Darier disease (DD) is an autosomal dominant disorder caused by mutation of ATP2A2 gene, located on chromosome 12q23-24.1 and encoding for sarco/endoplasmic reticulum Ca++ ATPase type 2 isoform. Mutations in the ATP2A2 gene have been shown to cause severe disruption of calcium homeostasis by altering protein expression and/or the calcium transport function.

Clinically, DD manifests with hyperkeratotic papules in seborrhoeic areas, palmo-plantar pits and distinctive nail dystrophy. At histology it is characterized by loss of adhesion and apoptosis of keratinocytes (acantolysis) [1,2].

Consistent extra-cutaneous manifestations of Darier disease have not been documented so far [2] and specifically the heart has been reported as non-affected [3].

In the present study a novel mutation of ATP2A2 is reported, severely affecting the skin and the myocardium. Clinical manifestations are supported by histological evidence of keratinocyte and cardiomyocyte disconnection. Clinical symptoms of muscle exhaustion, chest pain and cardiac arrhythmias have been attenuated by phosphodiesterase inhibitor administration.

A 62-year-old lady was admitted because of palpitations and chest pain at rest, increasing with effort and limiting remarkably the quality of life and resulting in a depressive syndrome with a failed attempt of suicide. She was affected since the age of nine by Darier disease manifesting with extensive greasy, crusted, yellow-brown papules on the seborrheic areas. Beyond skin lesions, clinical examination was unremarkable, she was afebrile and her blood pressure was normal. Routine blood and chemical tests were within normal limits. Indices of inflammation like erythrocyte sedimentation rate and C reactive protein were normal. ECG showed sinus rhythm at 54 bts/min with abnormal ST segment deflection (-1,-1.5 mm) in the infero-lateral leads and negative T wave (Figure 2 Panel G).

Heart tissue samples were treated as described [8]. The expression of sarcoplasmic or endoplasmic reticulum calcium (SERCA-2) antibody was visualized by using a mouse monoclonal antibody (1:100, Santa Cruz Biotechnology) and Anti-α-sarcomeric actin (1:500, Sigma-Aldrich), antibody was used for normalization. Signal was visualized using a secondary horseradish peroxidase-labeled goat anti-mouse antibody (goat anti-mouse IgG-HRP 1:5000, Santa Cruz Biotechnology) and enhanced chemiluminescence (ECL Clarity Biorad). The purity as well as equal loading of the fraction was determined by measuring β-actin protein levels. Digital images of the resulting bands were quantified by the Image Lab software package (Bio-Rad Laboratories, Munchen, Germany) and expressed as arbitrary densitometric units.

Although Darier disease is known as a rare disorder limited to the skin, it is likely it may affect additional systems. Indeed, incidence of psychiatric manifestations is so high [5] that has been suggested that central nervous system might be involved as well. The present study identifies a novel ATP2A2 (c.118G>A) gene mutation affecting both skin and myocardium. These tissues exhibit similar histological and ultrastructural changes consisting in alterations of keratinocyte and cardiomyocyte cell-to-cell interactions and suggest a pathway common to both tissues. To this regard it is known that function of proteins (such as connexins and tight junction proteins) responsible of lateral cell bonds are strictly Ca++dependent and that disruption of Ca++ homeostasis can compromise cell adhesion. Mutations in ATP2A2 gene have been shown to cause severe disruption of CA++ homeostasis by altering protein expression and/or the transport function in vitro [9,10] and lead to moderate depletion of calcium stores in keratinocytes of patients [11]. In DD, symptoms occur independently of ATP2A2 mutation type or which aspect of SERCA2 functionality is compromised, suggesting that ATP2A2 mutations exert their deleterious effect through haploinsufficiency, although also a dominant negative effect of the ATP2A2 mutants has been proposed to underlie the DD phenotype [12]. In our patient, despite the cardiac involvement, we cannot infer which specific aspect of SERCA2 functionality is compromised. We proved that the ATP2A2 c.118G>A mutation is associated to reduced mRNA expression at real-time quantitative PCR in peripheral blood, while the SERCA2 protein was normally expressed at western blot assessment, suggesting a sort of posttranscriptional adaptation that upregulate expression of the residual SERCA2 protein. At cardiac level, mutation consequences are derangement of cardiomyocyte organization (disarray) and remarkable intracellular changes. Specifically, at ultrastructural examination, sarcoplasmic reticulum appeared dilated and perinuclear areas of myofibrillolysis were commonly seen. Noteworthy, structure of intercalated disks was preserved confirming cell detachment to occur at lateral cell junction. It may be argued that in mouse model of Darier disease [13] there was no histological report of cardiomyocyte disconnection as well as of physiological derangements. However, it must be relieved that there was no previous endomyocardial biopsy study in human with Darier disease and that our patient developed cardiac manifestations several decades after the appearance of skin lesions. This may suggest that cardiac involvement may occur later compared with skin damage.

Clinical implications from morphological analysis are that cardiac manifestations may occur in DD. These mimic ischemic heart disease with precordial pain worsened by effort, abnormal ECG changes and polymorphic, repetitive ventricular ectopic beats.

Interestingly, phosphodiesterase inhibitors like aminophylline, reducing degradation of cyclic AMP may abolish chest pain and improve vital capacity through enhancement of SERCA2 protein phosphorylation. In our patient, in addition to disappearance of precordial pain, double product increased by 2.5 times without abnormal deflection of ST segment at on therapy stress ECG.

In conclusion, specific mutations of ATP2A2 may cause cardiac involvement in patients with DD. Cardiac pathologic changes are similar to those documented in the skin including cardiomyocyte disconnection that promotes precordial pain and cardiac arrhythmias.

Phosphodiesterase inhibitors, enhancing SERCA2 protein phosphorylation may substantially attenuate the symptoms.