with an incidence varying from 1/3,000 newborn males to 1  :  40,000 or 1  :  117,000 live male births , fabry is considered one of 7,000 known rare diseases that exist in the usa and elsewhere . however , the number of patients is probably underestimated , because their symptoms are quite variable and unspecific , often leading to confusion with rheumatoid diseases or chronic inflammatory conditions . a confirmatory diagnosis comes , on average , 14 years after the onset of the first symptoms for male adults and 16 years for females , three years for symptomatic children . considering the life - threatening aspect of the disease , this delay is unfortunate . because ocular manifestations are among the first to appear in fabry subjects , eye care practitioners are key players in detecting and screening for this disease . this paper aims to present a new clinical finding that may help them improve screening effort and alert them to potential fabry subjects while performing slit lamp examinations . it also underscores the importance of examining the external surface of the upper lid , an area usually hidden and left unexplored during routine anterior segment examination of the eye . the universit de montral , cole d'optomtrie , is conducting a longitudinal study on ocular manifestations related to fabry disease . details of the study design and methods have been published elsewhere   but are briefly described here . since 2010 , thirty - eight fabry subjects have enrolled in the study , matched for age and sex with 15 healthy subjects acting as a control group . enrollment required a confirmed diagnosis of fabry disease and consent to be seen on an annual basis for five years . for the control group , subjects had to be healthy , nonmedicated , and free of any ocular pathology at the moment of enrollment . the study was approved by the institutional ethics committee and respects the tenants of the declaration of helsinki . annual examination of both groups includes several refractive and ocular health tests , including a slit lamp examination , gonioscopy , high order aberration evaluation , corneal hysteresis measurement , fundus and anterior segment photography , oct assessment of the optic nerve , and threshold visual fields . at the very beginning of the longitudinal study , one subject showing a high sensitivity to light closed his eyes during a routine slit lamp procedure . the author then observed abnormal blood vessel tortuosity and microaneurysms on the external part of the upper lid . based on this anecdotal finding , all other subjects since then have been screened to confirm the presence of vessel tortuosity and/or microaneurysms affecting this area . this report analyzes the results of anterior segment photography from the last examination of every subject . images were kept and saved on a computer using image 2000 software provided by topcon canada ( montreal , quebec ) . in cases where multiple pictures were taken for the same patient , the image with the best definition was kept . subjects were asked to close their eyes . the upper lid area , from nasal to temporal sides , was carefully examined . any vessel tortuosity and/or microaneurysms were noted and documented by the same photographer for every patient . for some of them , vessels were best seen when the upper lid was stretched . they were classified into 4 groups based on the severity of the tortuosity observed : none , mild , moderate , and severe ( defined in table 1 ) . because this entity has never been reported before , a grading scale was developed using the canadian fabry disease initiative ( cfdi )   grading scale for conjunctival vessel tortuosity for reference purposes , given that it reflects an international consensus . group a comprised 38 fabry subjects : 16 males and 22 females , aged 40 ( 14 ) years old on average . a majority of male subjects ( 12 ) and a fewer females ( 7 ) were undergoing enzyme replacement treatment at the time of the visit . group b comprised 15 healthy subjects : 7 males and 8 females , aged 37 ( 12 ) years old . male subjects in general and those under enzyme replacement therapy in particular were found to be more symptomatic than female ones . male patients were more likely affected by angiokeratomas ( treated 91.7%/nontreated 71.5% ) , acroparesthesia ( 83.3% versus 50% ) and tinnitus ( 66.6% versus 50% ) , or renal dysfunctions ( 58.3% versus 50% ) . female patients were found with cardiopathy ( treated 85.7% versus nontreated 33.3% ) , angiokeratomas ( 71.4% versus 13.3% ) , and acroparesthesia ( 57% versus 53.3% ) . it is important to note that overall , one out of two patients was affected by fatigue / depression . about a third of them are also complaining about vertigo and respiratory problems ( clinical signs and symptoms of group a cohort blood vessels tortuosity was identified in 36/38 of the fabry patients ( 94.7% ) , while none of the subjects in group b showed similar finding ( see table 2 and figure 1 ) . male subjects and those under treatment were more likely to show severe tortuosities . in some cases , group b subjects had blood vessels visible under the slit lamp . however , the vessels observed in group b subjects were straight , nontortuous , nondilated , and free of telangiectasia and were located deeper in the skin ( less visible ) . in addition , microaneurysms ( mas ) were found in 10/38 group a subjects ( see table 3 and figures 2 , 3 , 4 , 5 and 6 ) while none in group b presented a similar finding . globally , 82.5% of the subjects presenting ma on the upper lid showed the same finding for bulbar conjunctiva . statistically , the differences observed between the 2 groups were highly significant ( wilcoxon test , p < 0.005 ) . to our knowledge , this is the first time that the presence of blood vessel tortuosity visible on the external side of the upper lid has been reported in fabry patients . it was probably not identified before because this area is rarely assessed during routine eye examinations . individuals under treatment are more likely to show severe manifestations of vessels tortuosity , in the lids and elsewhere in the body . such modification of the vascular tissue is not surprising considering the nature of fabry disease . fabry disease is an x - chromosome linked disease including 431 different mutations for the gla gene . it is characterized by a deficiency of the lysosomal enzyme alpha - galactosidase a ( gla or -gal a ) , secondary to protein misfolding and/or an inability to direct the enzyme towards the lysosomes . in fabry , the enzyme deficiency leads to an accumulation of substrate within the cells , with a preference for organs that naturally accumulate the greatest amount ( the heart and kidneys ) ; it also favours the vascular endothelial cells , renal dorsal root ganglion cells , the cornea , and the skin . this is why the observation of vascular changes on the palpebral area is quite likely . they can be identified very early in childhood , by age three   if not earlier . they usually occur at the same time as systemic symptoms , especially in hemizygous subjects . classic ocular manifestations include vortex pigmentation of the cornea ( verticillata ) , lens opacities ( anterior whitish opacities and posterior subcapsular cataract ) , conjunctival vessel anomalies , and retinal vessel tortuosities , although such manifestations do not usually impair vision or create visual symptoms . our findings suggest that upper lid blood vessels tortuosity must be added to the list of key ocular manifestations of fabry disease , as it is the case for other tortuosities affecting the eye . from the data presented , it is quite clear that most of group a subjects ( 94.7% ) were affected by blood vessel tortuosity similar to that found in the conjunctiva and elsewhere in the eye and their body ( angiokeratomas , see table 4 ) . males , under treatment , showed the most severe forms of vessels tortuosity , followed by females under treatment and then males and lastly females , both untreated . the only unique feature found on the lid , compared to the conjunctiva , was the presence of telangiectasia . this sign is habitually present when new blood vessels are generated in response to a lack of oxygen perfusion . the presence of the substrate within the blood vessels can contribute to alter the perfusion of the oxygen to the surrounding tissue . angiogenic factors can consequently be released , leading to the development of new blood vessels . based on their clinical features , vessels tortuosity observed in fabry subjects can not be confused with any kind of inflammation of the lid ( blepharitis ) . in addition to the absence of characteristic clinical findings related to lid inflammation , subjects did not complain of acute redness , lid swelling , debris , deposits , foreign body sensation , or lids stuck in the morning . clinical findings were found involving most of the area of the upper eye lid surface , not only the lid margins , contrary to other lid pathologies such as mebomitis or posterior blepharitis ( ocular rosacea ) . blood vessels on normal subjects are visible but do not present tortuosities , microaneurysms , nor telangiectasia . because this study is one of the few that have gathered together such a large number of fabry patients and because upper lid blood vessels tortuosity was observed in over 90% of these subjects , we are extremely confident in proposing this clinical feature as a characteristic of the disease .   based on the case of other tortuosities observed in fabry , we suspect that their likely cause is the accumulation of globotriaosylceramide ( gl3 ) within the endothelial blood vessel cells . as it is for the retina , we do not expect any long - term negative impact from the presence of vessel abnormalities on the upper lid . only long - term observation will tell if such tortuosities have the potential to affect ocular health in any manner .   the first element to consider as a bias in this study is the number of subjects recruited as control ( group b ) , being half of the fabry subjects ( group a ) . limited manpower to recruit and follow subjects explains in part the reason for this discrepancy . however , we do not feel that this factor can influence the outcome of the study considering the high number of subjects showing blood vessels tortuosities in group a while none showed the same finding in group b. even with more subjects in group b , the possibility to find a difference in the number of suspects with the same vessels tortuosity is minimal . a second bias can come from the fact that the study of the images was made by the same investigator who did the examination . it is true that analysis by a second reader , blinded to the subjects , would add some value to the findings . however , results are so obvious that the necessity to rely on an external validation appears to be limited in regard to the clinical findings found . we were obviously unable to perform histological comparisons of the two groups that participated in this study . it would be interesting , at some point , to investigate the cellular level in order to establish anatomical evidence of the blood vessel tortuosity characteristic of fabry 's disease in the affected subjects . this paper proposes that blood vessels tortuosity , visible on the external surface of the upper eyelid , be recognized as a new clinical entity for inclusion among the classic ocular manifestations of fabry 's disease . to classify this new entity , , it should be considered a benign sign contributing to evidence of suspected fabry 's disease , especially in male patients .
purpose . to report a new clinical finding related to fabry disease 
 . methods . 
 fabry subjects were enrolled in the study , matched for age and sex with healthy individuals as a control group . 
 this is a prospective review of all upper lid pictures taken for every subject at their last visit . 
 a 4-step grading scale is proposed to classify this new entity . 
 results . 
 group a ( fabry ) comprised 16 males and 22 females , aged 40 ( 14 ) years on average . 
 group b ( control ) comprised 7 males and 8 females , aged 37 ( 12 ) vessels tortuosity was identified on the external superior lid in 36 of the fabry patients ( 94.7% ) , while none of the subjects in group b showed similar vessels tortuosity . 
 in addition , microaneurysms ( mas ) were found in 10/38 group a subjects while none in group b presented a similar finding . 
 the differences are highly significant . conclusion . 
 this paper proposes that blood vessels tortuosity on the upper eyelid be recognized as a new clinical entity for inclusion among the classic ocular manifestations of fabry 's disease . without evidence of any negative impact 
 , it should be considered a benign sign contributing to evidence of suspected fabry disease .