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Year : 2022  |  Volume : 9  |  Issue : 1  |  Page : 15-19

Familial chiari malformation

Department of Neurosurgery, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India

Date of Submission12-Dec-2021
Date of Acceptance27-Dec-2021
Date of Web Publication9-Mar-2022

Correspondence Address:
Krishnakumar Kesavapisharady
Professor, Department of Neurosurgery, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram - 695 011, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/joss.joss_32_21

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Chiari malformation type 1 (CM 1) is defined as herniation of cerebellar tonsils 4-5 mm below the foramen magnum. Multiple developmental factors like defective development of pontine flexure and shallow posterior fossa are the proposed factors which predispose the development of this syndrome. These reports on familial occurrence of this syndrome correlates with the embryonal- developmental etiology of Chiari 1 malformation. Recent advances in the understanding of the influence of genes and pathogenesis of familial Chiari malformation are expected to improve management of affected patients and monitoring of at-risk family members.

Keywords: Chiari 1, malformation, monozygotic

How to cite this article:
Kesavapisharady K, Jamaluddin AM, Kamrudeen A, George T, Divakar G. Familial chiari malformation. J Spinal Surg 2022;9:15-9

How to cite this URL:
Kesavapisharady K, Jamaluddin AM, Kamrudeen A, George T, Divakar G. Familial chiari malformation. J Spinal Surg [serial online] 2022 [cited 2022 Aug 11];9:15-9. Available from: http://www.jossworld.org/text.asp?2022/9/1/15/339271

  Introduction Top

Chiari malformation type 1 (CM1) is defined as herniation of cerebellar tonsils 4–5 mm below the foramen magnum. Multiple developmental factors such as defective development of pontine flexure and shallow posterior fossa are the proposed factors which predispose the development of this syndrome. Although long thought to be sporadic, multiple case reports have raised the question whether genetic predisposition is the key culprit in the pathogenesis of CM1. These reports on familial occurrence correlate with the embryonal-developmental etiopathogenesis of CM1. We analyzed the clinical characteristics of CM1 in a family (mother and mono-zygotic twin siblings) and reviewed the literature to elucidate a management strategy for familial CM1 syndrome. CM1 coexisting with other hereditary syndromes were also reviewed, which denotes a strong correlation towards genetic factors which may have a role in the development of CM1.

  Methodology Top

Analysis of the symptomatology, clinical features, and radiological findings was done in three concerned individuals (mother and her monozygotic twins). A coherent literature review was performed for correlation of the clinicoradiological inferences from the index family with that of available details in case reports as well as articles related to genetic predisposition of CM1.

Twin 1: Male, at 17 years of age, presented with cough headache, gait unsteadiness, and horizontal diplopia. On examination, the patient had downbeat as well as gaze nystagmus, esotropia, and posterior column dysfunction. Magnetic resonance (MR) imaging of craniovertebral junction showed tonsillar herniation of 9 mm caudal to foramen magnum. He underwent foramen magnum decompression with duraplasty, and all symptoms improved on serial follow-up.

Twin 2: Male, at 22 years, was referred by a cardiologist in view of suboccipital paresthesia and numbness, noted while under follow-up for atrial septal defect closure. He was otherwise asymptomatic with an unremarkable neurological examination. Tonsillar tip was found 18 mm below foramen magnum with no syringomyelia. Due to the paucity of symptoms pertaining to CM1, he has been on follow-up with no neurological deterioration till date.

Mother: 50-year-old mother of the twins presented with nonspecific headache and paresthesia of both upper limbs in C5, C6, and C7 dermatomal distribution of 6 months duration. Her neurological examination was unremarkable, and magnetic resonance imaging of craniovertebral junction showed peg-shaped tonsillar descent of 16 mm with no syringomyelia. In the absence of adequate clinicoradiological correlation, the patient was kept on closed follow-up for CM1, and her sensory symptoms responded to pharmacological therapy [Figure 1].
Figure 1: (a) Postoperative T2 weighted Magnetic resonance mid-sagittal imaging of the Twin 1 showing decent of tonsil with good space obtained by posterior decompression surgery (b) T2 weighted Magnetic resonance mid-sagittal imaging of the Twin T2 showing descent of tonsils (c) T2 weighted Magnetic resonance mid-sagittal imaging of the mother of the twins

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  Results Top

It was observed that, in the index family, only one of the monozygotic twins was affected by the classical symptomatology and acquired complete relief of symptoms after posterior fossa decompression with no progression of syringomyelia. The mother and sibling did not show the clinical or radiological progression on long-term follow-up (more than 7 years). The modality employed for imaging was MR imaging of craniovertebral junction with flow studies of cerebrospinal fluid across the foramen magnum. Eighteen case reviews were also analyzed with an appropriate keyword search in Pubmed and Scopus [Table 1]. Genetic predisposition to CM1 was proposed considering the high rates of concordance in studies in twins and a general proposition to note a significant proportional risk for the first-degree relatives of symptomatic patients with CM1. The estimated heritability of CM1 in a monozygotic twin is almost 50% in two studies, while some reports indicate a heritability range of 30%–70%. A review of available literature showed that no specific locus has been implicated in the disease process of CM1. Some of the genes under study are PAX1 (Ch20p11.2), FGF2, Noggin (Hox), EFNB1 (Xq12), and TBX6 (Ch16p11.2).
Table 1: Case Reports on familial Chiari malformation Type 1

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Analysis of management options showed that only symptomatic patients with documented neurological deficits or progression during the period of observation required surgery. Surgical option exercised in all symptomatic patients was foramen magnum decompression and duraplasty. The natural history of familial Chiari syndrome is almost similar to sporadic ones, but clinical presentation and severity of symptoms differ among mono-zygotic twins who harbor the malformation.

  Discussion Top

Chiari malformation can be a congenital or acquired condition, in which the cerebellar tonsils protrude through the foramen magnum, and the disorder has traditionally been defined as downward herniation of the tonsils at least 5 mm or more.[1] Developmentally, small posterior fossa is postulated as the pathophysiology of CM1.[2] Syringomyelia is associated in 50%–70% of CM1.[3],[4] Most of CM1 are sporadic in origin. Although rare, few cases of CM1 in close family members and twins have been reported cough induced headache.[5],[6],[7],[8],[9],[10],[11],[12],[13] Analysis of these cases has shown both Mendelian autosomal dominant and autosomal recessive type of inheritance.[6],[7],[9],[13] The usual symptoms at presentation are cough headache, paresthesia, scoliosis, and nystagmus. Classical teaching dictates combined surgical decompression and enlargement of the posterior fossa as the treatment of choice, although patients may require additional treatment for syringomyelia and hydrocephalus.[15] The decision to proceed with surgical intervention often depends on disease severity and/or progression.

Chiari malformations, originally described by Hans Chiari in the late nineteenth century, are regarded as a pathological continuum of hindbrain maldevelopments characterized by downward herniation of the cerebellar tonsils.[14] The pathogenesis of most CM1 is unclear, but it is postulated to be due to small posterior fossa volume. Tubbs et al. had shown that small posterior fossa is not always associated with CM.[14] However, most of the authors uphold the conclusion that CM1 results from small posterior fossa due to underdevelopment of paraxial mesoderm.[17] Normal-sized hindbrain and small posterior fossa causes tonsils to herniate and obstruct CSF flow, resulting in syrinx formation, which ultimately leads to scoliosis and other symptomology.[14],[16]

The diagnosis of CM1 depends on the amount of tonsillar herniation. In a study of around 200 randomly selected subjects, Barkovich et al. found out that the normal mean position of cerebellar tonsils was 1 mm above FM.[17] The criterion for the diagnosis of a Chiari I malformation consists of tonsillar displacement of 5 mm or more below the foramen magnum.[18] Tonsillar herniation between 3 mm and 5 mm is regarded as indeterminate, and its significance must be correlated with the patient's clinical condition.[19],[20] This category may well represent a continuum from benign tonsillar ectopia to Chiari I malformation. Benign tonsillar ectopia was defined at tonsils between 1 and 3 mm below FM.[21],[22] The clinical significance of this degree of tonsillar herniation is uncertain; however, it has been suggested that this may represent a normal anatomical variant or perhaps a rudimentary form of Chiari I malformation. Mikulis and colleagues[19] have stated that a tonsillar position changes with age, i.e., it ascends with age, and using a single reference level for diagnosis is inaccurate. For all practical purposes, the classification scheme based on that of Barkovich et al. is most widely accepted.[17]

Chiari malformation once was thought to be sporadic, but now evidence is accumulating since 1987 through multiple case reports of occurrence of this disorder in twins, siblings, and close family members, raising the question of genetic predisposition. [Table 1] depicts the genetic predisposition of Chiari ranging from autosomal dominant, autosomal recessive, multifactorial, and variable penetrance. There are reports of only syringomyelia (Chiari-0) running in the family. A recent large retrospective series of 500 cases spanning the past 2 decades found the prevalence of familial CM1 to be about 3%, and a past study of 364 patients with Chairi Malformation 1 (CM 1) found that 12% of patients had a close relative with CMI and/or syringomyelia.[19]

The genetic basis for CM1 comes from several lines of evidence due to

  1. Familial aggregation.[5],[11],[21],[22],[23]
  2. Associated with other genetic disorder[4],[11],[12],[24],[25]
  3. Occurrence in monozygotic twins and triplets.[21],[26]

CM1 is most commonly associated with syringomyelia. The frequent association of syringomyelia with known genetic conditions also may support a genetic basis for the syringomyelia such as its association with phakomatoses Neurofibromatosis Type I[7],[27],[28] and spinal deformities.[27],[29],[30] The fact that syringomyelia may be a separate entity with genetic predisposition became questionable after the publication of Speer et al.[21] He found no cases of familial syringomyelia in the absence of CM1 in a population of over 150 families and suggested that previous reports of familial “isolated” syringomyelia could really be a volumetrically small posterior fossa. Milhorat et al. did a pedigree analysis of 21 families and showed transmission pattern was Mendelian inheritance.[24] It varied from autosomal dominant with variable penetrance to autosomal recessive. Mode of inheritance for syringomyelia has also been found to be variable.

Data from twin studies are most consistent for a genetic basis of any disease, but in these cases limited sample size is a confounding factor. Case reports of monozygotic twins or triplets with CM1 are listed in [Table 1]. Despite such strong evidence, literature also has case reports on the contrary. Cavender and Schmidt describe a unique case of monozygotic triplets in which only the first sibling was affected with CM1 and other two had tonsillar descent of 4 mm and 2.5 mm.[10] They proposed an autosomal dominant mode of inheritance with variable penetrance. Speer et al. recently reported three sets of dizygotic twins with CM1 and syringomyelia.[31] The first twins had both CM1 and syringomyelia. The second twin sisters had CM1, but only one had syringomyelia. Moreover, in the third twins, only one had CM1 and syringomyelia and other had neither.

The fact that many inherited syndromes [Table 2] whose associated genes are well elucidated and hypothesized to have pleiotropic effects influencing occipital region maldevelopment, tonsillar herniation across foramen magnum, the occurrence of syringomyelia in the course of disease give more evidence to CM1 occurring in a familial setting and many of these syndromes are seen to occur along with the presence of CM1.[21]
Table 2: Genetically transmitted syndromes seen in association with Chiari 1 malformation

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Focus has now shifted toward the identification of gene involved in the pathogenesis of CM1 as noted in one of the largest studies by Speer et al. where 364 CM1 patients from 150 families are undergoing genomic screening to identify the culprit gene.[21] Despite growing evidence of genetic influences in familial Chiari malformation, the underlying culprit genes have not been fully elucidated. Some of the candidate gene under study are PAX1[31] (Ch 20P11.2), FGF2,[38],[39] Noggin (Hox),[30] EFNB1 (Xq12),[40],[41] and TBX6 (Ch 16p11.2).[32]

  Conclusions Top

Recent advances in the understanding of the influence of genetics and pathogenesis of familial Chiari malformation are expected to improve the management of affected patients as well as the monitoring of at-risk family members. In the presence of neurological symptoms and/or signs pertaining to craniovertebral junction anomalies, siblings and close relatives of patients diagnosed to have CM1 should have a low threshold to undergo screening to exclude the presence of the disorder in them, and if imperative to treat them even though many could seem incidental. On the contrary, any neurological symptom localized to craniovertebral junction is noticed incidentally, should not allure the surgeon to mend them up in the absence of any compelling clinical indication. Genetic studies to screen the same should be reserved until further evidence is available regarding the usefulness of the same.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1]

  [Table 1], [Table 2]


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