ABSTRACT
PURPOSE: Incomplete partition type II (IP-II) is characterized by specific histological features and radiological appearance. It may occur in isolation or in association with an enlarged vestibular aqueduct (EVA). Among those with IP-II and EVA, a subset has a diagnosis of Pendred syndrome. This study aimed to explore the prevalence of isolated IP-II, IP-II with EVA, and cases with a genetic or syndromic basis in our cohort. METHODS: From a large, multicentre database of dysplastic cochleae (446 patients, 892 temporal bones), those with imaging features of IP-II were examined in detail, including whether there was a genetic or syndromic association. RESULTS: A total of 78 patients with IP-II were identified. Among these, 55 patients had bilateral IP-II and EVA (only 12 with typical Mondini triad), 8 with bilateral IP-II and normal VA, 2 with bilateral IP-II and unilateral EVA, and 13 with unilateral IP-II (9 with unilateral EVA). Among the group with bilateral IP-II and bilateral EVA in whom genetic analysis was available, 14 out of 29 (48%) had SLC26A4 mutations and a diagnosis of Pendred syndrome, 1 had a FOXI1 mutation, and a few other genetic abnormalities; none had KCNJ10 pathogenic variants. CONCLUSION: Bilateral IP-II-bilateral EVA may be seen in the context of Pendred syndrome (SLC26A4 or FOXI1 mutations) but, in the majority of our cohort, no genetic abnormalities were found, suggesting the possibility of unknown genetic associations. IP-II in isolation (without EVA) is favored to be genetic when bilateral, although the cause is often unknown.
Subject(s)
Hearing Loss, Sensorineural , Vestibular Aqueduct , Humans , Male , Female , Hearing Loss, Sensorineural/genetics , Hearing Loss, Sensorineural/diagnostic imaging , Child , Adolescent , Adult , Vestibular Aqueduct/diagnostic imaging , Vestibular Aqueduct/abnormalities , Child, Preschool , Middle Aged , Infant , Aged , Mutation , Goiter, Nodular/diagnostic imaging , Goiter, Nodular/genetics , Sulfate TransportersABSTRACT
INTRODUCTION: Pineal, sellar and suprasellar tumours in children comprise a wide range of diseases with different biological behaviours and clinical management. Neuroimaging plays a critical role in the diagnosis, treatment planning and follow up of these patients, but imaging interpretation can prove challenging due to the significant overlap in radiological features. MATERIALS AND METHOD: A review of the literature was performed by undertaking a search of the MEDLINE and EMBASE databases for appropriate MeSH terminology. Identified abstracts were screened for inclusion and articles meeting the objectives of the review were included. RESULTS AND CONCLUSION: In this article, we review radiological appearances of common and uncommon pineal, sellar and suprasellar tumours occurring in the paediatric population. We discuss the importance of anatomical localization, clinical information and cerebrospinal fluid tumour markers, and propose a practical approach to differential diagnosis. Lastly, we discuss future directions and prospective new imaging strategies to support state-of-the-art patient care.
Subject(s)
Neoplasms , Pineal Gland , Child , Diagnosis, Differential , Humans , Magnetic Resonance Imaging , Neuroimaging , Prospective StudiesABSTRACT
The neurodiagnostic criteria of Leigh syndrome have not yet been clearly redefined based on the expanding of molecular etiologies. We aimed to analyze 20 years of clinical, genetic, and magnetic resonance studies from our Leigh syndrome cohort to provide a detailed description of central nervous system lesions in Leigh syndrome and their biological evolution in view of their genetic and clinical findings. Our study adds new neurodiagnostic insights to the current knowledge of Leigh syndrome, including association with overlapping syndromes, and the correlation of pathogenic genetic variants with neuroimaging phenotypes. ANN NEUROL 2020;88:218-232.
Subject(s)
DNA, Mitochondrial/genetics , Genetic Variation/genetics , Leigh Disease/diagnostic imaging , Leigh Disease/genetics , Magnetic Resonance Imaging/methods , Child , Female , Follow-Up Studies , Humans , Male , Neuroimaging/methods , Retrospective StudiesABSTRACT
Ferritin, the iron storage protein, is composed of light and heavy chain subunits, encoded by FTL and FTH1 , respectively. Heterozygous variants in FTL cause hereditary neuroferritinopathy, a type of neurodegeneration with brain iron accumulation (NBIA). Variants in FTH1 have not been previously associated with neurologic disease. We describe the clinical, neuroimaging, and neuropathology findings of five unrelated pediatric patients with de novo heterozygous FTH1 variants. Children presented with developmental delay, epilepsy, and progressive neurologic decline. Nonsense FTH1 variants were identified using whole exome sequencing, with a recurrent de novo variant (p.F171*) identified in three unrelated individuals. Neuroimaging revealed diffuse volume loss, features of pontocerebellar hypoplasia and iron accumulation in the basal ganglia. Neuropathology demonstrated widespread ferritin inclusions in the brain. Patient-derived fibroblasts were assayed for ferritin expression, susceptibility to iron accumulation, and oxidative stress. Variant FTH1 mRNA transcripts escape nonsense-mediated decay (NMD), and fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. C-terminus variants in FTH1 truncate ferritin's E-helix, altering the four-fold symmetric pores of the heteropolymer and likely diminish iron-storage capacity. FTH1 pathogenic variants appear to act by a dominant, toxic gain-of-function mechanism. The data support the conclusion that truncating variants in the last exon of FTH1 cause a novel disorder in the spectrum of NBIA. Targeted knock-down of mutant FTH1 transcript with antisense oligonucleotides rescues cellular phenotypes and suggests a potential therapeutic strategy for this novel pediatric neurodegenerative disorder.
ABSTRACT
Ferritin, the iron-storage protein, is composed of light- and heavy-chain subunits, encoded by FTL and FTH1, respectively. Heterozygous variants in FTL cause hereditary neuroferritinopathy, a type of neurodegeneration with brain iron accumulation (NBIA). Variants in FTH1 have not been previously associated with neurologic disease. We describe the clinical, neuroimaging, and neuropathology findings of five unrelated pediatric patients with de novo heterozygous FTH1 variants. Children presented with developmental delay, epilepsy, and progressive neurologic decline. Nonsense FTH1 variants were identified using whole-exome sequencing, with a recurrent variant (p.Phe171∗) identified in four unrelated individuals. Neuroimaging revealed diffuse volume loss, features of pontocerebellar hypoplasia, and iron accumulation in the basal ganglia. Neuropathology demonstrated widespread ferritin inclusions in the brain. Patient-derived fibroblasts were assayed for ferritin expression, susceptibility to iron accumulation, and oxidative stress. Variant FTH1 mRNA transcripts escape nonsense-mediated decay (NMD), and fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. C-terminal variants in FTH1 truncate ferritin's E helix, altering the 4-fold symmetric pores of the heteropolymer, and likely diminish iron-storage capacity. FTH1 pathogenic variants appear to act by a dominant, toxic gain-of-function mechanism. The data support the conclusion that truncating variants in the last exon of FTH1 cause a disorder in the spectrum of NBIA. Targeted knockdown of mutant FTH1 transcript with antisense oligonucleotides rescues cellular phenotypes and suggests a potential therapeutic strategy for this pediatric neurodegenerative disorder.