Naxos Disease and Related Cardio-Cutaneous Syndromes

Abstract

Naxos disease is a rare autosomal recessive condition combining arrhythmogenic right ventricular cardiomyopathy, woolly hair, and palmoplantar keratoderma. The first identified causative variant was in the gene encoding the desmosomal protein plakoglobin. Naxos disease exhibits fibro-fatty myocardial replacement with immunohistological abnormalities in cardiac protein and signaling pathways, highlighting the role of inflammation and potential anti-inflammatory treatments. Childhood cutaneous signs precede cardiac features, which are diagnosed by familial and genetic evaluation, electrocardiography and cardiac imaging. Disease progression necessitates holistic care with risk management and lifestyle adjustments, often needing treatment for arrhythmia and heart failure. Similar phenotypes have been linked to desmoplakin and rarely desmocollin2 gene variants, highlighting the importance of familial and genetic evaluation. This document summarizes current knowledge on Naxos disease and related cardiocutaneous syndromes and initiates an international endeavor to collect and study all global cases, aiming to improve understanding, treatment, and patient care through shared data and research.

Keywords: Naxos disease; arrhythmogenic cardiomyopathies; arrhythmogenic right ventricular cardiomyopathy; cardio-cutaneous syndrome; desmoplakin; plakoglobin.

Graphical abstract

Figure 1

Summary Features in Naxos Disease Patients (JUP2157del2) (A) Characteristic cutaneous features in a patient with Naxos disease: 1. Woolly hair, 2. Palmar and 3. Plantar keratoderma. (B) Pedigree of a family with Naxos disease (JUP 2157), showing the autosomal recessive mode of patient distribution. Solid shapes: Homozygous carriers with 100% penetrance of disease. Half-marked shapes: Heterozygous carriers without clinically detectable heart and skin phenotype. (C) 12-lead ECG from an adult patient with Naxos disease (JUP 2157): QRS prolongation, epsilon waves in V1-V3, T-wave inversion in V1-V4 and low voltage. (D) Structural myocardial changes, detected in patients with Naxos disease (JUP 2157). 1: Myocardial histology (Masson’s trichrome stain) revealing degenerating myocardial fibres (red) surrounded by fibrous (blue) and fatty (white) tissue; 2: Postmortem sample of a whole heart, anterior view, revealing a dilated RV (inflow, apex and outflow) (2 arrows) and a small part of the dilated LV (one arrow). 3: Kinetic abnormalities appearing as “accordion sign” (arrows) on the RV-free wall as shown on CMR. CMR = cardiac magnetic resonance; ECG = electrocardiography; LV = left ventricular; JUP = junctional plakoglobin; RV = right ventricular.

Figure 2

Map of Global Distribution of Naxos Disease and Related Cardio-Cutaneous Cases, as Reported up to 2024 Global distribution of Naxos disease and related cardio-cutaneous cases. Each circle represents the presence of reported cases within a country, color-coded by the gene involved. Circle size is proportional to the number of cases reported, with larger circles indicating a higher number of cases. Jitter is added to minimize overlap. This map provides a visual summary of the global epidemiology of Naxos-like syndrome, highlighting the geographical distribution and prevalence of genetic variants associated with the condition.

Figure 3

Functional and Structural Myocardial Changes in Patients with Naxos Disease (JUP2157del2) (A) Diastole and (B) systole. On CMR: 1, and 2D-ECHO: 2 and 3. Arrows pointing on RV dyskinetic areas. RV free wall dyssynchronous contraction (accordion sign): 1B, RV posterior wall dyskinesia with systolic bulging (retraction sign): 2B, and apical RV aneurysm: 3A and 3B (akinesia/dyskinesia with diastolic bulging) C1: An electron micrograph shows a decreased gap junction profile length in the LV myocardium (Bar 0.5 μm). C2: Postmortem histology (haematoxylin and eosin stain; cell nuceli: blue, cytoplasm: pink, extracellular fibrosis: light pink,) from LV myocardium, showing myocyte loss with predominantly fibrous replacement of myocardial tissue. C3: Gross examination on postmortem (the patient died of heart failure waiting for heart transplantation), showing on the parasternal long-axis view of the heart, paper-thin RV walls, transmural myocardial loss (one arrow), subepicardial left ventricular fatty infiltration (two arrows), and calcified fibrous plaque at the level of the RV outflow tract (three arrows). ECHO = echocardiography; other abbreviations as in Figure 1.

Figure 4

Naxos Disease, Early Phenotype in JUP 2157del2 Homozygous Children Cutaneous features can be detected since early childhood: Woolly hair at 14 months (1A) and 7 Years (1B). PPK mild at 14 months (2A, 3A∗∗) is potentially associated with eczematous lesions on the external foot and leg surfaces that usually resolve with age (3A∗). PPK shows a striate appearance at the age of 7 years 2B, 3B. Cardiac phenotype usually presents with an arrhythmic profile. 1C: Ventricular ectopics (14,000/day) detected on an asymptomatic child screened because of woolly hair and PPK at the age of 4 years, while she presented a normal for her age 12-lead ECG and normal 2D-ECHO. 2C: Abnormal distribution of connexin43 and plakoglobin on the right and left ventricular myocardium, detected on postmortem, after a non-cardiac death, while 2D-ECHO, gross pathology and regular histology were normal. ARVC in Naxos disease may present as an episode of acute myocarditis. 3C: Late contrast-enhanced image in a 14-year-old boy with Naxos disease, homozygous for JUP 2157, showing LGE (arrow) in LV (3C∗∗) as compared to (3C∗) image taken taken one year prior to (3C∗∗). The boy, followed-up yearly since the age of one year due to cutaneous features of WH and PPK, was asymptomatic till the age of 14 years, when he first presented with chest pain and troponin elevation. PPK = palmoplantar keratoderma; other abbreviations as in Figures 1 and 3.

Figure 5

Electrocardiography Spectrum in Naxos Disease Patients Samples from 12-lead ECG precordial recordings in seven different patients with Naxos disease (JUP 2157del2): A broad spectrum of QRS width, amplitude and morphology, as well as the distribution of T-wave inversions, is noted. C-denotes the case number. Abbreviations as in Figure 1.

Central Illustration

Naxos Disease and Related Cardio-Cutaneous Syndromes: The Patient Pathway The Patient Pathway is an opinion statement. ∗Any new P/LP variant identified either on the already involved genes of JUP, DSP, DSC2 or in other genes. DSC2 = desmocollin 2; DSP = desmoplakin; other abbreviation as in Figure 1.