Theofanis Liatis # 1, Elizabeth Attree # 2, Laura Ruiz De Alejos Blanco 1, Patrick Santens 3, Alberta De Stefani 1, Androniki Psifidi 2
Background
Hypothalamic hamartomas are rare, non-neoplastic developmental lesions of the hypothalamus composed of ectopic grey matter. In humans, HH is associated with seizures and developmental abnormalities and can involve mutations in the sonic hedgehog (SHH) signaling pathway. Although HH has been documented in dogs, no genetic analysis had previously been reported. This study aimed to provide a phenotypic and genetic characterization of a suspected sporadic HH in a dog, drawing parallels to human HH, especially focusing on cilia-related genetic mutations.
Methods
A 7-month-old male Standard Schnauzer presenting with chronic left head tilt and continuous head-neck movements underwent clinical, neurological, and MRI evaluation. Based on imaging and clinical signs, HH was suspected. Whole genome sequencing (WGS) was performed using DNA extracted from blood to identify germline mutations, focusing on 27 candidate genes involved in SHH signaling and ciliogenesis.
Results
MRI revealed a non-enhancing, ovoid suprasellar mass isointense to grey matter, consistent with HH. WGS identified 118 unique variants, including a high-impact splice acceptor variant in the SEPTIN8 gene, a deleterious missense mutation in UBXN10, and a start loss variant in BLOC1S1. These genes are associated with ciliogenesis and neurodevelopment. Treatment with fluoxetine and levetiracetam was ineffective. One year post-diagnosis, the dog remained clinically stable without medication, exhibiting persistent neurological signs.
Limitations
The diagnosis was presumptive, as no histopathological confirmation was obtained due to the lack of tissue biopsy. Electroencephalography and cerebrospinal fluid analysis were not performed, and somatic mutations were not investigated. Thus, conclusions about the genetic etiology remain speculative.
Conclusions
This report presents the first genomic analysis of a suspected canine HH, identifying mutations in genes related to ciliogenesis. The findings support the hypothesis that canine HH, like its human counterpart, may be a ciliopathy. The study highlights the potential role of primary cilia dysfunction in HH pathogenesis and emphasizes the inclusion of HH in differential diagnoses of young dogs with persistent neurological signs. Further genetic and histological studies are necessary to validate these findings.
Magnetic resonance imaging of the head of a dog with suspected hypothalamic hamartoma, including T2W sagittal (A), T2W transverse (B), T2 FLAIR transverse (C), T1W pre- (D), and post- (E) contrast transverse sequences. There is a well-defined ovoid T2W, T1W, and FLAIR isointense compared to grey matter intra-axial mass (asterisk) without contrast enhancement at the level of the ventral middle cranial fossa extending along the cranial base within the region of hypothalamus.
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