A Novel Variant in the Desmoplakin Gene in One Case of the Rare Carvajal Syndrome with Dilated Cardiomyopathy: A Case Report and Literature Review

Introduction

As a hereditary cardiocutaneous syndrome, Carvajal syndrome is characterized by dilated cardiomyopathy, palmoplantar keratoderma, woolly hair, and dental dysplasia.¹ Carvajal syndrome was first identified by Rao et al in 1996² and then was described in detail by Carvajal⁃Huerta in 1998.³ Soon thereafter, in 2000, Norgett et al first found its etiology was mainly the variants of the desmoplakin (DSP) gene.⁴ Carvajal syndrome tends to develop in childhood and is mainly autosomal recessive, with occasional autosomal dominant inheritance.⁵ This syndrome is rare, and not many cases have been reported worldwide. Recently, we diagnosed one 7-year-old female with the Carvajal syndrome who visited hospital mainly due to the manifestations of de novo heart failure, which will be reported below with a literature review.

Case Presentation

The 7-year-old female patient was born normally as the first child of no-consanguineous parents of Chinese Han, with yellow-brown woolly hair on her forehead at birth. Before she was 4 years old, she had no health problems. Since then, palmoplantar keratoderma began to present on her palms and soles, and gradually spread to the fingers and toes. Meanwhile, she received irregular external ointment treatment. She developed dysplasia of deciduous teeth at the age of 5 years, with bilateral multiple incisors and molars oligodontia and dentition irregularity. At the age of 6 years, the child began to suffer from chest tightness, shortness of breath, and dyspnea when she was active, which gradually aggravated, and then unable to tolerate moderate daily activities. Shortly before coming to Shijiazhuang Great Wall Cardiovascular Hospital, she had been examined at Chongqing Children’s Hospital, diagnosed with dilated cardiomyopathy and the corresponding treatment. The patient has a healthy 4-year-old younger brother and their parents are also healthy. There is no similar patient in the family.

On physical examination, the patient was not in acute distress. Her intelligence was normal. Her weight was 21kg (25–30 centile), and her height was 125cm (25–30 centile). Her body temperature was 36.4 °C, pulse 76 beats/min, respiratory rate 20 breaths/min, and blood pressure 88/65mmHg. She had sparse, dark-brown, and woolly hair (Figure 1A and B). She also suffers from agenesis of primary teeth with multiple oligodontia (7 teeth) and odontoloxia (Figure 1C). Bilateral jugular veins were dilated slightly. Thick breath sounds could be heard in bilateral lungs, without obvious dry or wet rales. The apical beat was diffuse, cardiac boundaries were enlarged to both sides, and apical pulsation was located at the 7th intercostal of the left axillary-front line. The heart rate was 76 beats/min with premature beats, and a grade 2/6 systolic blowing-like murmurs could be detected at the mitral valve auscultation area. The abdomen was flat and soft, with no tenderness. The liver was palpable 3 cm below the costal margin, and the spleen was not touched. Striate palmoplantar keratoderma was observed on both palms, fingers, soles, halluces, and heels, with a rough and chapped surface (Figure 1D and F). Leukonychia also could be found on toenails (Figure 1E). There was mild edema in both legs and joints movements barrier-free.

Figure 1 Clinical manifestations of our Carvajal syndrome patient with novel variants in the desmoplakin (DSP) gene. (A and B) Sparse, dark-brown, and woolly hair; (C) Oligodontia and odontoloxia; (D) Palmoplantar keratoderma (PPK) on both palms; (E and F) PPK on both toes and soles.

Laboratory tests showed that routine blood tests, blood glucose, liver function, renal function, electrolytes, myocardial enzymes, coagulation function, erythrocyte sedimentation rate, thyroid function, immunoglobulin (IgA, IgG, IgM), complement (C3, C4), procalcitonin, 25-hydroxyvitamin D3, trace elements were all normal. Screening indicators of hepatitis B virus, hepatitis C virus, adenovirus, Coxsackie, Epstein-Barr, syphilis, and human immunodeficiency virus were all negative and/or within the normal range. The B-type natriuretic peptide was 18,883.5 pg/mL (reference value: 0–450pg/mL). The 24-hour dynamic electrocardiogram indicated sinus rhythm, increased P wave amplitude, average heart rate of 74 beats/min, lowest heart rate of 55 beats/min, fastest heart rate of 139 beats/min, and 3561 ventricular premature beats (Figure 2A). Chest X-ray showed double-lung texture increased, together with heart shadow enlarged (Figure 2B). Cardiac magnetic resonance imaging (MRI) revealed that the heart was enlarged, especially the left heart, and the ventricular systolic and diastolic functions decreased. Color Doppler echocardiography demonstrated left ventricular end-diastolic diameter was 55 mm, left atrium 28*36*56 mm, right ventricular end-diastolic diameter 29 mm, right atrial diameter 33mm, left ventricular ejection fraction 25%, global heart enlargement, partial myocardial non-compaction of the left ventricle, diffuse decrease in ventricular septum and left ventricular wall motion amplitude, mild aortic regurgitation, moderate mitral regurgitation, mild tricuspid regurgitation, pulmonary hypertension (mild), mild pulmonary artery regurgitation, the main pulmonary artery and its branches widened. The diastolic and contractile functions of the left and right ventricles all decreased (Figure 2C and D). Abdominal color ultrasound suggested mild hepatic congestion.

Figure 2 Electrocardiogram (ECG), Chest x-ray, and Echocardiography of our Carvajal syndrome patient with novel variants in the desmoplakin gene. (A) Echocardiography showing ventricular premature beats; (B) Chest x-ray showing dilated heart and increased cardiothoracic ratio; (C and D) Echocardiography showing dilated left and right ventricles.

Genetic testing was performed by high-throughput whole-exome sequencing (MyGenostics Inc., Beijing, China). The proband disclosed a homozygous missense variant c.4597C > T (p.Q1533X) in exon 6 of the DSP gene, ie the nucleotide at position 4597 in the coding region changed from cytosine to thymine, resulting in a senseless variant of the amino acid (Glutamine) at position 1533 (Figure 3). In reference to relevant document database, ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/), Gnomad database (http://www.gnomad-sg.org/), and the Human Gene Mutation Database (https://www.hgmd.cf.ac.uk/ac/index.php), up to now, there is no report on the variation of this gene locus. The proband’s parents were verified by Sanger sequencing (MyGenostics Inc., Beijing, China): they both carried the heterozygous variant c.4597C > T (p.Q1533X) in DSP gene and were both healthy (Figure 4).

Figure 3 Variant analysis in the proband and her parents. Both the parents carried a heterozygous variant c.4597C > T (p.Q1533X) in DSP gene; Proband disclosed a homozygous missense variant c.4597C > T (p.Q1533X) in exon 6 of DSP gene.

Figure 4 Pedigree chart of the family.

According to clinical manifestations and DSP gene test results, the patient was diagnosed as (1) Carvajal syndrome; (2) dilated cardiomyopathy, heart failure (NYHA grade III), and arrhythmia as ventricular premature contraction. Then, the patient received comprehensive treatments: for heart failure and ventricular premature, using the diuretic, cardiotonic, inhibition of myocardial remodeling, inhibition of sympathetic excitation, traditional Chinese medicine decoction, and the symptoms were significantly improved; for palmoplantar keratoderma, oral vitamin A and E capsules were given once every other day, and 0.1% retinoic acid ointment and urea ointment were applied externally twice a day. One month later, the hand and foot palmoplantar keratoderma was better than before. The electrocardiogram remained premature ventricular contraction. Three months later, there was a significant improvement in palmoplantar keratoderma, and premature ventricular contraction was found to be reduced, but there was no significant change in color Doppler echocardiography. At present, the cardiology department and dermatology department are following up.

Discussion

This study, for the first time, identified a novel DSP variant of c.4597C > T (p.Q1533X) in exon 6, leading to the Carvajal syndrome in a sporadic case of patient, who manifested as dilated cardiomyopathy, woolly hair, palmoplantar keratosis, and teeth loss. Both the parents carried this variant in a heterozygous state, and they were both healthy, which indicated that this novel variant causes Carvajal syndrome in an autosomal recessive manner.

At present, Carvajal syndrome is believed to be mainly secondary to DSP gene variant.⁵ Desmosomes are tough and strong intercellular junctions, particularly abundant in the myocardium and epidermis, and DSP is the most abundant protein of desmosome.⁶ Therefore, once the DSP gene variant occurs, the desmosome undergoes structural changes, resulting in phenotypic changes in the heart, skin and other related organs and tissues. We summarized the characteristics of patients with Carvajal syndrome in published literature in Table 1. Most patients with Carvajal syndrome are autosomal recessive inheritance, and the variant hotspots are mainly located in exons 23^7–12 or 24^4,13–16 of DSP gene, while a few of them were autosomal dominant inheritance, and the variant regions were mainly in other exons of DSP gene.^6,17–20 Furthermore, the earliest and most reports related to Carvajal syndrome were homozygous variants in DSP gene c.7901delG.⁴ To date, apart from a few special cases of Carvajal syndrome without DPS variant,⁵ many other DSP gene variants have been discovered successively^4,6–32 (Table 1). While, in this case, a novel homozygous missense variant c.4597C > T (p.Q1533X) in exon 6 of the DSP gene was found for the first time.

Table 1 Characteristics of Patients with Carvajal Syndrome in Published Literatures

The phenotype of DSP variant is related to its inheritance mode. In the past, it was believed that Carvajal syndrome caused by DSP variant was a recessive inheritance, and in fact most cases were reported to be so.^{4,7,10,11,13–17,24,26,27,32} Nevertheless, with the gradual increasing and deepening of studies, some reports have also found spontaneous variant^{9,10,16,20,21,28} and dominant inheritance.^{18,19,23,25,30} Whether inherited or acquired, the main clinical manifestations of Carvajal syndrome are woolly hair, palmoplantar keratoderma, and cardiomyopathy involving more frequently the left ventricle.³³ However, some cases showed biventricular^{7,14,17,18,21} or right ventricular^{4,12,13,21,23} involvement, and even no cardiac abnormalities.^{16,19,20,24,32} In this case, the main manifestations of the proband were global dilated cardiomyopathy, partial left ventricular myocardial no-compaction, wool hair, palmoplantar keratoderma, and leukonychia. Other reports suggest that other features of Carvajal syndrome include paratrichosis (alopecia^11,12,27 or hypotrichosis)^{4,7,14,20,21,24,28,29,32}, dental anomalies (oligodontia^5,18–22,25 or enamel abnormalities)¹⁴, fingernail/toenail abnormalities (onychodystrophy,^{5,11,14,20,21} leukonychia,^19,21,22,28 onychorrhexis,¹⁸ or onychogryphosis)²⁴, recurrent syncopes,^13,18,25 mucocutaneous blisters,^11,14,24 and other rare manifestations papules (such as bilateral external rotation of the fifth toe,²⁴ recurrent pharyngeal infections, recurrent diarrhea, left-sided hypoacusis,²⁵ and hand wart-like lesions).²⁶ The clinical phenotypes of Carvajal syndrome are varied, which is closely related to the variants of different DSP genes and their influence on the changes of N-terminal and C-terminal domain.^4,14,17

Furthermore, what counts is some related diseases with similar clinical phenotypes need to be differentiated, especially the Naxos disease. With the main clinical features of arrhythmogenic right ventricular cardiomyopathy (ARVC), woolly hair, and palmoplantar keratoderma, Naxos disease was first described by Protonotarios et al in four families from Naxos island of Greece in 1986.³⁴ Because both show similar heart, hair and skin lesions, earlier studies considered Carvajal syndrome and Naxos disease as one syndrome, or Carvajal syndrome as a variant of Naxos disease.^8,23,35,36 However, with the increasing number of case reports and the deepening of investigations, researchers began to realize that Carvajal syndrome and Naxos disease are two different diseases. First, left cardiac involvement was more common in Carvajal syndrome,^{5,9–11,21,22,24–26,28,29,31} while right-ventricle involvement was more common in Naxos disease.^23,36–38 Second, the plantopalmar keratoderma in Carvajal syndrome was often striate,^{4,18,21,29,32} which in Naxos disease was often diffuse.^33,35–38 Third, Carvajal syndrome was often accompanied by dental abnormalities^{5,14,18–22,25} or nail abnormalities,^{5,11,14,18–22,24,28} while Naxos disease was less seen. However, with the increasing number of cases reported, the phenotypic differences between them gradually become less obvious. Then, genetic testing can be used to differentiate them——Carvajal syndrome is mainly caused by DSP gene variant,^4,7–32,34 while Naxos disease is mainly caused by plakoglobin gene variant.^34,37,38

Moreover, woolly hair is generally the first sign that patients with Carvajal syndrome may be detected at birth. However, woolly hair is not unique to Carvajal syndrome; it is also found in Naxos disease, mentioned above, and in other rare diseases such as Menkes disease (MD),^39,40 skin fragility/woolly hair syndrome (SFWHS),^41,42 and tricho-dento-osseus syndrome (TDOS).^43,44 MD occurs due to X-linked genetic variant in the ATP7A gene. Woolly, sparse, lusterless, and tangled hair usually together with progressive neurodegeneration and connective tissue disturbances become the main features of MD.^39,40 Similar to Carvajal syndrome, SFWHS is also caused by variants of DSP gene and presents with woolly hair and palmokeratosis. However, SFWHS is often accompanied by increased skin fragility and recurrent blisters at birth.^41,42 TDOS is a rare autosomal-dominant ectodermal dysplasia, with woolly hair at birth, caused by variants in the DLX3 gene. However, as patients with TDOS age, their hair becomes thicker and straighter. Besides, almost all TDOS patients exhibit dental abnormalities.^43,44 It is worth noting that neither SFWHS nor TDOS will present with cardiac disease, which can be as the basis for distinguishing them from Carvajal syndrome.^41–44

Our study has several limitations. First, apart from the proband and her parents, we have been unable to trace the genotypes of other family members. Second, due to the limited information available, we could not further explore the function of the mutated exon. Third, more cases need to be collected to obtain the epidemiological data.

Conclusion

In this study, we presented a case of Carvajal syndrome performed as global dilated cardiomyopathy sparse woolly hair, striate palmoplantar keratoderma on both palms and soles, leukonychia, and dental dysplasia. A novel heterozygous variant c.4597C > T (p.Q1533X), never reported before, was found in exon 6 in DSP gene in our patient); there is moderate evidence for this variant to be considered pathogenic (MutationTaster, http://www.mutationtaster.org).⁴⁵ The parents were both heterozygous for the identified nonsense variant without the phenotype of Carvajal syndrome, implying that the novel variant in DSP caused the disease in an autosomal recessive manner. As more cases are reported, more clinical phenotypes of Carvajal syndrome are emerging. Thus, future studies need to pay more attention to the correlation between genotype and phenotype.