Introduction

Arachnoid cysts (ACs) are collections of fluid similar to cerebrospinal fluid within the arachnoid membranes. The detection of asymptomatic ACs has increased with the development of neuroimaging techniques [1]. The most common location for ACs is the middle fossa, although they may occur in any part of the nervous system where arachnoid exists [2, 3]. Headache and epilepsy are reported as the main symptoms in pediatric patients, and vertigo/nausea is the second most common complaint [4]. Computed tomography and magnetic resonance imaging findings are consistent with the density mass of cerebrospinal fluid (CSF), without enhancement [5]. ACs are often found incidentally on radiological examination and can be treated conservatively. However, cyst excision, fenestration, or shunting has been applied in symptomatic cases [6].

ACs are also considered congenital by most authors [3, 7]. Intracranial ACs specifically are most commonly found in the temporal fossa and in male patients, while a left side predominance of ACs in the middle fossa has been reported. These findings have been interpreted as indicating a genetic component in the origin of ACs [3]. Cases of familial ACs also have been reported [8, 9] with the development of genetic testing technology. We therefore prepared this review to summarize new findings related to familial ACs.

Materials and methods

We performed a review of the English literature published before April 2018 by searching the PubMed, Embase, and Web of Science databases. There was no lower date limit. The primary literature search was performed using the following terms: “arachnoid cyst,” “leptomeningeal cyst,” “arachnoid diverticula,” and one of the “twin,” “sibling,” “brother,” “sister,” “father,” “mother,” “family,” “familial,” “gene,” “karyotype,” and “mutation.” We also manually reviewed the reference lists of the articles included in the analysis to identify additional relevant studies. Searches were performed independently by two members of the study team. We included all case reports in English whether involving intracranial or spinal ACs, and duplicate cases were excluded. The report was excluded if the diagnosis of AC was not confirmed by neuroimaging or intraoperatively. For each report included, data including the first author’s name, date of publication, number of families, number of patients, location of ACs, patient age, patient sex, associated gene mutations, and associated diseases were extracted.

Results

A total of 546 articles were identified through database searches, and 170 reports were excluded as duplicates. Upon review of the titles and abstracts, another 322 reports were excluded for not fulfilling the inclusion criteria. Finally, 23 more reports were excluded after review of the full text because they did not report familial ACs. Two reports were added after review of the reference lists of the remaining reports, and thus, a total of 33 reports were included in the present analysis.

Epidemiological features

The 33 included reports were published between 1968 and 2017 and involved 35 families and 115 patients. 32 reports noted the patients’ gender, and among these reports, there were 46 males and 51 females. Only 30 reports provided the patients’ ages, and among these, there were 57 children (< 18 years) and 45 adults (≥ 18 years) (age at onset was analyzed, but if not reported, then age at examination was used). The specific data for each included study are listed in Table 1.

Table 1 Gender and age of patients in each included report
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The locations of the ACs were also extracted for all patients from the 35 families (Table 2). The ACs of patients within the same family were in similar locations (some in the same locations, some on different sides, etc.) for the 25 families. Specifically, 9 families had spinal extradural ACs, 8 families had middle fossa ACs, and another 7 families had posterior fossa ACs. Among all 115 patients, 26 had middle fossa ACs (13 (50%) on the left side, 10 (38%) on both sides, and only 3 (12%) on the right side), 10 had bilateral middle fossa ACs, 13 had left middle fossa ACs, and only 3 had right fossa ACs.

Table 2 Anatomical locations of reported ACs
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Genetics of ACs

The development of gene technology has resulted in the increased application of DNA testing in cases of familial conditions. Ten of the 33 reports provided findings of genetic testing (Table 3). A FOXC2 mutation was reported in two studies for three families with ACs, and all of the ACs in these patients were located in the spine. Some authors reported other syndromes in cases of ACs, but further karyotyping was not performed. The findings along with the location of the ACs are listed in Table 4. Specifically, lymphedema-distichiasis syndrome, glutaric aciduria type-1, autosomal dominant polycystic kidney disease, and oculopharyngeal muscular dystrophy were reported to co-exist with ACs.

Table 3 Genetic mutations reported in association with ACs
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Table 4 Syndromes reported in association with ACs
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It is assumed that formation of an AC somehow is governed by some genetic mechanisms, based on the sidedness and gender preponderances [2, 3, 41]. Aarhus et al. [42] performed a high-resolution mRNA microarray analysis to identify differences in gene expression between the normal arachnoid membrane and the cyst membrane. They only found that 9 of 33,096 genes showed differential expression between the two tissues: ASGR1, DPEP2, SOX9, SHROOM3, A2BP1, ATP10D, TRIML1, NMU, and BEND5. Future genetic studies of patients with familial ACs, even monozygotic twins with ACs, would provide more evidence for the genetic basis of this condition.

Discussion

The arachnoid cyst was first described by Bright in 1829 [43]. Likely, the first report of familial ACs was published in 1967 by Chynn et al. [40] who described congenital spinal extradural cysts in two siblings. The first four reports [37,38,39,40] found in the literature all involved cases of spinal extradural cysts, because modern neuroimaging technology was not yet available. Increasing numbers of familial cases of intracranial ACs have been reported in the last 30 years with the development of computed tomography (CT) and magnetic resonance imaging (MRI), and reports in recent years have begun to reveal relevant gene mutations.

Some authors reported a greater prevalence of ACs in males versus females and a greater prevalence of ACs in the middle fossa versus other locations [1,2,3, 44]. In our review of familial AC cases, we did not find a significant male predilection, and the middle fossa was not the most common location of ACs in this series. The discrepancies between our findings and those of previous studies may be due to several factors. Notably, the numbers of affected patients in different families have varied considerably, with Orlacchio et al. [9] reporting a family in which 18 members had ACs located at the cerebellopontine angle compared to fewer than five affected patients in most families described in other reports. At the same time, in almost 76% of families, ACs were located at similar sites among family members. After reviewing the families for which this was true, we found that spinal extradural cysts have been reported most, followed by ACs in the middle fossa and posterior fossa. A left-sided predominance in ACs of the middle fossa was also noticed, which was consistent with previous studies [1,2,3, 45].

Only 10 of the 33 included reports (11 of 35 families) clearly identified an associated genetic mutation. Notably, a FOXC2 mutation was reported twice in three families, although the authors of one study reported the mutation as a nonsense mutation [18] while the others reported a heterozygous FOXC2 loss-of-function mutation [14]. Also, lymphedema-distichiasis syndrome was believed to be associated with ACs in two reports [22, 37], and this syndrome is associated with the mutation of FOXC2 [18]. The FOXC2 gene is located at 16q24.1 and belongs to the forkhead family of transcription factors, which is characterized by a distinct DNA-binding forkhead domain. The specific function of the FOXC2 protein has yet to be determined, although several studies have shown that it may play a role in the development of mesenchymal tissues [46]. Arriola et al. [23] reported two brothers with intracranial ACs, for which karyotyping revealed a deletion in the pericentromeric heterochromatic region of the long arm of chromosome 16 (16qh-) in both brothers. Alehan et al. [26] reported cases of a father and daughter who each had a posterior fossa AC and asymptomatic autosomal dominant polycystic kidney disease (ADPKD), but they did not clearly determine the type of ADPKD. However, mutations in PKD1 can cause ADPKD type 1, and the PKD1 gene is located on chromosome 16 [47, 48]. Together, these findings indicate that we should pay attention to mutations of chromosome 16 in cases of ACs in the future. Koenigstein et al. [13] reported a pair of twins with a novel homozygous mutation in the GPSM2 gene. Both the girl and boy had an interhemispheric AC, but the patients were dizygotic twins. Mirror-image ACs in a pair of monozygotic twins were reported by Helland and Wester [21] and Zhou et al. [17], but unfortunately, karyotyping was not performed.

Conclusion

Although the exact gene(s) responsible for familial cases of ACs remain unclear at present, the continued development and use of neuroimaging and new genetic testing techniques will provide further insight into the mechanisms underlying this condition.