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Endocrine Status in Patients with Optic Nerve Hypoplasia: Relationship to Midline Central Nervous System Abnormalities and Appearance of the Hypothalamic-Pituitary Axis on Magnetic Resonance Imaging

Department of Paediatrics (N.H.B.), Aarhus University Hospital at Skejby, Denmark DK-8200; Department of Paediatric Endocrinology (N.H.B., L.P., S.S., C.M.H., D.A.P., P.E.C.), Central Manchester and Manchester Children’s University Hospitals, Manchester, United Kingdom M27 1HA; Department of Paediatric Radiology (N.B.W.), Alder Hey Children’s Hospital, Liverpool, United Kingdom L12 2AP; and Department of Ophthalmology (J.R.G., I.C.L.), Central Manchester and Manchester Children’s University Hospitals, Manchester, United Kingdom M13 0JH

Address all correspondence and requests for reprints to: Dr. Leena Patel, Senior Lecturer in Child Health, Academic Unit of Child Health, Booth Hall Children’s Hospital, Manchester, United Kingdom M9 7AA. E-mail: lp{at}man.ac.uk.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
We here: 1) describe the phenotypic spectrum, including magnetic resonance imaging (MRI) appearances of the pituitary stalk and anterior and posterior pituitary [H-P (hypothalamic-pituitary) axis], in children with optic nerve hypoplasia (ONH) with or without an abnormal septum pellucidum (SP); and 2) define endocrine dysfunction according to the MRI findings. Medical records of 55 children with ONH who had been assessed by ophthalmology and endocrine services were reviewed. All had MRI of the brain and H-P axis.

Forty-nine percent of the ONH patients had an abnormal SP on MRI, and 64% had a H-P axis abnormality. Twenty-seven patients (49%) had endocrine dysfunction, and 23 of these had H-P axis abnormality. The frequency of endocrinopathy was higher in patients with an abnormal SP (56%) than a normal SP (39%). Patients were divided into four groups based on SP and H-P axis appearance: 1) both normal; 2) abnormal SP and normal H-P axis; 3) normal SP and abnormal H-P axis; and 4) both abnormal. The frequency of multiple pituitary hormone deficiency was highest (56%) in group 4, lower (35%) in group 3, and even lower (22%) in group 2. Precocious puberty was most common in group 2. None of the patients in group 1 had endocrine dysfunction. Thus, SP and H-P axis appearances on MRI can be used to predict the likely spectrum of endocrinopathy.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
OPTIC NERVE HYPOPLASIA (ONH) is the most common congenital anomaly of the optic disc. It may be an isolated finding or part of a spectrum of anatomical and functional abnormalities, which include partial or complete agenesis of the septum pellucidum (SP), other midline brain defects (e.g. thin or absent corpus callosum, dysplasia of the anterior third ventricle), cerebral anomalies (of neuronal migration and axonal degeneration), pituitary dysfunction, and structural abnormalities of the pituitary (ectopic or absent posterior pituitary, truncated or absent infundibulum and hypoplastic anterior lobe) (1, 2, 3, 4, 5, 6, 7, 8). Septo-optic dysplasia describes the association of ONH with an absent SP, with or without pituitary dysfunction.

The clinical manifestations of the ophthalmic, neurological, and pituitary abnormalities vary considerably in patients with ONH. Hypopituitarism is a serious problem, and failure to recognize it carries a risk of adrenal crisis, hypoglycemia, and death (9, 10, 11). The symptoms and signs of an endocrinopathy are not always obvious in early childhood, and hormone deficiency can evolve with time (7, 12). Because biochemical tests of pituitary function are not simple to undertake at regular intervals in all children with ONH, there is a need to identify those children most at risk of an endocrinopathy and who therefore require close monitoring. Hellström et al. (13) analyzed ocular fundus photographs in 17 children with ONH and found that isolated retinal vein tortuosity distinguished the eight children with pituitary deficiency from those with normal endocrine function. The problem with using this sign as a marker of endocrinopathy is that a computer-assisted digital mapping system is required to identify it. Having recognized that pituitary dysfunction is not precluded by an intact SP (7, 12, 14), a number of investigators have examined whether neuroradiological abnormalities of the posterior pituitary and infundibulum can be used to diagnose pituitary dysfunction (3, 7, 15, 16). Brodsky and Glasier (3) found posterior pituitary ectopia and cerebral hemispheric abnormalities, on magnetic resonance imaging (MRI), to be predictive of pituitary hormone deficiency and neurodevelopmental deficits, respectively, in 40 patients with ONH. More recently, in 86 children with ONH, Phillips et al. (16) reported normal appearance of the neurohypophysis in all 41 children with normal endocrine function and also in 19 children under 4 yr of age classified as having uncertain endocrine function. Of the remaining 26 children who had pituitary hormone deficiency, MRI revealed an ectopic posterior pituitary in 16 and absence of the posterior pituitary bright spot and infundibulum in seven. Thus, three patients had an endocrinopathy without an abnormal neurohypophysis. These authors did not report on the appearances of the SP and anterior pituitary in their patients.

None of these previous studies have described the whole phenotypic spectrum of neuropathological and functional abnormalities in patients with ONH. Further, it is not clear, within this broad group of children with ONH with or without an abnormal SP, who is most at risk of pituitary dysfunction and what dysfunction might occur. In this study, we describe the spectrum of clinical, endocrine, and radiological abnormality in children with ONH, including MRI appearances of the pituitary stalk, anterior and posterior pituitary [H-P (hypothalamic-pituitary) axis], and SP in relation to endocrine dysfunction. By comparing the MRI abnormalities in the H-P axis with the endocrine dysfunction, we attempt to predict which patients with ONH are most likely to have an endocrinopathy.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
The study group comprised 55 children with ONH (48 bilateral), median age of 5.5 yr (range, 0.2–23.5), diagnosed clinically from direct ophthalmoscopic examination of the optic discs and retinal vessels at a single center. All were examined by a pediatric ophthalmologist and endocrinologist. Visual acuity, visual fields, nystagmus, squint, optic disc, and retina were assessed. Weight, length (children < 2 yr), height, and pubertal status were monitored. Data concerning presenting symptoms, perinatal history, development, and clinical examination were traced retrospectively from the medical records.

All children had a T1-weighted high-resolution MRI, including sagittal and coronal sequences through the H-P axis as previously described (17). The images were evaluated by the same method by one investigator (N. B. Wright) (17). The height of the anterior pituitary was measured in a midline sagittal scan, expressed as SD scores (SD scores) from normative data, and classified as hypoplastic when it was below -2 SDS (18). The neurohypophysis was classified as abnormal when no bright spot could be seen or the bright spot was ectopic. The pituitary stalk was classified as abnormal when it was truncated or absent. A structurally abnormal H-P axis was defined as a hypoplastic anterior pituitary or an abnormal neurohypophysis or an abnormal stalk. The SP was classified as abnormal if it was absent in whole or part.

Endocrine function was assessed by pediatric endocrinologists from clinical features and dynamic tests. The diagnosis of GHD was based on auxological data, IGF-I level, and GH responses to glucagon and arginine stimulation tests. An abnormal GH test response was defined as a peak plasma GH of less than 15 mU/liter (5.8 ng/ml). Serum IGF-I levels in patients with GHD were less than -1 SDS (median, -4.4; range, -1 to -11 SDS). Adrenocortical reserve was assessed by a short standard dose Synacthen test [abnormal if peak plasma cortisol was less than 500 nM (18 µg/dl)]. Thyrotrophic function was assessed by measuring plasma free T₄ and TSH at baseline and the TSH response to TRH stimulation. Gonadotrophin function was assessed by LH and FSH responses to GnRH stimulation test. Multiple anterior pituitary hormone deficiency (MPHD) was defined as two or more deficiencies of GH, ACTH, TSH, and gonadotrophins. Precocious puberty was diagnosed in girls with breast development before the age of 8 yr and in boys with testicular enlargement before the age of 9 yr, and a GnRH test with a dominant LH response. The diagnosis of antidiuretic hormone (ADH) deficiency was based on early morning paired serum and urine osmolality and, if necessary, a water deprivation test. All clinical assessments, endocrine investigations, and imaging were undertaken as part of routine clinical management and with parents’ and/or patients’ (for those older than age 16 yr) consent.

The ² test was used to compare observed frequencies with expected frequencies. Continuous variables that were normally distributed were compared using the t test, and the Kruskal-Wallis test was used for variables that were not normally distributed.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Clinical characteristics

The SP was abnormal in 27 of the 55 patients with ONH. In the group with a normal SP, males were overrepresented (P = 0.002) (Table 1). Height SDS and body mass index (BMI) SDS, at the last examination or the last examination before GH treatment, did not differ between the two groups (P = 0.3 and 0.09, respectively) (Table 1). Patients in both groups were shorter than expected but did not have abnormal BMI (mean height, -0.9 SDS, P = 0.01 and -1.4 SDS, P < 0.001, respectively, for those with abnormal and normal SP) (Table 1).

Of the 55 children with ONH, six were born at a gestational age of less than 36 wk, and three had intrauterine growth retardation. Alcohol and drug addiction were only noted in one mother. Two mothers had been treated with fluoxetine and paroxetine, respectively (serotonin re-uptake inhibitors), during the first trimester. Twenty-four children (46%) had moderate or severe developmental delay. The proportion of children with or without developmental delay did not differ between the groups with a normal and abnormal SP (P = 0.2) (Table 2).

Neuroradiological appearances

A structural abnormality of the H-P axis, on MRI, was found in 35 patients (64%) (Table 3) (Fig. 1, A and B). The most frequently observed abnormality was an ectopic or absent neurohypophysis (51%). All 15 children with an ectopic posterior pituitary had an abnormal stalk, hypoplastic anterior pituitary, or both. Six children (three with a SP, three without) had anterior pituitary hypoplasia only. A thin or absent corpus callosum was only seen in those with an absent SP. The proportion of patients with different H-P axis abnormalities did not differ between the groups with and without an abnormal SP (P = 0.8). Other cerebral malformations were seen in 14 children, including holoprosencephaly in two, fused frontal lobes in one, schizencephaly in two, gray matter heterotopia in two, enlargement of the suprasellar cistern in three, ventricular system enlargement in two, interhemispheric cyst in one, and Chiari malformation in one patient. They presented, at median age 0.15 yr (range, 0–11 yr), with eye (eight patients), endocrine (three patients), and neurodevelopmental (three patients) problems. Eleven of these children had developmental delay (severe in two and moderate in nine), and they were equally distributed between the groups with and without an intact SP. Seven of the 14 had endocrine dysfunction.

View larger version (27K): [in this window] [in a new window]   FIG. 1. H-P axis abnormalities, on MRI, in (A) 12 of the 28 patients with ONH and no endocrine dysfunction, and (B) 23 of the 27 patients with ONH and endocrine dysfunction. Numbers in circles represent the percentage of patients with specific H-P axis abnormalities out of the 12 with no endocrine dysfunction (A) and the 23 with an endocrinopathy (B).

Of the 55 children with ONH, 27 (49%) had endocrine dysfunction (all had GHD, with 18 having MPHD; median age at diagnosis, 2.9 yr; range, 0.1–12.0 yr) (Table 3); and of these, 23 had structural abnormalities of the H-P axis (hypoplastic anterior pituitary in 14; abnormality of the stalk or posterior pituitary in 20) (Table 4) (Fig. 1B). Four children had hormone deficiency without an H-P axis abnormality, whereas 12 had an abnormal H-P axis but no hormone deficit (Table 4). The use of the posterior pituitary and stalk appearances had a sensitivity of 74% in the diagnosis of endocrine dysfunction. This was improved to 85% by including anterior and posterior pituitary appearances (Table 4). Specificity was relatively low in both instances. Thus, an abnormal H-P axis is highly indicative of endocrine dysfunction, but a normal H-P axis does not exclude an endocrine disorder.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

The frequency of an absent SP in our patients with ONH (49%) was comparable with that reported by Brodsky and Glasier (3) (53%). In our series, 53% of patients with ONH had structural abnormalities of the posterior pituitary and infundibulum. The prevalence of H-P axis abnormality increased to 64% when a hypoplastic anterior pituitary was included. Structural abnormalities of the posterior pituitary and infundibulum, on MRI, were reported by Brodsky and Glasier (3) in 15% and Phillips et al. (16) in 34% of their patients with ONH recruited from ophthalmology departments. They did not mention MRI appearances of the anterior pituitary in their cases. In our study, an ectopic posterior pituitary was not seen as an isolated structural abnormality but was observed with an abnormal stalk or a hypoplastic anterior pituitary or both. An ectopic posterior pituitary, on MRI, is thought to arise secondary to injury to the infundibulum and represents a cluster of normally functioning posterior pituitary cells at the base of the infundibulum proximal to the site of injury (21). Although ADH secretion from this ectopic cluster may be sufficient to maintain normal posterior pituitary function, the disrupted neuroendocrine connections between the hypothalamus and anterior pituitary result in anterior pituitary deficiency and are associated with hypoplasia of the anterior lobe.

We found structural abnormalities of the H-P axis or the SP in all our patients with endocrine dysfunction and found no endocrinopathy in the ONH patients who did not have these midline defects. H-P axis abnormalities were also seen in 43% of the patients with normal endocrine function (Fig. 1A); and, because they were the youngest, it remains to be seen whether they will develop hormone dysfunction in the future. Phillips et al. (16) reported that, of 26 children with ONH and an endocrine deficit, 23 had an abnormal posterior pituitary, whereas 41 children with normal endocrine function had a normal posterior pituitary. We found that all children who had an endocrinopathy had either an abnormal SP or abnormal H-P axis, but the latter included both anterior and posterior pituitary appearances.

The frequency of MPHD in our patients increased in the three subgroups with midline structural defects, on MRI, being lowest with an absent SP and normal H-P axis, higher with a normal SP but abnormal H-P axis, and highest in those with an absent SP as well as abnormal H-P axis. Traggiai et al. (12) also noted a higher frequency of MPHD in patients with ONH and absent SP, compared with those with an intact SP. ADH deficiency was more prevalent in our patients with an absent SP. Although an absent posterior pituitary, on MRI, is expected in patients with ADH deficiency (20), two of our patients with central diabetes insipidus had normal pituitary anatomy but an absent SP. This has been described previously (22); and, in the context of intact synthesis and storage of ADH, a defect in hypothalamic function that impairs osmotic regulation has been proposed (23). Precocious puberty was most frequent in patients with an absent SP but structurally normal pituitary, and this is consistent with a hypothalamic or cerebral lesion being the primary trigger for initiating puberty and the pituitary retaining the ability to secrete gonadotrophins (24). Abnormal findings, on histological examination of the hypothalamus, in patients with ONH and endocrine dysfunction lend further support for a hypothalamic defect (25).

As previously described, the presenting features and functional deficits varied considerably in our patients (1, 3, 6, 16, 19, 26). We noted moderate or severe developmental delay in 46% of our patients, and this is consistent with the observations of Cameron et al. (10) in 25 children with ONH/septooptic dysplasia. However, unlike Brodsky and Glasier (3), we did not find an association between cerebral hemispheric abnormalities and neurodevelopmental deficits. Prenatal alcohol exposure has been correlated with ONH, but only one mother in our population admitted alcohol abuse during pregnancy (27, 28, 29). An association with serotonin re-uptake inhibitors in the first trimester of pregnancy and ONH has not been established. However, two mothers in our study and one in the population study by Tornqvist et al. (30) of 156 individuals with ONH had been treated with this group of drugs. Prematurity and perinatal complications were infrequent in our patients, but seven children with MPHD presented with hypoglycemia in the neonatal period.

From this study of 55 patients with ONH, we draw a number of conclusions and recommendations for practice. First, ONH, with or without an intact SP, covers a wide spectrum of disorders, in which eye symptoms are most obvious. In addition, an endocrinopathy and moderate-to-severe developmental delay are found in almost half of the patients. Therefore, these children should be managed by a multidisciplinary team with knowledge of the entire spectrum of manifestations. Second, all children with ONH should have a high-resolution MRI with thin-slice sections through the H-P axis, and those with an abnormal SP and/or abnormal H-P axis should have detailed endocrine evaluation. Although all patients with ONH should be followed at least until completion of linear growth and pubertal development, those with an abnormal SP and/or abnormal H-P axis are at greater risk of endocrine dysfunction than those with intact SP and normal H-P axis, and thus require closer monitoring. Finally, the diversity of phenotypes could imply that a range of genes linked with the development of the optic tract and HP development might be involved in this condition.

	Footnotes

 
Abbreviations: ADH, Antidiuretic hormone; BMI, body mass index; H-P, hypothalamic-pituitary; MPHD, multiple anterior pituitary hormone deficiency; MRI, magnetic resonance imaging; ONH, optic nerve hypoplasia; SDS, SD score; SP, septum pellucidum.

Received March 26, 2003.

Accepted July 30, 2003.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

1. Acers TE 1981 Optic nerve hypoplasia: septo-optic-pituitary dysplasia syndrome. Trans Am Ophthalmol Soc 79:425–457[Medline]
2. Arslanian SA, Rothfus WE, Foley Jr TP, Becker DJ 1984 Hormonal, metabolic, and neuroradiologic abnormalities associated with septo-optic dysplasia. Acta Endocrinol (Copenh) 107:282–288[Medline]
3. Brodsky MC, Glasier CM 1993 Optic nerve hypoplasia. Clinical significance of associated central nervous system abnormalities on magnetic resonance imaging. Arch Ophthalmol 111:66–74[Abstract]
4. De Morsier G 1956 Etudes sur les dysraphies cranio-encephaligues, III: agenesie du septum lucidum avec malformation du tractus optique. La dysplasie septo-optique. Schweiz Arch Neurol Neurochir Psychiatr 77:267–292
5. Hoyt WF, Kaplan SL, Grumbach MM, Glaser JS 1970 Septo-optic dysplasia and pituitary dwarfism. Lancet 1:893–894
6. Siatkowski RM, Sanchez JC, Andrade R, Alvarez A 1997 The clinical, neuroradiographic, and endocrinologic profile of patients with bilateral optic nerve hypoplasia. Ophthalmology 104:493–496[Medline]
7. Stanhope R, Preece MA, Brook CGD 1984 Hypoplastic optic nerves and pituitary dysfunction. Arch Dis Child 59:111–114[Abstract]
8. Zeki SM, Hollman AS, Dutton GN 1992 Neuroradiological features of patients with optic nerve hypoplasia. J Pediatr Ophthalmol Strabismus 29:107–112[Medline]
9. Brodsky M, Conte FA, Taylor D, Hoyt CS, Mrak RE 1997 Sudden death in septo-optic dysplasia. Arch Ophthalmol 115:66–70[Abstract]
10. Cameron FJ, Khadikar VV, Stanhope R 1999 Pituitary dysfunction, morbidity and mortality with congenital midline malformation of the cerebrum. Eur J Pediatr 158:97–102[CrossRef][Medline]
11. Gilbert JD, Scott G, Boyard RW 2001 Septo-optic dysplasia and unexpected adult death-autopsy approach. J Forensic Sci 46:913–915[Medline]
12. Traggiai C, Stanhope R 2002 Endocrinopathies associated with midline cerebral and cranial malformations. J Pediatr 140:252–255[CrossRef][Medline]
13. Hellström A, Wiklund LM, Svensson E, Albertsson-Wiklund K, Strömland K 1999 Optic nerve hypoplasia with isolated tortuosity of the retinal veins. Arch Ophthalmol 117:880–884[Abstract/Free Full Text]
14. Huseman CA, Kelch RP, Hopwood NJ, Zipf WB 1978 Sexual precocity in association with septo-optic dysplasia and hypothalamic hypopituitarism. J Pediatr 92:748–753[CrossRef][Medline]
15. Hellström A, Wiklund LM, Svensson E 1999 The clinical and morphological spectrum of optic nerve hypoplasia. J AAPOS 3:212–220
16. Philips PH, Spear C, Brodsky MC 2001 Magnetic resonance diagnosis of congenital hypopituitarism in children with optic nerve hypoplasia. J AAPOS 5:275–280
17. Tillmann V, Tang VWM, Price DA, Hughes DG, Wright NB, Clayton PE 2000 Magnetic resonance imaging of the hypothalamic-pituitary axis in the diagnosis of growth hormone deficiency. J Pediatr Endocrinol Metab 13:1577–1583[Medline]
18. Argyropoulou M, Perignon F, Brunelle F, Brauner R, Rappaport R 1991 Height of normal pituitary as a function of age evaluated by magnetic resonance imaging in children. Pediatr Radiol 21:247–249[CrossRef][Medline]
19. Costin G, Murphree AL 1985 Hypothalamic-pituitary function in children with optic nerve hypoplasia. Am J Dis Child 139:249–254[Abstract]
20. Sorkin JA, Davis PC, Meacham LR, Parks JS, Drack AV, Lambert SR 1996 Optic nerve hypoplasia: absence of posterior pituitary bright signal on magnetic resonance imaging correlates with diabetes insipidus. Am J Ophthalmol 122:717–723[Medline]
21. Kelly WM, Kucharczyk W, Kucharczyk J, Kjos B, Peck WW, Norman D, Newton TH1988 Posterior pituitary ectopia: an MR feature of pituitary dwarfism. Am J Neuroradiol 9:453–460
22. Abernethy LJ, Qunibi MA, Smith CS 1997 Normal MR appearances of the posterior pituitary in central diabetes insipidus associated with septo-optic dysplasia. Pediatr Radiol 27:45–47[CrossRef][Medline]
23. Masera N, Grant DB, Stanhope R, Preece MA 1994 Diabetes insipidus with impaired osmotic regulation in septo-optic dysplasia and agenesis of the corpus callosum. Arch Dis Child 70:51–53[Abstract]
24. Nanduri VR, Stanhope R 1999 Why is the retention of gonadotrophin secretion common in children with panhypopituitarism due to septo-optic dysplasia. Eur J Endocrinol 140:48–50[Abstract]
25. Roessmann U, Velasco MI, Small EJ, Hori A 1987 Neuropathology of "septo-optic dysplasia" (de Morsier syndrome) with immunohistochemical studies of the hypothalamus and pituitary gland. J Neuropathol Exp Neurol 46:597–608[Medline]
26. Hellström A, Aronsson M, Axelson C, Kyllerman M, Kopp S, Steffenburg S, Stromland K, Westphal O, Wiklund L, Albertsson-Wikland K 2000 Children with septo-optic dysplasia—how to improve and sharpen the diagnosis. Horm Res 53:19–25
27. Hellstrom A 1999 Optic nerve morphology may reveal adverse events during prenatal and perinatal life—digital image analysis. Surv Ophthalmol 44(Suppl 1):S63–S73
28. Coulter CL, Leech RW, Schaefer BB, Scheithauer BW, Brumback RA 1993 Midline cerebral dysgenesis, dysfunction of the hypothalamic-pituitary axis, and fetal alcohol effects. Arch Neurol 50:771–775[Abstract]
29. Stromland K, Pinazo-Duran MD 2002 Ophthalmic involvement in the fetal alcohol syndrome:clinical and animal model studies. Alcohol Alcohol 37:2–8[Abstract/Free Full Text]
30. Tornqvist K, Ericsson A, Källén B 2002 Optic nerve hypoplasia: risk factors and epidemiology. Acta Ophthalmol Scand 80:300–304[CrossRef][Medline]

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