Association Between Incomplete Partition Type III and Abnormal Hypothalamic Morphology: Further Imaging Evidence : Journal of Computer Assisted Tomography

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NEURORADIOLOGY

Association Between Incomplete Partition Type III and Abnormal Hypothalamic Morphology: Further Imaging Evidence

Oztunali, Cigdem MD; Saylisoy, Suzan MD; Toprak, Ugur MD; Incesulu, Armagan MD

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Journal of Computer Assisted Tomography 44(5):p 704-707, 9/10 2020. | DOI: 10.1097/RCT.0000000000001050
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Abstract

Incomplete partition III (IP-III) is a rare type of inner ear malformation associated with X-linked congenital deafness syndrome. The condition occurs because of a mutation in the POU3F4 gene, presents with bilateral sensorineural or mixed hearing loss, and carries an increased risk of gusher during stapes surgery.1–3 Its computed tomography (CT) findings have been well defined and include a bulbous internal acoustic canal (IAC) that shows incomplete separation from the cochlea because of a bony deficiency between its fundus and the basal turn of the cochlea. The normal-sized cochlea present in this anomaly lacks the bony modiolus and the spiral lamina; however, interscalar septa are present.3,4 Additional typical findings include abnormal vestibular aqueduct (medial origin and/or dilatation), abnormal facial nerve canal (high location of the labyrinthine segment of the facial nerve canal and/or enlargement of the first part of the facial nerve canal), dilated singular nerve canal, a thin otic capsule around the cochlea, and hypomineralized areas at the otic capsule.2,3,5,6

Recently, Siddiqui et al7 have described an association between IP-III and the presence of hypothalamic abnormalities in some of the subjects in their series. The reported abnormalities ranged from a subtle thickening and/or asymmetry of the tubercinereum to a marked hamartoma-like enlargement of the hypothalamus. Anderson et al8 have also reported 2 brothers with X-linked stapes gusher syndrome that had hamartoma-like masses of the tubercinereum. Because none of the reported subjects with IP-III had endocrinologic abnormalities or seizures, and the hypothalamic abnormalities were subtle in imaging studies of some IP-III subjects, a possibility of undetected IP-III cases with hypothalamic abnormalities was suggested.8

In this study, we aimed to determine if IP-III was associated with any morphologic abnormalities of the hypothalamus. For this purpose, we retrospectively evaluated hypothalamic morphology in magnetic resonance imaging (MRI) studies of the subjects who were diagnosed with IP-III at 1 institution.

MATERIALS AND METHODS

Using electronic patient record system, a total of 10 subjects diagnosed with IP-III based on clinical and characteristic CT findings were found at 1 institution (2 carrier mothers and 8 affected subjects). Two subjects (2 carrier mothers) were excluded from the study because they only had CT images. In the 8 affected subjects, hypothalamic morphology was evaluated on axial fluid attenuated inversion recovery (FLAIR) and T2-weighted oblique coronal multiple planar reformation (MPR) magnetic resonance (MR) images of the brain that were obtained as a part of standard temporal bone MRI protocol at our institution (axial FLAIR MR images: repetition time, 5.000 milliseconds; echo time, 95.5 milliseconds; slice thickness, 4.5 mm; interslice gap, 1.5 mm; field of view, 22.0 cm; matrix, 320 × 224; and T2-weighted MPR images: repetition time, 5.3 milliseconds; echo time, 2.2 milliseconds; slice thickness, 1.9 mm; field of view, 16 cm; matrix, 256 × 320; parallel to the long axis of IAC, from the midpart of the third ventricle to the skull base). Magnetic resonance images were analyzed in consensus by the first and second authors, who had 7 and 16 years of experience in neuroradiology and head and neck imaging, respectively. The hypothalamus was evaluated for any size, contour, or signal intensity abnormalities.

RESULTS

Of the 8 affected subjects included in the study (age range, 2–68 years), 1 was female and the others were male. Of the male subjects, 2 were brothers. All subjects had pathognomonic findings of IP-III on CT images (Fig. 1). One subject presented with sudden hearing loss, and 7 had sensorineural hearing loss. None of the patients had documented endocrinologic abnormalities, and none had a history of seizures. Genetic testing was not performed, except in 1 subject. The POU3F4 gene mutation was found in this subject. Age, sex, audiologic, and MRI findings of the cases are presented in Table 1.

F1
FIGURE 1:
Characteristic imaging findings of IP-III on CT. Bulbous dilatation at the lateral end of the IAC (star) and absence of the bony modiolus (arrow).
TABLE 1 - Age, Sex, and Audiologic and MRI Findings of the Patients
Case Number Age, y Sex Audiologic Findings Hypothalamus
1 2 M Profound SNHL Asymmetrical thickening
2 20 M Progressive sensorineural HL Asymmetrical mass-like enlargement
3 (Brother of case 2) 22 M Progressive sensorineural HL Asymmetrical mass-like enlargement
4 14 F Profound SNHL Asymmetrical thickening
5 68 M Sudden HL Normal
6 8 M Profound SNHL Asymmetrical mass-like enlargement
7 18 M Profound SNHL Symmetrical thickening
8 36 M Profound SNHL Asymmetrical mass-like enlargement
F indicates female; M, male; HL, hearing loss; SNHL, sensorineural hearing loss.

All affected subjects, except 1 (case 5), had some degree of hypothalamic abnormality that ranged from symmetrical/asymmetrical thickening to mass-like enlargement of the hypothalamus (Fig. 2). On axial FLAIR images, 3 subjects demonstrated thickening of the hypothalamus. In 2 of 3 subjects with hypothalamic thickening, coronal oblique T2-weighted images showed a right- or left-sided asymmetry in the caudal extension of the thickened hypothalamus, which was not readily visible on axial FLAIR images (Fig. 3). In 4 of 8 affected subjects, hypothalamus demonstrated a mass-like enlargement with bumpy contour abnormalities on axial FLAIR images. Coronal oblique images of these 4 subjects also demonstrated a right- or left-sided asymmetry in caudal component of the hypothalamic mass-like enlargement (with 3 subjects demonstrating a right-sided dominance). The morphologic abnormalities were not accompanied by any signal intensity alterations on FLAIR or T2-weighted images. In 3 of 4 subjects with mass-like hypothalamic enlargement, the entire hypothalami were included in the field of view on standard axial T1- and T2-weighted temporal MR images. The hypothalamic mass-like enlargement was isointense to gray matter on T1- and T2-weighted images. In 1 subject with mass-like hypothalamic enlargement, additional postcontrast T1-weighted image did not demonstrate contrast enhancement of the enlarged hypothalamus (Fig. 4). This patient also had unilateral S-shaped enlargement of the hypothalamus, which was not readily discernible on T1-weighted or FLAIR images. In 1 subject with mass-like enlargement of the hypothalamus, the hypothalamus was included in sagittal 3-dimensional (3D) fast imaging employing steady-state acquisition images and showed a vertical rather than horizontal orientation of the abnormality.

F2
FIGURE 2:
Axial FLAIR MRI images at the level of the mesencephalon. A, Hypothalamus is normal (case 5). B, Mild thickening of the hypothalamus (case 7). C, Mass-like enlargement of the hypothalamus (case 6).
F3
FIGURE 3:
T2-weighted coronal oblique MPR image of a subject with hypothalamic thickening shows right-dominant asymmetrical caudal extension of the abnormality (arrow).
F4
FIGURE 4:
Mass-like hypothalamic enlargement is isointense to gray matter on T2-weighted images (A) and isointense to gray matter on T1-weighted images (B). On postcontrast T1-weighted images, hypothalamic enlargement does not show enhancement (C).

DISCUSSION

Incomplete partition III, also known as X-linked stapes gusher syndrome, is one of the congenital inner ear abnormalities that is characterized by symmetrical dilatation of the internal auditory canals, absence of the modiolus, and absence of the bony plate between the cochlea and the IAC on temporal bone CT scans.1,4 Its audiologic findings include bilateral mixed or sensorineural hearing loss, which can be progressive.1,5,6 Genetically, this characteristic abnormality of the inner ear is associated with mutations of POU3F4 gene that is located on chromosome Xq12.3,7–9

As a nonsyndromic hereditary cause of hearing loss, IP-III had not been associated with neurological abnormalities or neuroradiological findings. Recently, 1 case report has described the presence of hamartoma-like masses in MRIs of 2 POU3F4 mutation-positive brothers who had autism-like neurodevelopmental abnormalities.8 Subsequently, a case series on neuroimaging findings of POU3F4-mutated patients reported the presence of hamartoma-like enlargement of the hypothalamus in 3 of 15 patients.7 Also, 9 patients in their series had less prominent imaging abnormalities, which were characterized by symmetrical or asymmetrical tortuous enlargement of the hypothalamus, with caudal displacement of the tubercinereum. Because it has been shown that the POU3F4 gene is involved in the development of the hypothalamus, as well as the inner ears and the pituitary gland, a possible association with POU3F4 mutated IP-3 patients and hypothalamic abnormalities was suggested.7,8

In evaluation of 8 affected IP-III subjects, we have observed morphological abnormalities of the hypothalamus (either in the form of thickening or mass-like enlargement) in 7 subjects, with only 1 subject demonstrating normal hypothalamic morphology. The prevalence of abnormal hypothalamic morphology was high among IP-III subjects in the present study (87.5%), as in reported by Siddiqui et al7 (12/15 patients, 80%). Hamartoma-like enlargement of the hypothalamus was observed in 4 subjects (50%) in our study population, which was higher in frequency than in reported by Siddiqui at al7 (3/15 patients, 20%). Although patient samples are too small to conclude on the frequency of the presence of this specific imaging appearance, higher frequency of mass-like hypothalamic enlargement in our study population might be due to reviewing only axial FLAIR and coronal obliqueT2-weighted images that were obtained as a part of temporal bone MR studies. Indeed, 1 subject in our study with mass-like enlargement of the hypothalamus on axial FLAIR images demonstrated an S-shaped enlargement on axial T2-weighted images. Siddique et al7 also reported the presence of double S–shaped hypothalamus in 4 of 15 patients. Therefore, axial thin slice thickness or 3D T2-weighted images may be better in demonstrating tortuous or S-shaped thickening of the hypothalamus in IP-III patients. In 6 of 7 subjects with hypothalamic thickening or mass-like enlargement, we found a right- or left-sided asymmetry in caudal extension of the hypothalamic abnormality, which was more apparent on coronal oblique T2-weighted images than axial FLAIR images. This finding was consistent with Siddiqui et al7 who also observed asymmetric cranio-caudal enlargement of the hypothalamus with caudal displacement of tubercinereum in their case series. The signal intensity and contrast-enhancement characteristics of hypothalamic abnormalities in the present study were similar with hypothalamic hamartomas (isointense to gray matter on FLAIR, T1- and T2-weighted images with no contrast enhancement) as in reported case series.7,8 In contrast to morphologic abnormalities of hypothalamus in IP-III patients, hypothalamic hamartomas mostly develop from somatic mutations and are frequently associated with endocrinologic and neurologic abnormalities, such as precocious puberty, developmental delay, or seizures.8,10 Although none of the subjects in our study were tested for laboratory abnormalities of the pituitary-hypothalamic functions, clinical records of the included subjects did not show any endocrinologic or neurologic abnormalities. The pineal gland was normal in appearance in all subjects. Syndromic causes of hypothalamic hamartomas (Pallister-Hall syndrome, Bardet-Biedl syndrome, and oral-facial-digital syndrome) have never been associated with characteristic inner ear abnormalities of IP-III, although Pallister-Hall syndrome may be associated with cochlear abnormalities.7,8

In conclusion, retrospective evaluation of MR images of IP-III patients showed high frequency of nonsymptomatic morphologic abnormalities of the hypothalamus. These abnormalities, ranging from symmetrical/asymmetrical thickening to mass-like enlargement of the hypothalamus, can be appreciated on standard axial FLAIR images if the hypothalamus is imaged as a part of temporal bone MR study. However, thin-section axial or 3D T2-weighted images may be better in showing the asymmetrical, tortuous thickening of the hypothalamus, and coronal images may be better in demonstrating asymmetrical involvement. This is the second largest article describing hypothalamic abnormalities in patients with the rare IP-III malformation. Because of small number of the cases, clinical significance of the hypothalamic abnormalities in IP-III patients remains unclear.

REFERENCES

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Keywords:

hypothalamus; incomplete partition III; magnetic resonance imaging; X-linked congenital progressive mixed deafness syndrome

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