Previous studies have reported various extrapituitary cerebral anomalies in patients with EPP such as craniofacial dysmorphism, a central maxillary incisor tooth, septoptic dysplasia (SOD), optic nerve hypoplasia, corpus callosal dysgenesis, vascular anomalies, cellular migration disorder, persistent cricopharyngeal canal, microcephaly, cerebellar atrophy, vermian dysplasia, Chiari malformation type1, and ophthalmic abnormalities [3, 6, 8]. It has been suggested that the coexistence of EPP with periventricular heterotopias occurs because both conditions share a common underlying causative mechanism of abnormal neuronal migration. Despite our protocol was only dedicated to the midline structures, patchy/poly/micro gyria complex was confidently documented in three of our patients, associated with EPP, reinforcing that the theory of abnormal neuronal migration and cleavage anomaly is possibly enrolled in the pathogenesis of EPP [9].
Interhypothalamic adhesion (IHA) was the most frequently observed structural abnormality in our series of patients with documented extra-pituitary abnormalities (11/36). It was not observed in any patient of the control group. To the best of our knowledge, this finding is not a common abnormality reported in patients with EPP, probably identified in this study as a result of T2 DRIVE resolution with very thin slices and contrast between cerebrospinal fluid (CSF) and hypothalamic structures.
IHA represents a gray matter-like linear band of tissue traversing the third ventricle anterior to the mammillary bodies, and is structurally similar, but anatomically distinct, from interthalamic adhesion. It has been incidentally observed through the routine acquisition of high-resolution T1 imaging [10]. This subtle anomaly is primarily apparent on isotropic T1 imaging, it is under-recognized, especially because smaller IHAs are more likely to be asymptomatic. However, as high-resolution MRI techniques become more routinely used, IHAs are likely to be increasingly identified and should prompt detailed scrutiny for additional brain malformation in several different scenarios, including healthy subjects. Ahmed et al. described IHA in 57 patients who underwent MRI for neurological symptoms (such as seizures, delayed development, and trauma), but only four of them had SOD. Forty of the 57 patients had no clinical symptoms referable to their IHA. The authors concluded that IHA in patients without specific referable symptoms, and with few or no other structural abnormalities, could be incidental and of no clinical significance [10].
In the group with EPP, none of our patients with SOD had IHA. We could not find any difference between the presence of MPHD or developmental delay that could indicate a more severe phenotype associated with IHA. Our results reinforce the hypothesis that IHA might be a frequent structural abnormality associated with EPP but not detected using only the FAST1 acquisition protocol, reinforcing the need for a high-resolution 3D acquisition to refine the structural analysis of midline structures, including to evaluate hypothalamus and pituitary gland.
It has previously been indicated that high-resolution imaging in all three planes (sagittal, coronal, and axial) is necessary to distinguish IHA from other hypothalamic disorders, such as hamartoma or glioma. Our proposed protocol (FAST1.2) is based on a 3D acquisition that allows IHA recognition based on its structural features by imaging, while at the same time reducing the time required for the examination and avoiding the need for gadolinium administration. Theoretical distinction of IHA from hamartoma or glioma will not represent a real difficulty, as these disorders are not commonly reported in association with EPP. Conversely, a round/ovoid lesion identified in a patient with confirmed EPP in the previously reported positions (crossing the third ventricle from one side to another of the hypothalamus), probably represented an IHA [10, 11].
Although the underlying etiology of IHA is unclear, it may be the result of incomplete hypothalamic cleavage, failed apoptosis, or abnormal neuronal migration. Ahmed et al. pointed out the association between IHA and the gray matter heterotopia (GMH), suggesting that abnormal neuronal migration could play an important role in the etiology of this condition [10]. In the presence of EPP or other midline abnormalities, the IHA could be part of a pleiad of structural abnormalities, potentially linked by an abnormal process of neuronal development or migration. Some of the pathogenic variants associated with EPP were in genes responsible for neuronal proliferation and migration, such as IFT172, SOX3, and LHX4 [8], suggesting that in certain settings FAST1.2 protocol could not be useful solely, needing an extended MRI acquisition to evaluate the whole brain.
In conclusion, FAST1.2 MRI protocol was useful to investigate patients with short stature allowing more confident recognition of regional anatomy of the hypothalamic-pituitary region and depicting midline structural abnormalities on the T2 DRIVE imaging, including the pituitary stalk and its disorders, as well as IHA, with rapid MRI acquisition without intravenous gadolinium administration. Our results support the suspicion that interhypothalamic adhesion could be associated with defects in neuronal migration, as might occur in patients with EPP. Further studies are required to define the clinical correlations and genetic basis of the midline and also whole-brain structural abnormalities associated with EPP, clarifying the molecular mechanisms involved, and refining the appropriated scenarios to the extended MRI protocols.