The Syndrome of Optic Nerve Hypoplasia Mark Borchert, MD, and Pamela Garcia-Filion, MPH Corresponding author In 1941, Reeves [4] identified absence of the septum Mark Borchert, MD The Vision Center at Childrens Hospital Los Angeles; pellucidum in a 7-month-old girl with bilateral optic Departments of Ophthalmology and Neurology, USC / Keck School nerve hypoplasia. Fifteen years later, de Morsier [5] of Medicine, 4650 Sunset Boulevard, MS #88, Los Angeles, CA described an association of absent septum pellucidum 90027, USA. with malformation of the optic chiasm in a single E-mail: [email protected] pathologic case of an 84-year-old woman. He provided Current Neurology and Neuroscience Reports 2008, 8:395–403 no description of vision problems or ophthalmoscopic Current Medicine Group LLC ISSN 1528-4042 abnormalities, but he noted that the corpus callosum Copyright © 2008 by Current Medicine Group LLC was normal. He also found a coexistence of unilateral or bilateral optic nerve abnormalities (or anophthalmia) with agenesis of the septum pellucidum in eight other The congenital malformation known as optic nerve radiology or pathology cases from the literature. He hypoplasia (ONH) has been recognized in the past termed the association septo-optic dysplasia, despite the 30 years as an epidemic cause of congenital blind- fact that descriptions of the optic nerve abnormalities ness. It was believed to occur either as an isolated were vague. It is important to note that de Morsier was anomaly or as a component of the syndrome of collecting pathology cases of agenesis of the septum pel- septo-optic dysplasia, which has evolved to include lucidum and that ONH was coincidentally found in 1 of midline brain malformations and hypopituitarism. his 36 cases. Nonetheless, agenesis of the septum pel- Evidence now suggests that ONH infrequently occurs lucidum was ascribed exaggerated clinical significance in in isolation. Most afflicted children will have hypo- much of the subsequent literature. It is now clear that thalamic dysfunction and/or neurodevelopmental absence of the septum pellucidum imparts no increased impairment, regardless of MRI findings or severity of risk for the myriad of problems associated with ONH. ONH. Adverse outcomes can often be ameliorated It is also clear that these associated problems are largely with early intervention. Thus, the syndrome of ONH due to miswiring of the brain, especially in the hypothal- should be suspected in all infants with signs of hypo- amus, that may not be detectable with neuroimaging. It thalamic dysfunction or vision impairment. is therefore suggested that the term septo-optic dysplasia be replaced with syndrome of optic nerve hypoplasia. In 1970, Hoyt et al. [6] noted an association of pitu- Introduction itary dwarfism in nine cases of ONH, four of whom were Optic nerve hypoplasia (ONH) is a congenital abnormal- found to be missing the septum pellucidum. They resur- ity characterized by small optic discs affecting one or rected de Morsier’s concept of septo-optic dysplasia and both eyes. It can occur in isolation or in combination with linked hypopituitarism to the syndrome. That same year, a myriad of functional and anatomic abnormalities of the a similar case was described by Ellenberger and Runyan central nervous system. Recently, ONH has been recog- [7], and a series of 25 cases of ONH had numerous nized as an increasingly frequent problem. Concomitantly, neurologic impairments without any described endo- our understanding of this epidemic of neuronal dysgenesis crine defects [8]. Because these reports preceded the era and its diverse impact on growth and development has of CT scans, the prevalence of midline brain defects in evolved considerably. these cases was unknown. In a subsequent large series of cases, hypopituitarism occurred at a high frequency and was present almost exclusively in bilateral severe cases, History and Epidemiology with or without agenesis of the septum pellucidum [9]. Because of insufficient documentation, it is uncertain Other studies disputed whether or not laterality of ONH when the first case of ONH without associated microph- or radiographic evidence of midline brain abnormalities thalmos or other ocular malformation was described. It affects the risk for hypopituitarism [7,10–16]. Reports dates to at least 1915 [1], but it may have been consider- also recognized the frequent association of other prob- ably earlier [2]. Nonetheless, prior to 1970, fewer than lems, including seizures, mental retardation, behavioral 30 cases had been reported in the English literature [3]. problems, speech and motor deficits, neonatal jaundice, 396 Neuro-ophthalmology and hypoglycemia [17,18]. Most of these reports suffered All ethnic groups are impacted by ONH, but in the from selection bias and incomplete clinical documenta- United States the prevalence is lower in persons of Asian tion, making it difficult to distinguish definite from descent [43,44••]. To date, there have been few reports coincidental associations. from Asian countries [45,46], so whether this is related to The prevalence of ONH in North America is relative genetic protection or differences in environment unknown. Prior to 1970, it was considered rare. In fact, or diet related to culture is uncertain. prior to 1962, only one case had been diagnosed (in Brit- Both male [47,48] and female [19,49] gender predis- ish Columbia), but 20 cases were subsequently diagnosed position have been reported in some studies, whereas by 1974, for an estimated prevalence of 1.8 per 100,000 other studies have reported no sexual predilection for [19]. Many authors have noted an increased incidence of ONH [17,43,44••] reported cases [20,21]. In 1981, Acers [20] estimated an incidence of 2 per 100,000 live births. ONH was identi- Gestational and exposure history fied in 12% of blind infants in Harris County in Texas Numerous perinatal and prenatal risk factors for ONH in the early 1980s [21]. Surveys of schools for the blind have been reported: preterm birth; low birth weight in the United States reveal a prevalence of ONH of [41,49]; intrauterine growth restriction [11]; twin-twin 5.7% to 12.9% in blind students [22,23]. Such surveys transfusion syndrome [50]; young maternal age [3,49]; underestimate the actual prevalence, because cognitive primiparity [3,49]; prenatal exposure to smoking [49], or behavioral impairments exclude most individuals with alcohol [51], recreational drugs [52,53], antidepressants ONH from schools for the blind. [11,18,49], anticonvulsants [54], antiemetics [14], antifun- In 1997, ONH surpassed retinopathy of prematurity gal agents, infertility treatment [49], and quinine [45,55]; as the single leading cause of infant blindness in Sweden, and prenatal complications [53] including gestational with a prevalence of 6.3 per 100,000 [24]. Only cortical diabetes [56], toxemia [3,19,50], viral infection [50], and visual impairment was more common than ONH in blind maternal anemia [14,50]. All of these reports are retro- children. But cortical visual impairment can be caused by spective or anecdotal and impacted by selection bias. many conditions, including trauma, ischemia, seizures, Although a broad spectrum of risk factors has been and hydrocephalus. The prevalence from each of these suggested, a paucity of maternal characteristics persists as causes does not appear to exceed that of ONH. Between potentially significant. The predominant enduring char- 1980 and 1999, the prevalence of ONH in Sweden rose acteristics are young maternal age and primiparity [49]. fourfold to 7.2 per 100,000. This occurred while all other The association of primiparity was reported by Tornqvist causes of childhood blindness declined [25]. By 2006, et al. [49] as a risk factor independent of maternal age. the prevalence of ONH in England had risen to 10.9 per Gestational diabetes, a well-described risk factor, is firmly 100,000 [26]. It is impossible to confirm whether or not related to a unique and uncommon form of ONH known the apparent increasing incidence of ONH in the past as superior segmental ONH [56]. Some researchers specu- two decades is caused by increasing detection sensitivity. late about the role of lifestyle factors in the development of This seems unlikely because increasing prevalence has ONH [26,41,49] These purported associations are suspect been reported from the same centers [25]. In addition, because of isolated cases of exposures and the limitations ONH is easily distinguishable by direct ophthalmoscopy, of using nonsystematically collected data. The role of nutri- the method used almost exclusively prior to 1960, when tion in the pathogenesis of ONH has not yet been studied. ONH was rarely detected. Diagnosis Prenatal Risk Factors The diagnosis of ONH is made by ophthalmoscopic Genetic risks confirmation of a small optic disc. Morphometric tech- Gene mutations affecting growth and transcription fac- niques have been described for measurement of the optic tors have been shown to have some impact on optic nerve disc based on photographs. Most of these have relied on or hypothalamic–pituitary axis development in humans measurement of disc area or diameter relative to other and mice. These gene mutations affect netrin, POUF1, landmarks, such as retinal vessels or distance to the mac- PROP1, SF-1, PITX2, NeuroD1, GATA-2, LHX3, ula. In all normal children, the ratio of the horizontal disc TPIT, SOX3, SOX2, and HESX1 [27–39]. Of these diameter (DD) to the distance between the macula and mutations, only HESX1 is reported to affect optic nerve the temporal edge of the disc (DM) has been greater than development as well as anterior pituitary gland forma- 0.35 (Fig. 1) [43,57,58]. DD/DM ratios less than 0.35 are tion in humans [40]. However, HESX1 mutations were generally described as ONH, although some patients with found to be present in less than 1% of a large sample of DD/DM ratios of 0.30 to 0.35 have normal vision.