Mbarka Bchetnia, Cherine Charfeddine, Selma Kassar, Hela Zribi, Haifa Tounsi Guettiti, Feten Ellouze, Mejda Cheour, Samir Boubaker, Amel Dhahri-Ben Osman, Sonia Abdelhak, Mourad Mokni. Clinical and Mutational Heterogeneity of Darier Disease in Tunisian Families. Arch Dermatol. 2009;145(6):654–656. doi:10.1001/archdermatol.2009.52
To study the mutation spectrum and phenotype-genotype correlation of Darier disease (DD) in Tunisian patients.
Referral center: Department of Dermatology (La Rabta Hospital), Tunis, Tunisia.
Eight large Tunisian families with DD, with a total of 23 patients and 9 unaffected family members.
Main Outcome Measure
Patients were investigated at the clinical, histological, and genetic levels. Families were genotyped with 5 microsatellite markers spanning the ATP2A2 gene. Mutation screening was performed by direct sequencing of the coding region and exon/intron boundaries of the ATP2A2 gene.
Typical clinical features of DD were constantly present. Phenotypic variation within and between the studied families was observed. Different neuropsychiatric disorders were seen in 5 families, and various cutaneous and extracutaneous original clinical associations were observed. The haplotype analysis led to the identification of different haplotypes cosegregating with the disease in the studied families. Mutation screening of the ATP2A2 gene revealed 3 recurrent mutations (119-120delAG, R677X, and D702N) and 4 novel variations: 2 missense mutations (G217A and L900R), one microinsertion (2772-2779 ins C), and one microdeletion (1747-1749 del 2T).
Our findings provide evidence for clinical and mutational heterogeneity of Tunisian families with DD. No obvious phenotype-genotype correlation was established. To our knowledge, this is the first molecular investigation of DD in the North African population.
Darier disease (DD; MIM 124200) is a rare dominantly inherited disorder that predominantly affects the skin.1 It is characterized by warty papules and plaques in seborrheic areas, palmoplantar pits, and distinctive nail dystrophy.2 The DD locus has been mapped to chromosome 12q23-24.1; mutations within the ATP2A2 gene have been shown to be responsible for DD.3
We report here clinical investigation and mutation spectrum of 8 families with DD and investigate phenotype-genotype correlation.
Eight Tunisian families with a total of 23 patients and 9 unaffected family members were investigated. The diagnosis of DD was established based on clinical examination and confirmed by histopathologic findings.
After obtaining informed consent, skin biopsy and blood samples were collected from all participating members. Haplotype analysis was performed using microsatellite markers spanning the ATP2A2 region (D12S234, D12S1339, D12S2257, D12S1343, and D12S2263). Mutation screening of the ATP2A2 gene was performed by direct sequencing.
The investigated families had the classical DD phenotype. Skin lesions had started during early childhood and around puberty. Keratotic papules were observed on the face, neck, both axillae, and inframammary regions. The severity of the disease was not constant even among patients from the same family (Table). One case was previously misdiagnosed as hidradenitis suppurativa, and several original clinical associations were observed. Among these, one patient presented with DD and pemphigus vulgaris and another with congenital ichthyosis, diffuse alopecia, corneal opacity, mental retardation, and ovarian cancer.
Neuropsychiatric disorders were recorded in 5 families and included bipolar disorder type II, major depressive disorder, mental retardation, auditory and visual hallucinations, cyclothymic disorder, and social phobia. Although the investigated patients were from different genetic, environmental, and socioeconomic backgrounds, constant association with neuropsychiatric disorders suggests that the symptoms occur owing to a susceptibility locus that co-segregates with ATP2A2.4 Linkage analysis to the ATP2A2 gene showed a haplotype heterogeneity that was confirmed by mutational screening. We identified 7 distinct mutations, among which 4 were novel (Table). For only 1 family, no mutation was found; however, a rare variant of single nucleotide polymorphism (rs35235621) was identified.
The mutation spectrum identified herein included 3 heterozygous missense mutations (G217A, D702N, and L900R), one nonsense mutation (R677X), two frameshift deletions (1747-1749 del 2T and 119-120 delAG), and one frame-shift insertion (2772-2779 ins C). No clustering or mutation hot spots have been noted.
The novel missense mutations G217A and L900R result in nonconservative amino acid substitutions. The novel frame-shift mutations 1747-1749 del 2T and 2772-2779 ins C are expected to result in a loss of function. The novel variations have not been found in the 50 Tunisians of the control group.
Herein we report the results of our clinical and genetic investigation of DD in families of Tunisian national origin (of a total population of 10 million). Phenotypic variation was observed within and between the families, but none had severe DD. Mutational heterogeneity was also observed, owing to the richness of the genetic background. No obvious genotype-phenotype correlation was established. The neuropsychiatric disorders listed herein were not associated with a specific type of mutation and were not constant among affected members within the same family.
In conclusion, this study, the first to our knowledge regarding the incidence of DD in the North African population, gives further evidence for the clinical and mutational heterogeneity of DD worldwide. Differences in the expression of DD could be explained not only by environmental factors but also by modifier loci.
Correspondence: Sonia Abdelhak, PhD, Institut Pasteur de Tunis, BP 74, 13 Place, Pasteur 1002 Tunis, Belvédère, Tunisia (email@example.com).
Author Contributions: Dr Abdelhak had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Bchetnia and Charfeddine contributed equally to this work. Study concept and design: Abdelhak and Mokni. Acquisition of data: Bchetnia, Charfeddine, Zribi, Tounsi Guettiti, Ellouze, Cheour, and Dhahri-Ben Osman. Analysis andinterpretation of data: Abdelhak, Bchetnia, Charfeddine, Kassar, Boubaker, and Mokni. Drafting of the manuscript: Bchetnia, Charfeddine, and Mokni. Critical revision of the manuscript for important intellectual content: Abdelhak, Kassar, Zribi, Tounsi Guettiti, Ellouze, Cheour, Boubaker, Dhahri-Ben Osman, and Mokni. Obtained funding: Abdelhak and Mokni. Administrative, technical, or material support: Bchetnia, Charfeddine, and Kassar. Study supervision: Abdelhak, Boubaker, and Mokni.
Financial Disclosure: None reported.
Funding/Support: This work was supported by the Tunisian Ministry of Higher Education and Scientific Research (Molecular Investigation of Genetic Orphan Disorders Research Unit and Hereditary Keratinisation Disorders Research Unit) and the Ministry of Health.
Additional Contributions: We are especially grateful to the patients and their family members for their interest and cooperation in this study.