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Epidermolysis Bullosa Letalis
Alternative Names
Epidermolysis Bullosa, Junctional, HerlitzPearson Type
Herlitz-Pearson Type Epidermolysis Bullosa
Epidermolysis Bullosa, Junctional, Herlitz Type
Epiligrin
WHO International Classification of Diseases
Congenital malformations, deformations and
chromosomal abnormalities
junctional epidermolysis bullosa characterized
by localized to generalized blistering, nail
dystrophy, scarring alopecia, and mucosal
involvement; and the Herlitz type of junctional
epidermolysis bullosa, associated with extensive
skin and mucosal blistering, nail dystrophy,
exuberant granulation tissue, enamel defects,
and a high perinatal mortality resulting from
overwhelming infections and respiratory
complications.
The junctional epidermolysis bullosa subtype,
generalized atrophic benign epidermolysis
bullosa, is characterized by life-long blistering,
resulting in cutaneous atrophy, diffuse scarring
alopecia, pigmentary changes, and nail and
tooth abnormalities.
OMIM Number
226700
Mode of Inheritance
Autosomal recessive
Gene Map Locus
18q11.2, 1q32, 1q25-q31
Description
Epidermolysis bullosa is a group of inherited
disorders of the epithelial basement membrane
zone that manifest with blistering of the skin
and mucous membranes after minor trauma.
The disease appears to be one of the most
frequent monogenic causes of infant mortality
among Arabs. The disease is traditionally
classified into three groups according to the
level of cleavage within the skin: Epidermolysis
bullosa simplex results from separation of the
skin above the basement membrane, junctional
epidermolysis bullosa is caused by blister
formation within the basement membrane, and
in the dystrophic form of epidermolysis bullosa,
blisters appear below the basement membrane.
To date, all cases of junctional epidermolysis
bullosa have been shown to be transmitted in an
autosomal recessive fashion.
Clinical and genetic heterogeneity are
characteristic of junctional epidermolysis
bullosa. Two major clinical variants of this
epidermolysis bullosa subtype have been
described: the moderately severe non-Herlitz
Molecular Genetics
The genetic basis of all major clinical variants
of epidermolysis bullosa has been delineated.
Specific mutations have been demonstrated in
10 different genes expressed within the
dermoepidermal adhesion zone, with at least six
different genes being involved in the
pathogenesis of junctional epidermolysis
bullosa.
Herlitz junctional epidermolysis
bullosa has been shown to be associated with
mutations in one of the 3 laminin-5 genes
(LAMB3, LAMA3, LAMC2), resulting in
premature termination of protein translation, or
reduced levels of mRNA transcripts resulting
from non-sense–mediated mRNA decay. NonHerlitz junctional epidermolysis bullosa cases
have also been assigned to mutations within the
laminin-5 genes.
The current mutation detection strategy
followed in the United States and Europe entails
analysis of patient samples for the recurrent
mutations in LAMB3 followed by sequential
screening of LAMB3, LAMC2, and finally
LAMA3.
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The observation of reduced type XVII
collagen/bullous
pemphigoid
antigen
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expression in the skin of generalized atrophic
benign epidermolysis bullosa patients led to the
identification of causative mutations within the
gene encoding this protein. Other clinical cases
of generalized atrophic benign epidermolysis
bullosa were shown to be caused by mutations
affecting laminin-5-encoding genes.
Epidemiology in the Arab World
Saudi Arabia
Nakano et al. (2002) identified two
consanguineous families originating from Saudi
Arabia
with
non-Herlitz
junctional
epidermolysis bullosa. Affected members of
both families were analyzed for mutations in
LAMB3, LAMA3, and LAMC2 genes. Both
patients turned out to be homozygous for the
Q46X mutation in the LAMC2 gene. Nakano et
al. (2002) further investigated the genealogic
relationship between the two unrelated families
and found out that both originated from a
Bedouin tribe of the Empty Quarter that is now
split between Saudi Arabia and the United Arab
Emirates.
Sudan
Nakano
et
al.
(2002)
identified
a
consanguineous family originating from Sudan
with generalized atrophic benign epidermolysis
bullosa. The affected member of the family
presented with milia over his face.
Immunofluorescence studies performed on
frozen skin sections indicated lack of staining
for type XVII collagen.
United Arab Emirates
Nakano
et
al.
(2002)
identified
a
consanguineous family originating from the
United Arab Emirates with non-Herlitz
junctional epidermolysis bullosa. The affected
child in the family was analyzed for mutations
in LAMB3, LAMA3, and LAMC2 genes. The
child turned out to be heterozygote for two
mutations, Q1083X and 1296insA, in the
LAMB3 gene. The Q1083X mutation has been
found in Haifa in Palestine. Interestingly, the
two grandmothers of the affected child
originated from that village. Nakano et al.
(2002) quoted the presence of two different
mutations in the affected child to emphasize the
fact that the presence of consanguinity does not
preclude compound heterozygosity.
Yemen
Nakano
et
al.
(2002)
identified
a
consanguineous family originating from Yemen
with non-Herlitz junctional epidermolysis
bullosa. The affected child in the family was
analyzed for mutations in LAMB3, LAMA3,
and LAMC2 genes. The child turned out to be
homozygous for the 1942delG aberration in the
LAMB3 gene.
References
Nakano A, Lestringant GG, Paperna T,
Bergman R, Gershoni R, Frossard P, Kanaan
M, Meneguzzi G, Richard G, Pfendner E,
Uitto J, Pulkkinen L, Sprecher E. Junctional
epidermolysis bullosa in the Middle East:
clinical and genetic studies in a series of
consanguineous families. J Am Acad
Dermatol. 2002; 46(4):510-6.
Contributors
Ghazi: 3.10.2004
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