Kindler Epidermolysis Bullosa

Mendelian MONDO:0008260 Pathograph 5 Dermatological Disease Genetic Disease

Kindler epidermolysis bullosa (Kindler syndrome) is the rarest form of EB, caused by autosomal recessive loss-of-function mutations in FERMT1 encoding kindlin-1, a focal adhesion protein critical for integrin activation. Characterized by mixed-level cleavage planes, childhood skin blistering that improves with age, progressive poikiloderma, photosensitivity, and mucosal involvement. Approximately 400 cases have been identified worldwide.

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Definitions

Histopathology

Differentials

Models

🏷

Classifications

Harrison's Chapter

🔗

Mappings

MONDO

MONDO:0008260 Kindler syndrome

Primary MONDO disease identifier for this Kindler EB entry.

ICD-10-CM

ICD10CM:Q81.8 Other epidermolysis bullosa

ICD-10-CM does not provide a Kindler-specific EB code; Q81.8 is the closest available code for this rare EB subtype.

👪

Inheritance

Autosomal recessive

Show evidence (1 reference)

PMID:21936020 SUPPORT Human Clinical

"Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder"

Confirms autosomal recessive inheritance of Kindler syndrome caused by FERMT1 mutations.

◆

Subtypes

Early Blistering-Predominant Phase

Neonatal and early childhood presentation dominated by acral skin blistering and skin fragility. Blistering typically improves with age but may persist in some patients. Photosensitivity is most prominent during childhood.

Late Poikiloderma-Predominant Phase

Progressive poikiloderma (atrophy, telangiectasia, pigmentary changes) becomes the dominant feature in adolescence and adulthood. Diffuse cutaneous atrophy, mucosal complications (colitis, esophageal and urethral stenosis), and risk of squamous cell carcinoma characterize this phase.

◈

Mechanistic Hypotheses

Wnt/Beta-Catenin Dysregulation Model for SCC Susceptibility

wnt_beta_catenin_scc_model CANONICAL

Loss of kindlin-1 induces nuclear translocation of beta-catenin-Lef1 in keratinocytes, leading to elevated Wnt-beta-catenin signaling. This dysregulation produces enlarged and hyperactive cutaneous epithelial stem cell compartments, resulting in hyperthickened epidermis, ectopic hair follicle development, and increased skin tumor susceptibility. Kindlin-1 normally inhibits Wnt-beta-catenin signaling through integrin-independent regulation of Wnt ligand expression, and simultaneously promotes TGF-beta-mediated growth-inhibitory signals via alphav-beta6 integrin. Loss of this dual control shifts the balance toward unchecked proliferation.

Show evidence (3 references)

PMID:24681597 SUPPORT Model Organism

"loss of Kindlin-1 in mouse keratinocytes recapitulates Kindler syndrome and also produces enlarged and hyperactive stem cell compartments, which lead to hyperthickened epidermis, ectopic hair follicle development and increased skin tumor susceptibility"

Mouse model demonstrates that kindlin-1 loss leads to stem cell hyperactivation and tumor susceptibility through Wnt pathway dysregulation.

PMID:24681597 SUPPORT Model Organism

"loss of Kindlin-1 induces nuclear translocation of β-catenin-Lef1 in KS and mouse skin leading to elevated Wnt-β-catenin signaling"

Demonstrates the specific mechanism of nuclear beta-catenin-Lef1 translocation in both mouse model and human KS skin.

PMID:24681597 SUPPORT Model Organism

"Kindlin-1 controls keratinocyte adhesion through β1-class integrins and proliferation and differentiation of cutaneous epithelial stem cells by promoting α(v)β(6) integrin-mediated transforming growth factor-β (TGF-β) activation and inhibiting Wnt-β-catenin signaling through integrin-independent..."

Defines the dual mechanism by which kindlin-1 normally suppresses tumorigenesis through TGF-beta activation and Wnt inhibition.

Oxidative Stress and Impaired ERK Signaling Model for Photosensitivity

oxidative_stress_photosensitivity_model CANONICAL

Kindlin-1-deficient keratinocytes have higher baseline levels of reactive oxygen species (ROS) and show decreased viability and increased DNA damage after oxidative stress (H2O2 or UVA irradiation). Kindlin-1 is required for full activation of ERK signaling after oxidative damage, and ERK activation protects cells from DNA damage. This integrin-dependent mechanism explains the photosensitivity characteristic of Kindler syndrome and may contribute to the predisposition to aggressive squamous cell carcinoma through accumulation of UV-induced DNA damage.

Show evidence (3 references)

PMID:28501563 SUPPORT In Vitro

"loss of Kindlin-1 sensitizes both SCC cells and keratinocytes to oxidative stress: Kindlin-1 deficient cells have higher levels of reactive oxygen species, decreased viability and increased DNA damage after treatment with either hydrogen peroxide (H2O2) or irradiation with UVA"

Demonstrates that kindlin-1-deficient cells have elevated ROS and increased susceptibility to oxidative DNA damage.

PMID:28501563 SUPPORT In Vitro

"Kindlin-1 is required to fully activate ERK signalling after oxidative damage, and that activation of ERK protects cells from DNA damage following oxidative stress"

Identifies impaired ERK signaling as the molecular mechanism linking kindlin-1 loss to oxidative stress vulnerability.

PMID:28501563 SUPPORT In Vitro

"Kindlin-1 dependent activation of ERK signalling is a key molecular mechanism that renders KS keratinocytes more sensitive to oxidative damage and contributes to the increased photosensitivity in KS patients"

Directly proposes this mechanism as the basis for photosensitivity in Kindler syndrome patients.

⚙

Pathophysiology

FERMT1 Mutations and Loss of Kindlin-1

Loss-of-function mutations in FERMT1 (also known as KIND1) lead to absence or dysfunction of the focal adhesion protein kindlin-1 (fermitin family homolog-1). Most mutations are predicted to lead to premature termination of translation and complete loss of kindlin-1 function, though missense mutations can cause milder phenotypes.

keratinocyte link

FERMT1 link

Downstream

Defective Focal Adhesion and Integrin Activation Loss of kindlin-1 disrupts focal adhesion formation and integrin activation at the basal keratinocyte-basement membrane zone interface.

Show evidence (2 references)

PMID:21936020 SUPPORT Human Clinical

"Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with..."

Confirms FERMT1 mutations cause Kindler syndrome through loss of the focal adhesion protein kindlin-1.

PMID:19945623 SUPPORT Human Clinical

"Kindler syndrome is caused by genetic defects in the focal contact-associated protein, fermitin family homologue 1 (FFH1), encoded by the gene FERMT1 (known as KIND1)"

Confirms FERMT1 encodes the focal contact-associated protein FFH1 (kindlin-1) and its defects cause Kindler syndrome.

Defective Focal Adhesion and Integrin Activation

Kindlin-1 is a FERM domain protein that activates integrin beta1 signaling at the basal keratinocyte-basement membrane zone interface. Loss of kindlin-1 results in reduced active beta1 integrin, altered distribution of basement membrane proteins (types IV, VII, and XVII collagens, laminin-332), and disruption of hemidesmosomal components. This causes impaired cell-ECM adhesion at multiple levels, explaining the mixed-level cleavage characteristic of Kindler EB.

keratinocyte link

focal adhesion assembly link ↓ DECREASED integrin-mediated signaling pathway link ↓ DECREASED cell-matrix adhesion link ↓ DECREASED

Downstream

Impaired Keratinocyte Migration and Wound Healing Defective integrin activation impairs keratinocyte migration and proliferation, leading to delayed wound healing.

Progressive Poikiloderma and Skin Atrophy Chronic adhesion defects lead to progressive skin atrophy, telangiectasia, and pigmentary changes (poikiloderma).

Show evidence (3 references)

PMID:19762710 SUPPORT Human Clinical

"active beta1 integrin was reduced but overexpression of fermitin family homolog-1 restored integrin activation and partially rescued the Kindler syndrome cellular phenotype"

Demonstrates that kindlin-1 deficiency reduces active beta1 integrin and that restoring kindlin-1 rescues integrin activation.

PMID:19762710 SUPPORT Human Clinical

"We identified altered distribution of several basement membrane proteins, including types IV, VII, and XVII collagens and laminin-332 in Kindler syndrome skin"

Shows disruption of multiple basement membrane components beyond focal adhesions in Kindler syndrome.

PMID:19945623 SUPPORT Human Clinical

"Defects in FFH1 lead to abnormal integrin activation and loss of keratinocyte epidermal adhesion to the underlying basal lamina, disruption in normal cell cytoskeleton within keratinocytes, and altered signaling pathways"

Confirms that kindlin-1 deficiency causes abnormal integrin activation and loss of keratinocyte adhesion.

Impaired Keratinocyte Migration and Wound Healing

Defective integrin activation and cell-matrix adhesion impair keratinocyte migration and proliferation, leading to poor wound healing. Loss of kindlin-1 also disrupts cytoskeletal organization within keratinocytes and reduces keratinocyte stem cell markers such as cytokeratin 15.

keratinocyte link

wound healing link ↓ DECREASED cell migration link ↓ DECREASED

Show evidence (1 reference)

PMID:19762710 SUPPORT Human Clinical

"lack of this protein leads to pathological changes beyond focal adhesions, with disruption of several hemidesmosomal components and reduced expression of keratinocyte stem cell markers"

Shows that kindlin-1 loss impairs keratinocyte biology beyond adhesion, including stem cell marker expression, which contributes to impaired wound healing.

Progressive Poikiloderma and Skin Atrophy

Progressive poikiloderma (atrophy, telangiectasia, pigmentary changes) is the hallmark feature of Kindler EB. The mechanism involves chronic defective keratinocyte adhesion leading to cumulative skin damage. Photosensitivity may contribute through oxidative stress in kindlin-1-deficient keratinocytes. Skin atrophy is diffuse and progressive, affecting both sun-exposed and non-exposed areas.

keratinocyte link

response to oxidative stress link ↑ INCREASED epidermis development link ⚠ ABNORMAL

Show evidence (2 references)

PMID:21936020 SUPPORT Human Clinical

"an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer"

Confirms the progressive nature of poikiloderma and skin atrophy in Kindler syndrome.

PMID:19057668 SUPPORT Model Organism

"deleting Kindlin-1 in mice gives rise to skin atrophy"

Mouse model confirms that kindlin-1 loss directly causes skin atrophy.

Mucosal Involvement

Kindler EB affects mucosal epithelium, causing colitis resembling ulcerative colitis, esophageal strictures, urethral stenosis, and oral mucosal fragility with hemorrhagic gingivitis and periodontitis. Mucosal manifestations result from the same integrin activation defect in epithelial cells lining these structures.

keratinocyte link

integrin-mediated signaling pathway link ↓ DECREASED cell-matrix adhesion link ↓ DECREASED

Show evidence (3 references)

PMID:19057668 SUPPORT Model Organism

"deleting Kindlin-1 in mice gives rise to skin atrophy and an intestinal epithelial dysfunction with similarities to human UC"

Mouse model demonstrates that kindlin-1 loss causes intestinal epithelial dysfunction resembling ulcerative colitis.

PMID:19057668 SUPPORT Model Organism

"This intestinal dysfunction results in perinatal lethality and is triggered by defective intestinal epithelial cell integrin activation, leading to detachment of this barrier followed by a destructive inflammatory response"

Demonstrates that intestinal involvement is caused by defective integrin activation in epithelial cells.

PMID:26937547 SUPPORT Human Clinical

"Mucosal manifestations are also common and include hemorrhagic mucositis and gingivitis, periodontal disease, premature loss of teeth, and labial leukokeratosis. Other mucosal findings can include ectropion, urethral stenosis, and severe phimosis"

GeneReviews confirms the spectrum of mucosal manifestations in Kindler syndrome.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Digestive 2

Colitis OCCASIONAL Colitis (HP:0002583)

Show evidence (2 references)

PMID:19057668 PARTIAL Human Clinical

"a few KS patients have been reported to also develop ulcerative colitis (UC), a causal link to the FERMT1 gene mutation is unknown"

Notes that some Kindler syndrome patients develop ulcerative colitis.

PMID:19057668 SUPPORT Model Organism

"deleting Kindlin-1 in mice gives rise to skin atrophy and an intestinal epithelial dysfunction with similarities to human UC"

Mouse model provides causal evidence linking kindlin-1 loss to colitis-like intestinal dysfunction.

Esophageal Stenosis OCCASIONAL Esophageal stricture (HP:0002043)

Show evidence (1 reference)

PMID:26937547 SUPPORT Human Clinical

"Severe long-term complications of KS include periodontitis, mucosal strictures, and aggressive squamous cell carcinomas"

GeneReviews identifies mucosal strictures as a severe long-term complication.

Genitourinary 1

Urethral Stenosis OCCASIONAL Urethral stenosis (HP:0008661)

Show evidence (1 reference)

PMID:26937547 SUPPORT Human Clinical

"Other mucosal findings can include ectropion, urethral stenosis, and severe phimosis"

GeneReviews lists urethral stenosis as a mucosal manifestation.

Head and Neck 1

Periodontal Disease VERY_FREQUENT Periodontitis (HP:0000704)

Show evidence (2 references)

PMID:26937547 SUPPORT Human Clinical

"Mucosal manifestations are also common and include hemorrhagic mucositis and gingivitis, periodontal disease, premature loss of teeth"

GeneReviews confirms periodontal disease as a common mucosal manifestation.

PMID:26937547 SUPPORT Human Clinical

"Severe long-term complications of KS include periodontitis, mucosal strictures, and aggressive squamous cell carcinomas"

Confirms periodontitis as a severe long-term complication.

Integument 7

Skin Blistering VERY_FREQUENT Abnormal blistering of the skin (HP:0008066)

Show evidence (2 references)

PMID:26937547 SUPPORT Human Clinical

"characterized by skin fragility and acral blister formation beginning at birth"

GeneReviews confirms acral blistering from birth as a cardinal feature.

PMID:21936020 SUPPORT Human Clinical

Confirms skin blistering as a key component of the Kindler syndrome phenotype.

Poikiloderma VERY_FREQUENT Poikiloderma (HP:0001029)

Show evidence (2 references)

PMID:21936020 SUPPORT Human Clinical

"progressive poikiloderma with extensive skin atrophy"

Confirms progressive poikiloderma as a defining feature.

PMID:19945623 SUPPORT Human Clinical

"Null mutations in FERMT1 result in skin blistering from birth and early childhood progressive poikiloderma, mucosal fragility, and increased risk of cancer"

Confirms progressive poikiloderma beginning in early childhood.

Cutaneous Photosensitivity VERY_FREQUENT Cutaneous photosensitivity (HP:0000992)

Show evidence (4 references)

PMID:26937547 SUPPORT Human Clinical

"photosensitivity (most prominent during childhood and usually decreasing after adolescence)"

GeneReviews confirms photosensitivity pattern in Kindler syndrome.

PMID:21936020 SUPPORT Human Clinical

"skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy"

Confirms photosensitivity as part of the progressive phenotype.

PMID:28501563 SUPPORT In Vitro

"Kindlin-1 deficient cells have higher levels of reactive oxygen species, decreased viability and increased DNA damage after treatment with either hydrogen peroxide (H2O2) or irradiation with UVA"

Demonstrates the molecular basis of photosensitivity through elevated ROS and increased DNA damage in kindlin-1-deficient cells after UVA exposure.

+ 1 more reference

Progressive Skin Atrophy VERY_FREQUENT Dermal atrophy (HP:0004334)

Show evidence (2 references)

PMID:26937547 SUPPORT Human Clinical

"diffuse cutaneous atrophy"

GeneReviews lists diffuse cutaneous atrophy as a key clinical characteristic.

PMID:19057668 SUPPORT Model Organism

"deleting Kindlin-1 in mice gives rise to skin atrophy"

Mouse model confirms kindlin-1 loss directly causes skin atrophy.

Palmoplantar Keratoderma FREQUENT Palmoplantar keratoderma (HP:0000982)

Show evidence (1 reference)

PMID:26937547 SUPPORT Human Clinical

"diffuse palmoplantar hyperkeratosis"

GeneReviews confirms palmoplantar hyperkeratosis as a feature of Kindler syndrome.

Nail Dystrophy FREQUENT Nail dystrophy (HP:0008404)

Nail dystrophy is reported in Kindler syndrome case series but specific abstract-level evidence is limited.

Squamous Cell Carcinoma Risk FREQUENT Squamous cell carcinoma (HP:0002860)

14.3% of adult KS patients develop SCC, with cumulative risk reaching 66.7% in patients over 60 years. SCCs are highly aggressive with 53.8% developing metastatic disease.

Show evidence (5 references)

PMID:21936020 SUPPORT Human Clinical

"propensity to skin cancer"

Confirms increased skin cancer risk in Kindler syndrome.

PMID:26937547 SUPPORT Human Clinical

"Severe long-term complications of KS include periodontitis, mucosal strictures, and aggressive squamous cell carcinomas"

GeneReviews identifies aggressive SCCs as a severe long-term complication.

PMID:31340837 SUPPORT Human Clinical

"SCC developed in 13 of the 91 patients"

Largest systematic study of SCC in KS quantifies the frequency at 14.3% of adult patients in this cohort.

+ 2 more references

🧬

Genetic Associations

FERMT1 (Causative)

Autosomal recessive

Show evidence (3 references)

PMID:26937547 SUPPORT Human Clinical

"The diagnosis of KS is established in a proband with suggestive clinical findings and biallelic pathogenic variants in FERMT1 identified by molecular genetic testing"

GeneReviews confirms biallelic FERMT1 variants as the molecular basis of Kindler syndrome.

PMID:21936020 SUPPORT Human Clinical

"Although most mutations are predicted to lead to premature termination of translation, and to loss of kindlin-1 function, significant clinical variability is observed among patients"

Confirms that most FERMT1 mutations are loss-of-function with variable clinical expression.

PMID:19762710 SUPPORT Human Clinical

"It results from loss-of-function mutations in the FERMT1 gene encoding the focal adhesion protein, fermitin family homolog-1"

Confirms FERMT1 loss-of-function mutations cause Kindler syndrome.

💊

Treatments

Wound Care and Skin Protection

Action: supportive care MAXO:0000950

Standard blister care with use of moisturizers and protection from mechanical trauma. Multidisciplinary management by a team experienced in skin fragility disorders is recommended.

Show evidence (1 reference)

PMID:26937547 SUPPORT Human Clinical

"Skin care includes standard blister care, use of moisturizers, and protection from trauma and the sun"

GeneReviews describes wound care and skin protection as key management strategies.

Photoprotection

Action: supportive care MAXO:0000950

Sun avoidance and sunscreen use to reduce photosensitivity-related skin damage. Sun exposure is listed as an agent to avoid.

Show evidence (1 reference)

PMID:26937547 SUPPORT Human Clinical

"Agents/circumstances to avoid: Sun exposure"

GeneReviews explicitly recommends avoiding sun exposure.

Gastrointestinal Management

Action: supportive care MAXO:0000950

Management of gastrointestinal complications including colitis and esophageal strictures. Gastroenterology input is part of the multidisciplinary team.

Show evidence (1 reference)

PMID:26937547 SUPPORT Human Clinical

"management of gastrointestinal and urethral complications"

GeneReviews includes GI management as part of treatment.

Dental Care

Action: supportive care MAXO:0000950

Regular dental care to ensure optimal oral hygiene and reduce periodontal disease. Screening for oral ulcerations, gingivitis, and periodontitis starting in adolescence with regular dental checkups.

Show evidence (1 reference)

PMID:26937547 SUPPORT Human Clinical

"regular dental care to ensure optimal oral hygiene to reduce periodontal disease"

GeneReviews recommends regular dental care for periodontal disease prevention.

Squamous Cell Carcinoma Surveillance

Action: cancer screening MAXO:0000126

Screening for premalignant keratoses and early squamous cell carcinomas starting in adolescence and repeated annually.

Show evidence (1 reference)

PMID:26937547 SUPPORT Human Clinical

"Screening for premalignant keratoses and early squamous cell carcinomas starting in adolescence and repeated annually"

GeneReviews recommends annual SCC screening starting in adolescence.

Genetic Counseling

Action: genetic counseling MAXO:0000079

Kindler syndrome is inherited in an autosomal recessive manner. Carrier testing for at-risk relatives, prenatal testing, and preimplantation genetic testing are possible once FERMT1 pathogenic variants have been identified.

Show evidence (1 reference)

PMID:26937547 SUPPORT Human Clinical

"KS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an FERMT1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected"

GeneReviews confirms autosomal recessive inheritance and recommends genetic counseling.

📊

Related Datasets

Kindler syndrome microarray study geo:GSE47642

Human skin-biopsy microarray dataset comparing Kindler syndrome and control samples to define transcriptional changes associated with FERMT1 deficiency.

human MICROARRAY n=6

Conditions: Kindler syndrome skin biopsies normal human skin biopsies

PMID:24681597

Show evidence (2 references)

GEO:GSE47642 SUPPORT Human Clinical

"Characterization of gene expression profile of normal human and Kindler Syndrome (KS) patients skin biopsies samples"

Confirms the dataset contains direct human tissue expression profiles from Kindler syndrome and control skin.

GEO:GSE47642 SUPPORT Human Clinical

"to extend the knowledge of transcriptional changes in the Kindler syndrome disease."

Supports this dataset as a disease-relevant transcriptomic resource for Kindler EB.

🔬

Clinical Trials

NCT04908215 PHASE_II COMPLETED

Completed phase II randomized trial of topical INM-755 (cannabinol) cream across multiple epidermolysis bullosa subtypes, including Kindler syndrome, to evaluate wound healing and symptom control.

Target Phenotypes: Wound healing impairment ↗

Show evidence (1 reference)

clinicaltrials:NCT04908215 SUPPORT Human Clinical

"The purpose of this study is to evaluate the safety of INM-755 (cannabinol) cream and obtain preliminary evidence of efficacy in treating symptoms and healing wounds over a 28-day period in patients with epidermolysis bullosa (EB)."

This ClinicalTrials.gov record supports a completed EB-enrollment trial of topical cannabinol cream relevant to Kindler syndrome because the current study condition list includes Kindler syndrome.

{ }

Source YAML

click to show

name: Kindler Epidermolysis Bullosa
creation_date: '2026-03-10T00:00:00Z'
updated_date: '2026-05-10T06:16:54Z'
category: Mendelian
description: >-
  Kindler epidermolysis bullosa (Kindler syndrome) is the rarest form of EB,
  caused by autosomal recessive loss-of-function mutations in FERMT1 encoding
  kindlin-1, a focal adhesion protein critical for integrin activation.
  Characterized by mixed-level cleavage planes, childhood skin blistering that
  improves with age, progressive poikiloderma, photosensitivity, and mucosal
  involvement. Approximately 400 cases have been identified worldwide.
parents:
- Dermatological Disease
- Genetic Disease
disease_term:
  preferred_term: Kindler syndrome
  term:
    id: MONDO:0008260
    label: Kindler syndrome
mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:Q81.8
      label: Other epidermolysis bullosa
    mapping_predicate: skos:closeMatch
    mapping_source: ICD-10-CM
    mapping_justification: >
      ICD-10-CM does not provide a Kindler-specific EB code; Q81.8 is the
      closest available code for this rare EB subtype.
  mondo_mappings:
  - term:
      id: MONDO:0008260
      label: Kindler syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for this Kindler EB entry.
classifications:
  harrisons_chapter:
  - classification_value: skin disorder
    evidence:
    - reference: PMID:21936020
      reference_title: "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder"
      explanation: Supports classifying Kindler EB as a skin disorder because the reference explicitly describes it as a skin disorder.
  - classification_value: hereditary disease
    evidence:
    - reference: PMID:21936020
      reference_title: "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder"
      explanation: Supports classifying Kindler EB as a hereditary disease because the syndrome is explicitly autosomal recessive.
has_subtypes:
- name: Early Blistering-Predominant Phase
  description: >
    Neonatal and early childhood presentation dominated by acral skin blistering
    and skin fragility. Blistering typically improves with age but may persist in
    some patients. Photosensitivity is most prominent during childhood.
- name: Late Poikiloderma-Predominant Phase
  description: >
    Progressive poikiloderma (atrophy, telangiectasia, pigmentary changes) becomes
    the dominant feature in adolescence and adulthood. Diffuse cutaneous atrophy,
    mucosal complications (colitis, esophageal and urethral stenosis), and risk of
    squamous cell carcinoma characterize this phase.
inheritance:
- name: Autosomal recessive
  evidence:
  - reference: PMID:21936020
    reference_title: "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder"
    explanation: Confirms autosomal recessive inheritance of Kindler syndrome caused by FERMT1 mutations.
prevalence:
- population: Global
  notes: >
    Approximately 400 individuals have been identified worldwide with biallelic
    FERMT1 pathogenic variants since the syndrome was first described in 1954.
    Clusters have been reported in Panamanian and Iranian populations. The
    condition is the rarest subtype of epidermolysis bullosa.
  evidence:
  - reference: PMID:38371949
    reference_title: "Battling a rarity: A case of kindler syndrome from a developing country."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To this date, about 400 cases have been reported worldwide for this disease only"
    explanation: Case report from 2024 confirms the approximate worldwide count of ~400 identified cases of Kindler syndrome.
  - reference: PMID:21936020
    reference_title: "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Herein we review the clinical and genetic data of 62 patients, and delineate the natural history of the disorder"
    explanation: The largest systematic review at the time (2011) catalogued 62 patients, contributing to the worldwide count of identified cases.
pathophysiology:
- name: FERMT1 Mutations and Loss of Kindlin-1
  description: >
    Loss-of-function mutations in FERMT1 (also known as KIND1) lead to absence or
    dysfunction of the focal adhesion protein kindlin-1 (fermitin family homolog-1).
    Most mutations are predicted to lead to premature termination of translation and
    complete loss of kindlin-1 function, though missense mutations can cause milder
    phenotypes.
  genes:
  - preferred_term: FERMT1
    term:
      id: hgnc:15889
      label: FERMT1
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  downstream:
  - target: Defective Focal Adhesion and Integrin Activation
    description: >
      Loss of kindlin-1 disrupts focal adhesion formation and integrin activation
      at the basal keratinocyte-basement membrane zone interface.
  evidence:
  - reference: PMID:21936020
    reference_title: "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer"
    explanation: Confirms FERMT1 mutations cause Kindler syndrome through loss of the focal adhesion protein kindlin-1.
  - reference: PMID:19945623
    reference_title: "Kindler syndrome pathogenesis and fermitin family homologue 1 (kindlin-1) function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kindler syndrome is caused by genetic defects in the focal contact-associated protein, fermitin family homologue 1 (FFH1), encoded by the gene FERMT1 (known as KIND1)"
    explanation: Confirms FERMT1 encodes the focal contact-associated protein FFH1 (kindlin-1) and its defects cause Kindler syndrome.
- name: Defective Focal Adhesion and Integrin Activation
  description: >
    Kindlin-1 is a FERM domain protein that activates integrin beta1 signaling at
    the basal keratinocyte-basement membrane zone interface. Loss of kindlin-1
    results in reduced active beta1 integrin, altered distribution of basement
    membrane proteins (types IV, VII, and XVII collagens, laminin-332), and
    disruption of hemidesmosomal components. This causes impaired cell-ECM adhesion
    at multiple levels, explaining the mixed-level cleavage characteristic of
    Kindler EB.
  biological_processes:
  - preferred_term: focal adhesion assembly
    modifier: DECREASED
    term:
      id: GO:0048041
      label: focal adhesion assembly
  - preferred_term: integrin-mediated signaling pathway
    modifier: DECREASED
    term:
      id: GO:0007229
      label: integrin-mediated signaling pathway
  - preferred_term: cell-matrix adhesion
    modifier: DECREASED
    term:
      id: GO:0007160
      label: cell-matrix adhesion
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  downstream:
  - target: Impaired Keratinocyte Migration and Wound Healing
    description: >
      Defective integrin activation impairs keratinocyte migration and proliferation,
      leading to delayed wound healing.
  - target: Progressive Poikiloderma and Skin Atrophy
    description: >
      Chronic adhesion defects lead to progressive skin atrophy, telangiectasia,
      and pigmentary changes (poikiloderma).
  evidence:
  - reference: PMID:19762710
    reference_title: "Loss-of-function FERMT1 mutations in kindler syndrome implicate a role for fermitin family homolog-1 in integrin activation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "active beta1 integrin was reduced but overexpression of fermitin family homolog-1 restored integrin activation and partially rescued the Kindler syndrome cellular phenotype"
    explanation: Demonstrates that kindlin-1 deficiency reduces active beta1 integrin and that restoring kindlin-1 rescues integrin activation.
  - reference: PMID:19762710
    reference_title: "Loss-of-function FERMT1 mutations in kindler syndrome implicate a role for fermitin family homolog-1 in integrin activation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified altered distribution of several basement membrane proteins, including types IV, VII, and XVII collagens and laminin-332 in Kindler syndrome skin"
    explanation: Shows disruption of multiple basement membrane components beyond focal adhesions in Kindler syndrome.
  - reference: PMID:19945623
    reference_title: "Kindler syndrome pathogenesis and fermitin family homologue 1 (kindlin-1) function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Defects in FFH1 lead to abnormal integrin activation and loss of keratinocyte epidermal adhesion to the underlying basal lamina, disruption in normal cell cytoskeleton within keratinocytes, and altered signaling pathways"
    explanation: Confirms that kindlin-1 deficiency causes abnormal integrin activation and loss of keratinocyte adhesion.
- name: Impaired Keratinocyte Migration and Wound Healing
  description: >
    Defective integrin activation and cell-matrix adhesion impair keratinocyte
    migration and proliferation, leading to poor wound healing. Loss of kindlin-1
    also disrupts cytoskeletal organization within keratinocytes and reduces
    keratinocyte stem cell markers such as cytokeratin 15.
  biological_processes:
  - preferred_term: wound healing
    modifier: DECREASED
    term:
      id: GO:0042060
      label: wound healing
  - preferred_term: cell migration
    modifier: DECREASED
    term:
      id: GO:0016477
      label: cell migration
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:19762710
    reference_title: "Loss-of-function FERMT1 mutations in kindler syndrome implicate a role for fermitin family homolog-1 in integrin activation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "lack of this protein leads to pathological changes beyond focal adhesions, with disruption of several hemidesmosomal components and reduced expression of keratinocyte stem cell markers"
    explanation: Shows that kindlin-1 loss impairs keratinocyte biology beyond adhesion, including stem cell marker expression, which contributes to impaired wound healing.
- name: Progressive Poikiloderma and Skin Atrophy
  description: >
    Progressive poikiloderma (atrophy, telangiectasia, pigmentary changes) is the
    hallmark feature of Kindler EB. The mechanism involves chronic defective
    keratinocyte adhesion leading to cumulative skin damage. Photosensitivity may
    contribute through oxidative stress in kindlin-1-deficient keratinocytes.
    Skin atrophy is diffuse and progressive, affecting both sun-exposed and
    non-exposed areas.
  biological_processes:
  - preferred_term: response to oxidative stress
    modifier: INCREASED
    term:
      id: GO:0006979
      label: response to oxidative stress
  - preferred_term: epidermis development
    modifier: ABNORMAL
    term:
      id: GO:0008544
      label: epidermis development
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:21936020
    reference_title: "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer"
    explanation: Confirms the progressive nature of poikiloderma and skin atrophy in Kindler syndrome.
  - reference: PMID:19057668
    reference_title: "Loss of Kindlin-1 causes skin atrophy and lethal neonatal intestinal epithelial dysfunction."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "deleting Kindlin-1 in mice gives rise to skin atrophy"
    explanation: Mouse model confirms that kindlin-1 loss directly causes skin atrophy.
- name: Mucosal Involvement
  description: >
    Kindler EB affects mucosal epithelium, causing colitis resembling ulcerative
    colitis, esophageal strictures, urethral stenosis, and oral mucosal fragility
    with hemorrhagic gingivitis and periodontitis. Mucosal manifestations result
    from the same integrin activation defect in epithelial cells lining these
    structures.
  biological_processes:
  - preferred_term: integrin-mediated signaling pathway
    modifier: DECREASED
    term:
      id: GO:0007229
      label: integrin-mediated signaling pathway
  - preferred_term: cell-matrix adhesion
    modifier: DECREASED
    term:
      id: GO:0007160
      label: cell-matrix adhesion
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:19057668
    reference_title: "Loss of Kindlin-1 causes skin atrophy and lethal neonatal intestinal epithelial dysfunction."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "deleting Kindlin-1 in mice gives rise to skin atrophy and an intestinal epithelial dysfunction with similarities to human UC"
    explanation: Mouse model demonstrates that kindlin-1 loss causes intestinal epithelial dysfunction resembling ulcerative colitis.
  - reference: PMID:19057668
    reference_title: "Loss of Kindlin-1 causes skin atrophy and lethal neonatal intestinal epithelial dysfunction."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This intestinal dysfunction results in perinatal lethality and is triggered by defective intestinal epithelial cell integrin activation, leading to detachment of this barrier followed by a destructive inflammatory response"
    explanation: Demonstrates that intestinal involvement is caused by defective integrin activation in epithelial cells.
  - reference: PMID:26937547
    reference_title: "Kindler Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mucosal manifestations are also common and include hemorrhagic mucositis and gingivitis, periodontal disease, premature loss of teeth, and labial leukokeratosis. Other mucosal findings can include ectropion, urethral stenosis, and severe phimosis"
    explanation: GeneReviews confirms the spectrum of mucosal manifestations in Kindler syndrome.
mechanistic_hypotheses:
- hypothesis_group_id: wnt_beta_catenin_scc_model
  hypothesis_label: Wnt/Beta-Catenin Dysregulation Model for SCC Susceptibility
  status: CANONICAL
  description: >
    Loss of kindlin-1 induces nuclear translocation of beta-catenin-Lef1 in
    keratinocytes, leading to elevated Wnt-beta-catenin signaling. This
    dysregulation produces enlarged and hyperactive cutaneous epithelial stem
    cell compartments, resulting in hyperthickened epidermis, ectopic hair
    follicle development, and increased skin tumor susceptibility. Kindlin-1
    normally inhibits Wnt-beta-catenin signaling through integrin-independent
    regulation of Wnt ligand expression, and simultaneously promotes
    TGF-beta-mediated growth-inhibitory signals via alphav-beta6 integrin.
    Loss of this dual control shifts the balance toward unchecked proliferation.
  evidence:
  - reference: PMID:24681597
    reference_title: "Kindlin-1 controls Wnt and TGF-β availability to regulate cutaneous stem cell proliferation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "loss of Kindlin-1 in mouse keratinocytes recapitulates Kindler syndrome and also produces enlarged and hyperactive stem cell compartments, which lead to hyperthickened epidermis, ectopic hair follicle development and increased skin tumor susceptibility"
    explanation: Mouse model demonstrates that kindlin-1 loss leads to stem cell hyperactivation and tumor susceptibility through Wnt pathway dysregulation.
  - reference: PMID:24681597
    reference_title: "Kindlin-1 controls Wnt and TGF-β availability to regulate cutaneous stem cell proliferation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "loss of Kindlin-1 induces nuclear translocation of β-catenin-Lef1 in KS and mouse skin leading to elevated Wnt-β-catenin signaling"
    explanation: Demonstrates the specific mechanism of nuclear beta-catenin-Lef1 translocation in both mouse model and human KS skin.
  - reference: PMID:24681597
    reference_title: "Kindlin-1 controls Wnt and TGF-β availability to regulate cutaneous stem cell proliferation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Kindlin-1 controls keratinocyte adhesion through β1-class integrins and proliferation and differentiation of cutaneous epithelial stem cells by promoting α(v)β(6) integrin-mediated transforming growth factor-β (TGF-β) activation and inhibiting Wnt-β-catenin signaling through integrin-independent regulation of Wnt ligand expression"
    explanation: Defines the dual mechanism by which kindlin-1 normally suppresses tumorigenesis through TGF-beta activation and Wnt inhibition.
- hypothesis_group_id: oxidative_stress_photosensitivity_model
  hypothesis_label: Oxidative Stress and Impaired ERK Signaling Model for Photosensitivity
  status: CANONICAL
  description: >
    Kindlin-1-deficient keratinocytes have higher baseline levels of reactive
    oxygen species (ROS) and show decreased viability and increased DNA damage
    after oxidative stress (H2O2 or UVA irradiation). Kindlin-1 is required
    for full activation of ERK signaling after oxidative damage, and ERK
    activation protects cells from DNA damage. This integrin-dependent
    mechanism explains the photosensitivity characteristic of Kindler syndrome
    and may contribute to the predisposition to aggressive squamous cell
    carcinoma through accumulation of UV-induced DNA damage.
  evidence:
  - reference: PMID:28501563
    reference_title: "Kindlin-1 protects cells from oxidative damage through activation of ERK signalling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "loss of Kindlin-1 sensitizes both SCC cells and keratinocytes to oxidative stress: Kindlin-1 deficient cells have higher levels of reactive oxygen species, decreased viability and increased DNA damage after treatment with either hydrogen peroxide (H2O2) or irradiation with UVA"
    explanation: Demonstrates that kindlin-1-deficient cells have elevated ROS and increased susceptibility to oxidative DNA damage.
  - reference: PMID:28501563
    reference_title: "Kindlin-1 protects cells from oxidative damage through activation of ERK signalling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Kindlin-1 is required to fully activate ERK signalling after oxidative damage, and that activation of ERK protects cells from DNA damage following oxidative stress"
    explanation: Identifies impaired ERK signaling as the molecular mechanism linking kindlin-1 loss to oxidative stress vulnerability.
  - reference: PMID:28501563
    reference_title: "Kindlin-1 protects cells from oxidative damage through activation of ERK signalling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Kindlin-1 dependent activation of ERK signalling is a key molecular mechanism that renders KS keratinocytes more sensitive to oxidative damage and contributes to the increased photosensitivity in KS patients"
    explanation: Directly proposes this mechanism as the basis for photosensitivity in Kindler syndrome patients.
phenotypes:
- category: Integument
  name: Skin Blistering
  description: >
    Acral skin blistering beginning at birth, caused by mixed-level cleavage at
    the dermal-epidermal junction. Blistering typically improves with age but is
    the presenting feature in neonates and infants.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: skin blistering
    term:
      id: HP:0008066
      label: Abnormal blistering of the skin
  evidence:
  - reference: PMID:26937547
    reference_title: "Kindler Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by skin fragility and acral blister formation beginning at birth"
    explanation: GeneReviews confirms acral blistering from birth as a cardinal feature.
  - reference: PMID:21936020
    reference_title: "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer"
    explanation: Confirms skin blistering as a key component of the Kindler syndrome phenotype.
- category: Integument
  name: Poikiloderma
  description: >
    Progressive poikiloderma is the hallmark feature of Kindler EB, characterized
    by reticulated hypopigmentation and hyperpigmentation, epidermal atrophy, and
    telangiectasia. Becomes increasingly prominent from childhood through adulthood.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: poikiloderma
    term:
      id: HP:0001029
      label: Poikiloderma
  evidence:
  - reference: PMID:21936020
    reference_title: "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive poikiloderma with extensive skin atrophy"
    explanation: Confirms progressive poikiloderma as a defining feature.
  - reference: PMID:19945623
    reference_title: "Kindler syndrome pathogenesis and fermitin family homologue 1 (kindlin-1) function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Null mutations in FERMT1 result in skin blistering from birth and early childhood progressive poikiloderma, mucosal fragility, and increased risk of cancer"
    explanation: Confirms progressive poikiloderma beginning in early childhood.
- category: Integument
  name: Cutaneous Photosensitivity
  description: >
    Photosensitivity is most prominent during childhood and typically improves
    with age, usually decreasing after adolescence. The mechanism involves
    increased oxidative stress in kindlin-1-deficient keratinocytes, which have
    higher baseline levels of reactive oxygen species and impaired ERK signaling
    after UV exposure, leading to increased DNA damage. The age-related
    improvement may reflect adaptive changes in skin physiology or behavioral
    sun avoidance.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: cutaneous photosensitivity
    term:
      id: HP:0000992
      label: Cutaneous photosensitivity
  evidence:
  - reference: PMID:26937547
    reference_title: "Kindler Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "photosensitivity (most prominent during childhood and usually decreasing after adolescence)"
    explanation: GeneReviews confirms photosensitivity pattern in Kindler syndrome.
  - reference: PMID:21936020
    reference_title: "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy"
    explanation: Confirms photosensitivity as part of the progressive phenotype.
  - reference: PMID:28501563
    reference_title: "Kindlin-1 protects cells from oxidative damage through activation of ERK signalling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Kindlin-1 deficient cells have higher levels of reactive oxygen species, decreased viability and increased DNA damage after treatment with either hydrogen peroxide (H2O2) or irradiation with UVA"
    explanation: Demonstrates the molecular basis of photosensitivity through elevated ROS and increased DNA damage in kindlin-1-deficient cells after UVA exposure.
  - reference: PMID:28501563
    reference_title: "Kindlin-1 protects cells from oxidative damage through activation of ERK signalling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Kindlin-1 dependent activation of ERK signalling is a key molecular mechanism that renders KS keratinocytes more sensitive to oxidative damage and contributes to the increased photosensitivity in KS patients"
    explanation: Proposes impaired ERK signaling as the mechanism underlying photosensitivity in Kindler syndrome.
- category: Integument
  name: Progressive Skin Atrophy
  description: >
    Diffuse cutaneous atrophy is a progressive and prominent feature, resulting
    from chronic defective keratinocyte adhesion and integrin activation defects.
    Skin becomes thin and fragile over time.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: diffuse cutaneous atrophy
    term:
      id: HP:0004334
      label: Dermal atrophy
  evidence:
  - reference: PMID:26937547
    reference_title: "Kindler Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "diffuse cutaneous atrophy"
    explanation: GeneReviews lists diffuse cutaneous atrophy as a key clinical characteristic.
  - reference: PMID:19057668
    reference_title: "Loss of Kindlin-1 causes skin atrophy and lethal neonatal intestinal epithelial dysfunction."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "deleting Kindlin-1 in mice gives rise to skin atrophy"
    explanation: Mouse model confirms kindlin-1 loss directly causes skin atrophy.
- category: Integument
  name: Palmoplantar Keratoderma
  description: >
    Diffuse palmoplantar hyperkeratosis is a common feature, contributing to
    hand and foot dysfunction.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  evidence:
  - reference: PMID:26937547
    reference_title: "Kindler Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "diffuse palmoplantar hyperkeratosis"
    explanation: GeneReviews confirms palmoplantar hyperkeratosis as a feature of Kindler syndrome.
- category: Integument
  name: Nail Dystrophy
  description: >
    Nail changes including dystrophy are observed in Kindler syndrome patients,
    reflecting the broader integumentary involvement.
  frequency: FREQUENT
  notes: >
    Nail dystrophy is reported in Kindler syndrome case series but specific
    abstract-level evidence is limited.
  phenotype_term:
    preferred_term: nail dystrophy
    term:
      id: HP:0008404
      label: Nail dystrophy
- category: Digestive
  name: Colitis
  description: >
    Colitis resembling ulcerative colitis occurs in Kindler syndrome patients,
    caused by defective intestinal epithelial cell integrin activation leading to
    epithelial detachment and inflammatory response.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: colitis
    term:
      id: HP:0002583
      label: Colitis
  evidence:
  - reference: PMID:19057668
    reference_title: "Loss of Kindlin-1 causes skin atrophy and lethal neonatal intestinal epithelial dysfunction."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "a few KS patients have been reported to also develop ulcerative colitis (UC), a causal link to the FERMT1 gene mutation is unknown"
    explanation: Notes that some Kindler syndrome patients develop ulcerative colitis.
  - reference: PMID:19057668
    reference_title: "Loss of Kindlin-1 causes skin atrophy and lethal neonatal intestinal epithelial dysfunction."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "deleting Kindlin-1 in mice gives rise to skin atrophy and an intestinal epithelial dysfunction with similarities to human UC"
    explanation: Mouse model provides causal evidence linking kindlin-1 loss to colitis-like intestinal dysfunction.
- category: Digestive
  name: Esophageal Stenosis
  description: >
    Mucosal strictures of the esophagus can develop as a severe long-term
    complication, resulting from mucosal fragility and scarring.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: esophageal stricture
    term:
      id: HP:0002043
      label: Esophageal stricture
  evidence:
  - reference: PMID:26937547
    reference_title: "Kindler Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe long-term complications of KS include periodontitis, mucosal strictures, and aggressive squamous cell carcinomas"
    explanation: GeneReviews identifies mucosal strictures as a severe long-term complication.
- category: Genitourinary
  name: Urethral Stenosis
  description: >
    Urethral stenosis can occur as part of the mucosal involvement in Kindler
    syndrome, caused by mucosal fragility and scarring.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: urethral stenosis
    term:
      id: HP:0008661
      label: Urethral stenosis
  evidence:
  - reference: PMID:26937547
    reference_title: "Kindler Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other mucosal findings can include ectropion, urethral stenosis, and severe phimosis"
    explanation: GeneReviews lists urethral stenosis as a mucosal manifestation.
- category: Head and Neck
  name: Periodontal Disease
  description: >
    Periodontal disease including periodontitis and gingivitis is a common and
    significant complication of Kindler syndrome. Hemorrhagic mucositis of the oral
    cavity, premature loss of teeth, and labial leukokeratosis are also observed.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: periodontitis
    term:
      id: HP:0000704
      label: Periodontitis
  evidence:
  - reference: PMID:26937547
    reference_title: "Kindler Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mucosal manifestations are also common and include hemorrhagic mucositis and gingivitis, periodontal disease, premature loss of teeth"
    explanation: GeneReviews confirms periodontal disease as a common mucosal manifestation.
  - reference: PMID:26937547
    reference_title: "Kindler Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe long-term complications of KS include periodontitis, mucosal strictures, and aggressive squamous cell carcinomas"
    explanation: Confirms periodontitis as a severe long-term complication.
- category: Neoplasm
  name: Squamous Cell Carcinoma Risk
  description: >
    Patients with Kindler syndrome have a markedly elevated risk of developing
    aggressive squamous cell carcinomas. In a retrospective study of 91 adult KS
    patients, SCC developed in 13 (14.3%), with cumulative risk reaching 66.7% in
    patients over 60 years of age. SCCs in KS are highly aggressive, with 53.8%
    developing metastatic disease and 38.5% of SCC-bearing patients dying from the
    tumor. Tumors concentrate in the hands and around the oral cavity, areas of
    chronic inflammation. Screening should begin in adolescence and continue
    annually.
  frequency: FREQUENT
  notes: >
    14.3% of adult KS patients develop SCC, with cumulative risk reaching 66.7%
    in patients over 60 years. SCCs are highly aggressive with 53.8% developing
    metastatic disease.
  phenotype_term:
    preferred_term: squamous cell carcinoma
    term:
      id: HP:0002860
      label: Squamous cell carcinoma
  evidence:
  - reference: PMID:21936020
    reference_title: "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "propensity to skin cancer"
    explanation: Confirms increased skin cancer risk in Kindler syndrome.
  - reference: PMID:26937547
    reference_title: "Kindler Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe long-term complications of KS include periodontitis, mucosal strictures, and aggressive squamous cell carcinomas"
    explanation: GeneReviews identifies aggressive SCCs as a severe long-term complication.
  - reference: PMID:31340837
    reference_title: "Assessment of the risk and characterization of non-melanoma skin cancer in Kindler syndrome: study of a series of 91 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SCC developed in 13 of the 91 patients"
    explanation: Largest systematic study of SCC in KS quantifies the frequency at 14.3% of adult patients in this cohort.
  - reference: PMID:31340837
    reference_title: "Assessment of the risk and characterization of non-melanoma skin cancer in Kindler syndrome: study of a series of 91 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the cumulative risk of SCC increased to 66.7% in patients over 60 years of age"
    explanation: Demonstrates that cumulative SCC risk increases dramatically with age, reaching two-thirds by age 60.
  - reference: PMID:31340837
    reference_title: "Assessment of the risk and characterization of non-melanoma skin cancer in Kindler syndrome: study of a series of 91 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "53.8% of the patients bearing SCCs develop metastatic disease"
    explanation: Confirms the highly aggressive nature of SCCs in KS with majority developing metastases.
treatments:
- name: Wound Care and Skin Protection
  description: >
    Standard blister care with use of moisturizers and protection from mechanical
    trauma. Multidisciplinary management by a team experienced in skin fragility
    disorders is recommended.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:26937547
    reference_title: "Kindler Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin care includes standard blister care, use of moisturizers, and protection from trauma and the sun"
    explanation: GeneReviews describes wound care and skin protection as key management strategies.
- name: Photoprotection
  description: >
    Sun avoidance and sunscreen use to reduce photosensitivity-related skin damage.
    Sun exposure is listed as an agent to avoid.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:26937547
    reference_title: "Kindler Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Agents/circumstances to avoid: Sun exposure"
    explanation: GeneReviews explicitly recommends avoiding sun exposure.
- name: Gastrointestinal Management
  description: >
    Management of gastrointestinal complications including colitis and esophageal
    strictures. Gastroenterology input is part of the multidisciplinary team.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:26937547
    reference_title: "Kindler Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "management of gastrointestinal and urethral complications"
    explanation: GeneReviews includes GI management as part of treatment.
- name: Dental Care
  description: >
    Regular dental care to ensure optimal oral hygiene and reduce periodontal
    disease. Screening for oral ulcerations, gingivitis, and periodontitis starting
    in adolescence with regular dental checkups.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:26937547
    reference_title: "Kindler Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "regular dental care to ensure optimal oral hygiene to reduce periodontal disease"
    explanation: GeneReviews recommends regular dental care for periodontal disease prevention.
- name: Squamous Cell Carcinoma Surveillance
  description: >
    Screening for premalignant keratoses and early squamous cell carcinomas starting
    in adolescence and repeated annually.
  treatment_term:
    preferred_term: cancer screening
    term:
      id: MAXO:0000126
      label: cancer screening
  evidence:
  - reference: PMID:26937547
    reference_title: "Kindler Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Screening for premalignant keratoses and early squamous cell carcinomas starting in adolescence and repeated annually"
    explanation: GeneReviews recommends annual SCC screening starting in adolescence.
- name: Genetic Counseling
  description: >
    Kindler syndrome is inherited in an autosomal recessive manner. Carrier testing
    for at-risk relatives, prenatal testing, and preimplantation genetic testing are
    possible once FERMT1 pathogenic variants have been identified.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:26937547
    reference_title: "Kindler Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an FERMT1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected"
    explanation: GeneReviews confirms autosomal recessive inheritance and recommends genetic counseling.
clinical_trials:
- name: NCT04908215
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Completed phase II randomized trial of topical INM-755 (cannabinol) cream
    across multiple epidermolysis bullosa subtypes, including Kindler syndrome,
    to evaluate wound healing and symptom control.
  target_phenotypes:
  - preferred_term: Wound healing impairment
    term:
      id: HP:0001058
      label: Poor wound healing
  evidence:
  - reference: clinicaltrials:NCT04908215
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The purpose of this study is to evaluate the safety of INM-755 (cannabinol) cream and obtain preliminary evidence of efficacy in treating symptoms and healing wounds over a 28-day period in patients with epidermolysis bullosa (EB)."
    explanation: This ClinicalTrials.gov record supports a completed EB-enrollment trial of topical cannabinol cream relevant to Kindler syndrome because the current study condition list includes Kindler syndrome.
genetic:
- name: FERMT1
  association: Causative
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:26937547
      reference_title: "Kindler Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "KS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an FERMT1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected"
      explanation: GeneReviews confirms autosomal recessive inheritance for FERMT1.
  notes: >
    FERMT1 (also known as KIND1) encodes kindlin-1 (fermitin family homolog-1),
    a focal adhesion protein that activates integrins. Located on chromosome
    20p12.3. Mutations include gross genomic deletions, splice site, nonsense,
    frameshift, and missense mutations. Missense and in-frame deletion mutations
    are associated with milder phenotypes and later onset of complications.
  evidence:
  - reference: PMID:26937547
    reference_title: "Kindler Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of KS is established in a proband with suggestive clinical findings and biallelic pathogenic variants in FERMT1 identified by molecular genetic testing"
    explanation: GeneReviews confirms biallelic FERMT1 variants as the molecular basis of Kindler syndrome.
  - reference: PMID:21936020
    reference_title: "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although most mutations are predicted to lead to premature termination of translation, and to loss of kindlin-1 function, significant clinical variability is observed among patients"
    explanation: Confirms that most FERMT1 mutations are loss-of-function with variable clinical expression.
  - reference: PMID:19762710
    reference_title: "Loss-of-function FERMT1 mutations in kindler syndrome implicate a role for fermitin family homolog-1 in integrin activation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It results from loss-of-function mutations in the FERMT1 gene encoding the focal adhesion protein, fermitin family homolog-1"
    explanation: Confirms FERMT1 loss-of-function mutations cause Kindler syndrome.
datasets:
- accession: geo:GSE47642
  title: Kindler syndrome microarray study
  description: >-
    Human skin-biopsy microarray dataset comparing Kindler syndrome and control
    samples to define transcriptional changes associated with FERMT1 deficiency.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 6
  conditions:
  - Kindler syndrome skin biopsies
  - normal human skin biopsies
  publication: PMID:24681597
  evidence:
  - reference: GEO:GSE47642
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characterization of gene expression profile of normal human and Kindler Syndrome (KS) patients skin biopsies samples"
    explanation: Confirms the dataset contains direct human tissue expression profiles from Kindler syndrome and control skin.
  - reference: GEO:GSE47642
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "to extend the knowledge of transcriptional changes in the Kindler syndrome disease."
    explanation: Supports this dataset as a disease-relevant transcriptomic resource for Kindler EB.
references:
- reference: PMID:26937547
  title: "Kindler Syndrome."
  tags:
  - GeneReviews
  findings:
  - statement: Youssefian L(1), Vahidnezhad H(1), Uitto J(1).
    supporting_text: Youssefian L(1), Vahidnezhad H(1), Uitto J(1).
    evidence:
    - reference: PMID:26937547
      reference_title: Kindler Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Youssefian L(1), Vahidnezhad H(1), Uitto J(1).
      explanation: Deep research cited this publication as relevant literature for Kindler Epidermolysis Bullosa.
  found_in:
  - Kindler_Epidermolysis_Bullosa-deep-research-falcon.md
- reference: DOI:10.1016/j.det.2009.10.016
  title: Animal Models of Epidermolysis Bullosa
  found_in:
  - Kindler_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Animal Models of Epidermolysis Bullosa
    supporting_text: Animal Models of Epidermolysis Bullosa
- reference: DOI:10.1038/s41389-024-00526-1
  title: Involvement of Kindlin-1 in cutaneous squamous cell carcinoma
  found_in:
  - Kindler_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Kindler syndrome (KS) is a rare genodermatosis resulting from loss-of-function mutations in FERMT1, the gene that encodes Kindlin-1.
    supporting_text: Kindler syndrome (KS) is a rare genodermatosis resulting from loss-of-function mutations in FERMT1, the gene that encodes Kindlin-1.
    evidence:
    - reference: DOI:10.1038/s41389-024-00526-1
      reference_title: Involvement of Kindlin-1 in cutaneous squamous cell carcinoma
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Kindler syndrome (KS) is a rare genodermatosis resulting from loss-of-function mutations in FERMT1, the gene that encodes Kindlin-1.
      explanation: Deep research cited this publication as relevant literature for Kindler Epidermolysis Bullosa.
- reference: DOI:10.1111/bjd.18921
  title: Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility
  found_in:
  - Kindler_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility
    supporting_text: Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility
- reference: DOI:10.1159/000320235
  title: Mild Clinical Phenotype of Kindler Syndrome Associated with Late Diagnosis and Skin Cancer
  found_in:
  - Kindler_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Kindler syndrome (KS) is a heritable skin disorder with a complex phenotype consisting of congenital skin blistering, photosensitivity, progressive generalized poikiloderma and extensive skin atrophy.
    supporting_text: Kindler syndrome (KS) is a heritable skin disorder with a complex phenotype consisting of congenital skin blistering, photosensitivity, progressive generalized poikiloderma and extensive skin atrophy.
    evidence:
    - reference: DOI:10.1159/000320235
      reference_title: Mild Clinical Phenotype of Kindler Syndrome Associated with Late Diagnosis and Skin Cancer
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Kindler syndrome (KS) is a heritable skin disorder with a complex phenotype consisting of congenital skin blistering, photosensitivity, progressive generalized poikiloderma and extensive skin atrophy.
      explanation: Deep research cited this publication as relevant literature for Kindler Epidermolysis Bullosa.
- reference: DOI:10.15690/vsp.v23i5.2808
  title: Congenital Epidermolysis Bullosa Epidemiology among Children of Russian Federation
  found_in:
  - Kindler_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: The prevalence of all types of congenital epidermolysis bullosa (СEB) worldwide is approximately 11 cases per 1 million according to the latest data from the American Epidermolysis Bullosa Registry.
    supporting_text: The prevalence of all types of congenital epidermolysis bullosa (СEB) worldwide is approximately 11 cases per 1 million according to the latest data from the American Epidermolysis Bullosa Registry.
    evidence:
    - reference: DOI:10.15690/vsp.v23i5.2808
      reference_title: Congenital Epidermolysis Bullosa Epidemiology among Children of Russian Federation
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The prevalence of all types of congenital epidermolysis bullosa (СEB) worldwide is approximately 11 cases per 1 million according to the latest data from the American Epidermolysis Bullosa Registry.
      explanation: Deep research cited this publication as relevant literature for Kindler Epidermolysis Bullosa.
- reference: DOI:10.3389/fped.2024.1425030
  title: Identification of a novel FERMT1 variant causing kindler syndrome and a review of the clinical and molecular genetic features in Chinese patients
  found_in:
  - Kindler_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: 'Kindler Syndrome (KS, OMIM #173650), a rare autosomal recessive genetic disorder, is characterized by a spectrum of symptoms such as cutaneous fragility, blistering, photosensitivity, and mucosal involvement.'
    supporting_text: 'Kindler Syndrome (KS, OMIM #173650), a rare autosomal recessive genetic disorder, is characterized by a spectrum of symptoms such as cutaneous fragility, blistering, photosensitivity, and mucosal involvement.'
    evidence:
    - reference: DOI:10.3389/fped.2024.1425030
      reference_title: Identification of a novel FERMT1 variant causing kindler syndrome and a review of the clinical and molecular genetic features in Chinese patients
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: 'Kindler Syndrome (KS, OMIM #173650), a rare autosomal recessive genetic disorder, is characterized by a spectrum of symptoms such as cutaneous fragility, blistering, photosensitivity, and mucosal involvement.'
      explanation: Deep research cited this publication as relevant literature for Kindler Epidermolysis Bullosa.
- reference: DOI:10.3389/froh.2024.1430698
  title: 'Unusual oral manifestation of Kindler syndrome: a case report and review of literature'
  found_in:
  - Kindler_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: 'Unusual oral manifestation of Kindler syndrome: a case report and review of literature'
    supporting_text: Kindler syndrome (KS) is a rare autosomal recessive genodermatosis characterized by congenital acral blistering, that typically presents in infancy and is followed by the development of characteristic poikilodermatous pigmentation and photosensitivity in later life.
    evidence:
    - reference: DOI:10.3389/froh.2024.1430698
      reference_title: 'Unusual oral manifestation of Kindler syndrome: a case report and review of literature'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Kindler syndrome (KS) is a rare autosomal recessive genodermatosis characterized by congenital acral blistering, that typically presents in infancy and is followed by the development of characteristic poikilodermatous pigmentation and photosensitivity in later life.
      explanation: Deep research cited this publication as relevant literature for Kindler Epidermolysis Bullosa.
- reference: DOI:10.3390/ijms26094237
  title: A Novel Homozygous 9385 bp Deletion in the FERMT1 (KIND1) Gene in a Malaysian Family with Kindler Epidermolysis bullosa and a Review of Large Deletions
  found_in:
  - Kindler_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Kindler Epidermolysis bullosa (KEB; OMIM 173650) is a rare autosomal recessive genodermatosis characterized by bullous poikiloderma and photosensitivity.
    supporting_text: Kindler Epidermolysis bullosa (KEB; OMIM 173650) is a rare autosomal recessive genodermatosis characterized by bullous poikiloderma and photosensitivity.
    evidence:
    - reference: DOI:10.3390/ijms26094237
      reference_title: A Novel Homozygous 9385 bp Deletion in the FERMT1 (KIND1) Gene in a Malaysian Family with Kindler Epidermolysis bullosa and a Review of Large Deletions
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Kindler Epidermolysis bullosa (KEB; OMIM 173650) is a rare autosomal recessive genodermatosis characterized by bullous poikiloderma and photosensitivity.
      explanation: Deep research cited this publication as relevant literature for Kindler Epidermolysis Bullosa.
- reference: DOI:10.3390/jcm13133742
  title: Epidemiological Characteristics of Inherited Epidermolysis Bullosa in an Eastern European Population
  found_in:
  - Kindler_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Epidermolysis bullosa (EB) is a hereditary condition characterized by skin and mucosal fragility, with various degrees of severity.
    supporting_text: Epidermolysis bullosa (EB) is a hereditary condition characterized by skin and mucosal fragility, with various degrees of severity.
    evidence:
    - reference: DOI:10.3390/jcm13133742
      reference_title: Epidemiological Characteristics of Inherited Epidermolysis Bullosa in an Eastern European Population
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Epidermolysis bullosa (EB) is a hereditary condition characterized by skin and mucosal fragility, with various degrees of severity.
      explanation: Deep research cited this publication as relevant literature for Kindler Epidermolysis Bullosa.
- reference: DOI:10.1002/humu.21576
  title: 'Kindler syndrome: Extension of FERMT1 mutational spectrum and natural history'
  found_in:
  - Kindler_Epidermolysis_Bullosa-deep-research-falcon.md
  findings: []
- reference: DOI:10.1007/978-3-662-45698-9_43
  title: Kindler Syndrome
  found_in:
  - Kindler_Epidermolysis_Bullosa-deep-research-falcon.md
  findings: []
- reference: DOI:10.1007/s13312-018-1239-y
  title: Kindler Syndrome
  found_in:
  - Kindler_Epidermolysis_Bullosa-deep-research-falcon.md
  findings: []
- reference: DOI:10.1016/j.det.2009.10.012
  title: Kindler Syndrome Pathogenesis and Fermitin Family Homologue 1 (Kindlin-1) Function
  found_in:
  - Kindler_Epidermolysis_Bullosa-deep-research-falcon.md
  findings: []
- reference: DOI:10.1016/j.det.2009.10.013
  title: Kindler Syndrome
  found_in:
  - Kindler_Epidermolysis_Bullosa-deep-research-falcon.md
  findings: []
- reference: DOI:10.1177/2050313x241231518
  title: 'Battling a rarity: A case of kindler syndrome from a developing country'
  found_in:
  - Kindler_Epidermolysis_Bullosa-deep-research-falcon.md
  findings: []
- reference: DOI:10.1186/s13023-019-1158-6
  title: 'Assessment of the risk and characterization of non-melanoma skin cancer in Kindler syndrome: study of a series of 91 patients'
  found_in:
  - Kindler_Epidermolysis_Bullosa-deep-research-falcon.md
  findings: []
- reference: DOI:10.1371/journal.pgen.1000289
  title: Loss of Kindlin-1 Causes Skin Atrophy and Lethal Neonatal Intestinal Epithelial Dysfunction
  found_in:
  - Kindler_Epidermolysis_Bullosa-deep-research-falcon.md
  findings: []

📚

References & Deep Research

References

PMID:26937547

Kindler Syndrome.

1 finding

Youssefian L(1), Vahidnezhad H(1), Uitto J(1).

"Youssefian L(1), Vahidnezhad H(1), Uitto J(1)."

Show evidence (1 reference)

PMID:26937547 SUPPORT Human Clinical

"Youssefian L(1), Vahidnezhad H(1), Uitto J(1)."

Deep research cited this publication as relevant literature for Kindler Epidermolysis Bullosa.

DOI:10.1016/j.det.2009.10.016

Animal Models of Epidermolysis Bullosa

1 finding

Animal Models of Epidermolysis Bullosa

"Animal Models of Epidermolysis Bullosa"

DOI:10.1038/s41389-024-00526-1

Involvement of Kindlin-1 in cutaneous squamous cell carcinoma

1 finding

Kindler syndrome (KS) is a rare genodermatosis resulting from loss-of-function mutations in FERMT1, the gene that encodes Kindlin-1.

"Kindler syndrome (KS) is a rare genodermatosis resulting from loss-of-function mutations in FERMT1, the gene that encodes Kindlin-1."

Show evidence (1 reference)

DOI:10.1038/s41389-024-00526-1 SUPPORT Human Clinical

"Kindler syndrome (KS) is a rare genodermatosis resulting from loss-of-function mutations in FERMT1, the gene that encodes Kindlin-1."

Deep research cited this publication as relevant literature for Kindler Epidermolysis Bullosa.

DOI:10.1111/bjd.18921

Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility

1 finding

Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility

"Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility"

DOI:10.1159/000320235

Mild Clinical Phenotype of Kindler Syndrome Associated with Late Diagnosis and Skin Cancer

1 finding

Kindler syndrome (KS) is a heritable skin disorder with a complex phenotype consisting of congenital skin blistering, photosensitivity, progressive generalized poikiloderma and extensive skin atrophy.

"Kindler syndrome (KS) is a heritable skin disorder with a complex phenotype consisting of congenital skin blistering, photosensitivity, progressive generalized poikiloderma and extensive skin atrophy."

Show evidence (1 reference)

DOI:10.1159/000320235 SUPPORT Human Clinical

Deep research cited this publication as relevant literature for Kindler Epidermolysis Bullosa.

DOI:10.15690/vsp.v23i5.2808

Congenital Epidermolysis Bullosa Epidemiology among Children of Russian Federation

1 finding

The prevalence of all types of congenital epidermolysis bullosa (СEB) worldwide is approximately 11 cases per 1 million according to the latest data from the American Epidermolysis Bullosa Registry.

"The prevalence of all types of congenital epidermolysis bullosa (СEB) worldwide is approximately 11 cases per 1 million according to the latest data from the American Epidermolysis Bullosa Registry."

Show evidence (1 reference)

DOI:10.15690/vsp.v23i5.2808 SUPPORT Human Clinical

Deep research cited this publication as relevant literature for Kindler Epidermolysis Bullosa.

DOI:10.3389/fped.2024.1425030

Identification of a novel FERMT1 variant causing kindler syndrome and a review of the clinical and molecular genetic features in Chinese patients

1 finding

Kindler Syndrome (KS, OMIM #173650), a rare autosomal recessive genetic disorder, is characterized by a spectrum of symptoms such as cutaneous fragility, blistering, photosensitivity, and mucosal involvement.

"Kindler Syndrome (KS, OMIM #173650), a rare autosomal recessive genetic disorder, is characterized by a spectrum of symptoms such as cutaneous fragility, blistering, photosensitivity, and mucosal involvement."

Show evidence (1 reference)

DOI:10.3389/fped.2024.1425030 SUPPORT Computational

Deep research cited this publication as relevant literature for Kindler Epidermolysis Bullosa.

DOI:10.3389/froh.2024.1430698

Unusual oral manifestation of Kindler syndrome: a case report and review of literature

1 finding

Unusual oral manifestation of Kindler syndrome: a case report and review of literature

"Kindler syndrome (KS) is a rare autosomal recessive genodermatosis characterized by congenital acral blistering, that typically presents in infancy and is followed by the development of characteristic poikilodermatous pigmentation and photosensitivity in later life."

Show evidence (1 reference)

DOI:10.3389/froh.2024.1430698 SUPPORT Human Clinical

Deep research cited this publication as relevant literature for Kindler Epidermolysis Bullosa.

DOI:10.3390/ijms26094237

A Novel Homozygous 9385 bp Deletion in the FERMT1 (KIND1) Gene in a Malaysian Family with Kindler Epidermolysis bullosa and a Review of Large Deletions

1 finding

Kindler Epidermolysis bullosa (KEB; OMIM 173650) is a rare autosomal recessive genodermatosis characterized by bullous poikiloderma and photosensitivity.

"Kindler Epidermolysis bullosa (KEB; OMIM 173650) is a rare autosomal recessive genodermatosis characterized by bullous poikiloderma and photosensitivity."

Show evidence (1 reference)

DOI:10.3390/ijms26094237 SUPPORT Human Clinical

"Kindler Epidermolysis bullosa (KEB; OMIM 173650) is a rare autosomal recessive genodermatosis characterized by bullous poikiloderma and photosensitivity."

Deep research cited this publication as relevant literature for Kindler Epidermolysis Bullosa.

DOI:10.3390/jcm13133742

Epidemiological Characteristics of Inherited Epidermolysis Bullosa in an Eastern European Population

1 finding

Epidermolysis bullosa (EB) is a hereditary condition characterized by skin and mucosal fragility, with various degrees of severity.

"Epidermolysis bullosa (EB) is a hereditary condition characterized by skin and mucosal fragility, with various degrees of severity."

Show evidence (1 reference)

DOI:10.3390/jcm13133742 SUPPORT Human Clinical

"Epidermolysis bullosa (EB) is a hereditary condition characterized by skin and mucosal fragility, with various degrees of severity."

Deep research cited this publication as relevant literature for Kindler Epidermolysis Bullosa.

DOI:10.1002/humu.21576

Kindler syndrome: Extension of FERMT1 mutational spectrum and natural history

No top-level findings curated for this source.

DOI:10.1007/978-3-662-45698-9_43

Kindler Syndrome

No top-level findings curated for this source.

DOI:10.1007/s13312-018-1239-y

Kindler Syndrome

No top-level findings curated for this source.

DOI:10.1016/j.det.2009.10.012

Kindler Syndrome Pathogenesis and Fermitin Family Homologue 1 (Kindlin-1) Function

No top-level findings curated for this source.

DOI:10.1016/j.det.2009.10.013

Kindler Syndrome

No top-level findings curated for this source.

DOI:10.1177/2050313x241231518

Battling a rarity: A case of kindler syndrome from a developing country

No top-level findings curated for this source.

DOI:10.1186/s13023-019-1158-6

Assessment of the risk and characterization of non-melanoma skin cancer in Kindler syndrome: study of a series of 91 patients

No top-level findings curated for this source.

DOI:10.1371/journal.pgen.1000289

Loss of Kindlin-1 Causes Skin Atrophy and Lethal Neonatal Intestinal Epithelial Dysfunction

No top-level findings curated for this source.

Deep Research

Falcon ▸

1. Disease Information

Edison Scientific Literature 54 citations 2026-05-09T23:16:53.313773

1. Disease Information

1.1 What is the disease? (concise overview)

Kindler syndrome/KEB is a distinct subtype of inherited epidermolysis bullosa characterized by skin fragility with blistering, photosensitivity, and progressive poikiloderma and atrophy, often accompanied by mucosal inflammation and fibrotic stenoses; it is caused by loss-of-function FERMT1 variants leading to kindlin‑1 deficiency. (laicheong2010kindlersyndrome. pages 3-5, laicheong2015kindlersyndrome pages 5-7, has2010mildclinicalphenotype pages 1-1)

1.2 Key identifiers and codes

OMIM disease: Kindler syndrome / Kindler epidermolysis bullosa: OMIM 173650 (explicitly stated in a peer-reviewed KS case report). (has2010mildclinicalphenotype pages 1-1)
Other identifiers (Orphanet ORPHA, ICD‑10/ICD‑11, MeSH, MONDO): Not extractable from the currently retrieved full-text set using available tools; these codes typically require direct database queries to OMIM/Orphanet/ICD/MeSH/MONDO services, which are not available in the current toolset. (has2010mildclinicalphenotype pages 1-1)

1.3 Synonyms and alternative names

Kindler syndrome (KS)
Kindler epidermolysis bullosa (KEB) (klausegger2025anovelhomozygous pages 12-13, has2020consensusreclassificationof pages 1-2)
Historic/legacy: “congenital poikiloderma with traumatic bulla formation and progressive cutaneous atrophy” (1954 description) (dsouza2010kindlersyndromepathogenesis pages 3-4)

1.4 Evidence source type

Most disease-level statements (inheritance, gene, canonical features, complications) are derived from aggregated disease resources and cohorts (e.g., consensus reclassification; multicenter cohorts) and complemented by case reports documenting phenotypic variability and resource-limited diagnostic pathways. (has2020consensusreclassificationof pages 1-2, guerreroaspizua2019assessmentofthe pages 1-2, ahmed2024battlingararity pages 4-5)

2. Etiology

2.1 Disease causal factors

Primary cause (genetic): autosomal recessive, bi-allelic FERMT1 pathogenic variants leading to loss or dysfunction of kindlin‑1. (laicheong2015kindlersyndrome pages 5-7, has2010mildclinicalphenotype pages 1-1, has2011kindlersyndromeextension pages 1-3)

Mechanistic cause: kindlin‑1 is a focal-adhesion/integrin-associated adaptor; deficiency impairs integrin activation and epithelial cell adhesion/migration, leading to mechanical fragility and abnormal dermal–epidermal junction integrity. (bhandary2024unusualoralmanifestation pages 1-2, dsouza2010kindlersyndromepathogenesis pages 1-3)

2.2 Risk factors

Genetic risk factors (causal variants): - Variant spectrum includes nonsense, frameshift, splice-site, missense, promoter changes, and large deletions; most are predicted to cause premature termination and kindlin‑1 loss. (klausegger2025anovelhomozygous pages 12-13, has2011kindlersyndromeextension pages 1-3) - A 2024 WES-based diagnostic example identified a novel frameshift variant c.567_579del (p.Ile190Serfs*10) interpreted using ACMG/AMP criteria (PVS1/PM2 cited in the report). (zhang2024identificationofa pages 2-3)

Non-genetic/clinical triggers that exacerbate symptoms: - Mechanical trauma (skin blistering with minor trauma) and sunlight/UV exposure (photosensitivity) are core disease triggers, consistent with a structural adhesion defect. (youssefian2022kindlersyndrome pages 1-1, ahmed2024battlingararity pages 4-5)

2.3 Protective factors

No specific genetic protective alleles were identified in the retrieved literature. Clinically, photoprotection and friction/trauma minimization are protective for lesion prevention, but these are management strategies rather than etiologic protective factors. (youssefian2022kindlersyndrome pages 1-1, laicheong2010kindlersyndrome. pages 3-5)

2.4 Gene–environment interactions

Evidence is largely clinical/phenomenological: UV exposure and chronic inflammation at high-friction sites appear to interact with kindlin‑1 deficiency to increase tissue injury and possibly malignancy risk; SCCs cluster at chronically inflamed sites (hands and perioral areas). (guerreroaspizua2019assessmentofthe pages 1-2, guerreroaspizua2019assessmentofthe pages 7-8)

3. Phenotypes (clinical spectrum)

3.1 Core cutaneous phenotype

Typical onset: infancy/early childhood with acral blistering. (youssefian2022kindlersyndrome pages 1-1, ahmed2024battlingararity pages 4-5)

Natural history: In a 59-patient KS natural history cohort, blistering occurred in 100% of patients younger than 10 years and decreased progressively with age. (has2011kindlersyndromeextension pages 5-6)

Key manifestations (suggested HPO terms): - Acral blistering / skin fragility — Skin blistering (HP:0000988) - Photosensitivity — (HP:0000992) - Poikiloderma — (HP:0001023) - Cutaneous atrophy — (HP:0008064) - Palmoplantar keratoderma/hyperkeratosis — (HP:0000982) - Nail dystrophy — (HP:0002164)

Frequency data in Chinese KS literature review: palmoplantar hyperkeratosis 91.70%, nail abnormalities 77.78%, finger/toe abnormalities 75.00%, eye abnormalities 57.14%, constipation 50.00%. (zhang2024identificationofa pages 2-3)

3.2 Mucosal/extracutaneous phenotypes

Common extracutaneous involvement includes oral, ocular, gastrointestinal and genitourinary manifestations.

Oral/periodontal (HPO suggestions): - Gingival bleeding/gingivitis/periodontitis — Gingivitis (HP:0000230), Periodontitis (HP:0000692) - Oral ulcers — (HP:0000155)

Mechanistic context from a 2024 oral-health-focused KS review: “These clinical manifestations arise from mutations in the FERMT-1 … that encodes kindlin-1, a protein localized to focal adhesions in keratinocytes… Kindlin-1 plays a crucial role in integrin receptor activation … essential for cell adhesion and migration.” (Sep 2024). (bhandary2024unusualoralmanifestation pages 1-2)

GI/GU stenoses (HPO suggestions): - Esophageal stenosis/dysphagia — (HP:0002043 / HP:0002015) - Anal stenosis/constipation — (HP:0002019) - Urethral stenosis — (HP:0008665)

These complications are repeatedly emphasized in clinical descriptions and management reviews. (youssefian2022kindlersyndrome pages 1-1, laicheong2015kindlersyndrome pages 5-7)

Ocular (HPO suggestions): - Ectropion — (HP:0000656)

3.3 Quality of life impact

Direct KS-specific QoL instruments were not identified in the retrieved corpus; however, KS is repeatedly described as requiring lifelong wound care, pain control, nutritional/dental support, and cancer surveillance, all of which plausibly impose substantial QoL burden. (ahmed2024battlingararity pages 4-5, laicheong2010kindlersyndrome. pages 3-5)

4. Genetic / Molecular Information

4.1 Causal gene

Gene: FERMT1 (aka KIND1) (laicheong2015kindlersyndrome pages 5-7, has2011kindlersyndromeextension pages 1-3)
Protein: kindlin‑1 (focal adhesion adaptor; integrin-binding) (dsouza2010kindlersyndromepathogenesis pages 1-3, bhandary2024unusualoralmanifestation pages 1-2)

4.2 Pathogenic variant classes and functional consequences

Predominant consequence: loss of kindlin‑1 expression or function; most reported variants cause premature termination and are expected to lead to absent/truncated protein. (has2011kindlersyndromeextension pages 1-3, guerreroaspizua2019assessmentofthe pages 1-2)
Large deletions / CNV-like events: a 2025 report highlights that routine testing may miss large deletions and used an EB gene panel plus breakpoint mapping and mRNA/protein verification to identify a ~9.4 kb homozygous deletion spanning exons 7–9 predicted to cause frameshift and non-functioning protein. (klausegger2025anovelhomozygous pages 1-2)

4.3 Modifier genes / phenotype modifiers

Direct human genetic modifiers were not identified in the retrieved texts. However, inflammatory and profibrotic signaling is implicated in progression (cytokines and TGF‑β-related profibrotic pathways). (has2011kindlersyndromeextension pages 5-6)

4.4 Epigenetics and chromosomal abnormalities

No KS-specific epigenetic signatures or recurrent chromosomal abnormalities were identified in the retrieved evidence.

5. Environmental Information

5.1 Environmental and lifestyle factors

No exogenous toxicant/infectious cause is implicated; disease expression is worsened by UV exposure (photosensitivity) and mechanical friction/trauma (blistering). (youssefian2022kindlersyndrome pages 1-1, ahmed2024battlingararity pages 4-5)

5.2 Infectious agents

Infections are secondary complications of skin barrier breakdown (e.g., colonization of erosions and sepsis risk), rather than primary causes. (ahmed2024battlingararity pages 4-5)

6. Mechanism / Pathophysiology

6.1 Molecular and cellular mechanism (causal chain)

1) Bi-allelic FERMT1 loss-of-function → kindlin‑1 deficiency (has2011kindlersyndromeextension pages 1-3, has2010mildclinicalphenotype pages 1-1) 2) Defective integrin activation and focal adhesion function in keratinocytes (impaired adhesion/migration) (bhandary2024unusualoralmanifestation pages 1-2, dsouza2010kindlersyndromepathogenesis pages 1-3) 3) Basement membrane zone abnormalities and mechanical fragility with multi-plane cleavage (intra-basal keratinocyte, lamina lucida, below lamina densa) and lamina densa reduplication on EM (dsouza2010kindlersyndromepathogenesis pages 3-4, laicheong2010kindlersyndrome. pages 3-5) 4) Chronic injury → inflammation and profibrotic remodeling, contributing to mucocutaneous fibrosis/stenoses and cancer-prone chronically inflamed sites. (has2011kindlersyndromeextension pages 5-6, guerreroaspizua2019assessmentofthe pages 7-8)

6.2 Representative pathways (ontology suggestions)

Integrin-mediated signaling / focal adhesion: GO:0007229 (integrin-mediated signaling pathway), GO:0005925 (focal adhesion)
Cell adhesion and migration: GO:0007155 (cell adhesion), GO:0016477 (cell migration)
TGF‑β signaling / fibrosis (downstream): GO:0007179 (TGF‑β receptor signaling pathway)

6.3 Cell types and tissues involved (ontology suggestions)

Basal keratinocytes (CL:0000312)
Intestinal epithelial cells (CL:0000584)
Fibroblasts / myofibroblasts (CL:0000057 / CL:0000186)

6.4 Cancer mechanism insights (recent, 2024)

A 2024 mechanistic cSCC paper states in its abstract: “Kindler syndrome (KS) is a rare genodermatosis resulting from loss-of-function mutations in FERMT1 … KS patients have a high propensity to develop aggressive and metastatic cutaneous squamous cell carcinoma (cSCC).” It further reports that kindlin‑1 loss can promote SCC tumor growth in vivo with hypoxia, increased glycolysis, and MMP13 upregulation driving invasion. (Jul 2024). (carrasco2024involvementofkindlin1 pages 1-2)

7. Anatomical Structures Affected

7.1 Organ and system level

Primary: skin (epidermis/dermal–epidermal junction), oral mucosa/periodontium (youssefian2022kindlersyndrome pages 1-1, bhandary2024unusualoralmanifestation pages 1-2)
Secondary/complications: gastrointestinal tract (esophagus/colon), genitourinary tract (urethra), eyes (ectropion), and cancer-prone sites (hands, perioral/oral). (youssefian2022kindlersyndrome pages 1-1, laicheong2015kindlersyndrome pages 5-7, guerreroaspizua2019assessmentofthe pages 1-2)

UBERON suggestions: - Skin (UBERON:0002097) - Oral mucosa (UBERON:0006956) - Esophagus (UBERON:0001043) - Colon (UBERON:0001155) - Urethra (UBERON:0000057)

8. Temporal Development (onset and course)

Onset: usually congenital/infantile acral blistering (youssefian2022kindlersyndrome pages 1-1)
Course: blistering tends to improve with age, while atrophy/poikiloderma and mucosal complications may progress. (has2011kindlersyndromeextension pages 5-6, youssefian2022kindlersyndrome pages 1-1)
Critical periods: adolescence/early adulthood is often when long-term complications and surveillance planning become central; a KS case report suggests adolescence as an appropriate time to start premalignant screening. (ahmed2024battlingararity pages 4-5)

9. Inheritance and Population

9.1 Inheritance

Autosomal recessive. (laicheong2015kindlersyndrome pages 5-7, has2010mildclinicalphenotype pages 1-1)

9.2 Epidemiology (recent registry data prioritized)

Because KS/KEB is ultra-rare, most epidemiology comes from registries.

Romania (registry-based, 2012–2024; point prevalence as of 31 Dec 2023): - EB total: 152 cases; point prevalence 6.77 per million. - KEB: 3 cases (2%), point prevalence 0.16 per million, and incidence 0 per million live births in 2012–2022 interval. (Jun 2024). (suru2024epidemiologicalcharacteristicsof pages 10-12, suru2024epidemiologicalcharacteristicsof pages 1-2)

Russian Federation pediatric registry (as of 1 Jan 2024): - 491 children with EB registered; pediatric prevalence 15.48 per 1,000,000 children. - Kindler syndrome: 8 patients. (Oct 2024). (murashkin2024congenitalepidermolysisbullosa pages 1-2, murashkin2024congenitalepidermolysisbullosa pages 2-3)

10. Diagnostics

10.1 Clinical diagnosis

A key clinical constellation includes acral blistering in infancy/childhood, progressive poikiloderma, skin atrophy, photosensitivity, and gingival fragility; mucosal stenoses may occur. (ahmed2024battlingararity pages 4-5)

10.2 Skin biopsy, histopathology, TEM (electron microscopy)

Diagnostic clues include multi-plane cleavage at the dermal–epidermal junction and lamina densa reduplication on TEM; histopathology may show atrophy, loss of rete ridges, pigmentary incontinence, and melanophages. (laicheong2010kindlersyndrome. pages 3-5, dsouza2010kindlersyndromepathogenesis pages 3-4)

10.3 Immunofluorescence mapping / kindlin‑1 staining

Immunofluorescence mapping with anti–kindlin‑1 antibody can show reduced labeling, but labeling can be variable and can appear preserved in some mutation contexts; therefore molecular confirmation is recommended. (laicheong2010kindlersyndrome. pages 3-5, laicheong2015kindlersyndrome pages 5-7)

10.4 Genetic testing

Sequencing-based diagnosis (single-gene or EB panels / WES) is used; WES plus Sanger confirmation is described in a 2024 KS case. (zhang2024identificationofa pages 2-3)
Copy-number/large deletions may require additional methods (panel design, breakpoint mapping, RNA/protein verification). (klausegger2025anovelhomozygous pages 1-2)

10.5 Differential diagnosis

Neonatal/early-life presentation can overlap other EB types (EBS/DEB) and porphyria-like photosensitive disorders; a 2024 KS case report notes initial differential included porphyria cutanea tarda in a pediatric case due to overlapping photosensitivity/fragility. (laicheong2010kindlersyndrome. pages 3-5, ahmed2024battlingararity pages 4-5)

11. Outcome / Prognosis

11.1 Life expectancy

Some reports state generally normal life expectancy but emphasize substantial morbidity and the importance of surveillance for malignancy and strictures. (ahmed2024battlingararity pages 4-5)

11.2 Cancer outcomes (high-impact prognosis determinant)

The largest retrieved KS SCC cohort (91 adults) quantified SCC severity and outcomes: - SCC in 13/91 (14.3%), youngest case 29 years, cumulative SCC risk 66.7% in those >60 years. - Metastatic disease in 53.8% of SCC-bearing patients (7/13). - Death from tumor in 38.5% (5/13) within 2–7 years (mean survival 40.8 months). (Jul 2019). (guerreroaspizua2019assessmentofthe pages 1-2)

12. Treatment

12.1 Standard of care (supportive / multidisciplinary)

No disease-modifying therapy is established; management is largely symptomatic.

Skin care & wound care (MAXO suggestions): - Nonadherent dressings, infection prevention, debridement as needed, and pain control are emphasized in case-based guidance; one report lists dressings (foams, hydrogel sheets, alginates, etc.) and analgesics including acetaminophen and opioids. (MAXO:0000015 Wound care; MAXO:0000046 Pain management) (ahmed2024battlingararity pages 4-5)

Photoprotection: broad-spectrum sunscreen and UV avoidance are recommended. (MAXO:0000075 Photoprotection) (youssefian2022kindlersyndrome pages 1-1)

Oral/dental care: regular dental care to manage gingivitis/periodontitis. (MAXO: Dental care) (laicheong2010kindlersyndrome. pages 3-5)

Management of stenoses and complications: esophageal dilatation for dysphagia; interventions for urethral strictures; nutrition support when needed. (laicheong2010kindlersyndrome. pages 3-5, laicheong2015kindlersyndrome pages 5-7)

Cancer surveillance: annual follow-up for premalignant keratoses and early malignancy. (youssefian2022kindlersyndrome pages 1-1, laicheong2015kindlersyndrome pages 5-7)

12.2 Experimental / clinical trials relevant to KEB

Oleogel‑S10 (birch bark extract; Episalvan/Filsuvez) for EB wound healing - A completed Phase III trial explicitly included Kindler EB among eligible EB subtypes and enrolled 223 participants (49 sites, 26 countries). Primary endpoint: first complete closure of a target wound within 45 days. ClinicalTrials.gov results were first submitted in 2023. NCT03068780. (NCT03068780 chunk 1)

Cannabinol cream for EB (not Kindler-specific): a completed Phase 2 EB trial exists (NCT04908215), but Kindler inclusion is not established in the extracted text; therefore it is not interpreted here as KEB-targeted evidence. (No KEB-specific evidence in provided excerpt.)

13. Prevention

13.1 Primary/secondary/tertiary prevention

Primary prevention of disease occurrence: genetic counseling and reproductive planning are central due to autosomal recessive inheritance. (MAXO:0000127 Genetic counseling) (youssefian2022kindlersyndrome pages 1-1)
Tertiary prevention: reduce blistering/injury through friction minimization and photoprotection; prevent complications via infection control, nutritional/dental care, and early treatment of strictures. (youssefian2022kindlersyndrome pages 1-1, laicheong2010kindlersyndrome. pages 3-5)
Cancer prevention/early detection: routine surveillance for premalignant lesions and SCC due to high risk and aggressiveness. (guerreroaspizua2019assessmentofthe pages 1-2, youssefian2022kindlersyndrome pages 1-1)

14. Other Species / Natural Disease

No naturally occurring non-human Kindler syndrome analogs were identified in the retrieved evidence.

15. Model Organisms

15.1 Mouse models (Fermt1/Kindlin‑1 knockout)

A Fermt1 (Kindlin‑1) knockout mouse model provides strong mechanistic evidence linking kindlin‑1 deficiency to epithelial barrier failure: - The PLoS Genetics study states in its abstract: “deleting Kindlin-1 in mice gives rise to skin atrophy and an intestinal epithelial dysfunction with similarities to human UC.” (Dec 2008). (ussar2008lossofkindlin1 pages 1-2) - Homozygous knockout pups die between P3–P5 due to intestinal epithelial detachment and destructive inflammation, attributed to defective integrin activation and loss of epithelial adhesion. (ussar2008lossofkindlin1 pages 2-3)

A review of EB animal models reports that Fermt1 knockout mice showed skin atrophy but did not show a classic blistering phenotype in that account, underscoring partial recapitulation and model limitations. (natsuga2010animalmodelsof pages 2-4)

Recent developments (2023–2024 highlights)

1) Epidemiology updates from national registries: Romania (KEB prevalence 0.16/million; 3 KEB cases) and Russia (8 pediatric Kindler cases) provide contemporary, registry-derived denominators useful for health-system planning. (suru2024epidemiologicalcharacteristicsof pages 10-12, murashkin2024congenitalepidermolysisbullosa pages 2-3) 2) Mechanistic cancer biology advances: 2024 work links kindlin‑1 loss to hypoxic, glycolytic tumor environments and MMP13-driven invasion in SCC models, addressing why KS-associated SCC can be particularly aggressive. (carrasco2024involvementofkindlin1 pages 1-2) 3) Clinical phenotyping refinement: 2024 Chinese KS review provides updated phenotype frequencies (e.g., palmoplantar hyperkeratosis 91.70%; oral involvement 70%). (zhang2024identificationofa pages 2-3)

Limitations of this report (tooling / evidence availability)

Orphanet ORPHA, ICD‑10/ICD‑11, MeSH, and MONDO identifiers were not retrievable using the current tools because direct ontology/database lookup services are not available in the toolset; only OMIM disease number could be extracted from accessible full text. (has2010mildclinicalphenotype pages 1-1)
Many KS publications are case reports; for several sections (epigenetics, specific modifier genes, KS-specific QoL instruments) the retrieved literature did not provide high-confidence, quantitative evidence.

Key URLs (most used sources)

2024 Romania EB registry epidemiology (includes KEB): https://doi.org/10.3390/jcm13133742 (Jun 2024). (suru2024epidemiologicalcharacteristicsof pages 10-12)
2024 Kindlin-1 and SCC mechanism: https://doi.org/10.1038/s41389-024-00526-1 (Jul 2024). (carrasco2024involvementofkindlin1 pages 1-2)
2019 KS SCC cohort (91 patients): https://doi.org/10.1186/s13023-019-1158-6 (Jul 2019). (guerreroaspizua2019assessmentofthe pages 1-2)
2008 Fermt1 knockout mouse model: https://doi.org/10.1371/journal.pgen.1000289 (Dec 2008). (ussar2008lossofkindlin1 pages 1-2)
EB wound trial including Kindler EB: https://clinicaltrials.gov/study/NCT03068780 (results first submitted 2023 per registry record). (NCT03068780 chunk 1)

References

(has2010mildclinicalphenotype pages 1-1): C. Has, Bettina Burger, A. Volz, J. Kohlhase, Leena Bruckner-Tuderman, and P. Itin. Mild clinical phenotype of kindler syndrome associated with late diagnosis and skin cancer. Dermatology, 221:309-312, Oct 2010. URL: https://doi.org/10.1159/000320235, doi:10.1159/000320235. This article has 31 citations and is from a peer-reviewed journal.
(youssefian2022kindlersyndrome pages 1-1): L Youssefian, H Vahidnezhad, and J Uitto. Kindler syndrome. Indian Pediatrics, 55:85, 2022. URL: https://doi.org/10.1007/s13312-018-1239-y, doi:10.1007/s13312-018-1239-y. This article has 66 citations and is from a peer-reviewed journal.
(bhandary2024unusualoralmanifestation pages 1-2): Rahul Bhandary, Geethu Venugopalan, and Padmaraj Hegde. Unusual oral manifestation of kindler syndrome: a case report and review of literature. Frontiers in Oral Health, Sep 2024. URL: https://doi.org/10.3389/froh.2024.1430698, doi:10.3389/froh.2024.1430698. This article has 2 citations and is from a peer-reviewed journal.
(klausegger2025anovelhomozygous pages 12-13): Alfred Klausegger, Fabian Leditzky, Susanne Krämer, Francis Palisson, María Joao Yubero, Sebastián Véliz, Mark Jean Aan Koh, Ene-Choo Tan, Martin Laimer, Johann Wolfgang Bauer, and Ignacia Fuentes. A novel homozygous 9385 bp deletion in the fermt1 (kind1) gene in a malaysian family with kindler epidermolysis bullosa and a review of large deletions. International Journal of Molecular Sciences, 26:4237, Apr 2025. URL: https://doi.org/10.3390/ijms26094237, doi:10.3390/ijms26094237. This article has 0 citations.
(laicheong2015kindlersyndrome pages 5-7): Joey E. Lai-Cheong and John A. McGrath. Kindler syndrome. Blistering Diseases, pages 433-439, Jan 2015. URL: https://doi.org/10.1007/978-3-662-45698-9_43, doi:10.1007/978-3-662-45698-9_43. This article has 2 citations.
(has2011kindlersyndromeextension pages 1-3): Cristina Has, Daniele Castiglia, Marcela del Rio, Marta Garcia Diez, Eugenia Piccinni, Dimitra Kiritsi, Jürgen Kohlhase, Peter Itin, Ludovic Martin, Judith Fischer, Giovanna Zambruno, and Leena Bruckner-Tuderman. Kindler syndrome: extension of fermt1 mutational spectrum and natural history. Human Mutation, 32:1204-1212, Nov 2011. URL: https://doi.org/10.1002/humu.21576, doi:10.1002/humu.21576. This article has 167 citations and is from a domain leading peer-reviewed journal.
(dsouza2010kindlersyndromepathogenesis pages 1-3): Maria-Anna M.A. D'Souza, Roy M. Kimble, and James R. McMillan. Kindler syndrome pathogenesis and fermitin family homologue 1 (kindlin-1) function. Dermatologic clinics, 28 1:115-8, Jan 2010. URL: https://doi.org/10.1016/j.det.2009.10.012, doi:10.1016/j.det.2009.10.012. This article has 40 citations and is from a peer-reviewed journal.
(has2020consensusreclassificationof pages 1-2): C. Has, J.W. Bauer, C. Bodemer, M.C. Bolling, L. Bruckner‐Tuderman, A. Diem, J.‐D. Fine, A. Heagerty, A. Hovnanian, M.P. Marinkovich, A.E. Martinez, J.A. McGrath, C. Moss, D.F. Murrell, F. Palisson, A. Schwieger‐Briel, E. Sprecher, K. Tamai, J. Uitto, D.T. Woodley, G. Zambruno, and J.E. Mellerio. Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility. British Journal of Dermatology, 183:614-627, Mar 2020. URL: https://doi.org/10.1111/bjd.18921, doi:10.1111/bjd.18921. This article has 908 citations and is from a highest quality peer-reviewed journal.
(ahmed2024battlingararity pages 4-5): Alina Ahmed, Tasheen Zehra, Alina Moin, and Shajie Ur Rehman Usmani. Battling a rarity: a case of kindler syndrome from a developing country. SAGE Open Medical Case Reports, Jan 2024. URL: https://doi.org/10.1177/2050313x241231518, doi:10.1177/2050313x241231518. This article has 8 citations and is from a peer-reviewed journal.
(laicheong2010kindlersyndrome. pages 3-5): Joey E. Lai-Cheong and John A. McGrath. Kindler syndrome. Dermatologic clinics, 28 1:119-24, Jan 2010. URL: https://doi.org/10.1016/j.det.2009.10.013, doi:10.1016/j.det.2009.10.013. This article has 111 citations and is from a peer-reviewed journal.
(has2011kindlersyndromeextension pages 5-6): Cristina Has, Daniele Castiglia, Marcela del Rio, Marta Garcia Diez, Eugenia Piccinni, Dimitra Kiritsi, Jürgen Kohlhase, Peter Itin, Ludovic Martin, Judith Fischer, Giovanna Zambruno, and Leena Bruckner-Tuderman. Kindler syndrome: extension of fermt1 mutational spectrum and natural history. Human Mutation, 32:1204-1212, Nov 2011. URL: https://doi.org/10.1002/humu.21576, doi:10.1002/humu.21576. This article has 167 citations and is from a domain leading peer-reviewed journal.
(guerreroaspizua2019assessmentofthe pages 1-2): Sara Guerrero-Aspizua, Claudio J. Conti, Maria Jose Escamez, Daniele Castiglia, Giovanna Zambruno, Leila Youssefian, Hassan Vahidnezhad, Luis Requena, Peter Itin, Gianluca Tadini, Ivelina Yordanova, Ludovic Martin, Jouni Uitto, Cristina Has, and Marcela Del Rio. Assessment of the risk and characterization of non-melanoma skin cancer in kindler syndrome: study of a series of 91 patients. Orphanet Journal of Rare Diseases, Jul 2019. URL: https://doi.org/10.1186/s13023-019-1158-6, doi:10.1186/s13023-019-1158-6. This article has 37 citations and is from a peer-reviewed journal.
(guerreroaspizua2019assessmentofthe pages 2-4): Sara Guerrero-Aspizua, Claudio J. Conti, Maria Jose Escamez, Daniele Castiglia, Giovanna Zambruno, Leila Youssefian, Hassan Vahidnezhad, Luis Requena, Peter Itin, Gianluca Tadini, Ivelina Yordanova, Ludovic Martin, Jouni Uitto, Cristina Has, and Marcela Del Rio. Assessment of the risk and characterization of non-melanoma skin cancer in kindler syndrome: study of a series of 91 patients. Orphanet Journal of Rare Diseases, Jul 2019. URL: https://doi.org/10.1186/s13023-019-1158-6, doi:10.1186/s13023-019-1158-6. This article has 37 citations and is from a peer-reviewed journal.
(zhang2024identificationofa pages 2-3): Qiang Zhang, Qi Yang, Fei Shen, Linlin Wang, and Jingsi Luo. Identification of a novel fermt1 variant causing kindler syndrome and a review of the clinical and molecular genetic features in chinese patients. Frontiers in Pediatrics, Sep 2024. URL: https://doi.org/10.3389/fped.2024.1425030, doi:10.3389/fped.2024.1425030. This article has 3 citations.
(dsouza2010kindlersyndromepathogenesis pages 3-4): Maria-Anna M.A. D'Souza, Roy M. Kimble, and James R. McMillan. Kindler syndrome pathogenesis and fermitin family homologue 1 (kindlin-1) function. Dermatologic clinics, 28 1:115-8, Jan 2010. URL: https://doi.org/10.1016/j.det.2009.10.012, doi:10.1016/j.det.2009.10.012. This article has 40 citations and is from a peer-reviewed journal.
(guerreroaspizua2019assessmentofthe pages 7-8): Sara Guerrero-Aspizua, Claudio J. Conti, Maria Jose Escamez, Daniele Castiglia, Giovanna Zambruno, Leila Youssefian, Hassan Vahidnezhad, Luis Requena, Peter Itin, Gianluca Tadini, Ivelina Yordanova, Ludovic Martin, Jouni Uitto, Cristina Has, and Marcela Del Rio. Assessment of the risk and characterization of non-melanoma skin cancer in kindler syndrome: study of a series of 91 patients. Orphanet Journal of Rare Diseases, Jul 2019. URL: https://doi.org/10.1186/s13023-019-1158-6, doi:10.1186/s13023-019-1158-6. This article has 37 citations and is from a peer-reviewed journal.
(klausegger2025anovelhomozygous pages 1-2): Alfred Klausegger, Fabian Leditzky, Susanne Krämer, Francis Palisson, María Joao Yubero, Sebastián Véliz, Mark Jean Aan Koh, Ene-Choo Tan, Martin Laimer, Johann Wolfgang Bauer, and Ignacia Fuentes. A novel homozygous 9385 bp deletion in the fermt1 (kind1) gene in a malaysian family with kindler epidermolysis bullosa and a review of large deletions. International Journal of Molecular Sciences, 26:4237, Apr 2025. URL: https://doi.org/10.3390/ijms26094237, doi:10.3390/ijms26094237. This article has 0 citations.
(carrasco2024involvementofkindlin1 pages 1-2): Giovana Carrasco, Ifigeneia Stavrou, Mairi Treanor-Taylor, Henry Beetham, Martin Lee, Roza Masalmeh, Artur Carreras-Soldevila, David Hardman, Miguel O. Bernabeu, Alex von Kriegsheim, Gareth J. Inman, Adam Byron, and Valerie G. Brunton. Involvement of kindlin-1 in cutaneous squamous cell carcinoma. Oncogenesis, Jul 2024. URL: https://doi.org/10.1038/s41389-024-00526-1, doi:10.1038/s41389-024-00526-1. This article has 3 citations and is from a domain leading peer-reviewed journal.
(suru2024epidemiologicalcharacteristicsof pages 10-12): Alina Suru, Sorina Dănescu, Alina Călinescu-Stîncanu, Denis Iorga, Mihai Dascălu, Adrian Baican, George-Sorin Țiplica, and Carmen Maria Sălăvăstru. Epidemiological characteristics of inherited epidermolysis bullosa in an eastern european population. Journal of Clinical Medicine, 13:3742, Jun 2024. URL: https://doi.org/10.3390/jcm13133742, doi:10.3390/jcm13133742. This article has 6 citations.
(suru2024epidemiologicalcharacteristicsof pages 1-2): Alina Suru, Sorina Dănescu, Alina Călinescu-Stîncanu, Denis Iorga, Mihai Dascălu, Adrian Baican, George-Sorin Țiplica, and Carmen Maria Sălăvăstru. Epidemiological characteristics of inherited epidermolysis bullosa in an eastern european population. Journal of Clinical Medicine, 13:3742, Jun 2024. URL: https://doi.org/10.3390/jcm13133742, doi:10.3390/jcm13133742. This article has 6 citations.
(murashkin2024congenitalepidermolysisbullosa pages 1-2): Nikolay N. Murashkin, Roman V. Epishev, Olga S. Orlova, Alena А. Kuratova, and Victoriya S. Polenova. Congenital epidermolysis bullosa epidemiology among children of russian federation. Current Pediatrics, 23:316-328, Oct 2024. URL: https://doi.org/10.15690/vsp.v23i5.2808, doi:10.15690/vsp.v23i5.2808. This article has 2 citations.
(murashkin2024congenitalepidermolysisbullosa pages 2-3): Nikolay N. Murashkin, Roman V. Epishev, Olga S. Orlova, Alena А. Kuratova, and Victoriya S. Polenova. Congenital epidermolysis bullosa epidemiology among children of russian federation. Current Pediatrics, 23:316-328, Oct 2024. URL: https://doi.org/10.15690/vsp.v23i5.2808, doi:10.15690/vsp.v23i5.2808. This article has 2 citations.
(NCT03068780 chunk 1): Phase III Efficacy and Safety Study of Oleogel-S10 in Epidermolysis Bullosa. Amryt Research Limited. 2017. ClinicalTrials.gov Identifier: NCT03068780
(ussar2008lossofkindlin1 pages 1-2): Siegfried Ussar, Markus Moser, Moritz Widmaier, Emanuel Rognoni, Christian Harrer, Orsolya Genzel-Boroviczeny, and Reinhard Fässler. Loss of kindlin-1 causes skin atrophy and lethal neonatal intestinal epithelial dysfunction. PLoS Genetics, 4:e1000289, Dec 2008. URL: https://doi.org/10.1371/journal.pgen.1000289, doi:10.1371/journal.pgen.1000289. This article has 257 citations and is from a domain leading peer-reviewed journal.
(ussar2008lossofkindlin1 pages 2-3): Siegfried Ussar, Markus Moser, Moritz Widmaier, Emanuel Rognoni, Christian Harrer, Orsolya Genzel-Boroviczeny, and Reinhard Fässler. Loss of kindlin-1 causes skin atrophy and lethal neonatal intestinal epithelial dysfunction. PLoS Genetics, 4:e1000289, Dec 2008. URL: https://doi.org/10.1371/journal.pgen.1000289, doi:10.1371/journal.pgen.1000289. This article has 257 citations and is from a domain leading peer-reviewed journal.
(natsuga2010animalmodelsof pages 2-4): Ken Natsuga, Satoru Shinkuma, Wataru Nishie, and Hiroshi Shimizu. Animal models of epidermolysis bullosa. Dermatologic clinics, 28 1:137-42, Jan 2010. URL: https://doi.org/10.1016/j.det.2009.10.016, doi:10.1016/j.det.2009.10.016. This article has 32 citations and is from a peer-reviewed journal.

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Classifications

Mappings

Inheritance

Subtypes

Mechanistic Hypotheses

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Treatments

Related Datasets

Clinical Trials

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

1.1 What is the disease? (concise overview)

1.2 Key identifiers and codes

1.3 Synonyms and alternative names

1.4 Evidence source type

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes (clinical spectrum)

3.1 Core cutaneous phenotype

3.2 Mucosal/extracutaneous phenotypes

3.3 Quality of life impact

4. Genetic / Molecular Information

4.1 Causal gene

4.2 Pathogenic variant classes and functional consequences

4.3 Modifier genes / phenotype modifiers

4.4 Epigenetics and chromosomal abnormalities

5. Environmental Information

5.1 Environmental and lifestyle factors

5.2 Infectious agents

6. Mechanism / Pathophysiology

6.1 Molecular and cellular mechanism (causal chain)

6.2 Representative pathways (ontology suggestions)

6.3 Cell types and tissues involved (ontology suggestions)

6.4 Cancer mechanism insights (recent, 2024)

7. Anatomical Structures Affected

7.1 Organ and system level

8. Temporal Development (onset and course)

9. Inheritance and Population

9.1 Inheritance

9.2 Epidemiology (recent registry data prioritized)

10. Diagnostics

10.1 Clinical diagnosis

10.2 Skin biopsy, histopathology, TEM (electron microscopy)

10.3 Immunofluorescence mapping / kindlin‑1 staining

10.4 Genetic testing

10.5 Differential diagnosis

11. Outcome / Prognosis

11.1 Life expectancy

11.2 Cancer outcomes (high-impact prognosis determinant)

12. Treatment

12.1 Standard of care (supportive / multidisciplinary)

12.2 Experimental / clinical trials relevant to KEB

13. Prevention

13.1 Primary/secondary/tertiary prevention

14. Other Species / Natural Disease

15. Model Organisms

15.1 Mouse models (Fermt1/Kindlin‑1 knockout)

Recent developments (2023–2024 highlights)

Limitations of this report (tooling / evidence availability)

Key URLs (most used sources)