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Familial ptotic lid elevation during ipsilateral abduction
Familial Ptotic Lid Elevation During Ipsilateral Abduction Arif O. Khan, MD,a Abdulrahman Al-Hommaidi, COA,b and Shahira Al-Turkmani, MDa Purpose: To report and discuss the clinical findings of a 17-member family with 2 siblings who exhibit ptosis and abnormal synkinetic lid elevation associated with ipsilateral abduction. Subjects and Methods: Sixteen members of the 17-member immediate family underwent ophthalmic examination. Results: Two siblings exhibited ptosis and abnormal synkinetic lid elevation associated with ipsilateral abduction. One was bilaterally affected and the other had unilateral findings. A third sibling had isolated bilateral congenital ptosis. A fourth demonstrated classic Duane syndrome Type I in the right eye. Other family members did not have ophthalmic abnormalities. Conclusions: A unifying mechanism of congenital cranial dysinnervation may underlie these and similar phenotypes of oculomotor and/or abducens nerve abnormalities with or without abnormal synkinesis. (J AAPOS 2004;8:571-575) “
ynkinesis” refers to the coordinated simultaneous contraction of different muscles. An abnormal synkinesis occurs when different muscles inappropriately co-contract, such as in acquired aberrant regeneration of the third cranial nerve after trauma. Congenital abnormal synkinesis involving ocular and periocular muscles is infrequent, most commonly seen in the Duane retraction syndrome1 and the Marcus Gunn jaw-winking phenomenon.2 Congenital abnormal synkinesis involving the eyelid has been associated with facial muscle contraction3,4 as well as extraocular muscle contraction.5 The Duane syndrome, the Marcus Gunn phenomenon, and other related congenital abnormal synkineses are typically sporadic although familial cases have been reported.6-20 A family has been identified that includes 2 siblings with ptosis and abnormal synkinetic lid elevation associated with ipsilateral abduction. Two other siblings exhibit related findings. The clinical features of affected members of this family are described and discussed.
S
SUBJECTS AND METHODS The proband, a 4-year-old girl, was referred for evaluation of abnormal eye movements since birth. A pedigree was obtained from her parents. All available family members underwent ophthalmic exam.
From the Department of Pediatric Ophthalmology,a King Khaled Eye Specialist Hospital, P.O. Box 7191, Riyadh 11462, Saudi Arabia; and Research Department,b King Khaled Eye Specialist Hospital, P.O. Box 7191, Riyadh 11462, Saudi Arabia. Submitted August 1, 2003. Revision accepted July 9, 2004. Address reprint requests to Dr. Arif O. Khan, MD, King Khaled Eye Specialist Hospital, P.O. Box 7191, Riyadh 11462, Saudi Arabia. Copyright © 2004 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2004/$35.00 ⫹ 0 doi:10.1016/j.jaapos.2004.07.010
Journal of AAPOS
REPORT OF CASES Sixteen members of the 17-member immediate family of Arab ancestry underwent ophthalmic examination, including cycloplegic refraction (Fig. 1). The father’s first wife was his cousin, while his second wife was not related to him. According to the father, the one family member unavailable for examination (patient 7, Fig. 1) did not have ophthalmic findings. No examined family member had significant medical history nor could cause lid movement by facial muscle contracture or jaw movement. Fourteen examined family members had unremarkable ophthalmic examinations, whereas 4 had abnormal ophthalmic findings. For these 4 patients with findings, pupillary and retinal exams were unremarkable; cycloplegic refractive error was ⬍⫹1.50 spherical equivalent in both eyes, and there was no strabismus other than noted below: Case 1 (the proband, patient 14, Fig. 2): A 4-year-old female presented with ptosis in the left eye that completely blocked the pupil in primary gaze and had been present since birth. There was a variable right face turn. Visual acuity was 20/30 in the right eye and 20/80 in the left eye. The left eyelid could elevate to a normal level only with abduction of the left eye. There was slight limitation of adduction of the left eye associated with slight globe retraction. Straight upgaze was not associated with levator activation but was associated with a 15 prism diopter esotropia. After 3 months of part-time occlusion of the right eye (4 hours/day), the vision in the left eye improved to 20/50. Case 2 (patient 9, Figure 3): A 15-year-old male exhibited bilateral ptosis that had been present since birth. In primary gaze he had a chin-up position. Visual acuity was 20/20 in both eyes. With abduction of either eye, the ipsilateral lid elevated to a normal level. Straight upgaze was associated with bilateral levator activation as well as a 20 prism diopter right esotropia. December 2004
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Journal of AAPOS Volume 8 Number 6 December 2004
FIG 1. The pedigree of the immediate family is shown. All numbered patients were examined except for patient 7.
Case 3 (patient 3): A 26-year-old female had a history of bilateral ptosis surgery at an early age. There was no abnormal head position. There was a mild astigmatic refractive error and best-corrected visual acuity was 20/30 in both eyes. There was residual congenital ptosis (palpebral fissure 6 mm in the right eye, 8 mm in the left eye). Case 4 (patient 16, Figure 4): A 4-year-old female exhibited the Duane syndrome in the right eye with a 15-degree right face turn. Vision was 20/30 in both eyes. There was a small-angle esotropia in forced primary gaze. Versions revealed ⫺2 abduction of the right eye, trace adduction defect of the right eye, and globe retraction with a large upshot during adduction of the right eye.
DISCUSSION Although abnormal synkinetic eyelid elevation during eye movement can often be seen after third cranial nerve injury and aberrant regeneration, it is otherwise rare, especially as a congenital phenomenon.1,5 There seems to be at least 4 previously reported cases of congenital eyelid elevation associated with adduction, 2 sporadic (originally reported in 1890 and 1919), and the other 2 in sisters.20 By history, the 2 previously reported sisters with this condition had 4 other family members in 3 generations with similar findings, but they were not examined by the authors of the report.20 There are at least 5 previously reported cases of congenital abnormal lid elevation during abduction as we describe in the current family: 3 sporadic5 and 2 in brothers (originally reported in 1887).20 In all of
these previously reported cases of abnormal lid synkinesis, there was no reported trauma or abnormality of ocular motility. Abnormal innervation from cranial nerve III to the levator in the cases associated with adduction and from cranial nerve VI to the levator in the cases associated with abduction is a likely explanation for the synkineses in these previously reported cases, but without anatomical evidence one cannot be sure of the underlying pathology. In addition to levator activation with abduction, 2 of the 4 affected siblings in the current family (patients 9 and 14) also demonstrated an abnormal synkinesis of adduction in upgaze with esotropia. In addition, patient 14 also demonstrated levator activation with straight upgaze. These additional findings suggest further “miswiring” within the oculomotor nerve, a type of abnormal synkinesis that has been described previously (between the superior rectus and the levator).21 Genetic and neuropathological studies of congenital fibrosis of the extraocular muscles (CFEOM), the Duane syndrome, and isolated congenital ptosis suggest abnormal cranial nerve motor neuron and/or axonal development (congenital cranial dysinnervation) as a cause for certain types of strabismus and ptosis with or without abnormal synkinesis.22-33 CFEOM1, the most common form of CFEOM, is autosomal dominant (AD), and typically includes bilateral congenital ptosis and bilateral ocular motility dysfunction. The globes are infraducted with restricted upgaze, variably restricted downgaze, and abnormal synkineses such as synergistic convergence on upgaze.
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FIG 2. (A) In primary gaze this unilaterally affected female (patient 14) exhibits complete ptosis of the left eye. (B) With ipsilateral abduction the lid elevates to a normal level. (C) In adduction, the lid is ptotic.
Most affected families map to the FEOM1 locus (chromosome 12p11.2-q12), and histopathological studies suggest a defect in development of the superior division of the oculomotor nerve.23 CFEOM2 is autosomal recessive (AR); affected patients exhibit bilateral ptosis and largeangle exotropia with severely limited globe motility. CFEOM2 results from mutation of ARIX (11q13.2) and murine models suggest that this gene is responsible for development of the oculomotor and trochlear nerves.24 CFEOM3 is diagnosed when an affected individual has some features of CFEOM, but typically without abnormal synkinesis and with neither the classic phenotype of CFEOM1 or CFEOM2. Inheritance is AD with incomplete penetrance. Most families map to the FEOM3 locus (16q24.2-q24.3), and it has been suggested that CFEOM3 results from a variable defect in oculomotor nucleus development.25 The Duane syndrome is associated with at least three genetic loci: 8q13 (DUR1),26
FIG 3. (A) In primary gaze, this bilaterally affected male (patient 9) has bilateral ptosis and uses his frontalis muscle to improve lid elevation. (B) In left gaze, the ptotic lid of the left eye elevates to a normal level. (C) In right gaze, the ptotic lid of the right eye elevates to a normal level. (D) In upgaze, the patient has bilateral levator activation as well as an esotropia.
2q31 (DURS2),27 and 20q13 (SALL4 mutation)28 In addition, isolated cases of the Duane syndrome. have been reported with deletions at chromosomes 22 and 4.29,30 Autopsy studies suggest the underlying pathogenesis of the Duane Syndrome to be maldevelopment of the abducens nerve associated with aberrant innervation of the lateral rectus by the oculomotor nerve.31
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Journal of AAPOS Volume 8 Number 6 December 2004 References
FIG 4. This girl (patient 16) has classic Duane syndrome of the right eye without ptosis. (A) There is limitation of attempted adduction of the left eye with associated globe retraction. An upshoot of the right eye occurred with further attempted adduction of the right eye (not shown). (B) In attempted abduction of the right eye, there is a significant limitation and some forward globe movement.
Isolated congenital ptosis has been associated with 2 loci: 1p32-p34.1 (PTOS1) associated with AD inheritance and incomplete penetrance32 and Xp24-27.1 (PTOS2) associated with an X-linked dominant pattern.33 These forms of ptosis may be due to abnormal development of the oculomotor subnucleus responsible for levator innervation. In addition to genetic studies of the above-mentioned disorders, studies of thalidomide embryopathy patients support the concept of developmental cranial dysinnervation underlying congenital incomitant strabismus with or without ptosis and/or aberrant innervation.34 The different phenotypes exhibited in affected members of the current family can similarly be explained by developmental cranial nerve dysinnervation. The findings in the 2 siblings with lid elevation during ipsilateral abduction (patients 9 and 14) can be explained by “miswiring” of cranial III as can be seen in CFEOM.23-25 In the patient with classic Duane syndrome (patient 16), aplasia of cranial nerve VI with aberrant innervation of cranial nerve III to the lateral rectus is the expected underlying mechanism.31 For the patient with isolated congenital ptosis (patient 3), findings can be explained by maldevelopment within cranial nerve III as seen in CFEOM23-25 or inherited congenital ptosis.32-33 The pedigree of current family suggests that a gene responsible for multiple cranial nerve development exists (an idea that has been suggested previously18,24) with an inheritance pattern that is AR or possibly AD with variable penetrance. Thanks are given to Jamal Roumeliotis and Adolph Cabañas, media artists at the King Khaled Eye Specialist Hospital, who helped to format the images.
1. Jampolsky A. Duane syndrome. In: Rosenbaum AL, Santiago AP, editors. Clinical Strabismus Management, Principles and Surgical Techniques, Chapter 24. Philadelphia, PA: Saunders, 1999:32546. 2. Sano K: Trigemino-oculomotor synkinesis. Neurologica 1949;1:53-9. 3. Bradley WG, Toone KB. Synkinetic movements of the eyelid: a case with some unusual mechanisms of paradoxical lid retraction. J Neurol Neurosurg Psychiatry 1967;30:578-9. 4. Kirkam TH. Paradoxical elevation of eyelid on smiling. Am J Ophthalmol 1971;72:207-8. 5. Rice CD, Weaver RG, Benjamin E, Troost BT. Unilateral blepharoptosis with synkinetic movements of the eyelids on horizontal gaze. J Pediatr Ophthalmol Strabismus 1986;23:201-5. 6. Leri A, Weill J. Phenomene de Marcus Gunn (synergie palpebromaxillaire) congenital et hereditaire. Bull Mem Soc Med Hop 1929; 45:875-80. 7. Falls HF, Kruse WT, Cotterman CW. Three cases of Marcus Gunn phenomenon in 2 generations. Am J Ophthalmol 1949;32:53-9. 8. Kirkham TH. Familial Marcus Gunn phenomenon. Br J Ophthalmol 1969;53:282-3. 9. Cooper H. A series of cases of congenital ophthalmoplegia externa (nuclear paralysis) in the same family. Br Med J 1910;1:917. 10. Waardenburg PJ. Congenital disturbances of motility. Am J Ophthalmol 1923;6:44-5. 11. Laughlin RC. Hereditary paralysis of the abducens nerve. Am J Ophthalmol 1937;20:396-8. 12. Zentmayer W. Mengel’s bilateral deficiency of abduction. Arch Ophthalmol 1935;13:984. 13. Goldfarb C, Gannon FL. Familial congenital lateral rectus palsy with retraction (Stilling-Duane-Turk syndrome). Dis Nerv Syst 1964;25: 17-21. 14. Temtamy SA, Shoukry AS, Ghaly I, et al. The Duane radial dysplasia syndrome: an autosomal dominant disorder. Birth Defects Orig Art Ser 1975;XI:344-5. 15. Okihiro MM, Tasaki T, Nakano KK, Bennett BK. Duane syndrome and congenital upper-limb anomalies: a familial occurrence. Arch Neurol 1977;34:174-9. 16. MacDermot KD, Winter RM. Radial ray defect and Duane anomaly: report of a family with autosomal dominant transmission. Am J Med Genet 1987;27:313-9. 17. Ott S, Borchert M, Chung M, et al. Exclusion of candidate genetic loci for Duane retraction syndrome. Am J Ophthalmol 1999;127: 358-60. 18. Chung M, Stout JT, Borchert MS. Clinical diversity of hereditary Duane’s retraction syndrome. Ophthalmology 2000;107:500-3. 19. Gutowski NJ. Duane’s syndrome. Eur J Neurol 2000;7:145-9. 20. Pang MP, Zweifach PH, Goodwin J. Inherited levator-medial rectus synkinesis. Arch Ophthalmol 1986;104:1489-91. 21. Harrad RA, Shuttleworth GN. Superior rectus-levator synkinesis: a previously unrecognized cause of failure of ptosis surgery. Ophthalmology 2000;107:1975-81. 22. Engle EC. Applications of molecular genetics to the understanding of congenital motility disorders. Ann NY Acad Sci 2002;956: 55-63. 23. Yamada K, Andrews C, Chan WM, et al. Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Nat Genet 2003;35:318-21. 24. Nakano M, Yamada K, Fain J, et al. Homozygous mutations in ARIX (PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. Nat Genet 2001;29:315-20. 25. Doherty EJ, Macy ME, Wang SM, et al. CFEOM3: a new extraocular congenital fibrosis syndrome that maps to 16q24.2-q24.3. Invest Ophthalmol Vis Sci 1999;40:1687-94. 26. Calabrese G, Stuppia L, Morizio E, et al. Detection of an insertion deletion of region 8q13-q21.2 in a patient with Duane syndrome:
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28.
29.
30.
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implications for mapping and cloning a Duane gene. Eur J Hum Genet 1998;6:187-93. Appukuttan B, Gillanders E, Juo S-H, et al. Localization of a gene for Duane retraction syndrome to chromosome 2q31. Am J Hum Genet 1999;65:1639-46. Al-Baradie R, Yamada K, St Hilaire C, et al. Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family. Am J Hum Genet 2002;71:1195-9. Tibiletti MG, Sala E, Colombo D, et al. Chromosome 22 marker in a child with Duane syndrome and urogenital abnormalities. Ann Genet 1996;39:168-72. Chew CK, Foster P, Hurst JA, Salmon JF. Duane’s retraction
31.
32.
33.
34.
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syndrome associated with chromosome 4q27-31 segment deletion. Am J Ophthalmol 1995;119:807-9. Hoyt W. Anomalies of ocular motor nerves: Neuro-anatomic correlates of paradoxical innervation in Duane’s. Am J Ophthalmol 1965;60:443. Engle EC, Castro AE, Macy ME, et al. A gene for isolated congenital ptosis maps to a 3-cM region within 1p32-p34.1. Am J Hum Genet 1997;60:1150-7. McMullan TF, Collins AR, Tyers AG, Robinson DOA. novel Xlinked dominant condition: X linked congenital isolated ptosis. Am J Hum Genet 2000;66:1455-60. Miller MT. Thalidomide embryopathy: A model for the study of congenital incomitant strabismus. Trans Am Ophthalmol Soc 1991;89:623-73.
An Eye on the Arts – The Arts on the Eye
Weeping Vergine. It was there that I—Domenico Onofrio Tempesta— witnessed a miracle! After a drought of seventy-seven years, tears were falling once again from the eyes of the statue! Of all the villagers—men, women, and children—it was I to whom the Weeping Vergine chose to reveal herself! The statue cried for a week. Its precious tears were collected and applied to the sores of the afflicted, the eyes of the blind, the legs of the lame. The miracle became the subject of many theories about past sin and predictions of coming doom. News of the Weeping Virgine had kept the village priest at his station by the grotto day and night, saying prayers for the faithful and listening to the emergency confessions of newly repentant siciliani! It was only after the statue’s eyes had dried and the number of pilgrims had dwindled that the padre was able to have a minute’s peace and to interpret the meaning of the miracle. The good priest visited our home the following Sunday and told Mama and Papa that my discovery of the Virgin’s tears had been a sign from Blessed Mary herself. I had been called to the priesthood, the padre said. The padre wrote a letter to Rome concerning my religious calling and campaigned amongst the villagers to hand over their coins on behalf of the room, board, and travel expenses that would be required to turn me into a priest. When my father protested, my mother resumed once again her screaming fits on behalf of my education and circulated in the village the news of an ominous dream she had had. In the dream, God Almighty took the form of a black falcon and pecked out the eyes of my father for flouting His will. In the end, Papa surrendered. —Wally Lamb (from I Know This Much Is True)
ynkinesis” refers to the coordinated simultaneous contraction of different muscles. An abnormal synkinesis occurs when different muscles inappropriately co-contract, such as in acquired aberrant regeneration of the third cranial nerve after trauma. Congenital abnormal synkinesis involving ocular and periocular muscles is infrequent, most commonly seen in the Duane retraction syndrome1 and the Marcus Gunn jaw-winking phenomenon.2 Congenital abnormal synkinesis involving the eyelid has been associated with facial muscle contraction3,4 as well as extraocular muscle contraction.5 The Duane syndrome, the Marcus Gunn phenomenon, and other related congenital abnormal synkineses are typically sporadic although familial cases have been reported.6-20 A family has been identified that includes 2 siblings with ptosis and abnormal synkinetic lid elevation associated with ipsilateral abduction. Two other siblings exhibit related findings. The clinical features of affected members of this family are described and discussed.
S
SUBJECTS AND METHODS The proband, a 4-year-old girl, was referred for evaluation of abnormal eye movements since birth. A pedigree was obtained from her parents. All available family members underwent ophthalmic exam.
From the Department of Pediatric Ophthalmology,a King Khaled Eye Specialist Hospital, P.O. Box 7191, Riyadh 11462, Saudi Arabia; and Research Department,b King Khaled Eye Specialist Hospital, P.O. Box 7191, Riyadh 11462, Saudi Arabia. Submitted August 1, 2003. Revision accepted July 9, 2004. Address reprint requests to Dr. Arif O. Khan, MD, King Khaled Eye Specialist Hospital, P.O. Box 7191, Riyadh 11462, Saudi Arabia. Copyright © 2004 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2004/$35.00 ⫹ 0 doi:10.1016/j.jaapos.2004.07.010
Journal of AAPOS
REPORT OF CASES Sixteen members of the 17-member immediate family of Arab ancestry underwent ophthalmic examination, including cycloplegic refraction (Fig. 1). The father’s first wife was his cousin, while his second wife was not related to him. According to the father, the one family member unavailable for examination (patient 7, Fig. 1) did not have ophthalmic findings. No examined family member had significant medical history nor could cause lid movement by facial muscle contracture or jaw movement. Fourteen examined family members had unremarkable ophthalmic examinations, whereas 4 had abnormal ophthalmic findings. For these 4 patients with findings, pupillary and retinal exams were unremarkable; cycloplegic refractive error was ⬍⫹1.50 spherical equivalent in both eyes, and there was no strabismus other than noted below: Case 1 (the proband, patient 14, Fig. 2): A 4-year-old female presented with ptosis in the left eye that completely blocked the pupil in primary gaze and had been present since birth. There was a variable right face turn. Visual acuity was 20/30 in the right eye and 20/80 in the left eye. The left eyelid could elevate to a normal level only with abduction of the left eye. There was slight limitation of adduction of the left eye associated with slight globe retraction. Straight upgaze was not associated with levator activation but was associated with a 15 prism diopter esotropia. After 3 months of part-time occlusion of the right eye (4 hours/day), the vision in the left eye improved to 20/50. Case 2 (patient 9, Figure 3): A 15-year-old male exhibited bilateral ptosis that had been present since birth. In primary gaze he had a chin-up position. Visual acuity was 20/20 in both eyes. With abduction of either eye, the ipsilateral lid elevated to a normal level. Straight upgaze was associated with bilateral levator activation as well as a 20 prism diopter right esotropia. December 2004
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FIG 1. The pedigree of the immediate family is shown. All numbered patients were examined except for patient 7.
Case 3 (patient 3): A 26-year-old female had a history of bilateral ptosis surgery at an early age. There was no abnormal head position. There was a mild astigmatic refractive error and best-corrected visual acuity was 20/30 in both eyes. There was residual congenital ptosis (palpebral fissure 6 mm in the right eye, 8 mm in the left eye). Case 4 (patient 16, Figure 4): A 4-year-old female exhibited the Duane syndrome in the right eye with a 15-degree right face turn. Vision was 20/30 in both eyes. There was a small-angle esotropia in forced primary gaze. Versions revealed ⫺2 abduction of the right eye, trace adduction defect of the right eye, and globe retraction with a large upshot during adduction of the right eye.
DISCUSSION Although abnormal synkinetic eyelid elevation during eye movement can often be seen after third cranial nerve injury and aberrant regeneration, it is otherwise rare, especially as a congenital phenomenon.1,5 There seems to be at least 4 previously reported cases of congenital eyelid elevation associated with adduction, 2 sporadic (originally reported in 1890 and 1919), and the other 2 in sisters.20 By history, the 2 previously reported sisters with this condition had 4 other family members in 3 generations with similar findings, but they were not examined by the authors of the report.20 There are at least 5 previously reported cases of congenital abnormal lid elevation during abduction as we describe in the current family: 3 sporadic5 and 2 in brothers (originally reported in 1887).20 In all of
these previously reported cases of abnormal lid synkinesis, there was no reported trauma or abnormality of ocular motility. Abnormal innervation from cranial nerve III to the levator in the cases associated with adduction and from cranial nerve VI to the levator in the cases associated with abduction is a likely explanation for the synkineses in these previously reported cases, but without anatomical evidence one cannot be sure of the underlying pathology. In addition to levator activation with abduction, 2 of the 4 affected siblings in the current family (patients 9 and 14) also demonstrated an abnormal synkinesis of adduction in upgaze with esotropia. In addition, patient 14 also demonstrated levator activation with straight upgaze. These additional findings suggest further “miswiring” within the oculomotor nerve, a type of abnormal synkinesis that has been described previously (between the superior rectus and the levator).21 Genetic and neuropathological studies of congenital fibrosis of the extraocular muscles (CFEOM), the Duane syndrome, and isolated congenital ptosis suggest abnormal cranial nerve motor neuron and/or axonal development (congenital cranial dysinnervation) as a cause for certain types of strabismus and ptosis with or without abnormal synkinesis.22-33 CFEOM1, the most common form of CFEOM, is autosomal dominant (AD), and typically includes bilateral congenital ptosis and bilateral ocular motility dysfunction. The globes are infraducted with restricted upgaze, variably restricted downgaze, and abnormal synkineses such as synergistic convergence on upgaze.
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FIG 2. (A) In primary gaze this unilaterally affected female (patient 14) exhibits complete ptosis of the left eye. (B) With ipsilateral abduction the lid elevates to a normal level. (C) In adduction, the lid is ptotic.
Most affected families map to the FEOM1 locus (chromosome 12p11.2-q12), and histopathological studies suggest a defect in development of the superior division of the oculomotor nerve.23 CFEOM2 is autosomal recessive (AR); affected patients exhibit bilateral ptosis and largeangle exotropia with severely limited globe motility. CFEOM2 results from mutation of ARIX (11q13.2) and murine models suggest that this gene is responsible for development of the oculomotor and trochlear nerves.24 CFEOM3 is diagnosed when an affected individual has some features of CFEOM, but typically without abnormal synkinesis and with neither the classic phenotype of CFEOM1 or CFEOM2. Inheritance is AD with incomplete penetrance. Most families map to the FEOM3 locus (16q24.2-q24.3), and it has been suggested that CFEOM3 results from a variable defect in oculomotor nucleus development.25 The Duane syndrome is associated with at least three genetic loci: 8q13 (DUR1),26
FIG 3. (A) In primary gaze, this bilaterally affected male (patient 9) has bilateral ptosis and uses his frontalis muscle to improve lid elevation. (B) In left gaze, the ptotic lid of the left eye elevates to a normal level. (C) In right gaze, the ptotic lid of the right eye elevates to a normal level. (D) In upgaze, the patient has bilateral levator activation as well as an esotropia.
2q31 (DURS2),27 and 20q13 (SALL4 mutation)28 In addition, isolated cases of the Duane syndrome. have been reported with deletions at chromosomes 22 and 4.29,30 Autopsy studies suggest the underlying pathogenesis of the Duane Syndrome to be maldevelopment of the abducens nerve associated with aberrant innervation of the lateral rectus by the oculomotor nerve.31
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Journal of AAPOS Volume 8 Number 6 December 2004 References
FIG 4. This girl (patient 16) has classic Duane syndrome of the right eye without ptosis. (A) There is limitation of attempted adduction of the left eye with associated globe retraction. An upshoot of the right eye occurred with further attempted adduction of the right eye (not shown). (B) In attempted abduction of the right eye, there is a significant limitation and some forward globe movement.
Isolated congenital ptosis has been associated with 2 loci: 1p32-p34.1 (PTOS1) associated with AD inheritance and incomplete penetrance32 and Xp24-27.1 (PTOS2) associated with an X-linked dominant pattern.33 These forms of ptosis may be due to abnormal development of the oculomotor subnucleus responsible for levator innervation. In addition to genetic studies of the above-mentioned disorders, studies of thalidomide embryopathy patients support the concept of developmental cranial dysinnervation underlying congenital incomitant strabismus with or without ptosis and/or aberrant innervation.34 The different phenotypes exhibited in affected members of the current family can similarly be explained by developmental cranial nerve dysinnervation. The findings in the 2 siblings with lid elevation during ipsilateral abduction (patients 9 and 14) can be explained by “miswiring” of cranial III as can be seen in CFEOM.23-25 In the patient with classic Duane syndrome (patient 16), aplasia of cranial nerve VI with aberrant innervation of cranial nerve III to the lateral rectus is the expected underlying mechanism.31 For the patient with isolated congenital ptosis (patient 3), findings can be explained by maldevelopment within cranial nerve III as seen in CFEOM23-25 or inherited congenital ptosis.32-33 The pedigree of current family suggests that a gene responsible for multiple cranial nerve development exists (an idea that has been suggested previously18,24) with an inheritance pattern that is AR or possibly AD with variable penetrance. Thanks are given to Jamal Roumeliotis and Adolph Cabañas, media artists at the King Khaled Eye Specialist Hospital, who helped to format the images.
1. Jampolsky A. Duane syndrome. In: Rosenbaum AL, Santiago AP, editors. Clinical Strabismus Management, Principles and Surgical Techniques, Chapter 24. Philadelphia, PA: Saunders, 1999:32546. 2. Sano K: Trigemino-oculomotor synkinesis. Neurologica 1949;1:53-9. 3. Bradley WG, Toone KB. Synkinetic movements of the eyelid: a case with some unusual mechanisms of paradoxical lid retraction. J Neurol Neurosurg Psychiatry 1967;30:578-9. 4. Kirkam TH. Paradoxical elevation of eyelid on smiling. Am J Ophthalmol 1971;72:207-8. 5. Rice CD, Weaver RG, Benjamin E, Troost BT. Unilateral blepharoptosis with synkinetic movements of the eyelids on horizontal gaze. J Pediatr Ophthalmol Strabismus 1986;23:201-5. 6. Leri A, Weill J. Phenomene de Marcus Gunn (synergie palpebromaxillaire) congenital et hereditaire. Bull Mem Soc Med Hop 1929; 45:875-80. 7. Falls HF, Kruse WT, Cotterman CW. Three cases of Marcus Gunn phenomenon in 2 generations. Am J Ophthalmol 1949;32:53-9. 8. Kirkham TH. Familial Marcus Gunn phenomenon. Br J Ophthalmol 1969;53:282-3. 9. Cooper H. A series of cases of congenital ophthalmoplegia externa (nuclear paralysis) in the same family. Br Med J 1910;1:917. 10. Waardenburg PJ. Congenital disturbances of motility. Am J Ophthalmol 1923;6:44-5. 11. Laughlin RC. Hereditary paralysis of the abducens nerve. Am J Ophthalmol 1937;20:396-8. 12. Zentmayer W. Mengel’s bilateral deficiency of abduction. Arch Ophthalmol 1935;13:984. 13. Goldfarb C, Gannon FL. Familial congenital lateral rectus palsy with retraction (Stilling-Duane-Turk syndrome). Dis Nerv Syst 1964;25: 17-21. 14. Temtamy SA, Shoukry AS, Ghaly I, et al. The Duane radial dysplasia syndrome: an autosomal dominant disorder. Birth Defects Orig Art Ser 1975;XI:344-5. 15. Okihiro MM, Tasaki T, Nakano KK, Bennett BK. Duane syndrome and congenital upper-limb anomalies: a familial occurrence. Arch Neurol 1977;34:174-9. 16. MacDermot KD, Winter RM. Radial ray defect and Duane anomaly: report of a family with autosomal dominant transmission. Am J Med Genet 1987;27:313-9. 17. Ott S, Borchert M, Chung M, et al. Exclusion of candidate genetic loci for Duane retraction syndrome. Am J Ophthalmol 1999;127: 358-60. 18. Chung M, Stout JT, Borchert MS. Clinical diversity of hereditary Duane’s retraction syndrome. Ophthalmology 2000;107:500-3. 19. Gutowski NJ. Duane’s syndrome. Eur J Neurol 2000;7:145-9. 20. Pang MP, Zweifach PH, Goodwin J. Inherited levator-medial rectus synkinesis. Arch Ophthalmol 1986;104:1489-91. 21. Harrad RA, Shuttleworth GN. Superior rectus-levator synkinesis: a previously unrecognized cause of failure of ptosis surgery. Ophthalmology 2000;107:1975-81. 22. Engle EC. Applications of molecular genetics to the understanding of congenital motility disorders. Ann NY Acad Sci 2002;956: 55-63. 23. Yamada K, Andrews C, Chan WM, et al. Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Nat Genet 2003;35:318-21. 24. Nakano M, Yamada K, Fain J, et al. Homozygous mutations in ARIX (PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. Nat Genet 2001;29:315-20. 25. Doherty EJ, Macy ME, Wang SM, et al. CFEOM3: a new extraocular congenital fibrosis syndrome that maps to 16q24.2-q24.3. Invest Ophthalmol Vis Sci 1999;40:1687-94. 26. Calabrese G, Stuppia L, Morizio E, et al. Detection of an insertion deletion of region 8q13-q21.2 in a patient with Duane syndrome:
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An Eye on the Arts – The Arts on the Eye
Weeping Vergine. It was there that I—Domenico Onofrio Tempesta— witnessed a miracle! After a drought of seventy-seven years, tears were falling once again from the eyes of the statue! Of all the villagers—men, women, and children—it was I to whom the Weeping Vergine chose to reveal herself! The statue cried for a week. Its precious tears were collected and applied to the sores of the afflicted, the eyes of the blind, the legs of the lame. The miracle became the subject of many theories about past sin and predictions of coming doom. News of the Weeping Virgine had kept the village priest at his station by the grotto day and night, saying prayers for the faithful and listening to the emergency confessions of newly repentant siciliani! It was only after the statue’s eyes had dried and the number of pilgrims had dwindled that the padre was able to have a minute’s peace and to interpret the meaning of the miracle. The good priest visited our home the following Sunday and told Mama and Papa that my discovery of the Virgin’s tears had been a sign from Blessed Mary herself. I had been called to the priesthood, the padre said. The padre wrote a letter to Rome concerning my religious calling and campaigned amongst the villagers to hand over their coins on behalf of the room, board, and travel expenses that would be required to turn me into a priest. When my father protested, my mother resumed once again her screaming fits on behalf of my education and circulated in the village the news of an ominous dream she had had. In the dream, God Almighty took the form of a black falcon and pecked out the eyes of my father for flouting His will. In the end, Papa surrendered. —Wally Lamb (from I Know This Much Is True)