In 1956 de Morsier pointed out that optic nerve hypoplasia was frequently associated with absence of the septum pellucidum.' He suggested the term septo-optic dysplasia and implied an embryologie defect in the formation of midline structures of the brain. The close proximity of the septum pellucidum, optic chiasm, and neurohypophysis in the developing human prosencephalon is readily apparent in embryonic material.2'1 Developmental defects in these midline structures might be expected to result in neurological and endocrine dysfunction. In 1970 Hoyt et al reported the association of septo-optic dysplasia with pituitary dwarfism,4 and thereafter a number of authors reported the association of optic nerve hypoplasia with anterior pituitary dysfunction.5"7 Less well known is the association of optic nerve hypoplasia with posterior pituitary dysfunction.8'9 We wish to report two patients with the combination of diabetes insipidus and bilateral hypoplasia of the optic nerves. In one of these patients the septum pellucidum was absent.
Patient No. 1
A boy born September 19, 1968, weighing 7 pounds, 10 ounces, was first examined by us at the age of 21 months because of poor vision. The child's gestation and delivery had been uneventful, but difficulty fixing on visual stimuli and unsteadiness of the eyes had been noted since two months of age. On examination the patient had irregular, wandering nystagmus with both horizontal and vertical components. A left esotropia was present and the left pupil reacted less well to direct light than did the right. The optic discs were small and paie with mottled pigmentation. The patient's frequent trips for a drink of water during the eye examination prompted neuroendocrine investigation.
When hospitalized at 22 months of age the patient was found to be in the 90th percentile for height and beyond the 97th percentile for weight. He hada widebased ataxic gait and a mild delay of motor milestones. When allowed to ingest water at will, he drank approximately two liters per day. Pertinent biochemical findings were a urine specific gravity of 1.003 to 1.004 despite serum osmolarities ranging from 297 to 302 mOsm/L, a serum sodium of 142 mEq/L, potassium of 4.8 mEq/L, chloride of 111 mEq/L, carbon dioxide of 26.3 mEq/L, and pH 7.34. The urine was free of protein and the blood urea nitrogen was 1 2.2 mg percent. There were no cells in the cerebrospinal fluid and the spinal fluid protein was 15 mg percent.
Pneumoencephalography revealed absence of the septum pellucidum (Fig. 1 ), a minor deformity of the lamina terminalis, and mild dilatation of the third and lateral ventricles. Radiographs of the optic foramina were within normal limits. An electroencephalogram showed asymmetrical background activity with occasional increased slow waves and frequent spike discharges in the occipital areas. A Hickey-Hare test demonstrated some ability to concentrate urine in response to intravenous hypertonic saline and a normal response to intravenous vasopressin which suggested a deficiency but not absence of antidiuretic hormone.10 The patient's polydypsia and polyuria were eventually controlled with lysine vasopressin nasal spray.
Further tests of pituitary function at five years of age failed to reveal any clear evidence of anterior pituitary dysfunction. A metyrapone test" demonstrated normal levels of adrenal corticosteroids and a normal pituitary-adrenal response to the induce3 inhibition of Cortisol synthesis. Thyroid hormone levels and the level of thyroid-stimulating hormone were within the normal range. Although growth hormone levels were low (0.9 to 1.4 ng/ml)andwere not increased by glucagon stimulation,12 the patient continued to grow steadily and at nine years of age his height was at the 75th percentile and his weight was still above the 97th percentile. At this age visual acuity was OD 20/70 and OS light perception with inaccurate projection. There was a small hypermetropic refractive error. The appearance of the ocular fundi was unchanged.
Fig. 1. Pneumoencephalographs of Patient No. 1 at two years of age showing absence of septum pellucidum on frontal and lateral views. A mild deformity of the lamina terminalis can a/so be seen on the lateral view.
Patient No. 2
A boy born September 24, 1971, weighing 8 pounds, 3 ounces, was brought to the Children's Hospital for eye examination at four months of age because of apparent poor vision. The infant's gestation had been unremarkable except for a maternal bladder infection at three and one-half months. Delivery had been by elective Caesarean section at term because of a small maternal pelvis. On examination the visual fixation and following responses were erratic and poorly sustained. The pupils reacted only slightly to direct light. A diagnosis of bilateral optic nerve hypoplasia was made on the basis of small, pale optic discs which were ringed by mottled pigment (Fig. 2).
By seven months of age it was evident that the patient had spastic quadriparesis and retarded mental development. Intermittent fevers without infectious cause developed after two years of age. At this time it was noted that the urine specific gravity was always less than 1.007 despite a serum osmolarity consistently above 306 mOsm/L When the patient was allowed to drink at will, he ingested 1.5 to 2.0 L of water per day. A neuroendocrine evaluation was therefore undertaken at Children's Hospital.
The patient's head circumference was found to be 48 cm (3rd percentile). His height and weight were also at the 3rd percentile level. Radiographs of the optic foramina were within normal limits. Pneumoencephalography revealed moderate dilatation of the ventricular system but no focal abnormalities. The septum pellucidum was present. Electroencephalography was normal. Examination of the spinal fluid revealed clear fluid with no cells and a spinal fluid protein of 9.3 mg percent. A blood urea nitrogen was 12 mg percent and the urine was free of protein. Water deprivation did not increase the patient's urine specific gravity above 1.007. A Hickey-Hare test demonstrated no response to the infusion of hypertonic saline.10 There was, however, rapid urine concentration to 1.013 following intravenous pitressin administration.
Fig. 2. Fundus photographs of Patient No. 2 showing small, pale optic discs. Arrows indicate actual disc border, beyond which are pale rings of lighter pigmentation with indistinct margins. Darker foveaf areas, incompletely shown in photographs, were within normal limits.
The patient was placed on lysine vasopressin nasal spray, whereupon his symptoms of diabetes insipidus were well controlled and the urine specific gravity rose to between 1.014 and 1.018. Evaluation of anterior pituitary function revealed no clear abnormalities. A metyrapone test demonstrated an increase in metabolic precursors in response to blockage of Cortisol synthesis, suggesting an intact adrenal-pituitary relationship." Growth hormone levels were normal (2.8 ng/ml) and were increased (5.0 ng/m() by glucagon stimulation.12
The patient's height continued at the 3rd percentile through age four years. His weight gradually rose to the 60th percentile by that time. Eye examination at five years of age showed some awareness of visual stimuli, but only a weak pupillary response to direct light and irregular horizontal and rotatory nystagmus. The visual acuity could not be quantitated. There was no significant refractive error. The optic discs continued to appear abnormally small and pale and the foveal areas were flattened with reduced highlights.
Optic nerve hypoplasia may occur in several different clinical settings. It may occur without other apparent central nervous system involvement,13'14 in which case the abnormality appears to be an isolated failure in the development of retinal ganglion cells. Isolated optic nerve hypoplasia is as often unilateral as bilateral,13'14 may be segmental,15'16 may be associated with maternal diabetes mellitus,16 and is rarely familial.17 Aside from its association with maternal diabetes mellitus, no cause has been identified.
Optic nerve hypoplasia can also occur with major central nervous system abnormalities such as anencephaly.18 It may also be associated with more limited midline cerebral defects, as in the deMorsier syndrome.1 In this case there appears to be a deficit in the formation of the optic chiasm at the base of the brain, presumably early in gestation between the 8th and 11th weeks.2'3 Various types of anterior pituitary dysfunction have been reported as part of this midline involvement.4"7 Few reports in the medical literature, however, refer to the association of posterior pituitary deficiency with optic nerve hypoplasia. Patel et al9 have recently published several case histories illustrating this combination of findings. One child who came to autopsy at 1 6 months of age had small, distorted hypothalamic cells and absence of the posterior lobe of the pituitary gland. Our cases appear clinically to have diabetes insipidus based on posterior pituitary or hypothalamic dysfunction, bilateral optic nerve hypoplasia, and in one case absence of the septum pellucidum. In neither case has anterior pituitary dysfunction been evident.
Two patients with the combination of bilateral optic nerve hypoplasia and diabetes insipidus are reported. One patient also had absence of the septum pellucidum (septo-optic dysplasia), which previously has been associated primarily with abnormalities of anterior pituitary function.
1. de Morsier G: Agenesie du septum lucidum avec malformation du tractus optique: la dysplasie septo -optique. Schweiz Archiv fur Neurol Psychol 77:267, 1956.
2. Rakic P, Yakovlev PI: Development of the corpus callosum and cavum septi in man. J Comp Neurol 132:45. 1968.
3. Mann I: The Development of the Human Eye, New York, Grune and Stratton, 1969, ? 136.
4. Hoyt WF, Kaplan SL, Grumbach MM et al: Septooptic dysplasia and pituitary dwarfism. Lancet 1:893, 1970.
5. Ellenberger C, Runyan T: Holoprosencephaly with hypoplasia of the optic nerves, dwarfism, and agenesis of the septum pellucidum. Am J Ophthalmol 70:960, 1970.
6. Brook CG, Sanders MD, Hoare RD: Septo-optic dysplasia. Br Med J 3:81 1, 1972.
7. Harris RJ, Haas L: Septo-optic dysplasia with growth hormone deficiency (de Morsier Syndrome). Arch Dis Child 47:973, 1972.
8. Billson F, Hopkins IJ: Optic hypoplasia and hypopituitarism. Lancet 1:905, 1972.
9. Patel H, Tze WJ, Crichton JU et al: Optic nerve hypoplasia with hypopituitarism. Am J Dis Child 129:175, 1975.
10. Dingman JF, Thorn GW: Disease of the neurohypophysis, in Wintrobe MM, Thorn GW, Adams RD et al (eds): Harrison's Principles of Internal Medicine, 7th ed. New York, McGraw Hill, 1 974, p 456.
11. Richmond L, Chappell J, Cleveland WW: Response of children to methopyrapone (Metopirone). J Pediatr 64:381, 1964.
12. AvRuskin TW, Crigler JF Jr, Sonksen PH: Growth hormone secretion after i.m. glucagon administration to normal children and adolescents and to patients with endocrine disorders. Clin Res 16:520, 1968.
13. Walton DS, Robb RM: Optic nerve hypoplasia. A report of 20 cases. Arch Ophthalmol 84:572, 1970.
14. Edwards WC, Layden WE: Optic nerve hypoplasia. Am J Ophthalmol 70:950, 1970.
15. Gardner HB, Irvine AR: Optic nerve hypoplasia with good visual acuity. Arch Ophthalmol 88:255, 1972.
16. Petersen RA, Walton DS: Optic nerve hypoplasia with good visual acuity and visual field defects. A study of children of diabetic mothers. Arch Ophthalmol 95:254, 1977.
17. Hackenbruch Y, Meerhoff E, Besio R et al: Familial bilaterial optic nerve hypoplasia. Am J Ophthalmol 79:315, 1975.
18. Barsky MD, Bebin J: Anencephaly. A case report with brain and ocular pathologic studies. J Pediatr Ophthalmol 4:18, 1967.