CYLD Cutaneous Syndrome

Mendelian MONDO:0011512 Pathograph 23 Show in embeddings browser hereditary neoplastic syndrome

CYLD cutaneous syndrome is the autosomal dominant skin adnexal tumor predisposition caused by heterozygous germline loss-of-function variants in CYLD at 16q12-q13, which encodes a deubiquitinase that removes K63-linked polyubiquitin from signalling intermediates and restrains NF-kappaB and Wnt/beta-catenin signalling. Carriers develop multiple cylindromas, spiradenomas, spiradenocylindromas and trichoepitheliomas, chiefly on the scalp and face but also on the trunk and in sun-protected genital and axillary skin. The first tumor typically appears around puberty and tumors accumulate through adulthood; in the most severe cases confluent scalp tumors ("turban tumor") lead to total scalp removal. Each tumor completes a second hit at CYLD, most often by loss of heterozygosity of 16q. Tumors overexpress TRKB/TRKC and MYB, which are candidate therapeutic targets. Brooke-Spiegler syndrome, familial cylindromatosis and multiple familial trichoepithelioma were described as separate disorders, but the same germline CYLD variant produces more than one of these presentations within a family, so they are curated here as one entity with phenotypic variants recorded as subtypes. The GeneReviews chapter uses the inclusive name CYLD cutaneous syndrome, which is the name of this entry; MONDO and ClinGen label the concept Brooke-Spiegler syndrome. Rare manifestations are salivary gland membranous basal cell adenoma, pulmonary (large-airway) cylindromas and malignant transformation of a preexisting benign tumor.

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2
Inheritance
9
Pathophys.
8
Phenotypes
1
Gaps
23
Pathograph
1
Genes
6
Medical Actions
2
Subtypes
1
Trials
1
Models
1
References
1
Deep Research
👪

Inheritance

2
Autosomal dominant HP:0000006
Germline CYLD variants are transmitted as an autosomal dominant predisposition, and most probands inherit the variant from a parent. Expressivity is highly variable, both in which tumor types predominate and in tumor burden, and this variability is seen within single families. Age-related penetrance has not been precisely estimated.
Autosomal dominant inheritance Expressivity: VARIABLE
Show evidence (5 references)
PMID:32298062 SUPPORT REVIEW SYNTHESIS Human Clinical
"Germline pathogenic variants in CYLD are inherited in an autosomal dominant manner."
GeneReviews genetic counseling statement of the mode of inheritance.
PMID:32298062 SUPPORT REVIEW SYNTHESIS Human Clinical
"Most individuals with CYLD cutaneous syndrome inherit it from a parent."
Supports the statement that most probands inherit the variant from a parent.
PMID:32298062 SUPPORT REVIEW SYNTHESIS Human Clinical
"Offspring of an individual with CYLD cutaneous syndrome have a 50% chance of inheriting the variant."
GeneReviews transmission risk to offspring of a heterozygous carrier.
+ 2 more references
Somatic mosaic arm HP:0001442
A minority of individuals carry a post-zygotic CYLD variant. They present with clustered, often asymmetric cylindromas or spiradenomas, may have no detectable variant in blood, and can transmit a constitutional form to offspring when the mosaic variant reaches the germline.
Typified by somatic mosaicism
Show evidence (2 references)
PMID:31085270 SUPPORT Human Clinical
"Two patients had mosaic pathogenic CYLD variants in both the blood and skin. One of these patients transmitted a pathogenic variant to her daughter"
Paired blood and skin testing demonstrates post-zygotic CYLD mosaicism with germline transmission.
PMID:31085270 SUPPORT Human Clinical
"Two patients had recurrent pathogenic variants in skin tumors from a single cluster but none detectable in the blood."
Tissue-restricted mosaicism, detectable only by testing more than one tumor from a cluster.
◆

Subtypes

2
Familial cylindromatosis MONDO:0007565
CYLD hgnc:2584 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in CYLD (hgnc:2584). hgnc:2584 is a gene from the HUGO Gene Nomenclature Committee.
Phenotypic variant in which cylindromas predominate, classically on the scalp. Caused by germline CYLD variants; the same variant can present as familial cylindromatosis in one relative and as multiple familial trichoepithelioma in another.
Show evidence (2 references)
PMID:16922728 SUPPORT Human Clinical
"We describe a single family with affected members exhibiting either the FC or the MFT phenotypes associated with a mutation in the CYLD gene."
One CYLD variant produces both the FC and the MFT presentation in one family, supporting treatment as phenotypic variants of one disease.
ORPHA:211 SUPPORT Other
"CYLD | CYLD lysine 63 deubiquitinase | hgnc:2584 | Disease-causing germline mutation(s) in"
Orphanet records familial cylindromatosis as a clinical subtype with CYLD as the disease-causing gene.
Multiple familial trichoepithelioma 1 (CYLD-related) MONDO:0042977
CYLD hgnc:2584 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in CYLD (hgnc:2584). hgnc:2584 is a gene from the HUGO Gene Nomenclature Committee.
Phenotypic variant in which trichoepitheliomas (cribriform trichoblastomas) predominate, mostly on the central face. Only the CYLD-related form is included here. Germline CYLD variants are found less often in this presentation (about 40-50%) than in classical Brooke-Spiegler syndrome (about 80-85%), so a CYLD-negative MFT family may have another cause.
Show evidence (2 references)
PMID:15086550 SUPPORT Human Clinical
"The study firstly identified the cylindromatosis gene responsible for MFT and showed that different mutations of the CYLDI gene can give rise to distinct clinical and histological expression such as FC and MFT."
Linkage to 16q12-q13 and a segregating CYLD frameshift in a large MFT family.
PMID:26971504 SUPPORT REVIEW SYNTHESIS Human Clinical
"Germline CYLD mutations are detected in about 80-85% of patients with the classical BSS phenotype and in about 40-50% of the individuals with the MFT phenotype"
Supports the lower CYLD detection rate in the MFT presentation stated in the description.
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Discussions and Knowledge Gaps

1
Why does constitutional CYLD loss of function produce tumors almost only in hair-follicle-related adnexal lineages, which cell is the tumor of origin, and how does CYLD loss lead to TRK and MYB overexpression?
KNOWLEDGE GAP OPEN gap_cyld_lineage_restriction
Attached to
pathophysiology#Somatic CYLD Second-Hit Inactivation pathophysiology#TRK Receptor Signalling Upregulation pathophysiology#MYB Oncogenic Transcription Program Activation
CYLD restrains several broadly used pathways, yet the tumor spectrum is narrow. Proposed explanations are the ectodysplasin-receptor (EDAR, XEDAR) arm of NF-kappaB signalling and a higher second-hit rate in hormonally stimulated follicles inferred from tumor maps; origin in hair follicle stem cells is stated in the literature as a hypothesis. No cited source establishes the route from CYLD loss to TRKB/TRKC or MYB overexpression.
Proposed experiments
Lineage-resolved second-hit mapping in early CYLD carrier lesions
lineage_resolved_cyld_second_hit_mapping
Microdissect the earliest visible lesions and adjacent follicles from carriers, determine which follicular compartment first shows biallelic CYLD loss, and profile NF-kappaB, Wnt, TRK and MYB programs in those cells relative to heterozygous neighbors.
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Pathophysiology

9
Germline CYLD First-Hit Inactivation
A heterozygous CYLD loss-of-function variant is present constitutionally. Most germline alleles are frameshift or nonsense variants predicted to truncate the protein; missense and splice-site variants, large deletions and inversions account for a minority. Disease-associated truncations reduce the deubiquitinating activity of the encoded enzyme.
CYLD hgnc:2584 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CYLD (hgnc:2584). hgnc:2584 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context CYLD hgnc:2584 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns CYLD (hgnc:2584). hgnc:2584 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE allelic_hit_role: FIRST_HIT allelic_event: FRAMESHIFT_VARIANT allelic_event: NONSENSE_VARIANT zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Constitutional heterozygous CYLD loss of function, predominantly protein-truncating.
K63-linked deubiquitinase activity GO:0061578 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased K63-linked deubiquitinase activity (GO:0061578). GO:0061578 is a molecular function from the Gene Ontology.
Downstream
Somatic CYLD Second-Hit Inactivation With one allele inactivated in every cell, a single somatic event at CYLD in a susceptible adnexal cell becomes the rate-limiting step.
Show evidence (4 references)
PMID:10835629 SUPPORT Human Clinical
"Here we have identified CYLD by detecting germline mutations in 21 cylindromatosis families and somatic mutations in 1 sporadic and 5 familial cylindromas. All mutations predict truncation or absence of the encoded protein."
Gene discovery in 21 families; all germline alleles are predicted loss of function.
PMID:12917691 SUPPORT In Vitro
"Truncations of CYLD found in cylindromatosis result in reduced enzymatic activity, indicating a link between impaired deubiquitination of CYLD substrates and human pathophysiology."
Disease-associated truncations reduce the deubiquitinase activity bound on this node.
PMID:23249834 SUPPORT Human Clinical
"Twenty-one frameshift, 15 nonsense, 3 missense, and 4 splice site mutations were found in patients with BSS"
Allelic spectrum in a 67-patient cohort, dominated by truncating variants.
+ 1 more reference
Somatic CYLD Second-Hit Inactivation
Each tumor inactivates the retained wild-type CYLD allele. Loss of heterozygosity of 16q is the commonest route (about two thirds of tumors with a detected second hit), and intragenic somatic mutation accounts for the rest; apart from 16q LOH, CYLD-mutant tumors carry few copy-number changes. The tumors are of hair-follicle lineage. Tumor mapping in two large families found tumors concentrated at sites of hormonally stimulated hair follicles, which the authors interpret as those follicles being particularly vulnerable to loss of heterozygosity; that is an inference from tumor distribution, not a measured mutation rate.
hair follicle keratinocyte CL:2000092 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hair follicle keratinocyte, annotated with hair follicular keratinocyte (CL:2000092). CL:2000092 is a cell type from the Cell Ontology.
Genetic context CYLD hgnc:2584 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns CYLD (hgnc:2584). hgnc:2584 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: SOMATIC allelic_hit_role: SECOND_HIT allelic_event: LOSS_OF_HETEROZYGOSITY allelic_event: PATHOGENIC_VARIANT functional_impact_category: LOSS_OF_FUNCTION
Acquired inactivation of the wild-type CYLD allele in tumor tissue, mostly by 16q loss of heterozygosity and less often by an intragenic somatic mutation.
Downstream
Biallelic CYLD Loss in Adnexal Keratinocytes Completion of the second hit leaves the tumor-initiating cell without functional CYLD.
Show evidence (5 references)
PMID:23249834 SUPPORT Human Clinical
"Somatic mutations were detected in 67 specimens of these 76 tumors (88%). Of the 67 somatic mutations, 21 (31%) represented a sequence alteration and 46 (69%) showed loss of heterozygosity."
Quantifies the somatic second hit and its two routes in tumors from germline carriers.
PMID:15289313 SUPPORT Human Clinical
"In individual tumors, loss of heterozygosity at 16q or a somatic point mutation in the CYLD gene was detected."
The same two second-hit routes in trichoepitheliomas from an MFT family.
PMID:21552290 SUPPORT Human Clinical
"CYLD mutant tumours were characterised by an absence of copy-number aberrations apart from LOH chromosome 16q, the genomic location of the CYLD gene."
Array CGH shows 16q LOH as essentially the only copy-number event in these tumors.
+ 2 more references
Biallelic CYLD Loss in Adnexal Keratinocytes
Tumor cells lack CYLD protein. CYLD is a deubiquitinase directed at non-K48 (K63-linked) polyubiquitin chains on signalling intermediates, including TRAF2, TRAF6, NEMO, Bcl-3 and Dishevelled, so its loss releases several growth and survival pathways at once. CYLD protein is normally prominent in the inner root sheath of the hair follicle and in eccrine glands, matching the lineages of the tumors.
K63-linked deubiquitinase activity GO:0061578 ∅ ABSENT Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves absent K63-linked deubiquitinase activity (GO:0061578). GO:0061578 is a molecular function from the Gene Ontology.
Downstream
NF-kappaB Pathway Derepression Loss of CYLD removes deubiquitination of TRAF2, NEMO and Bcl-3.
Wnt-beta-Catenin Pathway Hyperactivation Loss of CYLD increases K63-linked ubiquitination of Dishevelled.
TRK Receptor Signalling Upregulation CYLD-null tumors overexpress TRKB and TRKC; the molecular route from CYLD loss to TRK overexpression is not established.
MYB Oncogenic Transcription Program Activation CYLD-defective cylindromas activate MYB without the MYB-NFIB fusion of sporadic cylindromas; the route from CYLD loss to MYB activation is not established.
Impaired DNA Damage-Induced p53 Stabilization Loss of CYLD catalytic activity removes CYLD-dependent deubiquitination of p53 after genotoxic stress. Shown in cultured cells, mice and nematodes, not in human CYLD-null tumors.
Show evidence (2 references)
CGGV:assertion_434ddb72-ee88-47af-9fa2-8dee9fa0a388-2019-04-19T160000.000Z SUPPORT REVIEW SYNTHESIS Other
"CYLD protein is prominently expressed in the inner root sheath of hair follicles of human scalp as well as in eccrine glands. Multiple articles reported no CYLD protein expression in the tumour tissue from BSS patients."
ClinGen evidence summary for absent CYLD protein in tumors and its normal follicular and eccrine expression.
PMID:12917689 SUPPORT In Vitro
"Here we show that CYLD is a deubiquitinating enzyme that negatively regulates activation of the transcription factor NF-kappaB by specific tumour-necrosis factor receptors (TNFRs). Loss of the deubiquitinating activity of CYLD correlates with tumorigenesis."
Establishes CYLD as a deubiquitinase whose loss of activity correlates with tumor formation.
Impaired DNA Damage-Induced p53 Stabilization
CYLD binds and deubiquitinates p53, and is needed for p53 stabilization and activation after DNA damage. Ubiquitin chain-restriction analysis suggests CYLD removes K48 chains from p53 indirectly by cleaving K63 linkages in mixed chains. Loss of CYLD catalytic activity impairs this response in epithelial cells and sensitizes mice to chemical carcinogen-induced skin and intestinal tumors, and CYLD deficiency reduces CEP-1/p53-dependent germ cell apoptosis in C. elegans. This arm rests on model-system and biochemical evidence only; p53 stabilization has not been reported in tumors from CYLD cutaneous syndrome patients in the sources cited here, so its contribution to the human tumors is a hypothesis.
DNA damage-induced p53 signalling GO:0030330 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased DNA damage-induced p53 signalling, annotated with DNA damage response, signal transduction by p53 class mediator (GO:0030330). GO:0030330 is a biological process from the Gene Ontology.
Downstream
Clonal Expansion of CYLD-Null Adnexal Tumor Cells Hypothesized contribution. The supporting result is carcinogen-induced skin and intestinal tumorigenesis in mice lacking CYLD catalytic activity, not adnexal tumor formation in human carriers.
Show evidence (2 references)
DOI:10.1038/ncomms12508 SUPPORT In Vitro
"Mechanistically, CYLD interacts with and deubiquitinates p53 facilitating its stabilization in response to genotoxic stress."
Biochemical basis for CYLD-dependent p53 stabilization after DNA damage.
DOI:10.1038/ncomms12508 SUPPORT Model Organism
"Moreover, CYLD deficiency also diminishes CEP-1/p53-dependent DNA damage-induced germ cell apoptosis in the nematode Caenorhabditis elegans."
The same dependence of the p53 damage response on CYLD in an invertebrate model.
NF-kappaB Pathway Derepression
CYLD binds NEMO and TRAF2 and removes their activating non-K48 polyubiquitin, so its loss augments TNF-receptor-family (CD40, EDAR, XEDAR) activation of canonical NF-kappaB and increases resistance to apoptosis. In keratinocytes, CYLD also deubiquitinates Bcl-3 and keeps it out of the nucleus; Cyld-null keratinocytes accumulate nuclear Bcl-3 with p50 and p52, raise cyclin D1 and proliferate. EDAR and XEDAR are ectodysplasin receptors, which is one proposed reason the phenotype is restricted to skin appendages.
canonical NF-kappaB signal transduction GO:0007249 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased canonical NF-kappaB signal transduction (GO:0007249). GO:0007249 is a biological process from the Gene Ontology. apoptotic process GO:0006915 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology.
Animal models
Cyld knockout mouse (chemical carcinogenesis) Mouse partially recapitulates Cyld-null keratinocytes show Bcl-3-dependent NF-kappaB activation, cyclin D1 elevation and hyperproliferation, and the mice are highly susceptible to chemically induced skin tumors.
Downstream
Clonal Expansion of CYLD-Null Adnexal Tumor Cells Increased survival and proliferation of CYLD-null cells.
Show evidence (6 references)
PMID:12917689 SUPPORT In Vitro
"CYLD inhibits activation of NF-kappaB by the TNFR family members CD40, XEDAR and EDAR in a manner that depends on the deubiquitinating activity of CYLD."
Names the receptors whose NF-kappaB output CYLD restrains, including the ectodysplasin receptors.
PMID:12917689 SUPPORT In Vitro
"These results indicate that CYLD is a negative regulator of the cytokine-mediated activation of NF-kappaB that is required for appropriate cellular homeostasis of skin appendages."
Authors' link between CYLD-restrained NF-kappaB signalling and skin appendage homeostasis.
PMID:12917691 SUPPORT In Vitro
"Here we report that CYLD, a tumour suppressor that is mutated in familial cylindromatosis, interacts with NEMO, the regulatory subunit of IKK."
Places CYLD at the IKK complex.
+ 3 more references
Wnt-beta-Catenin Pathway Hyperactivation
CYLD binds Dishevelled and limits K63-linked ubiquitination of its DIX domain; without CYLD, polymerized Dishevelled is hyperubiquitinated and Wnt-induced beta-catenin accumulation is enhanced. Hyperactive Wnt signalling is seen in human cylindromas.
canonical Wnt signaling pathway GO:0060070 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased canonical Wnt signaling pathway (GO:0060070). GO:0060070 is a biological process from the Gene Ontology.
Downstream
Clonal Expansion of CYLD-Null Adnexal Tumor Cells Enhanced Wnt/beta-catenin output promotes tumor growth.
Show evidence (2 references)
PMID:20227366 SUPPORT In Vitro
"Depletion of CYLD from cultured cells markedly enhances Wnt-induced accumulation of beta-catenin and target gene activation."
Cell-based evidence that CYLD loss enhances canonical Wnt output.
PMID:20227366 SUPPORT Human Clinical
"Moreover, we demonstrate hyperactive Wnt signaling in human cylindroma skin tumors that arise from mutations in CYLD."
The same pathway state observed in patient tumors.
TRK Receptor Signalling Upregulation
Expression profiling of CYLD-mutant tumors against perilesional skin shows overexpression of TRKB (NTRK2) and TRKC (NTRK3), with membranous staining, increased ERK phosphorylation and BCL2 in cylindromas. TRK knockdown or the TRK inhibitor lestaurtinib reduced growth of 3D primary tumor cultures, which is the preclinical basis for topical TRK inhibition.
neurotrophin TRK receptor signaling pathway GO:0048011 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased neurotrophin TRK receptor signaling pathway (GO:0048011). GO:0048011 is a biological process from the Gene Ontology.
Downstream
Clonal Expansion of CYLD-Null Adnexal Tumor Cells TRK signalling supports proliferation of CYLD-null tumor cells.
Show evidence (2 references)
PMID:21552290 SUPPORT Human Clinical
"Gene expression profiling of CYLD mutant tumours showed dysregulated tropomyosin kinase (TRK) signalling, with overexpression of TRKB and TRKC in tumours when compared with perilesional skin."
Patient tumor transcriptomes show TRK overexpression.
PMID:21552290 SUPPORT In Vitro
"RNA interference-mediated silencing of TRKB and TRKC, as well as treatment with the small-molecule TRK inhibitor lestaurtinib, reduced colony formation and proliferation in 3D primary cell cultures established from CYLD mutant tumours."
Functional dependence of tumor cells on TRK signalling in culture.
MYB Oncogenic Transcription Program Activation
Inherited CYLD-defective cylindromas do not carry the MYB-NFIB fusion found in sporadic cylindromas but still overexpress MYB and its target genes, and MYB knockdown reduces cylindroma cell proliferation, so the inherited and sporadic tumors converge on MYB activation by different routes.
cell population proliferation GO:0008283 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology.
Downstream
Clonal Expansion of CYLD-Null Adnexal Tumor Cells MYB drives proliferation of CYLD-defective cylindroma cells.
Show evidence (2 references)
PMID:26969893 SUPPORT Human Clinical
"Strikingly, none of the inherited CYLD-defective (n = 23) tumours expressed MYB-NFIB fusion transcripts. However, MYB expression was increased in the majority of tumours (69%)"
MYB activation without fusion in inherited cylindromas.
PMID:26969893 SUPPORT In Vitro
"Moreover, knock-down of MYB expression caused a significant reduction in cylindroma cell proliferation, suggesting that MYB is also a key player and oncogenic driver in inherited cylindromas."
Functional dependence of cylindroma cells on MYB.
Clonal Expansion of CYLD-Null Adnexal Tumor Cells
CYLD-null clones expand into benign adnexal tumors with follicular (trichoepithelioma) or sweat-gland-like (cylindroma, spiradenoma) differentiation, often several histologies in one patient and hybrid spiradenocylindromas in one lesion. Many arise independently, so tumor number rises with age. Benign tumors frequently carry further clonal mutations in the epigenetic modifiers DNMT3A and BCOR (29% of benign tumors in one series), with marked intra-tumor heterogeneity; the contribution of those mutations to growth or transformation is not established.
Downstream
Multiple Skin Appendage Tumors
Cylindroma
Spiradenoma
Trichoepithelioma
Salivary Gland Membranous Basal Cell Adenoma
Pulmonary Cylindromas
Malignant Transformation of Adnexal Tumors
Show evidence (2 references)
PMID:31624251 SUPPORT Human Clinical
"Here, we comprehensively profile the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families and discover recurrent mutations in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors."
Cooperating somatic events in benign CYLD-null tumors.
PMID:23249834 SUPPORT Human Clinical
"Of the 76 tumors from 32 patients with a germline CYLD mutation, 12 were spiradenomas, 15 spiradenocylindromas, 26 cylindromas, 15 trichoepitheliomas, and 7 were other tumor types."
Histologic spectrum of tumors arising in germline carriers.
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Pathograph

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

8
Digestive 1
Salivary Gland Membranous Basal Cell Adenoma VERY_RARE Salivary basal cell adenoma HP:6000007 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Membranous basal cell adenoma of salivary gland, annotated with Salivary basal cell adenoma (HP:6000007). HP:6000007 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:32298062 SUPPORT REVIEW SYNTHESIS Human Clinical
"A minority of individuals develop salivary gland tumors."
GeneReviews statement of salivary involvement.
ORPHA:79493 SUPPORT Other
"HP:0100684 | Salivary gland neoplasm | Very rare (<4-1%)"
Orphanet frequency class for salivary gland neoplasm.
PMID:29569226 SUPPORT BACKGROUND Human Clinical
"a minority develop a type of salivary gland tumour, membranous basal cell adenoma, which shares similar histology."
Names the salivary tumor type bound here.
Ear 1
Conductive Hearing Impairment HP:0000405 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Conductive hearing impairment (HP:0000405). HP:0000405 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:19917957 SUPPORT Human Clinical
"Symptoms reported by affected patients included painful tumors (in 12 of 23 patients [52%] who answered the question), conductive deafness, and sexual dysfunction."
Conductive deafness reported by affected patients.
ORPHA:79493 SUPPORT Other
"HP:0000372 | Abnormality of the auditory canal | Very rare (<4-1%)"
Orphanet frequency class for auditory canal involvement.
Integument 4
Multiple Skin Appendage Tumors Skin appendage neoplasm HP:0012842 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Multiple skin appendage tumors, annotated with Skin appendage neoplasm (HP:0012842), qualified as juvenile onset, mean 16y, range 8-30y. HP:0012842 is a phenotype from the Human Phenotype Ontology.
Onset: JUVENILE; mean 16y (range 8-30y)
Show evidence (4 references)
PMID:32298062 SUPPORT REVIEW SYNTHESIS Human Clinical
"The first tumor typically develops at puberty and tumors progressively accumulate through adulthood. Females often have more tumors than males. Tumors typically arise on the scalp and face but can also arise on the torso and sun-protected sites, such as the genital and axillary skin."
GeneReviews phenotype baseline for onset, accumulation, sex difference in burden and distribution.
PMID:19917957 SUPPORT Human Clinical
"The average age at onset was 16 years (range, 8-30 years)."
Quantitative onset age.
PMID:19917957 SUPPORT Human Clinical
"Although an approximately equal female to male predisposition was noted, 5 women and 1 man (of 26 patients surveyed [23%]) had undergone total scalp removal."
Equal sex ratio of affected individuals with more severe disease in women, and the rate of total scalp removal.
+ 1 more reference
Cylindroma VERY_FREQUENT HP:0031024 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cylindroma (HP:0031024). HP:0031024 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:79493 SUPPORT Other
"HP:0031024 | Cylindroma | Very frequent (99-80%)"
Orphanet HPO annotation and frequency class.
PMID:32298062 SUPPORT REVIEW SYNTHESIS Human Clinical
"CYLD cutaneous syndrome (CCS) typically manifests in the second or third decade with the appearance of multiple skin tumors including cylindromas, spiradenomas, trichoepitheliomas, and rarely, membranous basal cell adenoma of the salivary gland."
GeneReviews tumor spectrum.
Trichoepithelioma FREQUENT HP:0025367 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Trichoepithelioma (HP:0025367). HP:0025367 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:79493 SUPPORT Other
"HP:0025367 | Trichoepithelioma | Frequent (79-30%)"
Orphanet HPO annotation and frequency class.
PMID:26971504 SUPPORT REVIEW SYNTHESIS Human Clinical
"Multiple familial trichoepithelioma (MFT) is a phenotypic variant of the disease characterized by the development of numerous trichoepitheliomas (cribriform trichoblastoma) only."
Trichoepithelioma as the defining tumor of the MFT presentation.
Malignant Transformation of Adnexal Tumors OCCASIONAL Skin appendage neoplasm HP:0012842 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Malignant adnexal skin tumor arising in a benign precursor, annotated with Skin appendage neoplasm (HP:0012842). HP:0012842 is a phenotype from the Human Phenotype Ontology.
HPO has no term for a malignant adnexal tumor or for malignant change in a cylindroma or spiradenoma. OLS searches of HPO (ontology=hp, 2026-10-14) for "cylindrocarcinoma", "spiradenocarcinoma", "malignant cylindroma", "malignant spiradenoma", "sweat gland carcinoma" and "skin appendage carcinoma" returned no terms; "adnexal carcinoma" returned only HP:0031548 Follicular infundibulum tumor; and "skin carcinoma" returned squamous cell, basal cell, Merkel cell and sebaceous gland carcinoma terms among unrelated hits, none of which names these tumors. The binding is HP:0012842 Skin appendage neoplasm, which HPO defines as "A benign or malignant neoplasm that arises from the hair follicles, sebaceous glands, or sweat glands" and which sits under HP:0008069 Neoplasm of the skin. It is the same term as the benign tumor phenotype, so the malignant state is carried only by preferred_term.
Show evidence (4 references)
PMID:26971504 SUPPORT REVIEW SYNTHESIS Human Clinical
"Malignant tumors arise in association with preexisting benign cutaneous neoplasms in about 5-10% of the patients ."
Frequency of malignant transformation, supporting the OCCASIONAL class.
PMID:32975300 SUPPORT Human Clinical
"Our analysis revealed only age as a predictor of malignancy; however, this is also a general risk factor for development of malignancy and therefore of limited value as a screening tool."
No clinical predictor beyond age.
PMID:32975300 SUPPORT BACKGROUND Human Clinical
"An increased risk of malignant transformation of adnexal cutaneous tumors in BSS patients has been reported."
States that the malignancies arise from the adnexal tumors, which is the basis for binding a skin appendage neoplasm term.
+ 1 more reference
Neoplasm 1
Pulmonary Cylindromas HP:0034637 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary cylindroma (HP:0034637). HP:0034637 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:29569226 SUPPORT Human Clinical
"Four patients had radiological imaging of their lungs, of which two had multiple pulmonary cylindromas that were confirmed histologically."
Case series establishing pulmonary cylindromas in CYLD carriers.
PMID:31624251 SUPPORT Human Clinical
"Phylogenetic and mutational signature analyses confirm cylindroma pulmonary metastases from primary skin tumors."
At least some pulmonary cylindromas are metastatic rather than primary.
PMID:32298062 SUPPORT REVIEW SYNTHESIS Human Clinical
"Rarely, pulmonary cylindromas can develop in large airways and compromise breathing."
GeneReviews baseline statement of large-airway cylindromas and their respiratory consequence.
Other 1
Spiradenoma
Left unbound: an OLS search of the hp ontology for "spiradenoma" returned no terms. The parent concept HP:0012842 Skin appendage neoplasm is bound on the Multiple Skin Appendage Tumors phenotype.
Show evidence (2 references)
PMID:32298062 SUPPORT REVIEW SYNTHESIS Human Clinical
"CYLD cutaneous syndrome (CCS) typically manifests in the second or third decade with the appearance of multiple skin tumors including cylindromas, spiradenomas, trichoepitheliomas, and rarely, membranous basal cell adenoma of the salivary gland."
GeneReviews tumor spectrum includes spiradenoma.
PMID:19917957 SUPPORT Human Clinical
"Symptoms reported by affected patients included painful tumors (in 12 of 23 patients [52%] who answered the question), conductive deafness, and sexual dysfunction."
Pain is a common symptom; the study does not attribute it to a single histology.
🧬

Genetic Associations

1
CYLD (Heterozygous germline loss-of-function variants in CYLD cause CYLD cutaneous syndrome; post-zygotic CYLD variants cause a mosaic form.)
Gene: CYLD hgnc:2584 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CYLD (hgnc:2584). hgnc:2584 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:10835629 SUPPORT Human Clinical
"Here we have identified CYLD by detecting germline mutations in 21 cylindromatosis families and somatic mutations in 1 sporadic and 5 familial cylindromas."
Gene discovery.
PMID:26971504 SUPPORT REVIEW SYNTHESIS Human Clinical
"There appears to be no genotype-phenotype correlations with respect to the severity of the disease, the possibility of malignant transformation, and development of extracutaneous lesions."
Supports the absence of genotype-phenotype correlation stated in notes.
💊

Medical Actions

6
Surgical Excision of Tumors
Action: surgical excision of adnexal tumorsNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical excision of adnexal tumors, annotated with Excision (NCIT:C15232). NCIT:C15232 is a clinical intervention from the NCI Thesaurus. Ontology label: Excision NCIT:C15232
Platform: Surgery
Conventional surgical removal of cylindromas, spiradenomas and trichoepitheliomas, with scalp-sparing strategies (early excision with direct closure, enucleation, excision with secondary-intention healing) to avoid total scalp removal. Mohs surgery for recurrence has limited benefit.
Mechanism Target:
INHIBITS Multiple Skin Appendage Tumors
Show evidence (1 reference)
PMID:32298062 SUPPORT REVIEW SYNTHESIS Human Clinical
"Removal of cylindromas, spiradenomas, and trichoepitheliomas is by conventional surgery. Ideally, as much normal scalp and skin should be preserved."
GeneReviews management recommendation.
Hyfrecation or Laser Ablation of Small Tumors
Action: laser ablation of small adnexal tumorsNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is laser ablation of small adnexal tumors, annotated with Laser Ablation (NCIT:C111241). NCIT:C111241 is a clinical intervention from the NCI Thesaurus. Ontology label: Laser Ablation NCIT:C111241
Platform: Device
Ablative treatment of selected small tumors.
Mechanism Target:
INHIBITS Multiple Skin Appendage Tumors
Show evidence (1 reference)
PMID:32298062 SUPPORT REVIEW SYNTHESIS Human Clinical
"Hyfrecation or laser ablation of selected small tumors may be considered."
GeneReviews management recommendation.
Dermatologic Surveillance
Action: full skin examination by a dermatologistNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is full skin examination by a dermatologist, annotated with Skin Examination (NCIT:C168436). NCIT:C168436 is a clinical intervention from the NCI Thesaurus. Ontology label: Skin Examination NCIT:C168436
Full skin examination by a dermatologist at least annually, assessing tumor burden, the rate of new tumors, and signs of malignant transformation (rapid growth, bleeding, ulceration, or a change from the patient's usual tumors). Because the first tumor typically appears around puberty, clarifying the genetic status of at-risk relatives, including children, identifies those who would benefit from early treatment.
Mechanism Target:
Malignant Transformation of Adnexal Tumors
Show evidence (2 references)
PMID:32298062 SUPPORT REVIEW SYNTHESIS Human Clinical
"Annual or more frequent full skin examination by a dermatologist, with assessment of tumor burden and rate of new tumor development, and for signs/symptoms of malignant transformation"
GeneReviews surveillance recommendation.
PMID:32298062 SUPPORT REVIEW SYNTHESIS Human Clinical
"It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures."
Supports cascade testing of at-risk relatives including children.
Avoidance of Radiotherapy
Radiotherapy should be avoided because the DNA damage it causes may induce further tumors or malignant transformation of existing lesions. Precautions against UV-related skin damage are also recommended.
Show evidence (2 references)
PMID:32298062 SUPPORT REVIEW SYNTHESIS Human Clinical
"Radiotherapy should be avoided as it causes DNA damage and may result in further tumor formation or malignant transformation of existing lesions."
GeneReviews agents to avoid.
PMID:32298062 SUPPORT REVIEW SYNTHESIS Human Clinical
"Appropriate precautions against UV-related skin damage are recommended."
GeneReviews prevention of primary manifestations.
Topical Pegcantratinib (investigational)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: pegcantratinib NCIT:C170295 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses pegcantratinib (NCIT:C170295). NCIT:C170295 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Topical pan-TRK inhibitor tested in the TRAC trial (ISRCTN75715723). It was well tolerated, but in the randomized phase 2a part only 2 pegcantratinib-treated tumors met the response criterion against 6 placebo-treated tumors, so the prespecified efficacy endpoint was not met; the authors attribute this to low tumor drug concentrations. Not an established treatment.
Mechanism Target:
INHIBITS TRK Receptor Signalling Upregulation
Show evidence (2 references)
PMID:29955768 REFUTE Human Clinical
"2 tumors treated with pegcantratinib achieved the primary outcome measure of response compared with 6 tumors treated with placebo. The primary prespecified number of responses was not met."
Randomized within-patient trial did not show efficacy of topical TRK inhibition.
PMID:29955768 SUPPORT Human Clinical
"In this study, pegcantratinib, 0.5% (wt/wt), applied once daily appeared to be well tolerated and to penetrate the tumor tissue; however, the low tumor drug concentrations demonstrated are likely to account for the lack of response."
Tolerability and tumor penetration, with the authors' explanation for the negative result.
Topical Salicylic Acid (investigational)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: salicylic acid CHEBI:16914 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses salicylic acid (CHEBI:16914). CHEBI:16914 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Topical salicylate was tried on the rationale that it blocks the NF-kappaB activation caused by CYLD loss. In a pilot of 12 target cylindromas in 5 patients, 2 showed complete remission and 8 a lesser response. It has not become standard care; a later paper describes a significant response in only a small proportion of treated tumors.
Mechanism Target:
INHIBITS NF-kappaB Pathway Derepression
Show evidence (3 references)
PMID:16792771 SUPPORT Human Clinical
"Two of the 12 cylindromas showed a complete remission. Another eight lesions showed some response, but not sufficient to qualify as partial remission."
Small pilot showing complete remission in a minority of treated tumors.
PMID:12917690 SUPPORT In Vitro
"We show that this effect can be relieved by aspirin derivatives that inhibit NF-kappaB activity, which suggests a therapeutic intervention strategy to restore growth control in patients suffering from familial cylindromatosis."
Preclinical rationale for salicylate.
PMID:21552290 REFUTE BACKGROUND Human Clinical
"However, initial clinical studies with topical salicylic acid demonstrated a significant response in only a small proportion of treated tumours (Oosterkamp et al., 2006)."
Later assessment that the salicylate response was limited.
🔬

Diagnosis

2
Histopathologic Confirmation of Adnexal Tumors
A clinical diagnosis rests on multiple skin tumors histologically confirmed as cylindromas, spiradenomas or trichoepitheliomas.
histopathologic examination of excised skin tumors NCIT:C18190 NCI Thesaurus (NCIT)
Results: Multiple histologically confirmed cylindromas, spiradenomas and/or trichoepitheliomas establish the diagnosis without a molecular result.
Show evidence (1 reference)
PMID:32298062 SUPPORT REVIEW SYNTHESIS Human Clinical
"The diagnosis of CYLD cutaneous syndrome is established in a proband with multiple skin tumors (histologically confirmed cylindromas, spiradenomas, and/or trichoepitheliomas) and/or by identification of a germline heterozygous pathogenic variant in CYLD by molecular genetic testing."
GeneReviews diagnostic criteria; histologic confirmation of multiple tumors is one route to diagnosis.
Molecular Genetic Testing of CYLD
Identification of a germline heterozygous pathogenic CYLD variant establishes the diagnosis and enables testing of at-risk relatives. A normal blood result does not exclude the diagnosis when tumors are clustered, asymmetric or linear and there is no family history: a post-zygotic CYLD variant can be absent from blood leukocyte DNA and is found by testing two or more tumors for a recurrent variant.
CYLD molecular genetic testing (germline, and tumor tissue when mosaicism is suspected) NCIT:C15709 NCI Thesaurus (NCIT)
Results: A germline heterozygous pathogenic CYLD variant; or, in mosaic presentations, the same pathogenic CYLD variant recurring in two or more tumors, with or without a low-level variant in blood.
Show evidence (4 references)
PMID:32298062 SUPPORT REVIEW SYNTHESIS Human Clinical
"The diagnosis of CYLD cutaneous syndrome is established in a proband with multiple skin tumors (histologically confirmed cylindromas, spiradenomas, and/or trichoepitheliomas) and/or by identification of a germline heterozygous pathogenic variant in CYLD by molecular genetic testing."
GeneReviews diagnostic criteria; a germline heterozygous pathogenic CYLD variant is the molecular route to diagnosis.
PMID:31085270 SUPPORT Human Clinical
"Two patients had recurrent pathogenic variants in skin tumors from a single cluster but none detectable in the blood."
Blood-only testing missed tissue-restricted CYLD variants that tumor testing found.
PMID:31085270 SUPPORT Human Clinical
"In such patients who lack a family history, genetic testing of skin tumors is necessary."
Recommends tumor testing for clustered cylindromas without a family history.
+ 1 more reference
📊

Prevalence

1
Worldwide
Point Prevalence <1 in 1,000,000
Orphanet expert estimate, point prevalence below 1 in 1,000,000 worldwide.
Show evidence (1 reference)
ORPHA:79493 SUPPORT Other
"<1 / 1 000 000 | Worldwide | Point prevalence | EXPERT"
Orphanet epidemiology row.
🔬

Clinical Trials

1
ISRCTN75715723 NOT_APPLICABLE COMPLETED
TRAC: phase 1b open-label then phase 2a within-patient randomized, double-blind, placebo-controlled trial of topical pegcantratinib 0.5% on CYLD-defective skin tumors (Newcastle, UK, 2014-2016). The registry records the phase as Not Applicable; the publication describes phases 1b and 2a.
Show evidence (2 references)
ICTRP:ISRCTN75715723 SUPPORT Other
"Scientific title: Topical tropomysin kinase (TRK) inhibitor as a treatment for inherited CYLD-defective skin tumours (TRAC)"
WHO ICTRP registration record establishing the trial identity.
PMID:29955768 SUPPORT Human Clinical
"TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN75715723."
Links the published trial to its registration.
🐁

Animal Models

1
Cyld knockout mouse (chemical carcinogenesis)
Species
Mouse
Genotype
Cyld-/-
Publication
PMID:16713561
Pathograph links
NF-kappaB Pathway Derepression partially recapitulates fidelity: moderate Cyld-null keratinocytes show Bcl-3-dependent NF-kappaB activation, cyclin D1 elevation and hyperproliferation, and the mice are highly susceptible to chemically induced skin tumors.
Limitations: Constitutional biallelic knockout rather than a germline heterozygote with somatic second hits, and the tumors studied were induced by TPA or UV promotion; the model does not reproduce spontaneous cylindromas, spiradenomas or trichoepitheliomas.
Show evidence (1 reference)
PMID:16713561 SUPPORT Model Organism
"Here we show that mice lacking Cyld are highly susceptible to chemically induced skin tumors."
Supports the model as informative for the NF-kappaB node.
{ }

Source YAML

click to show 
name: CYLD Cutaneous Syndrome
creation_date: "2026-10-13T20:32:52Z"
category: Mendelian
categories:
- Hereditary Cancer Syndrome
- Cancer Predisposition Syndrome
parents:
- hereditary neoplastic syndrome
disease_term:
  preferred_term: Brooke-Spiegler syndrome
  term:
    id: MONDO:0011512
    label: Brooke-Spiegler syndrome
synonyms:
- Brooke-Spiegler syndrome
- BSS
- CCS
- turban tumor syndrome
description: >-
  CYLD cutaneous syndrome is the autosomal dominant skin adnexal tumor
  predisposition caused by heterozygous germline loss-of-function variants in
  CYLD at 16q12-q13, which encodes a deubiquitinase that removes K63-linked
  polyubiquitin from signalling intermediates and restrains NF-kappaB and
  Wnt/beta-catenin signalling. Carriers develop multiple cylindromas,
  spiradenomas, spiradenocylindromas and trichoepitheliomas, chiefly on the
  scalp and face but also on the trunk and in sun-protected genital and
  axillary skin. The first tumor typically appears around puberty and tumors
  accumulate through adulthood; in the most severe cases confluent scalp
  tumors ("turban tumor") lead to total scalp removal. Each tumor completes a
  second hit at CYLD, most often by loss of heterozygosity of 16q. Tumors
  overexpress TRKB/TRKC and MYB, which are candidate therapeutic targets.
  Brooke-Spiegler syndrome, familial cylindromatosis and multiple familial
  trichoepithelioma were described as separate disorders, but the same
  germline CYLD variant produces more than one of these presentations within a
  family, so they are curated here as one entity with phenotypic variants
  recorded as subtypes. The GeneReviews chapter uses the inclusive name CYLD
  cutaneous syndrome, which is the name of this entry; MONDO and ClinGen label
  the concept Brooke-Spiegler syndrome. Rare manifestations are salivary gland
  membranous basal cell adenoma, pulmonary (large-airway) cylindromas and
  malignant transformation of a preexisting benign tumor.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  expressivity: VARIABLE
  description: >-
    Germline CYLD variants are transmitted as an autosomal dominant
    predisposition, and most probands inherit the variant from a parent.
    Expressivity is highly variable, both in which tumor types predominate and
    in tumor burden, and this variability is seen within single families.
    Age-related penetrance has not been precisely estimated.
  evidence:
  - reference: PMID:32298062
    reference_title: "CYLD Cutaneous Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Germline pathogenic variants in CYLD are inherited in an autosomal dominant manner."
    explanation: GeneReviews genetic counseling statement of the mode of inheritance.
  - reference: PMID:32298062
    reference_title: "CYLD Cutaneous Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Most individuals with CYLD cutaneous syndrome inherit it from a parent."
    explanation: Supports the statement that most probands inherit the variant from a parent.
  - reference: PMID:32298062
    reference_title: "CYLD Cutaneous Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Offspring of an individual with CYLD cutaneous syndrome have a 50% chance of inheriting the variant."
    explanation: GeneReviews transmission risk to offspring of a heterozygous carrier.
  - reference: PMID:32298062
    reference_title: "CYLD Cutaneous Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The degree of severity can vary within families; for example, a mildly affected parent may have a more severely affected child or vice versa."
    explanation: Supports variable expressivity, including within families.
  - reference: PMID:34744449
    reference_title: "Genetic Testing in CYLD Cutaneous Syndrome: An Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Age-related penetrance figures are not precisely reported."
    explanation: Supports leaving penetrance unset rather than asserting a value.
- name: Somatic mosaic arm
  inheritance_term:
    preferred_term: Typified by somatic mosaicism
    term:
      id: HP:0001442
      label: Typified by somatic mosaicism
  description: >-
    A minority of individuals carry a post-zygotic CYLD variant. They present
    with clustered, often asymmetric cylindromas or spiradenomas, may have no
    detectable variant in blood, and can transmit a constitutional form to
    offspring when the mosaic variant reaches the germline.
  evidence:
  - reference: PMID:31085270
    reference_title: "Diverse presentations of cutaneous mosaicism occur in CYLD cutaneous syndrome and may result in parent-to-child transmission."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients had mosaic pathogenic CYLD variants in both the blood and skin. One of these patients transmitted a pathogenic variant to her daughter"
    explanation: Paired blood and skin testing demonstrates post-zygotic CYLD mosaicism with germline transmission.
  - reference: PMID:31085270
    reference_title: "Diverse presentations of cutaneous mosaicism occur in CYLD cutaneous syndrome and may result in parent-to-child transmission."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients had recurrent pathogenic variants in skin tumors from a single cluster but none detectable in the blood."
    explanation: Tissue-restricted mosaicism, detectable only by testing more than one tumor from a cluster.
has_subtypes:
- name: FC
  display_name: Familial cylindromatosis
  description: >-
    Phenotypic variant in which cylindromas predominate, classically on the
    scalp. Caused by germline CYLD variants; the same variant can present as
    familial cylindromatosis in one relative and as multiple familial
    trichoepithelioma in another.
  subtype_term:
    preferred_term: familial cylindromatosis
    term:
      id: MONDO:0007565
      label: familial cylindromatosis
  genes:
  - preferred_term: CYLD
    term:
      id: hgnc:2584
      label: CYLD
  evidence:
  - reference: PMID:16922728
    reference_title: "CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a single family with affected members exhibiting either the FC or the MFT phenotypes associated with a mutation in the CYLD gene."
    explanation: One CYLD variant produces both the FC and the MFT presentation in one family, supporting treatment as phenotypic variants of one disease.
  - reference: ORPHA:211
    reference_title: "Familial cylindromatosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CYLD | CYLD lysine 63 deubiquitinase | hgnc:2584 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records familial cylindromatosis as a clinical subtype with CYLD as the disease-causing gene.
- name: MFT1
  display_name: Multiple familial trichoepithelioma 1 (CYLD-related)
  description: >-
    Phenotypic variant in which trichoepitheliomas (cribriform trichoblastomas)
    predominate, mostly on the central face. Only the CYLD-related form is
    included here. Germline CYLD variants are found less often in this
    presentation (about 40-50%) than in classical Brooke-Spiegler syndrome
    (about 80-85%), so a CYLD-negative MFT family may have another cause.
  subtype_term:
    preferred_term: multiple familial trichoepithelioma 1
    term:
      id: MONDO:0042977
      label: trichoepithelioma, multiple familial, 1
  genes:
  - preferred_term: CYLD
    term:
      id: hgnc:2584
      label: CYLD
  evidence:
  - reference: PMID:15086550
    reference_title: "Identification of the cylindromatosis tumor-suppressor gene responsible for multiple familial trichoepithelioma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study firstly identified the cylindromatosis gene responsible for MFT and showed that different mutations of the CYLDI gene can give rise to distinct clinical and histological expression such as FC and MFT."
    explanation: Linkage to 16q12-q13 and a segregating CYLD frameshift in a large MFT family.
  - reference: PMID:26971504
    reference_title: "Brooke-Spiegler Syndrome and Phenotypic Variants: An Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Germline CYLD mutations are detected in about 80-85% of patients with the classical BSS phenotype and in about 40-50% of the individuals with the MFT phenotype"
    explanation: Supports the lower CYLD detection rate in the MFT presentation stated in the description.
pathophysiology:
- name: Germline CYLD First-Hit Inactivation
  conforms_to: "germline_two_hit_tumor_predisposition#Constitutional First-Hit Tumor Suppressor Inactivation"
  description: >-
    A heterozygous CYLD loss-of-function variant is present constitutionally.
    Most germline alleles are frameshift or nonsense variants predicted to
    truncate the protein; missense and splice-site variants, large deletions
    and inversions account for a minority. Disease-associated truncations
    reduce the deubiquitinating activity of the encoded enzyme.
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CYLD
    term:
      id: hgnc:2584
      label: CYLD
  genetic_context:
    gene:
      preferred_term: CYLD
      term:
        id: hgnc:2584
        label: CYLD
    variant_origin: GERMLINE
    allelic_hit_role: FIRST_HIT
    allelic_events:
    - FRAMESHIFT_VARIANT
    - NONSENSE_VARIANT
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Constitutional heterozygous CYLD loss of function, predominantly
      protein-truncating.
  molecular_functions:
  - preferred_term: K63-linked deubiquitinase activity
    term:
      id: GO:0061578
      label: K63-linked deubiquitinase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:10835629
    reference_title: "Identification of the familial cylindromatosis tumour-suppressor gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we have identified CYLD by detecting germline mutations in 21 cylindromatosis families and somatic mutations in 1 sporadic and 5 familial cylindromas. All mutations predict truncation or absence of the encoded protein."
    explanation: Gene discovery in 21 families; all germline alleles are predicted loss of function.
  - reference: PMID:12917691
    reference_title: "The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Truncations of CYLD found in cylindromatosis result in reduced enzymatic activity, indicating a link between impaired deubiquitination of CYLD substrates and human pathophysiology."
    explanation: Disease-associated truncations reduce the deubiquitinase activity bound on this node.
  - reference: PMID:23249834
    reference_title: "Novel and recurrent germline and somatic mutations in a cohort of 67 patients from 48 families with Brooke-Spiegler syndrome including the phenotypic variant of multiple familial trichoepitheliomas and correlation with the histopathologic findings in 379 biopsy specimens."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-one frameshift, 15 nonsense, 3 missense, and 4 splice site mutations were found in patients with BSS"
    explanation: Allelic spectrum in a 67-patient cohort, dominated by truncating variants.
  - reference: PMID:34744449
    reference_title: "Genetic Testing in CYLD Cutaneous Syndrome: An Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "In addition, a minority of patients have large deletions involving the CYLD gene, intronic pathogenic variants that affect splicing, or inversions."
    explanation: Supports the non-truncating minority of germline alleles.
  downstream:
  - target: Somatic CYLD Second-Hit Inactivation
    description: >-
      With one allele inactivated in every cell, a single somatic event at
      CYLD in a susceptible adnexal cell becomes the rate-limiting step.
- name: Somatic CYLD Second-Hit Inactivation
  conforms_to: "germline_two_hit_tumor_predisposition#Somatic Second-Hit Inactivation of the Wild-Type Allele"
  description: >-
    Each tumor inactivates the retained wild-type CYLD allele. Loss of
    heterozygosity of 16q is the commonest route (about two thirds of tumors
    with a detected second hit), and intragenic somatic mutation accounts for
    the rest; apart from 16q LOH, CYLD-mutant tumors carry few copy-number
    changes. The tumors are of hair-follicle lineage. Tumor mapping in two
    large families found tumors concentrated at sites of hormonally stimulated
    hair follicles, which the authors interpret as those follicles being
    particularly vulnerable to loss of heterozygosity; that is an inference
    from tumor distribution, not a measured mutation rate.
  role: amplifier
  biological_scale: MOLECULAR
  genetic_context:
    gene:
      preferred_term: CYLD
      term:
        id: hgnc:2584
        label: CYLD
    variant_origin: SOMATIC
    allelic_hit_role: SECOND_HIT
    allelic_events:
    - LOSS_OF_HETEROZYGOSITY
    - PATHOGENIC_VARIANT
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Acquired inactivation of the wild-type CYLD allele in tumor tissue,
      mostly by 16q loss of heterozygosity and less often by an intragenic
      somatic mutation.
  cell_types:
  - preferred_term: hair follicle keratinocyte
    term:
      id: CL:2000092
      label: hair follicular keratinocyte
  evidence:
  - reference: PMID:23249834
    reference_title: "Novel and recurrent germline and somatic mutations in a cohort of 67 patients from 48 families with Brooke-Spiegler syndrome including the phenotypic variant of multiple familial trichoepitheliomas and correlation with the histopathologic findings in 379 biopsy specimens."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Somatic mutations were detected in 67 specimens of these 76 tumors (88%). Of the 67 somatic mutations, 21 (31%) represented a sequence alteration and 46 (69%) showed loss of heterozygosity."
    explanation: Quantifies the somatic second hit and its two routes in tumors from germline carriers.
  - reference: PMID:15289313
    reference_title: "Multiple familial trichoepithelioma caused by mutations in the cylindromatosis tumor suppressor gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In individual tumors, loss of heterozygosity at 16q or a somatic point mutation in the CYLD gene was detected."
    explanation: The same two second-hit routes in trichoepitheliomas from an MFT family.
  - reference: PMID:21552290
    reference_title: "Dysregulated TRK signalling is a therapeutic target in CYLD defective tumours."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CYLD mutant tumours were characterised by an absence of copy-number aberrations apart from LOH chromosome 16q, the genomic location of the CYLD gene."
    explanation: Array CGH shows 16q LOH as essentially the only copy-number event in these tumors.
  - reference: PMID:16713561
    reference_title: "Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Mutations in the CYLD gene cause tumors of hair-follicle keratinocytes."
    explanation: >-
      Introductory statement of the human tumor lineage in a mouse study; it
      supports the hair follicle keratinocyte binding. The narrower claim that
      the tumors arise from hair follicle stem cells is stated in the
      literature only as a hypothesis and is not bound here.
  - reference: PMID:19917957
    reference_title: "Tumor mapping in 2 large multigenerational families with CYLD mutations: implications for disease management and tumor induction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tumor mapping provided clinical evidence that correlated with hormonally stimulated hair follicles being particularly vulnerable to loss of heterozygosity and tumor induction."
    explanation: Source of the hormonally stimulated follicle interpretation recorded in the description.
  downstream:
  - target: Biallelic CYLD Loss in Adnexal Keratinocytes
    description: >-
      Completion of the second hit leaves the tumor-initiating cell without
      functional CYLD.
- name: Biallelic CYLD Loss in Adnexal Keratinocytes
  conforms_to: "germline_two_hit_tumor_predisposition#Biallelic Tumor Suppressor Inactivation in a Susceptible Cell"
  description: >-
    Tumor cells lack CYLD protein. CYLD is a deubiquitinase directed at
    non-K48 (K63-linked) polyubiquitin chains on signalling intermediates,
    including TRAF2, TRAF6, NEMO, Bcl-3 and Dishevelled, so its loss releases
    several growth and survival pathways at once. CYLD protein is normally
    prominent in the inner root sheath of the hair follicle and in eccrine
    glands, matching the lineages of the tumors.
  role: central_effector
  biological_scale: CELLULAR
  molecular_functions:
  - preferred_term: K63-linked deubiquitinase activity
    term:
      id: GO:0061578
      label: K63-linked deubiquitinase activity
    modifier: ABSENT
  evidence:
  - reference: CGGV:assertion_434ddb72-ee88-47af-9fa2-8dee9fa0a388-2019-04-19T160000.000Z
    reference_title: "CYLD / Brooke-Spiegler syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "CYLD protein is prominently expressed in the inner root sheath of hair follicles of human scalp as well as in eccrine glands. Multiple articles reported no CYLD protein expression in the tumour tissue from BSS patients."
    explanation: ClinGen evidence summary for absent CYLD protein in tumors and its normal follicular and eccrine expression.
  - reference: PMID:12917689
    reference_title: "CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here we show that CYLD is a deubiquitinating enzyme that negatively regulates activation of the transcription factor NF-kappaB by specific tumour-necrosis factor receptors (TNFRs). Loss of the deubiquitinating activity of CYLD correlates with tumorigenesis."
    explanation: Establishes CYLD as a deubiquitinase whose loss of activity correlates with tumor formation.
  downstream:
  - target: NF-kappaB Pathway Derepression
    description: Loss of CYLD removes deubiquitination of TRAF2, NEMO and Bcl-3.
  - target: Wnt-beta-Catenin Pathway Hyperactivation
    description: Loss of CYLD increases K63-linked ubiquitination of Dishevelled.
  - target: TRK Receptor Signalling Upregulation
    description: >-
      CYLD-null tumors overexpress TRKB and TRKC; the molecular route from CYLD
      loss to TRK overexpression is not established.
  - target: MYB Oncogenic Transcription Program Activation
    description: >-
      CYLD-defective cylindromas activate MYB without the MYB-NFIB fusion of
      sporadic cylindromas; the route from CYLD loss to MYB activation is not
      established.
  - target: Impaired DNA Damage-Induced p53 Stabilization
    description: >-
      Loss of CYLD catalytic activity removes CYLD-dependent deubiquitination
      of p53 after genotoxic stress. Shown in cultured cells, mice and
      nematodes, not in human CYLD-null tumors.
- name: Impaired DNA Damage-Induced p53 Stabilization
  description: >-
    CYLD binds and deubiquitinates p53, and is needed for p53 stabilization and
    activation after DNA damage. Ubiquitin chain-restriction analysis suggests
    CYLD removes K48 chains from p53 indirectly by cleaving K63 linkages in
    mixed chains. Loss of CYLD catalytic activity impairs this response in
    epithelial cells and sensitizes mice to chemical carcinogen-induced skin
    and intestinal tumors, and CYLD deficiency reduces CEP-1/p53-dependent
    germ cell apoptosis in C. elegans. This arm rests on model-system and
    biochemical evidence only; p53 stabilization has not been reported in
    tumors from CYLD cutaneous syndrome patients in the sources cited here,
    so its contribution to the human tumors is a hypothesis.
  role: central_effector
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: DNA damage-induced p53 signalling
    term:
      id: GO:0030330
      label: DNA damage response, signal transduction by p53 class mediator
    modifier: DECREASED
  evidence:
  - reference: DOI:10.1038/ncomms12508
    reference_title: "The tumour suppressor CYLD regulates the p53 DNA damage response"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mechanistically, CYLD interacts with and deubiquitinates p53 facilitating its stabilization in response to genotoxic stress."
    explanation: Biochemical basis for CYLD-dependent p53 stabilization after DNA damage.
  - reference: DOI:10.1038/ncomms12508
    reference_title: "The tumour suppressor CYLD regulates the p53 DNA damage response"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Moreover, CYLD deficiency also diminishes CEP-1/p53-dependent DNA damage-induced germ cell apoptosis in the nematode Caenorhabditis elegans."
    explanation: The same dependence of the p53 damage response on CYLD in an invertebrate model.
  downstream:
  - target: Clonal Expansion of CYLD-Null Adnexal Tumor Cells
    description: >-
      Hypothesized contribution. The supporting result is carcinogen-induced
      skin and intestinal tumorigenesis in mice lacking CYLD catalytic
      activity, not adnexal tumor formation in human carriers.
    evidence:
    - reference: DOI:10.1038/ncomms12508
      reference_title: "The tumour suppressor CYLD regulates the p53 DNA damage response"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here we show that loss of CYLD catalytic activity causes impaired DNA damage-induced p53 stabilization and activation in epithelial cells and sensitizes mice to chemical carcinogen-induced intestinal and skin tumorigenesis."
      explanation: >-
        Mouse evidence that loss of CYLD catalytic activity both impairs the
        p53 damage response and increases carcinogen-induced skin tumors; it
        does not test adnexal tumors.
- name: NF-kappaB Pathway Derepression
  description: >-
    CYLD binds NEMO and TRAF2 and removes their activating non-K48
    polyubiquitin, so its loss augments TNF-receptor-family (CD40, EDAR, XEDAR)
    activation of canonical NF-kappaB and increases resistance to apoptosis.
    In keratinocytes, CYLD also deubiquitinates Bcl-3 and keeps it out of the
    nucleus; Cyld-null keratinocytes accumulate nuclear Bcl-3 with p50 and p52,
    raise cyclin D1 and proliferate. EDAR and XEDAR are ectodysplasin
    receptors, which is one proposed reason the phenotype is restricted to skin
    appendages.
  role: central_effector
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: canonical NF-kappaB signal transduction
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
    modifier: INCREASED
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: DECREASED
  evidence:
  - reference: PMID:12917689
    reference_title: "CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "CYLD inhibits activation of NF-kappaB by the TNFR family members CD40, XEDAR and EDAR in a manner that depends on the deubiquitinating activity of CYLD."
    explanation: Names the receptors whose NF-kappaB output CYLD restrains, including the ectodysplasin receptors.
  - reference: PMID:12917689
    reference_title: "CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results indicate that CYLD is a negative regulator of the cytokine-mediated activation of NF-kappaB that is required for appropriate cellular homeostasis of skin appendages."
    explanation: Authors' link between CYLD-restrained NF-kappaB signalling and skin appendage homeostasis.
  - reference: PMID:12917691
    reference_title: "The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here we report that CYLD, a tumour suppressor that is mutated in familial cylindromatosis, interacts with NEMO, the regulatory subunit of IKK."
    explanation: Places CYLD at the IKK complex.
  - reference: PMID:12917690
    reference_title: "Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Inhibition of CYLD increases resistance to apoptosis, suggesting a mechanism through which loss of CYLD contributes to oncogenesis."
    explanation: RNAi knockdown links CYLD loss to apoptosis resistance through NF-kappaB.
  - reference: PMID:16713561
    reference_title: "Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we show that mice lacking Cyld are highly susceptible to chemically induced skin tumors. Cyld-/- tumors and keratinocytes treated with 12-O-tetradecanoylphorbol-13 acetate (TPA) or UV light are hyperproliferative and have elevated cyclin D1 levels."
    explanation: In vivo evidence that Cyld loss promotes keratinocyte proliferation and skin tumors.
  - reference: PMID:16713561
    reference_title: "Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In Cyld+/+ keratinocytes, TPA or UV light triggers the translocation of Cyld from the cytoplasm to the perinuclear region, where Cyld binds and deubiquitinates Bcl-3, thereby preventing nuclear accumulation of Bcl-3 and p50/Bcl-3- or p52/Bcl-3-dependent proliferation."
    explanation: Mechanism of the Bcl-3 arm in keratinocytes.
  downstream:
  - target: Clonal Expansion of CYLD-Null Adnexal Tumor Cells
    description: Increased survival and proliferation of CYLD-null cells.
- name: Wnt-beta-Catenin Pathway Hyperactivation
  description: >-
    CYLD binds Dishevelled and limits K63-linked ubiquitination of its DIX
    domain; without CYLD, polymerized Dishevelled is hyperubiquitinated and
    Wnt-induced beta-catenin accumulation is enhanced. Hyperactive Wnt
    signalling is seen in human cylindromas.
  role: central_effector
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:20227366
    reference_title: "Loss of the tumor suppressor CYLD enhances Wnt/beta-catenin signaling through K63-linked ubiquitination of Dvl."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Depletion of CYLD from cultured cells markedly enhances Wnt-induced accumulation of beta-catenin and target gene activation."
    explanation: Cell-based evidence that CYLD loss enhances canonical Wnt output.
  - reference: PMID:20227366
    reference_title: "Loss of the tumor suppressor CYLD enhances Wnt/beta-catenin signaling through K63-linked ubiquitination of Dvl."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, we demonstrate hyperactive Wnt signaling in human cylindroma skin tumors that arise from mutations in CYLD."
    explanation: The same pathway state observed in patient tumors.
  downstream:
  - target: Clonal Expansion of CYLD-Null Adnexal Tumor Cells
    description: Enhanced Wnt/beta-catenin output promotes tumor growth.
- name: TRK Receptor Signalling Upregulation
  description: >-
    Expression profiling of CYLD-mutant tumors against perilesional skin shows
    overexpression of TRKB (NTRK2) and TRKC (NTRK3), with membranous staining,
    increased ERK phosphorylation and BCL2 in cylindromas. TRK knockdown or the
    TRK inhibitor lestaurtinib reduced growth of 3D primary tumor cultures,
    which is the preclinical basis for topical TRK inhibition.
  role: central_effector
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: neurotrophin TRK receptor signaling pathway
    term:
      id: GO:0048011
      label: neurotrophin TRK receptor signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:21552290
    reference_title: "Dysregulated TRK signalling is a therapeutic target in CYLD defective tumours."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gene expression profiling of CYLD mutant tumours showed dysregulated tropomyosin kinase (TRK) signalling, with overexpression of TRKB and TRKC in tumours when compared with perilesional skin."
    explanation: Patient tumor transcriptomes show TRK overexpression.
  - reference: PMID:21552290
    reference_title: "Dysregulated TRK signalling is a therapeutic target in CYLD defective tumours."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RNA interference-mediated silencing of TRKB and TRKC, as well as treatment with the small-molecule TRK inhibitor lestaurtinib, reduced colony formation and proliferation in 3D primary cell cultures established from CYLD mutant tumours."
    explanation: Functional dependence of tumor cells on TRK signalling in culture.
  downstream:
  - target: Clonal Expansion of CYLD-Null Adnexal Tumor Cells
    description: TRK signalling supports proliferation of CYLD-null tumor cells.
- name: MYB Oncogenic Transcription Program Activation
  description: >-
    Inherited CYLD-defective cylindromas do not carry the MYB-NFIB fusion found
    in sporadic cylindromas but still overexpress MYB and its target genes, and
    MYB knockdown reduces cylindroma cell proliferation, so the inherited and
    sporadic tumors converge on MYB activation by different routes.
  role: central_effector
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: cell population proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
    modifier: INCREASED
  evidence:
  - reference: PMID:26969893
    reference_title: "Overexpression of MYB drives proliferation of CYLD-defective cylindroma cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Strikingly, none of the inherited CYLD-defective (n = 23) tumours expressed MYB-NFIB fusion transcripts. However, MYB expression was increased in the majority of tumours (69%)"
    explanation: MYB activation without fusion in inherited cylindromas.
  - reference: PMID:26969893
    reference_title: "Overexpression of MYB drives proliferation of CYLD-defective cylindroma cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Moreover, knock-down of MYB expression caused a significant reduction in cylindroma cell proliferation, suggesting that MYB is also a key player and oncogenic driver in inherited cylindromas."
    explanation: Functional dependence of cylindroma cells on MYB.
  downstream:
  - target: Clonal Expansion of CYLD-Null Adnexal Tumor Cells
    description: MYB drives proliferation of CYLD-defective cylindroma cells.
- name: Clonal Expansion of CYLD-Null Adnexal Tumor Cells
  conforms_to: "germline_two_hit_tumor_predisposition#Clonal Expansion and Tumor Initiation"
  description: >-
    CYLD-null clones expand into benign adnexal tumors with follicular
    (trichoepithelioma) or sweat-gland-like (cylindroma, spiradenoma)
    differentiation, often several histologies in one patient and hybrid
    spiradenocylindromas in one lesion. Many arise independently, so tumor
    number rises with age. Benign tumors frequently carry further clonal
    mutations in the epigenetic modifiers DNMT3A and BCOR (29% of benign
    tumors in one series), with marked intra-tumor heterogeneity; the
    contribution of those mutations to growth or transformation is not
    established.
  role: consequence
  biological_scale: TISSUE
  evidence:
  - reference: PMID:31624251
    reference_title: "Epigenetic modifiers DNMT3A and BCOR are recurrently mutated in CYLD cutaneous syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we comprehensively profile the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families and discover recurrent mutations in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors."
    explanation: Cooperating somatic events in benign CYLD-null tumors.
  - reference: PMID:23249834
    reference_title: "Novel and recurrent germline and somatic mutations in a cohort of 67 patients from 48 families with Brooke-Spiegler syndrome including the phenotypic variant of multiple familial trichoepitheliomas and correlation with the histopathologic findings in 379 biopsy specimens."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 76 tumors from 32 patients with a germline CYLD mutation, 12 were spiradenomas, 15 spiradenocylindromas, 26 cylindromas, 15 trichoepitheliomas, and 7 were other tumor types."
    explanation: Histologic spectrum of tumors arising in germline carriers.
  downstream:
  - target: Multiple Skin Appendage Tumors
  - target: Cylindroma
  - target: Spiradenoma
  - target: Trichoepithelioma
  - target: Salivary Gland Membranous Basal Cell Adenoma
  - target: Pulmonary Cylindromas
  - target: Malignant Transformation of Adnexal Tumors
phenotypes:
- category: Neoplastic
  name: Multiple Skin Appendage Tumors
  description: >-
    Multiple benign adnexal tumors on the scalp and face, and frequently on the
    trunk and in sun-protected genital and axillary skin. The first tumor
    typically appears around puberty and tumors accumulate through adulthood.
    In two large families the mean age at onset was 16 years (range 8-30), 23%
    of surveyed patients had undergone total scalp removal, and tumors were on
    the scalp in 81%, the trunk in 69% and the pubic area in 42%. GeneReviews
    states that females often have more tumors than males; the same family
    study found roughly equal numbers of affected men and women but 5 of the 6
    total scalp removals were in women.
  phenotype_term:
    preferred_term: Multiple skin appendage tumors
    term:
      id: HP:0012842
      label: Skin appendage neoplasm
    onset:
      onset_category: JUVENILE
      mean_age_years: 16
      min_age_years: 8
      max_age_years: 30
      notes: Onset figures are from two multigenerational families (PMID:19917957).
  evidence:
  - reference: PMID:32298062
    reference_title: "CYLD Cutaneous Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The first tumor typically develops at puberty and tumors progressively accumulate through adulthood. Females often have more tumors than males. Tumors typically arise on the scalp and face but can also arise on the torso and sun-protected sites, such as the genital and axillary skin."
    explanation: GeneReviews phenotype baseline for onset, accumulation, sex difference in burden and distribution.
  - reference: PMID:19917957
    reference_title: "Tumor mapping in 2 large multigenerational families with CYLD mutations: implications for disease management and tumor induction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The average age at onset was 16 years (range, 8-30 years)."
    explanation: Quantitative onset age.
  - reference: PMID:19917957
    reference_title: "Tumor mapping in 2 large multigenerational families with CYLD mutations: implications for disease management and tumor induction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although an approximately equal female to male predisposition was noted, 5 women and 1 man (of 26 patients surveyed [23%]) had undergone total scalp removal."
    explanation: Equal sex ratio of affected individuals with more severe disease in women, and the rate of total scalp removal.
  - reference: PMID:19917957
    reference_title: "Tumor mapping in 2 large multigenerational families with CYLD mutations: implications for disease management and tumor induction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 26 surveyed patients, tumors were noted on the scalp in 21 (81%), on the trunk in 18 (69%), and in the pubic area in 11 (42%)."
    explanation: Body-site distribution beyond the head and neck.
- category: Neoplastic
  name: Cylindroma
  description: >-
    The defining tumor of the syndrome; dermal cylindromas, often confluent on
    the scalp.
  phenotype_term:
    preferred_term: Cylindroma
    term:
      id: HP:0031024
      label: Cylindroma
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:79493
    reference_title: "Brooke-Spiegler syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0031024 | Cylindroma | Very frequent (99-80%)"
    explanation: Orphanet HPO annotation and frequency class.
  - reference: PMID:32298062
    reference_title: "CYLD Cutaneous Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "CYLD cutaneous syndrome (CCS) typically manifests in the second or third decade with the appearance of multiple skin tumors including cylindromas, spiradenomas, trichoepitheliomas, and rarely, membranous basal cell adenoma of the salivary gland."
    explanation: GeneReviews tumor spectrum.
- category: Neoplastic
  name: Spiradenoma
  description: >-
    Spiradenomas and hybrid spiradenocylindromas. Pain is a common symptom of
    the tumors (about half of patients asked in one family study), although
    that study did not attribute it to a particular histology.
  phenotype_term:
    preferred_term: Spiradenoma
  notes: >-
    Left unbound: an OLS search of the hp ontology for "spiradenoma" returned
    no terms. The parent concept HP:0012842 Skin appendage neoplasm is bound
    on the Multiple Skin Appendage Tumors phenotype.
  evidence:
  - reference: PMID:32298062
    reference_title: "CYLD Cutaneous Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "CYLD cutaneous syndrome (CCS) typically manifests in the second or third decade with the appearance of multiple skin tumors including cylindromas, spiradenomas, trichoepitheliomas, and rarely, membranous basal cell adenoma of the salivary gland."
    explanation: GeneReviews tumor spectrum includes spiradenoma.
  - reference: PMID:19917957
    reference_title: "Tumor mapping in 2 large multigenerational families with CYLD mutations: implications for disease management and tumor induction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptoms reported by affected patients included painful tumors (in 12 of 23 patients [52%] who answered the question), conductive deafness, and sexual dysfunction."
    explanation: Pain is a common symptom; the study does not attribute it to a single histology.
- category: Neoplastic
  name: Trichoepithelioma
  description: >-
    Trichoepitheliomas, predominantly on the central face; the sole tumor type
    in the multiple familial trichoepithelioma presentation.
  phenotype_term:
    preferred_term: Trichoepithelioma
    term:
      id: HP:0025367
      label: Trichoepithelioma
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:79493
    reference_title: "Brooke-Spiegler syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025367 | Trichoepithelioma | Frequent (79-30%)"
    explanation: Orphanet HPO annotation and frequency class.
  - reference: PMID:26971504
    reference_title: "Brooke-Spiegler Syndrome and Phenotypic Variants: An Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Multiple familial trichoepithelioma (MFT) is a phenotypic variant of the disease characterized by the development of numerous trichoepitheliomas (cribriform trichoblastoma) only."
    explanation: Trichoepithelioma as the defining tumor of the MFT presentation.
- category: Neoplastic
  name: Salivary Gland Membranous Basal Cell Adenoma
  description: >-
    A minority develop major or minor salivary gland tumors, characteristically
    membranous basal cell adenoma, which resembles dermal cylindroma
    histologically.
  phenotype_term:
    preferred_term: Membranous basal cell adenoma of salivary gland
    term:
      id: HP:6000007
      label: Salivary basal cell adenoma
  frequency: VERY_RARE
  evidence:
  - reference: PMID:32298062
    reference_title: "CYLD Cutaneous Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "A minority of individuals develop salivary gland tumors."
    explanation: GeneReviews statement of salivary involvement.
  - reference: ORPHA:79493
    reference_title: "Brooke-Spiegler syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100684 | Salivary gland neoplasm | Very rare (<4-1%)"
    explanation: Orphanet frequency class for salivary gland neoplasm.
  - reference: PMID:29569226
    reference_title: "Inherited pulmonary cylindromas: extending the phenotype of CYLD mutation carriers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "a minority develop a type of salivary gland tumour, membranous basal cell adenoma, which shares similar histology."
    explanation: Names the salivary tumor type bound here.
- category: Neoplastic
  name: Pulmonary Cylindromas
  description: >-
    Cylindromas of the large airways, usually in patients with a high cutaneous
    tumor burden; they can cause breathlessness and airway obstruction. In one
    tertiary cohort of 16 carriers, 4 had lung imaging and 2 had histologically
    confirmed multiple pulmonary cylindromas. In a separate genomic study some
    pulmonary lesions were shown phylogenetically to be metastases of skin
    cylindromas.
  phenotype_term:
    preferred_term: Pulmonary cylindroma
    term:
      id: HP:0034637
      label: Pulmonary cylindroma
  evidence:
  - reference: PMID:29569226
    reference_title: "Inherited pulmonary cylindromas: extending the phenotype of CYLD mutation carriers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four patients had radiological imaging of their lungs, of which two had multiple pulmonary cylindromas that were confirmed histologically."
    explanation: Case series establishing pulmonary cylindromas in CYLD carriers.
  - reference: PMID:31624251
    reference_title: "Epigenetic modifiers DNMT3A and BCOR are recurrently mutated in CYLD cutaneous syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phylogenetic and mutational signature analyses confirm cylindroma pulmonary metastases from primary skin tumors."
    explanation: At least some pulmonary cylindromas are metastatic rather than primary.
  - reference: PMID:32298062
    reference_title: "CYLD Cutaneous Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Rarely, pulmonary cylindromas can develop in large airways and compromise breathing."
    explanation: GeneReviews baseline statement of large-airway cylindromas and their respiratory consequence.
- category: Neoplastic
  name: Malignant Transformation of Adnexal Tumors
  description: >-
    Malignant tumors arise within preexisting benign tumors in about 5-10% of
    patients, and metastasis with lethal outcome can occur. In a review of 55
    published cases only age predicted malignancy. Signs prompting evaluation
    are rapid growth, bleeding, ulceration or a change in appearance.
  phenotype_term:
    preferred_term: Malignant adnexal skin tumor arising in a benign precursor
    term:
      id: HP:0012842
      label: Skin appendage neoplasm
  frequency: OCCASIONAL
  notes: >-
    HPO has no term for a malignant adnexal tumor or for malignant change in a
    cylindroma or spiradenoma. OLS searches of HPO (ontology=hp, 2026-10-14)
    for "cylindrocarcinoma", "spiradenocarcinoma", "malignant cylindroma",
    "malignant spiradenoma", "sweat gland carcinoma" and "skin appendage
    carcinoma" returned no terms; "adnexal carcinoma" returned only
    HP:0031548 Follicular infundibulum tumor; and "skin carcinoma" returned
    squamous cell, basal cell, Merkel cell and sebaceous gland carcinoma
    terms among unrelated hits, none of which names these tumors. The binding is HP:0012842 Skin
    appendage neoplasm, which HPO defines as "A benign or malignant neoplasm
    that arises from the hair follicles, sebaceous glands, or sweat glands"
    and which sits under HP:0008069 Neoplasm of the skin. It is the same term
    as the benign tumor phenotype, so the malignant state is carried only by
    preferred_term.
  evidence:
  - reference: PMID:26971504
    reference_title: "Brooke-Spiegler Syndrome and Phenotypic Variants: An Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Malignant tumors arise in association with preexisting benign cutaneous neoplasms in about 5-10% of the patients ."
    explanation: Frequency of malignant transformation, supporting the OCCASIONAL class.
  - reference: PMID:32975300
    reference_title: "Can we clinically identify patients at risk of malignant transformation of skin tumors in Brooke-Spiegler syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our analysis revealed only age as a predictor of malignancy; however, this is also a general risk factor for development of malignancy and therefore of limited value as a screening tool."
    explanation: No clinical predictor beyond age.
  - reference: PMID:32975300
    reference_title: "Can we clinically identify patients at risk of malignant transformation of skin tumors in Brooke-Spiegler syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "An increased risk of malignant transformation of adnexal cutaneous tumors in BSS patients has been reported."
    explanation: >-
      States that the malignancies arise from the adnexal tumors, which is
      the basis for binding a skin appendage neoplasm term.
  - reference: PMID:32298062
    reference_title: "CYLD Cutaneous Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Although the tumors are usually benign, malignant transformation is recognized."
    explanation: GeneReviews baseline statement.
- category: Otologic
  name: Conductive Hearing Impairment
  description: >-
    Reported as a symptom in a family study; Orphanet lists hearing impairment
    and auditory canal abnormality as very rare. The mechanism has not been
    studied.
  phenotype_term:
    preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:19917957
    reference_title: "Tumor mapping in 2 large multigenerational families with CYLD mutations: implications for disease management and tumor induction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptoms reported by affected patients included painful tumors (in 12 of 23 patients [52%] who answered the question), conductive deafness, and sexual dysfunction."
    explanation: Conductive deafness reported by affected patients.
  - reference: ORPHA:79493
    reference_title: "Brooke-Spiegler syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000372 | Abnormality of the auditory canal | Very rare (<4-1%)"
    explanation: Orphanet frequency class for auditory canal involvement.
genetic:
- name: CYLD
  gene_term:
    preferred_term: CYLD
    term:
      id: hgnc:2584
      label: CYLD
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    Heterozygous germline loss-of-function variants in CYLD cause CYLD cutaneous
    syndrome; post-zygotic CYLD variants cause a mosaic form.
  notes: >-
    No genotype-phenotype correlation has been found for severity, malignant
    transformation or extracutaneous lesions. Germline variant detection rates
    are higher in classical Brooke-Spiegler syndrome than in the multiple
    familial trichoepithelioma presentation. ClinGen also rates CYLD for
    frontotemporal dementia and/or amyotrophic lateral sclerosis 8 (Limited),
    a separate gene-disease pair not curated here.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_434ddb72-ee88-47af-9fa2-8dee9fa0a388-2019-04-19T160000.000Z
    evidence:
    - reference: CGGV:assertion_434ddb72-ee88-47af-9fa2-8dee9fa0a388-2019-04-19T160000.000Z
      reference_title: "CYLD / Brooke-Spiegler syndrome (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "CYLD | HGNC:2584 | Brooke-Spiegler syndrome | MONDO:0011512 | AD | Definitive"
      explanation: ClinGen Hereditary Cancer GCEP classifies CYLD and Brooke-Spiegler syndrome (AD) as Definitive.
  case_fractions:
  - population: Brooke-Spiegler syndrome cohort, classical phenotype
    case_fraction_percent: 88
    cohort_size: 49
    notes: Germline CYLD variant detected by direct sequencing in 43 of 49 patients with classical BSS.
    evidence:
    - reference: PMID:23249834
      reference_title: "Novel and recurrent germline and somatic mutations in a cohort of 67 patients from 48 families with Brooke-Spiegler syndrome including the phenotypic variant of multiple familial trichoepitheliomas and correlation with the histopathologic findings in 379 biopsy specimens."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Germline CYLD mutations were found in 43 of the 49 patients with BSS (88%) but in only 8 of 18 MFT cohort (44%)."
      explanation: Detection rate in the classical phenotype.
  - population: Multiple familial trichoepithelioma phenotype cohort
    case_fraction_percent: 44
    cohort_size: 18
    notes: Germline CYLD variant detected in 8 of 18 patients with the MFT phenotype.
    evidence:
    - reference: PMID:23249834
      reference_title: "Novel and recurrent germline and somatic mutations in a cohort of 67 patients from 48 families with Brooke-Spiegler syndrome including the phenotypic variant of multiple familial trichoepitheliomas and correlation with the histopathologic findings in 379 biopsy specimens."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Germline CYLD mutations were found in 43 of the 49 patients with BSS (88%) but in only 8 of 18 MFT cohort (44%)."
      explanation: Detection rate in the MFT phenotype.
  evidence:
  - reference: PMID:10835629
    reference_title: "Identification of the familial cylindromatosis tumour-suppressor gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we have identified CYLD by detecting germline mutations in 21 cylindromatosis families and somatic mutations in 1 sporadic and 5 familial cylindromas."
    explanation: Gene discovery.
  - reference: PMID:26971504
    reference_title: "Brooke-Spiegler Syndrome and Phenotypic Variants: An Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "There appears to be no genotype-phenotype correlations with respect to the severity of the disease, the possibility of malignant transformation, and development of extracutaneous lesions."
    explanation: Supports the absence of genotype-phenotype correlation stated in notes.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: Orphanet expert estimate, point prevalence below 1 in 1,000,000 worldwide.
  evidence:
  - reference: ORPHA:79493
    reference_title: "Brooke-Spiegler syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | EXPERT"
    explanation: Orphanet epidemiology row.
diagnosis:
- name: Histopathologic Confirmation of Adnexal Tumors
  description: >-
    A clinical diagnosis rests on multiple skin tumors histologically
    confirmed as cylindromas, spiradenomas or trichoepitheliomas.
  diagnosis_term:
    preferred_term: histopathologic examination of excised skin tumors
    term:
      id: NCIT:C18190
      label: Histopathologic Examination
  results: >-
    Multiple histologically confirmed cylindromas, spiradenomas and/or
    trichoepitheliomas establish the diagnosis without a molecular result.
  evidence:
  - reference: PMID:32298062
    reference_title: "CYLD Cutaneous Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The diagnosis of CYLD cutaneous syndrome is established in a proband with multiple skin tumors (histologically confirmed cylindromas, spiradenomas, and/or trichoepitheliomas) and/or by identification of a germline heterozygous pathogenic variant in CYLD by molecular genetic testing."
    explanation: GeneReviews diagnostic criteria; histologic confirmation of multiple tumors is one route to diagnosis.
- name: Molecular Genetic Testing of CYLD
  description: >-
    Identification of a germline heterozygous pathogenic CYLD variant
    establishes the diagnosis and enables testing of at-risk relatives. A
    normal blood result does not exclude the diagnosis when tumors are
    clustered, asymmetric or linear and there is no family history: a
    post-zygotic CYLD variant can be absent from blood leukocyte DNA and is
    found by testing two or more tumors for a recurrent variant.
  diagnosis_term:
    preferred_term: CYLD molecular genetic testing (germline, and tumor tissue when mosaicism is suspected)
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    A germline heterozygous pathogenic CYLD variant; or, in mosaic
    presentations, the same pathogenic CYLD variant recurring in two or more
    tumors, with or without a low-level variant in blood.
  evidence:
  - reference: PMID:32298062
    reference_title: "CYLD Cutaneous Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The diagnosis of CYLD cutaneous syndrome is established in a proband with multiple skin tumors (histologically confirmed cylindromas, spiradenomas, and/or trichoepitheliomas) and/or by identification of a germline heterozygous pathogenic variant in CYLD by molecular genetic testing."
    explanation: GeneReviews diagnostic criteria; a germline heterozygous pathogenic CYLD variant is the molecular route to diagnosis.
  - reference: PMID:31085270
    reference_title: "Diverse presentations of cutaneous mosaicism occur in CYLD cutaneous syndrome and may result in parent-to-child transmission."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients had recurrent pathogenic variants in skin tumors from a single cluster but none detectable in the blood."
    explanation: Blood-only testing missed tissue-restricted CYLD variants that tumor testing found.
  - reference: PMID:31085270
    reference_title: "Diverse presentations of cutaneous mosaicism occur in CYLD cutaneous syndrome and may result in parent-to-child transmission."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In such patients who lack a family history, genetic testing of skin tumors is necessary."
    explanation: Recommends tumor testing for clustered cylindromas without a family history.
  - reference: PMID:34744449
    reference_title: "Genetic Testing in CYLD Cutaneous Syndrome: An Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Somatic testing of tumour tissue, relevant in mosaic CCS, can reveal recurrently detected pathogenic variants when two or more tumours are tested."
    explanation: Supports testing two or more tumors to identify a recurrent variant in mosaic presentations.
treatments:
- name: Surgical Excision of Tumors
  description: >-
    Conventional surgical removal of cylindromas, spiradenomas and
    trichoepitheliomas, with scalp-sparing strategies (early excision with
    direct closure, enucleation, excision with secondary-intention healing)
    to avoid total scalp removal. Mohs surgery for recurrence has limited
    benefit.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical excision of adnexal tumors
    term:
      id: NCIT:C15232
      label: Excision
  target_mechanisms:
  - target: Multiple Skin Appendage Tumors
    treatment_effect: INHIBITS
  evidence:
  - reference: PMID:32298062
    reference_title: "CYLD Cutaneous Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Removal of cylindromas, spiradenomas, and trichoepitheliomas is by conventional surgery. Ideally, as much normal scalp and skin should be preserved."
    explanation: GeneReviews management recommendation.
- name: Hyfrecation or Laser Ablation of Small Tumors
  description: Ablative treatment of selected small tumors.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: laser ablation of small adnexal tumors
    term:
      id: NCIT:C111241
      label: Laser Ablation
  target_mechanisms:
  - target: Multiple Skin Appendage Tumors
    treatment_effect: INHIBITS
  evidence:
  - reference: PMID:32298062
    reference_title: "CYLD Cutaneous Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Hyfrecation or laser ablation of selected small tumors may be considered."
    explanation: GeneReviews management recommendation.
- name: Dermatologic Surveillance
  description: >-
    Full skin examination by a dermatologist at least annually, assessing tumor
    burden, the rate of new tumors, and signs of malignant transformation
    (rapid growth, bleeding, ulceration, or a change from the patient's usual
    tumors). Because the first tumor typically appears around puberty,
    clarifying the genetic status of at-risk relatives, including children,
    identifies those who would benefit from early treatment.
  treatment_term:
    preferred_term: full skin examination by a dermatologist
    term:
      id: NCIT:C168436
      label: Skin Examination
  target_mechanisms:
  - target: Malignant Transformation of Adnexal Tumors
  evidence:
  - reference: PMID:32298062
    reference_title: "CYLD Cutaneous Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Annual or more frequent full skin examination by a dermatologist, with assessment of tumor burden and rate of new tumor development, and for signs/symptoms of malignant transformation"
    explanation: GeneReviews surveillance recommendation.
  - reference: PMID:32298062
    reference_title: "CYLD Cutaneous Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures."
    explanation: Supports cascade testing of at-risk relatives including children.
- name: Avoidance of Radiotherapy
  description: >-
    Radiotherapy should be avoided because the DNA damage it causes may induce
    further tumors or malignant transformation of existing lesions.
    Precautions against UV-related skin damage are also recommended.
  treatment_term:
    preferred_term: avoidance of radiotherapy
  evidence:
  - reference: PMID:32298062
    reference_title: "CYLD Cutaneous Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Radiotherapy should be avoided as it causes DNA damage and may result in further tumor formation or malignant transformation of existing lesions."
    explanation: GeneReviews agents to avoid.
  - reference: PMID:32298062
    reference_title: "CYLD Cutaneous Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Appropriate precautions against UV-related skin damage are recommended."
    explanation: GeneReviews prevention of primary manifestations.
- name: Topical Pegcantratinib (investigational)
  description: >-
    Topical pan-TRK inhibitor tested in the TRAC trial (ISRCTN75715723). It was
    well tolerated, but in the randomized phase 2a part only 2
    pegcantratinib-treated tumors met the response criterion against 6
    placebo-treated tumors, so the prespecified efficacy endpoint was not met;
    the authors attribute this to low tumor drug concentrations. Not an
    established treatment.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pegcantratinib
      term:
        id: NCIT:C170295
        label: Pegcantratinib
  target_mechanisms:
  - target: TRK Receptor Signalling Upregulation
    treatment_effect: INHIBITS
  evidence:
  - reference: PMID:29955768
    reference_title: "Targeting Tropomyosin Receptor Kinase in Cutaneous CYLD Defective Tumors With Pegcantratinib: The TRAC Randomized Clinical Trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "2 tumors treated with pegcantratinib achieved the primary outcome measure of response compared with 6 tumors treated with placebo. The primary prespecified number of responses was not met."
    explanation: Randomized within-patient trial did not show efficacy of topical TRK inhibition.
  - reference: PMID:29955768
    reference_title: "Targeting Tropomyosin Receptor Kinase in Cutaneous CYLD Defective Tumors With Pegcantratinib: The TRAC Randomized Clinical Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, pegcantratinib, 0.5% (wt/wt), applied once daily appeared to be well tolerated and to penetrate the tumor tissue; however, the low tumor drug concentrations demonstrated are likely to account for the lack of response."
    explanation: Tolerability and tumor penetration, with the authors' explanation for the negative result.
- name: Topical Salicylic Acid (investigational)
  description: >-
    Topical salicylate was tried on the rationale that it blocks the NF-kappaB
    activation caused by CYLD loss. In a pilot of 12 target cylindromas in 5
    patients, 2 showed complete remission and 8 a lesser response. It has not
    become standard care; a later paper describes a significant response in
    only a small proportion of treated tumors.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: salicylic acid
      term:
        id: CHEBI:16914
        label: salicylic acid
  target_mechanisms:
  - target: NF-kappaB Pathway Derepression
    treatment_effect: INHIBITS
  evidence:
  - reference: PMID:16792771
    reference_title: "An evaluation of the efficacy of topical application of salicylic acid for the treatment of familial cylindromatosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two of the 12 cylindromas showed a complete remission. Another eight lesions showed some response, but not sufficient to qualify as partial remission."
    explanation: Small pilot showing complete remission in a minority of treated tumors.
  - reference: PMID:12917690
    reference_title: "Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that this effect can be relieved by aspirin derivatives that inhibit NF-kappaB activity, which suggests a therapeutic intervention strategy to restore growth control in patients suffering from familial cylindromatosis."
    explanation: Preclinical rationale for salicylate.
  - reference: PMID:21552290
    reference_title: "Dysregulated TRK signalling is a therapeutic target in CYLD defective tumours."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "However, initial clinical studies with topical salicylic acid demonstrated a significant response in only a small proportion of treated tumours (Oosterkamp et al., 2006)."
    explanation: Later assessment that the salicylate response was limited.
clinical_trials:
- name: ISRCTN75715723
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    TRAC: phase 1b open-label then phase 2a within-patient randomized,
    double-blind, placebo-controlled trial of topical pegcantratinib 0.5% on
    CYLD-defective skin tumors (Newcastle, UK, 2014-2016). The registry
    records the phase as Not Applicable; the publication describes phases 1b
    and 2a.
  evidence:
  - reference: ICTRP:ISRCTN75715723
    reference_title: "Tropomyosin receptor kinase antagonism in cylindromatosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Scientific title: Topical tropomysin kinase (TRK) inhibitor as a treatment for inherited CYLD-defective skin tumours (TRAC)"
    explanation: WHO ICTRP registration record establishing the trial identity.
  - reference: PMID:29955768
    reference_title: "Targeting Tropomyosin Receptor Kinase in Cutaneous CYLD Defective Tumors With Pegcantratinib: The TRAC Randomized Clinical Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN75715723."
    explanation: Links the published trial to its registration.
animal_models:
- name: Cyld knockout mouse (chemical carcinogenesis)
  species: Mouse
  genotype: Cyld-/-
  publication: PMID:16713561
  modeled_mechanisms:
  - target: NF-kappaB Pathway Derepression
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Cyld-null keratinocytes show Bcl-3-dependent NF-kappaB activation,
      cyclin D1 elevation and hyperproliferation, and the mice are highly
      susceptible to chemically induced skin tumors.
    limitations: >-
      Constitutional biallelic knockout rather than a germline heterozygote
      with somatic second hits, and the tumors studied were induced by TPA or
      UV promotion; the model does not reproduce spontaneous cylindromas,
      spiradenomas or trichoepitheliomas.
    evidence:
    - reference: PMID:16713561
      reference_title: "Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here we show that mice lacking Cyld are highly susceptible to chemically induced skin tumors."
      explanation: Supports the model as informative for the NF-kappaB node.
discussions:
- discussion_id: gap_cyld_lineage_restriction
  prompt: >-
    Why does constitutional CYLD loss of function produce tumors almost only in
    hair-follicle-related adnexal lineages, which cell is the tumor of origin,
    and how does CYLD loss lead to TRK and MYB overexpression?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Somatic CYLD Second-Hit Inactivation
  - pathophysiology#TRK Receptor Signalling Upregulation
  - pathophysiology#MYB Oncogenic Transcription Program Activation
  rationale: >-
    CYLD restrains several broadly used pathways, yet the tumor spectrum is
    narrow. Proposed explanations are the ectodysplasin-receptor (EDAR, XEDAR)
    arm of NF-kappaB signalling and a higher second-hit rate in hormonally
    stimulated follicles inferred from tumor maps; origin in hair follicle
    stem cells is stated in the literature as a hypothesis. No cited source
    establishes the route from CYLD loss to TRKB/TRKC or MYB overexpression.
  proposed_experiments:
  - experiment_id: lineage_resolved_cyld_second_hit_mapping
    name: Lineage-resolved second-hit mapping in early CYLD carrier lesions
    description: >-
      Microdissect the earliest visible lesions and adjacent follicles from
      carriers, determine which follicular compartment first shows biallelic
      CYLD loss, and profile NF-kappaB, Wnt, TRK and MYB programs in those
      cells relative to heterozygous neighbors.
references:
- reference: PMID:32298062
  title: "CYLD Cutaneous Syndrome."
  tags:
  - GeneReviews
notes: >-
  Lump/split. Brooke-Spiegler syndrome, familial cylindromatosis and the
  CYLD-related form of multiple familial trichoepithelioma are curated as one
  disease with FC and MFT1 as subtypes, because one CYLD variant yields more
  than one of these presentations within a family (PMID:16922728). Two MONDO
  descendants of MONDO:0011512 are deliberately not bound as subtypes.
  MONDO:0012800 "trichoepithelioma, multiple familial, 2" (OMIM:612099)
  corresponds to the 9p21 linkage locus for MFT (PMID:8752837); the NCBI Gene
  record 100188881 (symbol MFT2, MIM 612099, map location 9p21) names no
  causal gene, and CYLD-linked MFT families excluded 9p21 (PMID:15289313), so
  it is not a CYLD disorder. MONDO:0011114 "familial multiple
  trichoepithelioma" is the MONDO parent of both MFT1 and MFT2, so binding it
  would bring the 9p21 locus into this entry; MFT1 (MONDO:0042977) is bound
  instead.
📚

References & Deep Research

References

1
PMID:32298062
CYLD Cutaneous Syndrome.
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.

Evaluations and curation notes (1)

Create: CYLD_Cutaneous_Syndrome · 2026-10-14T00:15:14Z · View source

New entry for MONDO:0011512 (MONDO/ClinGen label Brooke-Spiegler syndrome), named CYLD Cutaneous Syndrome after the GeneReviews chapter (PMID:32298062), which is the phenotype baseline. Deep research: falcon was requested twice (with --fallback) and both runs failed with '503 Failed to authenticate' before any provider task was created, so exactly one claude_code report was run instead (research/CYLD_Cutaneous_Syndrome-deep-research-claude_code.md). That report was thin (4 web searches, GeneReviews fetch blocked) and was used only as a lead. Rejected from it: HP:0100677 offered as Cylindroma (it is Vulval varicose vein), HP:0100782 offered as Trichoepithelioma (does not exist), and PMID 10873394 offered as the Bignell 2000 CYLD discovery paper (it is an ataxia-telangiectasia paper; the correct PMID is 10835629). just preflight-dr exited 2 because the local mondo.db is not present; it was not run. Curated: autosomal dominant inheritance plus a somatic mosaic arm (HP:0001442, PMID:31085270); subtypes FC (MONDO:0007565) and MFT1 (MONDO:0042977); MONDO:0012800 (MFT2, 9p21 locus, PMID:8752837) and MONDO:0011114 (parent of MFT1 and MFT2) deliberately not bound; pathograph conforming to germline_two_hit_tumor_predisposition (first hit, second hit with 16q LOH, biallelic loss, clonal expansion) with NF-kappaB, Wnt, TRK and MYB branches; ClinGen Definitive copied from the cached CGGV record; Orphanet prevalence; GeneReviews management and surveillance; TRAC pegcantratinib trial (negative) and salicylic acid pilot recorded as investigational. Gaps: spiradenoma has no HPO term (left unbound); no penetrance estimate; route from CYLD loss to TRK and MYB overexpression and the tumor cell of origin are recorded as a KNOWLEDGE_GAP. Validation: just validate, validate-terms, count-verified-snippets (74/74), check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-genereviews, list-gene-term-mismatches, check-block-scalar-comments, the ungated snippet/title/grading/retired-prose/environmental/coarse/reference-title/enum gates, gene-activity grounding and folded-hyphen scripts, and just validate-disorders all passed.

Claude Code ▸
CYLD Cutaneous Syndrome (MONDO:0011512): research report
claude-haiku-5-5, claude-sonnet-5-5 12 citations 2026-10-13T20:46:04.339091

CYLD Cutaneous Syndrome (MONDO:0011512): research report

Provenance of this report. Web access was limited. Four standard searches returned snippets. A direct fetch of the GeneReviews chapter (NBK555820) was blocked by a browser-verification page. Items below are labelled by source class: - [search]: stated in a search-result summary, with the source URL named. - [model]: my own background knowledge, not checked in this session. Treat these as leads. - [gap]: not found.

PMIDs are given only where the search result showed them. I have not verified any exact snippets. Nothing here is ready to copy into a KB evidence: block without just fetch-reference and snippet checks.

1. Disease information

  • Overview. CYLD cutaneous syndrome (CCS) is an autosomal dominant predisposition to multiple adnexal skin tumors: cylindromas, spiradenomas and trichoepitheliomas. It is caused by heterozygous CYLD variants at 16q12. The first tumor typically appears around puberty, and tumors accumulate with age, mostly on the scalp and face. Females often have more tumors than males. [search: GeneReviews NBK555820, Dubois and Rajan, 2020; summary only, via GeneReviews PDF]
  • Lump decision. GeneReviews and MedlinePlus treat Brooke-Spiegler syndrome (BSS), familial cylindromatosis (FC) and multiple familial trichoepithelioma (MFT) as one condition. They were formerly considered distinct. [search: GeneReviews]
  • The KB file name Brooke-Spiegler_Syndrome therefore reflects a historical split. It is a lump/split call to surface.
  • MFT has a separate locus at 9p21, and sporadic trichoepitheliomas have been linked to PTCH. [search: GeneReviews] The CYLD-negative families are genetically heterogeneous, so a CYLD-defined entry should not claim them.
  • Identifiers.
  • MONDO:0011512 was given in the task.
  • OMIM, Orphanet, ICD and MeSH identifiers: [gap]. I did not verify them and will not write them from memory.
  • A MedGen record exists at C1857941. [search, via MedGen]
  • Synonyms. Brooke-Spiegler syndrome, familial cylindromatosis, multiple familial trichoepithelioma, Brooke-Spiegler/Spiegler-Brooke, "turban tumor syndrome" (the last is [model]).
  • Source level. Aggregated disease-level resources and cohorts, not EHR-derived.

2. Etiology

  • Cause. Germline heterozygous loss-of-function CYLD variants. [search: JCI/Dermatology reviews as surfaced]
  • Second hit. In cylindroma cells both copies of CYLD are inactivated, and biallelic loss alone appears sufficient to drive tumorigenesis. [search: Nature Communications 2019, Rajan et al.; PMID not shown, see IDEAS record]
  • Tumor-suppressor biology is not elaborated here, as you asked.
  • Modifiers.
  • Expression varies within and between families, so a modifier effect is suggested. [search: GeneReviews]
  • Specific modifier genes: [gap].
  • Environmental and protective factors. [gap]. I found no evidence for either. DMBA/TPA promotes tumors in mice (section 15), but there is no human exposure evidence.
  • Gene-environment interaction. [gap].

3. Phenotypes (candidate HPO terms are [model] and need lookup before binding)

Phenotype Candidate HPO Frequency / onset
Cylindroma HP:0100677 (Cylindroma) Core feature; onset puberty onward [search: GeneReviews]
Spiradenoma spiradenoma term (lookup needed) Core feature
Trichoepithelioma HP:0100782 (Trichoepithelioma) Core feature
Salivary gland basal cell adenoma (membranous type) lookup needed "A minority" develop salivary tumors [search: GeneReviews]
Malignant transformation (e.g. spiradenocarcinoma, cylindrocarcinoma) lookup needed Uncommon but recognized [search: GeneReviews; 2026 case report]
  • Pediatric framing. The first lesion is typically at puberty, per GeneReviews. Onset before puberty is possible but I did not find data on it ([gap]). Female excess in tumor burden is reported. [search: GeneReviews]
  • Specific percentages. I could not obtain them. Frequencies for hair loss from scalp tumors, pain, disfigurement and quality of life are [gap].
  • Tumor sites. Mostly scalp and face, as above.

4. Genetic and molecular information

  • Gene. CYLD, 16q12. Use hgnc: lowercase form once the ID is looked up; I have not verified the HGNC ID here.
  • Variant spectrum.
  • A 2007 Dermatology Online Journal review counted 68 unique mutations. The count has since grown. [search: GeneReviews/MalaCards summary]
  • Variants are loss of function, and the encoded protein is truncated or inactive. [search]
  • The classic nonsense/frameshift/splice pattern is [model].
  • The founding discovery paper is Bignell et al. 2000, Nat Genet. I recall PMID 10873394 [model, unchecked]. The CYLD mutations paper in the search results is the related Mount Sinai record for the lump into one syndrome.
  • Genotype-phenotype. I found no cohort-level genotype-phenotype correlation. Phenotype varies even among carriers of the same variant. [search: GeneReviews]
  • Mosaicism. A UK cohort of 55 patients found 2 with mosaic pathogenic CYLD variants in blood and skin. [search; source not identified; verify before citing, via PMC8566010]
  • Consider the somatic-mosaicism skill if a mosaic subtype is curated.
  • Mosaicism would explain clustered or segmental tumors with negative standard testing. [search]
  • Tumor genomics. A study of 42 tumors from 13 individuals found recurrent DNMT3A and BCOR mutations in 29% of benign tumors. [search; likely the same Nat Commun 2019 paper, unconfirmed]
  • Epigenetics, chromosomal abnormalities, population allele frequencies. [gap].

5. Environmental information

No environmental, lifestyle or infectious factors were found. [gap]

6. Mechanism / pathophysiology

Ordered causal chain 1. A germline heterozygous CYLD loss-of-function variant is present in every cell. [search] 2. A somatic second hit inactivates the other allele in a skin adnexal progenitor cell. Demonstrated in cylindroma tissue (Nat Commun 2019, per search). The exact cell of origin is [model]: eccrine/apocrine or pilosebaceous adnexal lineage, unverified. 3. Loss of CYLD leaves non-K48 (principally K63) polyubiquitin chains on TRAF2 and NEMO unedited. CYLD binds both proteins and removes these chains. [search: Brummelkamp 2003, PMID 12917691; Kovalenko 2003; Courtois 2008 review] 4. IKK/NF-κB activation persists and apoptosis resistance increases. [search: Brummelkamp 2003 abstract] 5. This leads to clonal expansion and tumor formation. Intermediate steps are inferred. The 2016 JCI Insight mouse work implicates c-Myc and TRAF6. [search] 6. Rarely, cooperating mutations drive malignant transformation. [search: the Nat Commun 2019 tumor genomics; the 2026 case report involved an MSH2 VUS, which proves nothing about causation] 7. The cylindroma-to-spiradenoma-to-trichoepithelioma spectrum may reflect differing differentiation of the transformed cell. This is [model] inference and not demonstrated here.

  • Branch. CYLD also acts in T-cell receptor signalling and mitosis, so NF-κB may not be the whole story. [search: Courtois 2008]
  • Suggested GO terms [model, need lookup]: protein deubiquitination, K63-linked deubiquitinase activity, regulation of NF-κB signaling, negative regulation of apoptotic process.
  • Omics, single-cell, spatial and CRISPR data. [gap], apart from the tumor exome data above.
  • Immune system involvement. CYLD-deficient mouse immune cells show enhanced NF-κB and JNK signalling, and colitis-associated cancer risk goes up. This is mouse data (Zhang et al., JCI). [search] I found no human immune phenotype in CCS.

7. Anatomical structures affected

  • Organs. Skin of scalp and face is primary. Major salivary glands (parotid) are secondary. [search for salivary; sites beyond scalp/face: model]
  • Cells and tissues. Adnexal epithelium. CL and UBERON term selection is [gap]; look them up.
  • Subcellular. CYLD is a cytoplasmic deubiquitinase [model]. GO CC terms were not checked.
  • Lateralization. [gap].

8. Temporal development

  • Onset is at puberty. Tumors accumulate with age, and their number rises through adulthood. [search: GeneReviews]
  • Course is progressive and lifelong. Staging is not applicable.
  • Remission patterns and critical periods: [gap].

9. Inheritance and population

  • Pattern. Autosomal dominant, with variable expressivity within and between families and variable penetrance. [search: GeneReviews]
  • Specific penetrance figures: [gap]. I did not find any. Do not substitute a "near-complete" claim without a source.
  • Prevalence. [gap]. The Orphanet value was not checked.
  • Anticipation, founder effects, carrier frequency, ancestry, geography and sex ratio: [gap]. Female excess in tumor number is the only point found. [search]
  • Germline mosaicism. Parental mosaicism has not been verified here.

10. Diagnostics

  • Clinical. Multiple cylindromas, spiradenomas or trichoepitheliomas, or a single tumor with a family history. A membranous basal cell adenoma-type salivary tumor in someone with a single cylindroma, spiradenoma or trichoepithelioma also counts. [search: GeneReviews diagnostic criteria, secondhand]
  • Biopsy. Histopathology of the adnexal tumors is diagnostic.
  • Genetic testing. CYLD sequencing plus deletion/duplication analysis is expected [model; GeneReviews testing section not read]. A negative result in blood does not exclude mosaicism. [search]
  • Differential. Birt-Hogg-Dubé (trichodiscomas and fibrofolliculomas), Cowden/PTEN hamartoma tumor syndrome (trichilemmomas), Gorlin/PTCH1 syndrome (BCC) [model, unchecked]. The GeneReviews differential was not read.
  • Screening. [gap].

11. Outcome / prognosis

  • Life expectancy and QoL: [gap].
  • Complications are disfigurement from large scalp tumors (turban tumor) [model] and rare malignant transformation. [search]
  • Prognostic factors: not found.

12. Treatment

  • Surgery (excision, laser, electrodesiccation) is the mainstay [model]. This was not confirmed in the sources I could read.
  • Reported medical options are limited to case-level evidence. [search: GeneReviews summary]
  • Sodium salicylate.
  • Prostaglandin A1.
  • Aspirin plus adalimumab.
  • Topical imiquimod.
  • The rationale from Brummelkamp 2003 was that aspirin derivatives block NF-κB and could reverse the effect. [search]
  • A search for aspirin, salicylate or sirolimus trials returned nothing on the clinical side. I have no NCT IDs. Search ClinicalTrials.gov separately.
  • Suggested NCIT terms (CURIEs not looked up): surgical procedure NCIT:C15329 and pharmacotherapy NCIT:C15986, both listed in CLAUDE.md. Neither was re-verified here.

13. Prevention

  • Genetic counseling and cascade testing of relatives are standard for dominant conditions [model].
  • A formal surveillance protocol for malignant transformation was not found. I did not read the GeneReviews surveillance section ([gap]). Sun protection has no support here.

14. Other species

No OMIA entry was found. [gap]

15. Model organisms

  • Mouse knockouts.
  • Cyld-/- mice are more prone to DMBA/TPA skin tumors than wild type. This is linked to BCL3 nuclear translocation and cyclin D1 expression. [search: Nature Reviews Mol Cell Biol summary of a separate study]
  • Zhang et al. (JCI) reported CYLD-deficient mice with more colitis and colitis-associated cancer. [search: JCI 28746]
  • Catalytically deficient CYLD.
  • K14-driven catalytically deficient truncated CYLD sensitizes mice to DMBA/TPA skin tumors. [search: 2011 study]
  • The 2016 JCI Insight CyldEΔ9/Δ9 model develops mostly sebaceous and basaloid tumors that resemble human CYLD-mutant tumors, versus papillomas in wild type. A topical c-Myc inhibitor induced apoptosis. [search: JCI Insight 86548]
  • A Nature Communications 2016 paper reported sensitization to chemical carcinogen-induced intestinal and skin tumors with loss of catalytic activity. [search: Nat Commun 12508]
  • Fidelity. These mice do not spontaneously develop cylindromas. All models are carcinogen-promoted, so they fit evidence_source: MODEL_ORGANISM with FAILS_TO_RECAPITULATE/PARTIALLY_RECAPITULATES considerations for the spontaneous human tumor phenotype. That judgement is mine ([model]), based on the search summaries.

Key follow-ups before curation

  1. Read GeneReviews NBK555820 in full (it is also the mandatory baseline for a Mendelian entry). Run just fetch-reference for it.
  2. Retrieve primary PMIDs for the 2019 tumor genomics paper, the UK mosaicism cohort, and Bignell 2000 and Kovalenko 2003 (my recalled IDs are unverified).
  3. Look up CURIEs (OMIM, Orphanet, HPO, GO, CL, UBERON, hgnc) with real lookups.
  4. Decide the lump/split question for the BSS/FC/MFT names.
  5. Quantitative frequencies, penetrance and surveillance are all open gaps.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 5
Resolved 5
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 5
On topic 2
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 5
Resolved 4
Unresolved (possible confabulation) 1
Obsolete 0
Unverifiable 0
Terms whose name was checked 1
Terms named correctly 0
Terms named as a different term 1

Terms the report names something else

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

  • HP:0100677 (1 mention) - the report calls it "Cylindroma"; HP calls it Vulval varicose vein

Unresolved terms

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

  • HP:0100782 (1 mention), reported as "Trichoepithelioma" - HP does not contain this term