ARTICLE
Auteur(s) : Jouni Uitto
Department of Dermatology and Cutaneous Biology, Thomas
Jefferson University, 233 South 10th Street, Suite 450,
Philadelphia, PA 19107
accepté le 5 Juillet 2005
Ehlers-Danlos syndrome (EDS) is a prototypic connective tissue
disorder with protean manifestations [1]. The first clinical
description detailing this disorder dates back to 1892 by Dr.
Tschernogobow, a Russian dermatologist, and subsequently, Drs.
Ehlers and Danlos, Danish and French dermatologists, respectively,
expanded on the systemic nature of this condition. The genetic
nature of EDS was recognized in 1949, and its clinical
manifestations were subsequently suggested to result from defects
in the collagen “wicker work”. The genetic heterogeneity of EDS was
established in the 1960s, and the first molecular defects in
collagen biosynthetic pathways were established in patients with
EDS in 1972 [2].The cutaneous features include loose and fragile
skin, poor wound healing, bruising tendency, and the scars are
characteristically atrophic, often resembling “cigarette-paper”. In
addition, there are a number of extracutaneous manifestations,
including hyperextensible joints with propensity to dislocations,
and in certain subtypes of EDS, fragility of blood vessels,
gastrointestinal tract and uterus can result in catastrophic
complications.Traditionally, EDS has been subdivided into 11
distinct variants (types I – XI), based on clinical observations,
mode of inheritance, and/or molecular characterization. However, a
consensus conference held in 1997 (Villefranche) proposed a revised
nosology, which recognizes six distinct subtypes (Table I( Table 1 ); [3]). In fact, several previously
described variants, some of them exceedingly rare and not well
defined, were excluded from the EDS category.The molecular basis of
the major forms of EDS is now well established, and the clinical
manifestations are based primarily on mutations in the genes
encoding collagen polypeptide subunits or enzymes that modify the
primary collagen translation products (Table I; [3]). Collagen
consists of a family of proteins, and there are as many as 27
distinct vertebrate collagens (types I-XXVII) [4]. Each collagen
molecule is composed of three α-chain subunits, which can be
identical in homotrimers, or consist of two or three different
kinds of polypeptides in heterotrimers. Thus, there are over 40
different genes encoding distinct α chains that are synthesized as
precursor polypeptides, proα-chains. These polypeptides are
hydroxylated and glycosylated in reactions catalyzed by specific
enzymes, three of the proα-chains then fold into the characteristic
triple-helical conformation, and the collagen molecules are
secreted into the extracellular milieu where they undergo
proteolytic processing, fiber assembly, and formation of
stabilizing inter- and intra-molecular crosslinks.In different
forms of EDS, specific mutations have been identified in type I,
III, and V collagen polypeptides, as well as in two enzymes that
modify the collagen molecules, viz. lysyl hydroxylase and
procollagen N-peptidase [4]. These molecular defects explain the
connective tissue weakness and ultrastructural abnormalities in
collagen fibrils. Specifically, as demonstrated by transmission
electron microscopy, the collagen fibrils show considerable
variability in their diameter, and although individual fibrils can
be unusually large with irregular contours, the density of collagen
fibrils is often reduced. Thus, EDS has been considered as a
disease of collagen. However, evidence of molecular heterogeneity
exists beyond the collagens. Specifically, the TNX gene, which
encodes tenascin-X, a connective tissue protein developmentally
associated with collagen fibrils, harbors mutations in a subset of
patients with EDS [5]. It was demonstrated by immunofluorescence of
the skin of these patients that they were lacking tenascin-X, and
their serum contained essentially undetectable levels of this
protein. The clinical features in these patients were similar to
those of the classical autosomal dominant type of EDS, except that
the tenascin-X deficient patients lack atrophic scars and wound
healing is not consistently delayed, findings characteristic of
classic EDS. Furthermore, while the classic forms of EDS display
autosomal dominant inheritance, the patients with tenascin-X
deficiency show autosomal recessive inheritance. The pathoetiologic
role of tenascin-X has been further confirmed by the development of
TNX null mice, which recapitulate many of the features of patients
with tenascin-X deficiency [6]. The latter findings add to the
molecular complexity of EDS beyond the collagens, but they also
provide a diagnostic test through serum assay of tenascin-X,
helpful in subclassification of EDS as well as in providing
information on the mode of inheritance with implications for
genetic counseling.In this issue of the Journal, Yeowell et al. [7]
describe a patient with EDS of the kyphoscoliotic type with some
unusual clinical features. The patients with this subtype of EDS
are clinically characterized by soft and hyperextensible skin, wide
scarring and easy bruisability, as well as laxity of joints, severe
muscle hypotonia at birth and severe kyphoscoliosis. In addition,
the young patient examined in this study had cystic malformations
of the meninges that the authors originally describing this case
[8] suggested to result from connective tissue weakness as part of
the EDS clinical spectrum. Mutation analysis identified a large,
8.9 kb, duplication in the LH1 gene that encodes lysyl hydroxylase,
a critical enzyme during collagen biosynthesis. Specifically, this
enzyme hydroxylates selected lysyl residues to form corresponding
hydroxylysine residues which then form hydroxylysyl-pyridinoline
crosslinks critical for stabilization of collagen fibers. In fact,
urinary cross-link analysis can be used to determine reduced lysyl
hydroxylase activity, thus confirming the diagnosis of the
kyphoscoliotic type of EDS, as reflected by a decrease in the
hydroxylysyl-pyridinoline/lysyl-pyridinoline ratio. Furthermore,
biochemical assays of the lysyl hydroxylase activity in this
patient’s skin fibroblasts revealed severe reduction (> 80%) in
the enzyme activity.Molecular genetic analysis revealed that the
duplication extended from intron 9 to intron 16, and extended the
length of the messenger RNA from 3.4 to 4.2 kb. This particular
mutation has been documented previously in a number of patients
with this subtype of EDS [9], and the authors’ calculations
indicate that close to 20% of mutations affecting the LH1 gene are
identical duplications [7]. Although this duplication does not
directly affect the catalytic site of the enzyme, it has been
speculated that lengthening of the protein causes major changes in
the conformation of the protein, resulting in reduction of lysyl
hydroxylase activity.Collectively, this interesting patient extends
the phenotypic spectrum of EDS to include cystic malformations of
the meninges. This study also attests to the power of molecular
genetics in providing information that is helpful in confirming the
subclassification of EDS as well as providing information for
accurate genetic counseling in individual families.
References
1 Uitto J, Ringpfeil F, Pulkkinen L. Heritable
Disorders of Connective Tissue – Ehlers-Danlos Syndrome,
Pseudoxanthoma Elasticum and Cutis Laxa. In: Bolognia JL,
Jorizzo JL, Rapini RP, eds. Dermatology. London: Harcourt
Publishers, 2003: 1519-30.
2 McKusick VA. Heritable disorders of connective tissue
(4th ed). St. Louis: CV Mosby, 1972.
3 Beighton P, De Paepe A, Steinmann B,
Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes:
revised nosology, Villefranche, 1997. Ehlers-Danlos National
Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med
Genet 1998; 77: 31-7.
4 Myllyharju J, Kivirikko KI. Collagens, modifying
enzymes and their mutations in humans, flies and worms. Trends
Genet 2004; 20: 33-43.
5 Schalkwijk J, Zweers MC, Steijlen PM,
Dean WB, Taylor G, van Vlijmen IM, et al. A
recessive form of the Ehlers-Danlos syndrome caused by tenascin-X
deficiency. N Engl J Med 2001; 345: 1167-75.
6 Mao JR, Taylor G, Dean WB, Wagner DR,
Afzal V, Lotz JC, et al. Tenascin-X deficiency
mimics Ehlers-Danlos syndrome in mice through alteration of
collagen deposition. Nat Genet 2002; 30: 421-5.
7 Yeowell HN, Walker LC, Neumann LM. An
Ehlers-Danlos syndrome type VIA patient with cystic malformations
of the meninges is homozygous for a pathogenic seven exon
duplication in the lysyl hydroxylase 1 gene; allelic frequency of
the mutation. Eur J Derm 2005: 353-8.
8 Brunk I, Stover B, Ikonomidou C,
Brinckmann J, Neumann LM. Ehlers-Danlos syndrome type VI
with cystic malformations of the meninges in a 7-year old girl. Eur
J Pediatr 2004; 163: 214-7.
9 Heikkinen J, Toppinen T, Yeowell HN,
Krieg T, Steinmann B, Kivirikko KI, et al.
Duplication of seven exons in the lysyl hydroxylase gene is
associated with longer forms of a repetitive sequence within the
gene and is a common cause for the type VI variant of Ehlers-Danlos
syndrome. Am J Hum Genet 1997; 60: 48-56.
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