Herlitz junctional epidermolysis bullosa: diagnostic features, mutational profile, incidence and population carrier...

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 (LAMB3, LAMA3 and LAMC2).

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.

All 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 GB3. In EM the hemidesmosomes and sub-basal dense plates were hypoplastic or absent. We identified mutations in all 22 patients: in 19 we found LAMB3 mutations, in two LAMA3 mutations, and in one LAMC2 mutations. We found three novel splice site mutations in LAMB3: (i) c.29-2A>G resulting in an out-of-frame skip of exon 3 and a premature termination codon (PTC); (ii) c.1289-2_1296del10 leading to an out-of-frame skip of exon 12 and a PTC; and (iii) c.3228+1G>T leading to an exon 21 skip.

All 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.