Middle Interhemispheric Variant of Holoprosencephaly With Septo-Optic Dysplasia: A Rare Association

Middle interhemispheric variant (MIH) of holoprosencephaly (HPE), also known as syntelencephaly, is a rare subtype of HPE characterized by abnormal midline connection of the posterior parts of the frontal lobes and the anterior parts of the parietal lobes with variable corpus callosum abnormalities. We report the case of a five-year-old girl with syntelencephaly presenting with a cleft lip and palate, developmental delay, cerebral palsy, and intermittent diabetes insipidus. Brain magnetic resonance imaging demonstrated the characteristic features of both syntelencephaly and septo-optic dysplasia, including midline fusion of the frontal and parietal lobes, partial agenesis of the corpus callosum with hypoplastic genu and splenium, absence of the septum pellucidum, and bilateral optic nerve hypoplasia. Additional radiologic findings included bilateral subependymal gray matter heterotopia, colpocephaly, and an azygos anterior cerebral artery. A literature search was conducted on 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." To the best of our knowledge, this represents the first published case of MIH-variant HPE associated with all three criteria for septo-optic dysplasia, expanding the known phenotypic spectrum of these rare malformations. The co-occurrence of syntelencephaly and septo-optic dysplasia in this patient may reflect a shared disruption of midline forebrain development during the fourth to eighth weeks of gestation, when interhemispheric cleavage and hypothalamic-pituitary-optic development overlap temporally and depend on interconnected signaling pathways, including SHH, ZIC2, and the SOX family of transcription factors. Recognition of this association may prompt clinicians to evaluate patients with MIH variant HPE for features of septo-optic dysplasia, including optic nerve abnormalities and hypothalamic-pituitary dysfunction, and highlights the need for interdisciplinary clinical management and long-term surveillance in these patients.