: 31696902). It manifests as multiple flat, skin-colored to verrucous keratotic papules concentrated on the dorsa of the hands and feet. It is now understood to be part of the ATP2A2/SERCA2 disease spectrum and allelic to Darier disease (PMID: 28498512).

Key identifiers.

Resource Identifier
OMIM (disease) #101900 (Acrokeratosis verruciformis of Hopf)
MONDO MONDO:0007048
Gene (OMIM) ATP2A2 *108740
Allelic disorder Darier disease, OMIM #124200
HGNC HGNC:812
NCBI Gene (Entrez) 488
Ensembl ENSG00000174437
Cytoband 12q24.11 (GRCh38 chr12:110,280,603–110,351,093)
UniProt P16615 (SERCA2)

(Gene identifiers verified via mygene.info; finding F007.)

Synonyms / alternative names. Acrokeratosis verruciformis of Hopf (AVH, AKV); Hopf disease; Hopf keratosis.

Information source. Knowledge for this disease is derived almost entirely from aggregated disease-level resources (OMIM, MONDO) and individual published case reports / small case series, rather than EHR-scale cohorts — a reflection of the disorder's rarity.

2. Etiology

Primary cause — genetic. AVH is a monogenic Mendelian disease caused by a heterozygous missense variant in ATP2A2. The characteristic, recurrent allele is p.(Pro602Leu) (c.1805C>T), which specifically associates with AVH and distinguishes it from Darier disease (PMID: 42205461; PMID: 28498512; PMID: 40256087). As stated in the 2026 review, AVH "is due to the heterozygous missense mutation p.(Pro602Leu) in the ATPase sarcoplasmic/endoplasmic reticulum Ca" transporter (PMID: 42205461).

Genetic risk factors. The single causal determinant is a pathogenic ATP2A2 variant inherited in an autosomal dominant fashion. No independent susceptibility loci or GWAS signals are described (consistent with a Mendelian disorder).

Environmental risk / protective factors. No established environmental risk factors cause AVH. However, within the allelic SERCA2 disorder spectrum, lesions can "wax and wane in response to environmental factors" — in Darier disease, well-documented exacerbating triggers include heat, sweat, sun exposure, friction, and infection (PMID: 38536168). No protective alleles or dietary/lifestyle protective factors have been defined for AVH.

Gene–environment interactions / two-hit mechanism. The strongest mechanistic insight into gene–environment interplay comes from the allelic condition Darier disease, where "All 11 persistent skin lesions were associated with second-hit somatic variants in the ATP2A2 gene" across 9 germline-heterozygous patients, with these variants classified as highly deleterious; transient lesions instead "wax and wane in response to environmental factors" (PMID: 38536168). This provides a molecular basis for localized, persistent lesions superimposed on a germline-heterozygous background (finding F009).

3. Phenotypes

Phenotype type: physical manifestations / clinical signs (cutaneous and nail).

Phenotype Description Suggested HPO term
Acral keratotic papules Multiple flat-topped, skin-colored to verrucous hyperkeratotic papules on dorsa of hands/feet HP:0000962 (Hyperkeratosis); HP:0007531 (Acral keratoses)
Verrucous/wart-like morphology Wart-like papules, cobblestone peripheral dermoscopy HP:0200043 (Verrucae)
Nail dystrophy V-shaped notch, longitudinal striations, nail-plate thickening, subungual hemorrhages HP:0008404 (Nail dystrophy); HP:0001809 (Longitudinal ridging of nails)
Palmoplantar involvement (variable) Punctate keratoses / pits may occur HP:0000982 (Palmoplantar keratoderma)

Characteristics. - Age of onset: Usually early life (infancy/childhood); rare sporadic adult/late-onset cases reported (PMID: 31696902). - Severity: Mild; benign; primarily cosmetic. - Progression: Stable to slowly progressive, with persistent lesions accruing over life (chronic, lifelong). - Frequency among affected: Acral papules and the "church-spire" histology are essentially universal diagnostic features; nail involvement is common but not invariable.

Clinical description. Lesions are "multiple flat skin colored papules, mainly localized at the dorsal region of the hands and feet" (PMID: 31696902), with keratotic lesions "primarily on the dorsal surfaces of the hands and feet" (PMID: 40256087). Additional sites (neck, inguinal region) and warty plaques have been reported. Dermoscopy of dorsal-hand lesions shows "a white network and papules with a central homogeneous area and a peripheral cobblestone appearance" (PMID: 41054640).

Quality-of-life impact. Impact is predominantly cosmetic and psychosocial; nail changes may cause minor functional/aesthetic concern. No formal EQ-5D/SF-36 data exist for this rare disorder. There is no organ-threatening or life-limiting involvement.

4. Genetic / Molecular Information

Causal gene. ATP2A2 (SERCA2), HGNC:812, Entrez 488, Ensembl ENSG00000174437, cytoband 12q24.11, UniProt P16615; OMIM gene *108740 (finding F007).

Pathogenic variant. - Variant: p.(Pro602Leu), c.1805C>T — recurrent missense change. - Classification: Pathogenic (disease-causing; recurrent across independent AVH families). - Variant type: Missense (single amino acid substitution Pro→Leu at residue 602 of SERCA2). - Origin: Germline, heterozygous, autosomal dominant. (Within the allelic spectrum, second-hit somatic variants drive persistent lesions — finding F009.) - Functional consequence: Reduced SERCA2 pump function. In contrast to the broad loss-of-function spectrum underlying Darier disease, the milder p.Pro602Leu substitution produces the AVH phenotype (hyperkeratotic/papillomatous lesions without overt acantholysis) (PMID: 28498512; PMID: 42205461).

Allele frequency. The p.Pro602Leu variant is a rare pathogenic allele; it is not a common population polymorphism (consistent with a rare Mendelian disorder). No high-frequency population data apply.

Modifier genes / epigenetics / chromosomal abnormalities. No specific modifier genes, epigenetic marks, or chromosomal abnormalities have been established for AVH. The second-hit somatic ATP2A2 model (finding F009) functions as a genetic modifier of lesion persistence within the SERCA2 spectrum.

5. Environmental Information

  • Environmental factors: None causal. Lesion activity in the allelic SERCA2 spectrum is modulated by environmental factors ("wax and wane"); Darier disease triggers (heat, sweat, UV, friction, infection) are the best-characterized analogues (PMID: 38536168).
  • Lifestyle factors: No established lifestyle determinants for AVH.
  • Infectious agents: AVH is not infectious. (Of note, the allelic Darier disease exhibits cutaneous microbial dysbiosis with Staphylococcus aureus/S. warneri expansion correlating with severity — PMID: 37496039 — but this is a secondary feature of the more severe allelic disorder, not AVH per se.)

6. Mechanism / Pathophysiology

Ordered causal chain (genotype → phenotype)

  1. A heterozygous germline missense variant in ATP2A2 (characteristically p.Pro602Leu) leads to production of a partially dysfunctional SERCA2 Ca²⁺-ATPase.
  2. Reduced SERCA2 pump activity results in impaired pumping of Ca²⁺ into the endoplasmic reticulum, leading to dysregulated ER/intracellular calcium stores (PMID: 41466489; PMID: 39207315).
  3. Calcium dysregulation impairs keratinocyte cell–cell adhesion, causing desmosomal dysfunction and mislocalization of desmosomal proteins (PMID: 41466489).
  4. Disrupted adhesion plus disordered epidermal differentiation leads to abnormal keratinization. Branch: in Darier disease (severe LOF alleles) this manifests as suprabasal acantholysis and dyskeratosis; in AVH (milder p.Pro602Leu) it manifests as hyperkeratosis/papillomatosis without overt acantholysis (PMID: 28498512; PMID: 40256087).
  5. The altered epidermal architecture produces the clinically visible flat-topped verrucous acral papules and "church-spire" histology.
  6. (Inferred/modifier branch) A second-hit somatic ATP2A2 variant in a clone of epidermal cells drives persistent, localized lesions, whereas transient lesions fluctuate with environmental triggers (PMID: 38536168).

Detail by category

  • Molecular pathway: ER calcium homeostasis via the SERCA2 pump (the ER Ca²⁺-ATPase). "Darier disease and Hailey-Hailey disease arise from mutations in the endoplasmic reticulum calcium pump, SERCA2, and the Golgi calcium/manganese pump, SPCA1, respectively" (PMID: 39207315). Suggested GO: GO:0006874 (cellular calcium ion homeostasis), GO:0070588 (calcium ion transmembrane transport), GO:0005388 (P-type calcium transporter / SERCA activity).
  • Cellular processes: Disrupted keratinocyte adhesion/desmosome assembly, epidermal differentiation; downstream barrier disruption. Suggested GO: GO:0007009 (plasma membrane organization / cell adhesion), GO:0030216 (keratinocyte differentiation), GO:0002009 (morphogenesis of epithelium).
  • Protein dysfunction: SERCA2 pump hypofunction (reduced Ca²⁺-ATPase activity); the AVH p.Pro602Leu allele is a milder functional change than the LOF alleles of Darier disease.
  • Immune/tissue mechanisms: Secondary barrier disruption; in the severe allelic disorder, inflammation, immune-defence pathway upregulation, and microbial dysbiosis occur (PMID: 37496039). These are not prominent in benign AVH.
  • Cell types involved: Epidermal keratinocytes (CL:0000312). Melanocyte–keratinocyte adhesion defects (via defective E-cadherin) are implicated in the guttate-leukoderma variant of the allelic disorder.

Key supporting quotes. "caused by mutations in the ATP2A2 gene, resulting in calcium dysregulation and impaired keratinocyte adhesion" and "including acantholysis, desmosomal dysfunction and barrier disruption, with mislocalisation of desmosomal proteins" (PMID: 41466489).

ATP2A2 p.Pro602Leu (germline, heterozygous)
│  reduced SERCA2 Ca2+-ATPase activity
▼
ER / intracellular Ca2+ dysregulation
│  impaired desmosome assembly & protein localization
▼
Impaired keratinocyte adhesion + disordered differentiation
├── (severe LOF alleles) → acantholysis/dyskeratosis → DARIER DISEASE
└── (mild p.Pro602Leu)   → hyperkeratosis/papillomatosis (no acantholysis) → AVH
│
▼ (+ second-hit somatic ATP2A2 variant)
Persistent, localized acral verrucous papules ("church-spire" histology)

7. Anatomical Structures Affected

  • Organ level: Skin (UBERON:0002097, skin of body) is the sole primary organ. No secondary organ involvement; the integumentary system alone is affected.
  • Tissue level: Epithelial tissue — the epidermis (UBERON:0001003, skin epidermis); specifically acral epidermis of the dorsal hands and feet. Nail apparatus (nail plate/matrix) is involved (onychopathy).
  • Cell level: Epidermal keratinocytes (CL:0000312).
  • Subcellular level: Endoplasmic reticulum (GO:0005783) — site of SERCA2 calcium pumping; desmosomes (GO:0030057) at the plasma membrane are functionally affected.
  • Localization / lateralization: Bilateral, roughly symmetric distribution over the dorsa of hands and feet; additional reported sites include the neck and inguinal region. Dermoscopy and nail findings as above (PMID: 41054640; PMID: 40256087).

8. Temporal Development

  • Onset: Typically congenital to childhood/early life; onset pattern is insidious and chronic. Rare sporadic adult/late-onset, non-familial cases are documented: "Usually, it arises in early life but rare sporadic cases with adult onset have been reported" (PMID: 31696902); patients without family history occur (PMID: 40256087).
  • Progression: Slow, stable-to-progressive; papules persist and slowly accrue.
  • Course pattern: Chronic, lifelong; benign. Persistent lesions do not spontaneously resolve (contrast transient lesions in the allelic spectrum that fluctuate with environment).
  • Remission / critical periods: No spontaneous remission; treatment-induced clearance is temporary (recurrence after ablation). No specific developmental critical window for intervention.

9. Inheritance and Population

  • Inheritance pattern: Autosomal dominant. "Acrokeratosis verruciformis of Hopf is a rare heritable autosomal dominant genodermatosis and keratinization disorder, first described in 1931 by Hopf" (PMID: 31696902; PMID: 28498512).
  • Penetrance / expressivity: Consistent with other ATP2A2 disorders — high penetrance with variable expressivity; precise penetrance figures are not established for AVH.
  • Sporadic/de novo: Non-familial cases without family history occur (PMID: 40256087; PMID: 31696902).
  • Germline mosaicism / founder effects / consanguinity / carrier frequency: Not specifically established for AVH. As an autosomal dominant disorder, recessive carrier-screening concepts do not apply.
  • Epidemiology: Very rare; true prevalence and incidence are not established (no registry data). Reported worldwide without a strong sex predilection; onset usually in childhood (finding F011).
  • Geographic / ethnic distribution: No defined endemic area; cases reported across populations (e.g., Indian, European, and other reports in the reviewed literature).

10. Diagnostics

Diagnostic approach — clinicopathologic, genetically confirmable.

  • Clinical: Characteristic acral flat-topped verrucous papules; nail changes; supportive dermoscopy (white network; central homogeneous area with peripheral cobblestone appearance) (PMID: 41054640).
  • Histopathology (diagnostic): "marked hyperkeratosis, acanthosis, papillomatosis, and church spire-like epidermal elevations, confirming the diagnosis of AVH," with absence of acantholysis/corps ronds (PMID: 40256087). Diagnosis relies "primarily on clinical presentation and histopathological characteristics" (PMID: 41054640).
  • Genetic testing: Single-gene ATP2A2 sequencing (or WES) identifying p.(Pro602Leu) confirms the diagnosis and distinguishes AVH from Darier disease (PMID: 28498512).
  • Biomarkers / labs / imaging: No specific blood or serum biomarker exists; imaging and electrophysiology are not applicable.

Differential diagnosis. "AVH poses diagnostic challenges due to its similarity to other conditions, such as seborrheic keratosis, lichen planus, and Darier disease" (PMID: 40256087). Also consider verruca plana/vulgaris, epidermodysplasia verruciformis, and stucco keratosis.

Differential Distinguishing feature from AVH
Darier disease (allelic) Suprabasal acantholysis + dyskeratosis; seborrheic distribution; broad LOF ATP2A2 variants
Seborrheic keratosis "Stuck-on" appearance; different histology; acquired, non-hereditary
Lichen planus Violaceous polygonal papules; Wickham striae; interface dermatitis histology
Verruca (viral warts) HPV-driven; koilocytes; no church-spire pattern; not hereditary

Screening. Cascade clinical/genetic evaluation of first-degree relatives is reasonable given autosomal dominant inheritance; no population-based newborn/carrier screening is indicated for this benign disorder.

11. Outcome / Prognosis

  • Survival / mortality: Benign disorder with normal life expectancy and no disease-specific mortality (finding F011).
  • Morbidity / function: Limited to cosmetic/psychosocial burden plus nail changes; no disability.
  • Disease course: Chronic lifelong; persistent lesions; treatment-induced clearance is temporary with recurrence.
  • Malignancy risk: Although Atp2a2(+/−) mice show squamous tumor predisposition (finding F005), an increased skin-cancer risk is NOT established in human AVH. "SERCA2 haploinsufficiency predisposes murine keratinocytes to neoplasia" (PMID: 11389134) — a model-organism observation that has not translated to a demonstrated human AVH cancer risk.
  • Prognostic factors / biomarkers: None established.

12. Treatment

No curative therapy exists. "Management typically involves keratolytic agents and retinoids, though superficial ablation is considered first-line treatment" (PMID: 41054640).

Modality Examples Evidence / notes Suggested NCIT
Superficial ablation (first-line) Cryotherapy, laser, electrodesiccation Destroys lesions; recurrence common NCIT:C15226 (Cryosurgery); NCIT:C15431 (Laser therapy)
Keratolytics Topical salicylic acid, urea Adjunct symptom control NCIT:C1516 (Keratolytic Agent)
Retinoids Acitretin, etretinate Variable/often refractory; one report of response to combined acitretin + cryotherapy; a 1987 report notes unsuccessful etretinate NCIT:C1570 (Retinoid); NCIT:C47587 (Acitretin)

Supporting evidence: "An Atypical Case of Acrokeratosis Verruciformis of Hopf Responding to Combined Acitretin and Cryotherapy" (PMID: 38854358); "the unsuccessful therapy with etretinate" (PMID: 3323700) — together documenting variable and frequently refractory response (finding F004).

Advanced / experimental therapeutics. No approved gene, cell, RNA-based, targeted, or immunotherapy for AVH; no registered AVH-specific clinical trials identified. Pharmacogenomics: not applicable.

13. Prevention

  • Primary prevention: Not possible for a monogenic inherited disorder; genetic counseling (autosomal dominant, 50% transmission risk) is the principal preventive tool, with options for prenatal/preimplantation genetic testing when the familial ATP2A2 variant is known.
  • Secondary/tertiary prevention: Early recognition and symptomatic management; avoidance of friction/irritation that may provoke lesions; treatment of secondary nail/skin issues.
  • Immunization / public health / prophylaxis: Not applicable (non-infectious, non-environmental disease).

14. Other Species / Natural Disease

  • Taxonomy: Human (Homo sapiens, NCBI:txid9606) is the species of clinical disease. Laboratory mouse (Mus musculus, NCBI:txid10090) is used experimentally.
  • Orthologous gene: Mouse Atp2a2 (NCBI Gene 11938, chromosome 5), ortholog of human ATP2A2 (finding F007).
  • Natural disease in other species: No well-characterized naturally occurring AVH analogue in companion animals/wildlife is documented in the reviewed literature; relevance to veterinary medicine is limited.
  • Comparative biology / conservation: SERCA2/ER calcium homeostasis is deeply evolutionarily conserved; the mouse recapitulates key epidermal consequences of SERCA2 haploinsufficiency (see Section 15).
  • Transmission / zoonotic potential: None (genetic, non-communicable disease).

15. Model Organisms

Principal model: Atp2a2(+/−) heterozygous null mouse (mammalian, in vivo).

  • Model type: Germline heterozygous null (knockout of one Atp2a2 allele), modeling SERCA2 haploinsufficiency.
  • Phenotype: "aged heterozygous mutant (Atp2a2(+/-)) mice develop squamous cell tumors of the forestomach, esophagus, oral mucosa, tongue, and skin" — observed in 13/14 aged mice versus 0/age-and-sex-matched wild-type controls, with reduced SERCA2 protein in skin and affected tissues (PMID: 11389134).
  • Mechanistic conclusion: "The development of squamous cell tumors in aged Atp2a2(+/-) mice indicates that SERCA2 haploinsufficiency predisposes murine keratinocytes to neoplasia" (PMID: 11389134) — the first direct demonstration that perturbed Ca²⁺ homeostasis can be a primary initiating event in cancer.
  • Phenotype recapitulation / limitations: The mouse captures SERCA2-dependent epidermal Ca²⁺ biology but models tumor predisposition rather than the benign human AVH papular phenotype — a notable divergence (human AVH has no established malignancy risk; finding F011).

In vitro / organoid models. Human epidermal organoids and SERCA2 keratinocyte systems reproduce the adhesion/calcium phenotype: these models show that ATP2A2 mutation causes "calcium dysregulation and impaired keratinocyte adhesion" with "acantholysis, desmosomal dysfunction and barrier disruption, with mislocalisation of desmosomal proteins" (PMID: 41466489). These are primarily Darier-disease models but inform the shared SERCA2 mechanism.

Resources: MGI (mouse Atp2a2), IMPC, and standard rodent repositories.

Mechanistic Model / Interpretation

AVH is best understood as the mild end of the ATP2A2/SERCA2 allelic spectrum. A single recurrent germline missense change, p.Pro602Leu, modestly reduces SERCA2 pump activity. Because the ER calcium pump is central to keratinocyte desmosome assembly and orderly differentiation, even a modest reduction in pump function destabilizes keratinocyte adhesion. The degree of SERCA2 dysfunction dictates which clinical disorder emerges along a shared pathway:

Feature AVH (p.Pro602Leu) Darier disease (broad LOF spectrum)
ATP2A2 variant class Recurrent mild missense Broad loss-of-function
SERCA2 functional deficit Mild More severe
Histology Hyperkeratosis, papillomatosis, "church-spire"; no acantholysis Suprabasal acantholysis + dyskeratosis
Distribution Dorsal hands/feet (acral) Seborrheic areas, flexures, nails
Severity Benign, cosmetic More morbid; malodour, dysbiosis, infections
Shared Autosomal dominant; nail changes; ER Ca²⁺/SERCA2 mechanism Same gene/pump

Within this framework, the two-hit somatic model explains lesion persistence: a germline-heterozygous background plus a second-hit somatic ATP2A2 variant in a skin clone yields a fixed, persistent lesion, while transient lesions track environmental triggers (PMID: 38536168). The mouse model additionally reveals a latent oncogenic potential of SERCA2 haploinsufficiency that, importantly, has not manifested as elevated cancer risk in human AVH — an instructive example of species-specific divergence between model and patient.

Evidence Base

PMID Title (abbrev.) Role in this report
28498512 Recurrent ATP2A2 p.(Pro602Leu) differentiates AVH from Darier Establishes AD inheritance, ATP2A2 cause, and p.Pro602Leu as molecular discriminator (F001, F010)
42205461 AVH: Genetic, clinicopathologic, therapeutic (Review, 2026) Confirms recurrent heterozygous p.(Pro602Leu) SERCA2 mutation (F001, F007)
40256087 AVH in a young Indian female — case report/review Histology, acral distribution, nail notch, differentials, rarity (F002, F006, F008, F010, F011)
31696902 Late-onset non-familial AVH AD genodermatosis, 1931 Hopf description, early-onset + rare adult onset (F002, F006)
41466489 Mimicking Darier in vitro — epidermal organoid Calcium dysregulation, desmosomal dysfunction, mislocalization (F003, mechanism)
39207315 Targeting calcium pumps in Darier/Hailey-Hailey/Grover SERCA2 as the ER calcium pump underlying the spectrum (F003)
11389134 Squamous cell tumors in Atp2a2(+/−) mice Mouse model; SERCA2 haploinsufficiency → keratinocyte neoplasia (F005, F011)
38536168 Persistent Darier lesions & second-hit somatic ATP2A2 Two-hit mechanism; environmental modulation (F009)
41054640 Sporadic AVH with unusual presentation First-line ablation; dermoscopy; nail changes; clinicopathologic diagnosis (F004, F008, F010)
38854358 AVH responding to acitretin + cryotherapy Documents a treatment response (F004)
3323700 Hopf AVH, non-familial case (1987) Unsuccessful etretinate — refractoriness (F004)

Supporting/contextual: 40933297 (AVH–Darier clinical overlap), 32155025 (guttate leukoderma + AVH in Darier), 21668031 (longitudinal erythronychia/nail associations), 37822398 (AVH case series with dermoscopy), 40565511 (Darier genetics/SERCA2), 37496039 (Darier microbial dysbiosis), 42555718 (metabolic stress adaptation in Darier), 36896697 (Darier KVE/immune context).

Limitations and Knowledge Gaps

  1. Rarity and evidence quality. Nearly all AVH knowledge comes from individual case reports and small series; there are no registries, no prevalence/incidence estimates, and no quality-of-life instruments applied to AVH.
  2. Genotype–phenotype resolution. While p.Pro602Leu is the recurrent AVH allele, the precise biophysical reason this specific substitution yields the AVH (vs Darier) phenotype is not fully resolved; functional assays comparing pump kinetics across alleles are limited.
  3. Mechanistic borrowing from Darier disease. Much mechanistic detail (desmosomal mislocalization, two-hit somatic lesions, dysbiosis, organoid phenotypes) derives from Darier-disease models/patients and is inferred to apply to AVH as the allelic, milder disorder — not all has been directly demonstrated in AVH tissue.
  4. Cancer risk translation. The mouse tumor phenotype has no demonstrated human AVH counterpart; whether any long-term neoplastic risk exists in human AVH is unknown but appears clinically negligible.
  5. Penetrance/expressivity figures and population genetics (founder effects, carrier data) are not quantified for AVH specifically.

Proposed Follow-up Experiments / Actions

  1. Functional characterization of p.Pro602Leu: Measure SERCA2 Ca²⁺-ATPase kinetics (Vmax, Ca²⁺ affinity) and ER store dynamics for p.Pro602Leu versus representative Darier LOF alleles in keratinocytes/organoids to explain the milder phenotype.
  2. AVH-specific lesional sequencing: Apply the paired lesional-vs-blood deep-sequencing strategy (PMID: 38536168) directly to persistent AVH papules to test whether second-hit somatic ATP2A2 variants drive AVH lesion persistence as in Darier disease.
  3. Transcriptomic/desmosomal profiling of AVH skin: Characterize desmosomal protein localization, barrier-gene expression (e.g., claudin-4, cadherin-4), and differentiation markers in AVH versus Darier versus normal acral epidermis.
  4. Natural-history / registry study: Establish a multicenter AVH registry to estimate prevalence, define penetrance/expressivity, document nail involvement frequency, and formally assess any long-term malignancy risk.
  5. Comparative treatment evaluation: Prospectively compare ablative modalities (cryotherapy, laser) ± retinoids/keratolytics for durable clearance and recurrence rates, given current reliance on anecdotal responses.
  6. Humanized/organoid AVH model: Engineer p.Pro602Leu into human epidermal organoids/iPSC-keratinocytes to create a dedicated AVH model distinct from Darier LOF models and test candidate SERCA2-modulating interventions.

Report compiled from 11 confirmed findings across 19 reviewed papers (5 completed investigation iterations). Evidence types span human clinical case reports/series, model-organism (mouse), and in vitro/organoid studies, as annotated per section.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 19
Resolved 19
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 17
Quoted claims found in source 16
Quoted claims not found in source 1
References weighed for topical relevance 19
On topic 14
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:28498512 (abstract only): "Acrokeratosis verruciformis of Hopf is a rare heritable autosomal dominant genodermatosis and keratinization disorder, first described in 1931 by Hopf"
  • closest text in source: "Darier disease and Acrokeratosis Verruciformis of Hopf (AKV) are rare disorders of keratinization with autosomal dominant inheritance and very distinct clinical pictures"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 24
Resolved 22
Unresolved (possible confabulation) 1
Obsolete 0
Unverifiable 1
Terms whose name was checked 12
Terms named correctly 4
Terms named as a different term 3
Terms whose name is worth a second look 5

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0007048 (2 mentions) - the report calls it "MONDO"; MONDO calls it acrokeratosis verruciformis
  • CL:0000312 (2 mentions) - the report calls it "keratinocytes", "Cell types involved: Epidermal keratinocytes", "Cell level: Epidermal keratinocytes"; CL calls it keratinocyte
  • NCIT:C1516 (1 mention) - the report calls it "Keratolytic Agent"; NCIT calls it Lisofylline

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • HP:0007531 (1 mention) - HP does not contain this term

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0006874 (1 mention) - the report calls it "cellular calcium ion homeostasis"; GO calls it intracellular calcium ion homeostasis, and lists "cellular calcium ion homeostasis" among its other names
  • GO:0005388 (1 mention) - the report calls it "P-type calcium transporter / SERCA activity"; GO calls it P-type calcium transporter activity
  • GO:0007009 (1 mention) - the report calls it "plasma membrane organization / cell adhesion"; GO calls it plasma membrane organization
  • GO:0002009 (1 mention) - the report calls it "morphogenesis of epithelium"; GO calls it morphogenesis of an epithelium
  • GO:0005783 (1 mention) - the report calls it "Endoplasmic reticulum", "Subcellular level: Endoplasmic reticulum"; GO calls it endoplasmic reticulum

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • CL:0000312 - called "keratinocytes", "Cell types involved: Epidermal keratinocytes", "Cell level: Epidermal keratinocytes"
  • GO:0005783 - called "Endoplasmic reticulum", "Subcellular level: Endoplasmic reticulum"