Familial aggregation of chiari malformation: presentation, pedigree, and review of the literature

Abstract

ABSTRACTprimary goals of the presentation of this family is to further illuminate the likely mode of genetic inheritance based on the large pedigree that is demonstrated below. █ CASE REpORTThis study is a case report of a patient's family of whom five individuals had a confirmed case of Chiari malformations and a total of eight were symptomatic (including the 5 confirmed). The incidence of Chiari malformations confirmed by CT scans occurred in two consecutive generations. The symptomatic individuals spanned three generations. The family of this child under our care also has a very large incidence of EhlersDanlos syndrome.Of the three daughters (III-7, III-8, and III-9) of the individual (II-3), all were radiographically confirmed cases of Chiari I Malformation (Figure 1). These patients lived in rural communities and thus were diagnosed with CT imaging instead of MRI, due to access and funding. However, in all of the patients the diagnosis was clear on the CT images, and was confirmed with MRI in some. Patient III-8 is the █ INTRODUCTION Chiari Malformation (CM) is typically considered to be the downward herniation of the cerebellar tonsils through the foramen magnum. The basic presentation of symptoms include occipital headaches, balance and coordination issues, and other associated cerebellar signs. This disease process affects both adult and pediatric patient populations, but symptoms vary by age. The presenting symptoms can be quite variable as well. Chiari malformations can be the result of a known etiology or can occur without any known causative factors. The Chiari that occurs from an unknown etiology is likely the result of a genetically determined small posterior fossa volume.There is a growing amount of data in the literature supporting a genetic basis for the Chiari malformation. However, familial aggregation in the literature is limited to twins, triplets, and a few cases of two consecutive generations being affected. While multiple projects are underway in the United States to identify a gene that can be specifically linked to the Chiari Malformation, none has yet elucidated the gene. One of the This article reports the largest familial aggregation of Chiari malformation in a single family to date as reported in the literature. This study is a retrospective case series of a family of whom five individuals have a confirmed case of Chiari malformation and three additional individuals have Chiari signs and symptoms. This contribution further supports the implication of genetics in the transmission of Chiari malformation. The family reported in this study also has a significant incidence of Ehlers-Danlos. Three sisters, including a set of twins, presented with confirmed cases of Chiari malformation and four of the five children of the twin sisters presented with confirmed or suspected Chiari malformation. Of note, the non-twin sister has three children who are unaffected. This report provides further evidence for a shared loci between the Chiari malformation and Ehlers-Danlos.

A combined RNA-seq and whole genome sequencing approach for identification of non-coding pathogenic variants in single families

“…Interestingly, vision phenotypes such as photophobia, vision loss and nystagmus have been reported as accompanying symptoms in some forms of Chiari malformations 57–60 . Unfortunately, despite evidence that Chiari malformations have a hereditable component 61–63 , the genes involved are not yet well defined 59, 64, 65 . For that reason we could not rule out the possibility that the vision phenotypes and Chiari malformations share a common genetic causality.…”

A genetic component in Chiari I malformation: Chiari 1 malformation in all five family members

“…Traditionally, CMI has been attributed to an embryological failure of the mesoderm and neuroectoderm; however, recent studies have attributed the cerebellar tonsil herniation to the inheritance of a small posterior fossa itself [ 12 , 14 ]. In a genetic inheritance sequencing study performed by Musolf et al., there was no phenotype found for CMI itself; however, there were genes linked to reduced posterior fossa volume.…”

“…Cerebellar tonsil herniation also disrupts the flow rate of cerebrospinal fluid through the CMJ. This disturbance in flow is more closely related to the severity of symptoms than the amount of herniation itself [ 3 , 14 , 19 ]. The severity of symptoms for each of the patients in this family supports this finding, as the mother and father, both of whom experienced aberrant CSF flow, experienced the most intense symptoms compared to their 3 sons.…”

Management of Uncommon Secondary Trigeminal neuralgia related to a rare Arnold Chiari type I malformation

“…ACM is classified into four types. [9][10][11] Specifically, type 1 is characterized by herniation of cerebellar tonsils alone, radiologically as simple tonsillar herniation 5mm or greater, below the foramen magnum.…”