Int Ophthalmol DOI 10.1007/s10792-015-0074-6
ORIGINAL PAPER
The eye as a window to a rare disease: ectopia lentis and homocystinuria, a Pakistani perspective Maeirah Shafique . Waqar Muzaffar . Mazhar Ishaq
Received: 26 October 2014 / Accepted: 23 April 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract Non-traumatic ectopia lentis has been associated with genetic diseases in a European population; however, no data are present in regards to this in a Pakistani demographic. In third world countries such as Pakistan, due to the lack of screening tests, this disease has the potential to remain undiagnosed till a later age, at which point the eye through the finding of ectopia lentis has potential to lead to the right diagnosis. Our purpose was to investigate Pakistani patients presenting with ectopia lentis who have underlying homocystinuria and establish a relationship between the two. Additionally, we elicited various systemic and ophthalmic features in these settings. Ten Pakistani patients presenting with decreased vision and ectopia lentis with concomitant homocystinuria were included in the study. Assessment of systemic and ophthalmic features was performed. All patients presented with visual deterioration. All 20 (100 %) eyes had ectopia lentis, of which, 15 (75 %) eyes had inferior subluxation, whereas five (25 %) eyes had anterior subluxation of the crystalline lens. Ectopia lentis and homocystinuria appear to have a strong correlation in Pakistani population. Ectopia lentis has the potential to serve as an important clue to its diagnosis, which may in turn
M. Shafique (&) W. Muzaffar M. Ishaq Armed Forces Institute of Ophthalmology, Rawalpindi, Pakistan e-mail: [email protected]
lead to decreased morbidity if diagnosed in a timely fashion. Keywords Ectopia lentis Homocystinuria Pakistan Non-traumatic
Introduction Ectopia lentis is a condition in which the crystalline lens is displaced from its normal position in the eye [1–3]. It may be congenital or acquired [4]. In the absence of trauma, this finding should elicit a search for an underlying hereditary systemic or associated ocular syndrome [5]. The lens is displaced because of laxity or rupture of the supporting zonules [6]. The zonular weakening may be stationary [7] or it may be progressive if it occurs in conjunction with a systemic disease like Homocystinuria [8] or Marfan syndrome [9]. Homocystinuria is a rare autosomal recessive disorder characterized by inborn error of metabolism due to deficiency of cystathionine beta synthase (CBS) [10]. This results in systemic accumulation of homocysteine and methionine causing multisystem disorder of connective tissues, muscles, nervous system, and cardiovascular system [8]. The disease is more common in males [8]. The prevalence of cases with ascertained CBS deficiency is only 1 in 4,330,000 worldwide [11]. In European populations, prevalence of homocystinuria is around 1 in 10,000, which is
123
Int Ophthalmol
much higher than the rest of the world [8]. This is possibly related to the higher incidence of mutation such as the Celtic variant G307S, which is the most common CBS mutation for this disease [12]. There is no statistical record of its prevalence in Pakistan. In our own experience, this entity is rare, as we have only encountered ten patients from a pediatric pool of 80,000 Pakistani children at one of the the largest tertiary care center for ophthalmology in Pakistan. International literature has evidence that ectopia lentis is seen in homocystinuria [8]. However, the literature of this entity being encountered in a Pakistani population in the setting of homocystinuria is non-existent.
Methods The study was conducted over from July 2009 to Feb 2013. It comprised ten individuals from four different families, who presented with decreased vision and were observed to have ectopia lentis. Homocysteine levels in plasma and urine samples were elevated. The age of the patients ranged between 5 and 12 years. Seven of a total of ten patients were males and three females. The detailed assessment of patients and final diagnosis of the disease was made in collaboration with pediatrician, pediatric cardiologist, and pathologist. Detailed history was obtained from the parents, and all patients were subjected to a complete systemic and ophthalmic examination. Mental status was assessed by history and assessment of their cognitive, language, social, and motor functions by a pediatrician. Hair color and texture, arm span versus height (in cm), and muscle tone were recorded. Clinical features of dolichocephalia (head being longer than expected compared to its width), dental deformities, low-set ears, arachnodactyly, and venous thrombosis in lower extremities were specifically looked for in all these patients. Cardiovascular system was also assessed for any abnormalities. Detailed ophthalmic examination of all eyes was carried out including assessment of visual acuity, inspection for nystagmus, and assessment for squint. Tonometry was performed to record intraocular pressure. Slitlamp biomicroscopy (Fundus examination) was carried out to examine the optic nerve head and retinal nerve fibers. Slitlamp biomicroscopy was
123
carried out to examine the optic nerve head and retinal nerve fibers.
Results SPSS 20.0 was used for statistical analysis. Frequency and percentages of the above-mentioned systemic and ophthalmic features in these patients were observed (Fig. 1). Ages of our patients ranged between 5 and 12 years. Of a total of ten patients, seven (70 %) were males and three (30 %) females. The systemic examination revealed the arm span to be more than height in all (100 %) patients (Fig. 2). Mental subnormality, arachnodactyly, and fair, coarse hair were seen in seven (70 %) patients. None of the patients, however, had venous thrombosis of lower limbs, heart abnormalities, or muscular hypotonia. The details of clinical features are shown in Table 1. Ophthalmic examination revealed visual deterioration in all 20 (100 %) eyes. Ectopia lentis was also present in all 20 (100 %) eyes, of which, 15 (75 %) eyes had inferior subluxation and 5 (25 %) eyes had anterior subluxation of the crystalline lens (Fig. 3). Neither squint nor nystagmus was observed in any of these eyes. Ophthalmic findings are mentioned in Table 2.
Discussion The etiology of pediatric lens subluxation has included trauma, Marfan syndrome, homocystinuria, and simple ectopia lentis [13]. Ectopia lentis is also been associated with rare diseases such as Weill–Marchesani syndrome [14], Sturge–Weber syndrome [15], and Stickler syndrome [16]. Homocystinuria is a metabolic disorder, which may present in the form of systemic or ophthalmic symptoms and signs. It is characterized by marfanoid habitus, mental subnormality, ectopia lentis [13, 17, 18], and thromboembolic phenomenon [19] resulting in stroke and ultimately death [20]. In developed countries, with increasing awareness and screening programs [21], the disease may be diagnosed before the onset of ectopia lentis at an earlier stage. However, in third world countries such as Pakistan, due to the lack of such screening tests, it has the potential to remain undiagnosed till it presents with decreased vision due to ectopia lentis.
Int Ophthalmol Fig. 1 Graph showing frequency of each systemic feature in our patients
Table 1 Non-ophthalmic features in selected patients
Fig. 2 a and b Arm span is more than height in the child having homocystinuria
An important simulating condition to homocystinuria is Marfan syndrome. Both of these conditions are characterized by tall stature, thin build, and arm span more than height, kyphoscoliosis and arachnodactyly [8, 22]. The main systemic features that differentiate patients of Homocystinuria are mental subnormality, coarse, fair hair [23], normal cardiovascular system and lack of joint hyperflexibility [8]. In ophthalmological findings, Homocystinuria is characterized by increased
Clinical features
Frequency
Percentage
Arm span more than height
10
100
Arachnodactyly
7
70
Fair and coarse hair
7
70
Kyphoscoliosis
5
50
Low-set ears
4
40
Abnormality of teeth
4
40
Dolicocefalia
3
30
Venous thrombosis
0
0
Cardiac abnormality
0
0
Muscular hypotonia
0
0
incidence of infero-nasal subluxation of lens in contrast to Marfan syndrome, which typically has superotemporal subluxation [24, 25]. Our study supported this as we found inferior subluxation of lens (Fig. 1) in 75 % of eyes. Anterior subluxation of lens occurred in 25 % of eyes, which is a known complication due to weakened zonules, usually occurring between ages of 4 and 10 years [8]. For systemic features, arachnodactyly was present in 70 % of our patients, whereas it is considered an infrequent feature of homocystinuria [10]. None of the patients in our study had muscular hypotonia, considered characteristic of the disease [8]. These may be potential areas of further clinical research in the Pakistani demographic.
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Int Ophthalmol
Conclusion Due to negligible data on homocystinuria as well as lack of screening tests in the Pakistani population, there is a potential for this disease to remain undetected till late childhood. It is a condition that causes multisystem disorder of connective tissues, muscles, nervous system, and cardiovascular system. Our paper shows that in a Pakistani population, one clue that may help is ectopia lentis and where an ophthalmologist can serve as an important clue to its diagnosis. If diagnosed early and treated in time, many of these complications may be avoided.
References Fig. 3 a and b Bilateral infero-nasal ectopia lentis in the same patient. A characteristic feature of homocystinuria
Table 2 Ophthalmic pathologies in selected patients Ophthalmic features
Frequency
Percentage
Visual deterioration
20
100
Inferior subluxation of lens
15
75
6 5
30 25
Nystagmus Glaucoma Anterior subluxation of lens
5
25
Retinal degeneration
4
20
Cataract
4
20
Optic atrophy
2
10
Squint
0
0
Of note, homocystinuria has markedly reduced life expectancy without treatment and 25 % of the untreated patients die by 30 years of age, due to thrombotic phenomenon [8]. If diagnosed in time, many of the sinister complications can be avoided as is shown in countries of high prevalence where routine screening programs have succeeded in substantially minimizing the complications of this disease [25]. Although our study has a small number of patients, this does shine a light to other means of detecting this disease in a third world setting and can be another area of further research.
123
1. Nelson LB, Maumenee IH (1982) Ectopialentis. Surv Ophthalmol 27(3):143–160 2. Jarrett WH II (1967) Dislocation of the lens. A study of 166 hospitalized cases. Arch Ophthalmol 78(3):289–296 3. Nirankari MS, Chaddah MR (1967) Displaced lens. Am J Ophthalmol 63(6):1719–1723 4. Noorani S, Khan A, Rubab S, Choudhary KA (2007) Management of ectopia lentis in children. Pak J Ophthalmol 23(4):181–187 5. Streeten BW (2000) Pathology of the lens. In: Albert DM, Jakobiec FA (eds) Principles and practice of ophthalmology. Saunders, Philadelphia, pp 2225–2239 6. Ahram D, Sato TS, Kohilan A, Tayeh M, Chen S, Leal S, AlSalem M, El-Shanti H (2009) A homozygous mutation in ADAMTSL4 causes autosomal-recessive isolated ectopia lentis. Am J Hum Genet 84(2):274–278 7. Marin S (1991) Inherited eye diseases: diagnosis and clinical management. MP Dekker, NewYork, pp 131–132 8. Singh D, Singh K, Singh R, Singh R (2005) Dislocated crystalline lenses. In: Wilson ME, Trivedi RH (eds) Pediatric cataract surgery. Lippincott Williams & Wilkins, Philadelphia, p 205 9. Li D, Yu J, Gu F, Pang X, Ma X, Li R, Liu N, Ma X (2008) The roles of two novel FBN1 gene mutations in the genotype-phenotype correlations of Marfan syndrome and ectopia lentis patients with marfanoid habitus. Genet Test 12(2):325–330 10. Kanski JJ (2011) Clinical ophthalmology. A systematic approach, 7th edn. Elsevier, London 11. Mudd SH, Levy HL, Skovby F (1989) Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, 7th edn. McGraw-Hill, New York, pp 1279–1327 12. Naughten ER, Yap S (1998) Mayne PD. Newborn screening for homocystinuria: Irish and world experience, Eur J Pediatr, p 157 13. Neely DE, Plager DA (2001) Management of ectopia lentis in children. Ophthalmol Clin N Am 14(3):493–499
Int Ophthalmol 14. Jensen AD, Cross HE, Paton D (1974) Ocular complications in the Weill-Marchesani syndrome. Am J Ophthalmol 77:261–269 15. Filato V, Guyer DR, Lustbuder JM et al (1992) Dislocation of lens in a patient with Sturge–Weber syndrome. Ann Ophthalmol 24:260–262 16. Weingeist IA, Hermsen V, Hanson JW, Bumsted RM, Weinstein SL, Olin WH (1982) Ocular and systemic manifestations of Stickler’s syndrome: a preliminary report. Birth Defects 18:539–560 17. Cross HE (1976) Differential diagnosis and treatment of dislocated lenses. In: Bergsma D, Bron AJ, Cotlier E (eds) The eye and inborn errors of metabolism. Alan R. Liss, New York, pp 335–346 18. Cross HE, Jensen AD (1973) Ocular manifestation in the Marfan syndrome and homocystinuria. Am J Ophthalmol 75:405–420 19. Van Beynum IM, Smeitink JA, den Heijer M, te Poele Pothoff MT, Blom HJ (1999) Hyperhomocysteinemia: a risk factor for ischemic stroke in children. Circulation 99:2070–2072 20. Cardo E, Campistol J, Caritg J, Ruiz S, Vilaseca MA, Kirkham F, Blom HJ (1999) Fatal haemorrhagic infarct in
21.
22.
23. 24.
25.
an infant with homocystinuria. Dev Med Child Neurol 41:132–135 Peterschmitt MJ, Simmons JR, Levy HL (1999) Reduction of false negative results in screening of newborns for homocystinuria. N Engl J Med 341:1572–1576 Bruno L, Tredici S, Mangiavacchi M, Colombo V, Mazzotta GF, Sirtori CF (1984) Cardiac, skeletal, and ocular abnormalities in patients with Marfan’s syndrome and in their relatives. Comparison with the cardiac abnormalities in patients with kyphoscoliosis. Br Heart J 51:220–230 Yayınlar Y (2010) Rook’s textbook of dermatology, 8th edn. Wiley Blackwell, Oxford Mir S, Wheatley HM, Hussels IE, Whittum-Hudson JA, Traboulsi EI (1998) A comparative histologic study of the fibrillin microfibrillar system in the lens capsule of normal subjects and subjects with Marfan syndrome. Investig Ophthalmol Vis Sci 39(1):84–93 The Wills Eye Manual (2008) Office and emergency room diagnosis and treatment of eye disease, 5th edn. Wolter Kluwer, Lippincott, Williams & Wilkins, Philadelphia
123
ORIGINAL PAPER
The eye as a window to a rare disease: ectopia lentis and homocystinuria, a Pakistani perspective Maeirah Shafique . Waqar Muzaffar . Mazhar Ishaq
Received: 26 October 2014 / Accepted: 23 April 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract Non-traumatic ectopia lentis has been associated with genetic diseases in a European population; however, no data are present in regards to this in a Pakistani demographic. In third world countries such as Pakistan, due to the lack of screening tests, this disease has the potential to remain undiagnosed till a later age, at which point the eye through the finding of ectopia lentis has potential to lead to the right diagnosis. Our purpose was to investigate Pakistani patients presenting with ectopia lentis who have underlying homocystinuria and establish a relationship between the two. Additionally, we elicited various systemic and ophthalmic features in these settings. Ten Pakistani patients presenting with decreased vision and ectopia lentis with concomitant homocystinuria were included in the study. Assessment of systemic and ophthalmic features was performed. All patients presented with visual deterioration. All 20 (100 %) eyes had ectopia lentis, of which, 15 (75 %) eyes had inferior subluxation, whereas five (25 %) eyes had anterior subluxation of the crystalline lens. Ectopia lentis and homocystinuria appear to have a strong correlation in Pakistani population. Ectopia lentis has the potential to serve as an important clue to its diagnosis, which may in turn
M. Shafique (&) W. Muzaffar M. Ishaq Armed Forces Institute of Ophthalmology, Rawalpindi, Pakistan e-mail: [email protected]
lead to decreased morbidity if diagnosed in a timely fashion. Keywords Ectopia lentis Homocystinuria Pakistan Non-traumatic
Introduction Ectopia lentis is a condition in which the crystalline lens is displaced from its normal position in the eye [1–3]. It may be congenital or acquired [4]. In the absence of trauma, this finding should elicit a search for an underlying hereditary systemic or associated ocular syndrome [5]. The lens is displaced because of laxity or rupture of the supporting zonules [6]. The zonular weakening may be stationary [7] or it may be progressive if it occurs in conjunction with a systemic disease like Homocystinuria [8] or Marfan syndrome [9]. Homocystinuria is a rare autosomal recessive disorder characterized by inborn error of metabolism due to deficiency of cystathionine beta synthase (CBS) [10]. This results in systemic accumulation of homocysteine and methionine causing multisystem disorder of connective tissues, muscles, nervous system, and cardiovascular system [8]. The disease is more common in males [8]. The prevalence of cases with ascertained CBS deficiency is only 1 in 4,330,000 worldwide [11]. In European populations, prevalence of homocystinuria is around 1 in 10,000, which is
123
Int Ophthalmol
much higher than the rest of the world [8]. This is possibly related to the higher incidence of mutation such as the Celtic variant G307S, which is the most common CBS mutation for this disease [12]. There is no statistical record of its prevalence in Pakistan. In our own experience, this entity is rare, as we have only encountered ten patients from a pediatric pool of 80,000 Pakistani children at one of the the largest tertiary care center for ophthalmology in Pakistan. International literature has evidence that ectopia lentis is seen in homocystinuria [8]. However, the literature of this entity being encountered in a Pakistani population in the setting of homocystinuria is non-existent.
Methods The study was conducted over from July 2009 to Feb 2013. It comprised ten individuals from four different families, who presented with decreased vision and were observed to have ectopia lentis. Homocysteine levels in plasma and urine samples were elevated. The age of the patients ranged between 5 and 12 years. Seven of a total of ten patients were males and three females. The detailed assessment of patients and final diagnosis of the disease was made in collaboration with pediatrician, pediatric cardiologist, and pathologist. Detailed history was obtained from the parents, and all patients were subjected to a complete systemic and ophthalmic examination. Mental status was assessed by history and assessment of their cognitive, language, social, and motor functions by a pediatrician. Hair color and texture, arm span versus height (in cm), and muscle tone were recorded. Clinical features of dolichocephalia (head being longer than expected compared to its width), dental deformities, low-set ears, arachnodactyly, and venous thrombosis in lower extremities were specifically looked for in all these patients. Cardiovascular system was also assessed for any abnormalities. Detailed ophthalmic examination of all eyes was carried out including assessment of visual acuity, inspection for nystagmus, and assessment for squint. Tonometry was performed to record intraocular pressure. Slitlamp biomicroscopy (Fundus examination) was carried out to examine the optic nerve head and retinal nerve fibers. Slitlamp biomicroscopy was
123
carried out to examine the optic nerve head and retinal nerve fibers.
Results SPSS 20.0 was used for statistical analysis. Frequency and percentages of the above-mentioned systemic and ophthalmic features in these patients were observed (Fig. 1). Ages of our patients ranged between 5 and 12 years. Of a total of ten patients, seven (70 %) were males and three (30 %) females. The systemic examination revealed the arm span to be more than height in all (100 %) patients (Fig. 2). Mental subnormality, arachnodactyly, and fair, coarse hair were seen in seven (70 %) patients. None of the patients, however, had venous thrombosis of lower limbs, heart abnormalities, or muscular hypotonia. The details of clinical features are shown in Table 1. Ophthalmic examination revealed visual deterioration in all 20 (100 %) eyes. Ectopia lentis was also present in all 20 (100 %) eyes, of which, 15 (75 %) eyes had inferior subluxation and 5 (25 %) eyes had anterior subluxation of the crystalline lens (Fig. 3). Neither squint nor nystagmus was observed in any of these eyes. Ophthalmic findings are mentioned in Table 2.
Discussion The etiology of pediatric lens subluxation has included trauma, Marfan syndrome, homocystinuria, and simple ectopia lentis [13]. Ectopia lentis is also been associated with rare diseases such as Weill–Marchesani syndrome [14], Sturge–Weber syndrome [15], and Stickler syndrome [16]. Homocystinuria is a metabolic disorder, which may present in the form of systemic or ophthalmic symptoms and signs. It is characterized by marfanoid habitus, mental subnormality, ectopia lentis [13, 17, 18], and thromboembolic phenomenon [19] resulting in stroke and ultimately death [20]. In developed countries, with increasing awareness and screening programs [21], the disease may be diagnosed before the onset of ectopia lentis at an earlier stage. However, in third world countries such as Pakistan, due to the lack of such screening tests, it has the potential to remain undiagnosed till it presents with decreased vision due to ectopia lentis.
Int Ophthalmol Fig. 1 Graph showing frequency of each systemic feature in our patients
Table 1 Non-ophthalmic features in selected patients
Fig. 2 a and b Arm span is more than height in the child having homocystinuria
An important simulating condition to homocystinuria is Marfan syndrome. Both of these conditions are characterized by tall stature, thin build, and arm span more than height, kyphoscoliosis and arachnodactyly [8, 22]. The main systemic features that differentiate patients of Homocystinuria are mental subnormality, coarse, fair hair [23], normal cardiovascular system and lack of joint hyperflexibility [8]. In ophthalmological findings, Homocystinuria is characterized by increased
Clinical features
Frequency
Percentage
Arm span more than height
10
100
Arachnodactyly
7
70
Fair and coarse hair
7
70
Kyphoscoliosis
5
50
Low-set ears
4
40
Abnormality of teeth
4
40
Dolicocefalia
3
30
Venous thrombosis
0
0
Cardiac abnormality
0
0
Muscular hypotonia
0
0
incidence of infero-nasal subluxation of lens in contrast to Marfan syndrome, which typically has superotemporal subluxation [24, 25]. Our study supported this as we found inferior subluxation of lens (Fig. 1) in 75 % of eyes. Anterior subluxation of lens occurred in 25 % of eyes, which is a known complication due to weakened zonules, usually occurring between ages of 4 and 10 years [8]. For systemic features, arachnodactyly was present in 70 % of our patients, whereas it is considered an infrequent feature of homocystinuria [10]. None of the patients in our study had muscular hypotonia, considered characteristic of the disease [8]. These may be potential areas of further clinical research in the Pakistani demographic.
123
Int Ophthalmol
Conclusion Due to negligible data on homocystinuria as well as lack of screening tests in the Pakistani population, there is a potential for this disease to remain undetected till late childhood. It is a condition that causes multisystem disorder of connective tissues, muscles, nervous system, and cardiovascular system. Our paper shows that in a Pakistani population, one clue that may help is ectopia lentis and where an ophthalmologist can serve as an important clue to its diagnosis. If diagnosed early and treated in time, many of these complications may be avoided.
References Fig. 3 a and b Bilateral infero-nasal ectopia lentis in the same patient. A characteristic feature of homocystinuria
Table 2 Ophthalmic pathologies in selected patients Ophthalmic features
Frequency
Percentage
Visual deterioration
20
100
Inferior subluxation of lens
15
75
6 5
30 25
Nystagmus Glaucoma Anterior subluxation of lens
5
25
Retinal degeneration
4
20
Cataract
4
20
Optic atrophy
2
10
Squint
0
0
Of note, homocystinuria has markedly reduced life expectancy without treatment and 25 % of the untreated patients die by 30 years of age, due to thrombotic phenomenon [8]. If diagnosed in time, many of the sinister complications can be avoided as is shown in countries of high prevalence where routine screening programs have succeeded in substantially minimizing the complications of this disease [25]. Although our study has a small number of patients, this does shine a light to other means of detecting this disease in a third world setting and can be another area of further research.
123
1. Nelson LB, Maumenee IH (1982) Ectopialentis. Surv Ophthalmol 27(3):143–160 2. Jarrett WH II (1967) Dislocation of the lens. A study of 166 hospitalized cases. Arch Ophthalmol 78(3):289–296 3. Nirankari MS, Chaddah MR (1967) Displaced lens. Am J Ophthalmol 63(6):1719–1723 4. Noorani S, Khan A, Rubab S, Choudhary KA (2007) Management of ectopia lentis in children. Pak J Ophthalmol 23(4):181–187 5. Streeten BW (2000) Pathology of the lens. In: Albert DM, Jakobiec FA (eds) Principles and practice of ophthalmology. Saunders, Philadelphia, pp 2225–2239 6. Ahram D, Sato TS, Kohilan A, Tayeh M, Chen S, Leal S, AlSalem M, El-Shanti H (2009) A homozygous mutation in ADAMTSL4 causes autosomal-recessive isolated ectopia lentis. Am J Hum Genet 84(2):274–278 7. Marin S (1991) Inherited eye diseases: diagnosis and clinical management. MP Dekker, NewYork, pp 131–132 8. Singh D, Singh K, Singh R, Singh R (2005) Dislocated crystalline lenses. In: Wilson ME, Trivedi RH (eds) Pediatric cataract surgery. Lippincott Williams & Wilkins, Philadelphia, p 205 9. Li D, Yu J, Gu F, Pang X, Ma X, Li R, Liu N, Ma X (2008) The roles of two novel FBN1 gene mutations in the genotype-phenotype correlations of Marfan syndrome and ectopia lentis patients with marfanoid habitus. Genet Test 12(2):325–330 10. Kanski JJ (2011) Clinical ophthalmology. A systematic approach, 7th edn. Elsevier, London 11. Mudd SH, Levy HL, Skovby F (1989) Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, 7th edn. McGraw-Hill, New York, pp 1279–1327 12. Naughten ER, Yap S (1998) Mayne PD. Newborn screening for homocystinuria: Irish and world experience, Eur J Pediatr, p 157 13. Neely DE, Plager DA (2001) Management of ectopia lentis in children. Ophthalmol Clin N Am 14(3):493–499
Int Ophthalmol 14. Jensen AD, Cross HE, Paton D (1974) Ocular complications in the Weill-Marchesani syndrome. Am J Ophthalmol 77:261–269 15. Filato V, Guyer DR, Lustbuder JM et al (1992) Dislocation of lens in a patient with Sturge–Weber syndrome. Ann Ophthalmol 24:260–262 16. Weingeist IA, Hermsen V, Hanson JW, Bumsted RM, Weinstein SL, Olin WH (1982) Ocular and systemic manifestations of Stickler’s syndrome: a preliminary report. Birth Defects 18:539–560 17. Cross HE (1976) Differential diagnosis and treatment of dislocated lenses. In: Bergsma D, Bron AJ, Cotlier E (eds) The eye and inborn errors of metabolism. Alan R. Liss, New York, pp 335–346 18. Cross HE, Jensen AD (1973) Ocular manifestation in the Marfan syndrome and homocystinuria. Am J Ophthalmol 75:405–420 19. Van Beynum IM, Smeitink JA, den Heijer M, te Poele Pothoff MT, Blom HJ (1999) Hyperhomocysteinemia: a risk factor for ischemic stroke in children. Circulation 99:2070–2072 20. Cardo E, Campistol J, Caritg J, Ruiz S, Vilaseca MA, Kirkham F, Blom HJ (1999) Fatal haemorrhagic infarct in
21.
22.
23. 24.
25.
an infant with homocystinuria. Dev Med Child Neurol 41:132–135 Peterschmitt MJ, Simmons JR, Levy HL (1999) Reduction of false negative results in screening of newborns for homocystinuria. N Engl J Med 341:1572–1576 Bruno L, Tredici S, Mangiavacchi M, Colombo V, Mazzotta GF, Sirtori CF (1984) Cardiac, skeletal, and ocular abnormalities in patients with Marfan’s syndrome and in their relatives. Comparison with the cardiac abnormalities in patients with kyphoscoliosis. Br Heart J 51:220–230 Yayınlar Y (2010) Rook’s textbook of dermatology, 8th edn. Wiley Blackwell, Oxford Mir S, Wheatley HM, Hussels IE, Whittum-Hudson JA, Traboulsi EI (1998) A comparative histologic study of the fibrillin microfibrillar system in the lens capsule of normal subjects and subjects with Marfan syndrome. Investig Ophthalmol Vis Sci 39(1):84–93 The Wills Eye Manual (2008) Office and emergency room diagnosis and treatment of eye disease, 5th edn. Wolter Kluwer, Lippincott, Williams & Wilkins, Philadelphia
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