Evidence for genetic heterogeneity in Carvajal syndrome

Abstract

Carvajal syndrome is a rare syndrome with woolly hair, palmoplantar keratosis and dilated cardiomyopathy. The inheritance of the mutation is autosomal recessive. As a causal gene, the desmoplakin gene (DSP) has so far been identified; it encodes an essential component of desmosomes, a cell-cell structure aimed at keeping cells attached to each other in tissues in which cells are often exposed to strong shear forces. 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. A patient was seen for cardiogenetic consultation at the University Hospital of Lyon with cardiac failure involving first degree atrioventricular block, complete left bundle branch block, non-compaction of the apex of the left ventricle and a dilated cardiomyopathy. A coronarography disclosed a complete thrombosis of the right coronary artery. At examination, he had also woolly hair, mild palmoplantar keratosis and missing teeth (essentially molars and premolars). His family history was uninformative. His DNA was screened for mutations in the DSP and plakoglobin genes but no mutation could be found. This case suggests that Carvajal syndrome with hypo/oligodontia is a heterogeneous condition in which genes other than DSP might be involved, although we cannot rule out a mutation in this gene consisting in a deletion of a single exon or a gene rearrangement.

Autosomal dominant Carvajal plus syndrome due to the novel desmoplakin mutation c.1678A > T (p.Ile560Phe)

“…In addition to woolly hair, palmo-plantar keratoma, and systolic dysfunction, the index patient presented with unilateral hypoacusis since birth, oligodontia, recurrent pharyngeal infections during 25 y, and recurrent diarrhoea. In addition, LVHT was detected in the index case, which had been reported in altogether 4 cases with Carvajal syndrome including this patient so far [2], [3], [5], [6]. Whether hypoacusis, pharyngeal infections, or recurrent diarrhoea can be attributed to the desmoplakin mutation remains speculative, since these abnormalities have not been reported in association with Carvajal syndrome.…”

“…Most likely the genetic heterogeneity is even broader than so far anticipated. In four cases was Carvajal syndrome associated with left ventricular hypertrabeculation, also known as noncompaction (LVHT) [2], [3], [5], [6]. Here we report a family with autosomal dominant Carvajal syndrome due to a novel mutation in the desmoplakin gene.…”

“…Phenotypically, Carvajal syndrome manifests as dilated cardiomyopathy (dCMP), woolly hair, and palmoplantar keratoma [2]. Additional phenotypic manifestations include dental abnormalities, arrhythmogenic right ventricular dysplasia (ARVD), or leukonychia (Table 1) [3].…”

Palmoplantar keratoderma with curly hair

“…Thus tissues subject to high mechanical stress, such as heart, palms, and soles, are more commonly affected . There may rarely be a dominant negative inheritance . Associated hypodontia, oligodontia, and leukonychia can be indicators of autosomal dominant inheritance.…”

Carvajal syndrome: a brief overview and clinical case of cardiomyopathy, associated with compound heterozygous mutations of the desmoplakin gene

“…Для синдрома Наксос, так же как и для СК, характерны курчавые волосы при рождении и развитие кератодермии на первом году жизни, однако патоморфологические изменения преобладают в правых отделах сердца, приводя к развитию АПЖК [3][4][5][6]. Патология СК обусловлена гомозиготными мутациями в хромосоме 6р24 -в гене DSP, кодирующем белок десмоплакин; мутации этого гена приводят к синтезу укороченного белка с нарушением его функций [2]. Гомозиготные мутации гена JUP, расположенного в хромосоме 17q21, детерминируют синтез дефектного десмосомального белка плакоглобина, что вызывает развитие болезни Наксос с фенотипом АПЖК [3][4][5][6][7][8].…”