A novel mutation in TRPV3 gene causes atypical familial Olmsted syndrome.

Olmsted syndrome (OS) is a rare keratinization disorder, typically characterized by two primary diagnostic hallmarks--mutilating palmoplanter and periorificial keratoderma. However, there's a growing body of literature reporting on the phenotypic diversity of OS, including the absence of aforementioned hallmarks and the presence of some unusual clinical features. Here we presented an atypical familial case of OS that could be confused with Huriez syndrome due to the presence of a scleodactyly-like appearance and tapered fingers in the proband. We ruled out this possibility and made a definitive diagnosis of OS based on clinical features and a genetic assay. Recently, mutations in TRPV3 associated with autosomal dominant or recessive OS continued to be reported, thus conducing to clarifying the underlying relationship between the genotype and phenotype of OS. So we further explored the genotype-phenotype correlation by integrating functionl assays with in silico predictions. Our research not only redefined the phenotypic spectrum of OS, but also provided concrete molecular insights into how mutations in a single gene can lead to significant differences in the severity of this rare disease.

Darier disease in Israel: combined evaluation of genetic and neuropsychiatric aspects.

BACKGROUND: Darier disease (DD) is a rare genodermatosis caused by heterozygous mutations in the ATP2A2 gene. It has been associated with neuropsychiatric manifestations. OBJECTIVES: To investigate the genetic basis of Israeli patients with DD, and its association with the neuropsychiatric phenotype. METHODS: A cohort of 32 families comprising 74 affected individuals and 13 unaffected family members was recruited from the Haemek Dermatology Department and other dermatology clinics in Israel. The individuals were evaluated by detailed questionnaires, physical examination and genetic analysis. The main outcome measures were genetic mutations, psychiatric profile and their association. RESULTS: Twenty-three mutations in ATP2A2 were scattered over the entire gene, 14 of them novel. Two families shared the same mutation. Twenty-one patients (28%) had a history of psychiatric disorders, most of them mood disorders. Another seven patients (9%) were highly suspected of having a psychiatric disorder; 21 (28%) reported suicidal thoughts and five (7%) had attempted suicide. The psychiatric phenotype demonstrated inter- and intrafamilial variability, and was not associated with disease severity, family history of psychiatric disease or mutation location. CONCLUSIONS: The cohort demonstrated genetic heterogeneity with no mutation cluster along the gene, and a high prevalence of psychiatric disorders. Although no clear genotype-phenotype correlation was found, the results point to a major effect of genetic background on psychiatric phenotype, together with other modifiers.

Novel mutations in two families with Darier's disease.

BACKGROUND: Darier's disease (DD) is an autosomal dominant skin disorder characterized by abnormal keratinization and acantholysis. Deleterious mutations in the gene ATP2A2 which encodes SERCA2, a calcium pump of the sarco/endoplasmic reticulum underlie the disease. OBJECTIVE: To identify the genetic defect in two Jewish families of eastern-European ancestry with DD. METHODS: DNA was extracted from peripheral blood of six patients and three healthy members of the two families. Polymerase chain reaction (PCR) was carried out to amplify the exons and flanking intron boundaries of the ATP2A2 gene followed by direct sequencing. Restriction fragment analysis verified the presence or absence of the mutations. Results Two novel mutations were identified. A nonsense mutation, a change of C391 to T (R131X) in exon 5, was found in one family and a missense mutation, a change of A530 to C (Q177P) in the second. The mutations were not present in 50 healthy individuals of the same ethnic origin. Both pathogenic mutations are in codons that are located in a highly conserved cytoplasmic beta-strand domain which functions as the transduction site. CONCLUSION: The existence of two mutations in two Jewish families of the same ancestry might confirm the previously published reports that most mutations in that gene are private.

Darier's disease in Singapore.

BACKGROUND: Darier's disease is a rare, dominantly inherited genodermatosis. Although it has been well studied in caucasians, very little is known about the clinical spectrum of this disorder among Asians. OBJECTIVES: To determine the demographic and clinical profile of Asian patients with Darier's disease. METHODS: This is a retrospective study of all new cases of Darier's disease seen in our centre over a 20-year period (1982-2002). Results Twenty-four nonrelated cases of Darier's disease were studied. The incidence rate was 3.1 per million per decade. The gender distribution was 19 males and five females, and the ethnic origin was 21 Chinese, two Malays and one Nepalese. The peak age of onset was between 11 and 20 years. Sun exposure exacerbated the disease in 13 of the patients, and three had neuropsychiatric disorders. The disease affected predominantly seborrhoeic areas in 19 patients, flexural in three, acral in one and was segmental in one patient. Hand involvement was common and included palmar pits in nine patients, acrokeratosis verruciformis in four and nail changes in 12 patients. Haemorrhagic macules were not seen. Rare features included oral mucosal lesions (two patients) and guttate leucoderma (three patients). Pathogens involved in cutaneous infections included herpes simplex virus, Staphylococcus aureus, Streptococcus species and Morganella morgani. All patients treated with oral retinoids had improvement of clinical signs. In contrast, the response to topical retinoids was poor. CONCLUSIONS: Compared with western studies, our results show a similar incidence rate, age of onset, distribution of disease patterns and association with neuropsychiatric disorders. Features that differ include co-occurrence of guttate leucoderma, rarity of acrokeratosis, absence of haemorrhagic macules and poor response to topical retinoids.

A novel missense mutation of the ATP2A2 gene in a Chinese family with Darier's disease.

Darier's disease (DD) is an autosomal dominant skin disorder that is characterized by multiple keratotic papules, focal loss of adhesion and abnormal keratinization. Mutations in the ATP2A2 gene encoding sarco/endoplasmic reticulum calcium pumping ATPase type 2 have been identified as the molecular basis of DD. We report here a three-generation family with DD, and examined ATP2A2 gene mutations in this family by direct sequencing. A novel missense mutation A-->G was identified in exon 12, nucleotide 1704, which leads to the substitution of lysine by arginine at codon 514 (K514R). This study contributes to the database on ATP2A2 in DD, and further illustrates the extensive diversity of mutational events that lead to the different phenotypes of DD.