ARTICLE
Ehlers-Danlos syndrome type IV (EDS type IV) results from mutations in
the COL3A1 gene, which encodes the chains of type III procollagen [1-3].
COL3A1 mutations cause variable clinical phenotypes including acrogeria
and vascular rupture [3]. Essential clinical features include atrophy,
dryness and wrinkling of skin, especially of the face and distal extremities,
causing localized premature senility, and bruising. In addition, affected
patients are at risk for arterial, bowel, and uterine rupture.
Here we describe a 21-year-old male with acrogeric EDS type IV who also
had ocular and some unusual skeletal abnormalities.
Case report
The proband was a 21-year-old male, from Southeastern Turkey, referred
to our hospital with contractures of the hands and feet. The parents were
non-consanguineous but from the same small village. His father was similarly
affected and suddenly died at the age of 45 years of unknown cause. The
other 9 sibs of the father were normal. He was third in an otherwise normal
sibship of five. No abnormalities were recorded in pregnancy or perinatally,
and his mother's milestones were normal.
His height was normal, and he had a decreased span compared with height
and relatively short legs. His voice was abnormally high-pitched but he
was of normal intelligence.
His facial features were typical of acrogeric EDS type IV and included
prominent eyes (pseudoexophthalmus), thin lips, lobeless ears (attached
lobules) and a large slightly beaked nose (Fig.
1). He also had a Class III malocclusion with a missing left upper
second incisor. Cephalometry showed prognathia of the mandible. Typically,
superficial veins were clearly visible over the anterior upper trunk.
The right nipple was hypoplastic. There was also a generalized loss of
subcutaneous tissue, especially on his hands and feet, with atrophic wrinkling
and mottled hyperpigmentation, and the hands were small and shortened
at the 3rd percentile (Fig.
2a). The terminal phalanges of both fingers and toes were also shortened
and broadened with slight flexion contractures of proximal interphalangeal
and metacarpophalangeal joints. Typically for acrogeria, the finger and
toes nails were dystrophic as were the hands. His feet shortened at 3rd
percentile with bilateral hallux valgus (Fig.
2b). Atrophic wrinkled scars on elbows and knees were noted. There
was inguinal hernia on the right side.
Eye examination showed evidence of glaucoma with increased intraocular
pressures but normal angle morphology suggesting a diagnosis of open-angle
glaucoma. Visual field examination showed scattered scotomas in the Bjerrum
areas.
Laboratory
No general biochemical abnormalities were detected and key radiological
features are listed in Table
I and illustrated in Figure
3.
Four millimeter punch biopsies were obtained from the dorsum of the
hand. They were subsequently processed for light microscopy, transmission
electron microscopy and fibroblast culture.
Histopathology
Light microscopy showed reduced dermal collagen fibres with a relative
increase in elastin staining (Fig.
4a). Subcutaneous fat was depleted.
Electron microscopy
Transmission electron microscopy of the mid and lower dermis was shown
in Figures 4b-c.
Collagen biochemistry
Cultured skin fibroblasts were grown from a 4 mm punch biopsy and radiolabelled
collagen proteins prepared by standard techniques [3]. Procollagen, and
collagen secretion are illustrated in Figure
5a and b with the intracellular collagens included as Figure
5c. The patient's pattern (track 3) is compared with 2 normal controls
and in each instance in the secreted proteins (Fig.
5a + 5b), track 3 is reduced compared with the normal control, a sharp
slightly overmodified product is retained in the cell layer-Figure
5c, track 3, compared with the control signals.
This demonstrates that the proband fails to secrete normal quantities
of collagen and procollagen type III, instead retaining a slightly overmodified
product within the cell layer. These changes are consistent with a defect
of secretion and delayed helical winding of the mutant type III collagen.
Discussion
The patient reported here exhibited typical cutaneous and biochemical
changes of collagen type III deficient acrogeric EDS type IV. His cutaneous
collagen fibres were unusually small, rather than in bimodal distribution
as is more usual. Glaucoma has not been described previously in acrogeric
EDS type IV, but Pollack et al. [4] reported a case of EDS type
IV complicated with glaucoma secondary to the development of spontaneous
carotid-cavernous sinus fistula. In addition, it has been described that
the trabecular basement membranes are associated with types I, III, and
V collagen and the glycoprotein fibronectin [5, 6]. In our case deficiency
of collagen type III in the trabecular meshwork may be the reason for
raised intraocular pressure as a result of abnormal trabecular meshwork
structure. But, glaucoma is not uncommon, and another possibility is that
the glaucoma was an unrelated accompaniment. If it is related, postmortem
ultrastructural study of the trabecular meshwork may be necessary to show
this presumed explanation.
Various skeletal abnormalities have been described in EDS type IV. These
skeletal changes include club foot, congenital dislocation of hip [7],
acroosteolysis, joint contractures [8], pectus excavatum [9], atlantoaxial
subluxation [10], dehiscence of the sagittal suture and bony defects of
the superior wall of the right maxillary sinus and of the ethmoid [11].
Our patient had multiple skeletal abnormalities. Although micrognathia
has been frequently reported in acrogeria of the Gottron type, our patient
was prognathic. In addition, impressio digitalis in the skull was present.
Since collagen type III is ubiquitously distributed in connective tissue,
the inherited defective synthesis may produce the maldevelopment of the
skull and other bones in addition to the more typical stigmata.
The relationship between EDS type IV and Gottron
type acrogeria has been indicated by some authors, whereas others stressed
the features evidently separating both diseases. No abnormality of collagen
type III is found in Gottron type acrogeria. Blaszczyk et al. [12]
described a 46-year-old mother and her 20-year-old son with presumed acrogeria
of the Gottron type. They excluded abnormalities of type III collagen.
They suggested that acrogeria is not a variant of EDS type IV but a separate
entity, it is however possible that acrogeria might be heterogeneous and
a subgroup of the patients could harbor a mutation in type III collagen.
EDS type IV is generally inherited in an autosomal dominant fashion
[1, 2], but autosomal recessive inheritance has also been reported [13,
14]. The most likely cause in our case is autosomal dominant collagen
III mutation in the father, as the mother was clinically normal.
It can be considered that EDS type IV is a very serious vascular disorder,
not just a skin disease. The major complications are arterial, bowel,
and uterine rupture. Most deaths result from arterial rupture. Because
of these dramatic complications, life expectancy is shortened to a mean
of < 50 years. Types of complications were not associated with specific
mutations in COL3A1 [7]. Our patient's father was similarly affected and
died suddenly at an early age. The cause of his death may be related to
a catastrophic vascular rupture.
CONCLUSION
In summary, the smallness of the collagen fibres, unusual skeletal defects
and possibly glaucoma are atypical features in this acrogeric case.
Article accepted on 11/7/02REFERENCES
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