Septo-optic dysplasia complex: Clinical and radiological manifestations in Omani children.

BACKGROUND: Septo-optic dysplasia (SOD), also known as de-Morsier's syndrome, is a rare disorder characterized by any combination of optic nerve hypoplasia (ONH), pituitary gland hypoplasia, and midline abnormalities of the brain including absence of septum pellucidum and corpus callosum dysgenesis. It is typically diagnosed in infancy and has a variable presentation that includes visual, neurologic, and/or hypothalamic-pituitary endocrine deficits.
PURPOSE: To demonstrate the ophthalmic, endocrine, and neurologic spectrum of SOD in five Omani children and address the crucial role of high-resolution neuroimaging for its early and accurate diagnosis.
MATERIALS AND METHODS: A retrospective chart review was performed in 2010 of all children in the pediatric ophthalmology database of Sultan Qaboos University Hospital (SQUH) who were diagnosed to have ONH. All relevantdemographic, ophthalmic, neurologic, endocrine, and neuro-radiological manifestations were recorded in a data collection form. All previous neuroimaging results were reviewed by a neuro-radiologist.
RESULTS: Five patients (four males, one female) with the diagnosis of ONH were included in the study. They presented during the period 1998-2008. All patients were born at term, with normal birth weights to healthy mothers with insignificant antenatal history. Age at presentation ranged from three months to one year. Manifestations at presentation included severe visual impairment (5/5), neonatal hypoglycemia (3/5), seizure disorder (2/5), and failure to thrive (4/5). ONH was bilateral in 3/5 patients and unilateral in (2/5). Brain and orbit imaging revealed varying anomalies in all patients. These included absent septum pellucidum (3/5), severe corpus callosum agenesis (1/5), ectopic pituitary (5/5), falx cerebri deficiency (1/5), optic nerve hypoplasia (5/5), optic chiasmal hypoplasia (5/5), and olfactory tract hypoplasia (1/5). Endocrine deficits were detected in 4/5 patients (3 with panhypopituitarism, and 1 with growth hormone deficiency) and necessitated replacement therapy.
CONCLUSION: SOD is a clinically heterogeneous disorder with a wide spectrum of ophthalmic, endocrine, and neurologic manifestations. All features might not be present in a single patient. A high consanguinity rate and lack of history of alcohol and drug use were observed in our cohort. Most affected children present first to the pediatrician with failure to thrive. Radiological confirmation of ONH necessitates high-resolution imaging and interpretation by an experienced neuro-radiologist. In our cohort, all patients with ONH had associated optic chiasmal hypoplasia. Early detection and treatment reduces disease-related morbidity, and can be life saving.

Introduction

Septo-optic dysplasia (SOD), also known as de-Morsier's syndrome (OMIM # 182230), is defined by any combination of (1) ONH, (2) midline neuro-radiological abnormalities, such as agenesis of the corpus callosum and absent of septum pellucidum, and (3) and pituitary hypoplasia with consequent panhypopituitarism.[1] Approximately 30% of all SOD cases have the complete manifestations. However, 62% showed the complication of hypopituitarism and 60% have absent septum pellucidum.[1] SOD is a rare congenital anomaly and has a reported incidence of 1/10,1000 and is equally prevalent in males and females.[1] Majority of cases are sporadic, but in rare cases a family history is present.[1] Pathogenic homozygous and heterozygous mutations in HESX1 have been identified SOD patients with positive family history.[2] Additionally, SOX2 mutations have also been associated with ONH,[3] often along with severe ocular malformations such as microphthalmos. With current genetic testing methodology, a genetic cause is reportedly identified in less than 1% of patients with ONH.[2]

ONH is a common congenital optic nerve anomaly and is considered as one of the leading causes of blindness in children in some recent studies.[4] ONH, is diagnosed clinically on the basis of an abnormally small optic nerve head. Other ophthalmoscopic findings include disc pallor, the double-ring sign, tortuous retinal vessels, and increased optic disc-to-macula/disc diameter ratio. The “double-ring” sign is formed by an inner yellow ring and an outer pigmented ring that would be about the size of normal-sized optic nerve.[5] The inner ring represents the junction of the termination of retinal pigment epithelium with the under-developed (hypoplastic) optic nerve head, while the outer ring is the junction of the sclera with the lamina cribrosa. The diameter of the outer ring corresponds approximately to size of normal disc. Histologically, ONH is characterized by a subnormal number of optic nerve axons. ONH represents a non-progressive, non-specific manifestation of axonal damage at any site of the visual pathways, sustained any time before its full development. We conducted a retrospective study to investigate the neuro-ophthalmic and neuro-radiological spectrum of SOD in five Omani children.

Materials and Methods

A retrospective chart review of all children in the pediatric ophthalmology data base of SQUH, Oman with a diagnosis of ONH was performed in 2010. Approval of the departmental research ethics committee was obtained prior to commencement of the study.

Demographic data was obtained from chart review. All patients had undergone a standard ophthalmic examination that included: best corrected visual acuity (or equivalent in young children) through standard age appropriate methods, orthoptic examination, pupillary reflex, slit lamp biomicroscopy, and dilated fundoscopic examination. Fundus photographs were obtained for all patients with either RetCam® or digital fundus camera (Ziess). The diagnosis of ONH was made by one of two pediatric ophthalmology authors (SZ and AG). If available, the fundus photographs were reviewed to confirm diagnosis. The clinical diagnosis of ONH was based on presence of functional (impaired visual acuity) and morphologic ophthalmic anomalies (pallor of the optic disc, double-ring sign, abnormal vascular pattern, small size of the optic disc, or a small neuroretinal rim area). All patients had been evaluated by a pediatric neurologist (AF) and endocrinologist (SY). All patients had magnetic resonance imaging (MRI) of brain and orbit at time of evaluation. Previous neuroimaging results were reviewed by a neuro-radiologist (FA) with special attention to midline structures, optic nerve, optic chiasm, hypothalamic-pituitary axis and cerebral cortex. The findings of the demographic details and ophthalmic, neurologic, endocrine manifestations of all patients as well as neuroimaging studies were recorded in a data collection sheet.

Results

Five patients (four males and one female), aged between 2 years-13 years at the time of the study, were enrolled in this study. All patients in this study had normal birth weight and were born at term to mothers younger than 35 years old, by normal un-assisted vaginal delivery. There were no significant events during the antenatal period. All mothers had no history of medication or alcohol intake during their pregnancy. All children, except one patient (#5), were born to consanguineous parents; two of them were first cousins. No similar problems could be identified in any family members. Three patients presented to the pediatrician with neonatal hypoglycemia (patients 1, 3, and 4) and neonatal seizure was detected in two of them (patients 1 and 3). Failure to thrive was detected in all patients except one patient (#5).

The clinical and radiological findings are detailed in Tables 1 and 2, respectively. Visual acuity examination revealed bilateral severe visual impairment in 3 patients (patients 1, 3, and 5) and unilateral impairment in patients 2 and 4. Horizontal, jerk nystagmus was noticed in all patients with bilateral visual involvement. Strabismus was seen in two patients (#2 exotropia and #3 esotropia). Congenital unilateral ptosis was observed in patient 2. Dilated fundoscopic examination showed bilateral small hypoplastic optic nerves with “double-ring” sign in three patients (#1, 3, and 5) and unilateral ONH in two patients (#2 and 4 Figures 1 and 2). These findings corresponded with their visual performance. Foveal hypoplasia was seen in patients 1 and 4. The biochemical profile of pituitary gland function revealed panhypopituitarism in 3 patients (#1, 3, and 4) and growth hormone deficiency in one patient (#4). However, patient 5 had normal hormonal profile. One incidental metabolic derangement was detected in patient 4, which showed low levels of phenylalanine, methionine, glycerin, and tyrosine.

Table 1

Demographic and clinical features of children with SOD complex

Table 2

Radiological features of children with SOD complex

Figure 1

Fundus photo (RetCam ®) of left eye of patient 1 shows small pale disc with double ring sign. The fovea is also hypoplastic and the retinal vessels are tortuous. This patient had bilateral optic nerve hypoplasia, and vision was at the light perception level in both eyes

Figure 2

Fundus photo of right eye of patient 5shows a pale disc with the double ring sign. The disc is vertically oval and has a greyish tinge. The vessels are tortuous and have an anomalous branching pattern

All patients had undergone MRI of the brain and orbit. The MRI studies revealed ONH and chiasmal hypoplasia in all five patients (bilateral in all patients except patient 4) [Figure 3]. Midline defects were identified in three patients, two of them had absent septum pellucidum (patients 2 and 3) [Figure 4] and one patient had corpus callosum hypoplasia (patient 1). Structural abnormalities of the pituitary gland were seen in all patients including ectopic posterior pituitary and hypoplastic pituitary stalk [Figure 5]. The MRI of patient 2 showed olfactory bulb agenesis [Figure 6]. Besides above malformations, other cerebral malformations were not detected in any patient in our cohort.

Figure 3

Coronal T1W MR image at suprasellar region of patient 2, shows hypoplasia of left optic nerve and hemiatrophy optic chiasm (arrow)

Figure 4

Coronal T2W MR image at 3rd ventricle level of patient 3, shows absent septum pellucidum (arrow head)

Figure 5

Sagittal T1W MR image at midline of patient 5, shows ectopic posterior pituitary and hypoplastic pituitary stalk (arrow head)

Figure 6

Coronal T2W MR image at frontal lobes level of patient 2 shows absent olfactory bulb (arrow head)

A multi-disciplinary team approach was employed in the management of these patients. This team included a pediatric endocrinologist, pediatric neurologist and pediatric ophthalmologist. Hormone replacement therapy and anti-epileptic medications were administered when indicated. After complete ophthalmic assessment, treatment of refractive errors and amblyopia was advised if considered appropriate. All patients with unilateral ONH were advised safety glasses and occlusion of the normal eye. All patients were advised continued follow-up by the separate specialties as considered appropriate.

Discussion

De Morsier first described the necropsy findings of patient with ONH and agenesis of septum pellucidum and defined this as “septo-optic dysplasia” in 1956.[6] Hoyt and co-workers described the association between SOD and hormonal insufficiency in 1970.[7] In our case series of five patients, 4/5 patients presented to the pediatrician for management of neonatal hypoglycemia (3/5) and failure to thrive (4/5). One patient presented to ophthalmologist for evaluation of severe visual impairment (patient 5). All of our patients had a normal prenatal period and were born at term to healthy young mothers by un-assisted vaginal delivery. None of the mothers reported use of medication or alcohol intake during pregnancy. We noticed male predominance in this case series (80%) and that was similar to observation made by other authors.[8910]

Although none of our patients have a family history of SOD or hypopituitarism, this does not exclude the possibility of a genetic cause for the syndrome especially in the presence of highly prevalent consanguinity in our cohort (80%). When considered with the fact that antenatal alcohol and drug abuse is almost non-existent in Omani children with SOD, unlike the Western cohorts, the possibility of a genetic etiology is more likely in Omani children with SOD. This observation warrants further studies.

SOD represents a clinical spectrum rather than a specific entity. The potential complex interaction between genetics and environmental factors in genesis of ONH is reflected by the phenotypic variability seen in patients with SOD. Affected patients may present early in life during infancy with systemic features including neonatal hypoglycemia, jaundice, seizures, failure to thrive, developmental delay, and microgentalia. In addition, several ophthalmic manifestations such as visual impairment, nystagmus, strabismus, and occasionally refractive errors are well described. Margalith and colleagues found a high prevalence of cerebral palsy (57%), mental retardation (71%), epilepsy (37%), and behavioral problems (20%) in their patients with SOD.[11] In our study, 2 patients had neonatal seizures, 3 had neonatal hypoglycemia, and 4 had failure to thrive.

Proper ocular evaluation plays very crucial role in the diagnosis of SOD. This includes assessment of visual response, orthoptic evaluation, evaluation of the pupil for afferent pupillary defect as well as a detailed fundoscopic examination.

ONH, the hallmark of this disease complex, may be unilateral or bilateral. Bilateral ONH is more common. In our case series, ONH was bilateral in 3/5 patients with very poor corresponding visual acuity in the affected eye ranging between no light perception to 6/60. Visual acuity in the affected eye has been reported to range from normal vision to no light perception, based on the number of affected ganglion cell axons. Optic disc size, initial visual acuity and VEP responses are useful predictors of visual outcome in infants with bilateral ONH according to Weiss et al.[12] One important factor in poor visual responses is the delayed visual maturation.

Nystagmus could be an associated feature and we found it in 3 of our patients (60%), all of whom had bilateral ONH. Strabismus is a known clinical finding, with esotropia being the most frequently encountered misalignment.[813] Generally, as was seen in our patients, patients with bilateral ONH have nystagmus, and those with unilateral ONH strabismus.

Hypothalmic-pituitary dysfunction is a predominant feature in SOD. It manifests as either structural malformation in the pituitary gland detected by high resolution neuroimaging, pituitary hormone insufficiencies (prevalence rate between 27 and 81%),[13] or both of them. The deficient hormone may be identified in first month of life as in neonatal hypoglycemia or later on as failure to thrive, hypothyroidism, hypogonadism, or diabetes insipidus. Early detection of this syndrome is life-saving due to fatal outcome of low cortisol level in response to stressful events like infections and hypoglycemia. Growth hormone deficiency was prevalent in several previous studies.[814] In our case series, all except one patient demonstrated some form of hypopituiarism. Growth hormone deficiency was noted 4 cases (80%), while thyroid stimulating hormone (TSH) and cortisol levels were low in 3 patients (60%). No deficiency was detected in posterior pituitary hormones in this group of patients. The presence of endocrinopathies is independent of bilaterality of ONH or neuroradiologic findings. Thus, all children with ONH should be considered at risk for endocrine dysfunction regardless of radiological documentation of SOD.[13] Since pituitary hormone insufficiencies may evolve over time, life-long medical follow-up is indicated in patients with SOD.

The diagnosis of SOD complex has been revolutionized with era of high resolution MR imaging studies, which are extremely valuable to identify optic nerve and chiasmal hypoplasia as well as congenital brain malformations, elucidate their embryogenesis,[15] and possible clinical impact. MR images focusing on the hypothalamus-pituitary region, including the visual pathway and midline structures, are reported to be nearly 100% sensitive in identifying ONH and chiasmal hypoplasia.[16] The heterogeneity of SOD is clearly demonstrated with advanced neuroimaging modalities. A wide spectrum of cerebral malformations in addition to central midline defects of absent septum pellucidum and agenesis of corpus callosum has been reported, including schizencephaly (17%), abnormal ventricles or gray or white matter development (45%), ventricular cyst in 6%, and SOD in 15% of patients. A total of 15% had a hydrocephalus/shunt, 12% had agenesis of corpus callosum with normal septum and 3% had Arnold Chiari malformation type II. Patients with schizencephaly often have seizures, focal neurological deficits, and variable degrees of mental retardation.[17] Brodsky and colleagues categorized a case series of 40 patients with ONH into 4 groups. Group 1 includes isolated ONH, group 2 absent septum pellucidum, group 3 posterior pituitary ectopia, and group 4 hemispheric migration anomalies.[17] They stated that ectopic posterior pituitary was a highly sensitive and specific neuro-radiologic marker for anterior pituitary hormone deficiency in patients with ONH. In our case series, ONH and chiasmal hypoplasia were detected in all five patients (100%), absent septum pellucidum noticed in 3 of them (case 2, 3, and 5), corpus callosum agenesis in 1 patient (case 1), ectopic posterior pituitary and pituitary stalk hypoplasia in all cases. A rare congenital malformation was observed in patient 2, which is olfactory bulb agenesis. Few cases have been reported in the literature with such an association.[1819] No cerebral malformations other than the ones described above were observed in our cohort.

To summarize, despite major advances in neuroimaging modalities and genetic studies, De-Morsier's syndrome (SOD) still represents a diagnostic challenge due the multifactorial and heterogeneous nature of the disorder. A standard protocol for evaluation of patients with midline defects, ONH and/or hypopituitarism with a high index of suspicion is necessary for accurate detection. Use of standard protocols and careful evaluation of MR studies is essential for delineating the malformations of visual pathway and cerebral phenotype of SOD.

Early detection of this syndrome is essential to reduce disease related morbidity and mortality, as it may prevent life-threatening sequelae.