Tag: Genetics

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Familial Chiari malformation: a systematic review and illustrative cases

J Neurosurg Spine 41:105–114, 2024

Chiari malformations (CMs) are a group of congenital or acquired disorders characterized by hindbrain overcrowding into an underdeveloped posterior cranial fossa. CM is considered largely sporadic—however, there exists growing evidence of transmissible genetic underpinnings. The purpose of this systematic review of all familial studies of CM was to investigate the existence of an inherited component and provide recommendations to manage and monitor at-risk family members.

METHODS This paper includes the following: 1) a unique case report of dizygotic twins who presented at the Toronto Western Hospital Spinal Cord Clinic with symptomatic CM type 1 (CM-1) and syringomyelia; and 2) a systematic review of familial CM. The EMBASE and MEDLINE databases were searched on June 27, 2023, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Only articles in the English language concerning the diagnosis of CM in > 1 human family member presented as a case study, case series, or literature review were included.

RESULTS Among the 29 articles included in the final analysis, a total of 34 families with CM were analyzed. An average of 3 cases of CM were found per family among all generations. Eighty-one cases (88%) reported CM-1, whereas the other 11 (12%) cases reported either CM-0, CM-1.5, or tonsillar ectopia. A syrinx was present in 37 (54%) cases, with 14 (38%) of these patients also reporting a skeletal abnormality, the most common comorbidity. Most family members diagnosed with CM were siblings (18; 35%), followed by monozygotic twins/triplets (12; 23%).

CONCLUSIONS Patients most often presented with headaches, sensory disturbances, or generalized symptoms. Overall, there exists mounting evidence for a hereditary component of CM. It is unlikely to be explained by a classic mendelian inheritance pattern, but is rather a polygenic architecture influenced by variable penetrance, cosegregation, and entirely nongenetic factors. For first-degree relatives of those affected by CM, the authors’ findings may influence clinicians to conduct closer clinical and radiographic monitoring, promote patient education, and consider earlier genetic testing.

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Prospective validation of a molecular prognostication panel for clival chordoma

J Neurosurg 130:1528–1537, 2019

There are currently no reliable means to predict the wide variability in behavior of clival chordoma so as to guide clinical decision-making and patient education. Furthermore, there is no method of predicting a tumor’s response to radiation therapy.

METHODS A molecular prognostication panel, consisting of fluorescence in situ hybridization (FISH) of the chromosomal loci 1p36 and 9p21, as well as immunohistochemistry for Ki-67, was prospectively evaluated in 105 clival chordoma samples from November 2007 to April 2016. The results were correlated with overall progression-free survival after surgery (PFSS), as well as progression-free survival after radiotherapy (PFSR).

RESULTS Although Ki-67 and the percentages of tumor cells with 1q25 hyperploidy, 1p36 deletions, and homozygous 9p21 deletions were all found to be predictive of PFSS and PFSR in univariate analyses, only 1p36 deletions and homozygous 9p21 deletions were shown to be independently predictive in a multivariate analysis. Using a prognostication calculator formulated by a separate multivariate Cox model, two 1p36 deletion strata (0%–15% and > 15% deleted tumor cells) and three 9p21 homozygous deletion strata (0%–3%, 4%–24%, and ≥ 25% deleted tumor cells) accounted for a range of cumulative hazard ratios of 1 to 56.1 for PFSS and 1 to 75.6 for PFSR.

CONCLUSIONS Homozygous 9p21 deletions and 1p36 deletions are independent prognostic factors in clival chordoma and can account for a wide spectrum of overall PFSS and PFSR. This panel can be used to guide management after resection of clival chordomas.

 

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Is there an inherited anatomical conformation favoring aneurysmal formation of the anterior communicating artery?

J Neurosurg 126:1598–1605, 2017

The pathophysiological mechanisms responsible for the formation of intracranial aneurysms (IAs) remain only partially elucidated. However, current evidence suggests a genetic component. The purpose of this study was to investigate the specific anatomical variations in the arterial complex that are associated with the presence of anterior communicating artery (ACoA) aneurysms in the familial forms of IAs.

METHODS This multicenter study investigated bifurcation IAs in patients who had a sporadic ACoA IA without a family history of IA (SACAA group), in patients who had an ACoA IA with a family history of IA (FACAA group), and in their healthy first-degree relatives (HFDRs). Through the use of MR angiography (MRA) reconstructions, the symmetry of the A1 segments and the angle between the A1 and A2 segments were analyzed on 3D models for each group. These measurements were then compared among the 3 groups.

RESULTS Twenty-four patients with SACAA, 24 patients with FACAA, and 20 HFDRs were included in the study. Asymmetrical configuration of the A1 segments was more frequent in the FACAA group than in the HFDR group (p = 0.002). The aneurysm-side A1-A2 angle was lower in the FACAA group (p = 0.003) and SACAA group (p = 0.007) than in the HFDR group. On the contralateral side, there was no difference in A1-A2 angles between groups.

CONCLUSIONS The anatomical shape of the ACoA complex seems to be similarly associated with the presence of ACoA IAs in both the FACAA and SACAA groups. This highlights the role played by hemodynamic constraints in aneurysm formation and questions the hypothesis of the hereditary character of these anatomical shapes.

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Pathophysiology of Intracranial Aneurysm: The ICAN Project

Neurosurgery 80:621–626, 2017

Understanding the pathophysiologic mechanism of intracranial aneurysm
 (IA) formation is a prerequisite to assess the potential risk of rupture. Nowadays, there are neither reliable biomarkers nor diagnostic tools to predict the formation or the evolution of IA. Increasing evidence suggests a genetic component of IA but genetics studies have failed to identify genetic variation causally related to IA.

OBJECTIVE: To develop diagnostic and predictive tools for the risk of IA formation and rupture.

METHODS: The French ICAN project is a noninterventional nationwide and multicentric research program. Each typical IA of bifurcation will be included. For familial forms, further IA screening will be applied among first-degree relatives. By accurate phenotype description with high-throughput genetic screening, we aim to identify new genes involved in IA. These potential genetic markers will be tested in large groups of patients. Any relevant pathway identified will be further explored in a large cohort of sporadic carriers of IA, which will be well documented with clinical, biological, and imaging data.

EXPECTED OUTCOMES: Discovering genetic risk factors, better understanding the pathophysiology, and identifying molecular mechanisms responsible for IA formation will be essential bases for the development of biomarkers and identification of therapeutic targets.

DISCUSSION: Our protocol has many assets. A nationwide recruitment allows for the inclusion of large pedigrees with familial forms of IA. It will combine accurate phenotyping and comprehensive imaging with high-throughput genetic screening. Last, it will enable exploiting metadata to explore new pathophysiological pathways of interest by crossing clinical, genetic, biological, and imaging information.

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