🏷

Classifications

Harrison's Part

🔗

Mappings

MONDO

MONDO:0014234 reticulate acropigmentation of Kitamura

Primary MONDO identifier for reticulate acropigmentation of Kitamura.

👪

Inheritance

1

Autosomal dominant HP:0000006

Autosomal dominant inheritance

Show evidence (2 references)

PMID:23666529 SUPPORT Human clinical

"Reticulate acropigmentation of Kitamura (RAK) is a rare genetic disorder of cutaneous pigmentation with an autosomal dominant pattern of inheritance and a high penetration rate."

States autosomal dominant inheritance with high penetrance.

PMID:29201043 SUPPORT REVIEW SYNTHESIS Human clinical

"RAPK is usually inherited in an autosomal dominant pattern with high penetrance, although sporadic cases have been reported"

Review confirms dominant inheritance and notes that sporadic cases occur.

⚙

Pathophysiology

3

ADAM10 Loss of Function

Heterozygous truncating, splice-site and missense ADAM10 variants reduce ADAM10 metalloprotease activity in the skin. ADAM10 carries out the ectodomain shedding of many membrane proteins in the epidermis.

ADAM10 hgnc:188

Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

membrane protein ectodomain proteolysis GO:0006509 ↓ DECREASED

ADAM10 zinc metalloprotease activity GO:0004222 ↓ DECREASED

Downstream

Impaired Notch Receptor Processing in Epidermis Notch receptors are among the ADAM10 substrates in the skin, so reduced ADAM10 activity is proposed to reduce Notch ectodomain cleavage.

Epidermal Melanocyte Expansion Loss of ADAM10 removes a restraint on melanocyte expansion in adult skin.

Show evidence (2 references)

PMID:23666529 SUPPORT INDIRECT Human clinical

"ADAM10 is known to be involved in the ectodomain shedding of various substrates in the skin."

Identifies the cutaneous function of the protein encoded by the causal gene.

PMID:22834956 SUPPORT Model organism

"Through linkage analysis, we find that the Pied mutation is a 1914 base pair loss-of-function deletion in the Adam10 zinc metalloprotease gene."

A heterozygous loss-of-function Adam10 allele in mice is sufficient for a dominant pigmentary phenotype, consistent with haploinsufficiency.

Impaired Notch Receptor Processing in Epidermis

Reduced ADAM10-mediated cleavage of Notch receptors is the proposed link between ADAM10 variants and the pigmentary phenotype. Epidermal deletion of Adam10 in mice strongly reduces Notch processing and Notch signaling, but the defect has not been measured in patient skin, where only one ADAM10 copy is affected. It would connect this disorder to Dowling-Degos disease, whose POFUT1, POGLUT1 and PSENEN forms also act on Notch processing.

keratinocyte CL:0000312

Notch receptor processing GO:0007220 ↓ DECREASED

Animal models

Epidermal Adam10 knockout mouse (K14-Cre) Mouse partially recapitulates Complete epidermal loss of Adam10 strongly reduces Notch processing and Notch signaling.

Downstream

Epidermal Melanocyte Expansion Disturbed Notch signaling is proposed to alter the maintenance of epidermal melanocytes. The direct step from Notch processing to melanocyte number has not been shown in this disorder.

Show evidence (2 references)

PMID:30692041 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"We speculate that the pathogenesis of RAK and Dowling-Degos disease (DDD, a pigmentary disease similar to RAK) is associated with the Notch signaling pathway."

The authors who identified the gene propose Notch signaling as the link, explicitly as speculation.

PMID:21205794 SUPPORT INDIRECT Model organism

"Notch processing is indeed strongly reduced resulting in decreased levels of Notch intracellular domain fragment and functional Notch signaling."

Measured in epidermis of K14-Cre Adam10-deleted mice, a homozygous deletion that is far more severe than the human heterozygous state.

Epidermal Melanocyte Expansion

Hyperpigmented lesions contain more basal melanocytes than perilesional skin, and more melanosomes are transferred into keratinocytes. In the Adam10 mouse model, macules are local clusters of epidermal melanocytes.

epidermal melanocyte CL:2000000

melanocyte proliferation GO:0097325 ↑ INCREASED

Animal models

Pied (Adam10 loss-of-function) Hairless mouse Mouse partially recapitulates A dominant Adam10 loss-of-function allele produces freckle-like macules made of clusters of epidermal melanocytes.

Downstream

Reticular hyperpigmentation Local melanocyte expansion and increased basal melanin produce the reticulate acral macules.

Show evidence (3 references)

PMID:29201043 SUPPORT REVIEW SYNTHESIS Human clinical

"examination of the hyperpigmented areas under electron microscopy shows a significant number of melanocytes in the basal layer and melanosomes in the keratinocyte cytoplasm"

Ultrastructure of patient lesions shows increased basal melanocytes and keratinocyte melanosomes compared with perilesional skin.

PMID:3994414 SUPPORT Human clinical

"It is concluded that the hyperpigmentation of RAPK is due to increased number of active melanocytes and to increased transfer of melanosomes to surrounding keratinocytes."

Histology and electron microscopy in four patients attribute the pigmentation to more active melanocytes and increased melanosome transfer.

PMID:22834956 SUPPORT Model organism

"The Pied macules require Hairless(Hr) homozygosity to form and are composed of localized clusters of epidermal melanocytes."

In the mouse model, the macules are local clusters of epidermal melanocytes. They form only on a Hairless background.

✶

Histopathology

1

Thinned elongated rete ridges with basal hypermelanosis

Thinning and elongation of rete ridges, hyperkeratosis without parakeratosis, and increased basal melanin without pigment incontinence. The absence of pigment incontinence distinguishes it from the other acral reticulate pigmentary disorders.

Show evidence (2 references)

PMID:29201043 SUPPORT REVIEW SYNTHESIS Human clinical

"On light microscopy, hyperpigmented lesions show thinning and elongation of the rete ridges along with hyperkeratosis without parakeratosis and increased melanin pigment in the basal layer of the epidermis without pigment incontinence"

Summarizes the lesional light-microscopic findings.

PMID:3994414 SUPPORT Human clinical

"Histologic findings revealed epidermal atrophy, elongation of the rete ridges with large amounts of melanin, and an increased number of dopa-positive basal melanocytes."

Primary histology from four patients showing atrophic epidermis, elongated melanin-laden rete ridges and more dopa-positive basal melanocytes.

⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

7

Head and Neck 1

Gingival overgrowth VERY_RARE HP:0000212

Show evidence (1 reference)

PMID:35978738 SUPPORT Human clinical

"bilateral clinodactyly of the 5th fingers and inferior gingival hyperplasia with teeth crowding"

Single case report of gingival hyperplasia in a patient with the disorder.

Integument 4

Reticular hyperpigmentation VERY_FREQUENT HP:0007588

Course: PROGRESSIVE

Show evidence (3 references)

PMID:23666529 SUPPORT Human clinical

"The characteristic skin lesions are reticulate, slightly depressed pigmented macules mainly affecting the dorsa of the hands and feet, which first appear before puberty and subsequently expand to the proximal limb and the trunk."

Describes the defining acral reticulate pigmentation, its onset and its spread.

PMID:29201043 SUPPORT REVIEW SYNTHESIS Human clinical

"The typical skin morphology of RAPK includes angulated, punctate, and slightly depressed hyperpigmented macules in a reticulated pattern with no areas of hypopigmentation"

Confirms the morphology and the absence of hypopigmentation.

PMID:26955585 SUPPORT BACKGROUND Human clinical

"The macules darken with time and continued sun exposure."

Documents progressive darkening with age and sun exposure.

Palmar pits FREQUENT HP:0010610

Show evidence (1 reference)

PMID:26955585 SUPPORT BACKGROUND Human clinical

"Palmoplantar pits and breaks in the epidermal ridge pattern are also typical."

Palmoplantar pits are a typical feature.

Plantar pits FREQUENT HP:0010612

Show evidence (1 reference)

PMID:26955585 SUPPORT BACKGROUND Human clinical

"Palmoplantar pits and breaks in the epidermal ridge pattern are also typical."

Palmoplantar pits are a typical feature.

Abnormal dermatoglyphics FREQUENT HP:0007477

Show evidence (1 reference)

PMID:26955585 SUPPORT BACKGROUND Human clinical

"Palmoplantar pits and breaks in the epidermal ridge pattern are also typical."

Breaks in the epidermal ridge pattern are a typical feature.

Limbs 2

Clinodactyly of the 5th finger VERY_RARE HP:0004209

Show evidence (1 reference)

PMID:35978738 SUPPORT Human clinical

"bilateral clinodactyly of the 5th fingers and inferior gingival hyperplasia with teeth crowding"

Single case report of fifth-finger clinodactyly in a patient with the disorder.

Aplasia of the distal phalanges of the toes VERY_RARE HP:0010645

Show evidence (1 reference)

PMID:8973039 SUPPORT Human clinical

"The patient had bony abnormalities in the form of absence of terminal phalanges of the 2nd, 3rd and 4th toes."

Single case report; the authors describe the association as never previously reported.

🧬

Genetic Associations

1

ADAM10 (Causative)

Gene: ADAM10 hgnc:188 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:23666529 SUPPORT Human clinical

"We identified a total of three truncating mutations, a splice site mutation and a missense mutation in ADAM10."

Exome sequencing of one pedigree plus Sanger sequencing of four unrelated patients identified five ADAM10 variants, mostly truncating.

PMID:23666529 SUPPORT Human clinical

"These results reveal that mutations in ADAM10 are a cause of RAK and that RAK is an independent clinical entity distinct from DDD."

Establishes ADAM10 as the causal gene.

💊

Medical Actions

1

Q-switched laser therapy

Action: Q-switched laser therapy Ontology label: Laser Therapy NCIT:C15466

Platform: Device

Q-switched lasers (532-nm Nd:YAG, 755-nm alexandrite) have lightened the hyperpigmented macules in single case reports. No treatment is established, and laser therapy removes pigment without acting on the underlying ADAM10 defect.

Show evidence (1 reference)

PMID:25473245 SUPPORT Human clinical

"In our case, the successful depigmentation with 532-nm QSND was made without a significant adverse reaction."

Single case with lasting depigmentation after 532-nm Q-switched Nd:YAG laser.

🔬

Diagnosis

2

Molecular Genetic Testing

Clinical features overlap with other hereditary reticulate pigmentary disorders, so the diagnosis is confirmed by identifying a heterozygous pathogenic ADAM10 variant. Testing also separates the disorder from Dowling-Degos disease (KRT5, POFUT1, POGLUT1, PSENEN) and dyschromatosis symmetrica hereditaria (ADAR1).

Genetic Testing NCIT:C15709

Results: Heterozygous truncating, splice-site or missense variant in ADAM10.

Show evidence (2 references)

PMID:29201043 SUPPORT REVIEW SYNTHESIS Human clinical

"However, each of these hereditary conditions possesses a unique genetic mutation, and genetic analysis is thus more useful in the diagnosis of these conditions."

Genetic analysis distinguishes the hereditary acral reticulate pigmentary disorders, which overlap clinically.

PMID:23666529 SUPPORT Human clinical

"These results reveal that mutations in ADAM10 are a cause of RAK and that RAK is an independent clinical entity distinct from DDD."

Establishes ADAM10 as the gene to test.

Skin Biopsy and Histopathology

Biopsy of a hyperpigmented macule shows thinned, elongated rete ridges with increased basal melanin and more dopa-positive basal melanocytes. Pigment incontinence is absent, which distinguishes it from the other acral reticulate pigmentary disorders.

Skin Biopsy NCIT:C51692

Results: Elongated, melanin-laden rete ridges, increased basal melanin and melanocytes, no pigment incontinence.

Show evidence (2 references)

PMID:29201043 SUPPORT REVIEW SYNTHESIS Human clinical

"A unique histopathological finding is noted in RAPK, namely, the absence of pigmentary incontinence of the hyperpigmented lesions."

Absent pigment incontinence is the histologic feature that sets this disorder apart.

PMID:3994414 SUPPORT Human clinical

"Histologic findings revealed epidermal atrophy, elongation of the rete ridges with large amounts of melanin, and an increased number of dopa-positive basal melanocytes."

Primary histology from four patients.

📊

Prevalence

1

Worldwide, predominantly Asian populations

Cases/families reported in the literature Rare

No population prevalence estimate exists. First observed in Japan in 1943; reported cases are mainly from Asian populations, with cases also described elsewhere.

Show evidence (1 reference)

PMID:29201043 SUPPORT REVIEW SYNTHESIS Human clinical

"many cases have been reported, mainly among Asian populations"

The review summarizes the published cases as mainly from Asian populations.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Reticulate Acropigmentation Of Kitamura:

Dowling-Degos disease MONDO:0008371

Overlapping Features Reticulate pigmentary genodermatosis with flexural rather than acral predominance, caused by KRT5, POFUT1, POGLUT1 or PSENEN variants. Overlap cases with features of both disorders are reported, and the two were once considered one disease, but ADAM10-positive patients lack KRT5 variants.

Distinguishing Features

Acral (dorsal hands and feet) rather than flexural distribution.
Palmoplantar pits and breaks in dermatoglyphics.
Different causal genes (ADAM10 versus KRT5 or Notch-glycosylation genes).

Show evidence (2 references)

PMID:26955585 SUPPORT BACKGROUND Human clinical

"Rebora and Crovato in 1983 first suspected that DDD and RAK were different phenotypic expressions of the same disease on the basis of their striking clinical and histopathological similarities."

Documents the long-standing clinical overlap between the two disorders.

PMID:23666529 SUPPORT Human clinical

"We searched for mutations in the KRT5 gene, a causative gene for the similar pigmentation disorder Dowling-Degos disease (DDD), in all the patients and found no KRT5 mutation."

The patients with ADAM10 variants carried no KRT5 variants, separating the two genetically.

🐁

Animal Models

2

Pied (Adam10 loss-of-function) Hairless mouse

Species

Mouse

Genotype

Adam10 heterozygous 1914-bp loss-of-function deletion (Pied) on a Hairless (Hr/Hr) background

Publication

PMID:22834956

Pathograph links

Epidermal Melanocyte Expansion partially recapitulates fidelity: moderate observes: tissue A dominant Adam10 loss-of-function allele produces freckle-like macules made of clusters of epidermal melanocytes.

Limitations: The macules form only on a Hairless (Hr/Hr) homozygous background, which itself causes epidermal pigmentation in aging mice, and the model was not reported to show acral distribution or palmoplantar pits.

Show evidence (1 reference)

PMID:22834956 SUPPORT Model organism

"The Pied macules require Hairless(Hr) homozygosity to form and are composed of localized clusters of epidermal melanocytes."

Shows that the model's lesions are melanocyte clusters and that they depend on the Hairless background.

Epidermal Adam10 knockout mouse (K14-Cre)

Species

Mouse

Genotype

Adam10 homozygous conditional deletion in epidermis (K14-Cre)

Publication

PMID:21205794

Pathograph links

Impaired Notch Receptor Processing in Epidermis partially recapitulates fidelity: low observes: tissue Complete epidermal loss of Adam10 strongly reduces Notch processing and Notch signaling.

Limitations: The deletion is homozygous, whereas patients carry one defective ADAM10 copy, and the mice die perinatally with barrier failure and absent sebaceous glands. No pigmentary phenotype resembling the human acral reticulate hyperpigmentation was reported.

Show evidence (1 reference)

PMID:21205794 SUPPORT Model organism

"Notch processing is indeed strongly reduced resulting in decreased levels of Notch intracellular domain fragment and functional Notch signaling."

Shows that the model measures the Notch-processing defect proposed for the human disorder.

{ }

Source YAML

click to show

name: Reticulate Acropigmentation Of Kitamura
creation_date: '2026-10-27T00:00:00Z'
description: Reticulate acropigmentation of Kitamura is a rare autosomal dominant pigmentary genodermatosis
  with high penetrance. Slightly depressed, angulated, freckle-like hyperpigmented macules in a reticulate
  pattern appear on the dorsa of the hands and feet before puberty, then spread to the proximal limbs
  and trunk and darken with time and sun exposure. Palmoplantar pits and breaks in the dermatoglyphic
  pattern are characteristic, and hypopigmented macules are absent. It is caused by heterozygous truncating,
  splice-site or missense variants in ADAM10, which encodes the zinc metalloprotease responsible for ectodomain
  shedding of membrane substrates in the skin, including Notch receptors. Lesional skin shows thinned,
  elongated rete ridges and increased basal melanin, with more basal melanocytes than perilesional skin.
  A dominant Adam10 loss-of-function mouse allele produces freckle-like clusters of epidermal melanocytes,
  supporting a role for ADAM10 in restraining melanocyte expansion. The disorder overlaps clinically with
  Dowling-Degos disease, but the two are genetically distinct.
category: Mendelian
disease_term:
  preferred_term: reticulate acropigmentation of Kitamura
  term:
    id: MONDO:0014234
    label: reticulate acropigmentation of Kitamura
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0014234
      label: reticulate acropigmentation of Kitamura
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO identifier for reticulate acropigmentation of Kitamura.
synonyms:
- RAK
- RAPK
- Kitamura reticulate acropigmentation
- Kitamura disease
parents:
- Dermatological Disease
- Pigmentary Disorder
classifications:
  harrisons_chapter:
  - classification_value: DERMATOLOGY
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:23666529
    reference_title: Whole-exome sequencing identifies ADAM10 mutations as a cause of reticulate acropigmentation
      of Kitamura, a clinical entity distinct from Dowling-Degos disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Reticulate acropigmentation of Kitamura (RAK) is a rare genetic disorder of cutaneous pigmentation
      with an autosomal dominant pattern of inheritance and a high penetration rate.
    explanation: States autosomal dominant inheritance with high penetrance.
  - reference: PMID:29201043
    reference_title: Clinical and Genetic Review of Hereditary Acral Reticulate Pigmentary Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: RAPK is usually inherited in an autosomal dominant pattern with high penetrance, although sporadic
      cases have been reported
    explanation: Review confirms dominant inheritance and notes that sporadic cases occur.
genetic:
- name: ADAM10
  gene_term:
    preferred_term: ADAM10
    term:
      id: hgnc:188
      label: ADAM10
  association: Causative
  relationship_type: CAUSATIVE
  notes: Heterozygous truncating (nonsense and frameshift), splice-site and missense variants in ADAM10
    cause the disorder; the spectrum, dominated by truncating alleles, points to loss of function. No
    ClinGen gene-disease validity tier is recorded here, so gene_disease_validity is left absent.
  evidence:
  - reference: PMID:23666529
    reference_title: Whole-exome sequencing identifies ADAM10 mutations as a cause of reticulate acropigmentation
      of Kitamura, a clinical entity distinct from Dowling-Degos disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified a total of three truncating mutations, a splice site mutation and a missense
      mutation in ADAM10.
    explanation: Exome sequencing of one pedigree plus Sanger sequencing of four unrelated patients identified
      five ADAM10 variants, mostly truncating.
  - reference: PMID:23666529
    reference_title: Whole-exome sequencing identifies ADAM10 mutations as a cause of reticulate acropigmentation
      of Kitamura, a clinical entity distinct from Dowling-Degos disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These results reveal that mutations in ADAM10 are a cause of RAK and that RAK is an independent
      clinical entity distinct from DDD.
    explanation: Establishes ADAM10 as the causal gene.
pathophysiology:
- name: ADAM10 Loss of Function
  description: Heterozygous truncating, splice-site and missense ADAM10 variants reduce ADAM10 metalloprotease
    activity in the skin. ADAM10 carries out the ectodomain shedding of many membrane proteins in the
    epidermis.
  biological_scale: MOLECULAR
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  genes:
  - preferred_term: ADAM10
    term:
      id: hgnc:188
      label: ADAM10
  molecular_functions:
  - preferred_term: ADAM10 zinc metalloprotease activity
    term:
      id: GO:0004222
      label: metalloendopeptidase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: membrane protein ectodomain proteolysis
    term:
      id: GO:0006509
      label: membrane protein ectodomain proteolysis
    modifier: DECREASED
  evidence:
  - reference: PMID:23666529
    reference_title: Whole-exome sequencing identifies ADAM10 mutations as a cause of reticulate acropigmentation
      of Kitamura, a clinical entity distinct from Dowling-Degos disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ADAM10 is known to be involved in the ectodomain shedding of various substrates in the skin.
    explanation: Identifies the cutaneous function of the protein encoded by the causal gene.
    directness: INDIRECT
  - reference: PMID:22834956
    reference_title: Adam10 haploinsufficiency causes freckle-like macules in Hairless mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Through linkage analysis, we find that the Pied mutation is a 1914 base pair loss-of-function
      deletion in the Adam10 zinc metalloprotease gene.
    explanation: A heterozygous loss-of-function Adam10 allele in mice is sufficient for a dominant pigmentary
      phenotype, consistent with haploinsufficiency.
  downstream:
  - target: Impaired Notch Receptor Processing in Epidermis
    description: Notch receptors are among the ADAM10 substrates in the skin, so reduced ADAM10 activity
      is proposed to reduce Notch ectodomain cleavage.
    evidence:
    - reference: PMID:30692041
      reference_title: 'Dyschromatosis symmetrica hereditaria and reticulate acropigmentation of Kitamura:
        An update.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: ADAM10 is known to be involved in the ectodomain shedding of Notch proteins as substrates
        in the skin.
      explanation: The review identifies Notch receptors as cutaneous ADAM10 substrates.
    - reference: PMID:21205794
      reference_title: The disintegrin/metalloproteinase Adam10 is essential for epidermal integrity
        and Notch-mediated signaling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: The data identify Adam10 as the major Site-2 processing enzyme for Notch in the epidermis
        in vivo
      explanation: In mouse epidermis, Adam10 is the main enzyme that processes Notch. The model is a
        complete epidermal deletion rather than the heterozygous loss seen in patients.
  - target: Epidermal Melanocyte Expansion
    description: Loss of ADAM10 removes a restraint on melanocyte expansion in adult skin.
    evidence:
    - reference: PMID:22834956
      reference_title: Adam10 haploinsufficiency causes freckle-like macules in Hairless mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: We have identified Adam10 as an inhibitor of melanocyte expansion in adult skin.
      explanation: In the mouse model, Adam10 loss leads to melanocyte expansion.
- name: Impaired Notch Receptor Processing in Epidermis
  description: Reduced ADAM10-mediated cleavage of Notch receptors is the proposed link between ADAM10
    variants and the pigmentary phenotype. Epidermal deletion of Adam10 in mice strongly reduces Notch
    processing and Notch signaling, but the defect has not been measured in patient skin, where only one
    ADAM10 copy is affected. It would connect this disorder to Dowling-Degos disease, whose POFUT1, POGLUT1
    and PSENEN forms also act on Notch processing.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: Notch receptor processing
    term:
      id: GO:0007220
      label: Notch receptor processing
    modifier: DECREASED
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:30692041
    reference_title: 'Dyschromatosis symmetrica hereditaria and reticulate acropigmentation of Kitamura:
      An update.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: We speculate that the pathogenesis of RAK and Dowling-Degos disease (DDD, a pigmentary disease
      similar to RAK) is associated with the Notch signaling pathway.
    explanation: The authors who identified the gene propose Notch signaling as the link, explicitly as
      speculation.
  - reference: PMID:21205794
    reference_title: The disintegrin/metalloproteinase Adam10 is essential for epidermal integrity and
      Notch-mediated signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: Notch processing is indeed strongly reduced resulting in decreased levels of Notch intracellular
      domain fragment and functional Notch signaling.
    explanation: Measured in epidermis of K14-Cre Adam10-deleted mice, a homozygous deletion that is far
      more severe than the human heterozygous state.
  downstream:
  - target: Epidermal Melanocyte Expansion
    description: Disturbed Notch signaling is proposed to alter the maintenance of epidermal melanocytes.
      The direct step from Notch processing to melanocyte number has not been shown in this disorder.
    evidence:
    - reference: PMID:30692041
      reference_title: 'Dyschromatosis symmetrica hereditaria and reticulate acropigmentation of Kitamura:
        An update.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: We speculate that the pathogenesis of RAK and Dowling-Degos disease (DDD, a pigmentary disease
        similar to RAK) is associated with the Notch signaling pathway.
      explanation: The proposed Notch-pathway pathogenesis is stated as speculation.
- name: Epidermal Melanocyte Expansion
  description: Hyperpigmented lesions contain more basal melanocytes than perilesional skin, and more
    melanosomes are transferred into keratinocytes. In the Adam10 mouse model, macules are local clusters
    of epidermal melanocytes.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: melanocyte proliferation
    term:
      id: GO:0097325
      label: melanocyte proliferation
    modifier: INCREASED
  cell_types:
  - preferred_term: epidermal melanocyte
    term:
      id: CL:2000000
      label: epidermal melanocyte
  evidence:
  - reference: PMID:29201043
    reference_title: Clinical and Genetic Review of Hereditary Acral Reticulate Pigmentary Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: examination of the hyperpigmented areas under electron microscopy shows a significant number
      of melanocytes in the basal layer and melanosomes in the keratinocyte cytoplasm
    explanation: Ultrastructure of patient lesions shows increased basal melanocytes and keratinocyte
      melanosomes compared with perilesional skin.
  - reference: PMID:3994414
    reference_title: Behavior of melanocytes in reticulate acropigmentation of Kitamura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: It is concluded that the hyperpigmentation of RAPK is due to increased number of active melanocytes
      and to increased transfer of melanosomes to surrounding keratinocytes.
    explanation: Histology and electron microscopy in four patients attribute the pigmentation to more
      active melanocytes and increased melanosome transfer.
  - reference: PMID:22834956
    reference_title: Adam10 haploinsufficiency causes freckle-like macules in Hairless mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The Pied macules require Hairless(Hr) homozygosity to form and are composed of localized clusters
      of epidermal melanocytes.
    explanation: In the mouse model, the macules are local clusters of epidermal melanocytes. They form
      only on a Hairless background.
  downstream:
  - target: Reticular hyperpigmentation
    description: Local melanocyte expansion and increased basal melanin produce the reticulate acral macules.
    evidence:
    - reference: PMID:29201043
      reference_title: Clinical and Genetic Review of Hereditary Acral Reticulate Pigmentary Disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: On light microscopy, hyperpigmented lesions show thinning and elongation of the rete ridges
        along with hyperkeratosis without parakeratosis and increased melanin pigment in the basal layer
        of the epidermis without pigment incontinence
      explanation: The hyperpigmented macules correspond to increased basal epidermal melanin.
phenotypes:
- category: Integument
  name: Reticular hyperpigmentation
  description: Angulated, punctate, slightly depressed hyperpigmented macules in a reticulate pattern
    on the dorsa of the hands and feet. They appear before puberty, spread to the proximal limbs and trunk,
    and darken with time and sun exposure. There are no hypopigmented macules.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Reticulate acral hyperpigmentation
    term:
      id: HP:0007588
      label: Reticular hyperpigmentation
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:23666529
    reference_title: Whole-exome sequencing identifies ADAM10 mutations as a cause of reticulate acropigmentation
      of Kitamura, a clinical entity distinct from Dowling-Degos disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The characteristic skin lesions are reticulate, slightly depressed pigmented macules mainly
      affecting the dorsa of the hands and feet, which first appear before puberty and subsequently expand
      to the proximal limb and the trunk.
    explanation: Describes the defining acral reticulate pigmentation, its onset and its spread.
  - reference: PMID:29201043
    reference_title: Clinical and Genetic Review of Hereditary Acral Reticulate Pigmentary Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: The typical skin morphology of RAPK includes angulated, punctate, and slightly depressed hyperpigmented
      macules in a reticulated pattern with no areas of hypopigmentation
    explanation: Confirms the morphology and the absence of hypopigmentation.
  - reference: PMID:26955585
    reference_title: 'Dowling-Degos disease with reticulate acropigmentation of Kitamura: Extended spectrum
      of a single entity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: The macules darken with time and continued sun exposure.
    explanation: Documents progressive darkening with age and sun exposure.
- category: Integument
  name: Palmar pits
  description: Pits on the palms, often with breaks in the epidermal ridge pattern.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Palmar pits
    term:
      id: HP:0010610
      label: Palmar pits
  evidence:
  - reference: PMID:26955585
    reference_title: 'Dowling-Degos disease with reticulate acropigmentation of Kitamura: Extended spectrum
      of a single entity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: Palmoplantar pits and breaks in the epidermal ridge pattern are also typical.
    explanation: Palmoplantar pits are a typical feature.
- category: Integument
  name: Plantar pits
  description: Pits on the soles, the plantar counterpart of the palmar pits.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Plantar pits
    term:
      id: HP:0010612
      label: Plantar pits
  evidence:
  - reference: PMID:26955585
    reference_title: 'Dowling-Degos disease with reticulate acropigmentation of Kitamura: Extended spectrum
      of a single entity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: Palmoplantar pits and breaks in the epidermal ridge pattern are also typical.
    explanation: Palmoplantar pits are a typical feature.
- category: Integument
  name: Abnormal dermatoglyphics
  description: Breaks in the epidermal ridge (dermatoglyphic) pattern of the palms.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Breaks in the epidermal ridge pattern
    term:
      id: HP:0007477
      label: Abnormal dermatoglyphics
  evidence:
  - reference: PMID:26955585
    reference_title: 'Dowling-Degos disease with reticulate acropigmentation of Kitamura: Extended spectrum
      of a single entity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: Palmoplantar pits and breaks in the epidermal ridge pattern are also typical.
    explanation: Breaks in the epidermal ridge pattern are a typical feature.
- category: Skeletal
  name: Clinodactyly of the 5th finger
  description: Bilateral fifth-finger clinodactyly reported in a single patient. Whether it is part of
    the disorder or a coincidence is unknown.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Clinodactyly of the 5th finger
    term:
      id: HP:0004209
      label: Clinodactyly of the 5th finger
  evidence:
  - reference: PMID:35978738
    reference_title: Novel Presentation of Reticulate Acropigmentation of Kitamura With Bilateral Clinodactyly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: bilateral clinodactyly of the 5th fingers and inferior gingival hyperplasia with teeth crowding
    explanation: Single case report of fifth-finger clinodactyly in a patient with the disorder.
- category: Oral
  name: Gingival overgrowth
  description: Inferior gingival hyperplasia reported in the same single patient as the clinodactyly.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Gingival hyperplasia
    term:
      id: HP:0000212
      label: Gingival overgrowth
  evidence:
  - reference: PMID:35978738
    reference_title: Novel Presentation of Reticulate Acropigmentation of Kitamura With Bilateral Clinodactyly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: bilateral clinodactyly of the 5th fingers and inferior gingival hyperplasia with teeth crowding
    explanation: Single case report of gingival hyperplasia in a patient with the disorder.
- category: Skeletal
  name: Aplasia of the distal phalanges of the toes
  description: Absent terminal phalanges of the second to fourth toes, reported in a single patient.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Absent terminal phalanges of the 2nd to 4th toes
    term:
      id: HP:0010645
      label: Aplasia of the distal phalanges of the toes
  evidence:
  - reference: PMID:8973039
    reference_title: Bony anomalies in a patient with reticulate acropigmentation of Kitamura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient had bony abnormalities in the form of absence of terminal phalanges of the 2nd,
      3rd and 4th toes.
    explanation: Single case report; the authors describe the association as never previously reported.
histopathology:
- name: Thinned elongated rete ridges with basal hypermelanosis
  description: Thinning and elongation of rete ridges, hyperkeratosis without parakeratosis, and increased
    basal melanin without pigment incontinence. The absence of pigment incontinence distinguishes it from
    the other acral reticulate pigmentary disorders.
  evidence:
  - reference: PMID:29201043
    reference_title: Clinical and Genetic Review of Hereditary Acral Reticulate Pigmentary Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: On light microscopy, hyperpigmented lesions show thinning and elongation of the rete ridges
      along with hyperkeratosis without parakeratosis and increased melanin pigment in the basal layer
      of the epidermis without pigment incontinence
    explanation: Summarizes the lesional light-microscopic findings.
  - reference: PMID:3994414
    reference_title: Behavior of melanocytes in reticulate acropigmentation of Kitamura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Histologic findings revealed epidermal atrophy, elongation of the rete ridges with large amounts
      of melanin, and an increased number of dopa-positive basal melanocytes.
    explanation: Primary histology from four patients showing atrophic epidermis, elongated melanin-laden
      rete ridges and more dopa-positive basal melanocytes.
prevalence:
- population: Worldwide, predominantly Asian populations
  measure_type: CASES_IN_LITERATURE
  prevalence_class: RARE
  notes: No population prevalence estimate exists. First observed in Japan in 1943; reported cases are
    mainly from Asian populations, with cases also described elsewhere.
  evidence:
  - reference: PMID:29201043
    reference_title: Clinical and Genetic Review of Hereditary Acral Reticulate Pigmentary Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: many cases have been reported, mainly among Asian populations
    explanation: The review summarizes the published cases as mainly from Asian populations.
diagnosis:
- name: Molecular Genetic Testing
  description: Clinical features overlap with other hereditary reticulate pigmentary disorders, so the
    diagnosis is confirmed by identifying a heterozygous pathogenic ADAM10 variant. Testing also separates
    the disorder from Dowling-Degos disease (KRT5, POFUT1, POGLUT1, PSENEN) and dyschromatosis symmetrica
    hereditaria (ADAR1).
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: Heterozygous truncating, splice-site or missense variant in ADAM10.
  evidence:
  - reference: PMID:29201043
    reference_title: Clinical and Genetic Review of Hereditary Acral Reticulate Pigmentary Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: However, each of these hereditary conditions possesses a unique genetic mutation, and genetic
      analysis is thus more useful in the diagnosis of these conditions.
    explanation: Genetic analysis distinguishes the hereditary acral reticulate pigmentary disorders, which
      overlap clinically.
  - reference: PMID:23666529
    reference_title: Whole-exome sequencing identifies ADAM10 mutations as a cause of reticulate acropigmentation
      of Kitamura, a clinical entity distinct from Dowling-Degos disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These results reveal that mutations in ADAM10 are a cause of RAK and that RAK is an independent
      clinical entity distinct from DDD.
    explanation: Establishes ADAM10 as the gene to test.
- name: Skin Biopsy and Histopathology
  description: Biopsy of a hyperpigmented macule shows thinned, elongated rete ridges with increased basal
    melanin and more dopa-positive basal melanocytes. Pigment incontinence is absent, which distinguishes
    it from the other acral reticulate pigmentary disorders.
  diagnosis_term:
    preferred_term: Skin Biopsy
    term:
      id: NCIT:C51692
      label: Skin Biopsy
  results: Elongated, melanin-laden rete ridges, increased basal melanin and melanocytes, no pigment incontinence.
  evidence:
  - reference: PMID:29201043
    reference_title: Clinical and Genetic Review of Hereditary Acral Reticulate Pigmentary Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: A unique histopathological finding is noted in RAPK, namely, the absence of pigmentary incontinence
      of the hyperpigmented lesions.
    explanation: Absent pigment incontinence is the histologic feature that sets this disorder apart.
  - reference: PMID:3994414
    reference_title: Behavior of melanocytes in reticulate acropigmentation of Kitamura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Histologic findings revealed epidermal atrophy, elongation of the rete ridges with large amounts
      of melanin, and an increased number of dopa-positive basal melanocytes.
    explanation: Primary histology from four patients.
treatments:
- name: Q-switched laser therapy
  description: Q-switched lasers (532-nm Nd:YAG, 755-nm alexandrite) have lightened the hyperpigmented
    macules in single case reports. No treatment is established, and laser therapy removes pigment without
    acting on the underlying ADAM10 defect.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Q-switched laser therapy
    term:
      id: NCIT:C15466
      label: Laser Therapy
  evidence:
  - reference: PMID:25473245
    reference_title: 'A Case of Reticulate Acropigmentation of Kitamura Treated with 532-nm Q-Switched
      Nd:YAG Laser: 10 Years of Follow-Up Observation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In our case, the successful depigmentation with 532-nm QSND was made without a significant
      adverse reaction.
    explanation: Single case with lasting depigmentation after 532-nm Q-switched Nd:YAG laser.
differential_diagnoses:
- name: Dowling-Degos disease
  description: Reticulate pigmentary genodermatosis with flexural rather than acral predominance, caused
    by KRT5, POFUT1, POGLUT1 or PSENEN variants. Overlap cases with features of both disorders are reported,
    and the two were once considered one disease, but ADAM10-positive patients lack KRT5 variants.
  disease_term:
    preferred_term: Dowling-Degos disease
    term:
      id: MONDO:0008371
      label: Dowling-Degos disease
  distinguishing_features:
  - Acral (dorsal hands and feet) rather than flexural distribution.
  - Palmoplantar pits and breaks in dermatoglyphics.
  - Different causal genes (ADAM10 versus KRT5 or Notch-glycosylation genes).
  evidence:
  - reference: PMID:26955585
    reference_title: 'Dowling-Degos disease with reticulate acropigmentation of Kitamura: Extended spectrum
      of a single entity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: Rebora and Crovato in 1983 first suspected that DDD and RAK were different phenotypic expressions
      of the same disease on the basis of their striking clinical and histopathological similarities.
    explanation: Documents the long-standing clinical overlap between the two disorders.
  - reference: PMID:23666529
    reference_title: Whole-exome sequencing identifies ADAM10 mutations as a cause of reticulate acropigmentation
      of Kitamura, a clinical entity distinct from Dowling-Degos disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We searched for mutations in the KRT5 gene, a causative gene for the similar pigmentation
      disorder Dowling-Degos disease (DDD), in all the patients and found no KRT5 mutation.
    explanation: The patients with ADAM10 variants carried no KRT5 variants, separating the two genetically.
animal_models:
- name: Pied (Adam10 loss-of-function) Hairless mouse
  species: Mouse
  genotype: Adam10 heterozygous 1914-bp loss-of-function deletion (Pied) on a Hairless (Hr/Hr) background
  publication: PMID:22834956
  modeled_mechanisms:
  - target: Epidermal Melanocyte Expansion
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: A dominant Adam10 loss-of-function allele produces freckle-like macules made of clusters
      of epidermal melanocytes.
    limitations: >-
      The macules form only on a Hairless (Hr/Hr) homozygous background, which itself causes epidermal
      pigmentation in aging mice, and the model was not reported to show acral distribution or palmoplantar
      pits.
    model_scale: TISSUE
    evidence:
    - reference: PMID:22834956
      reference_title: Adam10 haploinsufficiency causes freckle-like macules in Hairless mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: The Pied macules require Hairless(Hr) homozygosity to form and are composed of localized
        clusters of epidermal melanocytes.
      explanation: Shows that the model's lesions are melanocyte clusters and that they depend on the Hairless
        background.
- name: Epidermal Adam10 knockout mouse (K14-Cre)
  species: Mouse
  genotype: Adam10 homozygous conditional deletion in epidermis (K14-Cre)
  publication: PMID:21205794
  modeled_mechanisms:
  - target: Impaired Notch Receptor Processing in Epidermis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: Complete epidermal loss of Adam10 strongly reduces Notch processing and Notch signaling.
    limitations: >-
      The deletion is homozygous, whereas patients carry one defective ADAM10 copy, and the mice die
      perinatally with barrier failure and absent sebaceous glands. No pigmentary phenotype resembling the
      human acral reticulate hyperpigmentation was reported.
    model_scale: TISSUE
    evidence:
    - reference: PMID:21205794
      reference_title: The disintegrin/metalloproteinase Adam10 is essential for epidermal integrity and
        Notch-mediated signaling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Notch processing is indeed strongly reduced resulting in decreased levels of Notch intracellular
        domain fragment and functional Notch signaling.
      explanation: Shows that the model measures the Notch-processing defect proposed for the human disorder.

📚

References & Deep Research

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.

OpenScientist ▸

Reticulate Acropigmentation of Kitamura (RAK): A Comprehensive Disease Characterization Report

openscientist-autonomous 28 citations 2026-10-27T19:03:05.964216

Reticulate Acropigmentation of Kitamura (RAK): A Comprehensive Disease Characterization Report

Disease: Reticulate Acropigmentation of Kitamura (RAK; RAPK; Kitamura disease) MONDO ID: MONDO:0014234 · OMIM: #615537 · Causal gene: ADAM10 (HGNC:188; NCBI Gene 102; UniProt O14672; a disintegrin and metalloproteinase domain-containing protein 10) Category: Mendelian, autosomal dominant

Note on disease identity: The name "Reticulate Acropigmentation of Kitamura" is correctly matched to ADAM10. It should not be confused with the clinically similar Dowling-Degos disease (KRT5/POFUT1/POGLUT1/PSENEN/GLMN) or dyschromatosis symmetrica hereditaria (ADAR1), which are distinct genetic entities within the overlapping reticulate-pigmentary-disorder spectrum.

Summary

Reticulate Acropigmentation of Kitamura (RAK) is a rare, autosomal-dominant pigmentary genodermatosis caused by heterozygous loss-of-function variants in ADAM10, the gene encoding the zinc-metalloprotease and ectodomain sheddase ADAM10. First described by Kitamura in Japan in 1943, the disorder manifests before puberty as reticulate (net-like), slightly depressed, brown pigmented macules concentrated on the dorsa of the hands and feet. Over years the pigmentation extends proximally to the limbs and trunk, and characteristic palmar pits and breaks in the epidermal ridge pattern (dermatoglyphic interruptions) develop. It is a benign, lifelong, cosmetically significant condition with a normal life expectancy and no systemic organ failure in the great majority of patients.

The central molecular insight, established by whole-exome sequencing of a RAK pedigree in 2013, is that RAK results from ADAM10 haploinsufficiency. ADAM10 is the principal Site-2 (S2) sheddase that activates Notch signaling in the epidermis. Reduced ADAM10 activity is inferred to lower keratinocyte and melanocyte Notch signaling, dysregulating epidermal differentiation and melanocyte homeostasis. Histopathology shows epidermal atrophy, elongated rete ridges laden with melanin, an increased number of active (dopa-positive) basal melanocytes, and enhanced melanosome transfer to keratinocytes — together producing the reticulate hyperpigmentation. This Notch-centric mechanism places RAK within a larger spectrum of reticulate pigmentary disorders that share disruption of Notch processing/glycosylation genes, most notably Dowling-Degos disease (DDD; KRT5, POFUT1, POGLUT1, PSENEN, GLMN).

RAK predominantly affects East Asian (Japanese, Chinese) populations, though cases occur worldwide. Diagnosis rests on clinical and histopathologic recognition supported by ADAM10 genetic testing, which is the most reliable way to distinguish RAK from clinically overlapping reticulate disorders. No curative or disease-modifying therapy exists; treatment is limited to inconsistently effective cosmetic measures (topical/oral retinoids, laser). The principal disease model is the mouse epidermal (K14-Cre) Adam10 conditional knockout, which recapitulates epidermal Notch loss-of-function; global Adam10 knockout is embryonic lethal owing to Notch failure. No naturally occurring animal counterpart of RAK has been described.

1. Disease Information

RAK is a hereditary reticulate pigmentary disorder (RPD) of the acral skin. The causal gene is ADAM10. Key identifiers:

Resource	Identifier
MONDO	MONDO:0014234
OMIM	#615537
Gene (OMIM)	ADAM10, 602192
HGNC	HGNC:188 (ADAM10)
Orphanet	Listed under reticulate pigmentary disorders / acropigmentation of Kitamura
Synonyms	RAK; RAPK; Kitamura reticulate acropigmentation; Kitamura disease; reticulate acropigmentation

The disease-level information in this report derives from aggregated disease-level resources and primary case reports / case series, not from individual EHR datasets. RAK was first described by Kitamura et al. in 1943 (PMID: 40950988).

2. Etiology

Primary cause — genetic. RAK is a monogenic Mendelian disorder caused by heterozygous loss-of-function variants in ADAM10. Whole-exome sequencing of a RAK family, followed by Sanger sequencing of four additional unrelated patients, identified five heterozygous ADAM10 mutations — three truncating, one splice-site, and one missense — with no mutations in KRT5 (the Dowling-Degos gene), establishing RAK as a genetically distinct entity (PMID: 23666529). "A mutation in ADAM10 encoding a zinc metalloprotease… was identified in the RAK family."

Genetic risk factors. The causal variants themselves are the risk factor; inheritance is autosomal dominant with high penetrance. No additional susceptibility loci or validated modifier genes have been defined.

Environmental / lifestyle risk factors. None established. RAK is a constitutive genetic disorder; no toxin, infection, diet, or occupational exposure is known to cause or trigger it. Pigmentation is lifelong and not clearly photo-driven, though sun-exposed acral sites are prominently involved.

Protective factors. No genetic or environmental protective factors are known.

Gene–environment interactions. None demonstrated.

3. Phenotypes

RAK phenotypes are primarily physical manifestations / clinical signs of the skin.

Phenotype	Type	Onset	Frequency	Suggested HPO
Reticulate hyperpigmentation of dorsal hands/feet	Physical sign	Before puberty (childhood)	Hallmark / near-universal	HP:0007441 (Reticulated skin pigmentation)
Slightly depressed pigmented macules	Physical sign	Childhood	Characteristic	HP:0001000 (Abnormality of skin pigmentation)
Palmar pits	Physical sign	Childhood–adolescence	Common	HP:0010610 (Palmar pits)
Breaks/interruption of dermatoglyphics (epidermal ridges)	Physical sign	Childhood	Common	HP:0007477 (Abnormal dermatoglyphics)
Proximal extension to limbs/trunk	Progression feature	Later (years)	Variable	—
Skeletal anomalies (absent terminal phalanges of toes; clinodactyly)	Rare associated	Variable	Rare (isolated reports)	HP:0030084 (Clinodactyly)
Gingival hyperplasia	Rare associated	Variable	Rare (single report)	HP:0000212

Characteristics. Onset is pre-pubertal/childhood. Severity is mild–moderate and cosmetic; the course is chronic, slowly progressive, and non-remitting, with proximal spread over years. The acral reticulate pigmentation, palmar pits, and dermatoglyphic breaks are the core, highly frequent features; skeletal and gingival anomalies are exceptional.

Key quotations: "The characteristic skin lesions are reticulate, slightly depressed pigmented macules mainly affecting the dorsa of the hands and feet, which first appear before puberty and subsequently expand to the proximal limb and the trunk" (PMID: 23666529); "hyperpigmented macules or papules that may interrupt the dermatoglyphics with extra-dermatological manifestations" (PMID: 35978738). Bony anomalies (absent terminal phalanges of the 2nd–4th toes) were reported in a single case (PMID: 8973039).

Quality of life. Impact is cosmetic/psychosocial rather than functional or life-threatening; no disease-specific QoL instrument data exist.

4. Genetic / Molecular Information

Causal gene: ADAM10 (chromosome 15q21.3), encoding a zinc-dependent transmembrane metalloprotease ("a disintegrin and metalloproteinase domain-containing protein 10").

Pathogenic variants. Reported RAK variants are predominantly loss-of-function: truncating (nonsense/frameshift), splice-site, and missense. In the defining study: "We identified a total of three truncating mutations, a splice site mutation and a missense mutation in ADAM10" (PMID: 23666529). Additional novel ADAM10 mutations have since been reported in individual RAK cases, including functional-implication studies (PMID: 29192958; PMID: 26892935; PMID: 30488468).

Variant classification: pathogenic / likely pathogenic (ACMG), consistent with haploinsufficiency.
Variant type/class: nonsense, frameshift (truncating), splice-site, missense.
Allele frequency: private/family-specific; not common polymorphisms (ultra-rare).
Origin: germline, autosomal dominant.
Functional consequence: loss of function / haploinsufficiency (reduced functional ADAM10).

Modifier genes / epigenetics / chromosomal abnormalities. No validated modifiers, epigenetic marks, or chromosomal rearrangements are described for RAK.

Spectrum context. RAK is genetically distinct from Dowling-Degos disease, whose causal genes are KRT5, POFUT1, POGLUT1, PSENEN, and GLMN (PMID: 40674458). POFUT1 and POGLUT1 glycosylate Notch, and PSENEN/NCSTN are γ-secretase subunits — all converging on Notch, as does ADAM10 (PMID: 24387993; PMID: 37665193).

5. Environmental Information

No environmental factors, lifestyle factors, or infectious agents are implicated in RAK. It is a constitutive monogenic disorder. (ADAM10 is notably the cellular receptor exploited by Staphylococcus aureus α-toxin and participates in skin-microbiome regulation, but these are ADAM10 biology findings, not RAK triggers — PMID: 30324336; PMID: 34582748.)

6. Mechanism / Pathophysiology

Ordered causal chain

A heterozygous loss-of-function ADAM10 variant (truncating, splice-site, or missense) results in reduced functional ADAM10 protein (haploinsufficiency). [Demonstrated — human genetics, PMID 23666529]
Reduced ADAM10 leads to decreased Site-2 ectodomain shedding of the Notch receptor in epidermal keratinocytes and melanocytes. [Demonstrated in mouse epidermis; inferred for human RAK — PMID 21205794]
Decreased Notch shedding results in less generation of the Notch intracellular domain (NICD) and reduced Notch signaling. [Demonstrated — PMID 21205794]
Reduced epidermal Notch signaling leads to dysregulated keratinocyte differentiation (epidermal atrophy, elongated rete ridges) and, in parallel, altered melanocyte/melanocyte-precursor homeostasis. [Branch — keratinocyte arm demonstrated in mouse; melanocyte arm inferred — PMID 21205794, PMID 25705850]
Melanocyte dysregulation results in an increased number of active (dopa-positive) basal melanocytes and enhanced transfer of melanosomes to surrounding keratinocytes. [Demonstrated — human histology/ultrastructure, PMID 3994414]
These cellular changes manifest as pre-pubertal, slowly progressive, bilateral acral reticulate hyperpigmentation with palmar pits and dermatoglyphic breaks. [Demonstrated — clinical, PMID 23666529]

ADAM10 LoF variant (germline, heterozygous)
│  haploinsufficiency
▼
Reduced ADAM10 Site-2 sheddase activity
│
▼
↓ Notch shedding → ↓ NICD → ↓ epidermal Notch signaling
│
├──────────────┬───────────────────────────┐
▼              ▼                           ▼
Keratinocyte      Melanocyte / MC-precursor    Epidermal barrier/
differentiation   homeostasis dysregulated     adnexal changes
dysregulated      (↑ active basal              (modeled in mouse cKO)
(atrophy, long    melanocytes, ↑ melanosome
rete ridges)      transfer to keratinocytes)
│              │
└──────┬───────┘
       ▼
   Acral reticulate hyperpigmentation + palmar pits + dermatoglyphic breaks

Supporting detail

Molecular pathway: Notch signaling is the central axis. ADAM10 is "the major Site-2 processing enzyme for Notch in the epidermis in vivo, and thus… a central regulator of skin development and maintenance," and in its absence "Notch processing is indeed strongly reduced resulting in decreased levels of Notch intracellular domain fragment and functional Notch signaling" (PMID: 21205794). Suggested GO terms: GO:0007219 (Notch signaling pathway), GO:0006509 (membrane protein ectodomain proteolysis), GO:0004222 (metalloendopeptidase activity).
Protein dysfunction: ADAM10 is a promiscuous α-secretase/sheddase; "ADAM10 was found to exert many additional functions, cleaving about 100 different membrane proteins" (PMID: 37218105). Among its ~100 substrates (Notch, E-/N-cadherin, APP, ephrins, cytokine receptors), Notch is the essential one whose loss is lethal: "the even earlier fatal effects of ADAM10 deficiency exhibit key features of disabled Notch signalling and possibly also cadherin processing defects" (PMID: 18393804).
Cellular processes: melanocyte survival/proliferation and melanosome transfer. "Inhibition of Notch signaling reduced the proliferation of NCSC-like cells, induced cell death" (PMID: 25705850). The pigment mechanism is cell-biological: "the hyperpigmentation of RAPK is due to increased number of active melanocytes and to increased transfer of melanosomes to surrounding keratinocytes" (PMID: 3994414).
Cell types (CL): keratinocyte (CL:0000312), melanocyte (CL:0000148), epidermal/melanocyte stem cells.
Subcellular (GO cellular component): melanosome (GO:0042470), plasma membrane (GO:0005886).

7. Anatomical Structures Affected

Organ: skin (UBERON:0002097), the sole primary organ affected. No secondary systemic organ involvement in typical disease.
Body system: integumentary system (UBERON:0002416).
Regional sites: dorsum of hand (UBERON:0003401) and dorsum of foot (UBERON:0003402); palms and soles (palmar pits); later proximal limbs and trunk.
Tissue/cell: epidermis (UBERON:0001003) — epithelial tissue; affected cells are keratinocytes (CL:0000312) and melanocytes (CL:0000148) at the basal layer; adnexal structures (hair follicles, sebaceous glands) are affected in the mouse model but not clinically prominent in human RAK.
Subcellular: melanosome (GO:0042470).
Lateralization: bilateral and symmetric, acrally accentuated.

Histology: "epidermal atrophy, elongation of the rete ridges with large amounts of melanin, and an increased number of dopa-positive basal melanocytes" (PMID: 3994414).

8. Temporal Development

Onset: pediatric, before puberty; insidious/chronic onset.
Progression: slowly progressive — lesions begin acrally and extend proximally to limbs and trunk over years. No staging system; the disease is chronic and lifelong.
Course pattern: progressive-then-stable hyperpigmentation; no spontaneous remission.
Critical period: childhood/adolescence, when lesions emerge and spread.

"…first appear before puberty and subsequently expand to the proximal limb and the trunk" (PMID: 23666529).

9. Inheritance and Population

Inheritance: autosomal dominant, high penetrance; the RAK/DDD spectrum shows "rare genodermatoses inherited as an autosomal dominant trait with variable penetrance" (PMID: 26955585).
Penetrance/expressivity: high penetrance with variable expressivity (age of onset, extent of spread, rare skeletal associations).
Epidemiology: extremely rare; no formal prevalence/incidence figures are established (ultra-rare). East Asian (Japanese, Chinese) predominance: "Reticulate acropigmentation of Kitamura (RAK) predominantly affects East Asian populations, though isolated cases and familial occurrences have been reported globally" (PMID: 40950988); "Japanese researchers Kitamura et al. first described this condition in 1943" (PMID: 40950988).
Anticipation, germline mosaicism, founder effects, consanguinity, carrier frequency: not established/not applicable (dominant disorder; variants are private).
Sex ratio / age distribution: no strong sex predilection reported; onset in childhood.

10. Diagnostics

Clinical/histopathologic diagnosis + genetic confirmation.

Dermoscopy & clinical signs: reticulate, slightly depressed brown macules on dorsal hands/feet; pigmented palmar pits; dermatoglyphic breaks aid recognition (PMID: 32055533; PMID: 32055524; PMID: 23746125).
Histopathology/IHC: epidermal atrophy, elongated melanin-laden rete ridges, increased dopa-positive basal melanocytes; EM shows melanosome complexes in keratinocytes and melanosome-filled dendrites (PMID: 3994414).
Genetic testing (definitive): single-gene ADAM10 sequencing or exome/panel testing. Because features overlap heavily across RPDs, "each of these hereditary conditions possesses a unique genetic mutation, and genetic analysis is thus more useful in the diagnosis of these conditions" (PMID: 29201043); "The overlapping features often add confusion and cause delay in diagnosis" (PMID: 39139099).

Differential diagnosis (reticulate pigmentary disorders) with distinguishing genes:

Disorder	Gene	Distinguishing feature
Dowling-Degos disease	KRT5, POFUT1, POGLUT1, PSENEN, GLMN	Flexural distribution, comedo-like lesions
Dyschromatosis symmetrica hereditaria (DSH)	ADAR1	Mixed hyper-/hypopigmented acral macules
Dyschromatosis universalis hereditaria (DUH)	ABCB6	Generalized dyschromia
Naegeli-Franceschetti-Jadassohn / DPR	KRT14	Absent dermatoglyphics, hypohidrosis
Dyskeratosis congenita	Telomere genes	Nail dystrophy, leukoplakia, BM failure
X-linked reticulate pigmentary disorder	POLA1	X-linked, systemic

(References: PMID: 29201043; PMID: 37372478; PMID: 39139099; PMID: 30692041.)

Screening: no newborn/population screening; cascade genetic testing within families is possible once a pathogenic ADAM10 variant is known.

11. Outcome / Prognosis

RAK is benign with a normal life expectancy and no disease-specific mortality. Morbidity is cosmetic/psychosocial only. The hyperpigmentation is chronic, lifelong, and slowly progressive without spontaneous remission. No validated prognostic biomarkers are needed, as the disease does not threaten survival or organ function. "all three having limited treatment options" characterizes the therapeutic outlook for RAK and overlapping RPDs (PMID: 38646262).

12. Treatment

No curative or disease-modifying therapy exists. Management is cosmetic and often disappointing:

Topical: retinoids (adapalene), hydroquinone — inconsistent results. In clinically overlapping DDD, "The patient was unsuccessfully treated with adapalene gel and refused the recommended oral retinoid therapy, as well as laser therapy" (PMID: 36919394).
Systemic: oral retinoids — generally unsuccessful.
Device: laser (e.g., Er:YAG, Q-switched) — reported effective only in isolated cases.
Supportive: photoprotection, cosmetic camouflage, psychosocial support.

No pharmacogenomic, gene, cell, RNA, or targeted therapies are approved or in trials for RAK. Suggested NCIT concepts: retinoid therapy (NCIT:C1909 class), laser therapy (NCIT:C15193). "all three having limited treatment options" is explicitly documented (PMID: 38646262).

13. Prevention

No primary prevention is possible for a constitutive genetic disorder. Genetic counseling is the principal preventive tool: autosomal dominant inheritance implies a 50% transmission risk to offspring. Once a family's pathogenic ADAM10 variant is identified, cascade testing, prenatal testing, or preimplantation genetic diagnosis are theoretically available but rarely pursued given the benign nature of the disease. No immunization, behavioral, or public-health interventions apply.

14. Other Species / Natural Disease

Taxonomy / orthologs: ADAM10 is highly evolutionarily conserved — mouse Adam10 (NCBI Gene 11487), zebrafish adam10a/adam10b. Human ADAM10 is NCBI Gene 102.
Natural disease: No naturally occurring reticulate acropigmentation has been reported in companion animals or wildlife (OMIA lists no RAK entry).
Comparative biology: The ADAM10→Notch axis is deeply conserved, so mechanistic conclusions from mouse apply broadly; however, the specific human pigmentary phenotype has no documented animal counterpart.
Transmission: not applicable (non-infectious, non-zoonotic).

15. Model Organisms

Model	Type	Phenotype	Relevance
Epidermal (K14-Cre) Adam10 cKO mouse	Conditional knockout	Perinatal lethality, barrier impairment, absent sebaceous glands, reduced spinous layer, hair loss, cysts, reduced Notch processing	Key model; recapitulates epidermal Notch LoF (PMID: 21205794)
Global Adam10 KO mouse	Constitutive knockout	Embryonic lethal (Notch failure, cadherin defects)	Demonstrates Notch as essential substrate (PMID: 26522965; PMID: 18393804)
dsRNA-induced Adam10 ablation (upper HF)	Induced	Skin dysbiosis, ILC2-mediated hair-follicle destruction	Models ADAM10-Notch–microbiome axis (PMID: 34582748)

"K14-Cre driven epidermal Adam10 deletion leads to perinatal lethality, barrier impairment and absence of sebaceous glands" (PMID: 21205794).

Limitations of models: mouse epidermal knockouts are far more severe (lethal, barrier failure) than the mild human haploinsufficiency; crucially, no model reproduces the specific human acral reticulate hyperpigmentation, so models inform the ADAM10→Notch mechanism but not the pigmentary phenotype directly. No zebrafish/Drosophila/iPSC/organoid RAK-specific model is established.

Key Findings (with evidence)

ADAM10 loss-of-function causes RAK. WES of a RAK pedigree + Sanger of 4 unrelated patients found 5 heterozygous ADAM10 mutations (3 truncating, 1 splice, 1 missense); no KRT5 mutations — RAK is distinct from DDD (PMID: 23666529).
ADAM10 is the principal epidermal Site-2 Notch sheddase; its loss reduces NICD and Notch signaling and reproduces Notch-LoF skin phenotypes in mice (PMID: 21205794).
RAK belongs to a Notch-pathway reticulate pigmentary spectrum overlapping DDD (KRT5, POFUT1, POGLUT1, PSENEN, GLMN) — all Notch processing/glycosylation genes (PMID: 40674458; PMID: 24387993; PMID: 37665193).
Histopathology: epidermal atrophy, elongated melanin-laden rete ridges, increased active basal melanocytes, enhanced melanosome transfer (PMID: 3994414).
Clinical phenotype: pre-pubertal acral reticulate hyperpigmentation with dermatoglyphic breaks, palmar pits, rare skeletal anomalies (PMID: 23666529; PMID: 35978738; PMID: 8973039).
ADAM10 is a promiscuous sheddase (~100 substrates); Notch is the essential one whose loss is embryonic-lethal (PMID: 37218105; PMID: 18393804).
Epidemiology: extremely rare, East-Asian predominant, AD with variable penetrance/expressivity (PMID: 40950988; PMID: 26955585).
Diagnosis rests on clinical-dermoscopic-histologic correlation + ADAM10 genetic confirmation (PMID: 29201043; PMID: 39139099).
Notch regulates melanocyte/MC-stem-cell homeostasis, linking ADAM10 loss to altered pigmentation (PMID: 25705850).
Benign, chronic, limited-therapy disorder (PMID: 38646262; PMID: 36919394).
Mouse epidermal Adam10 cKO is the key model; no natural animal RAK (PMID: 21205794; PMID: 26522965).
Integrated causal model: ADAM10 haploinsufficiency → ↓ epidermal Notch → keratinocyte/melanocyte dysregulation → acral reticulate hyperpigmentation (PMID: 23666529; PMID: 21205794; PMID: 3994414).

Mechanistic Model / Interpretation

The twelve findings converge on a single, coherent causal narrative. RAK begins with a germline heterozygous ADAM10 loss-of-function allele. Because ADAM10 is the dominant Site-2 sheddase that activates Notch in the epidermis, halving its dose is sufficient to reduce Notch intracellular-domain generation and downstream Notch signaling. Notch is a master regulator of both keratinocyte differentiation and melanocyte homeostasis, so its attenuation branches into two coupled effects: aberrant keratinocyte differentiation (seen histologically as epidermal atrophy and elongated, melanin-laden rete ridges) and increased activity of basal melanocytes with enhanced melanosome transfer to keratinocytes. The net clinical readout is the slightly depressed, reticulate, acral hyperpigmentation with palmar pits and dermatoglyphic breaks. Critically, the same Notch axis — accessed through glycosylation (POFUT1, POGLUT1) or γ-secretase (PSENEN, NCSTN) — unifies the clinically overlapping Dowling-Degos spectrum, explaining why these disorders share reticulate pigmentation yet are genetically distinct.

The chain is firmly anchored at its endpoints (human genetics at the top; human histology and clinical phenotype at the bottom) but relies on mouse/in-vitro evidence for its middle steps (the quantitative reduction in Notch signaling and the keratinocyte/melanocyte response). This is the principal interpretive caveat: the Notch-reduction step is demonstrated in mouse epidermis and inferred, not directly measured, in human RAK skin.

Evidence Base

PMID	Role
23666529	Defining genetics — ADAM10 mutations cause RAK; distinct from DDD
21205794	Mechanism — ADAM10 is epidermal Site-2 Notch sheddase; mouse cKO
3994414	Histology/ultrastructure — melanocyte behavior in RAK
37218105	ADAM10 substrate breadth (~100) and pathophysiology
18393804	Notch as essential ADAM10 substrate (lethality)
25705850	Notch controls melanocyte-precursor fate/survival
40674458	DDD spectrum genes (Notch pathway)
24387993	POGLUT1/POFUT1 — Notch glycosylation in DDD
37665193	NCSTN/PSENEN — γ-secretase in DDD spectrum
30692041	Review of DSH and RAK, Notch hypothesis
37372478	Inherited RPD review, East-Asian predominance
29201043	Genetic testing as definitive diagnostic
39139099	Algorithmic diagnostic approach
40950988	Epidemiology, 1943 first description
38646262	Limited treatment options
34582748	ADAM10-Notch–microbiome axis (hair follicle)
26522965	ADAM10 biology; global KO embryonic lethal
36919394	DDD treatment refractoriness (overlapping disorder)
35978738 / 8973039	Rare extradermatological (skeletal) associations

Evidence source types: human clinical genetics and histopathology (23666529, 3994414, 35978738, 8973039); mouse model (21205794, 34582748, 26522965); in vitro / mechanistic (25705850, 37218105, 18393804); reviews (30692041, 37372478, 40674458).

Limitations and Knowledge Gaps

No direct human tissue proof that NICD/Notch signaling is reduced in RAK epidermis — the Notch-reduction step is inferred from the mouse model, not demonstrated in patient skin.
Genotype–phenotype correlation is unknown: why haploinsufficiency produces a pigmentary, acral phenotype in humans while the mouse epidermal null is lethal and barrier-focused is unexplained. The mild human phenotype vs. severe mouse phenotype gap limits model translation.
No formal epidemiology (prevalence/incidence) exists; estimates are impressionistic.
Melanocyte-arm mechanism is partly inferred: the link from reduced keratinocyte/melanocyte Notch to "increased active melanocytes + melanosome transfer" is supported by histology (3994414) and Notch-melanocyte biology (25705850) but not by a RAK-specific functional melanocyte study.
No modifier genes, epigenetic data, or therapeutics have been systematically investigated.

Proposed Follow-up Experiments / Actions

Patient-skin Notch readout: quantify NICD, HES1/HEY1, and ADAM10 protein in RAK lesional vs. non-lesional epidermis to directly test steps 2–3 of the causal chain.
RAK-relevant model: generate a melanocyte-specific or inducible heterozygous Adam10 mouse (or a human iPSC-derived keratinocyte–melanocyte co-culture / skin organoid carrying a patient ADAM10 LoF variant) to reproduce the pigmentary phenotype at physiologic haploinsufficiency.
Melanocyte functional assays: measure melanocyte activation (dopa positivity, tyrosinase), dendricity, and melanosome transfer under ADAM10 knockdown/Notch inhibition.
Genotype–phenotype registry: aggregate ADAM10 variants with age of onset, extent of spread, and rare skeletal/gingival features to define expressivity drivers.
Therapeutic exploration: test whether topical Notch-pathway modulators or targeted melanogenesis inhibitors improve pigmentation in controlled series, given the current therapeutic void.

Report compiled from a 5-iteration autonomous investigation; 12 confirmed findings; 44 papers reviewed.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome	Count
References checked	28
Resolved	28
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	28
On topic	13
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	22
Resolved	19
Unresolved (possible confabulation)	2
Obsolete	0
Unverifiable	1
Terms whose name was checked	11
Terms named correctly	7
Terms named as a different term	3
Terms whose name is worth a second look	1

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:0014234 (2 mentions) - the report calls it "MONDO"; MONDO calls it reticulate acropigmentation of Kitamura
HP:0007441 (1 mention) - the report calls it "Reticulated skin pigmentation"; HP calls it Hyperpigmented/hypopigmented macules
HP:0000212 (1 mention) - the report calls it "Rare (single report)"; HP calls it Gingival overgrowth

Unresolved terms

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

UBERON:0003401 (1 mention) - UBERON does not contain this term
UBERON:0003402 (1 mention) - UBERON 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:0042470 (2 mentions) - the report calls it "Subcellular: melanosome"; GO calls it melanosome**

Ask OpenScientist

OpenScientist Report

Classifications

Mappings

Inheritance

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Differential Diagnoses

Animal Models

Source YAML

References & Deep Research

Deep Research

Reticulate Acropigmentation of Kitamura (RAK): A Comprehensive Disease Characterization Report

Summary

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

Supporting detail

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Key Findings (with evidence)

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Unresolved terms

Terms whose name is worth a second look