Septo-optic dysplasia (SOD), also known as de Morsier syndrome, is a heterogeneous, congenital disorder of early brain development.1–3 The clinical diagnosis of SOD is made when two characteristics of the classic triad are met, including optic nerve hypoplasia (ONH), hypopituitarism, and midline brain defects of the septum pellucidum and/or corpus callosum. Other common findings include endocrine dysfunction, developmental delay, infantile hypotonia, and seizures.1–3 The etiology of SOD is considered multifactorial and is linked to young maternal age, though it has also been associated with mutations in homeobox genes HESX1, SOX2, and SOX3, which are essential in forebrain development.3
In this report, we describe a preterm male with SOD found to have a novel mutation in TUBA1A, a gene known to play a role in brain development through encoding a critical protein in microtubules.4,5 Complicating his congenital abnormality, our patient developed an asymmetric and aggressive posterior retinopathy of prematurity (AP-ROP). ROP is a retinal vasoproliferative disorder of infancy commonly associated with various risk factors, including early gestational age, low birth weight, and oxygen use, among others.6–8 Specifically, AP-ROP is a severe presentation of ROP characterized by plus disease, flat neovascularization in zone 1 or posterior zone 2, intraretinal shunting, hemorrhages, and rapid progression to retinal detachment.6–8 Moreover, a small number of previous reports describe ONH as a potentiating factor of ROP.9–12 To our knowledge, this is the first report associating SOD and ONH with a TUBA1A mutation and highlights the potential retinal vasculature complications of ONH.
A preterm male neonate was born at 25.3 weeks gestational age via cesarean section to a 33-year-old woman with a history of cervical insufficiency and preterm labor. The patient was born vigorous; however, he needed to be intubated as positive pressure ventilation and high levels of oxygen support were required. Physical exam was significant for birth weight of 605 grams, microcephaly with head circumference less than the third percentile, postaxial polydactyly, and low-set ears. Corpus callosum was not visible on ultrasound. Cytomegalovirus and Zika virus infections were ruled out, and a comprehensive brain malformation panel encompassing 93 genes revealed a heterozygous mutation in TUBA1A c.715A>C and variants of uncertain significance in ARL13B, FAT4, RPGRIP1L, and TSEN54.
Ophthalmological evaluation at 28 weeks postmenstrual age (PMA) detected minimal response to light, persistent tunica vasculosa and hyaloid artery, and significant optic nerve hypoplasia in both eyes (OU) (Figures 1A and 1B). Magnetic resonance imaging (MRI) revealed complete agenesis of the corpus callosum, severe optic nerve hypoplasia, decreased brain sulcation, band heterotopia, and cerebellar and vermis hypoplasia.
Fundus images of the right (A) and left (B) eyes at 40 weeks postmenstrual age showing optic nerve hypoplasia, disc pallor, and large vasculature relative to the disc.
At 35 weeks PMA, fundus examination revealed rapidly progressive bilateral ROP classified as stage 2 (6 clock hours) and stage 3 (6 clock hours) in zone I to II with plus disease and flat intraretinal neovascularization, characterizing AP-ROP (Figures 2A, 2B, 3A, and 3B). Intravitreal bevacizumab (0.625 mg/0.05 mL) (Avastin; Genentech, South San Francisco, CA) was subsequently given to both eyes, which resulted in regression of the ROP. The patient later had a recurrence of ROP OU at 61 weeks PMA that was bilaterally treated with simultaneous diode laser photocoagulation and intravitreal bevacizumab injections (0.625 mg/0.05 mL) with subsequent regression of the disease.
Fluorescein angiography of the right (A) and left (B) eyes at 34 weeks postmenstrual age demonstrating asymmetric, aggressive posterior retinopathy of prematurity.
Fundus images of the right (A) and left (B) eyes at 34 weeks postmenstrual age demonstrating asymmetric, aggressive posterior retinopathy of prematurity. Note the asymmetry in the temporal region of both eyes, with less vascularized retina in the temporal area of the right eye.
This report describes a premature newborn with SOD initially suspected on ultrasound and funduscopic examination that developed a severe AP-ROP presentation. The overall incidence of SOD, a highly heterogeneous condition characterized by ophthalmic and neurologic manifestations, is approximately one in 10,000 live births and is equally prevalent in males and females.1,3 Similar to our patient, 75% to 80% of SOD cases present with ONH, with bilateral involvement being more common.3 ONH has variable funduscopic manifestations, but diagnosis is made from the observation of a small optic disc with large vasculature relative to the disc, a double ring sign, a grayish or white disc, vascular anomalies, or retinal nerve fiber layer thinning.13 In our patient, ONH was evidenced by an extremely small and pale optic disc, and engorged surrounding vasculature. Although no ocular association is pathognomonic for ONH, there are reports of its conjunction with microphthalmos, aniridia, chorioretinal coloboma, and nystagmus.13
Although the majority of SOD cases are sporadic, suggested etiologies focus on the combination of antenatal drug and alcohol abuse, young maternal age, and embryonic vascular insults.2 A number of familial cases have also been described, suggesting a genetic origin. SOD has most frequently been linked to the homeobox genes HESX1, SOX2, and SOX3, all known to play a role in prosencephalon development.2,3 Despite the pregnancy history of cervical insufficiency, our patient's neurologic findings are likely the result of a heterozygous mutation in TUBA1A, a gene involved in neuronal migration and brain development through encoding a critical protein in microtubules.4,5TUBA1A is primarily known to be a cause of lissencephaly, polymicrogyria, and even agenesis of the corpus callosum. It has only been described in association with ONH found on MRI in one patient diagnosed at 2 years of age.4,5 Although our patient is the second to have a TUBA1A mutation associated with ONH, mutations in TUBA8, which also encodes a variant of alpha tubulin, have been linked to ONH.14 These observations suggest a role for alpha tubulin components encoded by TUBA1A and TUBA8 to be vital in the development of the optic nerve.
In the current case, the newborn developed bilateral AP-ROP at 34 weeks PMA that regressed after intravitreal bevacizumab injection and reoccurred at 7 months. AP-ROP is a severe form of ROP most commonly found in zone I that may rapidly progress to retinal detachment if left untreated.6,8 Intravitreal bevacizumab is recommended as treatment for AP-ROP as its immediate availability decreases the high levels of vascular endothelial growth factor in the vitreous compared to conventional laser therapy, though there is a high recurrence and retreatment rate.7,15 A small number of patients with ONH and asymmetric ROP, as well as patients with ONH and peripheral retinal nonperfusion, have been described,9–12 yet none report findings of asymmetric AP-ROP in patients with SOD. In one study, up to 75% of patients with ONH referred for pediatric retina consultation had severe peripheral nonperfusion and fibrovascular proliferation, and 63% developed traction retinal detachments.16 All eyes with unilateral optic nerve abnormalities had peripheral retinal nonperfusion only in the abnormal nerve eyes, suggesting an etiologic connection between retinal nonperfusion and abnormal optic nerves.16
In this case, we postulate that the severe optic nerve malformation may have compressed the retinal vessels, interfering with the vascular flow, which led to a rapid and aggressive presentation of ROP. Our hypothesis is supported by these prior reports that associate ONH and / or SOD with compromised retinal vasculature, as retinal blood vessels now emanate from a smaller optic nerve head that can physically diminish retinal blood flow. Other studies suggest that these simultaneous findings may be due to embryologic failure of retinal ganglion cell differentiation or homeobox gene abnormalities.11,12,16 However, to our knowledge, there have been no animal models investigating the association between optic nerve abnormalities and severe ROP phenotypes. Moreover, our patient's severe AP-ROP phenotype may be due to extreme prematurity and low birth weight.6,8 Nonetheless, we believe that patients with congenital ONH are at risk of developing ROP and peripheral retinal nonperfusion; thus, these patients should be followed closely with appropriate imaging as dictated by the physician to detect and treat potentially blinding retinal disease.
In summary, we report a second case in the literature of a patient with ONH and de Morsier syndrome that presented with a heterozygous TUBA1A mutation. Moreover, the patient developed AP-ROP likely exacerbated by physical compression of the retinal vessels by the abnormal optic nerves. Not only does this case strengthen the hypothesis that TUBA1A mutations are associated with ONH, but it also expands on the current literature associating ONH with peripheral retinal non-perfusion caused by an anatomic barrier.
- Acers TE. Optic nerve hypoplasia: Septo-optic-pituitary dysplasia syndrome. Trans Am Ophthalmol Soc. 1981;79:425–457.
- Ryabets-Lienhard A, Stewart C, Borchert M, Geffner ME. The optic nerve hypoplasia spectrum: Review of the literature and clinical guidelines. Adv Pediatr. 2016;63(1):127–146. doi:10.1016/j.yapd.2016.04.009 [CrossRef]
- Kelberman D, Dattani MT. Genetics of septo-optic dysplasia. Pituitary. 2007;10(4):393–407. doi:10.1007/s11102-007-0055-5 [CrossRef]
- Jansen AC, Oostra A, Desprechins B, et al. TUBA1A mutations: From isolated lissencephaly to familial polymicrogyria. Neurology. 2011;76(11):988–992. doi:10.1212/WNL.0b013e31821043f5 [CrossRef]
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- International Committee for the Classification of Retinopathy of P. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005;123(7):991–999. doi:10.1001/archopht.123.7.991 [CrossRef]
- Mintz-Hittner HA, Kennedy KA, Chuang AZ, Group B-RC.Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011;364(7):603–615. doi:10.1056/NEJMoa1007374 [CrossRef]
- Sanghi G, Dogra MR, Katoch D, Gupta A. Aggressive posterior retinopathy of prematurity in infants ≥ 1500 g birth weight. Indian J Ophthalmol. 2014;62(2):254–257. doi:10.4103/0301-4738.128639 [CrossRef]
- Arnold RW. Optic nerve hypoplasia potentiates retinopathy of prematurity. J Pediatr Ophthalmol Strabismus. 2008;45(4):247–249. doi:10.3928/01913913-20080701-02 [CrossRef]
- Hu J, Chow CC, Kiernan DF, et al. Peripheral retinal nonperfusion associated with optic nerve hypoplasia and lissencephaly. Arch Ophthalmol. 2012;130(3):398–400. doi:10.1001/archopthalmol.2011.1477 [CrossRef]
- Jordan MA, Montezuma SR. Septo-optic dysplasia associated with congenital persistent fetal vasculature, retinal detachment, and gastroschisis. Retin Cases Brief Rep. 2015;9(2):123–126. doi:10.1097/ICB.0000000000000113 [CrossRef]
- Kiernan DF, Al-Heeti O, Blair MP, et al. Peripheral retinal nonperfusion in septo-optic dysplasia (de Morsier syndrome). Arch Ophthalmol. 2011;129(5):671–673. doi:10.1001/archophthalmol.2011.92 [CrossRef]
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- Abdollahi MR, Morrison E, Sirey T, et al. Mutation of the variant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia. Am J Hum Genet. 2009;85(5):737–744. doi:10.1016/j.ajhg.2009.10.007 [CrossRef]
- VanderVeen DK, Melia M, Yang MB, Hutchinson AK, Wilson LB, Lambert SR. Anti-vascular endothelial growth factor therapy for primary treatment of type 1 retinopathy of prematurity: A report by the American Academy of Ophthalmology. Ophthalmology. 2017;124(5):619–633. doi:10.1016/j.ophtha.2016.12.025 [CrossRef]
- Shapiro MJ, Chow CC, Blair MP, Kiernan DF, Kaufman LM. Peripheral nonperfusion and tractional retinal detachment associated with congenital optic nerve anomalies. Ophthalmology. 2013;120(3):607–615. doi:10.1016/j.ophtha.2012.08.027 [CrossRef]