Kindler Epidermolysis Bullosa

Mendelian MONDO:0008260 Pathograph 5 Show in embeddings browser 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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2
Mappings
1
Inheritance
5
Pathophys.
11
Phenotypes
2
Hypotheses
3
Gaps
5
Pathograph
1
Genes
6
Medical Actions
2
Subtypes
1
Datasets
1
Trials
18
References
1
Deep Research
2
Hyp. Reports
🏷

Classifications

Harrison's Part
DERMATOLOGY GENETICS ENVIRONMENT DISEASE
IUIS Category
immune dysregulation
🔗

Mappings

MONDO
MONDO:0008260 Kindler syndrome
skos:exactMatch MONDO
Primary MONDO disease identifier for this Kindler EB entry.
ICD-10-CM
ICD10CM:Q81.8 Other epidermolysis bullosa
skos:closeMatch ICD-10-CM
ICD-10-CM does not provide a Kindler-specific EB code; Q81.8 is the closest available code for this rare EB subtype.
👪

Inheritance

1
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.
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Subtypes

2
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.
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Mechanistic Hypotheses

2
Wnt/Beta-Catenin Dysregulation Model for SCC Susceptibility
wnt_beta_catenin_scc_model CANONICAL
Evidence balance 8 support
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.
Retained as CANONICAL but with important asymmetric-arm and multi-hit qualifications from the 2026 openscientist hypothesis-search report (kb/hypotheses/Kindler_Epidermolysis_Bullosa/wnt_beta_catenin_scc_model). The **TGF-β arm** is robustly validated by independent skin-carcinogenesis literature (TGF-β1 knockout → rapid SCC; Smad2 ablation → accelerated SCC). The **Wnt arm** rests primarily on the foundational Rognoni 2014 mouse-model study and lacks independent replication of the specific kindlin-1→Wnt link in 12 years. At least four parallel/complementary mechanisms by which kindlin-1 loss promotes SCC have been independently demonstrated: oxidative-stress/ERK vulnerability, UV-induced NF-κB/JNK inflammation, hypoxia/MMP13-driven invasion, and EMT/fibrosis with Gstp1 suppression. Clinical SCC epidemiology (cumulative risk 66.7% by age >60, concentration at chronic-inflammation sites, 53.8% metastatic) is more consistent with a multi-hit model than a singular Wnt-driven-initiation model.
Deep research
OpenScientist citations 17 citations 2026-05-23T03:04:49.624426
Show evidence (8 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.
+ 5 more references
Oxidative Stress and Impaired ERK Signaling Model for Photosensitivity
oxidative_stress_photosensitivity_model CANONICAL
Evidence balance 8 support
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.
Retained as CANONICAL, with scope qualifications from the 2026 openscientist hypothesis-search report and its assessment (kb/hypotheses/Kindler_Epidermolysis_Bullosa/oxidative_stress_photosensitivity_model). The oxidative-stress phenotype is the best-supported component: three independent groups report increased UV/oxidative vulnerability and DNA damage in kindlin-1-deficient keratinocytes (PMID:28501563, PMID:27798104, PMID:27725201), and two of them (PMID:28501563, PMID:27798104) measure elevated ROS itself. The ERK arm rests on the single Emmert 2017 study, but it is not contradicted: neither the p38 study (PMID:27798104) nor the NF-κB/JNK study (PMID:27725201) assayed ERK, so they establish additional UV-response pathways rather than displacing ERK. The model is therefore best read as a multi-pathway signalling deficiency of which the ERK arm is one measured component. The "integrin-dependent" framing was tested rather than assumed — Emmert reports that the ERK activation and DNA-damage protection depend on kindlin-1's ability to bind integrins — so kindlin-1's separate integrin-independent functions (EGFR stabilization, microtubule/mitotic regulation) do not qualify it. UV-B additionally depletes the partially compensatory kindlin-2 paralog (PMID:21356350), though the resulting worsening of photosensitivity is inferred rather than demonstrated, and kindlin-2 does not compensate for UV-B apoptosis at all (PMID:27798104).
Deep research
OpenScientist citations 14 citations 2026-05-23T03:01:13.621387
Show evidence (8 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.
+ 5 more references
?

Discussions and Knowledge Gaps

3
Is impaired ERK activation the pathway that actually limits DNA-damage protection in kindlin-1-deficient human skin, or one of several parallel UV-response deficits none of which has been measured in a patient?
KNOWLEDGE GAP OPEN gap_keb_erk_arm_unreplicated_and_untested_in_patients
Attached to
mechanistic_hypotheses#oxidative_stress_photosensitivity_model phenotypes#Cutaneous Photosensitivity
Every measurement behind this hypothesis was made in cultured cells. Emmert (PMID:28501563) is the only study that assayed ERK at all, and the two studies usually cited against it did not: the p38 work (PMID:27798104) measured cytokine induction and the NF-κB/JNK work (PMID:27725201) measured DNA-repair readouts, so neither shows ERK is uninvolved or subordinate. What is missing is the comparison — ERK, p38, JNK and NF-κB assayed side by side after matched UVA and UVB doses, which matters because the ERK evidence comes from UVA and the competing evidence from UVB, two wavelengths with different primary mechanisms of damage. Nothing has been measured in patient tissue: no ROS, 8-OHdG, γH2AX or phospho-MAPK study of UV-exposed Kindler skin has been published. The gap is not academic, because the one therapeutic lead the mechanism has produced — topical antioxidants and luteolin, which reduce UV-B apoptosis in organotypic KS cultures (PMID:27798104) — has never been taken into a patient. The completed EB trial curated in this entry (NCT04908215) tested topical cannabinol for wound healing and does not address it.
Proposed experiments
Assay ERK, p38, JNK and NF-κB side by side after matched UVA and UVB doses
exp_keb_multi_mapk_uva_versus_uvb_head_to_head
Irradiate patient-derived kindlin-1-deficient keratinocytes and kindlin-1-reconstituted controls with matched biologically relevant UVA and UVB doses, and follow phospho-ERK, phospho-p38, phospho-JNK and NF-κB activation over a time course alongside viability, γH2AX foci and cyclobutane pyrimidine dimers. Then apply pathway-selective inhibition and rescue to each arm separately. The point is to test whether the ERK arm is the rate-limiting one, one of several additive deficits, or specific to the UVA condition in which it was originally found.
Would support
mechanistic_hypotheses#oxidative_stress_photosensitivity_model
Would refute
mechanistic_hypotheses#oxidative_stress_photosensitivity_model
Supporting outcome
  • ERK inhibition selectively worsens, and ERK activation selectively rescues, DNA damage and viability in kindlin-1-expressing but not kindlin-1-deficient cells across both wavelengths, with the other pathways contributing less.
Refuting outcome
  • ERK activation is unchanged or intact in kindlin-1-deficient cells, or no single-pathway rescue improves the DNA-damage endpoint while p38 or JNK inhibition does, indicating the ERK arm is not the operative deficit.
Measure oxidative damage and MAPK activation in UV-exposed Kindler skin
exp_keb_uv_response_biomarkers_in_patient_skin
Take paired punch biopsies from UV-exposed and habitually UV-protected sites in Kindler syndrome patients and age-matched controls, stratified by whether the FERMT1 genotype is predicted null or retains partial function, and stain for 8-OHdG, γH2AX, cyclobutane pyrimidine dimers and phospho-ERK/p38/JNK. This is the missing translational step: it would also test in patients the kindlin-1 abundance threshold seen in culture, where low residual kindlin-1 was enough to relieve UV-B apoptosis.
Would support
mechanistic_hypotheses#oxidative_stress_photosensitivity_model
Would refute
mechanistic_hypotheses#oxidative_stress_photosensitivity_model
Supporting outcome
  • UV-exposed Kindler skin shows higher oxidative DNA damage and altered MAPK activation than control skin, graded by residual kindlin-1 level.
Refuting outcome
  • Oxidative DNA damage and MAPK activation in UV-exposed Kindler skin are indistinguishable from controls, leaving the cultured-cell phenotype without an in vivo correlate.
Raised from the 2026 openscientist hypothesis-search report and its assessment (kb/hypotheses/Kindler_Epidermolysis_Bullosa/oxidative_stress_photosensitivity_model). The report's own claims of exhaustive negative searches are not auditable — no search log is committed — so this gap is stated as what the cited primary literature does and does not show, not as a claim that nothing else exists.
Show evidence (1 reference)
PMID:27798104 SUPPORT In Vitro
"antioxidants and the plant flavonoid luteolin represent feasible topical therapeutic approaches decreasing UV-B induced apoptosis in two-dimensional and organotypic KS cultures"
Establishes the untested therapeutic lead this gap turns on — a topical intervention that works on the proposed mechanism in organotypic Kindler cultures and has never been evaluated in patients.
How can loss of kindlin-1 drive squamous cell carcinoma in Kindler syndrome when elevated FERMT1 expression accompanies sporadic cutaneous SCC?
CONTROVERSY OPEN gap_keb_fermt1_direction_paradox_in_scc
Attached to
mechanistic_hypotheses#wnt_beta_catenin_scc_model phenotypes#Squamous Cell Carcinoma Risk
A single study reports both halves, so this is not a discrepancy between laboratories that can be argued away on methodology. Carrasco et al. (PMID:38982038) found FERMT1 expression rising from normal skin to actinic keratosis to cutaneous SCC in non-Kindler patients, consistent with a pro-tumorigenic role, and in the same paper found that depleting kindlin-1 increased SCC growth in vivo and in spheroids through a hypoxic, MMP13-driven route. Kindlin-1 therefore cannot be a simple tumour suppressor whose loss is oncogenic, and the direction of its effect appears to depend on cell state or tumour stage. This matters for how the Wnt/β-catenin model is read: if the relevant variable is context rather than dose, then a mechanism calibrated on germline null keratinocytes may not describe the sporadic disease at all, and any therapeutic inference drawn from one setting does not transfer to the other.
Proposed experiments
Map kindlin-1 level against tumour stage in Kindler and sporadic SCC
exp_keb_kindlin1_dose_and_stage_dependence_in_scc
Quantify kindlin-1 protein and FERMT1 transcript across matched lesion series — normal skin, actinic keratosis, in situ and invasive SCC — drawn from both Kindler syndrome patients and sporadic cases, and pair this with Wnt target-gene, hypoxia and MMP13 readouts in the same lesions. Then test directionality by titrating kindlin-1 up and down in the same SCC line and measuring growth and invasion, rather than comparing across models.
Would support
mechanistic_hypotheses#wnt_beta_catenin_scc_model
Would refute
mechanistic_hypotheses#wnt_beta_catenin_scc_model
Supporting outcome
  • Wnt target activation tracks kindlin-1 loss in both settings, with the sporadic FERMT1 elevation confined to a stage or compartment that does not overlap the Wnt-high population.
Refuting outcome
  • Wnt target activation is absent from Kindler SCC lesions, or tracks kindlin-1 in the opposite direction, leaving the hypoxia/MMP13 route rather than Wnt de-repression as the operative mechanism.
Raised from the 2026 openscientist hypothesis-search report and its assessment (kb/hypotheses/Kindler_Epidermolysis_Bullosa/wnt_beta_catenin_scc_model).
Show evidence (1 reference)
PMID:38982038 SUPPORT Human Clinical
"elevation of FERMT1 expression is increased in actinic keratoses compared to normal skin, with a further increase in cSCC supporting a pro-tumorigenic role in this population"
Documents the opposite-direction half of the paradox in human lesion tissue — FERMT1 rising with progression in sporadic disease — against which the loss-of-function mechanism in Kindler syndrome has to be reconciled.
Does kindlin-1 loss reduce TGF-β signalling, as the canonical model states, or increase it, as the mouse proteomic study reports — and are these the same signal?
INTERPRETATION OPEN gap_keb_tgf_beta_direction_autocrine_versus_paracrine
Attached to
mechanistic_hypotheses#wnt_beta_catenin_scc_model
The canonical model has kindlin-1 promoting αvβ6-integrin-mediated TGF-β activation, so that its loss removes a growth-inhibitory signal. Carrasco et al. (PMID:42091340) deleted Kindlin-1 in adult mouse epidermis and found increased TGF-β signalling with activation of dermal fibroblasts, a fibrotic matrix and suppressed Gstp1. Both cannot be the same claim about the same signal. The most likely reconciliation is compartmental — autocrine keratinocyte growth inhibition lost, paracrine keratinocyte-to-fibroblast signalling gained — and if that is right the entry should say which arm each piece of evidence speaks to, because a reader currently sees TGF-β cited in both directions in the same hypothesis block. The alternative, that the direction differs between germline and adult-induced deletion, would be a genuine limit on the mouse evidence rather than a labelling problem.
Proposed experiments
Resolve TGF-β signalling by compartment after kindlin-1 deletion
exp_keb_compartment_resolved_tgf_beta_signalling
In the same kindlin-1-deleted skin, measure Smad2/3 activation and TGF-β target genes separately in keratinocytes and in dermal fibroblasts, with αvβ6-blocking and TGF-β-neutralising arms, and repeat under germline versus adult-induced deletion. This distinguishes a compartmental split from a real reversal of direction.
Would support
mechanistic_hypotheses#wnt_beta_catenin_scc_model
Would refute
mechanistic_hypotheses#wnt_beta_catenin_scc_model
Supporting outcome
  • Keratinocyte-autonomous TGF-β/Smad activity falls after kindlin-1 loss while fibroblast TGF-β activity rises, confirming that the two reports describe different compartments of one mechanism.
Refuting outcome
  • Keratinocyte-autonomous TGF-β signalling is increased or unchanged after kindlin-1 loss, contradicting the loss-of-growth-inhibition arm of the canonical model.
Raised from the 2026 openscientist hypothesis-search report and its assessment (kb/hypotheses/Kindler_Epidermolysis_Bullosa/wnt_beta_catenin_scc_model).
Show evidence (1 reference)
PMID:42091340 SUPPORT Model Organism
"we found increased TGFβ signaling and activation of dermal fibroblasts in Kindlin-1 deleted skin, highlighting the importance of paracrine signaling in the control of skin homeostasis by Kindlin-1"
States the increased-TGF-β observation that sits in tension with the canonical model's loss-of-TGF-β-activation arm, and attributes it to paracrine signalling, which is the reconciliation this discussion proposes to test.
⚙

Pathophysiology

5
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 CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
FERMT1 hgnc:15889 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FERMT1 (hgnc:15889). hgnc:15889 is a gene from the HUGO Gene Nomenclature Committee.
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 CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
focal adhesion assembly GO:0048041 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased focal adhesion assembly (GO:0048041). GO:0048041 is a biological process from the Gene Ontology. integrin-mediated signaling pathway GO:0007229 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased integrin-mediated signaling pathway (GO:0007229). GO:0007229 is a biological process from the Gene Ontology. cell-matrix adhesion GO:0007160 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cell-matrix adhesion (GO:0007160). GO:0007160 is a biological process from the Gene Ontology.
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 CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
wound healing GO:0042060 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased wound healing (GO:0042060). GO:0042060 is a biological process from the Gene Ontology. cell migration GO:0016477 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cell migration (GO:0016477). GO:0016477 is a biological process from the Gene Ontology.
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 CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
response to oxidative stress GO:0006979 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. epidermis development GO:0008544 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal epidermis development (GO:0008544). GO:0008544 is a biological process from the Gene Ontology.
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 CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
integrin-mediated signaling pathway GO:0007229 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased integrin-mediated signaling pathway (GO:0007229). GO:0007229 is a biological process from the Gene Ontology. cell-matrix adhesion GO:0007160 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cell-matrix adhesion (GO:0007160). GO:0007160 is a biological process from the Gene Ontology.
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.
Pathograph: causal mechanism network for Kindler Epidermolysis Bullosa Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

11
Digestive 2
Colitis OCCASIONAL HP:0002583 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is colitis (HP:0002583). HP:0002583 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:19057668 SUPPORT 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 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is esophageal stricture (HP:0002043). HP:0002043 is a phenotype from the Human Phenotype Ontology.
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 HP:0008661 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is urethral stenosis (HP:0008661). HP:0008661 is a phenotype from the Human Phenotype Ontology.
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 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is periodontitis (HP:0000704). HP:0000704 is a phenotype from the Human Phenotype Ontology.
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 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is skin blistering, annotated with Abnormal blistering of the skin (HP:0008066). HP:0008066 is a phenotype from the Human Phenotype Ontology.
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
"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 skin blistering as a key component of the Kindler syndrome phenotype.
Poikiloderma VERY_FREQUENT HP:0001029 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is poikiloderma (HP:0001029). HP:0001029 is a phenotype from the Human Phenotype Ontology.
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 HP:0000992 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is cutaneous photosensitivity (HP:0000992). HP:0000992 is a phenotype from the Human Phenotype Ontology.
Show evidence (5 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.
+ 2 more references
Progressive Skin Atrophy VERY_FREQUENT Dermal atrophy HP:0004334 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is diffuse cutaneous atrophy, annotated with Dermal atrophy (HP:0004334). HP:0004334 is a phenotype from the Human Phenotype Ontology.
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 HP:0000982 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is palmoplantar keratoderma (HP:0000982). HP:0000982 is a phenotype from the Human Phenotype Ontology.
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 HP:0008404 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is nail dystrophy (HP:0008404). HP:0008404 is a phenotype from the Human Phenotype Ontology.
Nail dystrophy is reported in Kindler syndrome case series but specific abstract-level evidence is limited.
Squamous Cell Carcinoma Risk FREQUENT HP:0002860 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is squamous cell carcinoma (HP:0002860). HP:0002860 is a phenotype from the Human Phenotype Ontology.
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

1
FERMT1 (Causative)
Gene: FERMT1 hgnc:15889 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FERMT1 (hgnc:15889). hgnc:15889 is a gene from the HUGO Gene Nomenclature Committee.
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.
💊

Medical Actions

6
Wound Care and Skin Protection
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
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 careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
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 careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
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 careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
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 screeningNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cancer screening (NCIT:C15406). NCIT:C15406 is a clinical intervention from the NCI Thesaurus. Ontology label: Cancer Screening NCIT:C15406
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 CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
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.
📊

Prevalence

1
Global
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.
Show evidence (2 references)
PMID:38371949 SUPPORT Human Clinical
"To this date, about 400 cases have been reported worldwide for this disease only"
Case report from 2024 confirms the approximate worldwide count of ~400 identified cases of Kindler syndrome.
PMID:21936020 SUPPORT Human Clinical
"Herein we review the clinical and genetic data of 62 patients, and delineate the natural history of the disorder"
The largest systematic review at the time (2011) catalogued 62 patients, contributing to the worldwide count of identified cases.
📊

Related Datasets

1
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

1
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 HP:0001058 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Wound healing impairment, annotated with Poor wound healing (HP:0001058). HP:0001058 is a phenotype from the Human Phenotype Ontology.
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'
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: DERMATOLOGY
    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: GENETICS_ENVIRONMENT_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.
  iuis_category:
    classification_value: immune dysregulation
    notes: >-
      IUIS 2022 IEI classification (Tangye et al., PMID:35748970), Table 4
      "Diseases of immune dysregulation", section 3 "Regulatory T Cell
      Defects" — the "FERMT1 deficiency" row (AR, OMIM 173650). This
      assignment follows the IUIS committee's placement rather than a strong
      immunological phenotype: the row's associated-features cell describes a
      dermatosis (congenital blistering, skin atrophy, photosensitivity, skin
      fragility, scaling) and its functional-defect cell describes
      intracellular accumulation of IgG, IgM, IgA and C3 in colloid bodies
      under the basement membrane, and Kindler EB remains clinically a
      mechanobullous skin disease. Recorded so the entry is queryable as a
      Table 4 member without over-reading the immunological claim.
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "FERMT1 deficiency FERMT1 AR 173650"
      explanation: >-
        The quoted Table 4 row (section "Regulatory T Cell Defects") lists
        FERMT1 deficiency — Kindler epidermolysis bullosa — with its gene,
        inheritance and OMIM number, establishing its membership in the IUIS
        "diseases of immune dysregulation" category.
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
  conforms_to: "dermal_epidermal_junction_adhesion_failure#Basement Membrane Zone Attachment Component Defect"
  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
  conforms_to: "dermal_epidermal_junction_adhesion_failure#Loss of Adhesive Integrity at a Defined Cleavage Plane"
  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.
  notes: >-
    Retained as CANONICAL but with important asymmetric-arm and multi-hit
    qualifications from the 2026 openscientist hypothesis-search report
    (kb/hypotheses/Kindler_Epidermolysis_Bullosa/wnt_beta_catenin_scc_model).
    The **TGF-β arm** is robustly validated by independent skin-carcinogenesis
    literature (TGF-β1 knockout → rapid SCC; Smad2 ablation → accelerated
    SCC). The **Wnt arm** rests primarily on the foundational Rognoni 2014
    mouse-model study and lacks independent replication of the specific
    kindlin-1→Wnt link in 12 years. At least four parallel/complementary
    mechanisms by which kindlin-1 loss promotes SCC have been independently
    demonstrated: oxidative-stress/ERK vulnerability, UV-induced NF-κB/JNK
    inflammation, hypoxia/MMP13-driven invasion, and EMT/fibrosis with
    Gstp1 suppression. Clinical SCC epidemiology (cumulative risk 66.7% by
    age >60, concentration at chronic-inflammation sites, 53.8% metastatic)
    is more consistent with a multi-hit model than a singular
    Wnt-driven-initiation model.
  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.
  - reference: PMID:7958907
    reference_title: "Targeted deletion of the TGF-beta 1 gene causes rapid progression to squamous cell carcinoma."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "autocrine TGF-beta 1 suppresses the frequency and rate of malignant progression"
    explanation: >
      Independent validation of the TGF-β arm of the canonical model:
      keratinocyte-specific TGF-β1 deletion produces rapid SCC progression,
      directly testing the tumor-suppressive role of TGF-β signaling that
      kindlin-1 loss disrupts.
  - reference: PMID:18618014
    reference_title: "Keratinocyte-specific Smad2 ablation results in increased epithelial-mesenchymal transition during skin cancer formation and progression."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "enhanced Smad3/Smad4-mediated Snail transcription contributed to Smad2 loss-associated EMT during skin carcinogenesis"
    explanation: >
      Keratinocyte-specific Smad2 ablation accelerates SCC formation with
      EMT and Snail upregulation, independently validating that loss of
      TGF-β/Smad signaling is sufficient to accelerate skin
      carcinogenesis — supporting the TGF-β arm of the canonical model.
  - reference: PMID:38982038
    reference_title: "Involvement of Kindlin-1 in cutaneous squamous cell carcinoma."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "development of a hypoxic tumor environment and increased glycolysis"
    explanation: >
      Qualifies the canonical model: kindlin-1 loss in SCC also drives
      tumor progression through a hypoxic/MMP13-mediated invasion pathway
      independent of the Wnt-driven stem-cell expansion mechanism.
  - reference: PMID:42091340
    reference_title: "Epidermal deletion of Kindlin-1 drives matrix changes in the mouse skin and altered responses to ultraviolet radiation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Kindlin-1 deletion led to profound suppression of gene expression of the antioxidant enzyme Gstp1 and exacerbated ultraviolet radiation (UVR) induced DNA damage"
    explanation: >
      Qualifies the canonical model: kindlin-1 loss also drives EMT/fibrosis
      and suppresses Gstp1 antioxidant defense, providing a tumor-permissive
      microenvironment via UV-damage accumulation that operates in parallel
      with the Wnt arm.
  - 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: "concentrated in the hands and around the oral cavity, which are areas of high inflammation in this disease"
    explanation: >
      Largest clinical KS cohort (n=91) shows SCC body distribution
      concentrated at chronic-inflammation sites with 66.7% cumulative
      risk by age >60 and 53.8% metastatic rate, consistent with a
      multi-hit pathogenesis layered on the canonical model.
- 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.
  notes: >-
    Retained as CANONICAL, with scope qualifications from the 2026 openscientist
    hypothesis-search report and its assessment
    (kb/hypotheses/Kindler_Epidermolysis_Bullosa/oxidative_stress_photosensitivity_model).
    The oxidative-stress phenotype is the best-supported component: three
    independent groups report increased UV/oxidative vulnerability and DNA
    damage in kindlin-1-deficient keratinocytes (PMID:28501563,
    PMID:27798104, PMID:27725201), and two of them (PMID:28501563,
    PMID:27798104) measure elevated ROS itself. The ERK arm rests on the
    single Emmert 2017 study, but it is not contradicted: neither the p38
    study (PMID:27798104) nor the NF-κB/JNK study (PMID:27725201) assayed
    ERK, so they establish additional UV-response pathways rather than
    displacing ERK. The model is therefore best read as a multi-pathway
    signalling deficiency of which the ERK arm is one measured component.
    The "integrin-dependent" framing was tested rather than assumed —
    Emmert reports that the ERK activation and DNA-damage protection depend
    on kindlin-1's ability to bind integrins — so kindlin-1's separate
    integrin-independent functions (EGFR stabilization, microtubule/mitotic
    regulation) do not qualify it. UV-B additionally depletes the partially
    compensatory kindlin-2 paralog (PMID:21356350), though the resulting
    worsening of photosensitivity is inferred rather than demonstrated, and
    kindlin-2 does not compensate for UV-B apoptosis at all (PMID:27798104).
  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.
  - reference: PMID:28501563
    reference_title: "Kindlin-1 protects cells from oxidative damage through activation of ERK signalling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "the Kindlin-1 dependent activation of ERK and protection from DNA damage following oxidative stress depends on the ability of Kindlin-1 to bind integrins"
    explanation: >
      Substantiates the "integrin-dependent" wording of this hypothesis: the ERK
      activation and the DNA-damage protection it confers were both shown to
      require kindlin-1's integrin-binding ability. Integrin dependence is
      therefore a tested result here, not an assumption carried over from
      kindlin-1's canonical adhesion role, and kindlin-1's other
      integrin-independent activities do not bear on it.
  - reference: PMID:27798104
    reference_title: "UV-B-induced cutaneous inflammation and prospects for antioxidant treatment in Kindler syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These cytokines are dependent on p38 activation"
    explanation: >
      Qualifies the ERK-specific arm: independent KS-keratinocyte data show
      p38-dependent (not ERK-dependent) pro-inflammatory cytokine
      upregulation in response to UV-B, and antioxidant rescue confirms
      the ROS-driven photosensitivity phenotype broadly.
  - reference: PMID:27725201
    reference_title: "KIND1 Loss Sensitizes Keratinocytes to UV-Induced Inflammatory Response and DNA Damage."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "KIND1 loss impaired DNA repair, as indicated by the increased"
    explanation: >
      Qualifies the canonical ERK-centric model: KIND1 loss activates
      NF-κB and JNK inflammatory signaling pathways, drives CPD/γH2AX
      accumulation post-UVB, and JNK/NF-κB inhibition restores DNA repair —
      implicating multi-pathway signaling deficiency rather than ERK
      alone.
  - reference: PMID:21356350
    reference_title: "Kindlin-1 and -2 have overlapping functions in epithelial cells implications for phenotype modification."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "UV-B irradiation induced loss of kindlin-2 in keratinocytes"
    explanation: >
      Adds a "double-hit" qualification: UV-B exposure depletes the
      compensatory kindlin-2 paralog, worsening kindlin-1-deficient
      keratinocyte function and amplifying the photosensitivity phenotype.
  - reference: PMID:30248333
    reference_title: "Kindlin-1 Regulates Epidermal Growth Factor Receptor Signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "kindlin-1 can associate directly with EGFR in vitro and in keratinocytes in an EGF-dependent, integrin-independent manner"
    explanation: >
      Qualifies the "integrin-dependent" framing of the canonical model:
      kindlin-1 directly stabilizes EGFR in an integrin-independent
      manner. Kindlin-1 loss reduces EGFR levels, which may also
      contribute to photosensitivity through impaired
      survival/proliferative signaling.
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.
  - reference: PMID:27798104
    reference_title: "UV-B-induced cutaneous inflammation and prospects for antioxidant treatment in Kindler syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show a direct relationship between kindlin-1 abundance and UV-B induced apoptosis in keratinocytes, whereas kindlin-2 overexpression has no compensatory effect. Importantly, low levels of kindlin-1 are sufficient to relieve or rescue this feature."
    explanation: >
      Gives the photosensitivity phenotype a dose-dependent, kindlin-1-specific
      basis: UV-B-induced keratinocyte apoptosis tracks kindlin-1 abundance, the
      kindlin-2 paralog cannot substitute for it, and low residual kindlin-1
      suffices to relieve the phenotype. This is consistent with the milder
      course reported for missense and in-frame variants, though the cited work
      did not itself stratify patients by mutation class.
- 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: SUPPORT
    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: NCIT:C15747
      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: NCIT:C15747
      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: NCIT:C15747
      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: NCIT:C15747
      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: NCIT:C15406
      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: NCIT:C15240
      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
    reference_title: "A Randomised, Double-Blind, Vehicle-Controlled Phase 2 Study of Topically Applied INM-755 (Cannabinol) Cream in Patients With Epidermolysis Bullosa"
    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
  gene_term:
    preferred_term: FERMT1
    term:
      id: hgnc:15889
      label: 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
    reference_title: "Kindler syndrome microarray study"
    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
    reference_title: "Kindler syndrome microarray study"
    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.
discussions:
- discussion_id: gap_keb_erk_arm_unreplicated_and_untested_in_patients
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - mechanistic_hypotheses#oxidative_stress_photosensitivity_model
  - phenotypes#Cutaneous Photosensitivity
  prompt: >-
    Is impaired ERK activation the pathway that actually limits DNA-damage
    protection in kindlin-1-deficient human skin, or one of several parallel
    UV-response deficits none of which has been measured in a patient?
  rationale: >-
    Every measurement behind this hypothesis was made in cultured cells. Emmert
    (PMID:28501563) is the only study that assayed ERK at all, and the two studies
    usually cited against it did not: the p38 work (PMID:27798104) measured
    cytokine induction and the NF-κB/JNK work (PMID:27725201) measured DNA-repair
    readouts, so neither shows ERK is uninvolved or subordinate. What is missing
    is the comparison — ERK, p38, JNK and NF-κB assayed side by side after matched
    UVA and UVB doses, which matters because the ERK evidence comes from UVA and
    the competing evidence from UVB, two wavelengths with different primary
    mechanisms of damage. Nothing has been measured in patient tissue: no ROS,
    8-OHdG, γH2AX or phospho-MAPK study of UV-exposed Kindler skin has been
    published. The gap is not academic, because the one therapeutic lead the
    mechanism has produced — topical antioxidants and luteolin, which reduce UV-B
    apoptosis in organotypic KS cultures (PMID:27798104) — has never been taken
    into a patient. The completed EB trial curated in this entry (NCT04908215)
    tested topical cannabinol for wound healing and does not address it.
  proposed_experiments:
  - experiment_id: exp_keb_multi_mapk_uva_versus_uvb_head_to_head
    name: Assay ERK, p38, JNK and NF-κB side by side after matched UVA and UVB doses
    description: >-
      Irradiate patient-derived kindlin-1-deficient keratinocytes and
      kindlin-1-reconstituted controls with matched biologically relevant UVA and
      UVB doses, and follow phospho-ERK, phospho-p38, phospho-JNK and NF-κB
      activation over a time course alongside viability, γH2AX foci and
      cyclobutane pyrimidine dimers. Then apply pathway-selective inhibition and
      rescue to each arm separately. The point is to test whether the ERK arm is
      the rate-limiting one, one of several additive deficits, or specific to the
      UVA condition in which it was originally found.
    would_support:
    - mechanistic_hypotheses#oxidative_stress_photosensitivity_model
    supporting_outcome:
    - >-
      ERK inhibition selectively worsens, and ERK activation selectively rescues,
      DNA damage and viability in kindlin-1-expressing but not kindlin-1-deficient
      cells across both wavelengths, with the other pathways contributing less.
    would_refute:
    - mechanistic_hypotheses#oxidative_stress_photosensitivity_model
    refuting_outcome:
    - >-
      ERK activation is unchanged or intact in kindlin-1-deficient cells, or no
      single-pathway rescue improves the DNA-damage endpoint while p38 or JNK
      inhibition does, indicating the ERK arm is not the operative deficit.
  - experiment_id: exp_keb_uv_response_biomarkers_in_patient_skin
    name: Measure oxidative damage and MAPK activation in UV-exposed Kindler skin
    description: >-
      Take paired punch biopsies from UV-exposed and habitually UV-protected sites
      in Kindler syndrome patients and age-matched controls, stratified by whether
      the FERMT1 genotype is predicted null or retains partial function, and stain
      for 8-OHdG, γH2AX, cyclobutane pyrimidine dimers and phospho-ERK/p38/JNK.
      This is the missing translational step: it would also test in patients the
      kindlin-1 abundance threshold seen in culture, where low residual kindlin-1
      was enough to relieve UV-B apoptosis.
    would_support:
    - mechanistic_hypotheses#oxidative_stress_photosensitivity_model
    supporting_outcome:
    - >-
      UV-exposed Kindler skin shows higher oxidative DNA damage and altered MAPK
      activation than control skin, graded by residual kindlin-1 level.
    would_refute:
    - mechanistic_hypotheses#oxidative_stress_photosensitivity_model
    refuting_outcome:
    - >-
      Oxidative DNA damage and MAPK activation in UV-exposed Kindler skin are
      indistinguishable from controls, leaving the cultured-cell phenotype without
      an in vivo correlate.
  evidence:
  - reference: PMID:27798104
    reference_title: "UV-B-induced cutaneous inflammation and prospects for antioxidant treatment in Kindler syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "antioxidants and the plant flavonoid luteolin represent feasible topical therapeutic approaches decreasing UV-B induced apoptosis in two-dimensional and organotypic KS cultures"
    explanation: >
      Establishes the untested therapeutic lead this gap turns on — a topical
      intervention that works on the proposed mechanism in organotypic Kindler
      cultures and has never been evaluated in patients.
  notes: >-
    Raised from the 2026 openscientist hypothesis-search report and its assessment
    (kb/hypotheses/Kindler_Epidermolysis_Bullosa/oxidative_stress_photosensitivity_model).
    The report's own claims of exhaustive negative searches are not auditable — no
    search log is committed — so this gap is stated as what the cited primary
    literature does and does not show, not as a claim that nothing else exists.
- discussion_id: gap_keb_fermt1_direction_paradox_in_scc
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - mechanistic_hypotheses#wnt_beta_catenin_scc_model
  - phenotypes#Squamous Cell Carcinoma Risk
  prompt: >-
    How can loss of kindlin-1 drive squamous cell carcinoma in Kindler syndrome
    when elevated FERMT1 expression accompanies sporadic cutaneous SCC?
  rationale: >-
    A single study reports both halves, so this is not a discrepancy between
    laboratories that can be argued away on methodology. Carrasco et al.
    (PMID:38982038) found FERMT1 expression rising from normal skin to actinic
    keratosis to cutaneous SCC in non-Kindler patients, consistent with a
    pro-tumorigenic role, and in the same paper found that depleting kindlin-1
    increased SCC growth in vivo and in spheroids through a hypoxic,
    MMP13-driven route. Kindlin-1 therefore cannot be a simple tumour suppressor
    whose loss is oncogenic, and the direction of its effect appears to depend on
    cell state or tumour stage. This matters for how the Wnt/β-catenin model is
    read: if the relevant variable is context rather than dose, then a mechanism
    calibrated on germline null keratinocytes may not describe the sporadic
    disease at all, and any therapeutic inference drawn from one setting does not
    transfer to the other.
  proposed_experiments:
  - experiment_id: exp_keb_kindlin1_dose_and_stage_dependence_in_scc
    name: Map kindlin-1 level against tumour stage in Kindler and sporadic SCC
    description: >-
      Quantify kindlin-1 protein and FERMT1 transcript across matched lesion
      series — normal skin, actinic keratosis, in situ and invasive SCC — drawn
      from both Kindler syndrome patients and sporadic cases, and pair this with
      Wnt target-gene, hypoxia and MMP13 readouts in the same lesions. Then test
      directionality by titrating kindlin-1 up and down in the same SCC line and
      measuring growth and invasion, rather than comparing across models.
    would_support:
    - mechanistic_hypotheses#wnt_beta_catenin_scc_model
    supporting_outcome:
    - >-
      Wnt target activation tracks kindlin-1 loss in both settings, with the
      sporadic FERMT1 elevation confined to a stage or compartment that does not
      overlap the Wnt-high population.
    would_refute:
    - mechanistic_hypotheses#wnt_beta_catenin_scc_model
    refuting_outcome:
    - >-
      Wnt target activation is absent from Kindler SCC lesions, or tracks
      kindlin-1 in the opposite direction, leaving the hypoxia/MMP13 route rather
      than Wnt de-repression as the operative mechanism.
  evidence:
  - reference: PMID:38982038
    reference_title: "Involvement of Kindlin-1 in cutaneous squamous cell carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "elevation of FERMT1 expression is increased in actinic keratoses compared to normal skin, with a further increase in cSCC supporting a pro-tumorigenic role in this population"
    explanation: >
      Documents the opposite-direction half of the paradox in human lesion
      tissue — FERMT1 rising with progression in sporadic disease — against which
      the loss-of-function mechanism in Kindler syndrome has to be reconciled.
  notes: >-
    Raised from the 2026 openscientist hypothesis-search report and its assessment
    (kb/hypotheses/Kindler_Epidermolysis_Bullosa/wnt_beta_catenin_scc_model).
- discussion_id: gap_keb_tgf_beta_direction_autocrine_versus_paracrine
  kind: INTERPRETATION
  status: OPEN
  attaches_to:
  - mechanistic_hypotheses#wnt_beta_catenin_scc_model
  prompt: >-
    Does kindlin-1 loss reduce TGF-β signalling, as the canonical model states, or
    increase it, as the mouse proteomic study reports — and are these the same
    signal?
  rationale: >-
    The canonical model has kindlin-1 promoting αvβ6-integrin-mediated TGF-β
    activation, so that its loss removes a growth-inhibitory signal. Carrasco et
    al. (PMID:42091340) deleted Kindlin-1 in adult mouse epidermis and found
    increased TGF-β signalling with activation of dermal fibroblasts, a fibrotic
    matrix and suppressed Gstp1. Both cannot be the same claim about the same
    signal. The most likely reconciliation is compartmental — autocrine
    keratinocyte growth inhibition lost, paracrine keratinocyte-to-fibroblast
    signalling gained — and if that is right the entry should say which arm each
    piece of evidence speaks to, because a reader currently sees TGF-β cited in
    both directions in the same hypothesis block. The alternative, that the
    direction differs between germline and adult-induced deletion, would be a
    genuine limit on the mouse evidence rather than a labelling problem.
  proposed_experiments:
  - experiment_id: exp_keb_compartment_resolved_tgf_beta_signalling
    name: Resolve TGF-β signalling by compartment after kindlin-1 deletion
    description: >-
      In the same kindlin-1-deleted skin, measure Smad2/3 activation and TGF-β
      target genes separately in keratinocytes and in dermal fibroblasts, with
      αvβ6-blocking and TGF-β-neutralising arms, and repeat under germline versus
      adult-induced deletion. This distinguishes a compartmental split from a
      real reversal of direction.
    would_support:
    - mechanistic_hypotheses#wnt_beta_catenin_scc_model
    supporting_outcome:
    - >-
      Keratinocyte-autonomous TGF-β/Smad activity falls after kindlin-1 loss while
      fibroblast TGF-β activity rises, confirming that the two reports describe
      different compartments of one mechanism.
    would_refute:
    - mechanistic_hypotheses#wnt_beta_catenin_scc_model
    refuting_outcome:
    - >-
      Keratinocyte-autonomous TGF-β signalling is increased or unchanged after
      kindlin-1 loss, contradicting the loss-of-growth-inhibition arm of the
      canonical model.
  evidence:
  - reference: PMID:42091340
    reference_title: "Epidermal deletion of Kindlin-1 drives matrix changes in the mouse skin and altered responses to ultraviolet radiation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we found increased TGFβ signaling and activation of dermal fibroblasts in Kindlin-1 deleted skin, highlighting the importance of paracrine signaling in the control of skin homeostasis by Kindlin-1"
    explanation: >
      States the increased-TGF-β observation that sits in tension with the
      canonical model's loss-of-TGF-β-activation arm, and attributes it to
      paracrine signalling, which is the reconciliation this discussion proposes
      to test.
  notes: >-
    Raised from the 2026 openscientist hypothesis-search report and its assessment
    (kb/hypotheses/Kindler_Epidermolysis_Bullosa/wnt_beta_catenin_scc_model).
references:
- reference: PMID:26937547
  title: "Kindler Syndrome."
  tags:
  - GeneReviews
  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: HUMAN_CLINICAL
      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

18
PMID:26937547
Kindler Syndrome.
No top-level findings curated for this source.
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
"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."
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
"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."
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 Human Clinical
"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."
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
"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."
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.
No top-level findings curated for this source.
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.
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

1

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

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

  1. (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.

  2. (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.

  3. (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.

  4. (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.

  5. (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.

  6. (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.

  7. (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.

  8. (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.

  9. (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.

  10. (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.

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  12. (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.

  13. (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.

  14. (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.

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  16. (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.

  17. (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.

  18. (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.

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  21. (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.

  22. (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.

  23. (NCT03068780 chunk 1): Phase III Efficacy and Safety Study of Oleogel-S10 in Epidermolysis Bullosa. Amryt Research Limited. 2017. ClinicalTrials.gov Identifier: NCT03068780

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