Herlitz junctional epidermolysis bullosa: diagnostic features, mutational profile, incidence and population carrier frequency in the Netherlands.

[junctional epidermolysis bullosa]

Junctional epidermolysis bullosa , type Herlitz (JEB-H ) is a lethal , autosomal recessive blistering disease caused by null mutations in the genes coding for the lamina lucida /densa adhesion protein laminin-332 (LAMB 3 , LAMA 3 and LAMC 2 ).To present the diagnostic features and molecular analyses of all 22 patients with JEB-H in the Dutch Epidermolysis Bullosa Registry between 1988 and 2011 , and to calculate the disease incidence and carrier frequency in the Netherlands .A ll patients were analysed with immunofluorescence antigen mapping (IF ), electron microscopy (EM ) and molecular analysis .The mean lifespan of our patients with JEB-H was 5 ·8 months (range 0 ·5 -32 ·6 ). IF showed absent (91 %) or strongly reduced (9 %) staining for laminin-332 with monoclonal antibody GB 3 . In EM the hemidesmosomes and sub-basal dense plates were hypoplastic or absent . We identified mutations in all 22 patients : in 19 we found LAMB 3 mutations , in two LAMA 3 mutations , and in one LAMC 2 mutations . We found three novel splice site mutations in LAMB 3 : (i ) c .29 -2 A >G resulting in an out-of-frame skip of exon 3 and a premature termination codon (PTC ); (ii ) c .1289 -2 _1296 del 10 leading to an out-of-frame skip of exon 12 and a PTC ; and (iii ) c .3228 +1 G >T leading to an exon 21 skip .A ll diagnostic tools should be evaluated to clarify the diagnosis of JEB-H . We have identified 11 different mutations in 22 patients with JEB-H , three of them novel . In the Netherlands the incidence rate of JEB-H is 4 ·0 per one million live births . The carrier frequency of a JEB-H mutation in the Dutch population is 1 in 249 .