Lenticular Opacities in Carriers of Lowe's Syndrome GERHARD W. CIBIS, MD,*'t JOANNE M. WAELTERMANN, MD,* CHAUNCEY T. WHITCRAFT, MD,t RAMESH C. TRIPATHI, MD,* DAVID J. HARRIS, MD*

Abstract: Eleven possible and five obligate carriers of Lowe's syndrome from the same pedigree were examined for lens opacities. All of the obligate carriers and 4 of the 11 at risk had lens abnormalities. The lenticular abnormalities consisted of cortical dots of various shapes that increased in number with the age of the carriers in older obligate carriers, subcapsular plaques were common. Because the syndrome is X linked, such lens changes are explainable by the Lyon's hypothesis. When the number of opacities seen in these subjects were compared to those seen in 100 normal control females 10 to 20 years of age, cataractagenic cases such as diabetes, Down's and fetal nuclear opacities excluded, four probable carriers were identified among the eleven possible carriers in the pedigree. These subjects had significantly greater numbers of opacities, similar to those seen in obligate carriers, compared to controls. We conclude that progressive lens changes are present in carriers of Lowe's syn­drome and that young carrier females can be identified reliably when they are compared to age-matched controls by modifying the grading system of Brown and Gardner. [Key words: carrier state, cataracts, genetic counseling, Lowe's syndrome, Lyon hypothesis, X-linked recessive inheritance.] Ophthalmology 93:1041-1045, 1986

Lens opacities are known to be present in obligate car­riers of Lowe's syndrome. They represent a partial clinical expression of the X-linked inherited gene as postulated by Lyon.' There is controversy, however, over whether these opacities can be used successfully to identify carrier females for purposes of genetic counseling.2

The opacities are punctate, white to gray in appearance, and vary in size from microns to several millimeters. They, therefore, differ from cerulean or sutural cataracts. They are present in all layers of the cortex, indicating that they are formed well into adult life. They are not found in the nucleus, unlike congenital nuclear opacities. Although distinctive in their appearance, such lens opacities can also occur in females who are not Lowe gene carriers. The critical feature is the number of cortical opacities, which is high in carriers.

From Children's Mercy Hospital,* Kansas City, Missouri, and the Depart­ment of Ophthalmology, University of Kansas,t Kansas City, Kansas, and the Department of Ophthalmology, University of Chicago,:j: Chicago, Illinois.

Presented to the Missouri Ophthalmological Society.

Reprint requests to Gerhard W. Cibis, MD, 4620 J. C. Nichols Parkway, Suite 421, Kansas City, MO 64112.

Brown and Gardner investigated a large family affected by Lowe syndrome and attempted to identify carriers of the gene among daughters of obligate carriers.2 Obligate carriers are women from a Lowe pedigree who have more than one affected son or an affected brother and son. Half of their daughters can be expected to be carriers. Brown and Gardner studied the obligate carriers and compared them to controls.

As controls they studied 117 normal female subjects (234 eyes). Eighty percent of the controls were found to have some lens opacities. Only 55 of these subjects were younger than 41 years old and thus in the age range where genetic counseling is important. The number of opacities per lens quadrant was extremely small in the controls when compared to obligate Lowe carriers. Brown and Gardner recommended a recording system for counting the number of opacities per quadrant and rated them from 1 + to 4+.2 With this system six of seven obligate carriers scored 3+ or higher (the seventh was rated 2+). In their control population only seven ofthe 234 eyes (3%) scored 3+ or higher. When 2+ was used as a criterion for sus­pected carrier status, all of their obligate carriers were in­cluded, but so were 18% of the control eyes. The usefulness of counting opacities to identify Lowe carriers would

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OPHTHALMOLOGY • AUGUST 1986 • VOLUME 93 • NUMBER 8

II

III

IV

o Examined Cataracts (Lenticular Opacities)

• Examined, Affected

o Examined, Normal

I Propositus

+ Expired

o Male

o Female

Fig 1. The pedigree of the subjects studied.

therefore appear limited based on Brown and Gardner's experience.2

To identify carriers by counting opacities, we believe that Brown and Gardner overlooked appropriate age matched controls with respect to requirement of genetic counseling needs of potential carriers.2 Most of their con­trols were older, as were their obligate carriers. We there­fore undertook a study of control lenses of normal females in their second decade of life. This is the age group for which genetic counseling is most pertinent. We then compared our findings to a large family with the Lowe gene (Fig 1).

Our pedigree contained six obligate, mostly older car­riers and thirteen possible carriers, all of whom were less than 26 years of age. The family is well-known to have Lowe syndrome and has been reported before.3

-5 The re­

cent birth of two affected male infants, one of them born to a woman with six normal children, further prompted us to review all obligate and potential carrier females in this family in an attempt to rationalize genetic counseling.

METHODS

All subjects were dilated with cyclopentolate 1 % ophthalmic drops and examined with a slit lamp with full pupillery dilation. Both direct slit beam and retroillumi­nation were used and care was taken to inspect all layers of cortex. All obligate and possible carriers with significant opacities were photographed as were selected normal eyes (Figs 2-9).

For controls we examined 100 consecutive female pa­tients, aged 10 to 20 years, seen in our practice. These control patients were examined using the methods de­scribed above. Lens opacities were graded for each obligate

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and suspected carrier and for normals utilizing the cri­terion of Brown and Gardner {1-15 opacities, 1+; 16-80, 2+; 81-200, 3+; 4+, opacities too numerous to count).2 In normals with lens opacities, the type of opacity was also noted.

For 20 control patients two independent observers graded the lenses in a blind fashion. We compared the grading of opacities per quadrant statistically to insure reproducibility of results. The presence or absence oflen­ticular opacities, as determined by the two observers, was strongly associated (P < 0.0001 by a Fisher's exact test) in that the two observers would score the same individual similarly (P = 0.012). We also examined whether the ac­tual counting of lens opacities would agree by using a paired t-test. For these data 5 = 1.949 indicated that the number of opacities counted by the observers did not differ significantly (0.05 < P < 0.10).

RESULTS

We examined and photographed five of the six obligate and all eleven possible carriers. A possible carrier is a fe­male from a pedigree with Lowe syndrome. Four of the five obligate carriers were older than 40 years at the time of examination (Table 1). One (III-3), who had had bi­lateral cataract extraction when in her twenties, was rated as having had 4+ opacities. Photographs of the lens opac­ities offour of the obligate carriers are illustrated in Figures 4,6, 7, and 8. A sixth obligate female (1-2) was 70 years old and could not be photographed.

Of the eleven possible carriers screened, only two (III-6 and III-7) were over 20 years of age. One (III-7) already had had bilateral cataract extraction and was, therefore, classified as a probable carrier. A probably carrier is a

CIBIS, et al • LENTICULAR OPACITIES IN LOWE'S SYNDROME

Fig 2. Top left. a normal lens shown in retroillumination with a slit beam section of di­rect illumination in the right portion of the pupil. Note the homogeneous appearance of the lens in retroillumination. Fig 3. Top right. subjects 111-17, an 18-year-old probable carrier. Innumerable lentic­ular opacities are visible in both retro- and focal illumi­nation. In focal illumination. the lenticular opacities are seen as gray or white dots. The angle of the slit beam and illumination of the lens are critical. Not all lenticular opacities can be seen simul­taneously. Fig 4. Second row left. directly illuminated lens of the mother of the subject illustrated in Figure 3. The mother (11-7) is a 46-year-old obligate carrier. The number of gray-white opacities is greater than that seen in the younger daughter (Fig 3). Fig S. Second row rt., a posterior subcapsular cataract is pres­ent in subject 111-6, a twenty five year old probable carrier. Fig 6. Third row left. a pos­terior subcapsular cataract is evident in subject 11-3, the mother oflll-3 (Fig 7), a 51-year-old obligate carrier. In­numerable flecks are visible in retroillumination on the right side of the pupil. On the left side of the photograph, in direct illumination. is a uni­form distribution of white flecks throughout all layers of the cortex. This photograph again shows that not all len­ticular opacities can be seen with a single type of illumi­nation or simultaneously. Fig 7. Third row right. the right eye of the obligate carrier 111-3 is shown in retroillumina­tion. The flecks are obvious. The left eye had a small pos­terior subcapsular cataract when the subject was 26 years old. She is the daughter of the obligate carrier shown in Figure 6. Fig 8. Bottom left. obligate carrier 11-12 had the typical innumerable flecks in the cortex. as seen in both direct and retroillumination. She also had a posterior subcapsular plaque. Fig 9. Bottom right. the l6-year-old daughter III-22 of subject 11-12 (Fig 8) is a probable carrier. This photograph shows subtle expression of the probable carrier state when the lens is viewed in retroillumination. The diagnosis of probable carrier becomes more evident from the large number of flecks seen in direct slit beam illumination (right of figure).

possible carrier with abnormal numbers oflens opacities. What constitutes an "abnormal number" is the subject of this paper. The other nine were between 12 and 20

years of age. Four (including III-7) of the eleven possible carriers had 3+ or greater opacities (Table 2) and were classified as probable carriers. Photos of the lenses of these

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OPHTHALMOLOGY • AUGUST 1986 • VOLUME 93 • NUMBER 8

Table 1. Lenticular Opacities of Obligate Carriers

Obligate Carriers Age Grade (pedigree #) (years) (per Brown and Gardner2)*

11-3 51 4+ 11-5 49 4+ 11-7 46 4+ 11-12 41 4+ 111-3 26 4+

* One to fifteen opacities per quadrant, 1+, 16-80, 2+, 81-200, 3+; 4+ indicated that the opacities were too numerous to be counted.

Table 2. Lenticular Opacities of Probable Carriers

Probable Carriers Age Grade (pedigree #) (years) (per Brown and Gardner2)

111-6 25 4+ 111-7t 24 4+ 111-17 18 4+ 111-22 16 4+

* One to fifteen opacities per quadrant, 1+; 16-80,2+; 81-200, 3+; 4+ indicated that the opacities were too numerous to be counted.

t Had previous bilateral cataract extraction.

Table 3. Lenticular Opacities of Apparent Noncarriers

Apparent Noncarriers Age Grade (Normal) (pedigree #) (years) (per Brown and Gardner2

)

111-11 21 1+ 111-16 18 0 111-19 15 0 111-20 12 0 111-21 18 0 111-23 14 0 111-24 13 0

* One to fifteen opacities per quadrant, 1+; 16-80, 2+; 81-200, 3+; 4+ indicated that the opacities were too numerous to be counted.

Table 4. Lenticular Opacities for 100 Control Females 10 to 20 Years of Age (average age, 12.04 years)

No. Opacities/Quadrant Patients

o 1-2 3-4 5-15 >15

47 45 3 5 o

Brown and Gardner2

Grade

o 1+ 1+ 1+ 2+

Present Study Grade

o 1+ 1+ 2+ 3+

* One to fifteen opacities per quadrant, 1+; 16-80, 2+; 81-200, 3+; 4+ indicated that the opacities were too numerous to be counted.

suspects are shown in Figures 3, 5, and 9. The lenses of the seven others were either totally clear or classified as only 1 + (Table 3).

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Of the 100 consecutive female patients (200 eyes) be­tween the ages of 10 and 20 years presenting in our practice (Table 4) who served as controls, the median age was 12.04 years. Of this group 53% had some opacities and would be classified as 1 +. None had more than 15 opac­ities per quadrant that would have been classified as 2+ or higher. Five had fetal nuclear or sutural opacities, unlike those in Lowe carrier females. These were not counted as opacities for the purpose of this study.

In the control population 47/100 individuals (94 eyes) had no opacities, and decreasing numbers of patients each had one, two, or three opacities per quadrant. This portion of the control population fit a Poisson distribution with a mean of 0.3 opacities per quadrant. A small number of controls formed a second mode at five opacities per quad­rant. This may be an artifact of the method of data col­lection and not a true bimodal occurrence. It may also reflect unknown cataractogenic influences other than Lowe syndrome, for example diabetes or glucose-6-phos­phate dehydrogenase deficiency.6

DISCUSSION

According to Lyon's hypothesis, cells randomly deac­tivate one of their two X chromosomes early in the em­bryogenesis of the female. I In some carrier states, cells with an abnormal gene will manifest that gene clinically. For example, in sex-linked albinism and choroideremia, carrier females have mild clinical expression of the dis­order.

Brown and Gardner explored the possibility that in Lowe syndrome carriers such an expression of the perti­nent gene could result in greater numbers of lens opacities than are seen in normal controls.2 In their study five of seven obligate carriers were over 40 years of age, the oldest being 71 years old. The youngest two carriers were 22 and 39 years old. Brown and Gardner used a random, pri­marily older population of females for their control groUp.2 They only had 14 controls aged 0 to 20 years. Of these, 42% had some lens opacities. Our control group yielded a similar finding, with 53% offemales having some opacities. Thirty-five percent of their 14 controls 0 to 20 years old scored 1+, 7% scored 2+, and none had 3+ or 4+.

Of the 41 controls aged 20 to 41 years in the Brown and Gardner study, 77% had some opacities. Sixty-seven percent were graded 1 +, 10% were graded 2+, and none were graded 3+ or 4+. The older control groups (62/117 being over 41 years old) had a high incidence of opacities, making a differentiation from the older Lowe carrier fe­males difficult. The older patients, however, are not in the critical genetic counseling period. Brown and Gardner, from their limited younger controls and Lowe carriers, concluded that "a young woman carrying the Lowe gene is likely to have a score of at least 2+ while normal ho­mozygotes are unlikely to score above 1 +."2 Because of their selection of a mostly older control group who may naturally have a higher incidence of lenticular opacities than the 10 to 20-year-old females seeking genetic coun-

ClBIS, et al • LENTICULAR OPACITIES IN LOWE'S SYNDROME

seling, Brown and Gardner were unable to emphasize the reliability of identification of the carrier state. 2

The difference in number and density of opacities be­tween the younger probable and the older, obligate carrier females in our family suggests that there is a progression of the lens opacities with aging. Cataract extraction early in adult life in one obligate and one probable carrier also supports this view. The typical white punctate opacities of Lowe carriers are most frequent in the deep layers of the cortex just outside the nucleus, indicating formation beginning in infancy. The more superficial opacities point to continuation of their formation well into adult life. This is also true of the supcapsular, plaque-like cataracts seen predominantly in older obligate carriers. Progression of opacities can be explained by the fact that cells with the Lowe gene on their active X chromosome are abnor­mal and develop clinical opacification over time. The in­crease in opacities with time and sparing of the fetal nu­cleus in carriers is of interest since the Lyon's hypothesis indicates deactivation of the X chromosome occurs very early in embryogenesis. I The male Lowe patient is born with cataract. Why fetal cells do not show opacities in carrier females is unknown, but may reflect a gene inter­action within lens cells or other modifying factors.

Fifty percent of the female offspring of carrier females are expected to be carriers. In this study we classified 4 of 11 as carriers on the basis of 4+ lens opacities. In a sample of this size this deviation could easily occur by chance (P = 0.27). Only one of the remaining possible carriers had 1 + changes. (Brown and Gardner grading) (Table 3). Grade 1 + as per Brown and Gardner occured in half of our controls. The other half had no opacities, with none of the remainder having a score greater than 1+ (Tables 1-4). Our grading system subdivides the Gardner-Brown 1 + more finely (Fig 4).

CONCLUSION

From our family study it appears that carriers in their second decade of life have an identifiably higher number of lens opacities than are found in age matched controls. If this is accepted as fact, then a change in the scoring system of Brown and Gardner will improve one's ability

to detect carriers in the second decade of life, especially if cerulean, sutural and fetal nuclear opacities which are known not to be features of Lowe syndrome are excluded.2

Persons in the second decade oflife rarely have more than a few opacities per quadrant (1 + according to Brown and Gardner's original system). If 1-5 opacities per quadrant were graded as 1+, 5 to 15 as 2+, 15 to 25 as 3+ and more than 25 as 4+, then all of the obligate and probable carriers would be 4+. One of the seven probable non car­riers in the family would have 1 + and the remaining six would be O.

Of the normal control population 47% would be 0; 48%, 1 +; 5%, 2+; and none 3+ or 4+, which is distinctly dif­ferent from the probable carriers in this age group in number of opacities. A few opacities are common in nor­mal females of this age group, but only rarely are there more than five per quadrant. In contrast, carriers of the Lowe gene, even in this age group, already have too many lens opacities to count.

Lack of opacities cannot be thOUght of as proof of not being a carrier, but is highly suggestive. Similarly, a high number of opacities without a family history of Lowe's syndrome is meaningless. It may represent cataractogenic factors other than the Lowe gene. 6,

7 This also explains the high incidence of opacities in Brown and Gardner's older control population.2

REFERENCES

1. Lyon MF. Sex chromatin and gene action in the mammalian X-chro­mosome. Am J Hum Genet 1962; 14:135-48.

2. Brown N, Gardner RJM. Lowe syndrome: identification of the carrier state. Birth Defects 1976; 12:579-95.

3. Tripathi RC, Cibis GW, Tripathi BJ. Lowe's syndrome. Trans Ophthal­mol Soc UK 1980; 100:132-9.

4. Cibis GW, Tripathi RC, Tripathi BJ, Harris OJ. Corneal keloid in Lowe's syndrome. Arch Ophthalrnol1982; 100:1795-9.

5. Tripathi RC, Cibis GW, Harris OJ, Tripathi B. Lowe's Syndrome. Birth Defects 1982; 18:629-43.

6. Skalka HW, Prchal JT. Presenile cataract formation and decreased activity of galactosemic enzymes. Arch Ophthalmol 1980; 98:269-73.

7. Skalka HW, Prchal JT. The effect of diabetes mellitus and diabetic therapy on cataract formation. Ophthalmology 1981; 88:117-23.

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