Discussion

Syntelencephaly is associated with a constellation of radiologic and clinical features that vary in prevalence and severity among reported cases, as will be discussed below. Our patient demonstrated many of the characteristic imaging features of syntelencephaly while also exhibiting bilateral optic nerve hypoplasia and pituitary dysfunction in the form of diabetes insipidus, together fulfilling the diagnostic criteria for septo-optic dysplasia. Many of the neuroimaging findings observed in this case are characteristic of syntelencephaly and have been described previously; however, their co-occurrence with features consistent with all three criteria for septo-optic dysplasia distinguishes this case from those reported in the literature. A literature search was conducted of PubMed and Google Scholar with combinations of "middle interhemispheric variant" or "syntelencephaly" and "septo-optic dysplasia," "pituitary gland dysfunction," "endocrine dysfunction," or "optic nerve hypoplasia." Although endocrine dysfunction has been reported in some patients with MIH, no published cases found in our literature search described the coexistence of MIH and optic nerve hypoplasia with endocrine dysfunction.

For example, Rajalakshmi et al. described a patient with separate basal ganglia and thalami, absence of the septum pellucidum, and agenesis of the body of the corpus callosum, findings that were also present in our patient. Unlike our patient, however, their patient had an intact genu and splenium and vertically oriented Sylvian fissures, whereas our patient exhibited hypoplasia of the genu and splenium with horizontally oriented Sylvian fissures. Optic nerve hypoplasia and pituitary dysfunction were not reported in their case (Table 1) [8]. Bulakbasi et al. reported a series of five patients with syntelencephaly, all of whom lacked a septum pellucidum. An azygos anterior cerebral artery was identified in three patients, and partial absence of the genu and splenium with complete absence of the body of the corpus callosum was observed in two patients, findings that were also present in our patient. In contrast, all five patients demonstrated a central ventricular notch extending into non-cleaved heterotopic gray matter involving the body of the corpus callosum, three had vertically oriented Sylvian fissures, and three had normal genu and splenium, features not observed in our patient. None of the patients had optic nerve abnormalities; however, one patient had an ectopic neurohypophysis and hypoplastic pituitary stalk (Table 1) [9]. A series by Simon et al. evaluating 21 patients with syntelencephaly identified several findings similar to those in our patient, including heterotopic gray matter or dysplastic cerebral cortex in 18 of 21 patients and an azygos anterior cerebral artery in all 16 patients in whom the vessel could be assessed. Among the 18 patients in whom the corpus callosum could be evaluated, some portion of the corpus callosum was present in all cases. The genu and splenium were both identified in 11 patients, four had either the genu or splenium (but not both), and three had a portion of the body in addition to the genu, splenium, or both. Sylvian fissures were abnormally connected across the midline over the vertex in 18 of 21 patients, and dorsal cysts were present in five patients, neither of which was observed in our patient. The optic chiasm appeared normal in 12 of the 13 patients in whom it could be assessed. Although one patient had a small, presumably hypoplastic optic chiasm, optic nerve hypoplasia was not reported in any patient in the series. The pituitary gland was visualized in 16 of 21 patients and was noted to be subjectively small in four patients (Table 1) [5].

Finding | Present Case | Rajalakshmi et al. (n = 1) | Bulakbasi et al (n = 5) | Simon et al. (n = 21)
Fusion of posterior frontal/anterior parietal lobes | Yes | Yes | Yes | Yes
Absent septum pellucidum | Yes | Yes | Yes | No
Hypoplastic/absent body of corpus callosum | Yes | Yes | Yes | No (five patients were unable to be assessed)
Hypoplastic/absent genu of corpus callosum | Yes | No | 2/5 | 4/21 had either a splenium or genu but not both. Article does not specify further
Hypoplastic/absent splenium of corpus callosum | Yes | No | 2/5 | 4/21 had either a splenium or genu but not both. Article does not specify further
Separate thalami | Yes | Yes | 1/5 (two had abnormal orientation but were still separate) | 7/21
Gray matter heterotopia or cortical dysplasia | Yes | No | 5/5 had cortical dysplasia | 18/21 had gray matter heterotopia, cortical dysplasia, or both
Polymicrogyria or migrational anomaly | Yes | No | No | No
Azygos anterior cerebral artery | Yes | No | 3/5 | 16/21 (five patients were unable to be assessed)
Vertically oriented Sylvian fissures | No | Yes | 3/5 | 18/21
Dorsal cyst | No | No | No | 5/21 (one patient was unable to be assessed)
Optic nerve hypoplasia | Yes | No | No | No (one patient had a small optic chiasm that was presumed to be hypoplastic; optic nerve was otherwise not described)
Pituitary abnormality on MRI | No | No | 1/5 had ectopic neurohypophysis and hypoplastic stalk | 4/21 were subjectively small (five patients were unable to be assessed)
Endocrine dysfunction | Yes | No | Not reported | Not reported

Consistent with the rarity of pituitary dysfunction in the cases discussed above, other studies also suggest that endocrine abnormalities are uncommon in the middle interhemispheric variant (MIH) of holoprosencephaly despite being well-recognized features of the more classic forms of holoprosencephaly [1,10]. In a series of 15 patients with syntelencephaly, Lewis et al. reported no endocrinopathies [10]. In contrast, although our patient had a eutopic pituitary gland on MRI, she demonstrated pituitary dysfunction in the form of intermittent diabetes insipidus.

The coexistence of pituitary dysfunction and optic nerve hypoplasia in our patient raises the possibility of a shared developmental mechanism linking syntelencephaly and septo-optic dysplasia. Both disorders arise during an overlapping period of early forebrain morphogenesis, approximately between the fourth and eighth weeks of gestation, suggesting that their concurrence may reflect disruption of a common developmental process rather than two unrelated embryologic insults.

At approximately five weeks of gestation, the prosencephalon divides into the telencephalon and diencephalon [11]. Interhemispheric cleavage (approximately day 32) and falx differentiation (approximately day 56) occur in close temporal proximity to hypothalamic-pituitary induction, which is patterned during weeks 4 through 6 [12,13]. Optic nerve development follows a similar sequence, beginning with optic vesicle outpouching at approximately four weeks, followed by retinal ganglion cell differentiation at approximately six weeks and subsequent ingrowth of chiasmal fibers [14]. Failure of retinal ganglion cell development has been implicated in optic nerve hypoplasia [14]. Because these events occur during the same developmental window, a single disruptive event acting during early forebrain development could plausibly produce simultaneous but anatomically distinct midline abnormalities affecting the cerebral hemispheres, optic nerves, and hypothalamic-pituitary axis.

This embryologic overlap is further supported by shared developmental signaling pathways. Syntelencephaly is thought to result from localized disruption of dorsal roof plate and posterior midline patterning, with ZIC2 implicated in a subset of cases [12]. In a cohort of 509 patients with holoprosencephaly, Brown et al. identified 16 individuals with ZIC2 mutations, including one with the MIH variant [15]. The relatively mild in-frame deletion observed in that patient suggested that partial preservation of ZIC2 function may contribute to the less severe phenotype of syntelencephaly compared with classic forms of holoprosencephaly [15]. In contrast, septo-optic dysplasia has been associated with transcription factors involved in anterior midline and hypothalamic-pituitary development, including HESX1, SOX2, SOX3, OTX2, PROKR2, and FGF1/FGF8 [12,13]. Although these genes have distinct developmental roles, they function within interconnected dorsoventral and midline patterning networks that also involve SHH signaling [13,16,17]. Consequently, a genetic variant or environmental insult affecting these shared pathways could plausibly result in the combined phenotype observed in our patient.

Several authors have proposed that septo-optic dysplasia represents the mild end of the ventral induction and cleavage spectrum of holoprosencephaly, whereas others consider it a distinct disorder of midline development rather than a disorder of midline cleavage [11,12]. Regardless of classification, both models support the possibility that syntelencephaly and septo-optic dysplasia represent regional manifestations of a broader disturbance in early midline forebrain development.

Given the temporal overlap between interhemispheric cleavage, falx differentiation, and hypothalamic-pituitary-optic induction during the fourth through eighth gestational weeks, it is biologically plausible that a single disruption of midline developmental signaling produced both the interhemispheric fusion characteristic of syntelencephaly and the features of septo-optic dysplasia in our patient. However, because this report describes a single patient without confirmation of a shared molecular mechanism, causality cannot be established, and the coexistence of these conditions may alternatively represent two temporally coincident but mechanistically distinct developmental events.

Overall, our patient shares many of the hallmark neuroimaging features of syntelencephaly while also exhibiting bilateral optic nerve hypoplasia and pituitary dysfunction. To the best of our knowledge, this is the first reported case of syntelencephaly occurring in association with all three diagnostic features of septo-optic dysplasia, representing a novel finding in the published literature on syntelencephaly. This case highlights the importance of multidisciplinary care, including ophthalmologic and endocrinologic evaluation and longitudinal surveillance, in patients with syntelencephaly, particularly when clinical features raise concern for associated visual or pituitary abnormalities.