Case presentation

A five-year-old girl presented to our institution for preprocedural evaluation prior to direct laryngoscopy and bronchoscopy. She had been prenatally diagnosed with HPE based on fetal ultrasound findings of fusion of hemispheres across the midline. Brain magnetic resonance imaging (MRI) without intravenous contrast was obtained following physiologic myelination to further characterize the cerebral malformation.

She was born prematurely at 32 6/7 weeks' gestation with a birth length of 40.6 cm, weight of 1.56 kg, and head circumference of 29 cm. She was the product of her mother's sixth pregnancy, which was complicated by preeclampsia, intrauterine growth restriction, anemia, thrombocytopenia, and premature labor. There was no reported history of gestational diabetes, in utero exposure to infections, tobacco, or alcohol; however, the mother reported using unspecified anxiety medication during the first few weeks of pregnancy. There was no known family history of brain malformations, craniofacial abnormalities, or genetic disorders. One sibling was also born prematurely and had developmental delay, cerebral palsy, and a history of Wilms tumor of unknown etiology. At birth, the patient was noted to have a cleft lip and palate, a patent foramen ovale, and respiratory distress.

Over the ensuing years, she developed cerebral palsy with spasticity involving the upper and lower extremities, gastrostomy tube-dependent dysphagia, global developmental delay, laryngotracheomalacia, strabismus, amblyopia, recurrent respiratory infections, and intermittent diabetes insipidus treated as needed with desmopressin. At one year of age, ophthalmologic evaluation demonstrated decompensated V-pattern intermittent exotropia associated with inferior oblique overaction that was unresponsive to conservative management. She subsequently underwent bilateral lateral rectus recession (7.0 mm) and bilateral inferior oblique recession (10 mm). At the time of presentation, she weighed 16.2 kg (10th percentile) and measured 106.7 cm in height (18th percentile) [7].

Endocrine evaluation demonstrated elevated insulin-like growth factor-1 levels with normal growth hormone and insulin-like growth factor-binding protein-3 levels. Adrenocorticotropic hormone and cortisol levels were within normal limits. Previous genetic evaluation included chromosomal microarray analysis demonstrating a 133-kb gain at Xp22.33 encompassing the SHOX gene; because there was insufficient evidence supporting SHOX triplosensitivity, this finding was considered benign. Whole-exome sequencing identified a variant of uncertain significance consisting of an amplification of at least 51 kb within 15q15.3.

MRI of the brain without intravenous contrast demonstrated fusion of gyri across the midline involving the posterior parts of the frontal lobes (Figures 1, 2A) and anterior parts of the parietal lobes (Figures 3B, 4C), findings consistent with the MIH variant of HPE. The body of the corpus callosum was absent, and there was hypoplasia of the genu and splenium of the corpus callosum (Figure 5). Absence of the septum pellucidum (Figure 3) and optic nerve hypoplasia (Figure 6) were present, findings consistent with septo-optic dysplasia. The pituitary stalk and gland were normal. Bilateral migrational anomalies manifested by abnormal sulcations and polymicrogyria were noted (Figure 1). Additional findings included subependymal gray matter heterotopias along the bilateral frontal horns (Figures 4A, 4B), colpocephaly (Figure 2), and thinning of the periventricular white matter (Figure 2). An azygos anterior cerebral artery was present (Figure 7). Her cleft lip and palate were also evident on MRI (Figure 8). There was no fusion of the thalami or caudate nuclei.

Figure 1: MRI images demonstrating midline fusion of the posterior parts of the frontal lobes and polymicrogyriaAxial T1-weighted MRI images without intravenous contrast (A, D) show polymicrogyria (blue arrows) at abnormal fusion of the posterior parts of the frontal lobes. Axial T1-weighted MRI images without intravenous contrast (B, C) show polymicrogyria (blue arrows) at abnormal fusion of the posterior parts of the frontal lobes as well as abnormal sulcations and polymicrogyria bilaterally (red arrows).

Figure 2: MRI images demonstrating midline fusion of the posterior parts of the frontal lobes, midline fusion of the anterior parts of the parietal lobes, colpocephaly, and thin periatrial white matterAxial T1-weighted MRI image without intravenous contrast (A) shows abnormal fusion of the frontal lobes (blue arrow) and thin periatrial white matter (green arrows). Axial fluid attenuation inversion recovery (FLAIR) weighted image (B) shows abnormal fusion of the frontal lobes (blue arrow), colpocephaly (red arrows), and thin periatrial white matter (green arrows).

Figure 3: MRI images demonstrating midline fusion of the posterior parts of the frontal lobes, midline fusion of the anterior parts of the parietal lobes, subependymal gray matter heterotopia, and absence of the septum pellucidumCoronal T2-weighted MRI image (A) shows abnormal fusion of the frontal lobes (blue arrow), subependymal grey matter heterotopia (red arrows), and absence of the septum pellucidum (green arrow). Coronal T1-weighted MRI image without intravenous contrast (B) shows abnormal fusion of the parietal lobes (yellow arrow) and absence of the septum pellucidum (green arrow).

Figure 4: MRI images demonstrating midline fusion of the posterior parts of the frontal lobes, midline fusion of the anterior parts of the parietal lobes, and subependymal gray matter heterotopia.Coronal T1-weighted MRI image of the brain without intravenous contrast (A) shows abnormal fusion of the frontal lobes (blue arrow) and subependymal grey matter heterotopia (red arrow). Axial T2-weighted MRI image (B) shows abnormal fusion of the frontal lobes (blue arrow) and parietal lobes (yellow arrow) as well as subependymal grey matter heterotopia (red arrows). Coronal fluid attenuation inversion recovery (FLAIR) MRI image (C) shows abnormal fusion of the parietal lobes (yellow arrow).

Figure 5: MRI image demonstrating absence of the body of the corpus callosum and hypoplasia of the genu and splenium of the corpus callosumSagittal T1-weighted MRI image without intravenous contrast shows hypoplastic genu of the corpus callosum (red arrow), absent body of the corpus callosum (blue arrow), and hypoplastic splenium of the corpus callosum (green arrow).

Figure 6: MRI image demonstrating bilateral optic nerve hypoplasiaAxial short tau inversion recovery (STIR) MRI image of the patient shows bilateral hypoplastic optic nerves (red arrows).

Figure 7: MRI image demonstrating an azygous anterior cerebral arteryMR angiogram with 3D reconstruction shows an azygous anterior cerebral artery (red arrow).

Figure 8: MRI images demonstrating cleft palate and cleft lipCoronal T2-weighted MRI image in the plane of the globes (A) shows cleft palate (red arrow). Coronal T2-weighted MRI image in the anterior plane (B) shows the cleft lip (blue arrow).