Pain in Patients with Dystrophic Epidermolysis Bullosa: Association with Anxiety and Depression.

OBJECTIVE: We investigate the presence and the quality of pain in patients with dystrophic epidermolysis bullosa (DEB), and its correlation with the level of anxiety and depression. METHODS: We collected data from 27 DEB patients and 26 healthy individuals. DEB patients and controls completed 1 scale for the quality of pain, and 1 scale for anxiety and depression. Pain was assessed with the short form of the McGill Pain Questionnaire, whereas anxiety and depression were assessed with the Hamilton rating scale for anxiety and depression. RESULTS: DEB patients and healthy control individuals were homogeneous for age and gender (p>0.05). A statistically significant difference in the two groups was seen for sensory pain rating scale (p<0.001), affective pain rating scale (p=0.029), total pain rating scale (p<0.001), visual analogue scale (p=0.012) and present pain intensity (p=0.001), but not for anxiety (p=0.169) and depression (p=0.530). The characteristics of pain that showed a significant difference between DEB patients and healthy controls were shooting, splitting, tender and throbbing (p<0.05). In DEB patients pain was not correlated with anxiety or depression (p>0.05), whereas a slight correlation between pain and anxiety was found in healthy controls (p<0.05). No difference was found between quality of pain and anxiety-depression in DEB patients (p>0.05), but was between the DEB dominant and the recessive form of DEB (p=0.025). CONCLUSION: The perception of pain in DEB patients appears greater than in healthy individuals, with splitting and tender characteristics being the most significant ones, but was not associated with anxious and/or depressive symptoms.

Role of dystrophic epidermolysis bullosa in anxiety, depression and self-esteem: A controlled cross-sectional study.

The psychological aspect in patients with dystrophic epidermolysis bullosa (DEB) is poorly documented. We sought to determine the role of DEB in anxiety, depression and self-esteem. We conducted a cross-sectional study, collecting data from 27 DEB patients and 26 healthy individuals. DEB patients and healthy controls completed three different psychometric scales for anxiety and depression and one scale for self-esteem. DEB patients and healthy controls were homogeneous for age and sex (P > 0.05), but not for employment, marital status and economic level (P < 0.05). Median values of all psychometric battery scales were not statistically significant between DEB patients and healthy controls, except for Goldberg scale for anxiety (P = 0.003) and depression (P = 0.037) and slightly significant for Zung Scale for anxiety (P = 0.048) with no difference between DEB patients with dominant versus recessive form in all scales (P > 0.05). Among DEB patients, only employment showed a significant difference in all scales (P < 0.05) but Hamilton for depression, whereas self-esteem seemed to be affected by marriage (P = 0.04) and education (P = 0.016). DEB patients apparently are not more anxious and/or depressed and do not have less self-esteem than healthy individuals.

Evaluation of internal consistency of the epidermolysis bullosa oropharyngeal severity score (EBOS).

OBJECTIVE: To evaluate the internal consistency of the epidermolysis bullosa oropharyngeal severity score (EBOS). MATERIALS AND METHODS: Data from 92 patients of varying EB types/sub-types already described in a previous multi-center study were re-analyzed via the coefficient Cronbach's α (CR-α). Additionally, the corrected item total correlation between each item and the items' overall score with Pearson's product-moment correlation (ρ) was calculated. RESULTS: The alpha coefficient for the mean total score of 17 items is 0.941. The inter-observer reliability for disease severity score was excellent for oral medicine specialist (α = 0.924) and dermatologist (α = 0.916) and the intra-observer reliability was good at Time 1 (α = 0.895) and Time 2 (α = 0.897). The analysis of CR-α per single item revealed that alpha was greater than 0.904 for disease activity and 0.743 for structural damage, after the elimination of four items for oral medicine specialist and greater than 0.898 for disease activity and 0.769 for structural damage after the elimination of five items for dermatologist. Similarly the analysis of the corrected items-EBOS correlation showed that the same items do not correlate very well (ρ < 0.4) with the overall EBOS. CONCLUSIONS: The EBOS turned out to have a strong and reliable internal consistency, as the majority of the EBOS' items were consistent with each other.

Patterns of oral mucosa lesions in patients with epidermolysis bullosa: comparison and agreement between oral medicine and dermatology.

BACKGROUND: The oral mucosa in patients with epidermolysis bullosa (EB) can be affected with different lesions and degrees of severity. However, patterns of oral lesions in distinct types of EB are still unclear. OBJECTIVES: The purpose of this study was to determine the frequency and distribution of four types of lesions (erythema, erosion, atrophy, and blister) for each oral site and to calculate the interobserver reliability for each type of lesion in each site. METHODS: Ninety-two patients with different EB types were assessed independently by an oral medicine specialist and a dermatologist. The degree of agreement was calculated by the intraclass correlation coefficient (ICC). RESULTS: The most affected oral site was the tongue, with the most frequent lesion being erythema and atrophy [54(58.7%) patients] for the oral medicine specialist and erosion [54(58.7%) patients] for the dermatologist. Patients with recessive dystrophic EB-severe generalized (RDEB-sev gen) showed the highest mean of sites involved by each lesion for both oral medicine and dermatology. The interobserver reliability on the total of lesions was excellent on only 3 sites: lower lip (ICC: 0.89; 95%CI:0.83-0.92), hard palate (ICC:0.85; 95%CI:0.72-0.91), and tongue (ICC:0.89; 95%CI:0.84-0.92), whereas the interobserver reliability calculated for each single oral lesion showed a lower agreement. CONCLUSION: Total distribution of sites involved by four types of lesions was higher in RDEB-sev gen than in the rest of EB types, with a predominance of erythema followed by erosion. The agreement on the type of lesion was found to be poor-moderate for many oral sites.

Position effect on FGF13 associated with X-linked congenital generalized hypertrichosis.

X-linked congenital generalized hypertrichosis (Online Mendelian Inheritance in Man 307150) is an extremely rare condition of hair overgrowth on different body sites. We previously reported linkage in a large Mexican family with X-linked congenital generalized hypertrichosis cosegregating with deafness and with dental and palate anomalies to Xq24-27. Using SNP oligonucleotide microarray analysis and whole-genome sequencing, we identified a 389-kb interchromosomal insertion at an extragenic palindrome site at Xq27.1 that completely cosegregates with the disease. Among the genes surrounding the insertion, we found that Fibroblast Growth Factor 13 (FGF13) mRNA levels were significantly reduced in affected individuals, and immunofluorescence staining revealed a striking decrease in FGF13 localization throughout the outer root sheath of affected hair follicles. Taken together, our findings suggest a role for FGF13 in hair follicle growth and in the hair cycle.

Epidermolysis Bullosa Oropharyngeal Severity (EBOS) score: a multicenter development and reliability assessment.

BACKGROUND: Epidermolysis bullosa (EB) is a genetic mucocutaneous disorder characterized by blister formation upon mild trauma. All 4 EB types may show oropharyngeal lesions involving either hard or soft tissues. Currently, there are very few data on EB scoring that include the oropharyngeal cavity. OBJECTIVES: We sought to develop an oropharyngeal severity score that was objective, valid, reliable, reproducible, easy to perform, and appropriate for all EB types. METHODS: In this study, oral medicine specialists developed a new score, the EB Oropharyngeal Severity (EBOS) score. This measured oropharyngeal disease activity (erythema, atrophy, blisters, erosion/ulceration) and structural damage (microstomia, ankyloglossia, scarring phenotype beyond microstomia and ankyloglossia, enamel hypoplasia). It was tested on 92 patients with different types/subtypes of EB, and interobserver and intraobserver reliability were assessed. RESULTS: The EBOS mean total score was 12.9 ± 10.9 (range: 0-34). Both interobserver and intraobserver reliability for total score on all patients with EB were considered excellent (intraclass correlation coefficient 0.94; 95% confidence interval 0.90-0.96 and intraclass correlation coefficient 0.90; 95% confidence interval 0.84-0.94, respectively). Even analyzing each single parameter of the disease activity and structural damage, a substantial to excellent correlation was found in the interobserver (except for 4 sites) and intraobserver reliability. A significant correlation was found between EB types/subtypes and the EBOS median score (P < .001), but not between age and the EBOS mean total score in each group. LIMITATIONS: The sample size was small and the number of EB subtypes was limited. CONCLUSIONS: The EBOS score seems to represent an instrument capable of truly quantifying the oropharyngeal severity in different types/subtypes of EB, demonstrating excellent interobserver and intraobserver reliability.

Further insights in trichothiodistrophy: a clinical, microscopic, and ultrastructural study of 20 cases and literature review.

BACKGROUND: Trichothiodistrophy (TTD) is a rare autosomal recessive condition that is characterized by a specific congenital hair shaft dysplasia caused by deficiency of sulfur associated with a wide spectrum of multisystem abnormalities. In this article, we study clinical, microscopic, and ultrastructural findings of 20 patients with TTD with the aim to add further insights regarding to this rare condition. Additionally, analyses of our results are compared with those extracted from the literature in order to enhance its comprehensibility. MATERIALS AND METHODS: TWENTY CASES OF TTD WERE INCLUDED: 7 from Mexico and 14 from Spain. Clinical, microscopic, scanning electron microscopy (SEM) studies and X-ray microanalysis (XrMa) were carried out in all of them. Genetic studies were performed in all seven Mexican cases. Patients with xeroderma pigmentosum and xeroderma pigmentosum/TTD-complex were excluded. RESULTS: Cuticular changes and longitudinal crests of the hair shaft were demonstrated. These crests were irregular, disorganized, following the hair longest axis. Hair shaft sulfur deficiency was disposed discontinuously and intermittently rather than uniformly. This severe decrease of sulfur contents was located close to the trichoschisis areas. Only five patients did not show related disturbances. Micro-dolichocephaly was observed in five cases and represented the most frequent facial dysmorphism found. It is also remarkable that all patients with urologic malformations also combined diverse neurologic disorders. Moreover, three Mexican sisters demonstrated the coexistence of scarce pubic vellus hair, developmental delay, onychodystrophy, and maxillar/mandibullar hypoplasia. CONCLUSIONS: TTD phenotype has greatly varied from very subtle forms to severe alterations such as neurologic abnormalities, blindness, lamellar ichthyosis and gonadal malformations. Herein, a multisystem study should be performed mandatorily in patients diagnosed with TTD.

Fibroblast-derived dermal matrix drives development of aggressive cutaneous squamous cell carcinoma in patients with recessive dystrophic epidermolysis bullosa.

Patients with the genetic skin blistering disease recessive dystrophic epidermolysis bullosa (RDEB) develop aggressive cutaneous squamous cell carcinoma (cSCC). Metastasis leading to mortality is greater in RDEB than in other patient groups with cSCC. Here we investigate the dermal component in RDEB using mRNA expression profiling to compare cultured fibroblasts isolated from individuals without cSCC and directly from tumor matrix in RDEB and non-RDEB samples. Although gene expression of RDEB normal skin fibroblasts resembled that of cancer-associated fibroblasts, RDEB cancer-associated fibroblasts exhibited a distinct and divergent gene expression profile, with a large proportion of the differentially expressed genes involved in matrix and cell adhesion. RDEB cancer-associated fibroblasts conferred increased adhesion and invasion to tumor and nontumor keratinocytes. Reduction of COL7A1, the defective gene in RDEB, in normal dermal fibroblasts led to increased type XII collagen, thrombospondin-1, and Wnt-5A, while reexpression of wild type COL7A1 in RDEB fibroblasts decreased type XII collagen, thrombospondin-1, and Wnt-5A expression, reduced tumor cell invasion in organotypic culture, and restricted tumor growth in vivo. Overall, our findings show that matrix composition in patients with RDEB is a permissive environment for tumor development, and type VII collagen directly regulates the composition of matrix proteins secreted by dermal and cancer-associated fibroblasts.

Progress in epidermolysis bullosa: summary of a workshop in CILAD-2010*.

BACKGROUND: Epidermolysis bullosa (EB), a group of blistering disorders, manifests with fragility of skin and mucous membranes, with considerable phenotypic variability. As many as 15 distinct genes have been shown to harbor mutations inheritable forms of EB. The types and combinations of mutations in these genes and their consequences at the mRNA and protein levels, when placed on the affected individuals' genetic background and the external trauma, explain the spectrum of phenotypes encountered in this disorder. METHODS: A group of eminent researchers and physician-scientists convened in Cancún, Mexico, as part of the CILAD-2010 Meeting, to discuss the most recent progress in diagnosis and management of patients with EB, with emphasis on development of novel treatment strategies. RESULTS: The information on specific mutations in the candidate genes has been helpful in establishing genotype/phenotype correlations and has formed the basis for prenatal testing and preimplantation of genetic diagnosis for EB. CONCLUSIONS: In spite of the progress in molecular genetics of EB, there is no specific and effective treatment, and management of these patients continues to present tremendous clinical challenges. This overview summarizes the presentations and discussions in this international workshop.

Mutación en el gen EDA1, Ala349Thr en paciente con displasia ectodérmica hipohidrótica ligada a X / Mutation in the ED1, Ala349Thr in a patient with X-linked hypohidrotic ectodermal dysplasia

Hypohidrotic ectodermal dysplasia (HED) is a very rare disease characterized by the absence of eccrine glands, dry skin, scanty hair, and dental abnormalities. It is caused by mutations within the ED1 gene, which encodes a protein, ectodysplasin-A (EDA). Clinical characteristic are frontal bossing, saddle nose, pointed chin, a prominent supraorbital ridge with periorbital hyperpigmenta-tion, and anodontia. Those affected show great intolerance to heat. We report the first Mexican 2-year-old boy with an Ala349Thr missense mutation from Tamaulipas, México.

[Mutation in the ED1, Ala349Thr in a patient with X-linked hypohidrotic ectodermal dysplasia]. / Mutación en el gen EDA1, Ala349Thr en paciente con displasia ectodérmica hipohidrótica ligada a X.

Hypohidrotic ectodermal dysplasia (HED) is a very rare disease characterized by the absence of eccrine glands, dry skin, scanty hair, and dental abnormalities. It is caused by mutations within the ED1 gene, which encodes a protein, ectodysplasin-A (EDA). Clinical characteristic are frontal bossing, saddle nose, pointed chin, a prominent supraorbital ridge with periorbital hyperpigmenta-tion, and anodontia. Those affected show great intolerance to heat. We report the first Mexican 2-year-old boy with an Ala349Thr missense mutation from Tamaulipas, México.

Immunofluorescence mapping for the diagnosis of epidermolysis bullosa.

Immunofluorescence mapping is based on the detection of structural proteins of keratinocytes or of the dermo-epidermal junction using specific poly- or monoclonal antibodies. Through this method, the level of split formation can be determined by investigating the location of a given antigen in a natural or induced blister. This method also allows testing for the normal expression, reduction or absence of various structural proteins depending on the antibodies used. It has widely replaced transmission electron microscopy and is used as the initial laboratory test to prove the clinical diagnosis of epidermolysis bullosa.

Epidermolysis bullosa care in Mexico.

Epidermolysis bullosa (EB) in Mexico continues to be a rare genodermatosis that is still unknown for most of the health care professionals in the country. The spirit of DebRA MEXICO was born in 1994 when the Mexican health care team started to see patients with the main purpose to provide medical care, genetic counseling, and advice to patients with EB and their families; to promote collaboration and exchange information among people with EB; to research and find new therapeutic approaches; and finally, to diffuse knowledge and raise awareness of the issues of EB in general public and health care professionals.