Long-term follow-up of patients with recessive dystrophic epidermolysis bullosa in the Netherlands: expansion of the mutation database and unusual phenotype-genotype correlations.
BACKGROUND
The current classification of recessive dystrophic epidermolysis bullosa (RDEB) comprises two major subtypes: 'severe generalized RDEB' (RDEB-sev gen) with early-onset, extensive, generalized blistering and scarring, complete absence of type VII collagen, and bi-allelic COL7A1 null mutations; milder 'generalized other RDEB' (RDEB-O) with reduced-to-normal type VII collagen expression, and non-null genotypes.


OBJECTIVE
To search for previously unrecognized phenotype-genotype correlations in 33 Dutch RDEB families.


METHODS
We analyzed extensive clinical follow-up data, available for all patients up to 19 years, detailed type VII collagen immunostaining and genotypes, and correlated clinical phenotype to molecular phenotype and genotype.


RESULTS
We identified 20 novel COL7A1 mutations. In 14 of 15 RDEB-sev gen patients type VII collagen was completely absent, one had strongly reduced type VII collagen, and all carried bi-allelic null mutations. Five of 11 RDEB-O patients developed pseudosyndactyly of the fingers preceded by skin atrophy and flexion contractures later in childhood and adolescence. All five had esophageal involvement and growth retardation. Type VII collagen immunostaining ranged from strongly reduced to slightly reduced in RDEB-O patients with pseudosyndactyly, whereas RDEB-O patients without pseudosyndactyly had slightly reduced to normal type VII collagen staining. There was no difference in genotypes between both groups, although we unexpectedly found bi-allelic null mutations in two of five RDEB-O patients with pseudosyndactyly.


CONCLUSIONS
Pseudosyndactyly occurs in approximately half of RDEB-O patients when type VII collagen is strongly reduced. The prognosis in RDEB cannot always be simply predicted from the COL7A1 genotype.
van den Akker
Peter C
PC
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. p.c.van.den.akker@medgen.umcg.nl
van Essen
Anthonie J
AJ
Kraak
Marian M J
MM
Meijer
Rowdy
R
Nijenhuis
Miranda
M
Meijer
Gonnie
G
Hofstra
Robert M W
RM
Pas
Hendri H
HH
Scheffer
Hans
H
Jonkman
Marcel F
MF
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D024143:Collagen Type VII / Q000235:genetics* / Q000378:metabolism; D016108:Epidermolysis Bullosa Dystrophica / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005091:Exons / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D009154:Mutation; D009426:Netherlands; D010375:Pedigree; D010641:Phenotype; D012867:Skin / Q000473:pathology / Q000648:ultrastructure; D055815:Young Adult
D024143:Collagen Type VII