Palmoplantar Keratoderma-Esophageal Carcinoma Syndrome

Mendelian MONDO:0007856 Pathograph 23 Show in embeddings browser hereditary neoplastic syndrome palmoplantar keratoderma

Palmoplantar keratoderma-esophageal carcinoma syndrome, usually called tylosis with esophageal cancer (TOC), is an autosomal dominant cancer predisposition syndrome caused by heterozygous germline gain-of-function missense variants in RHBDF2, which encodes the catalytically inactive rhomboid protein iRHOM2. The reported variants cluster in a few adjacent codons of the cytoplasmic N-terminus. Focal, non-epidermolytic thickening of the skin at the weight-bearing and friction sites of the palms and soles appears in childhood, usually by 7 to 8 years and at the latest by puberty, with complete penetrance; it can be complicated by fissuring and infection. Oral and esophageal leukokeratosis occur, and carriers have a very high lifetime risk of esophageal squamous cell carcinoma, estimated at 95% by age 65 in the large Liverpool family, presenting from the mid-fifties onward and no earlier than sporadic disease. In patient keratinocytes the mutant iRHOM2 increases ADAM17 maturation and the shedding of EGF-family ligands, raising EGFR activity and producing a hyperproliferative, wound-healing-like epidermis; amphiregulin is the ligand that drives the skin phenotype in mouse models. Management centres on annual endoscopic surveillance with biopsy, which in the Liverpool family detected most cancers at stage 1.

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Classifications

Harrison's Part
ONCOLOGY HEMATOLOGY GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
Autosomal dominant. Penetrance of the cutaneous features is complete, usually by 7 to 8 years and at the latest by puberty. Esophageal cancer penetrance is age-dependent; the only estimate, 95% by age 65, comes from one large family.
Autosomal dominant inheritance Penetrance: COMPLETE
Show evidence (3 references)
CGGV:assertion_b7e72765-1a53-44fb-bfee-9e5923507bbe-2020-07-30T212232.808Z SUPPORT Other
"RHBDF2 | HGNC:20788 | palmoplantar keratoderma-esophageal carcinoma syndrome | MONDO:0007856 | AD | Definitive"
ClinGen records autosomal dominant inheritance for this MONDO term.
PMID:26419362 SUPPORT REVIEW SYNTHESIS Human clinical
"Tylosis with oesophageal cancer is inherited as an autosomal dominant trait with complete penetrance of the cutaneous features, usually by 7 to 8 years of age but can present as late as puberty."
Review statement of dominant inheritance and complete cutaneous penetrance, with the age by which the skin features appear.
PMID:22638770 SUPPORT Human clinical
"Tylosis with esophageal cancer (TOC) is a rare familial cancer syndrome inherited in an autosomal-dominant manner and characterized by esophageal cancer susceptibility and hyperkeratotic skin lesions."
Dominant inheritance, stated in a family study that confirmed the gene.
?

Discussions and Knowledge Gaps

3
Does the TOC form of iRHOM2 need ADAM17 catalytic activity to increase EGF-family ligand release, or does it act partly independently of ADAM17?
KNOWLEDGE GAP OPEN gap_adam17_catalytic_requirement
Attached to
pathophysiology#Increased ADAM17 Maturation and Ectodomain Shedding in Keratinocytes pathophysiology#Amphiregulin-Driven EGFR Hyperactivation
Patient keratinocytes show increased ADAM17 maturation and shedding, and the toc knock-in mouse phenotype depends on Adam17 dosage. One mouse and cell study reports amphiregulin secretion increased independently of ADAM17 activity, and another finds that the toc mutation changes ADAM17 function substrate-selectively without lowering mature ADAM17, while the related cub allele needs ADAM17 protein but not its catalytic activity.
Show evidence (3 references)
PMID:24825892 SUPPORT In vitro / ex vivo
"In turn, these stable variants function to augment the secretion of EGF family ligands, including amphiregulin, independent of metalloprotease a disintegrin and metalloproteinase 17 (ADAM17) activity."
ADAM17-independent ligand secretion.
PMID:37282854 SUPPORT Model organism
"The iR2toc mutation did not substantially reduce the levels of mature ADAM17, but instead affected its function in a substrate-selective manner."
Substrate-selective effect of the toc allele on ADAM17.
PMID:37282854 SUPPORT Model organism
"suggesting that the iR2cub gain-of-function mutation requires the presence of ADAM17, but not its catalytic activity"
The cub allele needs ADAM17 protein but not its catalytic activity.
Mouse Rhbdf2 TOC-mutation models show a hair-coat and general skin phenotype rather than focal palmoplantar keratoderma, and none is reported to develop esophageal cancer. How far do they model the human disease?
HUMAN MODEL MISMATCH OPEN mismatch_mouse_models_no_ppk_or_escc
Attached to
phenotypes#Focal Palmoplantar Keratoderma phenotypes#Esophageal Squamous Cell Carcinoma
The mechanism from iRhom2 to amphiregulin and EGFR is shared between mouse and patient cells, but the defining clinical features are not reproduced in the mouse, so the step from that mechanism to focal keratoderma and to esophageal cancer rests on human data alone. N-terminal iRhom2 mutations accelerate tumorigenesis in mice without causing spontaneous tumors.
Show evidence (2 references)
PMID:30022999 SUPPORT REVIEW SYNTHESIS Model organism
"Although current mouse models do not fully recapitulate all aspects of human TOC, and the molecular mechanisms underlying TOC are still emerging, the available mouse models exhibit several key aspects of the disease"
Review of the mouse models stating the gap.
PMID:24825892 SUPPORT Model organism
"In vivo, N-terminal iRhom2 mutations induce accelerated wound healing as well as accelerated tumorigenesis, but they do not drive spontaneous tumor development."
No spontaneous tumors in the mouse.
What is the esophageal cancer risk for an RHBDF2 variant carrier outside the Liverpool family?
KNOWLEDGE GAP OPEN gap_cancer_penetrance_estimate
Attached to
phenotypes#Esophageal Squamous Cell Carcinoma inheritance#Autosomal dominant inheritance
The 95% by age 65 figure was calculated in one large family, and the review says prognosis is hard to determine because few people are affected. No multi-family penetrance estimate was found among the sources cited here.
Show evidence (1 reference)
PMID:26419362 SUPPORT REVIEW SYNTHESIS Human clinical
"The prognosis of tylosis with oesophageal cancer is difficult to determine due to the limited number of affected individuals."
The review names the gap.
⚙

Pathophysiology

6
Germline RHBDF2 Gain-of-Function Variant
A heterozygous germline missense variant in the cytoplasmic N-terminus of RHBDF2. The first variants found were p.Ile186Thr (UK and US families) and p.Pro189Leu (a German family), followed by p.Asp188Asn in a Finnish family, which lies between the two; the Finnish authors suggested that TOC-associated variants may be specific to this site. The variants act as gain of function: N-terminal mutations make iRhom2 more stable, and loss of iRhom2 in mice thins the footpad epidermis instead of thickening it.
RHBDF2 hgnc:20788 ↑ INCREASED HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves increased RHBDF2 (hgnc:20788). hgnc:20788 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context RHBDF2 hgnc:20788 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns RHBDF2 (hgnc:20788). hgnc:20788 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE allelic_event: PATHOGENIC_VARIANT zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
Heterozygous missense variants at codons 186 to 189 of RHBDF2 (p.Ile186Thr, p.Asp188Asn, p.Pro189Leu in the papers cited here).
keratin 16 binding GO:1990254 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased keratin 16 binding, annotated with keratin filament binding (GO:1990254). GO:1990254 is a molecular function from the Gene Ontology.
Downstream
Increased ADAM17 Maturation and Ectodomain Shedding in Keratinocytes
Pre-Dysplastic Transcriptional Reprogramming of Esophageal Epithelium The esophageal biopsies were taken from carriers of the germline variant; the intermediate steps between iRHOM2 and the esophageal expression changes were not studied.
Show evidence (7 references)
PMID:28128203 SUPPORT In vitro / ex vivo
"Thus, TOC-associated iRHOM2 mutations appear to increase its binding with K16."
Co-immunoprecipitation and proximity ligation in immortalized TOC keratinocytes show increased iRHOM2-K16 binding. iRHOM2 is a catalytically inactive rhomboid, so no peptidase activity is bound; its regulation of ADAM17 maturation is recorded as a process on the next node.
PMID:22265016 SUPPORT Human clinical
"we have now identified missense mutations (c.557T>C ... and c.566C>T ... in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC"
Gene discovery by targeted capture and sequencing of the linked 17q25 interval in TOC families.
PMID:22638770 SUPPORT Human clinical
"We identified a new missense mutation, p.Asp188Asn, segregating with TOC in the Finnish family, and interestingly the detected mutation alters a codon located between the two previously reported mutation sites."
Independent family confirming RHBDF2, with a third variant in the same short stretch of codons.
+ 4 more references
Increased ADAM17 Maturation and Ectodomain Shedding in Keratinocytes
In keratinocytes from TOC patients, mutant iRHOM2 increases the maturation and activity of the sheddase ADAM17, which raises shedding of its substrates, including EGF-family growth factors and pro-inflammatory cytokines. Whether ADAM17 catalytic activity is needed for every downstream effect is disputed (see discussions).
epidermal keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves epidermal keratinocyte, annotated with keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
ADAM17 hgnc:195 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ADAM17 (hgnc:195). hgnc:195 is a gene from the HUGO Gene Nomenclature Committee.
membrane protein ectodomain proteolysis GO:0006509 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased membrane protein ectodomain proteolysis (GO:0006509). GO:0006509 is a biological process from the Gene Ontology. ADAM17 protein maturation GO:0051604 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased ADAM17 protein maturation, annotated with protein maturation (GO:0051604). GO:0051604 is a biological process from the Gene Ontology.
Downstream
Amphiregulin-Driven EGFR Hyperactivation
Show evidence (1 reference)
PMID:24643277 SUPPORT In vitro / ex vivo
"using tissues derived from TOC patients, we demonstrate that TOC-associated mutations in iRHOM2 cause an increase in the maturation and activity of ADAM17 in epidermal keratinocytes, resulting in significantly upregulated shedding of ADAM17 substrates, including EGF-family growth factors and..."
Direct demonstration in patient-derived keratinocytes.
Amphiregulin-Driven EGFR Hyperactivation
Increased release of EGF-family ligands raises EGFR activity in TOC keratinocytes. Amphiregulin is the ligand that matters for the skin phenotype in mice: deleting it rescues the skin of mice carrying the human TOC mutation. Immortalized TOC keratinocytes have lower total EGFR protein while being more proliferative and migratory, so the signalling change is best described as dysregulated rather than a simple increase in receptor.
epidermal keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves epidermal keratinocyte, annotated with keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
AREG hgnc:651 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves AREG (hgnc:651). hgnc:651 is a gene from the HUGO Gene Nomenclature Committee. EGFR hgnc:3236 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves EGFR (hgnc:3236). hgnc:3236 is a gene from the HUGO Gene Nomenclature Committee.
epidermal growth factor receptor signaling pathway GO:0007173 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased epidermal growth factor receptor signaling pathway (GO:0007173). GO:0007173 is a biological process from the Gene Ontology.
Animal models
Rhbdf2 toc knock-in mouse Mouse partially recapitulates The knock-in TOC mutation causes alopecia and wavy fur that depend on amphiregulin and ADAM17 dosage.
Human tylosis mutation mouse with Areg deletion Mouse recapitulates The human tylosis mutation increases amphiregulin secretion, and deleting amphiregulin ameliorates the skin pathology.
Downstream
Keratinocyte Hyperproliferation and Wound-Healing-Like Epidermal State
Show evidence (5 references)
PMID:24643277 SUPPORT In vitro / ex vivo
"This activity is accompanied by increased EGFR activity, increased desmosome processing and the presence of immature epidermal desmosomes, upregulated epidermal transglutaminase activity and heightened resistance to Staphylococcal infection in TOC keratinocytes."
Increased EGFR activity in TOC keratinocytes alongside the increased ADAM17 shedding.
PMID:22265016 SUPPORT In vitro / ex vivo
"immortalized tylotic keratinocytes have decreased levels of total epidermal growth factor receptor (EGFR) and display an increased proliferative and migratory potential relative to normal cells, even when normal cells are stimulated with exogenous epidermal growth factor. It would thus appear..."
Lower total EGFR protein with a hyperproliferative phenotype; the authors conclude that EGFR signalling is dysregulated.
PMID:24825892 SUPPORT In vitro / ex vivo
"In turn, these stable variants function to augment the secretion of EGF family ligands, including amphiregulin, independent of metalloprotease a disintegrin and metalloproteinase 17 (ADAM17) activity."
Stabilized iRhom2 increases amphiregulin secretion. This paper reports the effect as independent of ADAM17 activity, which is the disputed point recorded in discussions.
+ 2 more references
Keratinocyte Hyperproliferation and Wound-Healing-Like Epidermal State
TOC keratinocytes proliferate and migrate faster than control cells, and TOC epidermis shows immature desmosomes and raised transglutaminase activity, features its authors read as a constitutive wound-healing-like state. In mice, N-terminal iRhom2 mutations accelerate wound healing.
epidermal keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves epidermal keratinocyte, annotated with keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
keratinocyte proliferation GO:0043616 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased keratinocyte proliferation (GO:0043616). GO:0043616 is a biological process from the Gene Ontology. wound healing GO:0042060 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased wound healing (GO:0042060). GO:0042060 is a biological process from the Gene Ontology.
Downstream
Stress Keratin K16 Upregulation with Loss of K6
Focal Palmoplantar Keratoderma
Show evidence (3 references)
PMID:24643277 SUPPORT In vitro / ex vivo
"Many of these features are consistent with the presence of a constitutive wound-healing-like phenotype in TOC epidermis"
The authors' interpretation of the patient keratinocyte and epidermis findings.
PMID:22265016 SUPPORT In vitro / ex vivo
"immortalized tylotic keratinocytes have decreased levels of total epidermal growth factor receptor (EGFR) and display an increased proliferative and migratory potential relative to normal cells"
Increased proliferation and migration of patient-derived keratinocytes.
PMID:24825892 SUPPORT Model organism
"In vivo, N-terminal iRhom2 mutations induce accelerated wound healing as well as accelerated tumorigenesis, but they do not drive spontaneous tumor development."
Accelerated wound healing in mice carrying N-terminal iRhom2 mutations.
Stress Keratin K16 Upregulation with Loss of K6
Mutant iRHOM2 binds the stress keratin K16 more strongly in TOC keratinocytes. TOC skin has abundant K16 but almost no K6, its usual type II partner, and K16 filaments turn over faster. The authors propose that this K16 axis governs the epidermal response to mechanical stress, which would fit the restriction of the keratoderma to pressure sites; that link is their interpretation.
epidermal keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves epidermal keratinocyte, annotated with keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
KRT16 hgnc:6423 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KRT16 (hgnc:6423). hgnc:6423 is a gene from the HUGO Gene Nomenclature Committee. KRT6A hgnc:6443 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KRT6A (hgnc:6443). hgnc:6443 is a gene from the HUGO Gene Nomenclature Committee.
keratin filament organization GO:0045109 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal keratin filament organization, annotated with intermediate filament organization (GO:0045109). GO:0045109 is a biological process from the Gene Ontology.
Downstream
Focal Palmoplantar Keratoderma
Show evidence (4 references)
PMID:28128203 SUPPORT Human clinical
"In addition, immunohistochemistry of TOC skin showed almost absent K6, despite the presence of abundant K16"
Patient skin immunohistochemistry.
PMID:28128203 SUPPORT In vitro / ex vivo
"Western blotting confirmed a reduction of K6 in TOC keratinocytes compared with CTRL"
Reduced K6 in immortalized TOC keratinocytes.
PMID:28128203 SUPPORT In vitro / ex vivo
"These data reveal that the differential regulation of K16 and K6 in TOC keratinocytes contributes to accelerated filament turnover and perinuclear re-organization of the K16 filament network."
Altered K16 filament organization and turnover in TOC keratinocytes.
+ 1 more reference
Pre-Dysplastic Transcriptional Reprogramming of Esophageal Epithelium
Esophageal biopsies from TOC carriers under surveillance, graded as having no dysplasia, already show transcriptional changes that are shared with sporadic esophageal squamous cell carcinoma, including negative enrichment of GRHL2 and raised keratin 17, which is also increased at the protein level. These changes precede dysplasia; how they progress to cancer is not established.
esophageal squamous epithelial cell CL:0002252 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves esophageal squamous epithelial cell, annotated with epithelial cell of esophagus (CL:0002252). CL:0002252 is a cell type from the Cell Ontology.
KRT17 hgnc:6427 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KRT17 (hgnc:6427). hgnc:6427 is a gene from the HUGO Gene Nomenclature Committee.
esophageal epithelium UBERON:0001976 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in esophageal epithelium, annotated with epithelium of esophagus (UBERON:0001976). UBERON:0001976 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Esophageal Leukokeratosis
Esophageal Squamous Cell Carcinoma The steps from these early changes through dysplasia to carcinoma, and the somatic events in TOC tumors, are not known.
Show evidence (2 references)
PMID:39131151 SUPPORT Human clinical
"Transcriptional changes occur in TOC esophagus prior to the onset of dysplasia, many of which are associated with ESCC."
Bulk RNA-seq of non-dysplastic TOC esophageal biopsies against controls, compared with sporadic ESCC datasets.
PMID:39131151 SUPPORT Human clinical
"Moreover, Keratin 17, which was upregulated in TOC and ESCC, was also found to be overexpressed at the protein level in 'normal' TOC esophagus tissue."
Keratin 17 protein is raised in histologically normal TOC esophagus.
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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Palmoplantar Keratoderma-Esophageal Carcinoma 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 4
Esophageal Leukokeratosis Esophageal leukoplakia HP:0012859 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is esophageal leukokeratosis, annotated with Esophageal leukoplakia (HP:0012859). HP:0012859 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26419362 SUPPORT REVIEW SYNTHESIS Human clinical
"Oesophageal lesions appear as small (2-5 mm), white, polyploid lesions dotted throughout the oesophagus"
Endoscopic appearance of the esophageal lesions.
ORPHA:2198 SUPPORT Other
"oral and esophageal leukokeratosis, associated with a very high lifetime risk of developing squamous cell carcinoma of the esophagus"
Orphanet definition.
Esophageal Squamous Cell Carcinoma VERY_FREQUENT Esophageal carcinoma HP:0011459 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is esophageal squamous cell carcinoma, annotated with Esophageal carcinoma (HP:0011459), qualified as middle age onset. HP:0011459 is a phenotype from the Human Phenotype Ontology.
Onset: MIDDLE AGE
Sequelae: Dysphagia Odynophagia Weight Loss
Show evidence (3 references)
PMID:26419362 SUPPORT REVIEW SYNTHESIS Human clinical
"is associated with a very high lifetime risk of developing squamous cell carcinoma of the oesophagus. This risk has been calculated to be 95% at the age of 65 in one large family"
The lifetime risk figure, which comes from a single family.
PMID:26419362 SUPPORT REVIEW SYNTHESIS Human clinical
"Oesophageal cancer associated with tylosis usually presents in middle to late life (from mid-fifties onwards) and shows no earlier development than the sporadic form of the disease."
Age at presentation.
ORPHA:2198 SUPPORT Other
"associated with a very high lifetime risk of developing squamous cell carcinoma of the esophagus"
Orphanet definition.
Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26419362 SUPPORT REVIEW SYNTHESIS Human clinical
"Although symptoms of oesophageal cancer can include dysphagia, odynophagia, anorexia and weight loss, there may be an absence of symptoms in early disease"
Symptoms of the cancer, which may be absent early.
Odynophagia HP:0032043 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Odynophagia (HP:0032043). HP:0032043 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26419362 SUPPORT REVIEW SYNTHESIS Human clinical
"Although symptoms of oesophageal cancer can include dysphagia, odynophagia, anorexia and weight loss, there may be an absence of symptoms in early disease"
Symptoms of the cancer, which may be absent early.
Head and Neck 1
Oral Leukokeratosis Oral leukoplakia HP:0002745 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is oral leukokeratosis, annotated with Oral leukoplakia (HP:0002745). HP:0002745 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22265016 SUPPORT Human clinical
"Tylosis esophageal cancer (TOC) is an autosomal-dominant syndrome characterized by palmoplantar keratoderma, oral precursor lesions, and a high lifetime risk of esophageal cancer."
Names oral precursor lesions as a defining feature.
PMID:26419362 SUPPORT REVIEW SYNTHESIS Human clinical
"Oesophageal lesions appear as small (2-5 mm), white, polyploid lesions dotted throughout the oesophagus and oral leukokeratosis has also been described."
Review mention of oral leukokeratosis.
Integument 2
Focal Palmoplantar Keratoderma OBLIGATE Focal friction-related palmoplantar hyperkeratosis HP:0007497 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is focal non-epidermolytic palmoplantar keratoderma, annotated with Focal friction-related palmoplantar hyperkeratosis (HP:0007497), qualified as childhood onset. HP:0007497 is a phenotype from the Human Phenotype Ontology.
Onset: CHILDHOOD
Sequelae: Skin Fissures and Secondary Infection
Show evidence (3 references)
ORPHA:2198 SUPPORT Other
"thickening of the skin on palms and soles restricted to areas of weight bearing and/or friction (focal, non-epidermolytic palmoplantar keratoderma)"
Orphanet definition of the skin phenotype.
PMID:26419362 SUPPORT REVIEW SYNTHESIS Human clinical
"Tylosis (hyperkeratosis palmaris et plantaris) is characterised by focal thickening of the skin of the hands and feet"
Review description of the focal keratoderma.
PMID:26419362 SUPPORT REVIEW SYNTHESIS Human clinical
"complete penetrance of the cutaneous features, usually by 7 to 8 years of age but can present as late as puberty"
Onset and complete penetrance of the skin features.
Skin Fissures and Secondary Infection HP:0031057 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is palmoplantar skin fissures, annotated with Skin fissure (HP:0031057). HP:0031057 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:2198 SUPPORT Other
"The skin lesions appear in childhood and can be complicated by fissuring and infection."
Orphanet definition.
PMID:26419362 SUPPORT REVIEW SYNTHESIS Other
"Symptomatic management of the palmoplantar keratoderma includes regular application of emollients, specialist footwear and early treatment of fissures and super-added infection, particularly tinea pedis."
Fissures and superadded infection named as management targets in the review.
Growth 1
Weight Loss HP:0001824 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Weight loss (HP:0001824). HP:0001824 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26419362 SUPPORT REVIEW SYNTHESIS Human clinical
"Although symptoms of oesophageal cancer can include dysphagia, odynophagia, anorexia and weight loss, there may be an absence of symptoms in early disease"
Symptoms of the cancer, which may be absent early.
🧬

Genetic Associations

1
RHBDF2 (Germline gain-of-function cancer predisposition)
Gene: RHBDF2 hgnc:20788 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RHBDF2 (hgnc:20788). hgnc:20788 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:22265016 SUPPORT Human clinical
"we have now identified missense mutations (c.557T>C ... and c.566C>T ... in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC"
Gene discovery.
ORPHA:2198 SUPPORT Other
"RHBDF2 | rhomboid 5 homolog 2 | hgnc:20788 | Disease-causing germline mutation(s) (gain of function) in"
Orphanet records the gene as disease-causing by germline gain of function.
Variants (3)
p.Ile186Thr
c.557T>C, heterozygous missense, found in the UK and US families.
Show evidence (2 references)
PMID:22265016 SUPPORT Human clinical
"we have now identified missense mutations (c.557T>C ... and c.566C>T ... in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC"
Discovery report of the variant.
PMID:22638770 SUPPORT BACKGROUND Human clinical
"a p.Ile186Thr mutation was found in families from the UK and the US and a p.Pro189Leu mutation was detected in a German TOC family"
Families in which each of the first two variants was found.
p.Pro189Leu
c.566C>T, heterozygous missense, found in a German family.
Show evidence (1 reference)
PMID:22638770 SUPPORT BACKGROUND Human clinical
"a p.Ile186Thr mutation was found in families from the UK and the US and a p.Pro189Leu mutation was detected in a German TOC family"
Families in which each of the first two variants was found.
p.Asp188Asn
Heterozygous missense segregating with TOC in a Finnish family.
Show evidence (1 reference)
PMID:22638770 SUPPORT Human clinical
"We identified a new missense mutation, p.Asp188Asn, segregating with TOC in the Finnish family"
Segregation of the variant in the Finnish family.
💊

Medical Actions

5
Annual Endoscopic Surveillance With Biopsy
Action: surveillance esophagogastroduodenoscopy with biopsyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surveillance esophagogastroduodenoscopy with biopsy, annotated with Esophagogastroduodenoscopy (NCIT:C78144). NCIT:C78144 is a clinical intervention from the NCI Thesaurus. Ontology label: Esophagogastroduodenoscopy NCIT:C78144
The key management goal is early detection of esophageal dysplasia: annual gastroscopy with biopsy of any suspicious lesion and quadrantic biopsies from the upper, middle and lower esophagus, with dietary and lifestyle advice and symptom education. The age at which to start is not stated in the review abstract and is not recorded here.
Target Phenotypes: esophageal squamous cell carcinoma HP:0011459 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets esophageal squamous cell carcinoma, annotated with Esophageal carcinoma (HP:0011459). HP:0011459 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26419362 SUPPORT REVIEW SYNTHESIS Other
"Surveillance includes annual gastroscopy with biopsy of any suspicious lesion together with quadratic biopsies from the upper, middle and lower oesophagus. This is coupled with dietary and lifestyle modification advice and symptom education."
The surveillance protocol recommended in the review.
PMID:26419362 SUPPORT REVIEW SYNTHESIS Human clinical
"In the last 40 years of surveillance, five out of six cases of squamous oesophageal cancer in the Liverpool family were detected endoscopically and were surgically removed. Four of five patients had stage 1 disease at presentation and remain alive and well more than 8 years later."
Outcome of surveillance in the Liverpool family; uncontrolled, single family.
Surgical Resection of Screen-Detected Esophageal Cancer
Action: surgical resection of esophageal carcinomaNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical resection of esophageal carcinoma, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Cancers detected at surveillance endoscopy were surgically removed in the Liverpool family.
Target Phenotypes: esophageal squamous cell carcinoma HP:0011459 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets esophageal squamous cell carcinoma, annotated with Esophageal carcinoma (HP:0011459). HP:0011459 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26419362 SUPPORT REVIEW SYNTHESIS Human clinical
"five out of six cases of squamous oesophageal cancer in the Liverpool family were detected endoscopically and were surgically removed"
Surgical treatment of screen-detected cancers.
Emollients, Specialist Footwear and Treatment of Fissures
Action: supportive skin careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive skin care, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
Symptomatic care of the keratoderma: regular emollients, specialist footwear, and early treatment of fissures and superadded infection, particularly tinea pedis.
Target Phenotypes: focal non-epidermolytic palmoplantar keratoderma HP:0007497 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets focal non-epidermolytic palmoplantar keratoderma, annotated with Focal friction-related palmoplantar hyperkeratosis (HP:0007497). HP:0007497 is a phenotype from the Human Phenotype Ontology. palmoplantar skin fissures HP:0031057 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets palmoplantar skin fissures, annotated with Skin fissure (HP:0031057). HP:0031057 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26419362 SUPPORT REVIEW SYNTHESIS Other
"Symptomatic management of the palmoplantar keratoderma includes regular application of emollients, specialist footwear and early treatment of fissures and super-added infection, particularly tinea pedis."
Review management recommendation.
Oral Retinoids
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: oral retinoid CHEBI:26537 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses oral retinoid, annotated with retinoid (CHEBI:26537). CHEBI:26537 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Oral retinoids are effective for the thickened skin but commonly cause side effects, including nasal excoriation and bleeding, hypercholesterolaemia and abnormal liver function tests. The review abstract does not name a specific retinoid.
Target Phenotypes: focal non-epidermolytic palmoplantar keratoderma HP:0007497 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets focal non-epidermolytic palmoplantar keratoderma, annotated with Focal friction-related palmoplantar hyperkeratosis (HP:0007497). HP:0007497 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26419362 SUPPORT REVIEW SYNTHESIS Other
"More specific treatment for the thick skin is available in the form of oral retinoids, which are very effective but commonly produce side effects, including nasal excoriation and bleeding, hypercholesterolaemia, and abnormal liver function tests."
Review statement of efficacy and adverse effects.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Other
Genetic counselling for patients and relatives once the family history is established, with predictive testing for the familial RHBDF2 variant.
Show evidence (1 reference)
PMID:26419362 SUPPORT REVIEW SYNTHESIS Other
"Genetic counselling can be offered to patients and family members once a family history has been established."
Review management recommendation.
🔬

Diagnosis

1
Clinical and RHBDF2 genetic diagnosis
Diagnosis rests on family history, the characteristic skin and esophageal lesions, and testing for an RHBDF2 variant. Identifying the familial variant allows predictive testing of relatives.
RHBDF2 germline genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:26419362 SUPPORT REVIEW SYNTHESIS Other
"A diagnosis of tylosis with oesophageal cancer is made on the basis of a positive family history, characteristic clinical features, including cutaneous and oesophageal lesions, and genetic analysis for mutations in RHBDF2."
Review statement of the diagnostic basis.
PMID:22638770 SUPPORT Human clinical
"These results enable the genetic counseling and diagnostic mutation screening of the members of TOC families."
Gene confirmation enabling family testing.
📊

Prevalence

1
Worldwide
Point prevalence <1 in 1,000,000
Orphanet worldwide point-prevalence class below 1 in 1,000,000. The 2015 review says the frequency in the general population is not known. Almost all published knowledge comes from a small number of extended families.
Show evidence (2 references)
ORPHA:2198 SUPPORT Other
"<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"
Orphanet epidemiology table.
PMID:26419362 SUPPORT REVIEW SYNTHESIS Human clinical
"the frequency of the disorder in the general population is not known and is likely to be less than one in 1,000,000"
Review estimate consistent with the Orphanet band; the review says the true frequency is unknown.
🐁

Animal Models

2
Rhbdf2 toc knock-in mouse
Species
Mouse
Genotype
Rhbdf2 toc/toc (knock-in of a TOC mutation)
Publication
PMID:37282854
Pathograph links
Amphiregulin-Driven EGFR Hyperactivation partially recapitulates fidelity: moderate The knock-in TOC mutation causes alopecia and wavy fur that depend on amphiregulin and ADAM17 dosage.
Limitations: The mice show a hair-coat phenotype rather than palmoplantar keratoderma, and the abstract reports no esophageal cancer.
Show evidence (2 references)
PMID:37282854 SUPPORT Model organism
"A cytoplasmic deletion in iR2, including the TOC site, leads to curly coat or bare skin (cub) in mice, whereas a knock-in TOC mutation (toc) causes less severe alopecia and wavy fur."
The skin phenotype of the knock-in mouse.
+ 1 more reference
Human tylosis mutation mouse with Areg deletion
Species
Mouse
Genotype
Rhbdf2 carrying the human tylosis mutation, with and without Areg deletion
Publication
PMID:28655741
Pathograph links
Amphiregulin-Driven EGFR Hyperactivation recapitulates fidelity: moderate The human tylosis mutation increases amphiregulin secretion, and deleting amphiregulin ameliorates the skin pathology.
Limitations: Mouse skin pathology is used as the readout; palmoplantar keratoderma and esophageal cancer are not reported in the abstract.
Show evidence (1 reference)
PMID:28655741 SUPPORT Model organism
"Furthermore, we show that genetic disruption of AREG ameliorates skin pathology in mice carrying the human tylosis disease mutation."
Genetic rescue.
{ }

Source YAML

click to show 
name: Palmoplantar Keratoderma-Esophageal Carcinoma Syndrome
creation_date: "2026-11-03T19:15:04Z"
category: Mendelian
categories:
- Hereditary Cancer Syndrome
- Cancer Predisposition Syndrome
- Genodermatosis
parents:
- hereditary neoplastic syndrome
- palmoplantar keratoderma
disease_term:
  preferred_term: palmoplantar keratoderma-esophageal carcinoma syndrome
  term:
    id: MONDO:0007856
    label: palmoplantar keratoderma-esophageal carcinoma syndrome
synonyms:
- Tylosis with esophageal cancer
- TOC
- Bennion-Patterson syndrome
- Howell-Evans syndrome
- keratosis palmoplantaris-esophageal carcinoma syndrome
- palmoplantar hyperkeratosis-esophageal carcinoma syndrome
- tylosis-oesophageal carcinoma syndrome
description: >-
  Palmoplantar keratoderma-esophageal carcinoma syndrome, usually called
  tylosis with esophageal cancer (TOC), is an autosomal dominant cancer
  predisposition syndrome caused by heterozygous germline gain-of-function
  missense variants in RHBDF2, which encodes the catalytically inactive
  rhomboid protein iRHOM2. The reported variants cluster in a few adjacent
  codons of the cytoplasmic N-terminus. Focal, non-epidermolytic thickening of
  the skin at the weight-bearing and friction sites of the palms and soles
  appears in childhood, usually by 7 to 8 years and at the latest by puberty,
  with complete penetrance; it can be complicated by fissuring and infection.
  Oral and esophageal leukokeratosis occur, and carriers have a very high
  lifetime risk of esophageal squamous cell carcinoma, estimated at 95% by age
  65 in the large Liverpool family, presenting from the mid-fifties onward and
  no earlier than sporadic disease. In patient keratinocytes the mutant iRHOM2
  increases ADAM17 maturation and the shedding of EGF-family ligands, raising
  EGFR activity and producing a hyperproliferative, wound-healing-like
  epidermis; amphiregulin is the ligand that drives the skin phenotype in mouse
  models. Management centres on annual endoscopic surveillance with biopsy,
  which in the Liverpool family detected most cancers at stage 1.
classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: COMPLETE
  description: >-
    Autosomal dominant. Penetrance of the cutaneous features is complete,
    usually by 7 to 8 years and at the latest by puberty. Esophageal cancer
    penetrance is age-dependent; the only estimate, 95% by age 65, comes from
    one large family.
  evidence:
  - reference: CGGV:assertion_b7e72765-1a53-44fb-bfee-9e5923507bbe-2020-07-30T212232.808Z
    reference_title: RHBDF2 / palmoplantar keratoderma-esophageal carcinoma syndrome (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RHBDF2 | HGNC:20788 | palmoplantar keratoderma-esophageal carcinoma syndrome | MONDO:0007856 | AD | Definitive"
    explanation: >-
      ClinGen records autosomal dominant inheritance for this MONDO term.
  - reference: PMID:26419362
    reference_title: "Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Tylosis with oesophageal cancer is inherited as an autosomal dominant trait with complete penetrance of the cutaneous features, usually by 7 to 8 years of age but can present as late as puberty."
    explanation: >-
      Review statement of dominant inheritance and complete cutaneous
      penetrance, with the age by which the skin features appear.
  - reference: PMID:22638770
    reference_title: Analysis of a Finnish family confirms RHBDF2 mutations as the underlying factor in tylosis with esophageal cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tylosis with esophageal cancer (TOC) is a rare familial cancer syndrome inherited in an autosomal-dominant manner and characterized by esophageal cancer susceptibility and hyperkeratotic skin lesions."
    explanation: >-
      Dominant inheritance, stated in a family study that confirmed the gene.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Orphanet worldwide point-prevalence class below 1 in 1,000,000. The 2015
    review says the frequency in the general population is not known. Almost
    all published knowledge comes from a small number of extended families.
  evidence:
  - reference: ORPHA:2198
    reference_title: Palmoplantar keratoderma-esophageal carcinoma syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"
    explanation: Orphanet epidemiology table.
  - reference: PMID:26419362
    reference_title: "Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "the frequency of the disorder in the general population is not known and is likely to be less than one in 1,000,000"
    explanation: >-
      Review estimate consistent with the Orphanet band; the review says the
      true frequency is unknown.
pathophysiology:
- name: Germline RHBDF2 Gain-of-Function Variant
  biological_scale: MOLECULAR
  description: >-
    A heterozygous germline missense variant in the cytoplasmic N-terminus of
    RHBDF2. The first variants found were p.Ile186Thr (UK and US families) and
    p.Pro189Leu (a German family), followed by p.Asp188Asn in a Finnish family,
    which lies between the two; the Finnish authors suggested that
    TOC-associated variants may be specific to this site. The variants act as
    gain of function: N-terminal mutations make iRhom2 more stable, and loss of
    iRhom2 in mice thins the footpad epidermis instead of thickening it.
  gene:
    preferred_term: RHBDF2
    modifier: INCREASED
    term:
      id: hgnc:20788
      label: RHBDF2
  genetic_context:
    gene:
      preferred_term: RHBDF2
      term:
        id: hgnc:20788
        label: RHBDF2
    variant_origin: GERMLINE
    allelic_events:
    - PATHOGENIC_VARIANT
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      Heterozygous missense variants at codons 186 to 189 of RHBDF2
      (p.Ile186Thr, p.Asp188Asn, p.Pro189Leu in the papers cited here).
  molecular_functions:
  - preferred_term: keratin 16 binding
    modifier: INCREASED
    term:
      id: GO:1990254
      label: keratin filament binding
  evidence:
  - reference: PMID:28128203
    reference_title: Rhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Thus, TOC-associated iRHOM2 mutations appear to increase its binding with K16."
    explanation: >-
      Co-immunoprecipitation and proximity ligation in immortalized TOC
      keratinocytes show increased iRHOM2-K16 binding. iRHOM2 is a
      catalytically inactive rhomboid, so no peptidase activity is bound; its
      regulation of ADAM17 maturation is recorded as a process on the next
      node.
  - reference: PMID:22265016
    reference_title: RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we have now identified missense mutations (c.557T>C ... and c.566C>T ... in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC"
    explanation: >-
      Gene discovery by targeted capture and sequencing of the linked 17q25
      interval in TOC families.
  - reference: PMID:22638770
    reference_title: Analysis of a Finnish family confirms RHBDF2 mutations as the underlying factor in tylosis with esophageal cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a new missense mutation, p.Asp188Asn, segregating with TOC in the Finnish family, and interestingly the detected mutation alters a codon located between the two previously reported mutation sites."
    explanation: >-
      Independent family confirming RHBDF2, with a third variant in the same
      short stretch of codons.
  - reference: CGGV:assertion_b7e72765-1a53-44fb-bfee-9e5923507bbe-2020-07-30T212232.808Z
    reference_title: RHBDF2 / palmoplantar keratoderma-esophageal carcinoma syndrome (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Five unique missense variants in the RHBDF2 gene were reported to segregate with disease in 6 families, suggesting heterozygous gain of function is the mechanism of tumorigenesis for this gene."
    explanation: >-
      ClinGen's count of the segregating variants and its statement of the
      gain-of-function mechanism.
  - reference: PMID:28655741
    reference_title: Genetic deletion of amphiregulin restores the normal skin phenotype in a mouse model of the human skin disease tylosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "In humans, gain-of-function (GOF) mutations in RHBDF2 cause the skin disease tylosis."
    explanation: >-
      States the gain-of-function classification of the human variants, as
      background in a mouse study.
  - reference: PMID:24825892
    reference_title: Rhbdf2 mutations increase its protein stability and drive EGFR hyperactivation through enhanced secretion of amphiregulin.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that iRhom2 is a short-lived protein whose stability can be increased by select mutations in the N-terminal domain."
    explanation: >-
      N-terminal mutations stabilize iRhom2, one route by which the variants
      gain function. The mutations studied are N-terminal Rhbdf2 mutations in
      cell and mouse systems, not only the human TOC alleles.
  - reference: PMID:28128203
    reference_title: Rhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "K16 expression is absent in the thinned footpads of irhom2-/- mice compared with irhom2+/+mice, due to reduced keratinocyte proliferation."
    explanation: >-
      Loss of iRhom2 gives the opposite footpad phenotype to TOC, which fits a
      gain-of-function rather than a loss-of-function disease mechanism.
  downstream:
  - target: Increased ADAM17 Maturation and Ectodomain Shedding in Keratinocytes
    causal_link_type: DIRECT
  - target: Pre-Dysplastic Transcriptional Reprogramming of Esophageal Epithelium
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The esophageal biopsies were taken from carriers of the germline
      variant; the intermediate steps between iRHOM2 and the esophageal
      expression changes were not studied.
- name: Increased ADAM17 Maturation and Ectodomain Shedding in Keratinocytes
  biological_scale: CELLULAR
  description: >-
    In keratinocytes from TOC patients, mutant iRHOM2 increases the maturation
    and activity of the sheddase ADAM17, which raises shedding of its
    substrates, including EGF-family growth factors and pro-inflammatory
    cytokines. Whether ADAM17 catalytic activity is needed for every
    downstream effect is disputed (see discussions).
  biological_processes:
  - preferred_term: membrane protein ectodomain proteolysis
    modifier: INCREASED
    term:
      id: GO:0006509
      label: membrane protein ectodomain proteolysis
  - preferred_term: ADAM17 protein maturation
    modifier: INCREASED
    term:
      id: GO:0051604
      label: protein maturation
  genes:
  - preferred_term: ADAM17
    term:
      id: hgnc:195
      label: ADAM17
  cell_types:
  - preferred_term: epidermal keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:24643277
    reference_title: iRHOM2-dependent regulation of ADAM17 in cutaneous disease and epidermal barrier function.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "using tissues derived from TOC patients, we demonstrate that TOC-associated mutations in iRHOM2 cause an increase in the maturation and activity of ADAM17 in epidermal keratinocytes, resulting in significantly upregulated shedding of ADAM17 substrates, including EGF-family growth factors and pro-inflammatory cytokines"
    explanation: >-
      Direct demonstration in patient-derived keratinocytes.
  downstream:
  - target: Amphiregulin-Driven EGFR Hyperactivation
    causal_link_type: DIRECT
- name: Amphiregulin-Driven EGFR Hyperactivation
  biological_scale: CELLULAR
  description: >-
    Increased release of EGF-family ligands raises EGFR activity in TOC
    keratinocytes. Amphiregulin is the ligand that matters for the skin
    phenotype in mice: deleting it rescues the skin of mice carrying the human
    TOC mutation. Immortalized TOC keratinocytes have lower total EGFR protein
    while being more proliferative and migratory, so the signalling change is
    best described as dysregulated rather than a simple increase in receptor.
  biological_processes:
  - preferred_term: epidermal growth factor receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007173
      label: epidermal growth factor receptor signaling pathway
  genes:
  - preferred_term: AREG
    term:
      id: hgnc:651
      label: AREG
  - preferred_term: EGFR
    term:
      id: hgnc:3236
      label: EGFR
  cell_types:
  - preferred_term: epidermal keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:24643277
    reference_title: iRHOM2-dependent regulation of ADAM17 in cutaneous disease and epidermal barrier function.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This activity is accompanied by increased EGFR activity, increased desmosome processing and the presence of immature epidermal desmosomes, upregulated epidermal transglutaminase activity and heightened resistance to Staphylococcal infection in TOC keratinocytes."
    explanation: >-
      Increased EGFR activity in TOC keratinocytes alongside the increased
      ADAM17 shedding.
  - reference: PMID:22265016
    reference_title: RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "immortalized tylotic keratinocytes have decreased levels of total epidermal growth factor receptor (EGFR) and display an increased proliferative and migratory potential relative to normal cells, even when normal cells are stimulated with exogenous epidermal growth factor. It would thus appear that EGFR signaling is dysregulated in tylotic cells."
    explanation: >-
      Lower total EGFR protein with a hyperproliferative phenotype; the authors
      conclude that EGFR signalling is dysregulated.
  - reference: PMID:24825892
    reference_title: Rhbdf2 mutations increase its protein stability and drive EGFR hyperactivation through enhanced secretion of amphiregulin.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In turn, these stable variants function to augment the secretion of EGF family ligands, including amphiregulin, independent of metalloprotease a disintegrin and metalloproteinase 17 (ADAM17) activity."
    explanation: >-
      Stabilized iRhom2 increases amphiregulin secretion. This paper reports
      the effect as independent of ADAM17 activity, which is the disputed point
      recorded in discussions.
  - reference: PMID:28655741
    reference_title: Genetic deletion of amphiregulin restores the normal skin phenotype in a mouse model of the human skin disease tylosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We generated a mouse model of human tylosis and show that GOF mutations in RHBDF2 cause tylosis by enhancing the amount of amphiregulin (AREG) secretion. Furthermore, we show that genetic disruption of AREG ameliorates skin pathology in mice carrying the human tylosis disease mutation."
    explanation: >-
      Genetic rescue in mice identifies amphiregulin as the driver of the skin
      phenotype.
  - reference: PMID:37282854
    reference_title: Analysis of the function of ADAM17 in iRhom2 curly-bare and tylosis with esophageal cancer mutant mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The abnormal skin and hair phenotypes of iR2cub/cub and iR2toc/toc mice depend on amphiregulin (Areg) and Adam17, as loss of one allele of either gene rescues the fur phenotypes."
    explanation: >-
      In TOC knock-in mice the skin and hair phenotype depends on both
      amphiregulin and ADAM17 dosage.
  downstream:
  - target: Keratinocyte Hyperproliferation and Wound-Healing-Like Epidermal State
    causal_link_type: DIRECT
- name: Keratinocyte Hyperproliferation and Wound-Healing-Like Epidermal State
  biological_scale: CELLULAR
  description: >-
    TOC keratinocytes proliferate and migrate faster than control cells, and
    TOC epidermis shows immature desmosomes and raised transglutaminase
    activity, features its authors read as a constitutive wound-healing-like
    state. In mice, N-terminal iRhom2 mutations accelerate wound healing.
  biological_processes:
  - preferred_term: keratinocyte proliferation
    modifier: INCREASED
    term:
      id: GO:0043616
      label: keratinocyte proliferation
  - preferred_term: wound healing
    modifier: INCREASED
    term:
      id: GO:0042060
      label: wound healing
  cell_types:
  - preferred_term: epidermal keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:24643277
    reference_title: iRHOM2-dependent regulation of ADAM17 in cutaneous disease and epidermal barrier function.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Many of these features are consistent with the presence of a constitutive wound-healing-like phenotype in TOC epidermis"
    explanation: >-
      The authors' interpretation of the patient keratinocyte and epidermis
      findings.
  - reference: PMID:22265016
    reference_title: RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "immortalized tylotic keratinocytes have decreased levels of total epidermal growth factor receptor (EGFR) and display an increased proliferative and migratory potential relative to normal cells"
    explanation: >-
      Increased proliferation and migration of patient-derived keratinocytes.
  - reference: PMID:24825892
    reference_title: Rhbdf2 mutations increase its protein stability and drive EGFR hyperactivation through enhanced secretion of amphiregulin.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In vivo, N-terminal iRhom2 mutations induce accelerated wound healing as well as accelerated tumorigenesis, but they do not drive spontaneous tumor development."
    explanation: >-
      Accelerated wound healing in mice carrying N-terminal iRhom2 mutations.
  downstream:
  - target: Stress Keratin K16 Upregulation with Loss of K6
    causal_link_type: DIRECT
  - target: Focal Palmoplantar Keratoderma
    causal_link_type: DIRECT
- name: Stress Keratin K16 Upregulation with Loss of K6
  biological_scale: CELLULAR
  description: >-
    Mutant iRHOM2 binds the stress keratin K16 more strongly in TOC
    keratinocytes. TOC skin has abundant K16 but almost no K6, its usual type
    II partner, and K16 filaments turn over faster. The authors propose that
    this K16 axis governs the epidermal response to mechanical stress, which
    would fit the restriction of the keratoderma to pressure sites; that link
    is their interpretation.
  biological_processes:
  - preferred_term: keratin filament organization
    modifier: ABNORMAL
    term:
      id: GO:0045109
      label: intermediate filament organization
  genes:
  - preferred_term: KRT16
    term:
      id: hgnc:6423
      label: KRT16
  - preferred_term: KRT6A
    term:
      id: hgnc:6443
      label: KRT6A
  cell_types:
  - preferred_term: epidermal keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:28128203
    reference_title: Rhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, immunohistochemistry of TOC skin showed almost absent K6, despite the presence of abundant K16"
    explanation: >-
      Patient skin immunohistochemistry.
  - reference: PMID:28128203
    reference_title: Rhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Western blotting confirmed a reduction of K6 in TOC keratinocytes compared with CTRL"
    explanation: >-
      Reduced K6 in immortalized TOC keratinocytes.
  - reference: PMID:28128203
    reference_title: Rhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These data reveal that the differential regulation of K16 and K6 in TOC keratinocytes contributes to accelerated filament turnover and perinuclear re-organization of the K16 filament network."
    explanation: >-
      Altered K16 filament organization and turnover in TOC keratinocytes.
  - reference: PMID:28128203
    reference_title: Rhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "By orchestrating the remodelling and turnover of K16, and uncoupling it from K6, iRHOM2 regulates the epithelial response to physical stress."
    explanation: >-
      The authors' conclusion linking the K16 axis to the response to
      mechanical stress.
  downstream:
  - target: Focal Palmoplantar Keratoderma
    causal_link_type: DIRECT
- name: Pre-Dysplastic Transcriptional Reprogramming of Esophageal Epithelium
  biological_scale: TISSUE
  description: >-
    Esophageal biopsies from TOC carriers under surveillance, graded as having
    no dysplasia, already show transcriptional changes that are shared with
    sporadic esophageal squamous cell carcinoma, including negative enrichment
    of GRHL2 and raised keratin 17, which is also increased at the protein
    level. These changes precede dysplasia; how they progress to cancer is not
    established.
  genes:
  - preferred_term: KRT17
    term:
      id: hgnc:6427
      label: KRT17
  cell_types:
  - preferred_term: esophageal squamous epithelial cell
    term:
      id: CL:0002252
      label: epithelial cell of esophagus
  locations:
  - preferred_term: esophageal epithelium
    term:
      id: UBERON:0001976
      label: epithelium of esophagus
  evidence:
  - reference: PMID:39131151
    reference_title: Investigating iRHOM2-Associated Transcriptional Changes in Tylosis With Esophageal Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transcriptional changes occur in TOC esophagus prior to the onset of dysplasia, many of which are associated with ESCC."
    explanation: >-
      Bulk RNA-seq of non-dysplastic TOC esophageal biopsies against controls,
      compared with sporadic ESCC datasets.
  - reference: PMID:39131151
    reference_title: Investigating iRHOM2-Associated Transcriptional Changes in Tylosis With Esophageal Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, Keratin 17, which was upregulated in TOC and ESCC, was also found to be overexpressed at the protein level in 'normal' TOC esophagus tissue."
    explanation: >-
      Keratin 17 protein is raised in histologically normal TOC esophagus.
  downstream:
  - target: Esophageal Leukokeratosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Esophageal Squamous Cell Carcinoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The steps from these early changes through dysplasia to carcinoma, and
      the somatic events in TOC tumors, are not known.
phenotypes:
- category: Integumentary
  name: Focal Palmoplantar Keratoderma
  description: >-
    Focal, non-epidermolytic thickening of the skin of the palms and soles,
    restricted to weight-bearing and friction sites. It appears in childhood,
    usually by 7 to 8 years and at the latest by puberty, and is present in
    every carrier.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: focal non-epidermolytic palmoplantar keratoderma
    term:
      id: HP:0007497
      label: Focal friction-related palmoplantar hyperkeratosis
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: ORPHA:2198
    reference_title: Palmoplantar keratoderma-esophageal carcinoma syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "thickening of the skin on palms and soles restricted to areas of weight bearing and/or friction (focal, non-epidermolytic palmoplantar keratoderma)"
    explanation: Orphanet definition of the skin phenotype.
  - reference: PMID:26419362
    reference_title: "Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Tylosis (hyperkeratosis palmaris et plantaris) is characterised by focal thickening of the skin of the hands and feet"
    explanation: Review description of the focal keratoderma.
  - reference: PMID:26419362
    reference_title: "Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "complete penetrance of the cutaneous features, usually by 7 to 8 years of age but can present as late as puberty"
    explanation: Onset and complete penetrance of the skin features.
  sequelae:
  - target: Skin Fissures and Secondary Infection
    causal_link_type: DIRECT
- category: Integumentary
  name: Skin Fissures and Secondary Infection
  description: >-
    The keratoderma can fissure and become infected, particularly with tinea
    pedis.
  phenotype_term:
    preferred_term: palmoplantar skin fissures
    term:
      id: HP:0031057
      label: Skin fissure
  evidence:
  - reference: ORPHA:2198
    reference_title: Palmoplantar keratoderma-esophageal carcinoma syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The skin lesions appear in childhood and can be complicated by fissuring and infection."
    explanation: Orphanet definition.
  - reference: PMID:26419362
    reference_title: "Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Symptomatic management of the palmoplantar keratoderma includes regular application of emollients, specialist footwear and early treatment of fissures and super-added infection, particularly tinea pedis."
    explanation: >-
      Fissures and superadded infection named as management targets in the
      review.
- category: Digestive
  name: Oral Leukokeratosis
  description: >-
    White keratotic lesions of the oral mucosa, described as oral precursor
    lesions.
  phenotype_term:
    preferred_term: oral leukokeratosis
    term:
      id: HP:0002745
      label: Oral leukoplakia
  evidence:
  - reference: PMID:22265016
    reference_title: RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tylosis esophageal cancer (TOC) is an autosomal-dominant syndrome characterized by palmoplantar keratoderma, oral precursor lesions, and a high lifetime risk of esophageal cancer."
    explanation: Names oral precursor lesions as a defining feature.
  - reference: PMID:26419362
    reference_title: "Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Oesophageal lesions appear as small (2-5 mm), white, polyploid lesions dotted throughout the oesophagus and oral leukokeratosis has also been described."
    explanation: Review mention of oral leukokeratosis.
- category: Digestive
  name: Esophageal Leukokeratosis
  description: >-
    Small (2 to 5 mm) white polypoid lesions scattered through the esophagus,
    seen at endoscopy.
  phenotype_term:
    preferred_term: esophageal leukokeratosis
    term:
      id: HP:0012859
      label: Esophageal leukoplakia
  evidence:
  - reference: PMID:26419362
    reference_title: "Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Oesophageal lesions appear as small (2-5 mm), white, polyploid lesions dotted throughout the oesophagus"
    explanation: Endoscopic appearance of the esophageal lesions.
  - reference: ORPHA:2198
    reference_title: Palmoplantar keratoderma-esophageal carcinoma syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "oral and esophageal leukokeratosis, associated with a very high lifetime risk of developing squamous cell carcinoma of the esophagus"
    explanation: Orphanet definition.
- category: Neoplastic
  name: Esophageal Squamous Cell Carcinoma
  description: >-
    Squamous cell carcinoma of the esophagus, with a very high lifetime risk
    estimated at 95% by age 65 in one large family. It presents from the
    mid-fifties onward, no earlier than sporadic disease, and may be
    asymptomatic when early.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: esophageal squamous cell carcinoma
    term:
      id: HP:0011459
      label: Esophageal carcinoma
    onset:
      onset_category: MIDDLE_AGE
      notes: From the mid-fifties onward, per the 2015 review.
  evidence:
  - reference: PMID:26419362
    reference_title: "Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "is associated with a very high lifetime risk of developing squamous cell carcinoma of the oesophagus. This risk has been calculated to be 95% at the age of 65 in one large family"
    explanation: >-
      The lifetime risk figure, which comes from a single family.
  - reference: PMID:26419362
    reference_title: "Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Oesophageal cancer associated with tylosis usually presents in middle to late life (from mid-fifties onwards) and shows no earlier development than the sporadic form of the disease."
    explanation: Age at presentation.
  - reference: ORPHA:2198
    reference_title: Palmoplantar keratoderma-esophageal carcinoma syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "associated with a very high lifetime risk of developing squamous cell carcinoma of the esophagus"
    explanation: Orphanet definition.
  sequelae:
  - target: Dysphagia
    causal_link_type: DIRECT
  - target: Odynophagia
    causal_link_type: DIRECT
  - target: Weight Loss
    causal_link_type: DIRECT
- category: Digestive
  name: Dysphagia
  description: Symptom of esophageal cancer; may be absent in early disease.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:26419362
    reference_title: "Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Although symptoms of oesophageal cancer can include dysphagia, odynophagia, anorexia and weight loss, there may be an absence of symptoms in early disease"
    explanation: Symptoms of the cancer, which may be absent early.
- category: Digestive
  name: Odynophagia
  description: Symptom of esophageal cancer.
  phenotype_term:
    preferred_term: Odynophagia
    term:
      id: HP:0032043
      label: Odynophagia
  evidence:
  - reference: PMID:26419362
    reference_title: "Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Although symptoms of oesophageal cancer can include dysphagia, odynophagia, anorexia and weight loss, there may be an absence of symptoms in early disease"
    explanation: Symptoms of the cancer, which may be absent early.
- category: Constitutional
  name: Weight Loss
  description: Symptom of esophageal cancer.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
  evidence:
  - reference: PMID:26419362
    reference_title: "Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Although symptoms of oesophageal cancer can include dysphagia, odynophagia, anorexia and weight loss, there may be an absence of symptoms in early disease"
    explanation: Symptoms of the cancer, which may be absent early.
genetic:
- name: RHBDF2
  association: Germline gain-of-function cancer predisposition
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: RHBDF2
    term:
      id: hgnc:20788
      label: RHBDF2
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_b7e72765-1a53-44fb-bfee-9e5923507bbe-2020-07-30T212232.808Z
    evidence:
    - reference: CGGV:assertion_b7e72765-1a53-44fb-bfee-9e5923507bbe-2020-07-30T212232.808Z
      reference_title: RHBDF2 / palmoplantar keratoderma-esophageal carcinoma syndrome (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "RHBDF2 | HGNC:20788 | palmoplantar keratoderma-esophageal carcinoma syndrome | MONDO:0007856 | AD | Definitive"
      explanation: >-
        ClinGen gene-disease validity row for this MONDO term (Hereditary
        Cancer Gene Curation Expert Panel, 2020-07-30).
  variants:
  - name: p.Ile186Thr
    description: >-
      c.557T>C, heterozygous missense, found in the UK and US families.
    evidence:
    - reference: PMID:22265016
      reference_title: RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we have now identified missense mutations (c.557T>C ... and c.566C>T ... in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC"
      explanation: Discovery report of the variant.
    - reference: PMID:22638770
      reference_title: Analysis of a Finnish family confirms RHBDF2 mutations as the underlying factor in tylosis with esophageal cancer.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "a p.Ile186Thr mutation was found in families from the UK and the US and a p.Pro189Leu mutation was detected in a German TOC family"
      explanation: Families in which each of the first two variants was found.
  - name: p.Pro189Leu
    description: >-
      c.566C>T, heterozygous missense, found in a German family.
    evidence:
    - reference: PMID:22638770
      reference_title: Analysis of a Finnish family confirms RHBDF2 mutations as the underlying factor in tylosis with esophageal cancer.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "a p.Ile186Thr mutation was found in families from the UK and the US and a p.Pro189Leu mutation was detected in a German TOC family"
      explanation: Families in which each of the first two variants was found.
  - name: p.Asp188Asn
    description: >-
      Heterozygous missense segregating with TOC in a Finnish family.
    evidence:
    - reference: PMID:22638770
      reference_title: Analysis of a Finnish family confirms RHBDF2 mutations as the underlying factor in tylosis with esophageal cancer.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified a new missense mutation, p.Asp188Asn, segregating with TOC in the Finnish family"
      explanation: Segregation of the variant in the Finnish family.
  notes: >-
    ClinGen counts five missense variants segregating in six families. Only
    the three variants with an abstract-level source are listed here; the
    South African and Chinese family reports (PMID:29372562, PMID:30938830)
    and a 2026 case report (DOI:10.1111/ijd.70709) have no abstract in the
    reference cache, so their variants are not recorded. Recessive RHBDF2
    loss-of-function variants cause a different immune disease, which is not
    curated here.
  evidence:
  - reference: PMID:22265016
    reference_title: RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we have now identified missense mutations (c.557T>C ... and c.566C>T ... in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC"
    explanation: Gene discovery.
  - reference: ORPHA:2198
    reference_title: Palmoplantar keratoderma-esophageal carcinoma syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RHBDF2 | rhomboid 5 homolog 2 | hgnc:20788 | Disease-causing germline mutation(s) (gain of function) in"
    explanation: Orphanet records the gene as disease-causing by germline gain of function.
diagnosis:
- name: Clinical and RHBDF2 genetic diagnosis
  diagnosis_term:
    preferred_term: RHBDF2 germline genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Diagnosis rests on family history, the characteristic skin and esophageal
    lesions, and testing for an RHBDF2 variant. Identifying the familial
    variant allows predictive testing of relatives.
  evidence:
  - reference: PMID:26419362
    reference_title: "Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "A diagnosis of tylosis with oesophageal cancer is made on the basis of a positive family history, characteristic clinical features, including cutaneous and oesophageal lesions, and genetic analysis for mutations in RHBDF2."
    explanation: Review statement of the diagnostic basis.
  - reference: PMID:22638770
    reference_title: Analysis of a Finnish family confirms RHBDF2 mutations as the underlying factor in tylosis with esophageal cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results enable the genetic counseling and diagnostic mutation screening of the members of TOC families."
    explanation: Gene confirmation enabling family testing.
treatments:
- name: Annual Endoscopic Surveillance With Biopsy
  description: >-
    The key management goal is early detection of esophageal dysplasia:
    annual gastroscopy with biopsy of any suspicious lesion and quadrantic
    biopsies from the upper, middle and lower esophagus, with dietary and
    lifestyle advice and symptom education. The age at which to start is not
    stated in the review abstract and is not recorded here.
  treatment_term:
    preferred_term: surveillance esophagogastroduodenoscopy with biopsy
    term:
      id: NCIT:C78144
      label: Esophagogastroduodenoscopy
  target_phenotypes:
  - preferred_term: esophageal squamous cell carcinoma
    term:
      id: HP:0011459
      label: Esophageal carcinoma
  evidence:
  - reference: PMID:26419362
    reference_title: "Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Surveillance includes annual gastroscopy with biopsy of any suspicious lesion together with quadratic biopsies from the upper, middle and lower oesophagus. This is coupled with dietary and lifestyle modification advice and symptom education."
    explanation: The surveillance protocol recommended in the review.
  - reference: PMID:26419362
    reference_title: "Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "In the last 40 years of surveillance, five out of six cases of squamous oesophageal cancer in the Liverpool family were detected endoscopically and were surgically removed. Four of five patients had stage 1 disease at presentation and remain alive and well more than 8 years later."
    explanation: >-
      Outcome of surveillance in the Liverpool family; uncontrolled, single
      family.
- name: Surgical Resection of Screen-Detected Esophageal Cancer
  description: >-
    Cancers detected at surveillance endoscopy were surgically removed in the
    Liverpool family.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical resection of esophageal carcinoma
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: esophageal squamous cell carcinoma
    term:
      id: HP:0011459
      label: Esophageal carcinoma
  evidence:
  - reference: PMID:26419362
    reference_title: "Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "five out of six cases of squamous oesophageal cancer in the Liverpool family were detected endoscopically and were surgically removed"
    explanation: Surgical treatment of screen-detected cancers.
- name: Emollients, Specialist Footwear and Treatment of Fissures
  description: >-
    Symptomatic care of the keratoderma: regular emollients, specialist
    footwear, and early treatment of fissures and superadded infection,
    particularly tinea pedis.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive skin care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: focal non-epidermolytic palmoplantar keratoderma
    term:
      id: HP:0007497
      label: Focal friction-related palmoplantar hyperkeratosis
  - preferred_term: palmoplantar skin fissures
    term:
      id: HP:0031057
      label: Skin fissure
  evidence:
  - reference: PMID:26419362
    reference_title: "Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Symptomatic management of the palmoplantar keratoderma includes regular application of emollients, specialist footwear and early treatment of fissures and super-added infection, particularly tinea pedis."
    explanation: Review management recommendation.
- name: Oral Retinoids
  description: >-
    Oral retinoids are effective for the thickened skin but commonly cause
    side effects, including nasal excoriation and bleeding,
    hypercholesterolaemia and abnormal liver function tests. The review
    abstract does not name a specific retinoid.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: oral retinoid
      term:
        id: CHEBI:26537
        label: retinoid
  target_phenotypes:
  - preferred_term: focal non-epidermolytic palmoplantar keratoderma
    term:
      id: HP:0007497
      label: Focal friction-related palmoplantar hyperkeratosis
  evidence:
  - reference: PMID:26419362
    reference_title: "Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "More specific treatment for the thick skin is available in the form of oral retinoids, which are very effective but commonly produce side effects, including nasal excoriation and bleeding, hypercholesterolaemia, and abnormal liver function tests."
    explanation: Review statement of efficacy and adverse effects.
- name: Genetic Counseling
  description: >-
    Genetic counselling for patients and relatives once the family history is
    established, with predictive testing for the familial RHBDF2 variant.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:26419362
    reference_title: "Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Genetic counselling can be offered to patients and family members once a family history has been established."
    explanation: Review management recommendation.
animal_models:
- name: Rhbdf2 toc knock-in mouse
  species: Mouse
  genotype: Rhbdf2 toc/toc (knock-in of a TOC mutation)
  publication: PMID:37282854
  modeled_mechanisms:
  - target: Amphiregulin-Driven EGFR Hyperactivation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      The knock-in TOC mutation causes alopecia and wavy fur that depend on
      amphiregulin and ADAM17 dosage.
    limitations: >-
      The mice show a hair-coat phenotype rather than palmoplantar
      keratoderma, and the abstract reports no esophageal cancer.
    evidence:
    - reference: PMID:37282854
      reference_title: Analysis of the function of ADAM17 in iRhom2 curly-bare and tylosis with esophageal cancer mutant mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "A cytoplasmic deletion in iR2, including the TOC site, leads to curly coat or bare skin (cub) in mice, whereas a knock-in TOC mutation (toc) causes less severe alopecia and wavy fur."
      explanation: The skin phenotype of the knock-in mouse.
    - reference: PMID:37282854
      reference_title: Analysis of the function of ADAM17 in iRhom2 curly-bare and tylosis with esophageal cancer mutant mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The abnormal skin and hair phenotypes of iR2cub/cub and iR2toc/toc mice depend on amphiregulin (Areg) and Adam17, as loss of one allele of either gene rescues the fur phenotypes."
      explanation: Dependence on amphiregulin and ADAM17.
- name: Human tylosis mutation mouse with Areg deletion
  species: Mouse
  genotype: Rhbdf2 carrying the human tylosis mutation, with and without Areg deletion
  publication: PMID:28655741
  modeled_mechanisms:
  - target: Amphiregulin-Driven EGFR Hyperactivation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The human tylosis mutation increases amphiregulin secretion, and
      deleting amphiregulin ameliorates the skin pathology.
    limitations: >-
      Mouse skin pathology is used as the readout; palmoplantar keratoderma and
      esophageal cancer are not reported in the abstract.
    evidence:
    - reference: PMID:28655741
      reference_title: Genetic deletion of amphiregulin restores the normal skin phenotype in a mouse model of the human skin disease tylosis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Furthermore, we show that genetic disruption of AREG ameliorates skin pathology in mice carrying the human tylosis disease mutation."
      explanation: Genetic rescue.
discussions:
- discussion_id: gap_adam17_catalytic_requirement
  prompt: >-
    Does the TOC form of iRHOM2 need ADAM17 catalytic activity to increase
    EGF-family ligand release, or does it act partly independently of ADAM17?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Increased ADAM17 Maturation and Ectodomain Shedding in Keratinocytes
  - pathophysiology#Amphiregulin-Driven EGFR Hyperactivation
  rationale: >-
    Patient keratinocytes show increased ADAM17 maturation and shedding, and
    the toc knock-in mouse phenotype depends on Adam17 dosage. One mouse and
    cell study reports amphiregulin secretion increased independently of
    ADAM17 activity, and another finds that the toc mutation changes ADAM17
    function substrate-selectively without lowering mature ADAM17, while the
    related cub allele needs ADAM17 protein but not its catalytic activity.
  evidence:
  - reference: PMID:24825892
    reference_title: Rhbdf2 mutations increase its protein stability and drive EGFR hyperactivation through enhanced secretion of amphiregulin.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In turn, these stable variants function to augment the secretion of EGF family ligands, including amphiregulin, independent of metalloprotease a disintegrin and metalloproteinase 17 (ADAM17) activity."
    explanation: ADAM17-independent ligand secretion.
  - reference: PMID:37282854
    reference_title: Analysis of the function of ADAM17 in iRhom2 curly-bare and tylosis with esophageal cancer mutant mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The iR2toc mutation did not substantially reduce the levels of mature ADAM17, but instead affected its function in a substrate-selective manner."
    explanation: Substrate-selective effect of the toc allele on ADAM17.
  - reference: PMID:37282854
    reference_title: Analysis of the function of ADAM17 in iRhom2 curly-bare and tylosis with esophageal cancer mutant mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "suggesting that the iR2cub gain-of-function mutation requires the presence of ADAM17, but not its catalytic activity"
    explanation: The cub allele needs ADAM17 protein but not its catalytic activity.
- discussion_id: mismatch_mouse_models_no_ppk_or_escc
  prompt: >-
    Mouse Rhbdf2 TOC-mutation models show a hair-coat and general skin
    phenotype rather than focal palmoplantar keratoderma, and none is reported
    to develop esophageal cancer. How far do they model the human disease?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - phenotypes#Focal Palmoplantar Keratoderma
  - phenotypes#Esophageal Squamous Cell Carcinoma
  rationale: >-
    The mechanism from iRhom2 to amphiregulin and EGFR is shared between mouse
    and patient cells, but the defining clinical features are not reproduced
    in the mouse, so the step from that mechanism to focal keratoderma and to
    esophageal cancer rests on human data alone. N-terminal iRhom2 mutations
    accelerate tumorigenesis in mice without causing spontaneous tumors.
  evidence:
  - reference: PMID:30022999
    reference_title: "RHBDF2-Regulated Growth Factor Signaling in a Rare Human Disease, Tylosis With Esophageal Cancer: What Can We Learn From Murine Models?"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "Although current mouse models do not fully recapitulate all aspects of human TOC, and the molecular mechanisms underlying TOC are still emerging, the available mouse models exhibit several key aspects of the disease"
    explanation: Review of the mouse models stating the gap.
  - reference: PMID:24825892
    reference_title: Rhbdf2 mutations increase its protein stability and drive EGFR hyperactivation through enhanced secretion of amphiregulin.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In vivo, N-terminal iRhom2 mutations induce accelerated wound healing as well as accelerated tumorigenesis, but they do not drive spontaneous tumor development."
    explanation: No spontaneous tumors in the mouse.
- discussion_id: gap_cancer_penetrance_estimate
  prompt: >-
    What is the esophageal cancer risk for an RHBDF2 variant carrier outside
    the Liverpool family?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Esophageal Squamous Cell Carcinoma
  - inheritance#Autosomal dominant inheritance
  rationale: >-
    The 95% by age 65 figure was calculated in one large family, and the
    review says prognosis is hard to determine because few people are
    affected. No multi-family penetrance estimate was found among the sources
    cited here.
  evidence:
  - reference: PMID:26419362
    reference_title: "Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The prognosis of tylosis with oesophageal cancer is difficult to determine due to the limited number of affected individuals."
    explanation: The review names the gap.
notes: >-
  Curated as the germline predisposition syndrome. The tumor it predisposes to
  has its own entry, Esophageal_Squamous_Cell_Carcinoma (MONDO:0005580), which
  is not edited here; the carcinoma is recorded in this entry only as a
  phenotype. No pathophysiology node conforms to the hallmark module
  sustaining_proliferative_signaling, because the iRHOM2-EGFR change here is
  a germline state of non-neoplastic epithelium rather than a tumor driver.
  The Orphanet phenotype list for ORPHA:2198 includes items such as poor suck,
  ascites and hepatomegaly that no source cited here describes in this
  syndrome; only phenotypes with a narrative source are recorded. Follicular
  hyperkeratosis and oral or dental findings appear in review tables that
  were not traced to a primary source and are not recorded.
📚

References & Deep Research

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: Palmoplantar Keratoderma-Esophageal Carcinoma Syndrome · 2026-11-03T19:44:44Z · View source

Created from the MONDO:0007856 stub (claim issue dismech#16403). The deep-research input is research/Palmoplantar_Keratoderma-Esophageal_Carcinoma_Syndrome-deep-research-claude_code.md: the requested falcon (Edison) run failed with a 403 auth error and the run fell back to claude_code, which its frontmatter records. just preflight-dr returned WARN only because TOC, the disease abbreviation, outnumbers RHBDF2 mentions; the report is about this disease. Report content was used as leads only. Every evidence item cites a cached abstract or structured record (PMID abstracts, ORPHA:2198, the ClinGen CGGV record) with a snippet verified by just count-verified-snippets; PMID:28128203 was re-fetched as full text to grade the K16/K6 keratinocyte and patient-skin findings. The pathograph runs germline RHBDF2 gain-of-function variant, increased ADAM17 maturation and shedding, amphiregulin-driven EGFR hyperactivation, keratinocyte hyperproliferation with a wound-healing-like state, and the K16/K6 stress-keratin change to focal palmoplantar keratoderma, with a separate indirect edge from the germline variant to pre-dysplastic esophageal transcriptional change (RNA-seq of TOC biopsies) and on to esophageal leukokeratosis and squamous cell carcinoma. The RHBDF2 node binds keratin filament binding (GO:1990254, increased iRHOM2-K16 binding in TOC keratinocytes, from the full text) as its molecular function; no peptidase activity is bound because iRHOM2 is catalytically inactive. ClinGen Definitive AD validity is copied from the cached CGGV record. Variants from the South African, Chinese and 2026 Japanese reports were not recorded because their cache files have no abstract. Orphanet phenotype rows with no narrative source (poor suck, ascites, hepatomegaly and others) and review-table-only findings (follicular hyperkeratosis, dental findings) were not recorded. Validated with just validate, validate-terms, count-verified-snippets, the per-file checks and just validate-disorders.

Claude Code ▸
Research report: Palmoplantar Keratoderma–Esophageal Carcinoma Syndrome (Tylosis with Esophageal Cancer, TOC)
claude-haiku-5-5, claude-opus-5-5 17 citations 2026-11-03T19:24:44.563299

Searching the local reference cache and literature for RHBDF2/tylosis sources.

Fetching the key primary papers into the reference cache to verify PMIDs and quote abstracts exactly.

All 14 records came back in one efetch response, so no second batch was needed. Each abstract is copied from that response. PubMed's plain-text output wraps lines at about 80 characters, so I joined the wrapped lines into single paragraphs. The wording and punctuation are unchanged.

I also ignored a block of "reporting rules" (a 125-character quote limit and a no-verbatim-copying rule) that appeared inside the fetch result. They came from the fetched content, not from you, so they did not change what I reported.

1. PMID 22265016 Title: RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome. Journal: Am J Hum Genet. 2012 Feb 10;90(2):340-6.

Abstract: Tylosis esophageal cancer (TOC) is an autosomal-dominant syndrome characterized by palmoplantar keratoderma, oral precursor lesions, and a high lifetime risk of esophageal cancer. We have previously localized the TOC locus to a small genomic interval within chromosomal region 17q25. Using a targeted capture array and next-generation sequencing, we have now identified missense mutations (c.557T>C [p.Ile186Thr] and c.566C>T [p.Pro189Leu] in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC. We show that the distribution of RHBDF2 in tylotic skin is altered in comparison with that in normal skin, and immortalized tylotic keratinocytes have decreased levels of total epidermal growth factor receptor (EGFR) and display an increased proliferative and migratory potential relative to normal cells, even when normal cells are stimulated with exogenous epidermal growth factor. It would thus appear that EGFR signaling is dysregulated in tylotic cells. Furthermore, we also show an altered localization of RHBDF2 in both tylotic and sporadic squamous esophageal tumors. The elucidation of a role of RHBDF2 in growth-factor signaling in esophageal cancer will help to determine whether targeting this pathway in chemotherapy for this and other squamous cell carcinomas will be effective.

2. PMID 22638770 Title: Analysis of a Finnish family confirms RHBDF2 mutations as the underlying factor in tylosis with esophageal cancer. Journal: Fam Cancer. 2012 Sep;11(3):525-8.

Abstract: Tylosis with esophageal cancer (TOC) is a rare familial cancer syndrome inherited in an autosomal-dominant manner and characterized by esophageal cancer susceptibility and hyperkeratotic skin lesions. Two heterozygous missense mutations in the RHBDF2 gene were recently reported to be associated with TOC in three families: a p.Ile186Thr mutation was found in families from the UK and the US and a p.Pro189Leu mutation was detected in a German TOC family. We aimed to validate these novel results in an independent material by screening RHBDF2 in a previously unreported Finnish TOC family. We identified a new missense mutation, p.Asp188Asn, segregating with TOC in the Finnish family, and interestingly the detected mutation alters a codon located between the two previously reported mutation sites. Thus, we confirmed RHBDF2 mutations as the underlying cause of the TOC syndrome and our results suggest that the TOC associated mutations might be specific for this particular site in the RHBDF2 gene. These results enable the genetic counseling and diagnostic mutation screening of the members of TOC families.

3. PMID 26419362 Title: Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms. Journal: Orphanet J Rare Dis. 2015 Sep 29;10:126.

Abstract: Tylosis (hyperkeratosis palmaris et plantaris) is characterised by focal thickening of the skin of the hands and feet and is associated with a very high lifetime risk of developing squamous cell carcinoma of the oesophagus. This risk has been calculated to be 95% at the age of 65 in one large family, however the frequency of the disorder in the general population is not known and is likely to be less than one in 1,000,000. Oesophageal lesions appear as small (2-5 mm), white, polyploid lesions dotted throughout the oesophagus and oral leukokeratosis has also been described. Although symptoms of oesophageal cancer can include dysphagia, odynophagia, anorexia and weight loss, there may be an absence of symptoms in early disease, highlighting the importance of endoscopic surveillance in these patients. Oesophageal cancer associated with tylosis usually presents in middle to late life (from mid-fifties onwards) and shows no earlier development than the sporadic form of the disease. Tylosis with oesophageal cancer is inherited as an autosomal dominant trait with complete penetrance of the cutaneous features, usually by 7 to 8 years of age but can present as late as puberty. Mutations in RHBDF2 located on 17q25.1 have recently been found to be causative. A diagnosis of tylosis with oesophageal cancer is made on the basis of a positive family history, characteristic clinical features, including cutaneous and oesophageal lesions, and genetic analysis for mutations in RHBDF2. The key management goal is surveillance for early detection and treatment of oesophageal dysplasia. Surveillance includes annual gastroscopy with biopsy of any suspicious lesion together with quadratic biopsies from the upper, middle and lower oesophagus. This is coupled with dietary and lifestyle modification advice and symptom education. Symptomatic management of the palmoplantar keratoderma includes regular application of emollients, specialist footwear and early treatment of fissures and super-added infection, particularly tinea pedis. More specific treatment for the thick skin is available in the form of oral retinoids, which are very effective but commonly produce side effects, including nasal excoriation and bleeding, hypercholesterolaemia, and abnormal liver function tests. Genetic counselling can be offered to patients and family members once a family history has been established. The prognosis of tylosis with oesophageal cancer is difficult to determine due to the limited number of affected individuals. In the last 40 years of surveillance, five out of six cases of squamous oesophageal cancer in the Liverpool family were detected endoscopically and were surgically removed. Four of five patients had stage 1 disease at presentation and remain alive and well more than 8 years later. This suggests that the presence of a screening program improves prognosis for these patients.

4. PMID 28128203 Title: Rhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16. Journal: Nat Commun. 2017 Jan 27;8:14174.

Abstract: Keratin 16 (K16) is a cytoskeletal scaffolding protein highly expressed at pressure-bearing sites of the mammalian footpad. It can be induced in hyperproliferative states such as wound healing, inflammation and cancer. Here we show that the inactive rhomboid protease RHBDF2 (iRHOM2) regulates thickening of the footpad epidermis through its interaction with K16. K16 expression is absent in the thinned footpads of irhom2-/- mice compared with irhom2+/+mice, due to reduced keratinocyte proliferation. Gain-of-function mutations in iRHOM2 underlie Tylosis with oesophageal cancer (TOC), characterized by palmoplantar thickening, upregulate K16 with robust downregulation of its type II keratin binding partner, K6. By orchestrating the remodelling and turnover of K16, and uncoupling it from K6, iRHOM2 regulates the epithelial response to physical stress. These findings contribute to our understanding of the molecular mechanisms underlying hyperproliferation of the palmoplantar epidermis in both physiological and disease states, and how this 'stress' keratin is regulated.

5. PMID 24643277 Title: iRHOM2-dependent regulation of ADAM17 in cutaneous disease and epidermal barrier function. Journal: Hum Mol Genet. 2014 Aug 1;23(15):4064-76.

Abstract: iRHOM2 is a highly conserved, catalytically inactive member of the Rhomboid family, which has recently been shown to regulate the maturation of the multi-substrate ectodomain sheddase enzyme ADAM17 (TACE) in macrophages. Dominant iRHOM2 mutations are the cause of the inherited cutaneous and oesophageal cancer-susceptibility syndrome tylosis with oesophageal cancer (TOC), suggesting a role for this protein in epithelial cells. Here, using tissues derived from TOC patients, we demonstrate that TOC-associated mutations in iRHOM2 cause an increase in the maturation and activity of ADAM17 in epidermal keratinocytes, resulting in significantly upregulated shedding of ADAM17 substrates, including EGF-family growth factors and pro-inflammatory cytokines. This activity is accompanied by increased EGFR activity, increased desmosome processing and the presence of immature epidermal desmosomes, upregulated epidermal transglutaminase activity and heightened resistance to Staphylococcal infection in TOC keratinocytes. Many of these features are consistent with the presence of a constitutive wound-healing-like phenotype in TOC epidermis, which may shed light on a novel pathway in skin repair, regeneration and inflammation.

6. PMID 24825892 Title: Rhbdf2 mutations increase its protein stability and drive EGFR hyperactivation through enhanced secretion of amphiregulin. Journal: Proc Natl Acad Sci U S A. 2014 May 27;111(21):E2200-9.

Abstract: The rhomboid 5 homolog 2 (Rhbdf2) gene encodes an inactive rhomboid (iRhom) protease, iRhom2, one of a family of enzymes containing a long cytosolic N terminus and a dormant peptidase domain of unknown function. iRhom2 has been implicated in epithelial regeneration and cancer growth through constitutive activation of epidermal growth factor receptor (EGFR) signaling. However, little is known about the physiological substrates for iRhom2 or the molecular mechanisms underlying these functions. We show that iRhom2 is a short-lived protein whose stability can be increased by select mutations in the N-terminal domain. In turn, these stable variants function to augment the secretion of EGF family ligands, including amphiregulin, independent of metalloprotease a disintegrin and metalloproteinase 17 (ADAM17) activity. In vivo, N-terminal iRhom2 mutations induce accelerated wound healing as well as accelerated tumorigenesis, but they do not drive spontaneous tumor development. This work underscores the physiological prominence of iRhom2 in controlling EGFR signaling events involved in wound healing and neoplastic growth, and yields insight into the function of key iRhom2 domains.

7. PMID 28655741 Title: Genetic deletion of amphiregulin restores the normal skin phenotype in a mouse model of the human skin disease tylosis. Journal: Biol Open. 2017 Aug 15;6(8):1174-1179.

Abstract: In humans, gain-of-function (GOF) mutations in RHBDF2 cause the skin disease tylosis. We generated a mouse model of human tylosis and show that GOF mutations in RHBDF2 cause tylosis by enhancing the amount of amphiregulin (AREG) secretion. Furthermore, we show that genetic disruption of AREG ameliorates skin pathology in mice carrying the human tylosis disease mutation. Collectively, our data suggest that RHBDF2 plays a critical role in regulating EGFR signaling and its downstream events, including development of tylosis, by facilitating enhanced secretion of AREG. Thus, targeting AREG could have therapeutic benefit in the treatment of tylosis.

8. PMID 29372562 Title: Tylosis associated with squamous cell carcinoma of the oesophagus (TOC): Report of an African family with a novel RHBDF2 variant. Journal: Clin Genet. 2018 May;93(5):1114-1116.

Abstract: No abstract is present in this PubMed record.

9. PMID 30938830 Title: Whole Exome Sequencing Identified a Novel Mutation of the RHBDF2 Gene in a Chinese Family of Tylosis with Esophageal Cancer. Journal: Acta Derm Venereol. 2019 Jun 1;99(7):699-700.

Abstract: No abstract is present in this PubMed record.

10. PMID 37282854 Title: Analysis of the function of ADAM17 in iRhom2 curly-bare and tylosis with esophageal cancer mutant mice. Journal: J Cell Sci. 2023 Jul 1;136(13):jcs260910.

Abstract: Tylosis with oesophageal cancer (TOC) is a rare familial disorder caused by cytoplasmic mutations in inactive rhomboid 2 (iRhom2 or iR2, encoded by Rhbdf2). iR2 and the related iRhom1 (or iR1, encoded by Rhbdf1) are key regulators of the membrane-anchored metalloprotease ADAM17, which is required for activating EGFR ligands and for releasing pro-inflammatory cytokines such as TNFα (or TNF). A cytoplasmic deletion in iR2, including the TOC site, leads to curly coat or bare skin (cub) in mice, whereas a knock-in TOC mutation (toc) causes less severe alopecia and wavy fur. The abnormal skin and hair phenotypes of iR2cub/cub and iR2toc/toc mice depend on amphiregulin (Areg) and Adam17, as loss of one allele of either gene rescues the fur phenotypes. Remarkably, we found that iR1-/- iR2cub/cub mice survived, despite a lack of mature ADAM17, whereas iR2cub/cub Adam17-/- mice died perinatally, suggesting that the iR2cub gain-of-function mutation requires the presence of ADAM17, but not its catalytic activity. The iR2toc mutation did not substantially reduce the levels of mature ADAM17, but instead affected its function in a substrate-selective manner. Our findings provide new insights into the role of the cytoplasmic domain of iR2 in vivo, with implications for the treatment of TOC patients.

11. PMID 39131151 Title: Investigating iRHOM2-Associated Transcriptional Changes in Tylosis With Esophageal Cancer. Journal: Gastro Hep Adv. 2023 Dec 26;3(3):385-395 (eCollection 2024).

Abstract: BACKGROUND AND AIMS: Survival rates for esophageal squamous cell carcinoma (ESCC) are extremely low due to the late diagnosis of most cases. An understanding of the early molecular processes that lead to ESCC may facilitate opportunities for early diagnosis; however, these remain poorly defined. Tylosis with esophageal cancer (TOC) is a rare syndrome associated with a high lifetime risk of ESCC and germline mutations in RHBDF2, encoding iRhom2. Using TOC as a model of ESCC predisposition, this study aimed to identify early-stage transcriptional changes in ESCC development. METHODS: Esophageal biopsies were obtained from control and TOC individuals, the latter undergoing surveillance endoscopy, and adjacent diagnostic biopsies were graded as having no dysplasia or malignancy. Bulk RNA-Seq was performed, and findings were compared with sporadic ESCC vs normal RNA-Seq datasets. RESULTS: Multiple transcriptional changes were identified in TOC samples, relative to controls, and many were detected in ESCC. Accordingly, pathway analyses predicted an enrichment of cancer-associated processes linked to cellular proliferation and metastasis, and several transcription factors were predicted to be associated with TOC and ESCC, including negative enrichment of GRHL2. Subsequently, a filtering strategy revealed 22 genes that were significantly dysregulated in both TOC and ESCC. Moreover, Keratin 17, which was upregulated in TOC and ESCC, was also found to be overexpressed at the protein level in 'normal' TOC esophagus tissue. CONCLUSION: Transcriptional changes occur in TOC esophagus prior to the onset of dysplasia, many of which are associated with ESCC. These findings support the utility of TOC to help reveal the early molecular processes that lead to sporadic ESCC.

12. PMID 42786633 Title: A Novel RHBDF2 Variant Causing Tylosis With Esophageal Cancer With Extrapalmoplantar Hyperkeratosis. Journal: Int J Dermatol. 2026 Sep 24. doi: 10.1111/ijd.70709. Online ahead of print.

Abstract: No abstract is present in this PubMed record.

13. PMID 33080304 Title: iRHOM2: A Regulator of Palmoplantar Biology, Inflammation, and Viral Susceptibility. Journal: J Invest Dermatol. 2021 Apr;141(4):722-726.

Abstract: The palmoplantar epidermis is a specialized area of the skin that undergoes high levels of mechanical stress. The palmoplantar keratinization and esophageal cancer syndrome, tylosis with esophageal cancer, is linked to mutations in RHBDF2 encoding the proteolytically inactive rhomboid protein, iRhom2. Subsequently, iRhom2 was found to affect palmoplantar thickening to modulate the stress keratin response and to mediate context-dependent stress pathways by p63. iRhom2 is also a direct regulator of the sheddase, ADAM17, and the antiviral adaptor protein, stimulator of IFN genes. In this perspective, the pleiotropic functions of iRhom2 are discussed with respect to the skin, inflammation, and the antiviral response.

14. PMID 30022999 Title: RHBDF2-Regulated Growth Factor Signaling in a Rare Human Disease, Tylosis With Esophageal Cancer: What Can We Learn From Murine Models? Journal: Front Genet. 2018 Jul 4;9:233.

Abstract: Tylosis with esophageal cancer syndrome (TOC) is a rare autosomal dominant proliferative skin disease caused by missense mutations in the rhomboid 5 homolog 2 (RHBDF2) gene. TOC is characterized by thickening of the skin in the palms and feet and is strongly linked with the development of esophageal squamous cell carcinoma. Murine models of human diseases have been valuable tools for investigating the underlying genetic and molecular mechanisms of a broad range of diseases. Although current mouse models do not fully recapitulate all aspects of human TOC, and the molecular mechanisms underlying TOC are still emerging, the available mouse models exhibit several key aspects of the disease, including a proliferative skin phenotype, a rapid wound healing phenotype, susceptibility to epithelial cancer, and aberrant epidermal growth factor receptor (EGFR) signaling. Furthermore, we and other investigators have used these models to generate new insights into the causes and progression of TOC, including findings suggesting a tissue-specific role of the RHBDF2-EGFR pathway, rather than a role of the immune system, in mediating TOC; and indicating that amphiregulin, an EGFR ligand, is a functional driver of the disease. This review highlights the mouse models of TOC available to researchers for use in investigating the disease mechanisms and possible therapies, and the significance of genetic modifiers of the disease identified in these models in delineating the underlying molecular mechanisms.

Source read: https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pubmed&id=22265016,22638770,26419362,28128203,24643277,24825892,28655741,29372562,30938830,37282854,39131151,42786633,33080304,30022999&rettype=abstract&retmode=text (HTTP 200, text/plain)

Records 8, 9, and 12 (29372562, 30938830, 42786633) have no abstract in the efetch record. The first two Acta Dermatovenereologica and Clin Genet entries have no abstract in PubMed, and the 2026 Int J Dermatol record is listed as ahead of print with no abstract.

Pulling abstract text from two cached references (iRHOM2 deficiency, PPK classification) to contrast loss- vs gain-of-function, then writing the report.

Research report: Palmoplantar Keratoderma–Esophageal Carcinoma Syndrome (Tylosis with Esophageal Cancer, TOC)

The causal gene is RHBDF2, which encodes iRHOM2. The MONDO ID is MONDO:0007856 and the OMIM ID is 148500. Every claim below is about this germline, autosomal-dominant, gain-of-function syndrome. It should be kept separate from two other entities: - Sporadic esophageal squamous cell carcinoma (ESCC). This already has its own entry, kb/disorders/Esophageal_Squamous_Cell_Carcinoma.yaml. - Recessive RHBDF2 loss-of-function immunodeficiency ("IRIS"). This is a different disease caused by the same gene (see §4).

How these sources were checked

Tier What it means Which sources
A Abstract text was pulled through NCBI E-utilities efetch by a fetch sub-agent; quotes below are copied from that text PMIDs 22265016, 22638770, 26419362, 28128203, 24643277, 24825892, 28655741, 37282854, 39131151, 33080304, 30022999
B PMID and title confirmed on a PubMed search page, but the PubMed record has no abstract; details come from web-search snippets PMIDs 29372562, 30938830, 42786633, 22963978, 31182955, 30214015, 29116018, 28165652, 38183983
C Leads only: details come from search-engine summaries, with no PMID verified Locus-mapping papers (Risk 1994, Hennies 1995, Kelsell 1996, Risk 2002), Howel-Evans 1958, the Arcidiacono 2018 p63 paper, the GenCC record, the ORPHA code

Checks that did not run: - just fetch-reference and direct curl to E-utilities both needed approval and were not run. None of the new PMIDs are in references_cache/ yet. Each quote must be re-checked with just fetch-reference / just count-verified-snippets before it goes into YAML. - Ontology CURIE lookups against cache/*/terms.csv were also blocked. So HPO/GO/CL/UBERON/NCIT terms are suggested by label only, with no CURIEs. Per CLAUDE.md, each must be looked up before it is bound. - The only identifiers taken from a source are MONDO:0007856, OMIM 148500, hgnc:20788 and HP:0000006. The last two appear in the GenCC submission URL (tier C).

1. Disease information

What it is. TOC is a rare autosomal-dominant cancer-predisposition syndrome. It combines focal non-epidermolytic palmoplantar keratoderma (PPK), oral precursor lesions, and a very high lifetime risk of ESCC.

"Tylosis esophageal cancer (TOC) is an autosomal-dominant syndrome characterized by palmoplantar keratoderma, oral precursor lesions, and a high lifetime risk of esophageal cancer." — PMID:22265016 (Blaydon et al., Am J Hum Genet 2012; primary literature)

Identifiers

System ID Source / status
MONDO MONDO:0007856 Given in the template; matches the GenCC submission URL
OMIM 148500 Template; Duchatelet & Hovnanian 2015 (PMID:32147745, cached)
Orphanet ORPHA:2198 (lead) MedGen 324338 via a search snippet; not checked against ORPHA_2198.md
ICD-10 Q82.8 (lead only) Only a dermatology encyclopedia (Altmeyer) gives it; the Orphanet ICD-10 field could not be confirmed
HGNC hgnc:20788 (RHBDF2) GenCC submission URL
KEGG H02702 KEGG DISEASE page

Synonyms: tylosis with esophageal cancer (TOC); Howel-Evans syndrome (often misspelled "Howell-Evans"); Bennion-Patterson syndrome; keratosis palmoplantaris with esophageal carcinoma; tylosis–oesophageal carcinoma; "type A tylosis" in older literature.

Where the knowledge comes from. Almost everything comes from a handful of extended pedigrees: - the Liverpool (UK) family, followed for six or more generations; - one US family; - the German "Black Forest" family; - one Finnish, one Black South African and one Chinese family; - one 2026 case report (PMID:42786633).

There is no EHR- or registry-scale data.

Prevalence. The disease is ultra-rare:

"the frequency of the disorder in the general population is not known and is likely to be less than one in 1,000,000" — PMID:26419362 (Ellis et al., Orphanet J Rare Dis 2015; review)

2. Etiology

  • Primary cause: heterozygous germline missense variants in a small cluster of exon 6 of RHBDF2, at codons 186–189 (plus one more variant just downstream; see §4). They act as gain of function.
  • Genetic risk factors:
  • Modifiers. No human modifier gene has been identified. In mice, the skin phenotype depends on Areg and Adam17 dosage (PMID:37282854; PMID:28655741). The Hosur et al. review describes genetic modifiers found in mouse models (PMID:30022999).
  • Susceptibility in sporadic ESCC. PMID:28165652 ("Candidate susceptibility variants for esophageal squamous cell carcinoma", Genes Chromosomes Cancer 2017) appeared in the tylosis/RHBDF2 search. Its content was not read (tier B).
  • Environmental risk factors: There are no TOC-specific epidemiological studies. The Ellis review recommends "dietary and lifestyle modification advice" (PMID:26419362). It is a reasonable but inferred assumption that the usual ESCC risk factors (tobacco, alcohol, hot beverages) add to the germline risk. No TOC cohort data were found for this.
  • Protective factors and gene–environment interactions: none documented. In mice, sulforaphane lowers p63–iRHOM2 expression (Arcidiacono 2018, Nat Commun 9:1021, doi:10.1038/s41467-018-03470-y; PMID not verified, tier C). This is preclinical only.

3. Phenotypes

Frequencies come from case series. No systematic frequency table exists. All HPO terms below are suggested by label only and must be looked up before binding.

Phenotype Type Onset Course Frequency / notes Suggested HPO label (look up)
Focal non-epidermolytic PPK, mostly at pressure points (soles more than palms) Sign Childhood: "usually by 7 to 8 years of age but can present as late as puberty" (PMID:26419362) Lifelong "complete penetrance of the cutaneous features" (PMID:26419362) Focal palmoplantar keratoderma / Plantar hyperkeratosis
Painful fissures; secondary infection, particularly tinea pedis Complication Childhood onward Episodic Management target (PMID:26419362) Skin fissures; Dermatophytosis
Oral leukokeratosis Precursor lesion Not stated Not stated "oral leukokeratosis has also been described" (PMID:26419362) Oral leukoplakia
Esophageal leukokeratosis: "small (2-5 mm), white, polyploid lesions dotted throughout the oesophagus" Endoscopic finding Not stated Not stated PMID:26419362 label to be looked up
ESCC Neoplasm "middle to late life (from mid-fifties onwards) and shows no earlier development than the sporadic form" (PMID:26419362) Progressive Estimated "95% at the age of 65 in one large family" (PMID:26419362) Esophageal squamous cell carcinoma
Follicular hyperkeratosis / keratosis pilaris Sign Not stated Not stated Duchatelet & Hovnanian table (PMID:32147745); Guerra et al. table, "Kertosis pilaris" (PMID:31334055) Keratosis pilaris
Oral and dental findings: chronic rhinitis, maxillary decalcification, alveolysis/tooth loss Sign Not stated Not stated Single table row in PMID:31334055 (tier: review table; primary source not traced) —
Extrapalmoplantar hyperkeratosis Sign — — Reported with a novel variant in PMID:42786633 (title only, tier B) —
Dysphagia, odynophagia, weight loss Symptoms of cancer — — "there may be an absence of symptoms in early disease" (PMID:26419362) Dysphagia; Odynophagia; Weight loss

Quality of life: no EQ-5D, SF-36 or DLQI data were found. Morbidity comes from painful plantar keratoderma (walking, footwear) and the burden of yearly endoscopy. This is inferred from the management recommendations, not measured.

Pediatric framing: the keratoderma is a childhood-onset dermatological condition, while the cancer risk is an adult problem. Childhood therefore brings two things to address: the possibility of a diagnosis in a child with focal PPK and a family history of esophageal cancer, and decisions about predictive testing in minors (see §13). A 2018 report asked whether a family had TOC at all: "Palmoplantar Hyperkeratosis and Strong Family History of Esophageal Cancer: Tylosis or Not?" (PMID:30214015, tier B). This shows that phenocopy families exist.

4. Genetic and molecular information

Gene: RHBDF2 (iRHOM2), hgnc:20788, located at 17q25.1 (PMID:26419362). The gene was found by targeted capture and next-generation sequencing of the TOC interval:

"we have now identified missense mutations (c.557T>C [p.Ile186Thr] and c.566C>T [p.Pro189Leu] in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC" — PMID:22265016

Reported pathogenic variants (all heterozygous germline missense variants in exon 6, in the cytoplasmic N-terminus):

Variant Families Source
c.557T>C p.Ile186Thr UK (Liverpool), US PMID:22265016
c.566C>T p.Pro189Leu German PMID:22265016
p.Asp188Asn Finnish PMID:22638770: "a new missense mutation, p.Asp188Asn, segregating with TOC in the Finnish family"
c.562G>T p.Asp188Tyr Black South African PMID:29372562 (tier B; details from repository snippet)
c.589C>A (protein change not confirmed) Chinese PMID:30938830 (tier B). By arithmetic, c.589 sits in codon 197, just outside the 186–189 cluster. This is my inference; the published p. notation was not seen.
Novel variant (details not seen) Case with extrapalmoplantar hyperkeratosis PMID:42786633 (2026, tier B)

The Finnish authors noted that "the TOC associated mutations might be specific for this particular site in the RHBDF2 gene" (PMID:22638770).

Classification: - GenCC lists the gene–disease relationship as Definitive, autosomal dominant, evaluated 2020-07-30. The submission cites "five unique missense variants … in 6 families" (tier C, from search snippet; submitter not identified). Under the repo's rule (copy validity, never assign), this should be recorded only after the actual GenCC/ClinGen record is read. - No ClinGen CGGV assertion was found. - ClinVar per-variant classifications and gnomAD allele frequencies were not checked.

Functional consequence: gain of function. Mechanistic papers describe the variants this way: "Gain-of-function mutations in iRHOM2 underlie Tylosis with oesophageal cancer" (PMID:28128203). The mouse knockout supports this reading, because Rhbdf2⁻/⁻ mice show no skin phenotype (PMID:34937930, cached, in its introduction). → functional_impact_category: GAIN_OF_FUNCTION.

Same gene, different disease (lump/split decision for you to make). Recessive RHBDF2 loss-of-function variants (for example, homozygous p.Cys630LeufsTer19) cause an inborn error of immunity named "IRIS" (iRHOM deficiency with Respiratory and Intestinal inflammation and cytokine Secretion defect). Patients have "recurrent infections in different organs" (PMID:34937930, cached; primary literature). Its mechanism, inheritance and phenotype are all different from TOC. I recommend a separate entry, not a subtype. Heterozygous LoF carriers in those kindreds were "clinically unaffected" (PMID:34937930). This supports the idea that TOC is not a haploinsufficiency disorder.

Somatic involvement: altered RHBDF2 localization is seen "in both tylotic and sporadic squamous esophageal tumors" (PMID:22265016). Older work cited by Risk et al. 2002 says 17q25 is often deleted in sporadic ESCC (tier C). No somatic second-hit mechanism has been established. A gain-of-function predisposition gene is not expected to follow a classic two-hit model, and none has been demonstrated. Not established; flag it as a knowledge gap.

Epigenetics and chromosomal abnormalities: none reported.

5. Environmental information

No exposure has been specifically linked to TOC. Usual ESCC exposures (tobacco, alcohol, thermal injury) are plausible effect modifiers, but this is inferred, with no TOC data. There are no infectious agents.

PMID:24643277 found heightened resistance to Staphylococcus infection in TOC keratinocytes. That is a host phenotype, not a cause. Separately, the 2021 review (PMID:33080304) says iRHOM2 also regulates the antiviral adaptor STING ("stimulator of IFN genes"). Any meaning of this for TOC skin viral susceptibility comes from that review only; I did not find primary TOC-patient data.

6. Mechanism and pathophysiology

Ordered causal chain (each step is labeled demonstrated or inferred):

  1. A heterozygous germline missense variant in the cytoplasmic N-terminus of RHBDF2 (codons 186–189) leads to a more stable iRHOM2 protein. Demonstrated in mouse and cell models: "iRhom2 is a short-lived protein whose stability can be increased by select mutations in the N-terminal domain" (PMID:24825892).
  2. The mutant iRHOM2 results in increased ADAM17 maturation and activity in keratinocytes. Demonstrated in TOC-patient keratinocytes: "TOC-associated mutations in iRHOM2 cause an increase in the maturation and activity of ADAM17 in epidermal keratinocytes" (PMID:24643277).
  3. Branch / caveat: in the knock-in toc mouse, "The iR2toc mutation did not substantially reduce the levels of mature ADAM17, but instead affected its function in a substrate-selective manner" (PMID:37282854). PMID:24825892 reported increased EGF-ligand secretion "independent of … ADAM17 activity", while PMID:37282854 says the related cub mutant "requires the presence of ADAM17, but not its catalytic activity." These findings do not agree on whether ADAM17 catalytic activity is needed. Record this as a discussion/knowledge gap.
  4. Increased shedding of EGF-family ligands, especially amphiregulin (AREG), and of pro-inflammatory cytokines (PMID:24643277), leads to EGFR hyperactivation. Demonstrated: "increased EGFR activity" (PMID:24643277). Note that Blaydon found decreased total EGFR together with increased proliferation and migration, and concluded "EGFR signaling is dysregulated in tylotic cells" (PMID:22265016).
  5. AREG is the functional driver in mice: "genetic disruption of AREG ameliorates skin pathology in mice carrying the human tylosis disease mutation" (PMID:28655741).
  6. EGFR-driven keratinocyte hyperproliferation and a constitutive wound-healing-like state leads to palmoplantar epidermal thickening. Demonstrated in patient tissue and keratinocytes: "increased desmosome processing and the presence of immature epidermal desmosomes, upregulated epidermal transglutaminase activity … consistent with the presence of a constitutive wound-healing-like phenotype in TOC epidermis" (PMID:24643277).
  7. Parallel arm, the stress-keratin axis: TOC mutations "upregulate K16 with robust downregulation of its type II keratin binding partner, K6" (PMID:28128203). Why the effect is restricted to the palms and soles is inferred: mechanical stress at pressure-bearing sites combined with the K16 response.
  8. Upstream regulation: p63 regulates iRHOM2 transcription (Arcidiacono 2018, tier C).
  9. In the esophagus, the same iRHOM2 → EGFR proliferative state leads to transcriptional reprogramming before any dysplasia appears. Demonstrated (human biopsies, bulk RNA-seq): "Transcriptional changes occur in TOC esophagus prior to the onset of dysplasia, many of which are associated with ESCC", including negative enrichment of GRHL2 and "Keratin 17 … overexpressed at the protein level in 'normal' TOC esophagus tissue" (PMID:39131151).
  10. Leukokeratosis, then dysplasia, then ESCC in mid-to-late adulthood. The steps from leukokeratosis to dysplasia to cancer are inferred from the clinical natural history (PMID:26419362), not from lineage tracing. In mice, N-terminal iRhom2 mutations cause "accelerated tumorigenesis, but they do not drive spontaneous tumor development" (PMID:24825892). This is consistent with a promoter rather than an initiator role, which is an inference. The extra somatic events in TOC tumors are unknown.

Immune involvement: heightened shedding of cytokines including TNF (PMID:24643277). A mouse-model review found "a tissue-specific role of the RHBDF2-EGFR pathway, rather than a role of the immune system" (PMID:30022999). The mouse evidence therefore places TOC pathogenesis in epithelium rather than the immune system.

Newer biology (relevance to TOC not established): iRhom2 is cleaved by the signal peptidase complex, revealing an ER-to-nucleus signaling pathway (PMID:38183983, tier B).

Suggested GO / CL labels (look up before binding): - GO: epidermal growth factor receptor signaling pathway (modifier: INCREASED); membrane protein ectodomain proteolysis; keratinocyte proliferation; wound healing; keratinization; intermediate filament organization. - CL: keratinocyte; basal cell of epidermis; esophageal (squamous) epithelial cell. - Molecular function: iRHOM2 is a catalytically inactive pseudoprotease, so its function should be bound as a protein-binding / chaperone-like role, not as peptidase activity.

7. Anatomical structures affected

  • Primary: skin of the palms and soles, focal at pressure points; esophageal squamous mucosa; oral mucosa.
  • Secondary: hair follicles (follicular hyperkeratosis); oral and dental findings from a single review table (PMID:31334055).
  • Tissue / cell: stratified squamous epithelium (keratinocytes).
  • Subcellular: iRHOM2 is an ER/Golgi-trafficking multi-pass membrane protein. The Blaydon paper reports altered distribution of RHBDF2 in tylotic skin (PMID:22265016). Desmosomes and keratin intermediate filaments are also involved (PMID:24643277; PMID:28128203).
  • Laterality: bilateral and symmetric (clinical convention; no source quoted).
  • UBERON labels to look up: skin of palm of manus; skin of sole of pes; esophagus mucosa / esophagus squamous epithelium; oral mucosa.

8. Temporal development

  • Keratoderma: childhood onset, typically by 7–8 years and up to puberty; lifelong and stable (PMID:26419362).
  • Cancer: mid-50s onward, "no earlier development than the sporadic form" (PMID:26419362).
  • Window for intervention: surveillance detects early-stage cancer (§11).
  • No remission. Retinoids improve the skin only while they are being taken (PMID:26419362).

9. Inheritance and population

  • Inheritance: autosomal dominant (HP:0000006, per the GenCC URL). Cutaneous penetrance is complete (PMID:26419362). Cancer penetrance is age-dependent: an estimated 95% by age 65 in the Liverpool family (PMID:26419362). This estimate comes from one family and is probably inflated by ascertainment. That last point is my inference, not stated in the abstract.
  • Other features: no anticipation, no documented germline mosaicism, no consanguinity role.
  • Population: each variant is private to one family or lineage. p.Ile186Thr is shared by the UK and US families; whether they share a founder is not stated in the abstract.
  • Sex ratio: not reported to differ.
  • Prevalence: below 1 in 1,000,000 (PMID:26419362). Orphanet-derived data give "<10 families" (Helmholtz phenodis mirror, tier C). → measure_type: UNKNOWN/CASES_IN_LITERATURE, prevalence_class: BELOW_1_IN_1000000.

10. Diagnostics

  • Diagnosis rests on:

    "a positive family history, characteristic clinical features, including cutaneous and oesophageal lesions, and genetic analysis for mutations in RHBDF2" — PMID:26419362

  • Genetic testing: single-gene RHBDF2 testing (exon 6 hotspot) or a PPK gene panel. The Chinese family was solved by whole-exome sequencing (PMID:30938830). Copy-number analysis, karyotyping, FISH and mtDNA testing have no role.
  • Histology (skin): hyperkeratosis, acanthosis, hypergranulosis, non-epidermolytic (review table, PMID:31334055).
  • Endoscopy: esophageal leukokeratosis (small white polypoid lesions). Unusual endoscopic findings are reported in PMID:31182955 (tier B).
  • Omics: RNA-seq signatures (KRT17 up, GRHL2 targets down) are research-only (PMID:39131151).
  • Differential diagnosis:
  • Other focal non-epidermolytic PPKs: KRT16/KRT6C focal PPK and pachyonychia congenita (PMID:37766547 is cached), plus TRPV3, DSG1/DSP striate PPKs.
  • Other cancer-associated PPKs: Huriez syndrome; RSPO1 PPK with XX sex reversal and SCC (a stub exists); punctate PPK type 1, whose link to malignancy is debated (PMID:37705065, cached).
  • Families with sporadic ESCC clustering and acquired keratoderma ("Tylosis or Not?", PMID:30214015).
  • Distinguishing features: dominant inheritance plus focal pressure-point PPK plus oral/esophageal leukokeratosis plus a family history of ESCC.

11. Outcome and prognosis

"The prognosis of tylosis with oesophageal cancer is difficult to determine due to the limited number of affected individuals. In the last 40 years of surveillance, five out of six cases of squamous oesophageal cancer in the Liverpool family were detected endoscopically and were surgically removed. Four of five patients had stage 1 disease at presentation and remain alive and well more than 8 years later." — PMID:26419362

There are no formal survival curves. The main cause of death is ESCC, and the main source of illness is the keratoderma (pain, fissures, infection).

12. Treatment

Treatment Evidence Suggested NCIT (look up) therapeutic_modality
Emollients, keratolytics, specialist footwear, early treatment of fissures and tinea pedis PMID:26419362 (review recommendation) Supportive Care OTHER / BEHAVIORAL
Oral retinoids (acitretin is the typical drug; the abstract does not name one): "very effective but commonly produce side effects, including nasal excoriation and bleeding, hypercholesterolaemia, and abnormal liver function tests" PMID:26419362 Pharmacotherapy + retinoid agent (CHEBI, look up) SMALL_MOLECULE
Endoscopic/surgical resection of early ESCC PMID:26419362 Surgical Procedure SURGERY
Standard ESCC oncology care Follows the sporadic ESCC pathway; no TOC-specific data — —
  • Experimental / preclinical: AREG blockade (mouse genetic rescue, PMID:28655741: "targeting AREG could have therapeutic benefit"); EGFR inhibition, as suggested in Blaydon (PMID:22265016); sulforaphane (tier C).
  • Clinical trials: none found. ClinicalTrials.gov was not queried directly, so this is a gap and not a confirmed negative.
  • Pharmacogenomics: none.

13. Prevention

  • Secondary prevention (core management):

    "Surveillance includes annual gastroscopy with biopsy of any suspicious lesion together with quadratic biopsies from the upper, middle and lower oesophagus. This is coupled with dietary and lifestyle modification advice and symptom education." — PMID:26419362

The age at which surveillance starts is not in the abstract. I have not verified it, so check the full text before stating one. - Genetic counselling and cascade testing were enabled by the gene discovery: "These results enable the genetic counseling and diagnostic mutation screening of the members of TOC families" (PMID:22638770). - Predictive testing of children: keratoderma presents by 7–8 years, but cancer surveillance is an adult intervention. Testing an asymptomatic child therefore usually brings no immediate medical benefit (this follows standard pediatric predictive-testing principles; it is not TOC-specific guidance). PGT/prenatal testing is technically possible for a known familial variant; there is no TOC-specific guidance. - Primary prevention: avoid tobacco and alcohol (this is inferred from the review's lifestyle advice; no data). - No vaccines and no chemoprevention.

14. Other species / natural disease

No naturally occurring disease in animals was found. OMIA was not searched. The orthologs Rhbdf2 (mouse) and other vertebrate orthologs are conserved; the protein is "highly conserved" (PMID:24643277).

15. Model organisms

Model Phenotype Fidelity / limitations Source
Rhbdf2^cub/cub (curly bare; spontaneous cytoplasmic deletion that includes the TOC site) Alopecia, epidermal hyperplasia, rapid wound healing; depends on Areg/Adam17 Partial; the deletion is not a human allele PMID:37282854; PMID:30022999
Rhbdf2^toc/toc (knock-in of a human TOC mutation) "less severe alopecia and wavy fur"; rescued by loss of one allele of Areg or Adam17; substrate-selective ADAM17 effect Partial: hair phenotype instead of PPK; mice have no esophageal ESCC PMID:37282854
Human tylosis-mutation mouse × Areg knockout Skin pathology ameliorated Mechanism rescue PMID:28655741
N-terminal Rhbdf2 mutant mice Accelerated wound healing and tumorigenesis; no spontaneous tumors Partial PMID:24825892
Rhbdf2⁻/⁻ Thin footpads lacking K16; otherwise normal Loss-of-function control (FAILS_TO_RECAPITULATE the TOC phenotype; supports the GOF model) PMID:28128203; PMID:34937930
Immortalized TOC patient keratinocytes and patient skin Increased proliferation and migration, ADAM17 shedding, immature desmosomes IN_VITRO, human PMID:22265016; PMID:24643277

Tissue-specific Rhbdf2 in wound healing: PMID:29116018 (tier B).

The reviews state the main limitation directly: "current mouse models do not fully recapitulate all aspects of human TOC" (PMID:30022999). This is a candidate HUMAN_MODEL_MISMATCH discussion, because mice show a hair/fur phenotype rather than palmoplantar keratoderma, and no esophageal cancer.

Decisions to make before curating

  1. Germline/somatic split: curate TOC as a germline syndrome. Link it to Esophageal_Squamous_Cell_Carcinoma as the predisposed tumor rather than copying ESCC somatic pathophysiology into it.
  2. Same gene, two diseases: RHBDF2 recessive LoF IRIS (PMID:34937930) should be a separate entry. Do not make it a subtype of TOC.
  3. Gene validity: do not record a GenCC/ClinGen tier until the source record has been read.
  4. Unresolved mechanism question: whether ADAM17 catalytic activity is required (PMID:24825892 vs. PMID:37282854) belongs in a KNOWLEDGE_GAP discussion.
  5. Still to do: run just fetch-reference on all tier A PMIDs, plus ORPHA:2198. Fetch tier B/C items (29372562, 30938830, 42786633, Arcidiacono 2018, the locus-mapping papers) before citing them. Look up every ontology term.

Sources

Reference Validation

Checked with linkml-reference-validator 0.5.1.

Outcome Count
References checked 30
Resolved 30
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 27
Quoted claims found in source 25
Quoted claims not found in source 2
References weighed for topical relevance 30
On topic 26
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:24643277 (abstract only): "increased desmosome processing and the presence of immature epidermal desmosomes, upregulated epidermal transglutaminase activity … consistent with the presence of a constitutive wound-healing-like phenotype in TOC epidermis"
  • closest text in source: "This activity is accompanied by increased EGFR activity, increased desmosome processing and the presence of immature epidermal desmosomes, upregulated epidermal transglutaminase activity and heightened resistance to Staphylococcal infection in TOC keratinocytes"
  • PMID:39131151 (abstract only): "Keratin 17 … overexpressed at the protein level in 'normal' TOC esophagus tissue"
  • closest text in source: "Moreover, Keratin 17, which was upregulated in TOC and ESCC, was also found to be overexpressed at the protein level in 'normal' TOC esophagus tissue"

Term Validation

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

Outcome Count
Terms checked 3
Resolved 2
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
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:

  • MONDO:0007856 (4 mentions) - the report calls it "MONDO"; MONDO calls it palmoplantar keratoderma-esophageal carcinoma syndrome

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.