Unique reticular hyperkeratotic eruptions seen in a patient with Darier's disease and attention deficit hyperactivity disorder

概要

Darier’s disease (DD) is an autosomal dominant genetic disorder caused by mutations in the ATP2A2 gene which encodes a sarco/endplasmic reticulum Ca2+ATPase type 2 isoform (SERCA2).1 SERCA2 is expressed in epidermal keratinocytes in the skin and neurocytes in the brain .DD is characterized by brown keratotic lesions in the seborrheic areas of the skin. It is associated with neuropsychiatric diseases, such as mental retardation, mood disorders, schizophrenia and epilepsy.2,3

A 24-year-old female patient with no apparent family history of dermatological or psychiatric conditions presented with brown hyperkeratotic papules on the face, the abdomen and the limbs, with very greasy scales and desquamation (Fig. 1A, B) that had been present since age 14. Interestingly, the hyperkeratotic lesions showed apparently reticular patterns on the forearms. The patient’s DD lesions worsened in the summer and were sometimes itchy and sore. She had been treated with topical corticosteroid creams and maxacalcitol creams. In addition, she was diagnosed with attention deficit hyperactivity disorder (ADHD). A skin biopsy specimen from the forearm revealed acantholytic keratinocytes, dyskeratotic cells in the suprabasal layers, and clefts in the epidermis (Fig. 1C). Following ethical approval by the institutional review board in Nagoya University Graduate School of Medicine, written informed consent was obtained in compliance with the Declaration of Helsinki principles. Using genomic DNA as a template, genomic sequencing of ATP2A2 was performed as previously reported.1 The previously unreported heterozygous mutation c.364T>G (p.Tyr122Asp) was identified in ATP2A2 (Fig. 1D). Analysis of genomic DNA from her parents showed only wild-type ATP2A2 sequences, suggesting that the mutation occurred de novo. In silico analysis with PolyPhen- 2 (http://genetics.bwh.harvard.edu/pph2/) predicted the mutation to be ‘probably damaging’, and the SIFT program (http://sift.jcvi.org/) predicted it to be ‘damaging’. Thus, the mutation is thought to be functionally relevant. The patient was diagnosed with DD caused by the mutation in ATP2A2.

The present patient had ADHD as well as DD. It is well known that DD patients are sometimes complicated with neuropsychiatric manifestations. It was reported that individuals with DD had a 2.3 times higher risk of being diagnosed with schizophrenia than matched individuals from the general population.4 Various psychiatric disorders other than schizophrenia have been described in DD patients.2,4 Thus, although no DD case complicated with ADHD has been reported to date, we assume that her ADHD might be associated with the ATP2A2 mutation causative of DD. Further accumulation of ADHD cases with ATP2A2 mutations is needed to confirm the molecular pathogenesis of ADHD by ATP2A2 mutations.

Furthermore, the present patient showed unique reticular hyperkeratotic eruptions on the forearms. In the literature, we were unable to find any reports of similar eruptions in DD patients. Although a nonsense mutation of the same amino acid, p.Tyr122X, has been reported,5 no substitution mutation of Tyr122 has been described previously. Thus, we cannot assess genotype/phenotype correlations concerning the clinical features of patients with substitution mutations of Tyr122. We hypothesize that some genetic and/or environmental modifying factors might have contributed to the development of the unique reticular arrangement of her DD lesions. The patient’s hyperkeratotic DD lesions were itchy. The forearms are easily accessible regions, and the present patient with ADHD seemed to scratch the skin eruptions on the forearm frequently. We speculate that this intense scratching might have lead to Köbner phenomenon, resulting in the unique reticular pattern of the hyperkeratotic lesions in the present DD case with ADHD.

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