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ARTICLE
Year : 1963  |  Volume : 11  |  Issue : 4  |  Page : 87-95
 

Disciform macular degeneration associated with Ehler-Danlos syndrome (cutis hyperelestica)


Victoria Hospital, Jabalpur, India

Correspondence Address:
R K Mishra
Victoria Hospital, Jabalpur
India
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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 2014 Nov 1];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 Top


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 Top


 Ehlers-Danlos syndrome More Details 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 Top


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 Top


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 Top


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.[25]


   Acknowledgements Top


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 Top

1.Behr C. (1931) cited in 10 pp. 205, 207.  Back to cited text no. 1    
2.Bock J. (1938) cited in 10 p. 214.  Back to cited text no. 2    
3.Bonnet P. (1953) cited in 18 p. 150.  Back to cited text no. 3    
4.Brown A. and Stock V. F. (1937) Amer J. Dis. Child 54, 956.  Back to cited text no. 4    
5.Chakraborty A. N., Banerjee A. K. and Ghosh S. (1954). Journal Indian Med. Assn. 23, 344.  Back to cited text no. 5    
6.Danlos M. (1909) cited in 18 p. 136.  Back to cited text no. 6    
7.Duke-Elder S. W. (1940) Text Book of Ophthalmology Vol. Ill p. 2124. Henry Kimpton. London.  Back to cited text no. 7    
8.Durham 1). G. (1953) A. M. A. Arch. Ophth, 49, 220.  Back to cited text no. 8    
9.Ehlers E. (1901) cited in 18 p. 135.  Back to cited text no. 9    
10.Elwyn H. (1946) Diseases of the Retina pp. 199-202..1. & A. Churchill, London.  Back to cited text no. 10    
11.Freeman J. T. (1950) Amer J. Dis Child 79, 1049.  Back to cited text no. 11    
12.Hagedoorn A. (1939) cited in 10. p. 214.  Back to cited text no. 12    
13.Jansen L. H. (1955) cited in 18 p. 164.  Back to cited text no. 13    
14.Johnson S. A. M. and Falls H. F. (1949). Arch. Dcrmat. and Syph, 60, 82.  Back to cited text no. 14    
15.Junius P. and Kuhnt H. (1926) cited in 10, p. 199.  Back to cited text no. 15    
16.Junius P. (1930) cited in 7, p. 2124.  Back to cited text no. 16    
17.Mac Collurn D. W. (1938) J.A.M.A. 110, 1427.  Back to cited text no. 17    
18.McKusick V. (1960) Heritable Dis­orders of Connective Tissue, 2nd edition. pp. 1, 136, 150, 213. C. V. Moshy Co., St. Louis.  Back to cited text no. 18    
19.V. Meekeren (1682). cited in 18. p. 135.  Back to cited text no. 19    
20.Ota M. and Yasuda T. (1941) cited in 18 p. 136.  Back to cited text no. 20    
21.Sandoz Y. L. (1939) cited in 10, pp. 205, 207.  Back to cited text no. 21    
22.Schaper G. 1952) cited in 18, p. 150.  Back to cited text no. 22    
23.Sorsby A. and Wren N. (1960) A.M.A. Arch. Ophth. 63, 918.  Back to cited text no. 23    
24.Thomas C.. Cordier J. and Algan B. (1954) cited in 18. p. 150.  Back to cited text no. 24    
25.Verhoeff F. H. and Grossman H. P. (1937) Arch. of Ophthal 18, 561.  Back to cited text no. 25    


    Figures

  [Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5], [Figure - 6]



 

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