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A patient with de Morsier and Duane syndromes
A Patient With de Morsier and Duane Syndromes Blanca I. Aguirre-Aquino, MD,a Douglas G. Rogers, MD,b and Elias I. Traboulsi, MDa de Morsier syndrome, or septo-optic dysplasia, is a developmental malformation complex characterized by optic nerve hypoplasia, dysgenesis of the septum pellucidum, and hypothalamic-pituitary dysfunction.1,2 In Duane retraction syndrome, there is absence of the sixth nerve nucleus with congenital retraction of the globe and narrowing of the lid fissure in adduction, frequent abduction deficiency, and variable limitation to adduction of the affected eye.3 The purpose of this report is to present a patient with the uncommon and previously unreported concurrence of both of these congenital malformation complexes, presumably because of a common disturbance of neuronal development.
CASE REPORT A 4-year-old male patient was referred for evaluation of congenital strabismus. He was delivered after 35 weeks of gestation with a birth weight of 5 lb 6 oz. After delivery, he required mechanical ventilation for 24 hours because of insufficient respiratory effort, followed by a week of supplemental oxygen therapy. He was hospitalized in the neonatal intensive care unit for 3 months because of failure to thrive. He developed bronchial asthma at 2 years of age and is currently receiving beclomethasone dipropionate (Beclovent) and fluticasone propionate. His visual acuity could not be tested because of poor cooperation and mild developmental delay, but he was able to fixate on and follow a small target well with either eye. Pupillary reactions appeared normal and there was no afferent pupillary defect. There was no strabismus in primary position of gaze, but a marked limitation of abduction of the right eye was present (Figure 1). The ductions of the left eye were normal. Narrowing of the right palpebral fissure and globe retraction were noted on left gaze. There was no head turn or tilt. Fusion and stereopsis could not be measured. From the Department of Pediatric Ophthalmology and Strabismus, the Center for Genetic Eye Diseases, Cole Eye Institutea; and the Section of Pediatric Endocrinology, the Cleveland Clinic,b Cleveland, Ohio. Submitted August 12, 1999. Revision accepted December 13, 1999. Reprint requests: Elias Traboulsi, MD, Cole Eye Institute, i33, 9500 Euclid Ave, Cleveland, OH 44195 (e-mail: [email protected]). J AAPOS 2000;4:243-5. Copyright © 2000 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2000/$12.00 + 0 75/1/105303 doi:10.1067/mpa.2000.105303
Journal of AAPOS
FIG 1. Limitation of abduction of the right eye in dextroversion of patient with Duane syndrome.
The anterior segment was normal in both eyes. There was moderate bilateral optic nerve hypoplasia with prominent double ring signs. The macula and retinal periphery were normal in both eyes. Fundus photographs could not be taken because of the patient’s age and poor cooperation. There was no error of refraction. Because of his small stature (height, 92 cm and weight, 11 kg at 4.25 years of age; both significantly below the 5th percentile) and the history of neonatal failure to thrive, a diagnosis of de Morsier syndrome was suspected and the patient was referred for a neuroendocrinologic evaluation. Other physical findings included an undescended left testicle and a central incisor. A magnetic resonance imaging (MRI) study of the brain was performed and results revealed an ectopic posterior pituitary gland with a hypoplastic adenohypophysis, an abnormal attenuated infundibulum, dysgenesis of the corpus callosum, and dysplastic hippocampal formations (Figure 2). Orbital cuts showed that both optic nerves were small, with the right significantly smaller than the left (Figure 3). A growth hormone stimulation test revealed a highest growth hormone level of 6.4, consistent with growth hormone deficiency. Highest cortisol level was 21.9 µg/dL, indicating good adrenal function. Bone age was 3 years. Urine osmolality, serum osmolality, serum sodium, free thyroxine (T4), and total cholesterol values were all normal. The patient began receiving growth hormone supplements administered subcutaneously in doses of 0.3 mg each day. Three months later, this was increased to 0.4 mg
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Journal of AAPOS Volume 4 Number 4 August 2000
A FIG 3. Coronal section of the orbit behind the globe showing a small optic nerve diameter. This is more pronounced on the right side.
B FIG 2. Sagittal MRI view showing ectopic posterior pituitary tissue (bright area, arrow). The infundibulum is absent (A). MRI of coronal section showing dysgenesis of the corpus callosum (arrowhead) and dysplastic hippocampal formations (long arrow) (B).
and the patient’s height increased by 6 cm over the next 10 months.
DISCUSSION de Morsier1 defined a syndrome of agenesis of the septum pellucidum and anomalies of the optic nerve. Hoyt et al2 documented the association of de Morsier syndrome with hypothalamic pituitary dysfunction. Approximately 25%
of patients with bilateral nerve hypoplasia have hypothalamic-pituitary dysfunction.4 Half of the patients have schizencephaly.5 Brodsky and Glasier6 divided patients with optic nerve hypoplasia into 5 categories, depending on associated central nervous system malformations. They found that patients with posterior pituitary ectopia and those with hemispheric abnormalities were very likely to have pituitary hormone deficiency and neurodevelopmental deficits, respectively. Our patient had central nervous system abnormalities and the associated hormonal deficits. Optic nerve hypoplasia is present in 25% of patients with agenesis of the septum pellucidum, and conversely, 27% to 46% of patients with optic nerve hypoplasia have partial or complete absence of the septum pellucidum.4,7 It is postulated that septo-optic dysplasia results from a disturbance in the development of the brain during the seventh to eighth week of gestation when the optic nerve, germinal matrix, and septum pellucidum are forming. Once considered a rare anomaly, optic nerve hypoplasia is probably the most common congenital optic nerve anomaly encountered in pediatric ophthalmic practice. Neuroendocrinologic disorders such as growth hormone deficiency, hypothyroidism, diabetes insipidus, and panhypopituitarism should be suspected in patients with this malformation, especially in the presence of growth retardation or radiologic evidence of pituitary abnormalities.2,6 Optic nerve hypoplasia has been attributed to a primary failure of retinal ganglion cell differentiation at the 13- to 17-mm stage of embryogenesis.7,8 This hypothesis fails to account for the frequent coexistence of optic nerve hypoplasia with other central nervous system malformations.6-8 It has been
Journal of AAPOS Volume 4 Number 4 August 2000
suggested that an encephaloclastic process involving the afferent visual pathways in utero could cause direct axonal injury and subsequent degeneration.7 The frequent association of cerebral hemispheric anomalies with optic nerve hypoplasia may result from a diffuse disruption of neuronal guidance mechanisms that regulate the migration of both cerebral hemispheric neurons and optic nerve axons in utero. Toxic substances or structural abnormalities may augment the process of apoptosis by which superfluous optic nerve axons are eliminated between the 16th and 31st gestational weeks, and thereby result in optic nerve hypoplasia.7,8 Duane retraction syndrome is diagnosed in 1% to 4% of patients with strabismus. Most cases are sporadic, but familial occurrences have been reported in 5% to 10% of cases with an autosomal dominant mode of transmission. Patients with the sporadic form have a greater risk of other concurrent congenital malformations such as neurosensory hearing loss, cervical spine abnormalities, and limb malformations. A developmental disturbance between the fourth and tenth weeks of embryogenesis has been postulated to explain the various non-ocular abnormalities reported in combination with Duane retraction syndrome. These observations are corroborated by studies of children with thalidomide embryopathy in which the teratogenic effect of thalidomide was determined to have occurred between 34 and 39 days of gestation.9 There have been previous reports of the association of Duane syndrome with optic nerve hypoplasia or other optic nerve congenital anomalies such as morning glory syndrome.7,10,11 Khalid11 reported the case of a 21-yearold woman with congenital heart disease, Klippel-Feil anomaly, Duane retraction syndrome, and optic nerve hypoplasia.10 Denslow and Sims10 later reported the case of a 4-year-old boy with Duane syndrome and optic nerve hypoplasia and hypothesized that the malformations were the result of a developmental disturbance during the second gestational month.11 Although it is possible that some of the previously reported patients may have had midline brain abnormalities, our study clearly demonstrates this
Aguirre-Aquino, Rogers, and Traboulsi
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association with MRI. We postulate that, in the present case, a generalized disturbance of neuronal development in the second month of gestation, has not only affected the normal development of the optic nerves, the hypothalamus, pituitary gland, and other brain structures but has also led to underdevelopment of the sixth nerve nucleus and a clinical picture of Duane syndrome. This disturbance may have resulted from a mutation in a developmental gene, exposure to a teratogenic agent, or a combination of factors. The pediatric ophthalmologist plays an essential role in the identification of Duane and de Morsier syndromes and should be aware of their possible coexistence. References 1. de Morsier G. Etudes sur les dysraphies cranio-encéphaliques, III: agénésie du septum lucidum avec malformation du tractus optique: la dysplasie septo-optique. Schweiz Arch Neurol Psychiatr 1956; 77:267-92. 2. Hoyt WF, Kaplan SL, Grumback MM, Glaser JS. Septo-optic dysplasia and pituitary dwarfism. Lancet 1970;25:893-4. 3. DeRespinis PA, Caputo AR, Wagner RS. Duane’s retraction syndrome. Surv Ophthalmol 1993;38:257-88. 4. Siatkowski RM, Sanchez JC, Andrade R, Alvarez A. The clinical, neuiroradiographic and endocrinologic profile of patients with bilateral optic nerve hypoplasia. Ophthalmology 1997;104:493-6. 5. Lau KY, Tam W, Lam PK, Wood BP. Radiological cases of the month. Septo-optic dysplasia (De Morsier syndrome). Am J Dis Child 1993;14:71-2. 6. Brodsky MC, Glasier CM. Optic nerve hypoplasia. Clinical significance of associated central nervous system abnormalities on magnetic resonance imaging. Arch Ophthalmol 1993;111:66-74. 7. Margalith D, Jan JE, McCormick AQ, Tze WJ, Lapointe J. Clinical spectrum of congenital optic nerve hypoplasia: review of 51 patients. Dev Med Child Neurol 1984;26:311-22. 8. Sabah MZ, Gordon ND. Optic nerve hypoplasia in children. Br J Ophthalmol 1990;74:300-4. 9. Miller MT. Thalidomide embryopathy: a model for the study of congenital incomitant horizontal strabismus. Tr Am Ophthalmol Soc 1991;89:623-74. 10. Denslow GT, Sims M. Duane’s retraction syndrome associated with optic nerve hypoplasia. J Pediatr Ophthalmol Strabismus 1980;17:26-8. 11. Khalid JA. Association of ocular, cervical and cardiac malformations. Ann Ophthalmol 1977;9:1001-11.
CASE REPORT A 4-year-old male patient was referred for evaluation of congenital strabismus. He was delivered after 35 weeks of gestation with a birth weight of 5 lb 6 oz. After delivery, he required mechanical ventilation for 24 hours because of insufficient respiratory effort, followed by a week of supplemental oxygen therapy. He was hospitalized in the neonatal intensive care unit for 3 months because of failure to thrive. He developed bronchial asthma at 2 years of age and is currently receiving beclomethasone dipropionate (Beclovent) and fluticasone propionate. His visual acuity could not be tested because of poor cooperation and mild developmental delay, but he was able to fixate on and follow a small target well with either eye. Pupillary reactions appeared normal and there was no afferent pupillary defect. There was no strabismus in primary position of gaze, but a marked limitation of abduction of the right eye was present (Figure 1). The ductions of the left eye were normal. Narrowing of the right palpebral fissure and globe retraction were noted on left gaze. There was no head turn or tilt. Fusion and stereopsis could not be measured. From the Department of Pediatric Ophthalmology and Strabismus, the Center for Genetic Eye Diseases, Cole Eye Institutea; and the Section of Pediatric Endocrinology, the Cleveland Clinic,b Cleveland, Ohio. Submitted August 12, 1999. Revision accepted December 13, 1999. Reprint requests: Elias Traboulsi, MD, Cole Eye Institute, i33, 9500 Euclid Ave, Cleveland, OH 44195 (e-mail: [email protected]). J AAPOS 2000;4:243-5. Copyright © 2000 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2000/$12.00 + 0 75/1/105303 doi:10.1067/mpa.2000.105303
Journal of AAPOS
FIG 1. Limitation of abduction of the right eye in dextroversion of patient with Duane syndrome.
The anterior segment was normal in both eyes. There was moderate bilateral optic nerve hypoplasia with prominent double ring signs. The macula and retinal periphery were normal in both eyes. Fundus photographs could not be taken because of the patient’s age and poor cooperation. There was no error of refraction. Because of his small stature (height, 92 cm and weight, 11 kg at 4.25 years of age; both significantly below the 5th percentile) and the history of neonatal failure to thrive, a diagnosis of de Morsier syndrome was suspected and the patient was referred for a neuroendocrinologic evaluation. Other physical findings included an undescended left testicle and a central incisor. A magnetic resonance imaging (MRI) study of the brain was performed and results revealed an ectopic posterior pituitary gland with a hypoplastic adenohypophysis, an abnormal attenuated infundibulum, dysgenesis of the corpus callosum, and dysplastic hippocampal formations (Figure 2). Orbital cuts showed that both optic nerves were small, with the right significantly smaller than the left (Figure 3). A growth hormone stimulation test revealed a highest growth hormone level of 6.4, consistent with growth hormone deficiency. Highest cortisol level was 21.9 µg/dL, indicating good adrenal function. Bone age was 3 years. Urine osmolality, serum osmolality, serum sodium, free thyroxine (T4), and total cholesterol values were all normal. The patient began receiving growth hormone supplements administered subcutaneously in doses of 0.3 mg each day. Three months later, this was increased to 0.4 mg
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244 Aguirre-Aquino, Rogers, and Traboulsi
Journal of AAPOS Volume 4 Number 4 August 2000
A FIG 3. Coronal section of the orbit behind the globe showing a small optic nerve diameter. This is more pronounced on the right side.
B FIG 2. Sagittal MRI view showing ectopic posterior pituitary tissue (bright area, arrow). The infundibulum is absent (A). MRI of coronal section showing dysgenesis of the corpus callosum (arrowhead) and dysplastic hippocampal formations (long arrow) (B).
and the patient’s height increased by 6 cm over the next 10 months.
DISCUSSION de Morsier1 defined a syndrome of agenesis of the septum pellucidum and anomalies of the optic nerve. Hoyt et al2 documented the association of de Morsier syndrome with hypothalamic pituitary dysfunction. Approximately 25%
of patients with bilateral nerve hypoplasia have hypothalamic-pituitary dysfunction.4 Half of the patients have schizencephaly.5 Brodsky and Glasier6 divided patients with optic nerve hypoplasia into 5 categories, depending on associated central nervous system malformations. They found that patients with posterior pituitary ectopia and those with hemispheric abnormalities were very likely to have pituitary hormone deficiency and neurodevelopmental deficits, respectively. Our patient had central nervous system abnormalities and the associated hormonal deficits. Optic nerve hypoplasia is present in 25% of patients with agenesis of the septum pellucidum, and conversely, 27% to 46% of patients with optic nerve hypoplasia have partial or complete absence of the septum pellucidum.4,7 It is postulated that septo-optic dysplasia results from a disturbance in the development of the brain during the seventh to eighth week of gestation when the optic nerve, germinal matrix, and septum pellucidum are forming. Once considered a rare anomaly, optic nerve hypoplasia is probably the most common congenital optic nerve anomaly encountered in pediatric ophthalmic practice. Neuroendocrinologic disorders such as growth hormone deficiency, hypothyroidism, diabetes insipidus, and panhypopituitarism should be suspected in patients with this malformation, especially in the presence of growth retardation or radiologic evidence of pituitary abnormalities.2,6 Optic nerve hypoplasia has been attributed to a primary failure of retinal ganglion cell differentiation at the 13- to 17-mm stage of embryogenesis.7,8 This hypothesis fails to account for the frequent coexistence of optic nerve hypoplasia with other central nervous system malformations.6-8 It has been
Journal of AAPOS Volume 4 Number 4 August 2000
suggested that an encephaloclastic process involving the afferent visual pathways in utero could cause direct axonal injury and subsequent degeneration.7 The frequent association of cerebral hemispheric anomalies with optic nerve hypoplasia may result from a diffuse disruption of neuronal guidance mechanisms that regulate the migration of both cerebral hemispheric neurons and optic nerve axons in utero. Toxic substances or structural abnormalities may augment the process of apoptosis by which superfluous optic nerve axons are eliminated between the 16th and 31st gestational weeks, and thereby result in optic nerve hypoplasia.7,8 Duane retraction syndrome is diagnosed in 1% to 4% of patients with strabismus. Most cases are sporadic, but familial occurrences have been reported in 5% to 10% of cases with an autosomal dominant mode of transmission. Patients with the sporadic form have a greater risk of other concurrent congenital malformations such as neurosensory hearing loss, cervical spine abnormalities, and limb malformations. A developmental disturbance between the fourth and tenth weeks of embryogenesis has been postulated to explain the various non-ocular abnormalities reported in combination with Duane retraction syndrome. These observations are corroborated by studies of children with thalidomide embryopathy in which the teratogenic effect of thalidomide was determined to have occurred between 34 and 39 days of gestation.9 There have been previous reports of the association of Duane syndrome with optic nerve hypoplasia or other optic nerve congenital anomalies such as morning glory syndrome.7,10,11 Khalid11 reported the case of a 21-yearold woman with congenital heart disease, Klippel-Feil anomaly, Duane retraction syndrome, and optic nerve hypoplasia.10 Denslow and Sims10 later reported the case of a 4-year-old boy with Duane syndrome and optic nerve hypoplasia and hypothesized that the malformations were the result of a developmental disturbance during the second gestational month.11 Although it is possible that some of the previously reported patients may have had midline brain abnormalities, our study clearly demonstrates this
Aguirre-Aquino, Rogers, and Traboulsi
245
association with MRI. We postulate that, in the present case, a generalized disturbance of neuronal development in the second month of gestation, has not only affected the normal development of the optic nerves, the hypothalamus, pituitary gland, and other brain structures but has also led to underdevelopment of the sixth nerve nucleus and a clinical picture of Duane syndrome. This disturbance may have resulted from a mutation in a developmental gene, exposure to a teratogenic agent, or a combination of factors. The pediatric ophthalmologist plays an essential role in the identification of Duane and de Morsier syndromes and should be aware of their possible coexistence. References 1. de Morsier G. Etudes sur les dysraphies cranio-encéphaliques, III: agénésie du septum lucidum avec malformation du tractus optique: la dysplasie septo-optique. Schweiz Arch Neurol Psychiatr 1956; 77:267-92. 2. Hoyt WF, Kaplan SL, Grumback MM, Glaser JS. Septo-optic dysplasia and pituitary dwarfism. Lancet 1970;25:893-4. 3. DeRespinis PA, Caputo AR, Wagner RS. Duane’s retraction syndrome. Surv Ophthalmol 1993;38:257-88. 4. Siatkowski RM, Sanchez JC, Andrade R, Alvarez A. The clinical, neuiroradiographic and endocrinologic profile of patients with bilateral optic nerve hypoplasia. Ophthalmology 1997;104:493-6. 5. Lau KY, Tam W, Lam PK, Wood BP. Radiological cases of the month. Septo-optic dysplasia (De Morsier syndrome). Am J Dis Child 1993;14:71-2. 6. Brodsky MC, Glasier CM. Optic nerve hypoplasia. Clinical significance of associated central nervous system abnormalities on magnetic resonance imaging. Arch Ophthalmol 1993;111:66-74. 7. Margalith D, Jan JE, McCormick AQ, Tze WJ, Lapointe J. Clinical spectrum of congenital optic nerve hypoplasia: review of 51 patients. Dev Med Child Neurol 1984;26:311-22. 8. Sabah MZ, Gordon ND. Optic nerve hypoplasia in children. Br J Ophthalmol 1990;74:300-4. 9. Miller MT. Thalidomide embryopathy: a model for the study of congenital incomitant horizontal strabismus. Tr Am Ophthalmol Soc 1991;89:623-74. 10. Denslow GT, Sims M. Duane’s retraction syndrome associated with optic nerve hypoplasia. J Pediatr Ophthalmol Strabismus 1980;17:26-8. 11. Khalid JA. Association of ocular, cervical and cardiac malformations. Ann Ophthalmol 1977;9:1001-11.