Generalized verrucosis and abnormal T cell activation due to homozygous TAOK2 mutation.

BACKGROUND: Generalized verrucosis (GV) is a chronic and progressive cutaneous human papillomavirus (HPV) infection resulting in multiple warts and associated with acquired or genetic immune defects. We identified a consanguineous Arab family manifesting GV and recurrent bacterial and viral infections, in association with inflammatory bowel disease (IBD). OBJECTIVE: To identify the mutated gene responsible for GV, recurrent infections and IBD, in this family. METHODS: Flow cytometry of peripheral blood mononuclear cells was performed, as well as proliferation and cell cycle assays of T cells. Whole exome sequencing was utilized to detect candidate mutated genes, assuming an autosomal recessive mode of inheritance. Skin fibroblasts from a patient, the mother and control were incubated with sorbitol to detect the phosphorylation ability of TAOK2, and a clonogenic assay was performed to assess the survival and proliferative capacity of fibroblasts' colonies. RESULTS: Despite normal immunophenotyping of T and B cells, T cell proliferation upon activation was impaired in a patient compared to a heterozygous family member and a control. Genetic analyses identified a rare homozygous missense variant, c.2098C>T (p.R700C) in the TAOK2 gene, segregating with the disease phenotype in the family. TAOK2 encodes the TAO2 kinase, a mitogen activated protein kinase kinase kinase (MAP3K) in the p38-MAPK cascade. The mutation is predicted to disrupt its normal folding and molecular interaction; however, no impairment was observed in TAOK2 kinase activity toward its downstream target, MEK3/6, in patient's fibroblasts. Despite this normal kinase activity, a noticeably higher survival/proliferation of patient's skin fibroblasts was found. CONCLUSIONS: A mutation in TAOK2 appears to cause a novel form of primary immunodeficiency, characterized by an impaired T cell proliferation upon activation. This novel cause of GV gives further support to the importance of the p38-MAPK pathway in the immune response against HPV, and possibly also in the pathogenesis of IBD.

Prevalence of interdigital psoriasis of the feet ("psoriasis alba") in mild, moderate, and severe psoriasis.

Interdigital psoriasis of the feet ("psoriasis alba") is a rare form of inverse psoriasis. We conducted a cross-sectional study of the prevalence of interdigital psoriasis in mild, moderate, and severe psoriasis, compared to atopic dermatitis and normal controls. Data were collected during 2010-2013 from 232 psoriatic patients, 190 patients with atopic dermatitis, and 202 normal controls. The psoriatic and atopic dermatitis patients were from the dermatology department and outpatient clinic of the Hadassah-Hebrew University Medical Center in Jerusalem, Israel. The normal controls were healthy workers and volunteers from Hadassah Hospital who were not aware of any dermatological disease and had never consulted a general practitioner or dermatologist for skin problems of the feet. Our study revealed a prevalence of 2.6% of interdigital psoriasis of the feet in psoriatic patients, especially in men, and none in atopic dermatitis and normal controls. Three of the six affected patients with interdigital psoriasis of the feet complained of itching, both feet were involved in four patients, while two presented with additional palmoplantar psoriasis. The hematoxylin and eosin histopathological findings were in line with those found in inverse psoriasis. Dermatologists should be aware of this entity and treat it correctly. The diagnosis should be considered in psoriatic patients presenting with whitish plaque or patches in the toe-webs, in whom the fungal test is negative and are not responding to antimycotic treatment.

Two Novel Homozygous Desmoplakin Mutations in Carvajal Syndrome.

BACKGROUND: Mutations in various desmosomal proteins were shown to cause inherited forms of cardiomyopathy. Carvajal syndrome (Online Mendelian Inheritance in Man [OMIM] 605676) is characterized by the association of dilated cardiomyopathy, striate palmoplantar keratoderma, and woolly hair. It is caused by homozygous as well as heterozygous mutations in DSP, which encodes the desmosomal plaque protein desmoplakin. An overlapping cardiocutaneous phenotype was also described with homozygous mutations in genes encoding two other desmosomal proteins; plakoglobin (Naxos disease; OMIM 601214) and desmocollin-2 (OMIM 610476). METHODS: We performed clinical and molecular workups in two consanguineous Arab Palestinian families manifesting an autosomal recessive pattern of inheritance of the above mentioned clinical findings. Whole exome sequencing was employed in the search for the causing mutation. RESULTS: Affected family members suffered from biventricular involvement and arrhythmogenic right ventricular dysplasia based on echocardiography and magnetic resonance imaging. One patient who underwent implantation of an implantable cardioverter-defibrillator (ICD) is still alive at the age of 59 years. Whole exome sequencing revealed two novel homozygous mutations in DSP, each affecting one family. CONCLUSIONS: The association of woolly hair with palmoplantar keratoderma in a child should lead to a cardiac workup in the search for those at increased risk for sudden cardiac death. Early diagnosis and ICD implantation may be lifesaving. Whole exome sequencing should be utilized for rapid genetic analysis since the cardiocutaneous phenotype may result from mutations in one of several genes.

Excoriation (skin-picking) disorder in adults: a cross-cultural survey of Israeli Jewish and Arab samples.

OBJECTIVE: We sought to estimate the lifetime prevalence of Excoriation (Skin-Picking) Disorder (SPD) in the Israeli adult population as a whole and compare SPD prevalence in the Jewish and Arab communities. We also explored demographic, medical and psychological correlates of SPD diagnosis. METHODS: Questionnaires and scales screening for SPD, and assessing the severity of perceived stress, depression, obsessive-compulsive disorder (OCD), body dysmorphic disorder (BDD), alcohol use, illicit drug use, and medical disorders were completed in a sample of 2145 adults attending medical settings. RESULTS: The lifetime prevalence of SPD was 5.4% in the total sample; it did not differ between genders or within Jewish and Arab subsamples. Severity of depression (p<0.001), OCD (p<0.001) and perceived stress (p=<0.001) were greater in the SPD positive sample. Similarly, diagnoses of BDD (p=0.02) and generalized anxiety (p=0.03) were significantly more common in the SPD-positive respondents. Alcohol use and illicit substance use were significantly more common among SPD positive respondents in the total sample (both p's=0.01) and the Jewish subsample (p=0.03 and p=0.02, respectively). Hypothyroidism was more prevalent in the SPD-positive Jewish subsample (p=0.02). In the total sample, diabetes mellitus was more common in women than in men (p=0.04). CONCLUSION: Lifetime SPD appears to be relatively common in Israeli adults and associated with other mental disorders. Differences in the self-reported medical and psychiatric comorbidities between the Jewish and Arab subsamples suggest the possibility of cross-cultural variation in the correlates of this disorder.

Prevalence of tinea pedis in psoriasis, compared to atopic dermatitis and normal controls--a prospective study.

There are discrepancies in the literature regarding the prevalence of tinea pedis in psoriasis. The aim of this investigation was to conduct a cross-sectional study of the prevalence of tinea pedis in psoriasis compared to atopic dermatitis patients and normal controls. We enrolled 232 psoriatic patients, 190 atopic dermatitis patients and 202 normal controls, between the years 2010 and 2013. The prevalence of tinea pedis was 13.8% in psoriasis patients, not significantly different from that in atopic dermatitis patients 8.4% (P = 0.092)), but significantly higher than in normal controls 7.4% (P = 0.043). Both gender and age affected the prevalence of tinea pedis in psoriasis and normal controls, while only age affected the prevalence of tinea pedis in atopic dermatitis. Regarding gender, there was higher prevalence of tinea pedis in men: 19.1% (P = 0.019) in psoriasis and 12.1% (P = 0.013) in normal controls. Age affected the prevalence of tinea pedis in normal controls (P < 0.001), psoriasis patients (P = 0.001) and atopic dermatitis patients (P = 0.001), with higher prevalence with increasing age. Trichophyton rubrum was the most common species in psoriasis (71.9%), atopic dermatitis (75.0%) and normal controls (73.3%). Our study found a relatively high prevalence of tinea pedis among psoriasis patients.

Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair.

BACKGROUND: The combination of palmoplantar keratoderma and woolly hair is uncommon and reported as part of Naxos and Carvajal syndromes, both caused by mutations in desmosomal proteins and associated with cardiomyopathy. We describe two large consanguineous families with autosomal-recessive palmoplantar keratoderma and woolly hair, without cardiomyopathy and with no mutations in any known culprit gene. The aim of this study was to find the mutated gene in these families. METHODS AND RESULTS: Using whole-exome sequencing, we identified a homozygous missense c.2009C>T mutation in KANK2 in the patients (p.Ala670Val). KANK2 encodes the steroid receptor coactivator (SRC)-interacting protein (SIP), an ankyrin repeat containing protein, which sequesters SRCs in the cytoplasm and controls transcription activation of steroid receptors, among others, also of the vitamin D receptor (VDR). The mutation in KANK2 is predicted to abolish the sequestering abilities of SIP. Indeed, vitamin D-induced transactivation was increased in patient's keratinocytes. Furthermore, SRC-2 and SRC-3, coactivators of VDR and important components of epidermal differentiation, are localised to the nucleus of epidermal basal cells in patients, in contrast to the cytoplasmic distribution in the heterozygous control. CONCLUSIONS: These findings provide evidence that keratoderma and woolly hair can be caused by a non-desmosomal mechanism and further underline the importance of VDR for normal hair and skin phenotypes.