Septopreoptic Holoprosencephaly: A Mild Subtype Associated with Midline Craniofacial Anomalies

Discussion

Modern MR imaging has enabled detailed analysis of the cortical, white matter, and deep gray structural anomalies in HPE. This has allowed better classification of various types of HPE, identification of newer subtypes, and understanding of the pathogenesis. The sine qua non feature of HPE is an incomplete separation of the cerebral hemispheres, which results in a lack of cleavage (nonseparation) of midline telencephalic and diencephalic structures. Because the abnormally fused regions in septopreoptic HPE are telencephalic structures, this mild form meets the accepted criteria of HPE.⁷

However, classifying these mild midline abnormalities as HPE may be controversial.⁸ Many who study HPE consider the presence of the fornix, septum, and AC to essentially exclude the diagnosis of HPE (personal communication, A. James Barkovich, Jan. 5, 2005), especially when the 2 cerebral hemispheres appear nearly completely separated. Nevertheless, both the preoptic and septal regions are telencephalic structures (with the former being closely related in structure to the hypothalamus, a diencephalic structure). Therefore, by definition, a developmental nonseparation of telencephalic structures can be classified as HPE.⁷ The nonseparation of these midline structures would be consistent with the ventral patterning defect seen in classic HPE, though the affected midline region is much more restricted. We believe that the condition in these patients represents a milder form of lobar HPE, which is at the mildest end of the spectrum of HPE. These patients do not merely have a “microform of HPE,” which is defined as midline craniofacial anomaly in the absence of brain malformation.

Septopreoptic HPE is commonly included in the lobar spectrum, though distinct differences exist as outlined in the Table. In both subtypes, the frontal and occipital lobes are separated at least to some degree. However, in lobar HPE, there is fusion of the rostral/ventral aspects of the frontal lobes, whereas in septopreoptic HPE, there is no significant fusion of these regions. The anterior IHF and falx cerebri are present in both subtypes, though in lobar HPE, they are hypoplastic (ie, shallower than in septopreoptic HPE) due to the frontal lobe fusion.⁷

Similar to the finding of azygous ACA in lobar HPE,⁷ we found that an unpaired ACA was also present in septopreoptic HPE. However, in lobar HPE, the azygous ACA is located more anteriorly (rostrally) due to the shallow anterior IHF. In contrast, in septopreoptic HPE, the azygous ACA is located posteriorly, near the subcallosal region.

The septal region, a telencephalic structure, includes both cortical and subcortical areas that belong to the forebrain (Fig 1).⁹ It forms part of the medial wall of the cerebral hemispheres. The cortical areas, called the septal cortex, are found under the rostrum of the CC (subcallosal area). Nuclei that lie deep to this region are called the septal nuclei. The subcallosal area is bordered dorsally by the CC and caudally by the AC and the preoptic region (Fig 1).¹⁰ Functionally, the septal region includes major hypothalamic and limbic structures that are interconnected via the hippocampal formation. Lesions in the septal region have been known to be associated with behavioral over-reaction to external stimuli.¹⁰

The preoptic region is a narrow vertical strip flanking the rostralmost part of the V3 that extends from the AC to the rostral part of the optic chiasm (Fig 1).¹¹ Although most of the preoptic region is caudal to the lamina terminalis, a small portion is located rostrally.¹² The preoptic region is thought to be telencephalic in origin, though later studies show a diencephalic origin.¹² Regardless of its embryonic origin, it is closely related structurally and functionally to the hypothalamus. It contains 3 rather poorly differentiated cell masses: the preoptic periventricular nucleus, medial preoptic nucleus, and lateral preoptic nucleus. This region is implicated in regulating blood volume and pressure.

The primary defect in classic HPE is in the abnormal patterning signals from the rostral neural tube that occur during the first 4 weeks of gestation.¹ In normal embryonic forebrain development, a complex interaction between ventral patterning signals (primarily sonic hedgehog from the floor plate and prechordal plates) and dorsal patterning signals (molecules arising from the roof plate) modulate regional identity of tissues along the vertical axis of the neural tube.⁷ The gradients of ventral and dorsal signaling molecules induce a distinct combination of genes and transcription factors in populations of cells at different levels along the vertical axis. The presumed mechanism in HPE is thought to be the lack of production of ventralizing factors or an overproduction of dorsalizing factors resulting in noncleavage of the midline structures, and producing holoprosencephalic brains.¹ In septopreoptic HPE, the area of abnormal patterning seems to be restricted to a small forebrain region. As in classic HPE, the same signaling abnormalities can result in midline craniofacial malformations, albeit mild in phenotype.

The frequent association of anomalies of the fornix, SP, and anterior CC in septopreoptic HPE is most likely related to the embryonic relationship of these structures during weeks 6–8 of development. These structures all originate from the lamina reuniens. The lamina reuniens is located in the midline ventral region at the base of the interhemispheric cleft, dorsal to the lamina terminalis.¹³ The lamina reuniens will further develop into 2 distinct areas. The ventral part becomes the area praecommissuralis, which will develop into the septal region and AC. The dorsal part of the lamina reuniens becomes the hippocampal primordium, which will give rise to the fornix, hippocampal commissure, CC, and the cavum SP. It is likely that a disturbance in the development of the lamina reuniens leads to the structural abnormalities seen in septopreoptic HPE.

Patients with septopreoptic HPE are often referred to neuroimaging because of their mild midline malformations such as SMMCI and CNPAS. These midline malformations are also commonly seen in classic HPE. The otolaryngology literature is filled with examples of patients with mild HPE who first presented for nasal airway problems.^14–16 CNPAS has also been associated with a high incidence of hypothalamic-pituitary-adrenal axis dysfunction but is not necessarily associated with HPE.¹⁷ The presence of SMMCI may also be a clue to HPE.^18–21 When these extracerebral anomalies are found either clinically or on imaging studies, one should perform high-resolution MR imaging. If an obvious diagnosis of classic HPE is not readily evident, careful attention should be directed to the preoptic area and septal region to look for the milder forms of HPE.

Even with the restricted area of midline fusion, patients with septopreoptic HPE also have neurodevelopmental and endocrine abnormalities. Unlike classic HPE, motor function appears to be spared. This is likely due to the lack of hemispheric and basal ganglia fusion that is common in classic HPE. The 1 exception in our series was a neonate (case 3) who had multiple congenital anomalies and white matter injury that most likely had a significant effect on her developmental outcome. More detailed clinical studies are needed to more accurately determine the neurodevelopmental outcome in septopreoptic HPE.