Ismail K Jalili

FRCS, DO, FRCOphth

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18 Genetic Conditions in the West Bank and Gaza Strip: Results and Discussion
Introduction
18.1   Congenital cataract
18.2   Ectopia lentis
18.3   Congenital glaucoma
18.4   Small eyes (microphthalmia / anophthalmia)

18.5   Hereditary corneal conditions (congenital corneal oedema

18.6    Hypopigmentation
18.7  Retinal dystrophies
18.8 Vitreoretinopathies
18.9 SVL/BL in common conditions
18.10 Associated conditions and clinical aspects
18.11 Prevalence of common conditions
18.12 Other aspects of the survey
Educational performance
Red filter (glasses) trials
References  
Appendices    A  /  B

Introduction

This chapter will address the common clinical conditions encountered in the childhood onset visual impairment survey between 1985-1987 in the West Bank and Gaza Strip. This includes epidemiological and clinical aspects with discussion. These are lens disorders (congenital cataract / aphakia and ectopia lentis); small eyes (both anophthalmia and microphthalmia); corneal conditions, both acquired and congenital; albinism, and the common retinal disorders both stationary and progressive.

18.1  Congenital Cataract

Congenital cataract (CC) is the commonest treatable condition in the series and the second commonest genetic condition. Appendix Table A18.1 lists all cases, their birth sequence, ratios, and mode of inheritance.

Patients and Sibships
The number of patients with cataract as a primary pathology was 132 forming 91% of the lens group (n= 145). (Table 18.1) The figure rises to 164 when cases with cataract as a secondary cause of pathology are added. The figure rises further to 185 when all cases with childhood onset cataract (but which did not contribute essentially to visual impairment) were added.

Age Distribution
Regionally, congenital cataract affected 22.4% and 20.7% of children in the West Bank and Gaza Strip respectively. In the 16+ cohort, the percentage in the Gaza Strip was double that of the West Bank at 19.2 and 10.5 % respectively. Wide age-cohort differences in the ratio of congenital cataract are found between the <16 and 16+ age groups in the West Bank and Gaza Strip. In the <16, the ratio is 1.4:1 which is close to the population ratio of 1.78:1, whilst in the 16+, the ratio is reversed to become 0.58:1.

Male to female ratio in congenital cataract demonstrates male preponderance in both regions, especially in the Gaza Strip where there are twice as many males as females. (West Bank 1.4:1, the Gaza Strip 1.75:1)

Visual acuities in the congenital cataract patients on whom such figures were available (rather than an estimate ie other than WHO categories ‘6’ and ‘7’) were 4 (5%) in BL category ‘5’, 21 (25%) in the BL

Table  18.1  Patients families in the West Bank and Gaza Strip in cataract cases

 

Patients with Cataract

Primary

Secondary

Others

Total

West Bank

62

47

15

52

7

64

84

49

Gaza Strip

58

44

11

38

4

36

73

42

Either

12

9

3

10

0

0

15

9

Total

132

100

29

100

11

100

172

100

Percentages in bold Italic

     

category ‘4’, 10 (12.2%) in the SVI category ‘3’, 39 (47.5%) in the VI category ‘2’ and 8 (9.8%) in the NVI category’1’ (n=82). Cases in the combined SVI/BL category is 43% and 26% in the SVI/BL category (n=18/69)

Inheritance
Sixty one percent of congenital cataract cases are hereditary (n=81) and 9.8% are non-hereditary (n=13); this leaves 28.8% (n=38) of cases of undetermined aetiology. Excluding the latter group this brings the hereditary cases to 86% of the congenital cataract. The hereditary group comprises primarily genetic congenital cataract. The modes of inheritance in these patients are autosomal dominant (AD) in 11% (n=9); 84% autosomal recessive (AR) (n=68), 3% (n=4) were isolated cases and in 1 the aetiology was uncertain. Among the autosomal recessive cases, 4 resembled autosomal dominant (AD) inheritance and an additional 4 cases were associated with autosomal dominant myopia. Table A18.1
In comparison to the remainder of the congenital cataract series, the isolated group of patients included the largest proportion of cases recruited from the outpatient clinic which contained insufficient history, demography, and consanguinity data. Their inclusion in the study was necessary to provide additional information on the size of the problem of the various conditions, in particular lens disorders and their prevalence in the region.

Consanguineous marriage in these sibships was 81%. There were 94 patients (23.2% of the total study) in the <16 cohort with congenital cataract as a primary cause of visual disability and 110 (27%) when cases with congenital cataract as a secondary cause of blindness were included.

Prevalence
In the Palestinian population of the West Bank and Gaza Strip (this study) the prevalence in the 5-19 age cohort averaged 11.4/100,000 in both regions.

Mode of Inheritance
It was possible to establish the hereditary nature in 65% (94/145) of congenital cataract cases. Non-hereditary lens conditions formed 9.6% (14/145) of cases and in undetermined cases were 25.5% (37/145). When cases with the undetermined aetiologies are excluded, the percentage of hereditary conditions rises to 87% and non-hereditary to 13%.

Autosomal recessive mode of inheritance is the predominant mode with 76.6% confirmed cases, although this is more likely to be 85% when the possible autosomal recessive / autosomal dominant and isolated conditions are included as they are most likely to be recessive in origin. This leaves 9.6% (9/94) autosomal dominant cases and 4.25% (4/94) chromosomal in origin. (Updated prevalence in the 5-19 years age cohort in Appendix 3)

Aphakia
Aphakia was included under congenital cataract rather than as a separate entity. It was present in 109 patients (187 eyes) leaving 23 patients (134 eyes) with untreated cataract (both as a primary and secondary cause of blindness). This is in addition to 12 other cases of aphakia belonging to other categories (whole globe 5, retina 4, cornea 2, and optic nerve diseases. (Figure 18.1)

Posterior Capsular Fibrosis
This was reported in 14 eyes. Several children underwent surgical capsulotomy with sufficient visual improvement to enable their transfer to sighted schools with the appropriate visual aids.

Figure 18.1  Proportions of aphakia and untreated cataract

Congenital cataract was also found in patients with ectopia lentis (n=15, 7.4%), congenital glaucoma (n=12, 6%), retinal dystrophies (n=10, 5%) and microphthalmos (n=10, 5%). This tops up the number of patients with lens related conditions to 202 patients (30.2% of the series), 112 of the patients were aphakic. (Tables 18.2, 18.3)

Associated Systemic Conditions
The commonest associated feature with congenital cataract in the survey was mental retardation / subnormality. The distribution of this in the various congenital and cataract cases is shown in Tables 18.2 and 18.3.

Discussion

The diverse aetiologies and different definitions used to identify congenital cataract have led to difficulties in evaluating this condition in epidemiological studies.

In addition, the figures in this survey are nearly 3-fold those reported some 6 years later in 1993 (6.9%). This indicates that the recommendations put forward at the time of this study by the author of ensuring proper refractive correction, and transferring pupils to normal schools had been implemented. Also the possible improvement in cataract surgery outcomes with more prescription of glasses from an earlier age. (1)


The lower numbers of the 16+ in the West Bank may be explained as an under representation due to the absence of those patients who would have been working in contrast to the Gaza Strip where it was easier to achieve a better cover of cases (10.4% versus 20.8%), yet the total proportion in the whole study is very close in both regions (20.5% and 21.5% respectively). (Table 18.1)


The proportion of congenital cataract in the survey (West Bank 26.6%, Gaza Strip 22%) makes it the commonest avoidable blindness. The figures are fairly close to those reported in Turkey (1) and very similar to those reported among the Palestinians in Israel (21%) (2) This is somewhere in between those reported in Thailand and the Philippines (44%), (3) and the lower figures (<10%) in some other countries, including the Established Market Economies countries and many of the developing countries. (4), (5), (6), (7), (8), (9)


Globally, it has been estimated that congenital cataract is the cause of blindness in 190,000 children (14% of the total childhood blindness). There is a wide variation in the prevalence, ranging from nil in Scotland (4) to 39% in Jamaica. (10) The incidence is variable and ranges from 1 to 3/10,000 live births or 10 per million of the total population in low-income countries. (11)


Lowest figures are from the industrialised countries where they have shown a marked decline since the 19th Century reaching 0% in 1986 as a result of improved rubella immunisation, early detection and improved surgical techniques. (4), (5), (6), (7), (8)(12) Highest 8% 84% 8% Untreated Cataract figures are from the developing world, in particular the Caribbean, Africa and to a lesser extent Asia.  (10), (13), (14), (15), (16), (17) In India, wide interregional variations have been reported ranging between 2.9% in Uttar Pradesh to 23.6% in Kerala. (18) In the Nordic countries the prevalence was 36 per 100,000. The occurrence rate for dense bilateral and all unilateral cases were both 14 per 100,000 each.(19) In another study it was reported as ranging from 15-41/100,000 and in a small study in Sweden with an incidence rate of 12-23/ 100,000 live births. (20)


The higher proportion of congenital cataract of undetermined aetiology encountered in epidemiological studies is reflected in this study in the <16 cohort and is due to a lack of detailed history. Congenital cataract of hereditary aetiology formed 54% of the cases whilst in the 16+ cohort, it amounted to 92.5% as it was easier in these to obtain full detailed history and establish the mode of inheritance, especially as more affected siblings are born. It is, therefore, most likely that hereditary aetiology is very high in all age groups.

Rubella cataract is a rarity in this study and also in Lebanon, Saudi Arabia, Cyprus and Nigeria, as rubella is usually contracted at pre-childbearing age in these countries. Rubella cataract in Nigeria remains a major cause (19%) with only 5 of the 26 cases being genetic in aetiology. (21)


These figures differ from other Muslim countries who also have a high rate of consanguinity such as Uzbekistan where not only the percentage of familial cases of congenital cataract was lower (49%, 72/147), but there was a much higher proportion of the autosomal dominant mode of inheritance than in this study (28% autosomal dominant, 31% autosomal recessive and 13% undetermined). Other differences between our study and that of Uzbekistan, include the proportion of the sporadic cases of congenital cataract which formed 44% (65/147) of the series compared to 25% in this study, associated microphthalmia at 22% compared to 5% and ectopia lentis 7% (10/177) compared to 9% from the total lens conditions.(9)  


The visual morbidity in the aphakic congenital cataract patients in the West Bank and Gaza Strip is high, with over 60% in the VI/SVI and 26% in the SVI/BL category. This is the result of amblyopia from long-term neglect and the absence of wearing aphakic correction. It is also, to a lesser extent, secondary to post-operative complications, in particular posterior capsule fibrosis, and in a few patients from surgical complication such as glaucoma and retinal detachment. During the course of the study, glasses were prescribed and the posterior capsular fibrosis was treated surgically, resulting in improvement in a proportion of these patients, some of whom were transferred to sighted schools. Similar findings were reported in the developing countries such as India where uncorrected aphakia and amblyopia contributed to 12.3% of blindness. (22)


Multidisciplinary efforts and organisation are required to combat the problem of amblyopia. Visual morbidity resulting from congenital cataract has considerably improved in industrialised countries in recent decades with optimised after care of aphakia and complications from a very early stage, before the onset of intractable amblyopia.


Nevertheless, the problems encountered in the rehabilitation process in developing countries are considerable. Diagnosis may not be made until well into childhood and even when made, referral for surgery may not be contemplated until beyond the age of cortical plasticity. In addition advances in paediatric anaesthesia have not reached many of the developing countries. Periodic post-operative and orthoptic care is lacking and frequently proper follow-up of these children is difficult for economic and logistical reasons. In addition, surgical techniques used such as extracapsular techniques or lens aspiration, without posterior capsulectomy, have created the problem of posterior capsule opacification, some of which will proceed to secondary glaucoma. Optical correction for these children is therefore suboptimal.

Table 18.2  Associated conditions with congenital cataract as a primary condition
 

Sex

Age

Findings

West Bank

F

15.9

Very slow mentation, very shy

M

10.8

Slow mentation, cryptorchidism

M

3.7

Bat ears, extra digit, cryptorchidism, bright

M

7.2

Mentally subnormal

Gaza Strip

F

19.6

Mentally subnormal

M

16.9

Hypoplastic maxilla, slurred speech a

M

7.2

Mentally subnormal, extra digit, bulgy sternum, undescended testes

F

2.9

Mentally subnormal, Down syndrome

F

8.9

Allergic rhinitis

Retinal dystrophies

West Bank

M

4.1

Trichomegaly, nails abnormality

M

41.7

Mentally retarded, spastic, unilateral CDH, small for age

3 M

12-15

Mentally subnormal

F

10

Region uncertain

M

7.8

Prominent first incisor

Congenital glaucoma

West Bank

F

3.2

Limbs weakness

M

6.0

Spastic

Region uncertain

M

0.8

Mentally retarded

M

0.9

Mentally retarded, homocystinurea

F

9.4

mentally retarded, epileptic; grand and petit mal seizures

Other Conditions

West Bank

M

7.4

Mentally subnormal

F

13.4

Very bright child, IDDM

a Cataract absent in the other affected siblings
IDDM: Insulin dependent diabetes mellitus
  CDH: Congenital dislocation of the hip

Table 18.3  Mental subnormality in patients with cataract

 

Cohort size

Total

Hereditary cases

Primary

132

8

6

5

62

Primary and secondary

164

10

6

7

70

Total cases

185

18

19

13

72

Percentages in bold Italic

18.2 Ectopia Lentis

Ectopia lentis is a small subgroup of lens conditions (EL) (n=13), 9 were from the West Bank and 4 from Gaza Strip with a ratio of 2.25:1. The M:F ratio was 1.6:1 but in the Gaza Strip, all cases were male. The group consisted of 9 sibships from 7 pedigrees. All the conditions associated with EL were autosomal recessive and are shown in Table 18.4) (Updated prevalence in the 5-19 years age cohort in Appendix 3)


This condition is usually inherited as part of several syndromes such as homocystinurea and Marfan syndrome. Simple ectopia lentis is usually inherited as an autosomal dominant trait but recessive conditions are also known to occur and have been reported in 19 patients in 2 Arab families in Jordan. (23) In this study, one sibship exhibits the simple form (3 patients) and in another 3 EL was associated with high myopia. The remainder of the cases are syndromatic and include a new association with infra-temporal quadrantic iris anomaly, dysmorphic features and one of the siblings suffers from arthritis of the ankle and fingers in one hand. Another patient also had cryptorchidism, shawl scrotum, mental subnormality and minor skeletal abnormalities (25) The rest are part of homocystinurea and Marfan syndrome.

     
Table 18.4  Conditions associated with ectopia lentis

Condition

No.

%

Sibships

Isolated autosomal recessive ectopia lentis

3

23

1

High myopia

3

23

2a

Infra-quadrantic iris anomaly, dysmorphic features, unilateral arthritis in ankle and fingers in one.

2

15.9

1

Syndromatic: shawl scrotum, cryptorchidism (undescended testicles), feminine complexion, course scalp hair (absent in other siblings), flat feet, educationally subnormal (brother undescended testicles) - (Plates 26 to 29)

1

7.7

1

Marfanoid features

1

7.7

1

Homocystinurea

3

23

3 b

Total

13

100

9

a Same pedigree. b two pedigrees, 2 cousins from 1 pedigree.

18.3

Congenital Glaucoma

 

Demography Congenital glaucoma encompasses 68 patients, 32 from the West Bank, 29 from the Gaza Strip, 6 unidentified and 1 from Israel. These patients originate from 45 pedigrees, 20 from the West Bank, 18 from the Gaza Strip and 7 from either region of the OPT. There were an additional 2 patients in whom buphthalmos was a secondary pathology.


Age Distribution
The age distribution in the congenital glaucoma cohort is 43 patients <16 years and 25 adult patients; a ratio of 1.72:1.


Gender
There are a total of 40 males and 28 females in the congenital glaucoma group giving rise to a M:F ratio of 1.43:1 for the total and 1.38:1 for the < 16. Among those whose family history is known (n=62), the ratio drops to 1.2:1 (1.1:1 general population, 0.9:1 in the congenital glaucoma sibships (n=224 sibs). Ratios between the two regions are comparable including male predominance except in the <16 cohort in the West Bank where it is 1:1.

Visual Acuities
Table 18.5 Visual acuities in congenital glaucoma. Visual morbidity in this series is considerable. Prognosis is very poor whether left alone or if treated surgically. (Table 18.5) Both trabeculotomies and trabeculectomies were performed in this series but all procedures showed diminishing success rates with time although the latter was the most successful. (24) In many cases, corneal decompensation ensued. normalisation of the IOP soon after surgery and with a tendency for some eyes to become atrophic. In 1 case of simple infantile glaucoma, which was followed closely by the author of this study, corneal decompensation developed 7 months after an uneventful surgery and soon after, corneal opacification ensued. The initial high intraocular pressure and higher cup:disc ratios were found to be predictive factors for failure of the first procedure in a recent study on a similar population and the former was the only independent predictive factor for failure as the final outcome. In addition, the absence of family history carried a better prognosis.
(25),(26),(27) Not surprisingly, therefore, we find a high proportion of severe visual disability and blindness in the series with 79% of congenital glaucoma falling into the SVI/BL category, two thirds of whom have NLP.
 

Table 18.5  Visual acuities in congenital glaucoma
 

Total series

5 to 19

WHO Visual Category

No.

%

No.

%

         

NPL ‘5’

14

20.6

7

22.6

Blind ‘4’

21

30.9

10

32.3

Category '7'

15

22.1

5

16.1

SVI  ('3')

 3

4.4

2

6.5

SVI/BL (3’, ‘4’, ‘5’, ‘7)

(53)

(78.0)

(24) (77.5)

VI  (‘2’)

8

11.8

4

12.9

Category 6'

1

1.5

0

 

NVI ('1')

5

7.4

3

9.7

n/a

1

1.5

0

0.0

Total

68

100

31

100

Clinical Characteristics

It is possible that 50 cases (74%) are primary congenital glaucoma (PCG) and 10 (15%) are anterior cleavage syndrome including 7 with Peter’s anomaly and 2 with Reiger’s syndrome. One case is probably non-genetic.

There is considerable ocular morbidity in these conditions which made ascertainment of clinical details and type difficult. Twenty two eyes were phthisic or atrophic and 1 removed, 7 with cor­neal scarring and probable Peter’s anomalies. (30)

It is possible that 50 cases are primary infantile glaucoma (PIG) and 10 are anterior cleavage syndrome including 7 of probable Peter’s anomaly and 2 of Reiger’s syndrome. One case is probably non-genetic. The severe ocular morbidity made ascertainment of clinical details and type difficult; 22 eyes were phthisical or atrophic and 1 removed. In 80% of cases, it presented at, or soon after, birth with the classical features of buphthalmos.

Inheritance

It was possible to establish the hereditary nature of congenital glaucoma in 57 cases; in 9 information was not available and in 2, the condition was non hereditary. In the hereditary cases, autosomal recessive mode of inheritance was the norm in 90% of cases with known family history, and 3 were isolated cases. The percentage of affected sibs to the total sibship averaged 27.7%. The ratio within the gender was 32% and 24% of the affected male and females to respectively.

Prevalence
Congenital glaucoma ranks third amongst the causes of childhood blindness and is the second major congenital condition treated surgically. It represents 10.2% of patients in the whole series. The prevalence of congenital glaucoma in all the OPT is 5/100,000 (West Bank 3/100,000, Gaza Strip 6.6/100,000). In the <16, the figures are 6, 4, 8 / 100,000 respectively. (Updated prevalence in the 5-19 years age cohort in Appendix 3)

In this study, however, incidence rates average 1:28,000 in the OPT (West Bank 1:34,000 and Gaza Strip 1:22,000). It is difficult to explain this low rate in comparison to the rest of the region as it is found in both the <16 who are well represented in the schools cohorts and adults.

The number of congenital glaucoma cases per 100,000 in the West Bank and Gaza Strip showed an increase between the 1950s and the 1970s when it levelled off (Figure 18.2).

Figure 18.2  Congenital glaucoma per decade in the West Bank and Gaza Strip.

         
     

Associated Findings and Conditions
Several additional conditions were associated with congenital glaucoma. These are enumerated in Table A18.2 together with the family sequence and other data.

Discussion
Male preponderance ranging from 1.55:1 to 1.9:1 have been reported in the various studies, (12), (28) although it was absent in the non-gypsy population of Slovakia which was 1:1. (28) Male preponderance and the lower than expected number of affected sibs in the familial cases have raised questions on the validity of autosomal recessive inheritance mode. This, together with the transmission of disease in successive generations, is suggestive of autosomal dominant inheritance. Some light has, however, been shed on this in recent molecular genetic studies and is attributed to the high inbreeding in these communities where there is a high chance of marriage between homozygous and heterozygous subjects. In this study, only 1 sibship showed pseudodominance and heavy consanguinity in this community supports the argument that pseudodominance in congenital glaucoma is not an independent phenomenon. (29) As an observation, the ratio of males to the total numbers of males is higher than the equivalent percentage in females at 32% and 24%. (30)


The marked visual morbidity in this series and poor prognosis, whatever the surgical procedure used, explains the high proportion of severe visual disability and blindness in the series with 79% of cases falling into the SVI/BL category, two thirds of whom have NLP depicts a comparison between this series and the Slovakian study. (28) The initial high intraocular pressure and higher cup: disc ratios were found to be predictive factors for failure of the first procedure in a recent study on a similar population and the former was the only independent predictive factor for failure as the final outcome. In addition, the absence of family history carried a better prognosis. (25), (26), (27)

The autosomal recessive mode of inheritance of congenital glaucoma in the West Bank and Gaza Strip survey is in line with the pattern documented in other parts of the Middle East. The percentage of affected sibs is 27.7% which is indicative of the recessive mode. The variable penetrance is well demonstrated in these sibships. The autosomal recessive mode of inheritance was noted in 90% of sibships where family data were available (and most likely to be autosomal recessive) and 3 cases were sporadic.


The largest group in this subcategory is that of isolated. Consanguinity ranging from first to third cousin marriages were recorded in 28/32 sibships (87%), 79% of whom were first cousin marriages. This is higher than the Saudi Arabian figures of 68%. An additional 3 were from the same locality and in 1 sibship only was no relationship found. Parental consanguinity has been reported in several studies on congenital glaucoma. (25), (29), (31)


Congenital glaucoma formed the third commonest disorder in the series amounting to 10.2% of cases in the series where cases of unknown localities. (West Bank 9.2%, Gaza Strip 10%, excluding cases of unknown localities). (Chapter 14) It occupies a midway position between Jordan (15%) and Saudi Arabia (17%) on the one hand, and Lebanon, Cyprus (6% each) and Uzbekistan 4.7% on the other hand (9), (13), (32), (33), (34) The former 2 countries have the highest recorded rates in literature after Nigeria and followed by the Dominic Republic and Peru. (21), (35), (39) Incidence rates in Europe ranged from 1:1,250 (the highest reported) in Slovakian Gypsies and 1:5,000 (Switzerland) to as low as 1:22,000 in Slovakia, averaging 1:10,000. (12) (Table 18.6)


The incidence rate in the Middle East is 1:2,500 compared to the rest of the world which is generally less than 1:10,000. (12), (37)


Incidence rates in the West Bank and Gaza Strip in this survey (averaged 1:28,000 in the OPT, West Bank 1:34,000 and Gaza Strip 1:22,000) are difficult to explain in comparison to the rest of the region as found in both the <16 who are well represented in both the schools and in the 16+ cohorts. The number of congenital glaucoma cases per 100,000 in the West Bank and Gaza Strip showed an increase between the 1950s and the 1970s when it levelled off (Figure 18.2). This pattern is also reflected in worldwide trends which demonstrated an increase in the incidence of primary congenital glaucoma (PCG) in the 1930s till the 1970s raising the share of this condition in childhood blindness from 10 to 20%, followed by a decline after the 1970s. (12) (Updated prevalence in the 5-19 years age cohort in Appendix 3)


Associated conditions with congenital glaucoma are scarce in literature, which makes the West Bank and Gaza Strip unique in the frequency of associated conditions with congenital cataract.

Table 18.6  Comparison of congenital glaucoma in the survey and Slovakia

 

West Bank and Gaza Strip (This study)

Slovaks

Sinti

Sample size

68

87

118

Families

50 (45a)

81

41

Prevalence

OPT 1/25,000

West Bank  1/28,000

Gaza Strip  1/16,000

1/51,000

1/1,250

Incidence

OPT 1/28,000

West Bank 1/34,000

Gaza Strip 1/22,2000

1/22,000

1/2,120

 

M:F Ratio

1.38:1/1.2:1b

1.55:1

1:1

Course

Severe

Severer in Sinti than non-Sinti

Prognosis

Poor

worse in Sinti than non Sinti

Bilaterality

100%

73%

100%

Diagnosis at Birth

80% birth

6 months

82% birth

Inheritance

87%  A/R

-

highly probable A/R

Familial

76%

12%

85%

Sporadic Cases

23.5%c

88%

15%

Consanguinity

87%

5.9%

45%

a Number of extended genetic families.  b Ratio of patients with known pedigree information.
In 3 cases, the ratio of affected/total siblings was 1:5 or less. In another 3, ratios were 1:8, 1:10, and 1:11.

     
18.4

Small Eyes (Microphthalmia/ Anophthalmia


Small eyes, microphthalmos, (as defined by the WHO are eyes with a corneal diameter of less than 11mm), and form the fourth largest genetic group of conditions.

Age Distribution in MC

Children formed 62% of the series (23/37), 9 in the West Bank and 14 in the Gaza Strip.


Gender in MC
Male predominance in observed in all the groups. (Table A18.3)

Inheritance
Of the total group of 60 patients, 53 (88%) were hereditary, 7 (12%) were prenatal. Sixty three percent of sibships showed a definite familial occurrence (>1 affected sibling in the family). (Table A18.3)

Prevalence and Incidence of MC
Microphthalmia and anophthalmia account for 5.1% and 0.4% respectively with marked regional variations being significantly higher in the Gaza Strip (7.3%) than the West Bank (3.0%). This is due to a large pedigree that comprises 5 sibships with 10 patients. The mutation rate, however, is only marginally higher as demonstrated by the ratio of pedigrees between the two regions. The associated ocular findings in the Gaza Strip were also higher (9%) and compares to published figures for the regions in 1993 (8.7%); (38) however, these were based on the compiled data of this author which was archived locally. (Tables 18.7, 18.8) (Updated prevalence in the 5-19 years age cohort in Appendix 3)

Table 18.7  Microphthalmia patients, and sibships

 

Patients

Sibships

Pedigrees

Hereditary

MC as a primary cause of blindness

West Bank

13

9

8

Gaza Strip

20

10

6

subtotal

33

19

14

West Bank:Gaza Stripb

0.7

0.9

1.3

MC as a secondary cause of blindness

West Bank

13

5

4

Gaza Strip

6

5

3

subtotal a

20a

11

8

Total

53

30

22

West Bank:Gaza Strip b

2.2

1.0

1.3

Non-hereditary (all prenatal)

West Bank

2

2

2

Gaza Strip

5

5

5

total

7

7

7

West Bank:Gaza Strip b

0.4

0.4

0.4

All MC cases

West Bank

28

16

14

Gaza Strip

31

20

14

Total a

60

37

29

West Bank:Gaza Strip b

0.9

0.8

1

Grand total a

60

37

29

West Bank:Gaza Strip b

1.75

1.5

1.2

a Includes 1 patient from either region.
b Average West Bank/Gaza Strip population ratio is 1.78:1

Phenotypes and Regional Distribution
The total number of patients with MC is 60. This includes those in whom the condition was the primary site of pathology (n=38) and secondary contributor to the visual impairment (n=28). The primary cohort formed 4.3% of the West Bank cohort, 7.6% of the Gaza Strip cohort and 5.5% of the total cohort. (Table 18.7). All MC cases, however, form 8%, 10.7% and 9% of the total Occupied Palestinian Territories series in both regions.


On the basis of aetiology MC can be grouped into three categories:
Group A: MC is the primary cause of blindness (WHO anatomical classification) in 33 patients. The VA is in the SVI/BL category in 30 patients (91%) with 23 blind (70%) and 17 (51%) with NLP. Three patients from 3 unrelated sibships had anophthalmia. Five patients from one pedigree from the West Bank have an appearance of anterior cleavage syndrome (ACS). Colobomas were part of the microphthalmia in 7 patients (21%). In 2 patients out of 3 from one sibship from the Gaza Strip, total absence of the iris identical to aniridia was seen with anterior cleavage syndrome. Group A also showed a wide interfamilial and intrafamilial variability in the phenotypic expression in the MC patients with a clinical picture that varies from a rudimentary eye bud that can be detected moving behind the conjunctiva, to a well-formed eyeball.

Group B MC is a secondary pathology contributing to the visual problem in 20 patients. In the majority of these patients (n=16, 80%), congenital cataract was the primary pathology, and in the remaining 4 (20%), uveal coloboma was the primary cause of visual loss. SVI/BL in this group was present in 9 cases (47%), Blind in 5 (26%) with none in the NLP category. Seven (37%) were in the VI category. (<6/18 to 6/60).
Group C MC in the non-hereditary cases were present in 7 cases. Six of the patients were blind; half with NLP.

Associated Finding and Conditions

Cataract and Microphthalmia
The overlap between cataract and microphthalmia was such that 11% of children in the SVI/BL category. both diagnoses in Uzbekistan. (9)

Other Features
Six patients (6/38) with MC had other associations and special features. (Table A18.3)
 

Group B was not associated with other systemic associations or unusual features. Patients and other siblings sequence are depicted in the box under each case. For siblings sequence refer to Table A18.3.

Special abilities (autosomal recessive inheritance, first cousin marriage). One sibship was unique in this characteristic. All were of above average intelligence. One had exceptional auditory abilities whereby he could cycle around town despite NLP vision; the brother had superior photographic memory in addition to suicidal tendency; he had jumped twice from a high window.
Marfanoid features: (above average height, high arched palate), and anterior open bite. (autosomal recessive, second cousin marriage).

Muscular-skeletal associations: (a) Muscular dystrophy, hands weakness; (b) kyphoscoliosis, (had surgery on one foot); and (c) telecanthus. An isolated case from a first cousin marriage.

Mental retardation plus: deafness and failure to thrive: feeble cry, spasticity, microcephaly, and myotonic jerks (IUI, unrelated parents).

Male predominance was almost equal in both groups averaging 1.55:1. This was not observed in Sweden where bilaterality was found in 53-60% of patients with other malformations and 27% of patients with isolated microphthalmia. (39) This is in contrast to the West Bank and Gaza Strip where cases encountered in both groups were bilateral, however, the selection criteria could have created a bias as all cases registered in the study had to be bilaterally visually impaired Visual morbidity in this study was worse than other series with 63% of cases in both subgroups having NLP, versus 20% in Uzbekistan. (9)
 

Discussion

Male predominance was almost equal in both groups averaging 1.55:1. This was not observed in Sweden where bilaterality was found in 53-60% of patients with other malformations and 27% of patients with isolated microphthalmia.(39)This is in contrast to the West Bank and Gaza Strip where cases encountered in both groups were bilateral, however, the selection criteria could have created a bias as all cases registered in the study had to be bilaterally visually impaired.

Visual morbidity in this study was worse than other series with 63% of cases in both subgroups having NLP, versus 20% in Uzbekistan.(9)


Data on the prevalence of MC worldwide is scarce. Figures on the birth prevalence of microphthalmia and anophthalmia, based on population-based registers, are 14 and 3 per 100,000 births respectively. Large regional differences exist in the proportion of congenital malformations in blind school children ranging from 10.7% with microphthalmia, 2.3% with anophthalmia, and 1.3% with coloboma.(40), (41) The prevalence of severe visual loss from these abnormalities is estimated to affect between 0.4 and 16.2/100,000 children; the underlying cause could not be identified in 84.2%.(40) The prevalence of microphthalmia (as a primary pathology, Group A) in the West Bank and Gaza Strip are 10 and 38 per 10,000 (averaging 2/100,000 in both regions). The figures are higher when both types are included (35 and 58 per 10,000). This is considerably higher than the estimated prevalence of 1.9/10,000 in Uzbekistan and those derived from birth registries from France, Sweden and California (0.4 to 5.9 / 10,000).(9)   (Updated prevalence in the 5-19 years age cohort in Appendix 3)


In blind schools, the condition formed 23% (129/671) of the total children examined in Uzbekistan,(9)  including a significant proportion with associated cataract. No cases of microphthalmos were reported in the Jordanian study,(33) but were present in 1.9% (4/208) of the Lebanese series, (34) 6.7% (6/89) in Cyprus (32) and 5% (21/439) in the recent UK study.(6) Figures from Uzbekistan were in line with those reported in other parts of Southern Asia.(9)  


It has been suggested that 23% of children with microphthalmia or anophthalmia have chromosomal anomalies and 30% have other major malformations in comparison to a possible 5-6% in this study. In group A, autosomal recessive inheritance was the norm, but autosomal dominant mode was suggestive in a third of cases in Group B. (42)

Table 18.8   Prevalence of microphthalmia / anophthalmia conditions

Region

Prevalence

Incidence

<19

Total Series

1 in 1000s

Group A

 

 

 

West Bank

2

1

56

Gaza Strip

4

4

23

OPT

4

2

27

Group B

 

 

 

West Bank

2

1

51

Gaza Strip

2

0

64

OPT

2

1

55

All MC Cases

 

 

West Bank

5

3

22

Gaza Strip

7

5

15

OPT

5

4

18

18.5 Hereditary Corneal Conditions

This is a small group of conditions with 14 patients from 9 sibships.

Clinical Patterns

Two entities were found in the series. one is an isolated congenital cornea oedema and the other Peter’s like anomalies. They are distributed as follows:

a. Congenital corneal oedema, 4. (Table A18.4)
b. Peter’s or suspected Peter’s anomaly, 10. These can be divided into:

i. Uncomplicated Peter’s anomaly (without glaucoma).
ii. Definite Peter’s anomaly with congenital glaucoma: 3 cases.
iii. Suspected Peter’s with complicated congenital glaucoma.

Congenital Corneal Oedema (CCO)
Four cases belonged to 2 unrelated sibships, with 2 patients each. Gender comprised 3 females and I male, a ratio of 1:3. In one sibship (CE-02), both patients were mentally retarded and in both autosomal recessive mode was obvious. Vision in these patients was severely compromised with all patients in the SVI/BL category. (Table A18.4)  (Updated prevalence in the 5-19 years age cohort in Appendix 3)

18.6 Hypopigmentation

Prevalence Albinism made up 28 of the genetic retina cases out of the total 315 retina cases, thus forming, as a primary pathology, 2.3% (n=8) of the total series in the West Bank and 6.6% (n=19) in the Gaza Strip, averaging 4.1% in both regions. These patients belonged to 12 sibships (West Bank 5, Gaza Strip 7) and 11 pedigrees. Including other affected members of the sibships who were not examined (West Bank 18/45 Gaza Strip 20/60), the total is 38 affected out of the 105 siblings, that is a ratio of 0.33:1. Prevalence based on the numbers of all the affected in the sibships studied per 100,000 populations were at least West Bank 1.7 (n=19), Gaza Strip 3.5 (n=21) and OPT 2.4 (n=40). (Table A18.5)

Gender
Male/female ratio in the total hypopigmentation series was 1.25:1 with marked variation between the two Palestinian regions. In the West Bank the ratio was 0.3:1 (n=8) and in the Gaza Strip 2.2:1 (n=19).

Clinical Types and Associated Conditions

Three clinical entities are identified in (Table A18.5).

a. Oculo-cutaneous albinism (9 patients).
b. Ocular albinism (9 patients).
c. Others (2 cases).
Visual Morbidity in Hypopigmentation
Twenty (57%) of the patients with hypopigmentation were visually impaired (category ‘2’), 4 (14%) had SVI (category ‘3’) and a further 4 had good visual acuity (category ‘1’). The remaining (14%) 4 were in category ‘6’ which were moved to category ’2’.

Inheritance of Hypopigmentation Cases
Of the total group of 60 patients, 53 (88%) were hereditary, 7 (12%) were prenatal. Sixty three percent of sibships showed a definite familial occurrence (more than 1 affected sibling in the family). Patients sequence within the sibships in the three groups is shown in (Table A18.5).

Discussion
Hypopigmentation, in particular albinism, are common conditions but their true prevalence is not reflected in the series. The majority of these cases have sufficient vision for education in ordinary sighted schools. The true prevalence of the condition per 100,000 people is bound to be higher than 1.7 (n=19) in the West Bank and 3.5 (n=21) in the Gaza Strip with the average of 2.4 in both regions of the OPT (n=40) because the majority of these cases attend normal sighted schools. The percentages of albinism is lower than those reported in other Arab countries (34), (42) but compares well to Sri Lanka, (43) possibly for the above reason.  (Updated prevalence in the 5-19 years age cohort in Appendix 3)


The association with skin lesion and night blindness in the patient from the Gaza Strip has not been reported previously in the literature. The inheritance was most probably autosomal recessive in all sibships including the sibship with only males affected (6 affected males out of 12 siblings) especially as there was a distant connection with another sibship who had both affected males and females.


Three syndromatic cases were found in the series. One patient with oculocutaneous albinism had night blindness and reduced ERG together with scattered spots of skin fibrosis). The other was an albinoid who had congenital blindness, possibly Leber congenital amaurosis with large head circumference and delayed milestones. The third patient was albinoid combined with Waanderburg-like features including white forelock.

18.7 Retinal Dystrophies


Retinal dystrophies comprised 250 patients out of the 304 patients with hereditary retinal conditions, thus forming 80% of the total retina series. These patients were spread out over 109 pedigrees / 148 sibships. (Table 18.9) There are more sibships per pedigree in the Gaza Strip (ratio 1.8) than in the West Bank (ratio 1.2:1). (Table 18.9) The various phenotypes are listed in Table A18.6, A18.7, A18.8. The prevalence of retinal dystrophies per 100,000 population in the <16 population in the West Bank, Gaza Strip and the total region was 18, 24 and 21 respectively and in the total population the prevalence was 13, 17 and 15. (Two cases of atypical syndromatic cone-rod dystrophies in association with optic atrophy, one of whom also had Friedreich Ataxia, cardiomyopathy, and vitreous condensation have not been included in the above figures).

(Updated prevalence in the 5-19 years age cohort in Appendix 3)

Table 18.9  Retinal dystrophies: numbers, gender and ratio by region

 

West Bank

Gaza Strip

Whole Series

West Bank/Gaza Strip

 

M

F

Both

M:F

M

F

Both

M:F

M

F

Both

M:F

retinal dystrophies

Population a

<16

38

45

83

0.8

37

27

64

1.4

77

74

151

1

1.30

1.67

16+

25

36

61

0.7

18

19

37

0.9

43

56

99

0.8

1.65

1.79

Total

63

81

144

0.8

55

46

101

1.2

120

130

250

0.9

1.43

1.76

Pedigrees

 

 

80

 

 

 

25

 

 

 

109

3.2:1

Sibships

 

 

98

 

 

 

46

 

 

 

148

2.1:1

S:P b

1.2

 

 

 

1.8

 

 

 

1.4

 

a Ration of the value in the West Bank to the Gaza Strip. b S:P ratio: Ratio of sibships to extended genetic families

Table 18.10  Patients, sibships and pedigrees in achromatopsia

 

West Bank

Gaza Strip

Total a

West Bank:Gaza Strip ratio b

Patients

9

23

33a

0.4:1

Pedigrees

5

6

12

0.86:1

Sibships

7

11

19

0.64:1

 This figures includes one additional case from either regions. 
b
  The ratio of the general population between the West Bank and Gaza Strip is 1.78:1.

     
Stationary Cone Disorders (Achromatopsia / Rod-monochromatism)

Patients and Prevalence
Achromatopisa (Rod monochromatism) cohort comprised 33 patients who fell within 12 pedigrees and 19 sibships. Table 18.10 shows their distribution between the West Bank and the Gaza Strip and demonstrates the preponderance of the condition. (Updated prevalence in the 5-19 years age cohort in Appendix 3)

The prevalence of achromatopsia per 100,000 including all reported cases was 1 in the West Bank and 3.6 in the Gaza Strip averaging 2 in both regions. The corresponding figures in the <16 are 1.5, 5.5 and 3.

Gender
Gender differences in achromatopsia are shown in Table 18.10. Male to female ratios are 0.3:1, 0.8:1 in the West Bank and Gaza Strip respectively. (Table 18.11)

Visual Acuities in Achromatopsia
Nearly three quarters of the achromatopes were visually impaired (category ‘2’), 2 were in the NVI category ‘1’ and the remaining 7 had either SVI/BL. The lowest visual acuity was 2/60 and the mode was 6/60. The mean visual acuity was approximately 6/36. (Table 18.12)

There were no associated findings in any of the achromatopsia cases; however other siblings exhibited the following: extra digit, 1 male; deaf-mutism, 1 female; and mental retardation, 1 female. The remainder were educationally normal and, if anything, performed above average academically. (http://Jalili.co/educatt.pdf)

Achromatopsia inheritance was autosomal recessive in 100% of cases.

sequence and ranks of siblings(Table A18.7)

Table 18.10  Patients, sibships and pedigrees in achromatopsia

 

West Bank

Gaza Strip

Total a

West Bank:Gaza Strip ratio b

Patients

9

23

33a

0.4:1

Pedigrees

5

6

12

0.86:1

Sibships

7

11

19

0.64:1

a   This figures includes one additional case from either regions. 
b  The ratio of the general population between the West Bank and Gaza Strip is 1.78:1.

     
Table 18.11  Gender and age distribution of achromatopsia by region

 

West Bank

Gaza Strip

Total OPT

West Bank:Gaza Strip Ratio

 

M  

 F

Both

M:F

M

F

Both

M:F

M

F

Both

M:F

Cases

Populationa

<16

2

5

7

0.4

7

8

15

0.9

10

13

23

0.8

0.47

1.67

16+

0

2

2

-

3

5

8

0.6

3

7

10

0.4

0.25

1.79

Total

2

7

9

0.3

10

13

23

0.8

13

20

33

0.7

0.4

1.76

 Pedigrees

 

5

 

 

6

 

 

 

12

 

0.86:1

 Sibships

 

7

 

 

11

 

 

 

19

 

0.64:1

 S:P b

1.4:1

 

 

1.8:1

 

 

 

1.6:1

 

 

a Ratio of the value in the West Bank to the Gaza Strip. b S:P ratio: Ratio of sibships to extended genetic families

 

Table 18.12  Visual acuities in achromatopsia

WHO Visual Impairment Categories

 

 ‘1’

 ‘2’

‘3’

‘4’

‘5’

 7’

SVI//BL

No.

2

24

4

3

0

0

7

%

6

73

12

9

0

0

21

Progressive Cone and Cone-Rod Dystrophies

Patients and Pedigrees
The total number of patients affected in the progressive types of photoreceptors disorders, cone dystrophies, (CD) and cone-rod dystrophies (CRD) was 70 thus forming 28% of retinal cases. Of these, 27 came from the West Bank, 42 from the Gaza Strip. The M:F ratio averaged 1:1. (Table 18.11) These patients who suffered from progressive cone and cone-rod disorders were distributed among 20 pedigrees forming 40 sibships. Of these, 18 sibships (13 pedigrees) were from the West Bank, 21 sibships from the Gaza Strip (6 pedigrees) and 1 uncertain.

Prevalence of Cone Disorders
The prevalence of cone dystrophies and cone-rod dystrophies combined per 100,000 population in the West Bank, Gaza Strip and both combined was 4, 9, 6 in the <16 and 2, 7, and 4 in all ages respectively. For cone-rod dystrophies and cone dystrophies individually, the figures are 1, 7.7 and 3.5 for the former and 1, 0.73, 0.9 respectively. This represents a West Bank:Gaza Strip ratio of 0.6:1. (Updated prevalence in the 5-19 years age cohort in Appendix 3)

Age Distribution and Gender
Ages in cone and cone-rod dystrophies ranged from 3 months to 53 years, the M:F ratio being close to that of the general population except for the 16+ group. (Table 18.11)

Visual Acuities in Cone Disorders
These varied between visual impairment (category ‘2’), 28 cases, SVI (category ‘3’), 11 cases, blindness (category ‘4’), 29 cases; I case with NLP (category ‘5); and 1 cannot see (category ‘7’). (Table 18.14)

Table 18.13  Progressive cone dystrophies (cone degeneration and  cone-rod dystrophies by gender, age and region

West Bank

Gaza Strip

M

F

Both

M:F

M

F

Both

M:F

8

9

17

0.9

14

12

26

1.2

3

7

10

0.4

10

6

16

1.7

11

16

27

0.7

24

18

42

1.3

  13       6    
  18       21    
  181.4       3.4    


a
Ratio of the value in the West Bank to the Gaza Strip. b S:P ratio: Ratio of sibships to extended genetic families

     
Table 18.14  Visual acuities in the clinical subtypes of retinal dystrophies

Retinal dystrophies Phenotypes

Cohort

WHO Visual Acuity Category in %

Total

1

2

3

4

5

7

achromatopsia

33

6

73

12

9

-

-

100

cone dystrophies

12

-

92

0

0

8

-

100

cone-rod dystrophies

47

-

30

19

34

2

2

100

Leber congenital amaurosis

94

-

1

9

64

9

5

100

rod-cone dystrophies

21

2

2

2

14

1

-

100

Percentages in bold Italic  VA: visual acuity

 

     

Rod-Cone Dystrophies

Prevalence of rod-cone dystrophies
The prevalence of rod-cone dystrophies per 100,000 populations was 10.5, 3.6 and 8.2 in West Bank, Gaza Strip and the total OPT. (Table A18.8)  (Updated prevalence in the 5-19 years age cohort in Appendix 3)

Visual Acuities
These ranged between NVI (category ‘1’) to NLP in the following proportions. (Tables 18.17)

Rod-Cone Dystrophies  Phenotypes

According to their time of onset, they can be divided into 2 subcategories; congenital (infancy) onset and childhood onset. The distribution, sex ratios and pedigrees/sibships in the each subgroup and both combined are shown in Tables 18.6, A18.8.

Table 18.15   Rod and rod-cone dystrophies by age, gender and region

 

West Bank

Gaza Strip

Whole Series

West Bank:Gaza Strip

 

M

 F

Both

M:F

M

F

Both

M:F

M

F

Both

M:F

RC

Population a

<16

21

26

47

0.8

8

6

14

1.3

30

33

63

0.9

3.4

1.67:1

16+

16

24

40

0.7

4

4

8

1

20

29

49

0.7

5.0

1.79:1

Total

37

50

87

0.7

12

10

22

1.2

50

62

112

0.8

4

1.76:1

 Pedigrees

48

9

60

3.3:1

 Sibships 

57

10

69

5.7:1

 S'ship/Pedigree ratio b

1.2

1.11

1.15

 

a Ratio of the value in the West Bank to the Gaza Strip. b S:P ratio: Ratio of sibships to extended genetic families

Table 18.16  West Bank:Gaza Strip ratios of <16 cases, genetic families and M:F in retinal dystrophies.
 

retinal dystrophies Type

Cohort

<16

Sibships

Pedigrees b

West Bank

Gaza Strip

OPT c

Cone and Cone Rod disorders

cone dystrophies

12

1

4

5

2

2

2

cone-rod dystrophies

47

0.3

0.35

1

0.5

1.3

1

CACR

11

West Bank only

1

-

1

achromatopsia

33

0.47

0.64

0.86

0.4

0.6

0.4

Rod Cone disorders

Leber congenital amaurosis

88

3.6

5.7

5.3

0.85

1.4

0.9

RC

21

1.5

6.5

6.5

0.8

1.4

1

Total retinal dystrophies

 

250

1.3

2

3.2

0.8

1.4

1

Table 18.17  WHO visual acuities in 109 cases with rod-cone dystrophies in %
 

VA

Congenital a

Childhood b

Total c

NVI  ‘1’

-

9.5

1.8

‘2’ VI

1.1

9.5

2.7

SVI‘ 3’

10.2

9.5

9.2

BL ‘3’ ‘4’

72

66.6

72

NLP ‘5’

10.2

4.7

9.2

‘6’ d

0

0

0

‘7’e

5

0

9.2

Total

100

100

100

SVI/BL

99

81

95.4


a
Congenital onset rod-cone dystrophies   b Childhood onset rod-cone dystrophies  c Total West Bank & Gaza Strip may contain other cases of uncertain region
d Category ‘6’ Can See;  e Category ‘7’ Cannot See

Inheritance
All cases were inherited in autosomal recessive mode.

Birth Rank and Sequence of Patients
Table A18.8 lists the rank and sequence of RC patients, and the ratio of affected to the total number of the sibships.

Discussion
This study is marked by a heavy emphasis on retinal dystrophies which stemmed from being the largest and most interesting group of disorders encountered in the survey in the presence of some fascinating arrays of new findings in large pedigrees. (44) Minute clinical details were studied and analysed. The study shed light on several new conditions and associations. Among these were cone-rod dystrophy with amelogenesis imperfecta where there were 34 cases from 3 pedigrees with the youngest ever reported case of bull’s eye. (45), (46), (47), (48), (49), (50) These data have been left out of this study for future reporting.
 

There was a female preponderance in the West Bank that is possibly caused by the predominantly female residential schools in that region which could have skewed the results, although this is partly balanced by the boys only school, Al-Ala’iyya. However, this may well also reflect a true preponderance of blindness in girls in this region. This is especially so as the gender disparity persists in the patients recruited from the outpatients (0.7:1) in all the age groups and is absent in two of the conditions; namely cone dystrophies and CACR, (51) where the ratio compares to that of the general population. There are also variations in female preponderance within the conditions. In achromatopsia, the number of females is nearly double that of males and is found across the board in both regions in patients, sibships and pedigrees.


In line with the recognized clinical characteristics of retinal dystrophies, ((44), (52), (56), (57), (58) cone disorders have better visual, acuities than rod disorders, with the widest spectrum of visual acuities being exhibited by cone-rod dystrophies. Rod monochromatism (achromatopsia) scores the best of acuities with the worst being in the congenital form of blindness, Leber congenital amaurosis. (Table 18.14)

Prevalence of Phenotypes
It has long been recognised that retinal dystrophies forms the largest group of conditions attributable to childhood blindness and constitutes the bulk of conditions in countries where infections and malnutrition have been eliminated.(57) In the Middle East, a similar preponderance has been reported including Jordan.(9), (13) (32), (33), (34), (38) In this study, retinal dystrophies are common in both Palestinian regions. However, the higher number of patients affected in the Gaza Strip per sibship has given rise to a preponderance of patients with retinal dystrophies in the Gaza Strip, well depicted in the West Bank:Gaza Strip ratio of 1.43:1 (<16, 1.3:1; 16+, 1.65:1). This is despite the significantly higher numbers of pedigrees and sibships in the West Bank (West Bank:Gaza Strip pedigrees ratio 3.2:1, sibships 2:1).


The prevalence, based on the total number of patients encountered per 100,000 were at least 13 in the West Bank, 17 in the Gaza Strip and 15 in both regions combined. A more meaningful figure is that of the <16 in the Gaza Strip as the UNRWA blind school is the only blind institute in the Strip and the social worker knew all cases not enrolled in the school and those on the waiting list for admission when they reach school age.


Worldwide data, in particular in the Middle East, on the proportions and prevalence of the various subtypes of retinal dystrophies are lacking.  (44), (52), (56), (57), (58) In this study, regional variations in the prevalence of various types of retinal dystrophies are found which show that cone-rod dystrophies and achromatopsia are predominantly Gaza Strip conditions, but RC disorders and cone-rod congenital amaurosis (CACR, Jalili 1989) are West Bank conditions. (Table 18.15)


The preponderance of cone disorders including achromatopsia in the Gaza Strip, is found in a number of patients and sibships but not in pedigrees. This is the result of the presence of one large extended family with syndromatic cone-rod dystrophies with multiple sibships and 30 affected patients. There are also higher numbers of female patients in the 16+ cohort in the West Bank.


The number of pedigrees in the West Bank is 2-fold that of the Gaza Strip, that is above the population ratio between the two regions (1.78:1). These figures are reversed when it comes to sibships ratio (0.75:1) and patients’ ratio 0.54:1 (<16= 0.46:1, 16+= 0.67:1). This preponderance is also seen in the stationary type (achromatopsia). In contrast, rod-cone dystrophies are preponderant in the West Bank at 4:1 (<16= 3.3:1) in both patients and pedigrees. (Table 18.15)

Molecular Biology
This work, with its detailed genealogy, also presented valuable material for the molecular biologist and has resulted in several new findings including the detection of increased band sharing in DNA fingerprints in inbred populations and more recently a new locus was found on chromosome 2q11 at which recessive amelogenesis imperfecta and cone-rod dystrophies were found to cosegregate  More recently the genetic mutation has been isolated. (47), (59)

18.8 Vitreo-Retinopathies

This is an heterogeneous group of conditions where vitreoretinal pathology is the hallmark of the condition. Each pedigree has its characteristic features with marked intra sibships variability in the extended pedigree. The group comprised 12 patients belonging to 7 sibships, part of 6 pedigrees. These are mainly concentrated in the West Bank with 10 of the patients coming from there. Only one pedigree with 1 sibship originates from the Gaza Strip. Five of the patients belonged to a single pedigree with 2 sibships. There is also male predominance with 9 out of the 12 patients being males. Ten of the patients were <16. (Updated prevalence in the 5-19 years age cohort in Appendix 3)

18.9 SVI/BL in Common Genetic Ocular Conditions in the Est Bank and Gaza Strip

Figure 18.3 depicts the severity of visual loss in the common conditions encountered in the blind school survey by condition. In descending order of the severity of visual impairment are: congenital corneal oedema, Leber congenital amaurosis, optic nerve disorders, microphthalmia, congenital glaucoma, cone-rod dystrophies, congenital cataract, achromatopsia and albinism.(Updated prevalence in the 5-19 years age cohort in Appendix 3)

     
Figure 18.3  Proportion of SVI/BL in common clinical conditions

18.10 Associated Conditions


This study demonstrated the wide range of associations in the various genetic conditions and their variability. Some sort of association existed in 32% of the series (38% including medical problems). The proportion of additional morbidity, hearing, or mental deficiency in the visually impaired in the UK ranged between one-third and one-half of the total cohorts.(63), (64) Mental retardation is the most important and commonly defined association reported in conjunction with CB in many studies including the UK, the Nordic countries and Germany.(6), (63), (64), (65) It was present in 27% of the UK study (6) and 60% in the Nordic countries in those with the severest visual impairment; many of these children had multiple impairments due to brain injury such as cerebral palsy and epilepsy.(63), (64) In these countries, mental retardation is explained by periventricular keratomalacia in the majority of cases. (65) In this study, mental retardation was present in 7.6% of the total cohorts and found in a wide range of disorders showing certain patterns that are worth noting.


It was manifested predominantly in the two commonest groups of disorders namely; congenital cataract and rod-cone dystrophies. In congenital cataract, mental retardation was found in 10% of the total series but the figure rises considerably to 71% and 60% when congenital cataract is associated with retinal dystrophies and congenital glaucoma respectively; in other words, in syndromatic conditions. Rod disorders on the other hand were stigmatised by the frequency of associations and subnormal mentation. Submentation in this group reached as high as 12% of the total RC series with some 25% of the childhood onset cases having some degree of mental subnormality.


Although congenital glaucoma cohorts showed a wide spectrum of associations in 30% of the patients (20/68), mental retardation did not present as a part of the conditions; the mental deficiency in the two congenital glaucoma cases was acquired from a post systemic infection in one case and was part of an autosomal recessive inherited mental retardation coexisting with congenital glaucoma; the sibling’s sister had the same pattern of mental retardation but without having congenital glaucoma. The same is applicable on the microphthalmia series where mental retardation only existed in 1 patient of 3 suffering from anophthalmia. It is interesting to note that another 3 siblings of this patient who also had anophthalmia, died from different causes. The rest of the retinal dystrophies, which were very rich in their systemic associations did not show any significant association with mental abnormalities; cone dystrophies escaped any association with submentation, as did patients with cone-rod dystrophies. The latter, apart from the pedigrees with BBS, encompassed one pedigree only with 2 siblings out of 3 having subnormal mentation. In fact, cone-rod dystrophies patients, especially cone-rod dystrophies and amelogenesis imperfecta (Jalili syndrome), were characterised not only by normal mentation but also with above average school performance. (Table A18.9)


In summary, rod-cone dystrophies and congenital cataract, especially syndromatic cases, have the highest proportion of mental impairment, especially when there are several associations, and in syndromatic cases. This is in contrast to the European data where mental deficiency was associated with brain injury as a consequence of prematurity, frequently with multiple impairments, such as cerebral palsy and epilepsy.(63), (64) Epilepsy was present in 5 cases only in the series, 3 of whom are rod-cone dystrophies.

     
18.11

Prevalence of Common Conditions

(Updated prevalence in the 5-19 years age cohort in Appendix 3)


The prevalence is worked out by combining the numbers of the patients registered and examined in the study with other affected members with the same condition extracted from the history and pedigree charts. The results are enumerated in Table 18.18.

Demonstrable differences and similarities exist between the West Bank and Gaza Strip in the M:F ratio in several conditions. Tables A18.10, A18.11 depict the conditions according to their male and female preponderance and gender ratios in both regions. The general trend is a male preponderance in the Gaza Strip and female preponderance in the West Bank.

     
Table 18.18 Prevalence of common blinding conditions in the study (Updated prevalence in the 5-19 years age cohort in Appendix 3)

Hereditary Condition

West Bank

Gaza Strip

OPT

 

 

                      Per 100,000 population  

Hereditary conditions

32

50

39

 

Congenital cataract

6

10

8

 

<16 years

10.5

12

13

 

Congenital glaucoma

3.6

6.4

5

 

Microphthalmos

1

3.8

2

 

Microphthalmos

3.5

5.8

4.4

 

Albinism

1.6

3.3

2.2

 

High myopia

1

3.8

2

 

Retinal dystrophies               All ages

13

17

15

 

Under 16

18

23

21

 

Cone degeneration

1

0.73

0.9

 

Cone-rod dystrophies

1

7.7

3.5

 

All progressive cone disorders

3.2

8.4

5

 

Congenital rod-cones

6.8

4

7.1

 

Rod-cone disorders

10.5

3.6

8.2

 

Rod monochromatism

1

4

2.2

 
OPT: Occupied Palestinian territories

 

18.12

 Other Aspects of the Survey
 

 
Clinical Details of Retinal Dystrophies

The comprehensive review of the clinical findings in retinal dystrophies, including their presentations, symptoms and clinical features combined with electrophysiological and electrodiagnostic findings were compiled during the study. This information has been removed from this study and will be published separately. (45), (46), (47), (48), (49), (50), (51), (58), (60). (67)

Dental Associations
In addition to the ophthalmic screening, a comprehensive dental screening shed light on the dental problems and helped in establishing the diagnosis and pattern of the dental associations in this group. The discovery of an association between cone-rod dystrophies and amelogenesis imperfecta, a rare condition of enamel defect, has already been addressed elsewhere. (45), (46), (47), (58), (59)

Red Filters Trials in Photophobia
The efficacy of red transmittance 550 nm as compared to ordinary dark or non-tinted glasses was assessed in 24 diagnosed cases of these conditions (cone-rod dystrophy 14, rod-cone dystrophy 2, rod-monochromatism 5 and central areolar dystrophy 3). Independent observers evaluated improvements in; (a) visual acuity on Sheridan Gardiner testing in normal daylight illumination; (b) photophobia as assessed by reduction in blinking and orbicularis spasms; and (c) subjective comfort. Twelve out of 14 (86%) cases of cone-rod dystrophy and 3 out of 5 (60%) of patients with achromatopsia (rod monochromatism) demonstrated marked improvement on all three parameters with red as compared to dark glasses. Only 2 cases (14%) of cone-rod dystrophy preferred dark tinted to red glasses. There was no improvement in the three cases of
Congenital onset central chorioretinal dystrophy associated with high myopia (Iqbal M, Jalili IK. Eye 1998; 12: 260-265) resembling central areolar choroidal dystrophy, or in the two cases of rod-cone dystrophy. In spite of the small sample size, it seems that patients with cone-rod dystrophy, especially in its early stages, would benefit from red glasses which help by cutting down the short and middle wave length radiation. Red glasses attenuate the ambient illumination that would otherwise saturate the patient's rods, and thus prevent them from seeing in normal daylight illumination.
(http://jalili.co/covi/redfilter.pdf)

Educational Performance
School marks as an indication of intelligence were collected where available. This was done despite the limited sample and the possible bias that could have resulted from the selection procedure whereby results made available for the study skewed towards the better performers. This by itself worked as an indicator for the IQ levels in these conditions, and in particular congenital RC dystrophies (Leber congenital amaurosis). (Table A18.9) list the available school grades of 83 pupils (44 from the West Bank and 38 from the Gaza Strip) and demonstrates a pattern where patients with certain conditions achieve higher academically and vice versa.
 

The sample shows a whole range of educational abilities with the very bright and high performers, such as those patients with albinism and the syndromatic cone-rod dystrophies, in particular the type associated with AI. This also includes the 2 cases with CACR, one of whom is musically gifted. The rest of the CACR series are educationally subnormal. This is in contrast to the rod-cone types of retinal dystrophies, which score worse; the observations are supported by the clinical observations whereby this condition harbours a very high predominance of mental retardation.


Congenital glaucoma follows cone conditions in terms of better educational performance. Congenital cataract cases are a mix of good and poor performers. It is interesting to note that all the congenital cataract associated with small eyes (8/20) performed better than the rest of the congenital cataract sample. Congenital cataract patients show a wider range of IQs but it is worth noting that all patients with small eyes (n=8/20) are educationally better than the rest of the sample.


The optic nerve group showed a disparity between the two syndromatic and acquired cases and the two post inflammatory/meningitis cases.


In the small eyes group, at the top came a male patient with rudimentary globe the second was the eldest of two sibs whose brother is educationally subnormal as seen from the marks.
Both siblings suffer from a syndromatic type of microphthalmia associated with high myopia and cataract. The worst performer was a girl with anophthalmia.


No gender differences in performances existed except marginally in humanities/history. (Table 18.19) To the best of my knowledge no such aspect exists in the literature for comparison.
(http://jalili.co/covi/educatt.pdf)

Table 18.19  Comparison of school performance by gender

Gender

Nos.

Mean Total

Arabic/English

Science / Maths

Arts/Craft

History

Sports

Males

43

66

66

66

75

71

76

Females

39

65

68

68

73

67

78

Appendices 
     
Table A18.1 Patients’ sequence, ratios, and mode of inheritance in congenital cataract
Table A18.2  Congenital glaucoma: associated finding and patients’ sequence
     
Table A18.Patients with small eyes: sequence, ratio and age (microphthalmia and anophthalmia as a primary pathology causing blindness
 
Table A18.4  Congenital corneal oedema cases from two unrelated sibships
Table A18.5  Hypopigmentation (Albinism)
Table A18.6  Sequence and ranks of patients in Achromatopsia
Table A18.7  Cone-rod dystrophies
Table A18.8 Rod cone dystrophies: patients’ sequence, ratios
Table A18.9 School performance by school marks and condition
Table A18.10  West Bank:Gaza Strip ratio of the prevalence of clinical conditions.
Table A18.11 Gender differences in clinical conditions by region
Table 18.12 West Bank:Gaza Strip ratio of the prevalence of clinical conditions.
(Updated prevalence in the 5-19 years age cohort in Appendix 3)

Appendix B

Abbreviations and symbols used in family sequence and degree of consanguinity

a             Abortion
c             Miscarriage 
F, m       (lower case) non-affected male or female
F, M       (upper case) affected male or female
M, F       An affected male of female
(bold)     who was examined
M, F       The affected male or female
(bold)     in question when more than one is affected in the sibship.
n/a          Siblings sequence and pedigree information is not available
p            Pregnant
s             Still birth (followed by f or m if gender is known) e.g sf, sm, indicate a female still birth and a male still birth
U            Uncertain gender
[  ]          Twins such as [mm], [ff], [mf]
-             Minus sign following f, F, m, M indicate deceased sibling.
,  *   ~  ’ To denote specific information data in the preceeding symbol which is explained in the text
{ }          To denote specific information contained inside the bracket
?             ’?’ preceding a symbol indicates uncertainty of the information that follows eg ‘?-‘  means possibly dead, ?m possibly male.
mfMcFf           Siblings not in sequence, when several symbols underlined

Abbreviations Used Referring to Types of Consanguinity

Cn          Degree of cousin marriage eg C1 is first cousin and so on.
C1PM    Double first cousin (if both paternal and maternal)              
NR        No relation
SV/ST   Same village/same town or locality
Cn1h     Cousin once removed eg C1h is first cousin once removed.
P           Paternal
M          Maternal
 

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Ismail K Jalili 2000-2016