Lack of plakoglobin leads to lethal congenital epidermolysis bullosa: a novel clinico-genetic entity.

Epidermal integrity is essential for skin functions. It is maintained by adhesive structures between keratinocytes, mainly the desmosomes and adherens junctions, which provide resistance against mechanical stress and regulate the formation of the skin barrier. As a constituent of both types of intercellular junctions, plakoglobin has multiple interaction partners and mutations in its gene [junction plakoglobin (JUP)] have been associated with mild cutaneous disease, palmoplantar keratoderma and arrhythmogenic heart disease. Here we report a novel lethal phenotype caused by a homozygous nonsense JUP mutation, c.1615C>T, p.Q539X, which is very different from any human or murine JUP phenotype described so far. The patient suffered from severe congenital skin fragility with generalized epidermolysis and massive transcutaneous fluid loss, but apparently no cardiac dysfunction. In contrast to previously reported JUP mutations where truncated proteins were still present, in this case there was complete loss of plakoglobin in the patient's skin, as demonstrated by immunofluorescence and immunoblot analysis. As a consequence, only very few abnormal desmosomes were formed and no adhesion structures between keratinocytes were recognizable. The expression and distribution of desmosomal components was severely affected, suggesting an essential role for plakoglobin in desmosomal assembly. Adherens junction proteins were localized to keratinocyte plasma membrane, but did not provide proper cell-cell adhesion. This lethal congenital epidermolysis bullosa highlights the fundamental role of plakoglobin in epidermal cohesion.

[Hereditary epidermolysis bullosa: clinical and ultrastructural analysis of 21 cases]. / Epidermolyses bulleuses héréditaires: etude clinique et ultrastructurale de 21 cas.

Hereditary epidermolysis bullosa (HEB) constitute a genodermatosis group with variable clinical severity. The aim of the study was to confront the diagnosis established by electron microscopy (EM), with the clinical presentation and evolution, genetic analysis and immunofluorescence, and to observe if there was concordance. Biopsies diagnosed as HEB in the last 15 years, were retrieved from the database of the C.H.U. Saint-Pierre EM lab. Each corresponding medical file was reviewed and the following data were recorded: date of birth, sex, age, age at biopsy, ultrastructural characteristics, degree of certainty regarding the EM diagnosis, family history, clinical lesions and their evolution as well as other diagnostic tests performed. 21 patients, aged 1 day to 26 year old were included. A HEB simplex was diagnosed in 10 cases, a junctional EBH in 5 cases and a dystrophic HEB in 6 cases. Immunofluorescence was requested in 4 cases. 7 patients benefited from a genetic analysis. Physical examination revealed hyperpigmented spots in 1 case. A patient with dystrophic HEB had a family history of symptoms restricted to the nails. 4 patients died. In conclusion, the accurate clinical diagnosis of the HEB sub-type is difficult because of the symptomatology heterogeneity. EM remains the gold standard for diagnosis even if immunofluorescence and genetic analysis should be more systematically considered.

Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience, 1986-2006.

BACKGROUND: Case series have demonstrated that potentially lethal cutaneous squamous cell carcinomas arise in patients with recessive dystrophic epidermolysis bullosa (RDEB), although the magnitude of this risk is undefined. METHODS: Systematic case finding and data collection were performed throughout the continental United States (1986-2002) by the National EB Registry on 3280 EB patients to determine cumulative and conditional risks for squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and malignant melanoma (MM) within each major EB subtype, as well as the cumulative risk of death from each tumor. Study design was cross-sectional, with a nested randomly sampled longitudinal subcohort (N = 450). RESULTS: SCCs arose primarily in RDEB, especially the Hallopeau-Siemens subtype (RDEB-HS), first beginning in adolescence. Less frequently, SCCs occurred in junctional EB (JEB). Cumulative risks rose steeply in RDEB-HS, from 7.5% by age 20 to 67.8%, 80.2%, and 90.1% by ages 35, 45, and 55, respectively. In Herlitz JEB, the risk was 18.2% by age 25. SCC deaths occurred only in RDEB, with cumulative risks in RDEB-HS of 38.7%, 70.0%, and 78.7% by ages 35, 45, and 55, respectively. MM arose in RDEB-HS, with a cumulative risk of 2.5% by age 12. BCCs arose almost exclusively in the most severe EB simplex subtype (Dowling-Meara) (cumulative risk = 43.6% by age 55). LIMITATIONS: Mutational analyses were performed on only a minority of enrollees in the National EB Registry, preventing evaluation of the possible influence of specific genotypes on the risk of developing or dying from cutaneous SCCs. CONCLUSIONS: SCC is the most serious complication of EB within adults, especially those with RDEB-HS. By mid-adulthood, nearly all will have had at least one SCC, and nearly 80% will have died of metastatic SCC despite aggressive surgical resection. When compared with SCCs arising within the normal population, the remarkably high risk of occurrence of and then death from SCCs among RDEB patients suggests likely differences in pathogenesis. Additional studies of EB-derived tumors and SCC cell lines may not only provide new insights into the mechanisms of carcinogenesis but also means whereby these particular tumors may be prevented or more effectively treated.

Cause-specific risks of childhood death in inherited epidermolysis bullosa.

OBJECTIVE: To determine the cause-specific risks of death in children with epidermolysis bullosa (EB). STUDY DESIGN: Data were collected throughout the continental United States between 1986 and 2002 by the National EB Registry. The study design is cross-sectional (n = 3280), containing within it a nested randomly sampled longitudinal subcohort (n = 450). RESULTS: The risk of death during infancy and childhood was greatest in junctional EB (JEB), with cumulative and conditional risks of 40% to 44.7% by age 1 in both JEB subtypes, rising to 61.8% in children with JEB, Herlitz subtype and 48.2% in those with JEB, non-Herlitz subtype (JEB-nH) by age 15. In decreasing order, sepsis, failure to thrive, and respiratory failure were the major causes of death in children with JEB, plateauing by age 2 to 6. A small minority of children with epidermolysis bullosa simplex, Dowling-Meara subtype was at risk for death by age 1 (cumulative risk, 2.8%), with sepsis and respiratory failure accounting for cumulative risks of 1.9% and 0.9%. Only a minority of children with recessive dystrophic epidermolysis bullosa, Hallopeau-Siemens subtype was at risk of death (cumulative risk = 8% by age 15). Renal failure also rarely accounted for death in children with JEB-nH. CONCLUSIONS: Infants and children with inherited EB, particularly those with JEB, are at significant risk of death as a result of disease complications.

Age and etiology of childhood epidermolysis bullosa mortality.

Epidermolysis bullosa (EB) is a heterogeneous group of congenital blistering diseases that are usually present in the neonatal period. They are characterized by blister formation in response to rubbing or frictional trauma. EB is classified into three major categories, each with many subtypes based on the precise location at which separation or blistering occurs, namely epidermolysis bullosa simplex (EBS), junctional epidermolysis bullosa (JEB), and dystrophic epidermolysis bullosa (DEB). We describe the causes and ages of death of three cases of EB in Hong Kong. A 24-year-old male with EBD diagnosed in the neonatal period lived a withdrawn life after completing secondary school and died of metastaic squamous cell carcinoma. Two neonates of consanguineous Pakistani parents, one with JEB and the other with EB-Pyloric Atresia variant, died of sepsis in infancy. We performed an extensive literature review of the causes and ages of death of these diseases. EB is a heterogeneous inherited blistering skin disease associated with significant morbidity and mortality. EBS is occasionally associated with death at early ages with sepsis. Patients with JEB usually died of sepsis at young age. DEB patients often survive to adulthood and die of cardiopulmonary and renal complications. Squamous cell carcinoma and metastases are unique in DEB.

Lethal epidermolytic epidermolysis bullosa: a new autosomal recessive type of epidermolysis bullosa.

A distinctive form of epidermolysis bullosa is reported among several members of a large Sudanese family. Although on ultrastructural grounds this appears to be simplex type, it is inherited as an autosomal recessive trait and is associated with a high mortality.

Association of generalized dystrophic epidermolysis bullosa with positive acetylcholinesterase and markedly elevated maternal serum and amniotic fluid alpha-fetoprotein.

A case of fatal generalized dystrophic epidermolysis bullosa is described in a prematurely born female whose mother had strikingly elevated mid-trimester serum and amniotic fluid alpha-fetoprotein concentrations, a positive amniotic fluid acetylcholinesterase band, and negative serial ultrasound studies. This case lends further support to an association between autosomal recessive generalized dystrophic epidermolysis bullosa and increased levels of alpha-fetoprotein, positive amniotic fluid acetylcholinesterase, and normal ultrasound findings.