Dermatology

The Biology of EKC: Glue, Gaps, and Look-Alikes

At a Glance

EKC syndrome is linked to DSP gene changes that weaken the cell connections supporting skin and heart tissue. This can cause red, thickened skin and heart muscle changes, while genetic testing, skin biopsy, and cardiac imaging help distinguish EKC from similar disorders.

Understanding the biology of Erythrokeratodermia-cardiomyopathy (EKC) syndrome helps explain why two seemingly unrelated parts of the body—the skin and the heart—are affected at the same time. At its core, EKC is related to a weakness in the microscopic structures that hold your cells together ^[1]^[2].

The Genetic “Blueprints” and the Cellular Glue

Your body relies on the DSP gene to provide instructions for making a protein called desmoplakin ^[3]. Desmoplakin is a critical component of desmosomes, which act like heavy-duty “glue” or rivets between cells ^[1].

These rivets don’t just hold cells together; they anchor the cells to an internal structural scaffold (the intermediate-filament scaffold) that gives tissues their strength ^[3]^[4]. In EKC, a pathogenic variant in the DSP gene means the desmoplakin protein is either diminished or misshapen. Without strong “glue,” the cells in your skin and heart can’t handle the normal mechanical stress of daily life ^[2]^[5].

When the Glue Weakens: Acantholysis

In the skin, this can lead to a process called acantholysis ^[6]. Because the cell-to-cell bridges are weak, the skin cells (keratinocytes) begin to pull apart from one another. Under a microscope, a doctor might see widened gaps between cells and “spiky” cell borders as the cells struggle to stay connected ^[7]^[6].

The body reacts to this instability by overproducing skin cells, leading to the hyperkeratosis (thickening) and erythema (redness) that define the “erythrokeratodermia” part of the diagnosis ^[8]^[6].

In the heart, every time the heart beats, it creates mechanical tension. In EKC, this tension causes the heart muscle cells to separate slightly over time ^[2]. The body responds by creating scar tissue (fibrosis) and variable fat deposits to fill the gaps, which eventually disrupts the heart’s electrical signals and its ability to pump blood ^[4]^[9].

Distinguishing EKC from “Look-Alikes”

Because many rare diseases involve both the skin and the heart, doctors must perform a differential diagnosis—a process of ruling out other conditions. A genetic and clinical evaluation is needed to confirm which condition is present.

Condition	Primary Gene	Key Differences from EKC
Carvajal Syndrome	DSP	Often recessive; features “woolly” hair and thickened skin mostly on palms/soles, whereas EKC skin is widespread ^[10]^[11].
Naxos Disease	JUP	Associated with a different “glue” protein (plakoglobin) ^[12]^[13].
Chanarin-Dorfman	ABHD5	A lipid metabolism disorder, not a “glue” issue; can be investigated by seeing fat droplets (Jordan’s anomaly) in white blood cells if suspected ^[14]^[15].
PERP-related Disease	PERP	Can cause similar skin thickening but typically involves severe dental issues ^[16].
Isolated ARVC	Various	Primarily affects the heart; usually lacks the accompanying skin, hair, or nail involvement ^[17].

How the Diagnosis is Evaluated

To move past the “look-alikes” and support an EKC diagnosis, doctors look for specific markers:

Genetic Testing: EKC is associated with pathogenic variants in the DSP gene. While some cases involve missense mutations in a specific part (the SR6 region) that are de novo (new in the patient), DSP disease includes different pathogenic variant classes and inheritance patterns (both heterozygous and biallelic) ^[18]^[6]. A variant’s location and classification must be interpreted in context.
Skin Biopsy: Seeing the specific “spiky” pattern of desmosomal-type acantholysis is a supportive test that can help dermatologists, though it is optional when molecular testing is available ^[7].
Cardiac Evaluation: While standard tests focus on how well the heart pumps, a cardiac MRI can complement this by finding early scar tissue (late gadolinium enhancement) that is a feature of DSP-related heart disease ^[19]^[17].

Common questions in this guide

What gene change is associated with EKC syndrome?

EKC syndrome is associated with a pathogenic variant in the DSP gene, which provides instructions for desmoplakin, a protein that helps cells stick together. The variant may be inherited or, in some cases, arise de novo, meaning it is new in the affected person.

Why can EKC affect both the skin and the heart?

Desmoplakin helps reinforce cell connections in tissues that experience repeated mechanical stress. When these connections are weak, skin cells can pull apart and become red and thickened, while heart muscle may develop scarring or fat deposits that affect electrical signals and pumping.

What does acantholysis mean in an EKC skin biopsy?

Acantholysis means skin cells have separated from one another because their connecting structures are weak. A biopsy showing the characteristic cell-connection pattern, including gaps and spiky cell borders, can support EKC, although molecular testing may make a biopsy unnecessary.

How do doctors tell EKC apart from similar skin-and-heart disorders?

Doctors combine clinical findings with genetic testing and, when needed, skin biopsy and heart imaging. The gene involved, inheritance pattern, distribution of skin changes, hair or dental findings, and whether the condition mainly affects the heart help distinguish EKC from Carvajal syndrome, Naxos disease, Chanarin-Dorfman syndrome, PERP-related disease, and isolated ARVC.

Can cardiac MRI help evaluate DSP-related heart disease?

Yes. Cardiac MRI can show early scar tissue through a finding called late gadolinium enhancement, complementing tests that measure how well the heart pumps. Your cardiology team can decide whether this imaging is appropriate.

Should relatives be tested for a DSP variant?

If a pathogenic DSP variant is found, a genetics professional can review whether it may be inherited and whether relatives should have targeted testing or heart evaluation. Family screening decisions depend on the variant’s classification, inheritance pattern, and each person’s clinical findings.

Get notified when new evidence is published on Erythrokeratodermia-cardiomyopathy syndrome.

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Key takeaways

Pathogenic DSP variants can weaken desmosomes, the cell connections that help skin and heart tissue withstand mechanical stress.
In the skin, weakened connections can cause acantholysis, redness, and thickening; in the heart, they can contribute to fibrosis, fat deposits, electrical disturbances, and impaired pumping.
Genetic and clinical evaluation helps distinguish EKC from Carvajal syndrome, Naxos disease, Chanarin-Dorfman syndrome, PERP-related disease, and isolated ARVC.
DSP genetic testing, skin biopsy findings, and cardiac MRI may support diagnosis, with cardiac MRI helping identify scar tissue associated with DSP-related heart disease.
Whether a DSP variant is inherited or de novo, and what its classification means, should be interpreted by a genetics professional in the context of the clinical findings.

References (19)

1
Functional investigation of two simultaneous or separately segregating DSP variants within a single family supports the theory of a dose-dependent disease severity.
Vermeer MCSC, Andrei D, Kramer D, et al.
Experimental dermatology 2022; (31(6)):970-979 doi:10.1111/exd.14571.
PMID: 35325485
2
Desmoplakin Haploinsufficiency Underlies Cell-Cell Adhesion Failure in DSP Cardiomyopathy and is Rescued by Transcriptional Activation.
Smith ED, Jin K, Ferguson B, et al.
bioRxiv : the preprint server for biology 2025; doi:10.1101/2025.06.01.657304.
PMID: 40502028
3
Cellular biomechanics impairment in keratinocytes is associated with a C-terminal truncated desmoplakin: An atomic force microscopy investigation.
Puzzi L, Borin D, Martinelli V, et al.
Micron (Oxford, England : 1993) 2018; (106()):27-33 doi:10.1016/j.micron.2017.12.005.
PMID: 29291530
4
Desmoplakin Cardiomyopathy: Gene Dose-Dependent Myocardial Remodeling, Arrhythmias, and Premature Death.
Guazzo A, Perumal Vanaja I, Di Bona A, et al.
JACC. Clinical electrophysiology 2026; (12(4)):747-764 doi:10.1016/j.jacep.2025.10.031.
PMID: 41411472
5
PANoptosis is a prominent feature of desmoplakin cardiomyopathy.
Olcum M, Rouhi L, Fan S, et al.
The journal of cardiovascular aging 2023; (3(1)) doi:10.20517/jca.2022.34.
PMID: 36818425
6
Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome.
Boyden LM, Kam CY, Hernández-Martín A, et al.
Human molecular genetics 2016; (25(2)):348-57 doi:10.1093/hmg/ddv481.
PMID: 26604139
7
Partial Spiky Acantholysis due to Loss of Desmosomal Attachments in Erythrokeratodermia Cardiomyopathy Syndrome.
Ko CJ, MacGibeny M, Choate K
Journal of cutaneous pathology 2026; (53(2)):186-189 doi:10.1111/cup.70016.
PMID: 41255294
8
Cardiac features in a patient with erythrokeratodermia cardiomyopathy syndrome.
Ichikawa Y, Shibuya Y, Tanaka M, et al.
Cardiology in the young 2022; (32(6)):993-995 doi:10.1017/S1047951121004108.
PMID: 34629121
9
Desmoplakin Mutations in Cardiac Fibroblasts Cause TGFβ1-Mediated Pathological Fibrogenesis in Desmoplakin Cardiomyopathy Via Beclin-1 Regulation.
Wei C, Shou W, Chan SF, et al.
Circulation research 2026; (139(7)):e325512 doi:10.1161/CIRCRESAHA.124.325512.
PMID: 42615127
10
Noncompaction and dilated cardiomyopathy in carvajal syndrome.
Tosun D, Akçay N, Bingöl İ, Akbulut DG
Cardiology in the young 2025; (35(5)):1073-1075 doi:10.1017/S1047951125001532.
PMID: 40260958
11
Hair and skin predict cardiomyopathies: Carvajal and erythrokeratodermia cardiomyopathy syndromes.
Sun Q, Wine Lee L, Hall EK, et al.
Pediatric dermatology 2021; (38(1)):31-38 doi:10.1111/pde.14478.
PMID: 33275305
12
Naxos Disease and Related Cardio-Cutaneous Syndromes.
Protonotarios A, Asimaki A, Basso C, et al.
JACC. Advances 2025; (4(2)):101547 doi:10.1016/j.jacadv.2024.101547.
PMID: 39877668
13
Cardiocutaneous syndrome (Naxos disease) in a Bangladeshi boy.
Islam AM, Rahman MT, Chowdhury AH
Cardiovascular diagnosis and therapy 2016; (6(5)):462-465 doi:10.21037/cdt.2016.03.07.
PMID: 27747171
14
Maternal Isodisomy of Chromosome 3 Combined with a De Novo Mutation in the ABHD5 Gene Causes Autosomal Recessive Chanarin-Dorfman Syndrome.
Kopp J, Has C, Hotz A, et al.
Genes 2021; (12(8)) doi:10.3390/genes12081164.
PMID: 34440338
15
Four cases of Chanarin-Dorfman syndrome presenting with different types of erythrokeratoderma.
Çetinarslan T, Yazıcı H, Erdoğan KM, et al.
Pediatric dermatology 2024; (41(6)):1174-1178 doi:10.1111/pde.15654.
PMID: 38886172
16
Mutations in PERP Cause Dominant and Recessive Keratoderma.
Duchatelet S, Boyden LM, Ishida-Yamamoto A, et al.
The Journal of investigative dermatology 2019; (139(2)):380-390 doi:10.1016/j.jid.2018.08.026.
PMID: 30321533
17
Clinical characteristics and risk stratification of desmoplakin cardiomyopathy.
Wang W, Murray B, Tichnell C, et al.
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 2022; (24(2)):268-277 doi:10.1093/europace/euab183.
PMID: 34352074
18
Erythrokeratodermia-Cardiomyopathy Syndrome: Expanding the DSP Mutational Spectrum Beyond Proline Substitutions.
Hamzehlou S, Mortlock RD, Echeandia-Francis C, et al.
Pediatric dermatology 2026; (43(2)):444-447 doi:10.1111/pde.70048.
PMID: 41088746
19
Diagnostic Criteria and Disease Staging for Desmoplakin Cardiomyopathy.
Smith E, Gasperetti A, Carrick RT, et al.
medRxiv : the preprint server for health sciences 2025; doi:10.1101/2025.06.16.25329734.
PMID: 40666337

This page is for informational purposes only and does not constitute medical advice. Your dermatologist, cardiologist, and genetics team should interpret your results and recommend care.