|Year : 1963 | Volume
| Issue : 4 | Page : 87-95
Disciform macular degeneration associated with Ehler-Danlos syndrome (cutis hyperelestica)
RK Mishra, IB Goel
Victoria Hospital, Jabalpur, India
|Date of Web Publication||2-Feb-2008|
R K Mishra
Victoria Hospital, Jabalpur
|How to cite this article:|
Mishra R K, Goel I B. Disciform macular degeneration associated with Ehler-Danlos syndrome (cutis hyperelestica). Indian J Ophthalmol 1963;11:87-95
|How to cite this URL:|
Mishra R K, Goel I B. Disciform macular degeneration associated with Ehler-Danlos syndrome (cutis hyperelestica). Indian J Ophthalmol [serial online] 1963 [cited 2015 Mar 29];11:87-95. Available from: http://www.ijo.in/text.asp?1963/11/4/87/38965
Disciform macular degeneration is not an uncommon cause of permanent loss of central vision in old people with arteriosclerotic changes. In children and young adults a similar picture can be seen with an ophthalmoscope, but there is a considerable tendency to recovery.- Duke Elder (1940).
As far as we know its association with Cutis Hyperelestica (Ehler-Danlos syndrome) has so far not been reported. We are reporting two cases of unilateral disciform macular degeneration in two brothers who exhibited in addition many of the classical signs of cutis hyperelestica.
| Case Reports|| |
CASE 1. S. K., male, 15 years, attended the eye OP.D. of Jabalpur medical college, on 15th February 1958 with a complaint of gradual fall of vision in the right eye. On examination he was found to be a well built boy of average intelligence. On external examination, the eyes were found to be normal.
Vision in the right eye was 6/18 which could not be improved and in the left, 6/6.
Fundus examination of the left eye revealed nothing abnormal. On the right side the media, the disc, the blood vessels were found to be normal. In the macular region. there was seen a large mass raised about 3 D, with a silvery ring around it. The colour of the mass was dull yellowish white. The macular vessels were seen over the mound and were of normal colour. The entire mass lay between the two temporal vessels and gave an impression of something solid in the outer layers of the retina or in the choroid. No hemorrhages or exudates were seen. The remaining retina appeared quite unaffected.
Systemic Examination: - The central nervous, the cardiovascular, the respiratory and the genitourinary systems were all found to be normal. He had bleeding piles for which he was successfully operated in the college hospital.
The skin and the joints were of special interest in this case. The skin was of normal colour but there were many large pink coloured papery thin scars over the knees, the legs, the shin and the forehead. The skin could be pinched easily and could be stretched for a good length without a complaint of pain by the patient. The stretched skin recoiled like rubber on being released. The pinna of the ears could be pulled down almost to the shoulder and the cheek could be pulled abnormally and on being released the skin recoiled with a snap. The carpal, the metacarpal and the wrist joints were very flexible.
Investigations of blood cytology, blood-chemistry and urine analysis were non-contributory. X' Ray examination of the skull the long and the flat bones showed no abnormality.
Before all these reports could reach us from the laboratory we lost contact of the patient for nearly three years. Then suddenly he presented himself again in the O.P.D. This time the vision of the affected eye had dropped to 6/36. The left eye vision had remained normal. The fundus picture of the right eye basically remained the same though there were some dark red spots on the macular area over the old mound. The spots appeared to us like hemorrhages in the choroid. All the systemic examinations and investigations were repeated, but no significant change was noted.
On his second visit the patient was accompanied by his younger brother who complained of similar trouble.
CASE 2 :- K. was a male aged 4 years. He complained of poor vision in the left eye, which he noticed accidentally.
On examination, he was found to be a well-built boy and active. External examination of the eye showed no abnormality. Vision right eye was 6/6, left eye 6/24. The media were clear. Fundus examination under mydriasis showed the presence of a large dull yellowish grey mass in the central area, almost twice the size of the disc. It was raised about 4D as in the previous case. The tumor mass appeared to be of a solid nature. No dark spot suggestive of any recent haemorrhage could be seen. The optic disc, the blood-vessels and the rest of the retina showed no abnormality.
The left Fundus was quite normal.
Systemic Examination : - The skin and the joints showed identical changes as in the previous case. There were many large, pink papery thin scars over the legs and the forehead. The skin was hyper elastic and resilient. The joints were flexible. All
other investigations were non-contributory.
Family History:- The three sisters of these two brothers are all healthy and apparently normal. They are all free from the ocular and the skin-joint disease.
The two brothers are our two patients who have both the skin, joint and ocular manifestations.
The grandfather (now dead) is said to have had cutis hyperelestica. The father of the child has similar scars on the legs and the knees but he has no ocular trouble. The mother has no cutis hyperelestica and no macular degeneration but she has a coloboma of the iris, the ciliary body and the choroid. The coloboma extended almost to the macular area.
| Discussion|| |
EHLERS-DANLOS SYNDROME has been listed by McKusick (1960) as an inheritable disorder of connective tissue, under which term, Marfan syndrome, Pseudoxanthoma Elasticum. Osteogenesis-Imperfecta, and Hurler's disease have been grouped. It is characterized by peculiar skin and joint manifestations and occasional ocular involvement. It manifests a dominant autosomal heredity with a variable penetrance, more common in males. --Johnson and Falls (1949).
The first case of this syndrome was described by v. Meekeren (1682) in a Spaniard. Since then many cases have been recorded particularly in dermatological literature. Ehlers (1901) and Danlos (1908) have described it in detail. Schaper (1952) found only 93 cases in European Medical literature but many minimal and moderate forms must have escaped detection. Cases from Japan-Ota and Yasuda (1941) and India are also known. Chakraborty, Banerjee, Ghosh (1954) reported a case in a young Hindu girl, but without any eye manifestation.
Cutaneous manifestations: The skin has a peculiar velvety feel, resembling wet chamois leather, it is hyper elastic and can be stretched like a rubber sheet for 6-8". There are typical papery. blotting paper scars over those bony prominences which are liable to be subject to trauma, viz. elbows, knees, tibial surfaces etc. The skin is also very friable, bruising and hematomas are the rule. Minor trauma and operations tend to cause gaping fish-mouth wounds. Sutures cut through, so that surgeons resort to the use of adhesive tape for closing a wound.- Brown and Stock (1937). These features were well marked in the cases presented.
Another feature. absent in our cases, is the presence of small tumors or cysts at pressure-points viz. heels, elbows.
Joint Manifestations:- -Hyper laxity and hyper extensibility of the joints is a remarkable feature of the disease, and many of these cases are discovered at circus side-shows. Both the cases presented this feature. Extreme mobility often results in frequent dislocations of the hip and shoulder joints, and sprains.
Other side-characteristics reported are prominent widely spaced eyes and mental retardation--Johnson and Falls (1949) lop-ears---Mac Collum (1938) wide-bridge of the nose and dental deformities-Freeman (1950), club foot and flat feet----Bonnet (1953).
Systemic Manifestations:- Cardiovascular malformations with congenital manifestations have been noted. Gastro-intestinal defect in the form of diverticula and umbilical hernias have been mentioned. Dissecting aneurysms of the aorta and intra-cranial arteriovenous aneurysms have been reported.- McKusick (1960) Cardiovascular, pulmonary or gastro-intestinal catastrophe in the form of spontaneous rupture can be the cause of death. No such manifestations were to be found in our cases.
Ophthalmic Sins: The commonest changes lie in the skin of the lids which lies in redundant folds and can be pulled out a considerable degree. Epicanthal folds, squint, blue sclerotics. microcornea with associated glaucoma - Durham (1953). keratocouns and ectopia lentis- Thomas, Cordier and Algan (1954) have been reported. In the fundus, retinitis poliferans, pigment spots, and exudative detachment of the retina have been described.-Bonnet (1953).
The disciform type of macular degeneration seen in our two cases has hitherto not been described.
Pathology:- -The basic pathology, according to Jansen (1955) and McKusick (1960) lies in the abnormal wicker-work of collagen, with elastic hyperplasia in some places e.g. joints and skin, this being stimulated by repeated stretching. Loss of normal tensile strength due to the defect in the collagen fibers allows the stretching of skin, joints and ligaments beyond their normal excursions. This anomaly may be limited to only one part of the body or may be generalised. Due to marked fragility, minimal trauma may produce hematomas and characteristic scars.
DISCIFORM MACULAR DEGENERATION was first described in detail by Junius and Kuhnt (1926). when it was pointed out by them, that earlier reports with histopathological findings had been published by Axenfeld and Elsching.
The disease essentially occurs in advanced age between the ages of 60 and 70 years. Reduction of vision to 6/60 or less is ushered in by metamorphopsia. Generally the affection of one eye precedes the other.
The Fundus picture reveals an irregular round mound, greyish yellow in colour raised 2 to 3D, over which retinal vessels may course. A small dark choroidal hemorrhage, as seen in Case 1, may precede or follow the mound formation. After reaching its maximum size, the mound begins to flatten due to cicatrization with permanent loss of vision. During this stage there may be a light peppering of pigment over the macular region.
Onset, in the third decade or earlier constitutes the juvenile form of disciform macular degeneration-Duke Elder (1940). Attention to it was first drawn by Junius (1930). The ophthalmoscopic picture is similar to that of the senile variety with marked fall of visual acuity but then gradual improvement of vision takes place till it becomes normal again in 6 to 8 months.
The basic pathological features in disciform degeneration as summarised by Elwyn (1948) are :-
1) Irregular thinning of Bruch's membrane in the macular region, which may lead to holes or ruptures.
2) A transudate from the chorio-capillaries between the pigment epithelium and the hyaline membrane. lifting up the former to form the mound.
3) Permeation of the transudate to the neuro-epithelium causing destruction of the latter.
4) Pigment proliferation and connective tissue replacing the transudate lead to 'peppering', cicatrization and local atrophy of the neural elements and sclerosis of chorio-capillaries.
A very critical study of 84 reported cases (129 eyes) of disciform macular degeneration has been carried out by Verhoeff and Grossman (1937) to which they have added the reports of three more eyes, enucleated for a mistaken diagnosis of malignancy and which have been studied histologically.
In the first two cases it could be established that the mound formation was due to hemorrhage from choriocapillaries, the subsequent replacement of the clotted blood by connective tissue led to its whitening.
In his third case, aged 63, where the vision was less affected and behaved more like the juvenile form of the disease, there was a serous exudate instead of a hemorrhage. which formed the mound.
It is noteworthy that in all the three cases there were breaks in Bruch's membrane, being minutest in case 3. The authors, from a restudy of published records and from their own cases conclude that in both the varieties, primarily there is a disturbance of the chorio-capillaries causing a transudate or/and a hemorrhage to accumulate beneath the pigment epithelium which is responsible for the mound. Breaks in Bruch's membrane may occur, through which reparatory processes act on the extravasate leading to the different end results of the two varieties.
No histopathological report of the juvenile form is available but in view of the similarity of the fundus picture and the comparative pathological study of Verhoeff and Grossman (1937) it may be assumed that the pathological process is not dissimilar. In both, the senile and the juvenile forms the mound formation is due to a transudate. In the juvenile variety where the vision recovers the transudate can be inflammatory, without breaks in Bruch's membrane, which gets absorbed with minimal amount of fibrous tissue formation. In the senile form (see later) where there are breaks in Bruch's membrane, due to degeneration, the transudate and/or haemorrhage from the chorio-capillaries is replaced by fibrous tissue with permanent loss of vision. The cause of this extavasate in the young as well as the old is as yet undetermined and probably varies in different cases. In most cases, the predisposing factor may be a localised vascular lesion of a degenerative or infective origin, picking selectively the macular region.
In our cases, case I showed 'the semblance of a hemorrhage over the macular region and some degree of peppering but in both the cases the central vision was a complete loss.
In the cases reported in this paper three problems require clarification?
I. What was the nature of the macular lesion?
a) Was it akin to the familial macular degeneration described by Sorsby?
b) Was it incidental and therefore unrelated to the skin-joint condition?
c) Was it of a degenerative type (abiotrophy)?
II What was the relation of the macular lesion with the hyperelastic skin-joint condition, in which collagen and elastic tissues are involved?
III The problem of genetics.
The unusual features of the macular condition of these cases were (a) early onset, (b) unilaterality, (c) permanent loss of vision, (d) familial association in two brothers and (e) association with cutis hyperelestica.
Looking to the familial incidence, one is reminded of the familial macular degeneration described by Sorsby (1960) but Sorsby's cases were asymptomatic, stationary and without mound formation.
As retinal conditions have been described in cutis hyperelastica, though rarely,-McKusick (1960), in our two cases the macular condition does not appear to be a separate entity but part of the complex of Ehlers-Danlos syndrome. (also see discussion later).
The answer to the problem of the real nature of the macular condition and its relationship with Ehlers-Danlos Syndrome in our two cases, may lie in a consideration of the relationship between Ehlers-Danlos syndrome and another inheritable connective tissue disorder, Pseudoxanthoma elasticum, on the one hand and that between disciform macular degeneration and angioid streaks on the other.
In pseudoxanthoma elasticum there is also a disturbance of collagen and elastic tissues together with skin, arterial and ocular manifestations.
The latter are in the form of angioid streaks (Groenblad-Strandberg syndrome), macular hemorrhage and choroiditis or central choroidal sclerosis. At least three instances of coincident cutis hyperelastica with pseudoxanthoma elasticum have been reported those by Collini, Nato and Palbois and Rollier-McKusick (1960).
In both, pseudoxanthoma elasticum and cutis hyperelastica there is a disturbance of the collagen and elastic fibers. It is not yet certain whether these diseases are the result of a defect of collagen or elasten. Brown and Stock, Jansen and McKusick attribute the defect to abnormal wicker-work and abnormal whorls of interlacing collagenous fibrils.
There is now strong histologic, histopathologic and electron microscopic evidence that what was earlier described as elastic tissue degeneration is more an elastotic degeneration of collagen fibrils. Since senility appears to be responsible as one of its causes it may be assumed that abiotrophy can also form a cause.
Coming to the discussion on the relation between discoid macular degeneration and angioid streaks, we find that cases of the two conditions associated together have been frequently reported. They may exist together in the same eye or in opposite eyes, where the mound formation may precede or follow the formation of angioid streaks.
As the pathology of angiod streaks which are described in pseudoxanthoma elasticum and that of discifrom degeneration is somewhat similar, a resume of the histological studies and their comparison will be useful.
In Bruch's membrane, the inner homogenous layer is the product of the pigment epithelium whereas the outer layer, though known as lamina elastica consists of both elastic and collagenous fibrils.
The two cases of angioid streaks studied histo-pathologically very thoroughly have been by Bock (1938) and Hagedoorn (1939). In both there were thickening, thinning, and irregularity of I. elastica. Studies by reconstruction of serial sections showed that the streaks were basically caused by ruptures in the outer layer of Bruch's membrane in which there were also holes, the larger of which were filled with collagenous fibers and some fibroblasts. The interesting part is that in the macular region, between Brush's membrane and the pigment epithelium there was a mound characteristic of disciform macular degeneration, consisting of connective tissue which contained vessels, proliferated pigment epithelium and newly formed elastic tissue.-Elwyn (1946). Can this be elastotic degeneration of collagenous tissue? In any case, angioid streaks and disciform macular degeneration have been proved to co-exist.
Studies of Verhocff and Grossman (1937) as already stated have led them to believe that the primary change in disciform degeneration is in the choriocapillaries and that can be initiated by a degenerative or toxi-infective factor. In all three of their cases there were breaks in Brush's membrane.
Studies of Elwyn of the same condition on the other hand have led him to consider a degenerative condition of the outer layer of Bruch's membrane, where there are collagenous fibers, as the primary cause.
A compromise can be brought about between these two views. It is possible that the toxi-infective factor of Verhoeff and Grossman may be inducing a vascular change in chorio-capillaries at the same time setting up an elastotic degeneration of collagenous fibers in the outer layer of Bruch's membrane. The one or the other change may prevail according to other contributory factors. In senile disciform degeneration per se, the vascular change may prevail with secondary connective tissue reaction. In our two cases since there is an association of the macular condition in a syndrome where there is a definite disturbance of connective tissue, it is more likely that the theory of collagen disturbance prevails. The characteristic fragility of the tissues and tendency to bleed in Ehler-Danlos syndrome may be responsible for an extravasate (transudate and/or hemorrace) at the macula with formation of a mound.
Since primary changes in Ehler-Danlos are of a familial hereditary type involving the elastic and collagen tissues, it may be assumed that the primary change in the maculae of our cases were of a heredodegenerative type in Bruch's membrane especially of the collagen bearing outer layers.
This establishes the pathogenic relationship between disciform degeneration and angioid streaks since both can be due to ruptures in Bruch's membrane either primary or due to elastic degeneration or an elastotic degeneration of collagen.
These considerations establish the nature of the macular lesion and its relationship with cutis hyperelastica in our two cases and the close relationship between cutis hyperelastica and pseudoxanthoma elasticum. Both are of a hereditary and familial nature. In both there is a degradation of elastic and/or collagen fibers. In the retinal manifestations, angioid streaks have been reported in pseudoxanthoma elasticum and disciform degeneration in cutis elastica by us.
| Conclusions From Pathological Considerations|| |
Pathological studies indicate a close relationship between angioid streaks and disciform macular degeneration, both having been found together in the `same eye ophthalmoscopically as well as in reconstruction section studies and both being due to breaks in Bruch's membrane due to a pathogenesis similar to that of pseudoxanthoma elastica and cutis hyperelastica.
Typical disciform degeneration is found in elderly people and is due to fragility of chorio-capillaries and senile degeneration of Bruch's membrane. A similar pathology in our two young patients though from a different pathogenesis, with permanent loss of vision puts the ocular condition of our reported cases into an abiotrophy.
The association of this disciform degeneration with Ehlers-Danlos syndrome makes it a part of a general disease of collagen tissue of a heredodegenerative type, this ocular manifestation being the first to be described in two brothers in this report.
| Genetics|| |
The problem of genetics involves a consideration of the following facts.
1. Ehlers-Danlos Syndrome in which the accepted type of heredity is autosomal and dominant, was present in the grandfather, father and the two sons. The daughters were unaffected.
2. In senile disciform degeneration a hereditary factor is suspected by Behr (1931) and Sandoz (1939), though the type of heredity has not been worked out.
3. Congenital coloboma of the choroid in which the abnormality is transmitted as irregularly dominant was present only in the mother.
Since no histological study was possible in our cases, it is not possible to establish any definite similarity between the macular conditions here and senile macular disciform degeneration accept for the ophthalmoscopic picture and the clinical course.
It is plain that an inherited type of degeneration tendency which manifests itself at a variable time after birth cannot have anything in common with a fully established developmental defect at birth, like coloboma of the choroid.
To our mind the association of these two entirely different types of hereditary conditions present separately in the mother and father can be purely accidental and could have taken no part in the ocular manifestation of Ehler Danlos in the two male siblings.
The pathological similarity between the macular condition and skin-joint manifestations of this syndrome does not need any additional hereditary factor for this ocular manifestation to be present along with the skin-joint ones.
| Summary|| |
Two cases of Ehlers-Danlos Syndrome in two brothers having a disciform macular degeneration in one eye are described. This ocular manifestation is the first to be reported. The family history suggests a dominant hereditary factor.
By a pathological study of reported cases of Ehlers-Danlos, Pseudoxanthoma elasticum, angioid streaks and disciform macular degeneration an attempt is made to show the similarity between disciform degeneration and angioid streaks. From these comparisons the primary pathological change of disciform degeneration in the cases here reported is speculated as being due to an elastotic degeneration of collagenous fibers in the outer layers of Bruch's membrane. In senile disciform degeneration the vascular change (fragility of chorio-capillaries) may prevail.
The dominant type of hereditary degenerative tendency of these cases have nothing in common with the fully established developmental defect of coloboma of choroid that was present only in the mother.
| Acknowledgements|| |
We acknowledge here our sincere appreciation for the considerable help given by Dr. Mrs. H. H. Vakil (Bombay) and Dr. S. N. Cooper in the preparation of this paper.
| References|| |
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[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5], [Figure - 6]