Cowden Syndrome 4

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Retrieved

2019-09-22

Source

Omim

Trials

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Genes

PTEN, SDHB, PIK3CA, KLLN, AKT1, SDHD, SEC23B, SDHC, FGFR2, EGFR, TNF, NOD2, TEP1, IL10, BMPR1A, TP53, IL23R, OSR1, BRCA1, MTOR, ATG16L1, SDS, CEACAM6, SARDH, CRP, HLA-DQA1, TGM2, IFNG, SMAD4, KLK3

PTEN, SDHB, PIK3CA, KLLN, AKT1, SDHD, SEC23B, SDHC, FGFR2, EGFR, TNF, NOD2, TEP1, IL10, BMPR1A, TP53, IL23R, OSR1, BRCA1, MTOR, ATG16L1, SDS, CEACAM6, SARDH, CRP, HLA-DQA1, TGM2, IFNG, SMAD4, KLK3, IL17A, BRCA2, ACAD8, SORD, IL6, PLAG1, PIK3CG, NPEPPS, TGFBI, TESC, PIK3CD, PIK3CB, IL1B, PSAT1, NR3C1, GTF2H1, GTF2H2, GTF2H3, GTF2H4, HIF1A, IBD5, TGFB1, MAPK1, HSP90B1, ADA, TLR2, TLR4, STK11, BDNF, SST, MIR21, SLC12A3, GTF2H5, IL15, TPMT, TSC1, LTA, LCN2, TNFSF15, VWF, IL15RA, PROS1, ERCC2, ERCC3, HEPH, DGCR2, DNAJC6, GDF15, GRAP2, CLOCK, TP63, ARHGEF2, HMGA2, TIMP1, TNFRSF1A, TNNI3, TSC2, UBC, VEGFA, VIM, AIMP2, GPR68, SLC16A3, BFSP2, RASAL1, RABEPK, NR1I2, SQSTM1, SGCE, USP8, SLC16A4, ABCB6, ACAT1, LANCL1, SEMA4D, LYPD1, TAGAP, SLCO6A1, SIRPA, SPRED1, TMPRSS6, USF3, IL27, TCERG1L, ARMH1, GSTK1, ASPG, MIR19A, MIR206, MIR29B1, MIR29B2, DEFA1A3, POU5F1P3, POU5F1P4, DEFB4B, MIR1290, LINC01672, OCLN, RN7SL263P, LOC110806263, IL17F, LMLN, KAT8, IL23A, AHSA1, TXNIP, CCR9, EBNA1BP2, KIF3A, FSTL1, TBC1D9, RNF19A, PTPN22, HAVCR1, IL19, MPC1, TMPRSS13, IL17D, SLC38A2, IL26, MYDGF, SUCNR1, SLURP1, HAMP, GORASP1, P2RY12, WNK1, CYREN, POLDIP2, SCD, TG, PTK2B, ACE, DEFB4A, DMBT1, DSC2, DSG2, TOR1A, EGF, ERCC5, ERCC6, EYA1, EYA2, FAP, CYBB, FGF2, FKBP5, FN1, GABPA, GAPDH, GCH1, GH1, GHSR, GLS, FFAR2, GPX1, CYP11A1, CCN2, TFF3, CASP3, ALB, ALDH1A1, APC, AR, ARSD, ATF3, BAX, BCL2, BGLAP, DDR1, CAMP, CAT, CSH2, CAV1, SERPINH1, CCNH, CD86, CD40, CDH2, CDK7, ERCC8, CRK, MAPK14, CSH1, HFE, HLA-DPB1, HLA-DQA2, CCL2, PMS2, POMC, POU5F1, PPIA, MAPK8, PROX1, PSMD7, RAP1A, RELA, RET, ACHE, CCL11, HLA-DQB1, CCL20, SDC1, SLC2A1, SLC6A4, SLC11A1, STAT3, STAT5A, STAT5B, SYT1, ADAM17, TRBV20OR9-2, ABCB1, PGF, TNFRSF11B, NFE2L2, HLA-DRB4, HSPA9, IFNA1, IFNA13, IL4, IL9, JAK2, KCNN4, RPSA, LBR, EPCAM, SMAD2, SMAD7, MAOA, MAT1A, MBL2, MAP3K5, MMP9, MSMB, MST1, MUC4, MUTYH, MYCN, H3P28

Drugs

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A number sign (#) is used with this entry because of evidence that Cowden syndrome-4 (CWS4) is caused by heterozygous germline hypermethylation of the KLLN gene (612105) on chromosome 10q23.

For a general phenotypic description and a discussion of genetic heterogeneity of Cowden syndrome, see CWS1 (158350).

Molecular Genetics

The KLLN gene on chromosome 10q23.31 shares the same transcription site as the PTEN (601728) gene, but is transcribed in the opposite direction. Killin is necessary and sufficient for TP53 (191170)-induced apoptosis. Among 123 patients with a clinical diagnosis of Cowden or Cowden-like syndrome without germline PTEN, SDHB (185470), or SDHD (602690) mutations, Bennett et al. (2010) found that 45 (37%) had germline hypermethylation and epigenetic inactivation of the KILLIN promoter. Of the 45 patients, 20 had classic Cowden syndrome, and 25 had Cowden-like syndrome. Hypermethylation of this region was not observed in 50 controls. One proband had a family history of the disorder, and genetic analysis showed that 3 of the 4 affected family members also had germline methylation in this region. Germline methylation was found to transcriptionally downregulate KLLN expression 250-fold, and exclusively disrupted TP53 activation of KLLN by 30%. Analysis of clinical features showed that individuals with KLLN promoter methylation had a 3-fold increased prevalence of breast cancer and a greater than 2-fold increase of kidney cancer compared to individuals with germline PTEN mutations. Bennett et al. (2010) emphasized that the findings needed to be replicated.