Opinion statement
Background: Optic nerve hypoplasia (ONH) has developed into a leading cause of congenital blindness. The frequently associated features of hypopituitarism and absent septum pellucidum were felt to have embryonic linkage as “septo-optic dysplasia” or “de Morsier’s syndrome.” More recent studies have suggested these associations are independent of one another. This review provides an assessment of the historical and recent evidence linking neuroradiologic, endocrinologic and developmental morbidity in patients with ONH. The prenatal risk factors, heritability, and genetic mutations associated with ONH are described. Results: Recognition of the critical association of ONH with hypopituitarism should be attributed to William Hoyt, not Georges de Morsier. De Morsier never described a case of ONH or recognized its association with hypopituitarism or missing septum pellucidum. Hypopituitarism is caused by hypothalamic dysfunction. This, and other more recently identified associations with ONH, such as developmental delay and autism, are independent of septum pellucidum development. Other common neuroradiographic associations such as corpus callosum hypoplasia, gyrus dysplasia, and cortical heterotopia may have prognostic significance. The predominant prenatal risk factors for ONH are primiparity and young maternal age. Presumed risk factors such as prenatal exposure to drugs and alcohol are not supported by scrutiny of the literature. Heritability and identified gene mutations in cases of ONH are rare. Conclusion: Children with ONH require monitoring for many systemic, developmental, and even life-threatening problems independent of the severity of ONH and presence of brain malformations including abnormalities of the septum pellucidum. “Septo-optic dysplasia” and “de Morsier’s syndrome” are historically inaccurate and clinically misleading terms.
Similar content being viewed by others
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Schwarz O. Ein fall von mangelhafter bildung beider sehnerven. Albrecth von Graefes Arch Klin Ophthalmol. 1915;90:326.
Reeves D. Congenital absence of the septum pellucidum. Bull Johns Hopkins. 1941;69:61–71.
Borchert M. Reappraisal of the optic nerve hypoplasia syndrome. J Neuroophthalmol. 2012;32(1):58–67. This review article provides a critical discussion on the history and evolution of the term "septo-optic dysplasia" relative to optic nerve hypoplasia.
De Morsier G. Etudes sur les dysraphies cranio-encephaliques: agenesis du septum lucidum acec malformatnio du tractus optique. La dysplasie septo-optique. Schweiz Arch Neurol Psychiatr. 1956;77:267–92.
Gross H. and Hoff H. Sur les malformations ventruculaires dependantes des dysgenesies commisurales., in Malformations congentales du cerveau., G. Heuyer, M. Feld, and J. Gruner, Editors. 1959, Paris: Masson. p. 329–351.
Hoyt WF, et al. Septo-optic dysplasia and pituitary dwarfism. Lancet. 1970;1(7652):893–4.
Ahmad T, et al. Endocrinological and auxological abnormalities in young children with optic nerve hypoplasia: a prospective study. J Pediatr. 2006;148(1):78–84.
Garcia-Filion P, et al. Neuroradiographic, endocrinologic, and ophthalmic correlates of adverse developmental outcomes in children with optic nerve hypoplasia: a prospective study. Pediatrics. 2008;121(3):e653–9.
Vedin AM, et al. Serum prolactin concentrations in relation to hypopituitarism and obesity in children with optic nerve hypoplasia. Horm Res Paediatr. 2012;77(5):277–80. This article reports a high prevalence of hyperprolactinemia in children with ONH as a marker of underlying hypothalamic dysfunction.
Blohme J, Tornqvist K. Visual impairment in Swedish children. III. Diagnoses. Acta Ophthalmol Scand. 1997;75(6):681–7.
Blohme J, Bengtsson-Stigmar E, Tornqvist K. Visually impaired Swedish children. Longitudinal comparisons 1980–1999. Acta Ophthalmol Scand. 2000;78(4):416–20.
Patel L, et al. Geographical distribution of optic nerve hypoplasia and septo-optic dysplasia in Northwest England. J Pediatr. 2006;148(1):85–8.
Jan J, et al. Blindness due to optic-nerve atrophy and hypoplasia in children: an epidemiological study (1944–1974). Dev Med Child Neurol. 1977;19(3):353–63.
Williamson WD. Visually impaired infants in the 1980s. A survey of etiologic factors and additional handicapping conditions in a school population. Clin Pediatr (Phila). 1987;26(5):241–4.
DeCarlo DK, Nowakowski R. Causes of visual impairment among students at the Alabama school for the blind. J Am Optom Assoc. 1999;70(10):647–52.
Mets MB. Childhood blindness and visual loss: an assessment at two institutions including a "new" cause. Trans Am Ophthalmol Soc. 1999;97:653–96.
Hatton D, et al. Babies count: the national registry for children with visual impairments, birth to 3 years. J AAPOS. 2007;11(4):351–5.
Margalith D, et al. Clinical spectrum of optic nerve hypoplasia: a review of 51 patients. Dev Med Child Neurol. 1984;26:311–22.
McNay DE, et al. HESX1 mutations are an uncommon cause of septooptic dysplasia and hypopituitarism. J Clin Endocrinol Metab. 2007;92(2):691–7.
Murray PG, Paterson WF, Donaldson MD. Maternal age in patients with septo-optic dysplasia. J Pediatr Endocrinol Metab. 2005;18(5):471–6.
Tornqvist K, Ericsson A, Kallen B. Optic nerve hypoplasia: risk factors and epidemiology. Acta Ophthalmol Scand. 2002;80:300–4.
Webb EA, Dattani MT. Septo-optic dysplasia. Eur J Hum Genet. 2010;18(4):393–7.
Garcia-Filion P, et al. Optic nerve hypoplasia in North America: a re-appraisal of perinatal risk factors. Acta Ophthalmol. 2010;88(5):527–34. This article reports the etiologic correlates of ONH identified from a systematic, standardized prenatal questionnaire in a cohort study of near-consecutive cases of ONH.
Birkebaek N, et al. 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. J Clin Endocrinol Metab. 2003;88(11):5281–6.
Hellstrom A, Wiklund L, Svensson E. The clinical and morphological spectrum of optic nerve hypoplasia. J AAPOS. 1999;3(4):212–20.
Hotchkiss M, Green W. Optic nerve aplasia and hypoplasia. J Pediatr Ophthalmol Strabismus. 1979;16:225–40.
Hoyt C, Billson F. Maternal anticonvulsants and optic nerve hypoplasia. Br J Ophthalmol. 1978;62:3–6.
McMahon C, Braddock S. Septo-optic dysplasia as a manifestation of valproic acid embryopathy. Teratology. 2001;64:83–6.
Siatkowski R, et al. The clinical, neuroradiographic, and endocrinologic profile of patients with bilateral optic nerve hypoplasia. Ophthalmology. 1997;104(3):493–6.
West J, Burke J, Strachan I. Carbamazepine, epilepsy, and optic nerve hypoplasia. Br J Ophthalmol. 1990;74:511.
Burke J, O'Keefe M, Bowell R. Optic nerve hypoplasia, encephalopathy, and neurodevelopmental handicap. Br J Ophthalmol. 1991;75(4):236–9.
Hittner H, Desmond M, Montgomery J. Optic nerve manifestations of cytomegalovirus infection. Am J Ophthalmol. 1976;81:661–5.
Kim R, et al. Superior segmental optic nerve hypoplasia: a sign of maternal diabetes. Arch Ophthalmol. 1989;107:1312–5.
Ribeiro I, et al. Ocular manifestations in fetal alcohol syndrome. Eur J Ophthalmol. 2007;17(1):104–9.
Stromland K. Ocular involvement in the fetal alcohol syndrome. Surv Ophthalmol. 1987;31(4):277–84.
Ang SL, et al. A targeted mouse Otx2 mutation leads to severe defects in gastrulation and formation of axial mesoderm and to deletion of rostral brain. Development. 1996;122(1):243–52.
Brinkmeier ML, et al. Discovery of transcriptional regulators and signaling pathways in the developing pituitary gland by bioinformatic and genomic approaches. Genomics. 2009;93(5):449–60.
Dattani MT, et al. Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet. 1998;19(2):125–33.
Rizzoti K, et al. SOX3 is required during the formation of the hypothalamo-pituitary axis. Nat Genet. 2004;36(3):247–55.
Svingen T, et al. Prokr2-deficient mice display vascular dysmorphology of the fetal testes: potential implications for Kallmann syndrome aetiology. Sex Dev. 2011;5(6):294–303.
Taranova OV, et al. SOX2 is a dose-dependent regulator of retinal neural progenitor competence. Genes Dev. 2006;20(9):1187–202.
Cohen RN, et al. Enhanced repression by HESX1 as a cause of hypopituitarism and septooptic dysplasia. J Clin Endocrinol Metab. 2003;88(10):4832–9.
Tajima T, et al. Sporadic heterozygous frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient. J Clin Endocrinol Metab. 2003;88(1):45–50.
Gorbenko Del Blanco D., et al. A novel OTX2 mutation in a patient with Combined Pituitary Hormone Deficiency, pituitary malformation and an underdeveloped left optic nerve. Eur J Endocrinol, 2012.
Raivio T, et al. Genetic overlap in kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia. J Clin Endocrinol Metab. 2012;97(4):E694–9.
Mellado C, et al. Candidate gene sequencing of LHX2, HESX1, and SOX2 in a large schizencephaly cohort. Am J Med Genet A. 2010;152A(11):2736–42.
Benner JD, et al. Septo-optic dysplasia in two siblings. Am J Ophthalmol. 1990;109(6):632–7.
Cidis MB, et al. Mirror-image optic nerve dysplasia with associated anisometropia in identical twins. J Am Optom Assoc. 1997;68(5):325–9.
Hackenbruch Y, et al. Familial bilateral optic nerve hypoplasia. Am J Ophthalmol. 1975;79:314–20.
Kytila J, Miettinen P. On bilateral aplasia of the optic nerve. Acta Ophthalmol (Copenh). 1961;39:416–9.
Missiroli S. Una nuova sindrome congenita a caratterie famigliare: ipoplasia del nervo ottico ed emiangopsia binasale. Boll Ocul. 1947;26:683–98.
Hellstrom A, et al. Reduced retinal vascularization in children with growth hormone deficiency. J Clin Endocrinol Metab. 1999;84(2):795–8.
Mosier MA, et al. Hypoplasia of the optic nerve. Arch Ophthalmol. 1978;96(8):1437–42.
Borchert M, et al. Clinical assessment, optic disk measurements, and visual-evoked potential in optic nerve hypoplasia. Am J Ophthalmol. 1995;120(5):605–12.
Zeki SM, Dudgeon J, Dutton GN. Reappraisal of the ratio of disc to macula/disc diameter in optic nerve hypoplasia. Br J Ophthalmol. 1991;75(9):538–41.
McCulloch DL, et al. Clinical electrophysiology and visual outcome in optic nerve hypoplasia (ONH). Br J Ophthalmol. 2010;94:1017–23.
Jacobson L, Hellstrom A, Flodmark O. Large cups in normal-sized optic discs: a variant of optic nerve hypoplasia in children with periventricular leukomalacia. Arch Ophthalmol. 1997;115(10):1263–9.
Brodsky MC. Periventricular leukomalacia: an intracranial cause of pseudoglaucomatous cupping. Arch Ophthalmol. 2001;119(4):626–7.
Fink C., et al. Newborn thyroid-stimulating hormone in children with optic nerve hypoplasia: Associations with hypothyroidism and vision. J AAPOS, 2012. In Press.
Magoon EH, Robb RM. Development of myelin in human optic nerve and tract. A light and electron microscopic study. Arch Ophthalmol. 1981;99(4):655–9.
Patel H, et al. Optic nerve hypoplasia with hypopituitarism. Septo-optic dysplasia with hypopituitarism. Am J Dis Child. 1975;129(2):175–80.
Brodsky 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.
Williams J, et al. Septo-optic dysplasia: the clinical insignificance of an absent septum pellucidum. Dev Med Child Neurol. 1993;35(6):490–501.
Wilson DM, et al. Computed tomographic findings in septo-optic dysplasia: discordance between clinical and radiological findings. Neuroradiology. 1984;26(4):279–83.
Kelberman D, Dattani MT. Septo-optic dysplasia - novel insights into the aetiology. Horm Res. 2008;69(5):257–65.
Miller SP, et al. Septo-optic dysplasia plus: a spectrum of malformations of cortical development. Neurology. 2000;54(8):1701–3.
Glass HC, et al. Agenesis of the corpus callosum in California 1983–2003: a population-based study. Am J Med Genet A. 2008;146A(19):2495–500.
Szabo N, et al. Corpus callosum anomalies: birth prevalence and clinical spectrum in Hungary. Pediatr Neurol. 2011;44(6):420–6.
Schell-Apacik CC, et al. Agenesis and dysgenesis of the corpus callosum: clinical, genetic and neuroimaging findings in a series of 41 patients. Am J Med Genet A. 2008;146A(19):2501–11.
Phillips PH, Spear C, Brodsky MC. Magnetic resonance diagnosis of congenital hypopituitarism in children with optic nerve hypoplasia. J AAPOS. 2001;5(5):275–80.
Kucharczyk W, et al. The effect of phospholipid vesicles on the NMR relaxation of water: an explanation for the MR appearance of the neurohypophysis. AJNR Am J Neuroradiol. 1990;11(4):693–700.
Birkebaek NH, 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.
Hellstrom A, Wiklund LM, Svensson E. Diagnostic value of magnetic resonance imaging and planimetric measurement of optic disc size in confirming optic nerve hypoplasia. J AAPOS. 1999;3(2):104–8.
Brodsky MC, et al. Optic nerve hypoplasia. Identification by magnetic resonance imaging. Arch Ophthalmol. 1990;108(11):1562–7.
Haddad 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.
Reidl S, et al. Auxological, ophthalmological, neurological and MRI findings in 25 Austrian patients with septo-optic dysplasia (SOD). Horm Res. 2002;58 suppl 3:16–9.
Ma NS, et al. Evolving central hypothyroidism in children with optic nerve hypoplasia. J Pediatr Endocrinol Metab. 2010;23(1–2):53–8.
Melmed S, et al. Diagnosis and treatment of hyperprolactinemia: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:273–88.
Costin G, Murphree AL. Hypothalamic-pituitary function in children with optic nerve hypoplasia. Am J Dis Child. 1985;139(3):249–54.
Elmquist JK. Hypothalamic pathways underlying the endocrine, autonomic, and behavioral effects of leptin. Physiol Behav. 2001;74(4–5):703–8.
Rivkees SA. Arrhythmicity in a child with septo-optic dysplasia and establishment of sleep-wake cyclicity with melatonin. J Pediatr. 2001;139(3):463–5.
Rivkees SA, et al. Prevalence and risk factors for disrupted circadian rhythmicity in children with optic nerve hypoplasia. Br J Ophthalmol. 2010;94(10):1358–62.
Moore RY. Circadian rhythms: basic neurobiology and clinical applications. Annu Rev Med. 1997;48:253–66.
Panda S, Hogenesch JB, Kay SA. Circadian rhythms from flies to human. Nature. 2002;417(6886):329–35.
Weaver DR. The suprachiasmatic nucleus: a 25-year retrospective. J Biol Rhythms. 1998;13(2):100–12.
Edgar DM, Dement WC, Fuller CA. Effect of SCN lesions on sleep in squirrel monkeys: evidence for opponent processes in sleep-wake regulation. J Neurosci. 1993;13(3):1065–79.
Moore-Ede MC, Czeisler CA, Richardson GS. Circadian timekeeping in health and disease. Part 1. Basic properties of circadian pacemakers. N Engl J Med. 1983;309(8):469–76.
Garcia M, et al. Systemic and ocular findings in 100 patients with optic nerve hypoplasia. J Child Neurol. 2006;21(11):949–56.
Griffiths P, Hunt S. Specific spatial defect in a child with septo-optic dysplasia. Dev Med Child Neurol. 1984;26(3):395–400.
Brown R, et al. Are there "autistic-like" features in congenitally blind children? J Child Psychol Psychiatry. 1997;38(6):693–703.
Ek U, Fernell E, Jacobson L. Cognitive and behavioural characteristics in blind children with bilateral optic nerve hypoplasia. Acta Paediatr. 2005;94(10):1421–6.
Parr J.R., et al. Social communication difficulties and autism spectrum disorder in young children with optic nerve hypoplasia and/or septo-optic dysplasia. Dev Med Child Neurol, 2010.
Fink C, Borchert M. Optic nerve hypoplasia and autism: common features of spectrum diseases. J Vis Impair Blind. 2011;105(6):334–8.
Disclosure
No potential conflicts of interest relevant to this article were reported.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Garcia-Filion, P., Borchert, M. Optic Nerve Hypoplasia Syndrome: A Review of the Epidemiology and Clinical Associations. Curr Treat Options Neurol 15, 78–89 (2013). https://doi.org/10.1007/s11940-012-0209-2
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11940-012-0209-2