Discussion

Our patient presented with phenotypic findings similar to the previously reported cases (Table 1). The child exhibited the characteristic phenotype of woolly hair, palmoplantar keratosis, and signs of heart failure. Woolly scalp hair is often present since birth, and symmetric palm/sole hyperkeratosis appears in infancy or early childhood.^{Reference Binfadel, Aleem and Alhabdan17} Beyond these classical symptoms, it can also show some phenotypical variations with dental anomalies, oligodontia, nail dystrophy, or leukonychia.^{Reference Akdogan, Incel-Uysal, Cavdarli, Topcu and Yalcin8–Reference Antonov, Kingsbery and Rohena10,Reference Barber, Day, Judge, Toole and Fayle16} These distinctions are observed more commonly in Carvajal than in Naxos, a closely related disease. In contrast to early onset of dermatological manifestations, our case presented with cardiac symptoms such as heart failure, arrhythmias, and cardiogenic shock, which usually manifest between ages 5 and 12 years.^{Reference Zhao, Bai and Li5}

Table 1.

Published paediatric Carvajal syndrome cases: cardiac and dermatological manifestations with outcomes

Table 1 Long description

The table presents data on pediatric Carvajal syndrome cases, focusing on clinical features, genetic findings, cardiac involvement, dermatological findings, and treatment outcomes. It has 18 rows and 6 columns. The columns are labeled Author, Clinical features, Genetic findings, Cardiac involvement, Dermatological findings, and Treatment and outcome. Each row provides specific details for different cases. For example, Row 1: Mohammadpour et al., 9-year F, dyspnoea, epistaxis; affected cousins, Not tested, Cardiomegaly; dilated LV with prominent non-compaction; LVEF; mild-moderate MR; abnormal LFTs, Widespread crusted hyperkeratosis (palms/soles/trunk), Oxygen, digoxin, diuretics, ACEi, spironolactone, CoQ; discharged stable. Row 2: Zhao et al., 7-year F, breathlessness since 6 years. parents heterozygous carriers, Homozygous DSP c.4597C>T (p.Q1533X), Severe global DCM (NYHA III); biventricular dilation; PVCs; TBPN, Fine woolly scalp hair; focal striate PPK; toenail leukonychia; deciduous oligodontia, ACEi, β-blocker; topical/systemic retinoids; symptomatic improvement.

Notes: ACE = angiotensin-converting enzyme; LV = left ventricle; EF = ejection fraction; MR = mitral regurgitation; DSP = desmoplakin; DCM = dilated cardiomyopathy; PVC = premature ventricular contraction; BNP = B-type natriuretic peptide (brain natriuretic peptide); PPK = palmoplantar keratoderma; CHF = congestive heart failure; LVAD = left ventricular assist device; ICD = implantable cardioverter-defibrillator; SCD = sudden cardiac death; TR = tricuspid regurgitation; EKV = erythrokeratoderma variabilis.

Thus, early recognition of hair/keratosis clues is critical, since left ventricular dilation appears in most affected children by their early teens. Given the hereditary nature of the disease, family history is also significant. Similar to our case, many cases involve consanguineous parents and siblings may be at risk. Genetic counselling and screening of relatives is recommended.^{Reference Ramoğlu, Uçar, Ceylaner, Atalay and Tutar6,Reference Akdogan, Incel-Uysal, Cavdarli, Topcu and Yalcin8,Reference Turkay, Odemis and Karadag13–Reference Barber, Day, Judge, Toole and Fayle16}

These familial patterns reflect the underlying genetic architecture: Carvajal is commonly due to biallelic mutations in the DSP gene (encoding desmoplakin), on chromosome 6 (OMIM #605676), which anchors intermediate filaments to desmosomes in skin and heart. Over 120 DSP gene mutations (both dominant and recessive) have been reported in human skin/heart disease.Reference Pigors, Schwieger-Briel and Cosgarea ¹⁸

Genetic data across reported cohorts show a clear predominance of biallelic truncating DSP gene variants underlying classic Carvajal syndrome, with consanguinity frequently reported and homozygous loss-of-function mutations accounting for most paediatric cases.^{Reference Zhao, Bai and Li5,Reference Ramoğlu, Uçar, Ceylaner, Atalay and Tutar6,Reference Akdogan, Incel-Uysal, Cavdarli, Topcu and Yalcin8,Reference Arıcı, Akalın and Geckinli14} Occasional heterozygous or de novo missense DSP gene variants produce milder or atypical phenotypes, expanding the genetic spectrum.^{Reference Bitar, Najjar and Hayashi15,Reference Pigors, Schwieger-Briel and Cosgarea18} Overall, DSP gene mutations reliably segregate with the clinical triad of dilated cardiomyopathy, woolly hair, and palmoplantar keratoderma, although additional features such as leukonychia, dental anomalies, alopecia, and rare associations (e.g., neuroblastoma) have been described.^{Reference Zhao, Bai and Li5,Reference Ramoğlu, Uçar, Ceylaner, Atalay and Tutar6,Reference Akdogan, Incel-Uysal, Cavdarli, Topcu and Yalcin8,Reference Antonov, Kingsbery and Rohena10} Our patient likewise carried a homozygous nonsense DSP gene mutation (homozygous p.Glu1730Ter, c.5188G>T), NM_004415.4, based on the Hg19 genome reference build, consistent with the recessive, truncating-variant pattern. Viewed in the context of existing genotype–phenotype correlations, our case expands the molecular spectrum of DSP gene-related disease by identifying a novel homozygous truncating variant associated with a classic Carvajal phenotype. Biallelic truncating DSP gene variants tend to produce severe left ventricular dysfunction with fibrofatty change, malignant arrhythmias, and high sudden-death risk, whereas heterozygous DSP gene alleles more often present as arrhythmogenic right or biventricular cardiomyopathy without prominent cutaneous signs.^{Reference Caiazzo, De Simone and Monda3,Reference Pigors, Schwieger-Briel and Cosgarea18–Reference Protonotarios, Asimaki and Basso20} Importantly, the extent of skin involvement does not always predict cardiac severity, so dermatologic clues should prompt genetic testing and cardiac surveillance.^{Reference Bolling and Jonkman2,Reference Pigors, Schwieger-Briel and Cosgarea18,Reference Pantou, Gourzi and Vlagkouli19,Reference Heliö, Brandt and Vaara21}

Within this framework, Carvajal syndrome represents the full phenotypic expression of recessive DSP gene truncations, while heterozygous variants occupy variable points along the arrhythmogenic cardiomyopathy spectrum, reinforcing the notion that the skin can serve as a “window to the heart.” Closely related to this condition is Naxos disease caused by plakoglobin (JUP) mutations, which manifests in adolescence with right ventricular arrhythmias, woolly hair, and diffuse palmoplantar keratoderma.

Thus, a practical distinction is that DSP gene mutations primarily affect the left ventricle, whereas plakoglobin mutations involve the right ventricle.^{Reference Protonotarios, Asimaki and Basso20} Beyond paediatric syndromic cases, DSP gene variants are also increasingly recognised in adults as arrhythmogenic left ventricular cardiomyopathy, often first manifesting as arrhythmias before progression to heart failure.^{Reference Binfadel, Aleem and Alhabdan17,Reference Heliö, Brandt and Vaara21}