Autosomal dominant cardiocutaneous syndrome caused by heterozygous, often de novo, missense or in-frame variants in the spectrin repeat 6 (SR6) region of the N-terminal plakin domain of desmoplakin (DSP). Affected individuals combine a progressive, potentially fatal cardiomyopathy (biventricular dilated cardiomyopathy, or a right-dominant arrhythmogenic picture with ventricular arrhythmia and sudden death) with woolly or sparse hair, palmoplantar keratoderma, nail abnormalities and congenital tooth agenesis (hypodontia to oligodontia, typically premolars and molars). It is the dominant counterpart of recessive Carvajal syndrome (biallelic DSP truncation; entry Carvajal_Syndrome) and is distinct from the heterozygous DSP loss-of-function arrhythmogenic cardiomyopathy in DSP_Cardiomyopathy, whose carriers show at most curly hair and mild keratoderma and no tooth agenesis. MONDO and Orphanet treat erythrokeratodermia-cardiomyopathy (EKC) syndrome, caused by de novo proline substitutions slightly further along SR6, as the same disease; it is carried here as a subtype with generalized erythrokeratodermia, alopecia, enamel defects and absent secondary teeth.
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name: Dilated Cardiomyopathy with Woolly Hair, Keratoderma, and Tooth Agenesis
creation_date: "2026-10-12T14:48:06Z"
category: Mendelian
description: >-
Autosomal dominant cardiocutaneous syndrome caused by heterozygous, often de
novo, missense or in-frame variants in the spectrin repeat 6 (SR6) region of
the N-terminal plakin domain of desmoplakin (DSP). Affected individuals
combine a progressive, potentially fatal cardiomyopathy (biventricular
dilated cardiomyopathy, or a right-dominant arrhythmogenic picture with
ventricular arrhythmia and sudden death) with woolly or sparse hair,
palmoplantar keratoderma, nail abnormalities and congenital tooth agenesis
(hypodontia to oligodontia, typically premolars and molars). It is the
dominant counterpart of recessive Carvajal syndrome (biallelic DSP
truncation; entry Carvajal_Syndrome) and is distinct from the heterozygous
DSP loss-of-function arrhythmogenic cardiomyopathy in DSP_Cardiomyopathy,
whose carriers show at most curly hair and mild keratoderma and no tooth
agenesis. MONDO and Orphanet treat erythrokeratodermia-cardiomyopathy (EKC)
syndrome, caused by de novo proline substitutions slightly further along
SR6, as the same disease; it is carried here as a subtype with generalized
erythrokeratodermia, alopecia, enamel defects and absent secondary teeth.
notes: >-
The evidence base is a handful of case reports and one three-patient series:
a three-member family with p.Ser597Leu (PMID:20940358), two unrelated de novo
cases with p.Leu583Pro and p.Thr564Ile (PMID:22949226), a family with
p.Ile560Phe (PMID:28649555), a de novo case with oligodontia and nail
fragility (PMID:35574671), and three de novo EKC syndrome cases with Q616P,
H618P and L622P (PMID:26604139). Further letters without abstracts
(PMID:22795705, PMID:26833927, PMID:16628197) report the same phenotype but
are not quoted here. No phenotype frequencies are recorded because no source
reports a denominator larger than three. Several features reported in single
individuals are deliberately not curated as disease phenotypes: unilateral
hearing loss, recurrent pharyngeal infection, recurrent diarrhoea and left
ventricular hypertrabeculation in the p.Ile560Phe index patient (the authors
judge the first three probably unlinked), a bicuspid aortic valve in the
p.Leu583Pro case, and corneal opacities, transient spasticity and
developmental delay in one EKC case. Tooth agenesis is not an obligate
feature: the p.Leu583Pro patient had no dental abnormality. A clinically
identical patient with woolly hair, keratoderma, missing molars and
premolars and dilated cardiomyopathy but no detectable DSP or JUP variant
(PMID:22350851) suggests either locus heterogeneity or a DSP variant missed
by exon sequencing. The dominant SR6 variant H586P causes a different
disorder (severe dermatitis, multiple allergies and metabolic wasting, SAM
syndrome), so position within SR6 matters and this entry does not cover
every SR6 missense variant. The plakin-domain repeat called spectrin repeat
4 in PMID:28649555 is the same repeat called SR6 in PMID:26604139, which
numbers repeats by homology to plectin. No GeneReviews chapter covers this
syndrome.
disease_term:
preferred_term: cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis
term:
id: MONDO:0014355
label: cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis
synonyms:
- cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis
- dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis
- DCWHKTA
- autosomal dominant Carvajal syndrome
- erythrokeratodermia-cardiomyopathy syndrome
- EKC syndrome
parents:
- Cardiocutaneous Syndrome
- Desmosomal Disease
- Dilated Cardiomyopathy
classifications:
mechanistic_category:
- classification_value: desmosomopathy
has_subtypes:
- name: Dominant Carvajal
display_name: Dominant Carvajal phenotype (woolly hair, keratoderma, tooth agenesis)
description: >-
The originally described presentation: woolly hair, palmoplantar
keratoderma (often striate), nail changes, hypodontia or oligodontia, and
dilated or arrhythmogenic cardiomyopathy, caused by heterozygous missense or
in-frame variants between roughly residues 560 and 600 of desmoplakin.
genes:
- preferred_term: DSP
term:
id: hgnc:3052
label: DSP
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Heterozygosity for an in-frame insertion or a missense mutation within SR6
has been shown to cause dominant Carvajal syndrome, which features limited
skin involvement (isolated PPK) with woolly hair and cardiomyopathy (OMIM
#615821)
explanation: >-
The EKC syndrome report summarizes the earlier dominant Carvajal reports
and places them in SR6 under OMIM 615821, the record MONDO:0014355 maps to.
- name: EKC
display_name: Erythrokeratodermia-cardiomyopathy (EKC) syndrome
description: >-
Severe congenital or infantile generalized erythrokeratodermia with
alopecia, absent eyebrows and eyelashes, nail dystrophy, enamel defects,
absent secondary teeth and initially silent progressive dilated
cardiomyopathy, caused by de novo proline substitutions (Q616P, H618P,
L622P) clustered within seven residues near the end of SR6. The former
MONDO term for EKC syndrome (MONDO:0018774) is obsolete and merged into
MONDO:0014355, so the subtype carries no term of its own.
genes:
- preferred_term: DSP
term:
id: hgnc:3052
label: DSP
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We show that de novo missense mutations clustered tightly within a single
spectrin repeat of DSP cause this novel cardio-cutaneous disorder, which
we term erythrokeratodermia-cardiomyopathy (EKC) syndrome.
explanation: >-
Defines EKC syndrome as a dominant de novo SR6 DSP disorder.
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Additional differences compared to Carvajal syndrome, the dominant form of
which is also caused by substitution mutations in DSP SR6, include a more
mild PPK, more profound and consistent alopecia, itch, and variable
features of failure to thrive, developmental delay, visual impairment, and
hoarse voice observed in our EKC syndrome subjects.
explanation: >-
States what separates the EKC presentation from the dominant Carvajal
presentation caused by the same SR6 region.
inheritance:
- name: Autosomal Dominant
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
Heterozygous DSP variants act dominantly. Most reported variants arose de
novo in the proband (confirmed by parental testing and, in two cases,
paternity testing), with subsequent vertical transmission in the
p.Ser597Leu and p.Ile560Phe families.
evidence:
- reference: PMID:20940358
reference_title: "A new hypo/oligodontia syndrome: Carvajal/Naxos syndrome secondary to desmoplakin-dominant mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This familial case report and two other previous reports demonstrate that
autosomal-dominant mutations in the DSP gene are associated with
hypo/oligodontia in the setting of Carvajal/Naxos syndrome.
explanation: >-
The founding report establishes dominant DSP mutation as the cause of the
tooth-agenesis cardiocutaneous phenotype.
- reference: PMID:22949226
reference_title: "De novo heterozygous desmoplakin mutations leading to Naxos-Carvajal disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We therefore conclude that the probands both carried a de novo mutation in
DSP.
explanation: >-
Parental and paternity testing confirmed de novo heterozygous DSP
variants in two unrelated affected individuals.
- reference: PMID:28649555
reference_title: "Autosomal dominant Carvajal plus syndrome due to the novel desmoplakin mutation c.1678A > T (p.Ile560Phe)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
According to the family tree a paternal autosomal dominant transmission is
most likely.
explanation: >-
Father-to-child transmission of the p.Ile560Phe phenotype supports
autosomal dominant inheritance.
pathophysiology:
- name: DSP Spectrin Repeat 6 Missense Variant
description: >-
A single heterozygous missense or in-frame variant alters a conserved
residue in spectrin repeat 6 of the desmoplakin plakin domain, the
N-terminal region that binds plakoglobin and the plakophilins. Structural
modelling and the recurrent introduction of helix-breaking proline
residues suggest that the variants destabilize the repeat. Whether the
mutant protein acts through insufficient recruitment of desmoplakin to
desmosomes or through a dominant-negative effect on other desmosomal
proteins has not been tested.
biological_scale: MOLECULAR
genes:
- preferred_term: DSP
term:
id: hgnc:3052
label: DSP
genetic_context:
variant_origin: DE_NOVO
zygosity: HETEROZYGOUS
molecular_functions:
- preferred_term: desmoplakin structural linkage of the desmosomal plaque
term:
id: GO:0005200
label: structural constituent of cytoskeleton
modifier: ABNORMAL
cellular_components:
- preferred_term: desmosome
term:
id: GO:0030057
label: desmosome
evidence:
- reference: PMID:22949226
reference_title: "De novo heterozygous desmoplakin mutations leading to Naxos-Carvajal disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In each patient we identified a single heterozygous de novo mutation in
the desmoplakin gene DSP, p.Leu583Pro and p.Thr564Ile, leading to severe
combined cardiac/dermatological and cardiac/dermatological/dental
phenotypes. The DSP missense mutations are localised in the N terminal
domain of desmoplakin.
explanation: >-
Two unrelated de novo cases place the causal variants in the N-terminal
domain.
- reference: PMID:22949226
reference_title: "De novo heterozygous desmoplakin mutations leading to Naxos-Carvajal disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This observation suggests a key role for the desmoplakin region (564-597),
which may be involved in the interactions with plakophilin or plakoglobin.
explanation: >-
Clustering of the dominant variants defines a critical region of the
plakin domain implicated in binding the armadillo plaque proteins.
- reference: PMID:28649555
reference_title: "Autosomal dominant Carvajal plus syndrome due to the novel desmoplakin mutation c.1678A > T (p.Ile560Phe)."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: >-
Structural modelling indicated that the mutation changed one amino acid
located in the repeat spectrin 4 of the plakin domain of the protein
leading probably to loss of the structural integrity of this domain.
explanation: >-
In silico modelling of p.Ile560Phe predicts destabilization of the same
spectrin repeat.
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All three mutations substitute proline for the native amino acid, and are
clustered in exon 14 within a span encoding seven amino acids, at sites
completely conserved in orthologs
explanation: >-
The EKC variants are conserved-site proline substitutions tightly
clustered in the same repeat.
downstream:
- target: Epidermal Desmosome Aggregation and Plaque Protein Mislocalization
description: >-
Mutant desmoplakin is still incorporated at keratinocyte junctions but
forms focal aggregates and disturbs the localization of other desmosomal
plaque proteins.
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We demonstrate that DSP mutations in our EKC syndrome subjects affect
localization of desmosomal proteins and connexin 43 in the skin, and
result in desmosome aggregation, widening of intercellular spaces, and
lipid secretory defects.
explanation: >-
Patient skin shows the junctional consequence of the SR6 variants.
- target: Myocardial Desmosome Dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The same plaque defect is presumed to occur at cardiomyocyte intercalated
discs, where desmoplakin is equally abundant; no myocardium from a
patient with this syndrome has been studied at the molecular level.
- target: Desmosome-Dependent Tooth Development Defect
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Dominant SR6 variants are associated with failure of permanent tooth
formation, implicating desmosomal function in odontogenesis.
evidence:
- reference: PMID:20940358
reference_title: "A new hypo/oligodontia syndrome: Carvajal/Naxos syndrome secondary to desmoplakin-dominant mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In addition, this study reveals the role of desmosomes in the
development of teeth
explanation: >-
The founding family links the dominant DSP variant to defective tooth
development.
- name: Epidermal Desmosome Aggregation and Plaque Protein Mislocalization
conforms_to: "desmosomal_adhesion_failure#Failure of Desmosome Assembly and Intermediate Filament Anchorage"
description: >-
In affected epidermis desmosomes are internalized or shed into large
aggregates in the spinous layer, so fewer remain at suprabasal cell
borders, and desmoplakin, desmoglein 1 and plakoglobin show weaker, more
diffuse junctional staining. This has been studied only in EKC syndrome
skin.
biological_scale: CELLULAR
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
biological_processes:
- preferred_term: desmosome organization
term:
id: GO:0002934
label: desmosome organization
modifier: ABNORMAL
cellular_components:
- preferred_term: desmosome
term:
id: GO:0030057
label: desmosome
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This is likely due to marked aggregation of desmosomes either via shedding
or internalization seen in spinous layer keratinocytes (Fig. 5A).
explanation: >-
Electron microscopy of patient skin shows desmosome aggregation in
spinous keratinocytes.
downstream:
- target: Loss of Suprabasal Keratinocyte Adhesion
description: >-
Removal of desmosomes from the cell surface widens the intercellular
spaces between suprabasal keratinocytes.
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Loss of desmosomes leads to widening of intercellular spaces in
suprabasal cells (Fig. 5B).
explanation: >-
Direct ultrastructural link from desmosome loss to impaired adhesion.
- target: Reduced Connexin 43 Junctional Localization
description: >-
Mutant desmoplakin reduces the membrane localization of the gap junction
protein connexin 43 in keratinocytes.
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Both constructs expressing a DSP mutation (H618P, L622P) demonstrate
Cx43 membrane intensity reduced to <80% of that observed in cells
expressing wild-type DSP
explanation: >-
Expression of the EKC variants in primary human keratinocytes reduces
junctional connexin 43.
- name: Loss of Suprabasal Keratinocyte Adhesion
conforms_to: "desmosomal_adhesion_failure#Loss of Desmosomal Intercellular Adhesion"
description: >-
Suprabasal keratinocytes separate at widened intercellular spaces, and
lamellar bodies are secreted prematurely with defective structure. The
histological result in EKC syndrome is a psoriasiform, hyperkeratotic
epidermis with a reduced granular layer. The same weakness of
desmosome-dependent epithelia is the presumed basis of the keratoderma,
hair and nail findings shared by both presentations.
biological_scale: CELLULAR
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
biological_processes:
- preferred_term: cell-cell adhesion
term:
id: GO:0098609
label: cell-cell adhesion
modifier: DECREASED
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Marked deficits in lipid processing and secretion are also observed on
ruthenium tetroxide staining, with premature secretion of lamellar bodies
which have defective structure and supramolecular organization (Fig. 5D).
explanation: >-
Patient skin shows a lamellar body secretory defect accompanying the
adhesion defect.
downstream:
- target: Erythrokeratodermia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Adhesion and lipid secretory failure in the suprabasal epidermis are the
tissue abnormalities underlying the generalized erythrokeratodermia of
EKC syndrome.
- target: Palmoplantar Keratoderma
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Desmosomal weakness in the mechanically loaded palmoplantar epidermis
produces keratoderma, as in other desmoplakin disorders.
- target: Woolly Hair
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Desmosome-dependent hair follicle epithelium yields an abnormally curled
hair shaft.
- target: Alopecia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
In EKC syndrome the hair defect extends to near-absent scalp hair.
- target: Sparse Eyebrows
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Eyebrow and eyelash hair is scarce or absent.
- target: Nail Dystrophy
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Desmosome-dependent nail matrix epithelium produces dystrophic nails.
- target: Leukonychia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Nail involvement can take the form of leukonychia.
- target: Fragile Nails
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Nail involvement can take the form of nail fragility.
- name: Reduced Connexin 43 Junctional Localization
description: >-
Connexin 43 membrane staining is weaker and more diffuse in EKC syndrome
skin, and EKC variants reduce junctional connexin 43 in cultured
keratinocytes. The same desmosome to gap junction coupling is the presumed
route to ventricular conduction disturbance and arrhythmia, but connexin 43
has not been examined in patient myocardium.
biological_scale: CELLULAR
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
biological_processes:
- preferred_term: protein localization to plasma membrane
term:
id: GO:0072659
label: protein localization to plasma membrane
modifier: DECREASED
cellular_components:
- preferred_term: connexin complex
term:
id: GO:0005922
label: connexin complex
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Both constructs expressing a DSP mutation (H618P, L622P) demonstrate Cx43
membrane intensity reduced to <80% of that observed in cells expressing
wild-type DSP
explanation: >-
Cultured keratinocyte data show reduced connexin 43 membrane localization
with EKC variants.
downstream:
- target: Ventricular Electrical Instability
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Extrapolated from skin and cultured keratinocytes: loss of junctional
connexin 43 in cardiomyocytes would impair conduction and favour
ventricular arrhythmia.
- name: Myocardial Desmosome Dysfunction
description: >-
Desmoplakin is a core component of cardiomyocyte intercalated disc
desmosomes. The dominant SR6 variants are presumed to weaken these
junctions as they do in skin, initiating progressive myocardial damage
with left ventricular fibrosis and, in some patients, fatty change of the
right heart.
biological_scale: CELLULAR
mechanism_confidence: PROVISIONAL
cell_types:
- preferred_term: cardiac muscle cell
term:
id: CL:0000746
label: cardiac muscle cell
locations:
- preferred_term: heart
term:
id: UBERON:0000948
label: heart
biological_processes:
- preferred_term: cell-cell adhesion
term:
id: GO:0098609
label: cell-cell adhesion
modifier: DECREASED
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: >-
DSP encodes desmoplakin, a primary component of desmosomes, intercellular
adhesion junctions most abundant in the epidermis and heart.
explanation: >-
Establishes the shared desmosomal substrate in skin and heart that makes
the variants cardiocutaneous.
downstream:
- target: Myocardial Fibrosis
description: >-
Desmosome-dependent myocardial injury is followed by replacement
fibrosis of the ventricular wall.
- target: Progressive Ventricular Dilation and Systolic Dysfunction
description: >-
Myocardial injury progresses to ventricular dilation with falling
ejection fraction.
- target: Ventricular Electrical Instability
description: >-
Damaged, fibrotic myocardium provides the substrate for ventricular
ectopy and tachyarrhythmia.
- name: Progressive Ventricular Dilation and Systolic Dysfunction
conforms_to: "cardiomyopathy_maladaptive_remodeling#Progressive Contractile Dysfunction"
description: >-
Left, right or biventricular dilation develops in childhood or
adolescence, is initially asymptomatic, and can progress rapidly to severe
systolic dysfunction and fatal heart failure.
biological_scale: TISSUE
cell_types:
- preferred_term: cardiac muscle cell
term:
id: CL:0000746
label: cardiac muscle cell
locations:
- preferred_term: heart
term:
id: UBERON:0000948
label: heart
biological_processes:
- preferred_term: cardiac muscle contraction
term:
id: GO:0060048
label: cardiac muscle contraction
modifier: DECREASED
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We have identified subjects with a novel DOK featuring erythrokeratodermia
and initially-asymptomatic, progressive, potentially fatal cardiomyopathy,
a finding not previously associated with erythrokeratodermia.
explanation: >-
The cardiomyopathy is progressive and initially silent.
downstream:
- target: Dilated Cardiomyopathy
description: >-
Ventricular dilation with systolic dysfunction is the defining cardiac
phenotype.
evidence:
- reference: PMID:20940358
reference_title: "A new hypo/oligodontia syndrome: Carvajal/Naxos syndrome secondary to desmoplakin-dominant mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we describe a familial case with Carvajal/Naxos syndrome associating
woolly hair, palmoplantar keratoderma, and biventricular dilated
cardiomyopathy
explanation: >-
Biventricular dilated cardiomyopathy in the founding family.
- target: Right Ventricular Dilatation
description: >-
Some patients have predominantly right ventricular involvement.
- target: Left Ventricular Dilatation
description: >-
Left ventricular dilation is the first cardiac finding in several
patients.
- target: Congestive Heart Failure
description: >-
Progressive dilation can end in fatal heart failure.
- name: Ventricular Electrical Instability
description: >-
Ventricular premature beats, conduction abnormalities (left hemiblock and
an epsilon wave in one patient) and ventricular tachyarrhythmia occur,
sometimes before overt dilation, and cause syncope and sudden death.
biological_scale: TISSUE
cell_types:
- preferred_term: cardiac muscle cell
term:
id: CL:0000746
label: cardiac muscle cell
locations:
- preferred_term: heart
term:
id: UBERON:0000948
label: heart
biological_processes:
- preferred_term: ventricular cardiac muscle cell action potential
term:
id: GO:0086005
label: ventricular cardiac muscle cell action potential
modifier: ABNORMAL
evidence:
- reference: PMID:28649555
reference_title: "Autosomal dominant Carvajal plus syndrome due to the novel desmoplakin mutation c.1678A > T (p.Ile560Phe)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The father of the two had woolly hair, dCMP, and experienced recurrent
ventricular tachycardias, from which he died despite implantation of an
ICD.
explanation: >-
Recurrent, ultimately fatal ventricular tachyarrhythmia in an affected
family member.
downstream:
- target: Ventricular Tachycardia
description: Electrical instability manifests as ventricular tachycardia.
- target: Ventricular Fibrillation
description: Electrical instability can degenerate into ventricular fibrillation.
- target: Premature Ventricular Contractions
description: Electrical instability manifests as frequent ventricular ectopy.
- target: Syncope
description: Ventricular arrhythmia causes recurrent syncope.
- target: Sudden Cardiac Death
description: Malignant ventricular arrhythmia causes sudden death.
- name: Desmosome-Dependent Tooth Development Defect
description: >-
Permanent teeth, most often the second premolars and the second and third
molars, fail to form, and in EKC syndrome the enamel of the primary teeth
is soft and poorly mineralized. The developmental step at which the dental
epithelium depends on desmoplakin is not known.
biological_scale: TISSUE
mechanism_confidence: PROVISIONAL
locations:
- preferred_term: tooth
term:
id: UBERON:0001091
label: calcareous tooth
biological_processes:
- preferred_term: odontogenesis
term:
id: GO:0042476
label: odontogenesis
modifier: DECREASED
evidence:
- reference: PMID:20940358
reference_title: "A new hypo/oligodontia syndrome: Carvajal/Naxos syndrome secondary to desmoplakin-dominant mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
all three affected family members had hypo/oligodontia ranging from
absence of the lower left second molar to 15 missing teeth, the typical
pattern of oligodontia being absent 2nd premolars and absent 2nd and 3rd
molars
explanation: >-
Defines the tooth agenesis pattern produced by the dominant DSP variant.
downstream:
- target: Tooth Agenesis
description: Failed odontogenesis leaves permanent teeth congenitally absent.
- target: Abnormal Dental Enamel
description: >-
In EKC syndrome enamel formation of the primary teeth is also defective.
phenotypes:
- category: Cardiovascular
name: Dilated Cardiomyopathy
description: >-
Left-dominant or biventricular dilated cardiomyopathy, beginning in
childhood or adolescence and often progressing to severe systolic
dysfunction.
phenotype_term:
preferred_term: Dilated cardiomyopathy
term:
id: HP:0001644
label: Dilated cardiomyopathy
evidence:
- reference: PMID:20940358
reference_title: "A new hypo/oligodontia syndrome: Carvajal/Naxos syndrome secondary to desmoplakin-dominant mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we describe a familial case with Carvajal/Naxos syndrome associating
woolly hair, palmoplantar keratoderma, and biventricular dilated
cardiomyopathy
explanation: Dilated cardiomyopathy in the founding family.
- reference: PMID:35574671
reference_title: "A new de novo heterozygous missense mutation in the desmoplakin gene, causing Naxos and Carvajal disease, associating oligodontia and nail fragility."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In addition to woolly hair, palmoplantar keratoderma and cardiomyopathy,
she had oligodontia and nail fragility.
explanation: Cardiomyopathy in a de novo case.
- category: Cardiovascular
name: Right Ventricular Dilatation
description: >-
Severe right ventricular dilatation, sometimes predominating over left
ventricular involvement and resembling arrhythmogenic right ventricular
cardiomyopathy.
phenotype_term:
preferred_term: Right ventricular dilatation
term:
id: HP:0005133
label: Right ventricular dilatation
evidence:
- reference: PMID:22949226
reference_title: "De novo heterozygous desmoplakin mutations leading to Naxos-Carvajal disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Echocardiographic findings were consistent with severe RV dilatation and
slight LV enlargement from the apical-4 chamber view
explanation: Right-dominant ventricular dilatation in the p.Thr564Ile patient.
- reference: PMID:28649555
reference_title: "Autosomal dominant Carvajal plus syndrome due to the novel desmoplakin mutation c.1678A > T (p.Ile560Phe)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Autopsy of the brother's heart showed marked right-ventricular dilatation
and fatty degeneration of the right atrium.
explanation: Right ventricular dilatation at autopsy in a p.Ile560Phe carrier.
- category: Cardiovascular
name: Left Ventricular Dilatation
description: >-
Left ventricular dilation, initially with preserved or low-normal systolic
function, found on screening echocardiography in EKC syndrome.
subtype: EKC
phenotype_term:
preferred_term: Left ventricular dilatation
term:
id: HP:4000141
label: Left ventricular dilatation
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Echocardiogram revealed a moderately dilated left ventricle (Z +4.4) with
low normal systolic function.
explanation: Left ventricular dilatation on the first cardiac work-up of an EKC patient.
- category: Cardiovascular
name: Congestive Heart Failure
description: Progressive cardiomyopathy can cause fatal heart failure in early childhood.
phenotype_term:
preferred_term: Congestive heart failure
term:
id: HP:0001635
label: Congestive heart failure
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Subsequent echocardiography showed marked left atrial and ventricular
dilation and right ventricular dilation with an ejection fraction of 20%,
and he died of heart failure after a brief hospitalization.
explanation: Fatal heart failure at age three in an EKC patient.
- category: Cardiovascular
name: Ventricular Tachycardia
phenotype_term:
preferred_term: Ventricular tachycardia
term:
id: HP:0004756
label: Ventricular tachycardia
evidence:
- reference: PMID:28649555
reference_title: "Autosomal dominant Carvajal plus syndrome due to the novel desmoplakin mutation c.1678A > T (p.Ile560Phe)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The father of the two had woolly hair, dCMP, and experienced recurrent
ventricular tachycardias, from which he died despite implantation of an
ICD.
explanation: Recurrent ventricular tachycardia in an affected parent.
- category: Cardiovascular
name: Premature Ventricular Contractions
phenotype_term:
preferred_term: Premature ventricular contraction
term:
id: HP:0006682
label: Premature ventricular contraction
evidence:
- reference: PMID:22949226
reference_title: "De novo heterozygous desmoplakin mutations leading to Naxos-Carvajal disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Her Holter ECG recordings showed frequent ventricular premature beats.
explanation: Frequent ventricular ectopy in the p.Thr564Ile patient before any cardiac symptoms.
- category: Cardiovascular
name: Syncope
phenotype_term:
preferred_term: Syncope
term:
id: HP:0001279
label: Syncope
evidence:
- reference: PMID:28649555
reference_title: "Autosomal dominant Carvajal plus syndrome due to the novel desmoplakin mutation c.1678A > T (p.Ile560Phe)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The brother had a history of recurrent syncopes, dental abnormalities, and
dCMP.
explanation: Recurrent syncope in an affected sibling who later died suddenly.
- category: Cardiovascular
name: Sudden Cardiac Death
phenotype_term:
preferred_term: Sudden cardiac death
term:
id: HP:0001645
label: Sudden cardiac death
evidence:
- reference: PMID:28649555
reference_title: "Autosomal dominant Carvajal plus syndrome due to the novel desmoplakin mutation c.1678A > T (p.Ile560Phe)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Father and brother were also affected and had died suddenly, the father
despite implantation of a cardioverter defibrillator (ICD).
explanation: Two sudden deaths in one affected family.
- category: Cardiovascular
name: Myocardial Fibrosis
description: >-
Patchy left ventricular fibrosis on cardiac MRI late enhancement.
phenotype_term:
preferred_term: Myocardial fibrosis
term:
id: HP:0001685
label: Myocardial fibrosis
evidence:
- reference: PMID:22949226
reference_title: "De novo heterozygous desmoplakin mutations leading to Naxos-Carvajal disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
revealed inhomogeneous areas of probable fibrosis in the LV but no late
enhancement of the RV
explanation: >-
Cardiac MRI late enhancement in the p.Leu583Pro patient shows probable
left ventricular fibrosis.
- category: Cardiovascular
name: Ventricular Fibrillation
description: >-
Ventricular fibrillation during exercise, terminated by an appropriate
ICD shock, in a patient with dilated cardiomyopathy.
phenotype_term:
preferred_term: Ventricular fibrillation
term:
id: HP:0001663
label: Ventricular fibrillation
evidence:
- reference: PMID:22949226
reference_title: "De novo heterozygous desmoplakin mutations leading to Naxos-Carvajal disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
when ventricular fib-rillation occurring during exercise was terminated by
ad-equate ICD shock
explanation: >-
Exercise-induced ventricular fibrillation in the p.Leu583Pro patient. The
cached full text splits two words across line breaks, and the snippet
reproduces the cached hyphenation.
- category: Dermatologic
name: Woolly Hair
description: >-
Curly, woolly hair, sometimes sparse or with a high frontal hairline.
phenotype_term:
preferred_term: Woolly hair
term:
id: HP:0002224
label: Woolly hair
evidence:
- reference: PMID:20940358
reference_title: "A new hypo/oligodontia syndrome: Carvajal/Naxos syndrome secondary to desmoplakin-dominant mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we describe a familial case with Carvajal/Naxos syndrome associating
woolly hair, palmoplantar keratoderma, and biventricular dilated
cardiomyopathy
explanation: Woolly hair in the founding family.
- reference: PMID:35574671
reference_title: "A new de novo heterozygous missense mutation in the desmoplakin gene, causing Naxos and Carvajal disease, associating oligodontia and nail fragility."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In addition to woolly hair, palmoplantar keratoderma and cardiomyopathy,
she had oligodontia and nail fragility.
explanation: Woolly hair in a de novo case.
- category: Dermatologic
name: Palmoplantar Keratoderma
description: >-
Palmoplantar keratoderma, striate in some patients and mild in others; in
EKC syndrome it is overshadowed by generalized erythrokeratodermia.
phenotype_term:
preferred_term: Palmoplantar keratoderma
term:
id: HP:0000982
label: Palmoplantar keratoderma
evidence:
- reference: PMID:20940358
reference_title: "A new hypo/oligodontia syndrome: Carvajal/Naxos syndrome secondary to desmoplakin-dominant mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we describe a familial case with Carvajal/Naxos syndrome associating
woolly hair, palmoplantar keratoderma, and biventricular dilated
cardiomyopathy
explanation: Palmoplantar keratoderma in the founding family.
- reference: PMID:22949226
reference_title: "De novo heterozygous desmoplakin mutations leading to Naxos-Carvajal disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
At the age of two years, the patient developed striate palmoplantar
keratoderma and progressive erythemato-squamous plaques
explanation: Striate keratoderma from age two in the p.Leu583Pro patient.
- category: Dermatologic
name: Erythrokeratodermia
description: >-
Severe congenital or early-onset generalized erythema with thickened,
corrugated, finely scaling skin, resistant to most treatment.
subtype: EKC
phenotype_term:
preferred_term: Erythrokeratodermia
term:
id: HP:0001019
label: Erythroderma
notes: >-
HPO has no erythrokeratodermia term; Erythroderma is the closest term and
the keratotic component is carried in preferred_term.
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Index case 244 was noted to have severe congenital erythrokeratodermia,
with scant eyebrow, eyelash and scalp hair (Fig. 1C and D).
explanation: Congenital erythrokeratodermia in an EKC patient.
- category: Dermatologic
name: Pruritus
subtype: EKC
phenotype_term:
preferred_term: Pruritus
term:
id: HP:0000989
label: Pruritus
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Additional differences compared to Carvajal syndrome, the dominant form of
which is also caused by substitution mutations in DSP SR6, include a more
mild PPK, more profound and consistent alopecia, itch, and variable
features of failure to thrive, developmental delay, visual impairment, and
hoarse voice observed in our EKC syndrome subjects.
explanation: Itch is a feature of the EKC presentation.
- category: Dermatologic
name: Alopecia
description: >-
Sparse to near-absent scalp hair in EKC syndrome.
subtype: EKC
phenotype_term:
preferred_term: Alopecia
term:
id: HP:0001596
label: Alopecia
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Faces of index cases 614, 244, and 380, respectively, show absence of
eyebrow and eyelash hair, with minimal wispy scalp hair in cases 614 and
244 and sparse, curly hair in case 380.
explanation: Scalp hair loss with absent eyebrows and eyelashes in all three EKC patients.
- category: Dermatologic
name: Sparse Eyebrows
description: Scarce or absent eyebrows, usually with sparse eyelashes.
phenotype_term:
preferred_term: Sparse eyebrow
term:
id: HP:0045075
label: Sparse eyebrow
evidence:
- reference: PMID:22949226
reference_title: "De novo heterozygous desmoplakin mutations leading to Naxos-Carvajal disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The eyebrows and eyelashes were scarce
explanation: Sparse eyebrows in the p.Leu583Pro patient.
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Faces of index cases 614, 244, and 380, respectively, show absence of
eyebrow and eyelash hair, with minimal wispy scalp hair in cases 614 and
244 and sparse, curly hair in case 380.
explanation: Absent eyebrows in EKC syndrome.
- category: Dermatologic
name: Nail Dystrophy
description: Dystrophy of finger and toe nails.
phenotype_term:
preferred_term: Nail dystrophy
term:
id: HP:0008404
label: Nail dystrophy
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He had onychodystrophy of all nails (Fig. 1G).
explanation: Nail dystrophy in an EKC patient.
- category: Dermatologic
name: Leukonychia
phenotype_term:
preferred_term: Leukonychia
term:
id: HP:0001820
label: Leukonychia
evidence:
- reference: PMID:22949226
reference_title: "De novo heterozygous desmoplakin mutations leading to Naxos-Carvajal disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Nail examination revealed bilateral leu-conychia of third and fourth toe
whereas finger nails were normal.
explanation: >-
Primary observation of toenail leukonychia in the p.Thr564Ile patient.
The snippet reproduces the cached line-break hyphenation.
- reference: PMID:28649555
reference_title: "Autosomal dominant Carvajal plus syndrome due to the novel desmoplakin mutation c.1678A > T (p.Ile560Phe)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
In this domain at least two further missense mutations have been described
leading to Carvajal/Naxos syndrome with leukonychia and oligodontia
explanation: >-
Summarizes earlier reports of leukonychia with dominant plakin-domain
DSP variants.
- category: Dermatologic
name: Fragile Nails
phenotype_term:
preferred_term: Fragile nails
term:
id: HP:0001808
label: Fragile nails
evidence:
- reference: PMID:35574671
reference_title: "A new de novo heterozygous missense mutation in the desmoplakin gene, causing Naxos and Carvajal disease, associating oligodontia and nail fragility."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In addition to woolly hair, palmoplantar keratoderma and cardiomyopathy,
she had oligodontia and nail fragility.
explanation: Nail fragility in a de novo case.
- category: Dental
name: Tooth Agenesis
description: >-
Congenital absence of one to fifteen permanent teeth (hypodontia to
oligodontia), typically the second premolars and second and third molars.
phenotype_term:
preferred_term: Tooth agenesis
term:
id: HP:0009804
label: Tooth agenesis
evidence:
- reference: PMID:20940358
reference_title: "A new hypo/oligodontia syndrome: Carvajal/Naxos syndrome secondary to desmoplakin-dominant mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
all three affected family members had hypo/oligodontia ranging from
absence of the lower left second molar to 15 missing teeth, the typical
pattern of oligodontia being absent 2nd premolars and absent 2nd and 3rd
molars
explanation: Tooth agenesis in all three affected members of the founding family.
- reference: PMID:22949226
reference_title: "De novo heterozygous desmoplakin mutations leading to Naxos-Carvajal disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
she had dental agenesis with missing teeth numbers 14, 15, 17, 25, 27,
35, 37, 45 and 47
explanation: Nine missing premolars and molars in the p.Thr564Ile patient.
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Dental examination revealed congenital absence of 11 secondary teeth,
gingival recession and erythema, and poor mineralization of primary
teeth, with widespread caries.
explanation: Absent secondary teeth in an EKC patient.
- category: Dental
name: Abnormal Dental Enamel
description: >-
Soft, chalky, poorly mineralized enamel of the primary teeth with
progressive caries, reported in EKC syndrome.
subtype: EKC
phenotype_term:
preferred_term: Abnormal dental enamel morphology
term:
id: HP:0000682
label: Abnormal dental enamel morphology
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Dental exams noted marked enamel defects, with recurrent caries of primary
teeth and soft, chalk-like, poorly mineralized enamel.
explanation: Enamel defect in an EKC patient.
sequelae:
- target: Carious Teeth
description: Poorly mineralized enamel predisposes to rapid caries.
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Dental exams noted marked enamel defects, with recurrent caries of
primary teeth and soft, chalk-like, poorly mineralized enamel.
explanation: Caries accompany the enamel defect.
- category: Dental
name: Carious Teeth
subtype: EKC
phenotype_term:
preferred_term: Carious teeth
term:
id: HP:0000670
label: Carious teeth
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Dental examination revealed congenital absence of 11 secondary teeth,
gingival recession and erythema, and poor mineralization of primary
teeth, with widespread caries.
explanation: Widespread caries in an EKC patient.
- category: Growth
name: Failure to Thrive
description: Variable failure to thrive in infancy in EKC syndrome.
subtype: EKC
phenotype_term:
preferred_term: Failure to thrive
term:
id: HP:0001508
label: Failure to thrive
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He experienced failure to thrive, at 3rd percentile for height and 15th
percentile for weight at 2.5 years of age.
explanation: Failure to thrive in an EKC patient.
genetic:
- name: DSP
association: Causative
relationship_type: CAUSATIVE
variant_origin: DE_NOVO
gene_term:
preferred_term: DSP
term:
id: hgnc:3052
label: DSP
features: >-
Heterozygous missense or in-frame variants clustered in spectrin repeat 6
of the desmoplakin plakin domain (about residues 560 to 625). Most arose de
novo; two families show subsequent dominant transmission. Heterozygous
truncating DSP variants instead cause arrhythmogenic cardiomyopathy
(DSP_Cardiomyopathy), and biallelic truncations cause recessive Carvajal
syndrome (Carvajal_Syndrome).
inheritance:
- name: Autosomal Dominant
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
variants:
- name: DSP c.1790C>T (p.Ser597Leu)
description: >-
De novo missense variant in the founding three-member family with
biventricular dilated cardiomyopathy and hypo/oligodontia.
type: missense variant
variant_type: single nucleotide variant
gene:
preferred_term: DSP
term:
id: hgnc:3052
label: DSP
evidence:
- reference: PMID:20940358
reference_title: "A new hypo/oligodontia syndrome: Carvajal/Naxos syndrome secondary to desmoplakin-dominant mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mutation screening in the desmoplakin gene (DSP) revealed a de novo
missense mutation (c.1790 C>T, p.Ser597Leu) changing a serine residue
conserved in all vertebrates.
explanation: Identifies the founding variant.
- name: DSP c.1748T>C (p.Leu583Pro)
description: >-
De novo missense variant in a patient with woolly hair, striate
keratoderma, nail dystrophy and severe biventricular dilated
cardiomyopathy with ventricular fibrillation, without dental anomalies.
type: missense variant
variant_type: single nucleotide variant
gene:
preferred_term: DSP
term:
id: hgnc:3052
label: DSP
evidence:
- reference: PMID:22949226
reference_title: "De novo heterozygous desmoplakin mutations leading to Naxos-Carvajal disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In each patient we identified a single heterozygous de novo mutation in
the desmoplakin gene DSP, p.Leu583Pro and p.Thr564Ile
explanation: Identifies the de novo p.Leu583Pro variant.
- name: DSP c.1691C>T (p.Thr564Ile)
description: >-
De novo missense variant in a patient with woolly hair, mild keratoderma,
toenail leukonychia, nine missing permanent teeth and right-dominant
cardiomyopathy.
type: missense variant
variant_type: single nucleotide variant
gene:
preferred_term: DSP
term:
id: hgnc:3052
label: DSP
evidence:
- reference: PMID:22949226
reference_title: "De novo heterozygous desmoplakin mutations leading to Naxos-Carvajal disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In each patient we identified a single heterozygous de novo mutation in
the desmoplakin gene DSP, p.Leu583Pro and p.Thr564Ile
explanation: Identifies the de novo p.Thr564Ile variant.
- name: DSP c.1678A>T (p.Ile560Phe)
description: >-
Missense variant segregating with woolly hair, keratoderma, oligodontia,
cardiomyopathy and sudden death in a family with paternal transmission.
type: missense variant
variant_type: single nucleotide variant
gene:
preferred_term: DSP
term:
id: hgnc:3052
label: DSP
evidence:
- reference: PMID:28649555
reference_title: "Autosomal dominant Carvajal plus syndrome due to the novel desmoplakin mutation c.1678A > T (p.Ile560Phe)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Genetic studies revealed the novel pathogenic mutation c.1678A > T in
the desmoplakin gene resulting in the amino acid change Ile to Phe at
position 560 in the index case and her brother.
explanation: Identifies p.Ile560Phe in two affected siblings.
- name: DSP Q616P, H618P and L622P (EKC syndrome)
description: >-
Three de novo proline substitutions clustered within seven residues of
SR6, each in a child with EKC syndrome.
type: missense variant
variant_type: single nucleotide variant
gene:
preferred_term: DSP
term:
id: hgnc:3052
label: DSP
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All three of these subjects were heterozygous for tightly clustered
missense mutations in DSP: Q616P, H618P and L622P, respectively
explanation: Identifies the EKC syndrome variants.
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Sanger sequencing confirmed these mutations and showed that none were
present in the unaffected parents of the subjects; thus, these mutations
arose de novo
explanation: Parental testing establishes de novo origin.
evidence:
- reference: PMID:20940358
reference_title: "A new hypo/oligodontia syndrome: Carvajal/Naxos syndrome secondary to desmoplakin-dominant mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This familial case report and two other previous reports demonstrate that
autosomal-dominant mutations in the DSP gene are associated with
hypo/oligodontia in the setting of Carvajal/Naxos syndrome.
explanation: Establishes heterozygous DSP variants as causal.
- reference: PMID:35574671
reference_title: "A new de novo heterozygous missense mutation in the desmoplakin gene, causing Naxos and Carvajal disease, associating oligodontia and nail fragility."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A new de novo heterozygous mutation in the desmoplakin gene, causing Naxos
and Carvajal disease, has been reported in a 13-year-old Caucasian girl,
with expanded clinical phenotype.
explanation: An independent de novo heterozygous DSP case.
- reference: PMID:22350851
reference_title: "Evidence for genetic heterogeneity in Carvajal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: >-
Recently, familial cases of an autosomal dominant Carvajal syndrome were
documented with a new feature: hypo/oligodontia. A mutation in the DSP
gene was also evidenced in these latter cases.
explanation: >-
Independent summary that the dominant tooth-agenesis form is DSP-related.
diagnosis:
- name: DSP genetic testing
description: >-
Sequencing of DSP (usually within a desmosomal or cardiomyopathy gene
panel, or exome) identifies the heterozygous SR6 variant; parental testing
establishes de novo origin.
diagnosis_term:
preferred_term: Genetic testing
term:
id: NCIT:C15709
label: Genetic Testing
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Prior to our discovery of pathogenic DSP mutations, neither case 244 nor
case 380 had been diagnosed with cardiomyopathy; case 380 had never
previously received a cardiac workup.
explanation: >-
Genetic diagnosis led to detection of previously unrecognized
cardiomyopathy.
- name: Cardiac evaluation in patients with the cutaneous or dental phenotype
description: >-
Because the cardiomyopathy is initially silent, echocardiography and
rhythm monitoring are indicated when woolly hair or keratoderma occur with
tooth agenesis, or when erythrokeratodermia is found.
diagnosis_term:
preferred_term: Echocardiography
term:
id: NCIT:C16525
label: Echocardiography Test
evidence:
- reference: PMID:20940358
reference_title: "A new hypo/oligodontia syndrome: Carvajal/Naxos syndrome secondary to desmoplakin-dominant mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
dentists discovering oligo/hypodontia should screen for woolly hair and
palmoplantar keratoderma because of the probable cardiac involvement with
an inherent high risk of severe cardiomyopathy
explanation: >-
Recommends looking for the cutaneous signs, and so the cardiac risk, in
patients presenting with tooth agenesis.
treatments:
- name: Implantable Cardioverter-Defibrillator
description: >-
ICD implantation for prevention of sudden arrhythmic death; the
p.Ile560Phe report recommends it as soon as the diagnosis is made, and one
p.Leu583Pro patient received an appropriate shock for exercise-induced
ventricular fibrillation. The recommendation rests on case reports only.
therapeutic_modality: DEVICE
treatment_term:
preferred_term: implantable cardioverter-defibrillator placement
term:
id: NCIT:C80435
label: Implantable Cardioverter-Defibrillator Placement
target_mechanisms:
- target: Ventricular Electrical Instability
treatment_effect: MODULATES
description: >-
Terminates malignant ventricular arrhythmia without correcting the
underlying substrate.
target_phenotypes:
- preferred_term: Sudden cardiac death
term:
id: HP:0001645
label: Sudden cardiac death
- preferred_term: Ventricular fibrillation
term:
id: HP:0001663
label: Ventricular fibrillation
evidence:
- reference: PMID:28649555
reference_title: "Autosomal dominant Carvajal plus syndrome due to the novel desmoplakin mutation c.1678A > T (p.Ile560Phe)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
these patients require implantation of an ICD as soon as their diagnosis
is established
explanation: Case-report authors recommend early ICD implantation.
- reference: PMID:22949226
reference_title: "De novo heterozygous desmoplakin mutations leading to Naxos-Carvajal disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
when ventricular fib-rillation occurring during exercise was terminated by
ad-equate ICD shock
explanation: >-
An implanted ICD terminated exercise-induced ventricular fibrillation in
the p.Leu583Pro patient.
- name: Oral Acitretin for Erythrokeratodermia
description: >-
Systemic retinoid therapy for the skin disease of EKC syndrome, with
inconsistent results in the two treated patients.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: acitretin
term:
id: CHEBI:50172
label: acitretin
target_phenotypes:
- preferred_term: Erythrokeratodermia
term:
id: HP:0001019
label: Erythroderma
evidence:
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Oral acitretin improved scaling, though she remains erythrodermic.
explanation: Partial response of scaling in one EKC patient.
- reference: PMID:26604139
reference_title: "Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: >-
Treatment with oral acitretin at doses ranging from 0.5 to 2 mg/kg
throughout his life, a 2-month course of cyclosporine at 0.5 mg/kg, and
multiple topical steroids failed to improve erythroderma or pruritus.
explanation: No response to acitretin in a second EKC patient.
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.
Create: Dilated_Cardiomyopathy_with_Woolly_Hair_Keratoderma_and_Tooth_Agenesis · 2026-10-12T15:09:19Z · View source
New entry for the autosomal dominant DSP cardiocutaneous syndrome MONDO:0014355 (OMIM 615821). Lump/split: kept separate from Carvajal_Syndrome (recessive biallelic DSP truncation, MONDO:0011581) and DSP_Cardiomyopathy (heterozygous DSP loss-of-function arrhythmogenic cardiomyopathy, MONDO:0011831), because the literature defines this disease by heterozygous, mostly de novo, missense or in-frame variants in spectrin repeat 6 of the DSP plakin domain with tooth agenesis (PMID:20940358, PMID:22949226, PMID:28649555, PMID:35574671). MONDO lists erythrokeratodermia-cardiomyopathy (EKC) syndrome as an exact synonym (the former MONDO:0018774 is obsolete and merged here; Orphanet 476096), so EKC syndrome (PMID:26604139, de novo Q616P/H618P/L622P) is curated as a has_subtypes entry with its own subtype-stratified phenotypes. Pathograph: SR6 variant to epidermal desmosome aggregation, loss of suprabasal adhesion and reduced connexin 43 junctional localization (conforming to desmosomal_adhesion_failure nodes), a provisional myocardial desmosome node leading to progressive ventricular dilation (conforming to cardiomyopathy_maladaptive_remodeling) and ventricular electrical instability, and a provisional tooth-development node; 19 of 21 phenotypes causally connected. No frequencies recorded because no source has more than three patients. One openscientist deep-research report was used: 28/28 references resolved, 0 off topic; term validation flagged three mislabelled CURIEs (none bound here). Its body conflates this dominant disease with recessive Carvajal syndrome and DSP-ERADOS dominant LoF cardiomyopathy (states inheritance is predominantly autosomal recessive), so its inheritance, Wnt-mechanism and cohort claims were not used; it contributed only cross-confirmation of PMID:20940358 and the pointer to PMID:26833927 (no abstract, not quoted). just preflight-dr could not run because the local MONDO build is absent and was not downloaded; the named-entity check was done by reading the report. Validation: validate, validate-terms, count-verified-snippets (67/67), entity-refs, causal-targets, duplicate-keys, qualifier-terms, genereviews (no chapter), coarse-phenotypes, snippet-length passed; validate-disorders passed (schema, terms, 67 snippets).
Disease: Dilated Cardiomyopathy with Woolly Hair, Keratoderma, and Tooth Agenesis MONDO ID: MONDO:0014355 | OMIM: #615821 | Category: Mendelian (desmosomal cardiocutaneous syndrome) Causal gene: DSP (desmoplakin), HGNC:3052, chromosome 6p24.3
Dilated Cardiomyopathy with Woolly Hair, Keratoderma, and Tooth Agenesis is a rare Mendelian cardiocutaneous syndrome caused by pathogenic variants in DSP, the gene encoding desmoplakin, the principal obligate plaque protein of the desmosome. It sits on the Carvajal/Naxos desmosomal-disease spectrum and is distinguished from "classic" arrhythmogenic right ventricular cardiomyopathy (ARVC) by its characteristic ectodermal triad — congenital woolly hair, palmoplantar keratoderma (PPK), and, in the variant that defines this entry, hypodontia/oligodontia (tooth agenesis) — combined with a left-dominant or biventricular dilated cardiomyopathy that manifests in childhood and carries a high burden of ventricular arrhythmia and sudden cardiac death.
The unifying molecular mechanism is a failure of intermediate-filament anchoring at the desmosome. Desmoplakin normally links the desmosomal cadherin–plakoglobin–plakophilin plaque to keratin filaments (in epithelia) and desmin filaments (in cardiomyocytes). When DSP is truncated or its C-terminal filament-binding tail is lost, two consequences follow: (1) mechanical junctions fail in tissues subject to shear stress — skin, hair, and heart; and (2) the armadillo protein plakoglobin relocates to the nucleus, where it suppresses canonical Wnt/β-catenin signaling roughly two-fold through Tcf/Lef1. In the heart, this reprograms second-heart-field cardiac progenitors toward adipogenic/fibrogenic fates, producing the fibrofatty myocardial replacement, chamber dilation, electrical instability, and progressive heart failure that dominate prognosis. The dental and ectodermal branch is best explained by the same Wnt deficit: independent human genetics shows that mutations in the canonical Wnt ligand WNT10A reproduce the identical triad of tooth agenesis, palmoplantar keratoderma, and hair defects, supporting a shared Wnt/β-catenin basis for the appendageal phenotype (though direct demonstration in DSP-mutant dental epithelium is still lacking).
Inheritance is predominantly autosomal recessive (biallelic C-terminal DSP truncations, the configuration first described in three Ecuadorian families in 2000), but heterozygous (dominant) DSP variants cause an allelic, later-onset, left-dominant "DSP cardiomyopathy" with milder or absent cutaneous findings. Cardiac penetrance in the recessive syndrome approaches 100% by adolescence. Management is entirely organ-directed and supportive — heart-failure pharmacotherapy, antiarrhythmics, implantable cardioverter-defibrillators (ICDs) for sudden-death prevention, exercise restriction, and cardiac transplantation — with no disease-specific cure; EGFR inhibition is an emerging experimental concept for the cutaneous phenotype. This report synthesizes nine confirmed findings drawn from 45 reviewed papers into a complete characterization across all requested domains.
The defining genetic cause of this syndrome is mutation in DSP (desmoplakin). Chalabreysse et al. identified a de novo DSP missense mutation c.1790C>T, p.Ser597Leu — altering a serine conserved in all vertebrates and absent from 100 controls — in a family presenting woolly hair, palmoplantar keratoderma, biventricular dilated cardiomyopathy, and hypo/oligodontia (absent second premolars, second/third molars; 1–15 missing teeth), with no mutation in plakoglobin (JUP) [PMID: 20940358]. This is the finding that specifically ties tooth agenesis into the DSP cardiocutaneous phenotype, framing it as a "Carvajal/Naxos variant with hypo/oligodontia."
"Mutation screening in the desmoplakin gene (DSP) revealed a de novo missense mutation (c.1790 C>T, p.Ser597Leu) changing a serine residue conserved in all vertebrates" [PMID: 20940358]
"this study reveals the role of desmosomes in the development of teeth and suggests that other genes encoding proteins of the desmosome could be involved in oligo/hypodontia" [PMID: 20940358]
Multiple independent reports confirm DSP causation of the syndrome, including a Lebanese Carvajal patient with tooth agenesis [PMID: 26833927], a biventricular DCM case with homozygous c.4297C>T (p.Gln1433*) [PMID: 38433550], and a pediatric Carvajal case [PMID: 21193976].
The central disease mechanism was established by Garcia-Gras et al.: siRNA suppression of desmoplakin in atrial myocytes caused nuclear localization of plakoglobin and a ~2-fold reduction in canonical Wnt/β-catenin signaling through Tcf/Lef1, driving adipogenic and fibrogenic gene expression and accumulation of fat droplets [PMID: 16823493]. Cardiac-restricted Dsp deletion was embryonic-lethal when homozygous and, in heterozygotes, caused fibrofatty replacement, apoptosis, cardiac dysfunction, and arrhythmias.
"suppression of DP expression leads to nuclear localization of the desmosomal protein plakoglobin and a 2-fold reduction in canonical Wnt/beta-catenin signaling through Tcf/Lef1 transcription factors. The ensuing phenotype is increased expression of adipogenic and fibrogenic genes and accumulation of fat droplets" [PMID: 16823493]
Lineage tracing showed the excess adipocytes in DSP-deficient hearts derive from Nkx2.5+/Mef2C+ second-heart-field progenitors, explaining the regionality of the remodeling [PMID: 19359597].
"the majority of adipocytes in the hearts of Nkx2.5- and Mef2C-regulated lineage tracer mice, expressed enhanced yellow fluorescent protein" [PMID: 19359597]
Endurance exercise accelerates this remodeling: Tg-DSP(R2834H) mice developed RV dilation, fat infiltration, and cytoplasmic aggregates of desmoplakin/plakoglobin/connexin-43 with perturbed GSK3-β/AKT Wnt signaling [PMID: 26545710] — the experimental basis for clinical exercise restriction.
The cardiomyopathy dominates prognosis and is strikingly severe in childhood. In a cohort of 10 Saudi pediatric patients (Binfadel et al.), all had woolly hair, all had severely dilated/depressed LV systolic function, 9/10 had depressed RV function, and 9/10 had frequent PVCs/VT; 3 received an ICD, 4 underwent heart transplantation, and 3 died suddenly while awaiting transplant [PMID: 40108711].
"four patients underwent heart transplantation, and three died suddenly while waiting for a heart donation" [PMID: 40108711]
A representative single case: a 7-year-old girl with EF 22%, biventricular dilation, and moderate–severe mitral/tricuspid regurgitation, homozygous for DSP c.4297C>T (p.Gln1433) [PMID: 38433550]. Protonotarios and Tsatsopoulou defined the Carvajal variant as showing predominantly left-ventricular involvement*, early morbidity, and clinical overlap with dilated cardiomyopathy [PMID: 15210133].
"truncates the intermediate filament-binding site of desmoplakin results in a variant of Naxos disease with predominantly left ventricular involvement, early morbidity and clinical overlapping with dilated cardiomyopathy (Carvajal syndrome)" [PMID: 15210133]
The temporal sequence is consistent: woolly hair is present from birth, palmoplantar keratoderma develops during the first year of life, and cardiomyopathy manifests by adolescence with 100% penetrance [PMID: 16722579]. The Carvajal variant manifests during childhood and more frequently leads to heart failure than the right-dominant Naxos (plakoglobin) form.
"Woolly hair appears from birth, palmoplantar keratoderma develop during the first year of life and cardiomyopathy is clinically manifested by adolescence with 100% penetrance" [PMID: 16722579]
In the large DSP-ERADOS Network cohort (800 P/LP DSP variant carriers), over 3.7 years the rate of sustained ventricular arrhythmia was 17.4% (3.9%/yr) and HF hospitalization 9.0% (1.8%/yr); notably 32.5% did not meet existing ARVC diagnostic criteria, confirming DSP cardiomyopathy as a distinct arrhythmogenic entity featuring acute myocarditis-like "hot phases" [PMID: 39288222].
"the relevance of acute myocarditis-like episodes for subsequent disease course is largely unknown" [PMID: 39288222]
Naxos disease (the related JUP syndrome) has a founder-driven prevalence of ~1:1000 on Naxos island; the DSP Carvajal variant is rarer and reported worldwide, often in consanguineous families.
Management is organ-directed and supportive. A Carvajal patient was managed with diuretics, enalapril, carvedilol, and amiodarone and remained stable on follow-up [PMID: 21193976]. ICDs are implanted for uncontrolled VT and for sudden-death prevention, and transplantation is used for end-stage disease [PMID: 40108711]. The 2019 HRS expert consensus on arrhythmogenic cardiomyopathy provides class-of-recommendation guidance on risk stratification, ICD use, and exercise [PMID: 31078652]. Early ICD implantation can be lifesaving — one recipient was alive at age 59 [PMID: 25824144].
"Early diagnosis and ICD implantation may be lifes[aving]" [PMID: 25824144]
For the cutaneous phenotype, EGFR inhibition restored DSP membrane expression and reduced keratinocyte fragility in DSP-mutant cells — a candidate mechanism-based dermatologic therapy [PMID: 38509711].
"EGFR inhibition in patient's keratinocytes strongly increased DSP expression at the plasma membrane, improved intermediate filament connection with the membrane edges and reduced the cell-cell fragility" [PMID: 38509711]
DSP produces a graded allelic spectrum best captured by the umbrella term "desmoplakinopathies" [PMID: 20738328]. The phenotype depends on gene dose and which protein domain is affected:
"The complexity of the desmoplakin and its variable presentations warrant introducing the term 'desmoplakinopathies' to describe all the phenotypes related to defects in the desmoplakin" [PMID: 20738328]
DSP cardiomyopathy frequently mimics acute myocarditis. A young patient with chest pain and labs/imaging suspicious for acute myocarditis was ultimately found to have desmoplakin cardiomyopathy on genetic testing [PMID: 38652395].
"Desmoplakin cardiomyopathy may be considered in patients with recurrent acute myocarditis or a family history of cardiac disease to avoid the potential for misdiagnosis" [PMID: 38652395]
The NAXCARE global registry has been established to systematically document clinical outcomes, genetic profiles, and care pathways for Naxos disease and related cardiocutaneous syndromes [PMID: 40316016]. Recent case reports continue to reinforce that dermatologic signs serve as early warning of severe cardiac disease [PMID: 42803515].
The disease was first defined genetically by Norgett et al., who described the first recessive human DSP mutation, 7901delG, homozygous in three Ecuadorian families, causing generalized striate keratoderma, woolly hair, and dilated left-ventricular cardiomyopathy; the frameshift creates a premature stop that removes the C-domain of the desmoplakin tail, and patients suffered heart failure in their teenage years [PMID: 11063735].
"we describe the first recessive human mutation, 7901delG, in the desmoplakin gene which causes a generalized striate keratoderma particularly affecting the palmoplantar epidermis, woolly hair and a dilated left ventricular cardiomyopathy" [PMID: 11063735]
The DSP gene spans ~45 kb on chromosome 6 and comprises 24 exons [PMID: 10594734]. Two major splice variants exist: DSPI and DSPII. Recessive loss of DSPI (with normal DSPII) causes epidermolytic PPK + woolly hair + severe arrhythmogenic DCM, whereas total DSP haploinsufficiency causes dominant striate PPK; DSPII is key for intermediate-filament stability and desmosome adhesion under stress [PMID: 22454510].
"complete absence of DSPI and the minor isoform DSPIa but normal levels of DSPII, and is associated with autosomal recessive epidermolytic PPK, woolly hair and severe arrhythmogenic dilated cardiomyopathy" [PMID: 22454510]
The dental and ectodermal components of the syndrome are mechanistically linked to Wnt/β-catenin by independent genetic convergence. Mutations in WNT10A, a canonical Wnt ligand, produce the same triad — tooth agenesis (hypodontia/oligodontia), palmoplantar keratoderma, and alopecia/hair defects — all attributed to Wnt/β-catenin disruption [PMID: 42089627].
"ranging from isolated tooth agenesis to complex multisystem disorders, including hypodontia, enamel and root defects, palmoplantar keratoderma, alopecia, nail dystrophy" [PMID: 42089627]
"linking phenotypes of WNT10A mutations to disruptions in Wnt/β-catenin signaling" [PMID: 42089627]
A signaling-threshold framework places Wnt/β-catenin at the center of odontogenesis alongside BMP/FGF/SHH [PMID: 42196506]. Because DSP loss suppresses canonical Wnt/β-catenin ~2-fold via nuclear plakoglobin [PMID: 16823493], the dental/ectodermal branch of the DSP syndrome plausibly shares the Wnt-deficit mechanism — though direct demonstration in DSP-mutant dental epithelium remains lacking (inferred by convergence).
"We focus on the coordinated roles of Wnt/β-catenin, bone morphogenetic protein (BMP), fibroblast growth factor (FGF), and Sonic hedgehog (SHH) pathways" [PMID: 42196506]
| Phenotype | Type | HPO term | Onset | Frequency | Progression |
|---|---|---|---|---|---|
| Woolly hair | Physical/hair | HP:0002224 (woolly hair) | Congenital (birth) | ~100% | Stable |
| Palmoplantar keratoderma | Skin sign | HP:0000982 | First year of life | ~100% | Progressive/stable |
| Dilated/arrhythmogenic cardiomyopathy | Clinical sign | HP:0001644 (DCM); HP:0004756 (ventricular arrhythmia) | Childhood–adolescence | ~100% penetrance by adolescence | Progressive |
| Hypodontia/oligodontia (tooth agenesis) | Physical | HP:0000668 (hypodontia); HP:0006349 (oligodontia) | Congenital (eruption age) | Variable (defines this subtype) | Stable |
| Heart failure | Clinical sign | HP:0001635 | Childhood | High | Progressive |
| Ventricular tachycardia / sudden death | Clinical sign | HP:0004756 / HP:0001645 | Childhood–young adult | High | Episodic/fatal |
| Skin fragility / hyperkeratosis | Skin sign | HP:0000962 (hyperkeratosis) | Infancy | Variable | Stable |
Ordered causal chain:
Branch B (ectoderm/teeth): same adhesion defect + shared Wnt deficit in ectodermal appendages → woolly hair, palmoplantar keratoderma, and hypo/oligodontia (tooth agenesis), paralleling WNT10A-related oligodontia. (inferred by convergence) [PMID: 42089627, 42196506]
Molecular pathways: Canonical Wnt/β-catenin (central); GSK3-β/AKT (perturbed with exercise) [PMID: 26545710].
| Model | Type | Phenotype recapitulation | PMID |
|---|---|---|---|
| Dsp^rul (ruffled) mouse | Spontaneous recessive frameshift (C-terminal truncation) | Woolly coat, epidermal blistering, abnormal ECG, ventricular fibrosis — strong Carvajal model | [25659760] |
| Dsp knock-in mouse | Engineered knock-in | Gene dose-dependent myocardial remodeling, arrhythmias, premature death | [41411472] |
| Tg-DSP(R2834H) mouse | Transgenic (mutant overexpression) | Exercise-accelerated RV dilation, fat infiltration, desmoplakin/plakoglobin/Cx43 aggregates, perturbed Wnt | [26545710] |
| Cardiac-restricted Dsp deletion | Conditional knockout | Embryonic lethal (homozygous); fibrofatty replacement, apoptosis, arrhythmias (heterozygous) | [16823493] |
| Patient-derived keratinocytes (in vitro) | Cellular | Cell–cell fragility; corrected by EGFR inhibition | [38509711] |
DSP mutation (biallelic truncation / dominant LOF)
|
v
Loss of desmoplakin C-terminal tail -> cannot bind keratin / desmin
|
+--------------------+--------------------+
| |
Mechanical junction failure Plakoglobin released
(shear-stressed tissues) |
| v
| Nuclear plakoglobin -> Tcf/Lef1
| ~2x suppression of canonical
| Wnt/beta-catenin signaling
| |
SKIN / HAIR / TEETH HEART: 2nd-heart-field progenitors
- woolly hair (congenital) redirected to adipogenic/fibrogenic fate
- palmoplantar keratoderma |
- tooth agenesis <----- shared v
(WNT10A-convergent, inferred) fibrofatty myocardial replacement
|
v
biventricular / left-dominant DCM,
VT / sudden death, heart failure,
myocarditis-like "hot phases"
The model's great strength is that a single lesion — failure of intermediate-filament anchoring at the desmosome — produces both a mechanical failure (skin/hair/heart fragility) and a signaling failure (nuclear plakoglobin → Wnt suppression). The heart branch is experimentally demonstrated end-to-end [PMID: 16823493, 19359597]. The ectodermal/dental branch is anchored mechanically (keratin-binding loss [PMID: 29878302]) and linked to Wnt by convergence with WNT10A oligodontia [PMID: 42089627], which remains the key inferred (not yet directly demonstrated) step.
| PMID | Role | Contribution |
|---|---|---|
| 20940358 | Supports F1 | De novo DSP p.Ser597Leu causing triad with tooth agenesis; links desmosomes to odontogenesis |
| 16823493 | Supports F2 | Core mechanism: nuclear plakoglobin → ~2× Wnt suppression → fibrofatty fate |
| 19359597 | Supports F2 | Adipocytes derive from second-heart-field progenitors |
| 26545710 | Supports F2/F5 | Exercise accelerates remodeling; basis for exercise restriction |
| 40108711 | Supports F3/F5 | Pediatric cohort: transplant and sudden death outcomes |
| 15210133 | Supports F3 | Defines left-dominant Carvajal DCM phenotype |
| 38433550 | Supports F1/F3 | Biventricular DCM, EF 22%, homozygous p.Gln1433* |
| 16722579 | Supports F4 | Onset sequence and 100% cardiac penetrance by adolescence |
| 39288222 | Supports F4 | 800-carrier cohort; distinct arrhythmogenic entity; hot phases |
| 25824144 | Supports F5 | Early ICD lifesaving |
| 31078652 | Supports F5 | HRS guideline for ACM management |
| 38509711 | Supports F5 | EGFR inhibition corrects keratinocyte phenotype |
| 20738328 | Supports F6 | "Desmoplakinopathies" spectrum; skin-only alleles |
| 11841538 | Supports F6 | Compound-het haploinsufficiency; skin histology |
| 29878302 | Supports F6 | Keratin + desmin binding loss (dual-tissue lesion) |
| 41411472 | Supports F6 | Gene dose-dependent knock-in mouse |
| 38652395 | Supports F7 | Myocarditis mimicry / misdiagnosis risk |
| 40316016 | Supports F7 | NAXCARE registry |
| 11063735 | Supports F8 | Foundational recessive 7901delG, Ecuador |
| 22454510 | Supports F8 | DSPI vs DSPII isoform specificity |
| 10594734 | Supports F8 | DSP gene structure (24 exons, ~45 kb) |
| 42089627 | Supports F9 | WNT10A reproduces same triad via Wnt disruption |
| 42196506 | Supports F9 | Wnt/β-catenin central to tooth agenesis |
| 25659760 | Supports §14/15 | Dsp^rul spontaneous mouse model |
| 21668431 | Differential | JUP (plakoglobin) cause of related CAPK syndrome |
Evidence source types: predominantly human clinical (case reports, cohorts, registries) and model-organism (mouse) data, with in-vitro cellular mechanistic studies; the dental/Wnt link is supported by cross-disease human genetic convergence (computational/comparative inference).
Checked with linkml-reference-validator 0.3.0.
| Outcome | Count |
|---|---|
| References checked | 28 |
| Resolved | 28 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 28 |
| On topic | 23 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 26 |
| Resolved | 25 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 1 |
| Terms whose name was checked | 13 |
| Terms named correctly | 7 |
| Terms named as a different term | 3 |
| Terms whose name is worth a second look | 3 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
HP:0000982 (1 mention) - the report calls it "Skin sign"; HP calls it Palmoplantar keratodermaHP:0001635 (1 mention) - the report calls it "Clinical sign"; HP calls it Congestive heart failureGO:0060215 (1 mention) - the report calls it "fat cell differentiation"; GO calls it primitive hemopoiesisThe report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
GO:0016055 (1 mention) - the report calls it "Wnt signaling"; GO calls it Wnt signaling pathwayCL:0000746 (2 mentions) - the report calls it "cardiac muscle cell", "Tissues/cells: Cardiac muscle"; CL calls it cardiac muscle cell**GO:0030057 (1 mention) - the report calls it "Subcellular: Desmosome"; GO calls it desmosome**, and lists "spot desmosome" among its other namesThe report gives these identifiers more than one name of its own:
CL:0000746 - called "cardiac muscle cell", "Tissues/cells:** Cardiac muscle"