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)

• 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

• GeneReviews PDF NBK555820 and GeneReviews NBK555820 (summary only; page fetch blocked)
• MedGen C1857941
• CYLD mutations underlie BSS, FC and MFT
• Brummelkamp 2003, PMID 12917691
• JCI 28746 (Zhang et al.)
• Nat Commun 2019 tumor genomics
• 2026 Frontiers case report
• PMC8566010
• JCI Insight 86548
• Nat Commun 12508
• Nature Reviews Mol Cell Biol, nrm1977

Reference Validation

Checked with linkml-reference-validator 0.3.0.

All extracted references resolved successfully.

Term Validation

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

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