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. 2022 Jul 18;33(6):3012–3025. doi: 10.1093/cercor/bhac257

Familial and syndromic forms of arachnoid cyst implicate genetic factors in disease pathogenesis

Hanya M Qureshi 1,#, Kedous Y Mekbib 2,3,#, Garrett Allington 4,5,#, Aladine A Elsamadicy 6, Phan Q Duy 7, Adam J Kundishora 8, Sheng Chih Jin 9, Kristopher T Kahle 10,11,12,13,14,15,✉
PMCID: PMC10388392  PMID: 35851401

Abstract

Arachnoid cysts (ACs) are the most common space-occupying lesions in the human brain and present significant challenges for clinical management. While most cases of ACs are sporadic, nearly 40 familial forms have been reported. Moreover, ACs are seen with increased frequency in multiple Mendelian syndromes, including Chudley–McCullough syndrome, acrocallosal syndrome, and autosomal recessive primary ciliary dyskinesia. These findings suggest that genetic factors contribute to AC pathogenesis. However, traditional linkage and segregation approaches have been limited in their ability to identify causative genes for ACs because the disease is genetically heterogeneous and often presents asymptomatically and sporadically. Here, we comprehensively review theories of AC pathogenesis, the genetic evidence for AC formation, and discuss a different approach to AC genomics that could help elucidate this perplexing lesion and shed light on the associated neurodevelopmental phenotypes seen in a significant subset of these patients.

Keywords: arachnoid cyst, genomics, whole-exome sequencing, multiomics, neurodevelopmental disorders

Introduction

Arachnoid cysts (ACs) refer to collections of cerebrospinal fluid (CSF) in the central nervous system covered by thin membranes contiguous with normal surrounding arachnoid characterized by hyperplastic arachnoid cells, increased collagen, and a lack of normal spider-like trabeculations (Rengachary et al. 1978; Schievink et al. 1995; Hall et al. 2019). Historically thought to account for approximately 1% of all intracranial mass lesions, (Robinson 1971) with the advent and widespread use of advanced neuroimaging, intracranial arachnoid cysts (IACs) are being noted at higher rates across various age groups (Banna 1976; Katzman et al. 1999; Kim et al. 2002; Eskandary et al. 2005; Weber and Knopf 2006; Vernooij et al. 2007; Al-Holou et al. 2010; Al-Holou et al. 2013) than autopsy studies previously suggested (Pradilla and Jallo 2007). In a review of over 60,000 pediatric and adult brain magnetic resonance imaging (MRI) scans, IACs were present in 1.4% (Al-Holou et al. 2013) and 2.6% (Al-Holou et al. 2010) of the adult and pediatric population, respectively.

Spinal ACs include both extradural and intradural cysts. Spinal extradural cysts (SEDACs) are cysts of the arachnoid layer that protrude into the epidural space of the spinal cord. Studies suggest that SEDACs are slightly rarer than their intracerebral counterparts, representing 1% of all primary spinal masses, and most often occur in the posterior thoracic spine, rarely with progressive symptoms due to spinal cord compression (Ogura et al. 2013). Spinal intradural arachnoid cysts (SIDACs) are even rarer and most often present in the cervical or thoracic spine (Wang et al. 2003).

Despite being a relatively common finding in the general population, AC pathogenesis remains poorly understood. While some IACs were thought to be secondary to gestational ischemic, traumatic, or infectious insults (Jafrani et al. 2019), most are considered primary or sporadic in origin. One prominent theory suggests that IACs may result from the congenital splitting of the arachnoid mater before the fetal neurocranium fully develops (Rengachary and Watanabe 1981), resulting in subsequent CSF entrapment. Incomplete merging of arachnoid layers during fetal Sylvian fissure development could also explain the prevalence of ACs in the middle temporal fossa (Wester 1999). More controversial are IAC theories of expansion, which include (i) active cyst wall secretion of fluid (Go et al. 1984; Helland et al. 2010; Berle et al. 2013), (ii) osmotic gradient diffusion of fluid into cyst (Sandberg et al. 2005), and (iii) CSF flow through one-way slit-valve (Santamarta et al. 1995; Halani et al. 2013). Support for these theories, particularly the active cyst wall fluid secretion theory, stems from a combination of ultracytochemistry, western blot, mRNA microarray expression, and quantitative proteomic studies (Go et al. 1984; Helland et al. 2010; Berle et al. 2013).

ACs are often incidentally diagnosed during neuroimaging after head trauma or unrelated headache, hence termed “incidentalomas” in these otherwise healthy patients (Jafrani et al. 2019). Similar to dermoid and epidermoid cysts, IACs are well-circumscribed, extra-axial, simple cystic lesions that appear isodense to CSF on computerized tomography and isointense to CSF on all MRI sequences, without exhibiting diffusion restriction (Jafrani et al. 2019). They are often located in the temporal fossa and can be classified according to 1 of 3 Galassi types (Aarhus et al. 2010).

While significant controversy exists regarding the role of neuropsychiatric symptoms in AC management, classically, ACs are typically considered symptomatic if patients present with various nonspecific symptoms such as headache, seizure, visual disturbance, or other neurologic deficits attributable to hydrocephalus or mass effect caused by the AC (Mustansir et al. 2018). Though most patients are asymptomatic, 5%–12% are not, with 4%–7% requiring neurosurgical intervention (Al-Holou et al. 2010; Al-Holou et al. 2013; Hall et al. 2019). Symptomatic patients most often present with headaches (31%), nausea/vomiting (21.7%), cranial nerve dysfunction (21.7%), and macrocephaly (15%) (Hall et al. 2019). Some recent studies have suggested that many incidental IACs may cause clinically relevant symptoms such as cognitive impairment and psychiatric disorders, which may be alleviated with neurosurgical intervention (Wester 1999; Agopian-Dahlenmark et al. 2020; Sandvik et al. 2020). Secondary or acquired, ACs have also been reported after head trauma or intraventricular hemorrhage of prematurity (Hall et al. 2019).

Current treatment options for IACs include endoscopic versus open cyst fenestration, cyst shunting, cyst wall resection, and medical management with acetazolamide (Gangemi et al. 2011; Jafrani et al. 2019; Ichinose et al. 2020). Although all these approaches are used, other factors such as the risk of shunt infection, risk of fenestration-refractory cysts, cyst location, cyst shape, risk of damage to adjacent structures, and surgeon experience must be considered (Kandenwein et al. 2004; Duz et al. 2012; Huang et al. 2015). The current treatment of choice for symptomatic patients with spinal ACs is complete cyst resection (Fam et al. 2018). However, many AC patients experience refractory symptoms following AC removal, (Tan et al. 2015), suggesting not all symptomatic ACs should undergo surgical intervention. Consequently, some studies propose using additional metrics, like cyst size and location to determine the best treatment strategy (Galassi et al. 1981; Kandenwein et al. 2004; Huang et al. 2015).

This review provides the first comprehensive report on the known genetic alterations associated with AC. Further understanding of this relationship is not only critical to understanding the molecular mechanisms underlying AC but also lends itself to improved clinical care and outcomes for AC patients.

Clinical significance

Most AC patients are considered asymptomatic, with only 5%–12% of AC patients being considered symptomatic (Al-Holou et al. 2010; Al-Holou et al. 2013; Hall et al. 2019). As most large cohort studies evaluating AC symptoms are retrospective reviews limited to patients who have already undergone neuroimaging, they likely select for symptomatic AC patients, suggesting the true rate of asymptomatic ACs may actually be even higher. Symptomatic ACs have been largely defined by the presence of AC triggering clinical symptoms with clear and actionable neurosurgical interventions, including obstructive hydrocephalus, increased intracranial pressure, or focal neurologic deficits (Tan et al. 2015; Jafrani et al. 2019). However, various neurodevelopmental phenotypes, such as autism (Zeegers et al. 2006), developmental delay (Wilson et al. 1987; Wisniewska et al. 2012; Schoch et al. 2017; Sleven et al. 2017; Wang et al. 2018), seizures (Guzel et al. 2007; Huang et al. 2015), and psychiatric disorders (Wong et al. 1993; Bahk et al. 2002; da Silva et al. 2007; Mironov et al. 2014; Khan and Ahmed 2017; Gjerde et al. 2019), are also common findings in AC patients.

In a review of 488 IAC pediatric cases, 8.1% presented with new onset epilepsy (Huang et al. 2015). IACs presenting with epilepsy were more likely to be localized to the temporal lobe middle cranial fossa, with studies reporting a significantly higher proportion of ACs in patients with focal epilepsy than in healthy controls (Mazurkiewicz-Bełdzińska and Dilling-Ostrowska 2002; Recio et al. 2007; Nikolić et al. 2017). Nearly 86% of patients with chronic pharmacoresistant epileptic seizure disorders are found to have some structural lesion in the imaging (Wolf et al. 1993), suggesting ACs can often cause focal neurologic disruption resulting in seizures, particularly in the temporal lobe. Although many studies have found higher rates of epilepsy among AC patients (Morioka et al. 2003; Betting et al. 2006; Jiménez-Genchi et al. 2007; Rabiei et al. 2016), one study did not (Rabiei et al. 2016). This may have been because unlike the other studies, Rabiei et al. was a cross-sectional study of a non-hospital-based population that all underwent new neuroimaging. While this may have protected against selection bias for more symptomatic patients, this approach also likely resulted in an extremely small cohort of symptomatic AC patients. Therefore, the ability of this study to evaluate rare phenotypes like epilepsy is limited (Rabiei et al. 2016). In fact, multiple case reports have already found instances of epilepsy in AC patients that improved with pharmacologic management, suggesting that AC removal should only be considered in pharmacoresistant epilepsy patients (Morioka et al. 2003; Betting et al. 2006; Jiménez-Genchi et al. 2007; Rabiei et al. 2016; Orduna Martínez et al. 2021).

More recent studies have found an association between IACs and increased depression/anxiety symptoms in both pediatric and adult patients alike (Park et al. 2009; Gjerde et al. 2019). Men, in particular, may face a higher prevalence of IAC-related anxiety and a greater reduction in quality of life than women. In fact, one study found that middle fossa IACs in adult males had significant associations with depression, attention deficit, paranoia, schizophrenia, and schizotypal personality disorder (Lee et al. 2019). Increased cyst size also positively correlated with increased psychopathology (Lee et al. 2019). Multiple studies indicate IAC removal or electroconvulsive therapy can result in complete resolution of depressive or anxiety symptoms (Desseilles et al. 2009; Boomkens et al. 2010; Grover et al. 2013; Shettar et al. 2018). Several case reports also describe IAC removal correlating with improvement or resolution of acute onset psychiatric symptoms, including psychosis (Wong et al. 1993; Bahk et al. 2002; da Silva et al. 2007; Mironov et al. 2014; Khan and Ahmed 2017), schizophreniform-like behavior (Kuhnley et al. 1981; Krzyzowski et al. 1998), dyscognition (Torgersen et al. 2010), personality disorders (Bechter et al. 2010; Torgersen et al. 2010), and other psychiatric symptoms (Geniş and Coşar 2020). However, most of these studies were individual case reports. Whether AC removal actually improves psychiatric symptoms among AC patients with comorbid psychiatric conditions remains unclear.

Separately, several studies have found an association between temporal and Sylvian fissure IACs and cognitive impairment (Gjerde et al. 2013; Sandvik et al. 2020). One radiological study examining children with severe intellectual disability reported ACs in 3.1% of the participants (Lingam et al. 1982). A later study by Zeegers et al. (2006) on children with autism and developmental delays reported that 49% had abnormalities on MRI, 8% of which were attributable to IACs. Still, this correlational study had a small sample size and only included children seen very early in life for the developmental delay, thereby potentially selecting only for those patients with more severe developmental disorders. While this study did not investigate the nature of this relationship, it nonetheless suggests that ACs are associated with severe neurodevelopmental disorders. Several case reports have also reported cognitive impairment and intellectual disability in AC patients alongside a host of other clinical symptoms and comorbidities (Gjerde et al. 2013; Kwiatkowska et al. 2020; Sandvik et al. 2020).

Although multiple studies have found that cognitive functioning as measured by various neuropsychological tests improved in symptomatic patients who underwent AC surgery for another classical symptom (Raeder et al. 2005; Helland and Wester 2006, 2007a; Agopian-Dahlenmark et al. 2020), all these patients had other indications for AC surgery related to mass effect or increased intracranial pressure, which may have also contributed to the observed cognitive dysfunction. It is still unclear whether AC patients with cognitive dysfunction but no other signs of mass effect or pressure would also improve with neurosurgical intervention. In some patients, these neurodevelopmental phenotypes may not be a direct consequence of the AC but may represent just one clinical manifestation of a deeper neurological pathology. Human genetic research may provide a greater understanding of the underlying pathogenic mechanism and inform surgical decision-making.

In summary, ACs present with a highly heterogeneous and complex clinical presentation. Our historically poor understanding of AC pathogenesis has significantly impaired our clinical management. Our systematic review below describes the current literature on AC genetics and our understandings of its molecular mechanisms.

Evidence for a genetic contribution to AC pathogenesis

The molecular genetics underlying AC formation remains poorly understood because most cases are sporadic, limiting traditional linkage and segregation approaches. Incomplete penetrance and variable expressivity in many AC candidate genes pose another significant barrier to understanding the true genetic etiology underlying AC pathogenesis. Moreover, ACs can be clinically silent, meaning many affected individuals may be unaware they have AC, in turn masking familial forms. Although some genetic variants have been reported in AC patients, most have come from smaller familial case reports (Table 1). Strong evidence exists for a genetic contribution to AC pathogenesis from multiplex families, twin studies, and various Mendelian syndromes associated with AC (Handa et al. 1981; Wilson et al. 1987; Pomeranz et al. 1991; Helland and Wester 2007b). However, to date, there are no sizeable, well-phenotyped genome-wide association studies (GWAS) or whole-exome/genome sequencing studies that aim to uncover disease-associated common and rare variants for nonsyndromic AC in a systematic, unbiased manner. Further, efforts to isolate severe AC-risk genes are complicated by frequent coetaneous symptoms of neurodevelopmental delay, seizures, and hypotonia. Based on our systematic review, we report nearly 40 separate case reports of familial cases of AC along with their associated mutations (Table 1). We also report studies and case reports that noted increased AC prevalence within syndromes or associated AC with specific syndromes, respectively (Table 2). Our review of syndromic and familial AC found that genes involved in microtubule dynamics, transcription regulation, and various signaling pathways during early brain development contributed to AC pathogenesis and may also contribute to sporadic AC.

Table 1.

Pedigrees with multiple affected family members in which ACs are the predominant phenotype.

Authors and year Location of ACs (patients [n/N]) Directly reported or associated syndromes (OMIM) Reported gene/loci
Bilguvar et al. (2009) Left middle fossa (2/3); posterior fossa (1/3) 11p15
Arriola et al. (2005) Posterior fossa (2/3); temporal (1/3) 16qh
Bayrakli et al. (2012) Posterior fossa (3/6); left middle fossa (2/6); convexity (1/6) 6q22.31-23.2
Değerliyurt et al. (2012) Left middle fossa (1/3) Tortuosity of retinal arteries (180000); hereditary angiopathy, with neuropathy, aneurysms, and muscle cramps (611773); brain small vessel disease w or wo ocular anomalies (175780); microangiopathy and leukoencephalopathy, pontine (AD) (618564); susceptibility to intracerebral hemorrhage (614519) COL4A1
Ogura et al. (2013) Spinal (7/7) AD Lymphedema–distichiasis syndrome (153400) FOXC2
Ogura et al. (2018) Spinal (11/11) AD Lymphedema–distichiasis syndrome (153400) FOXC2
Sánchez-Carpintero et al. (2010) Spinal (7/7) AD Lymphedema–distichiasis syndrome (153400) FOXC2
Schwartz et al. (1980) Spinal (2/2) AD Lymphedema–distichiasis syndrome (153400) FOXC2
Yabuki et al. (2007) Spinal (7/7) AD Lymphedema–distichiasis syndrome (153400) FOXC2
Kurt et al. (2016) Posterior fossa (1/2); left middle fossa (1/2) Friedreich ataxia, Friedreich ataxia with retained reflexes (229300) FXN
Jamjoom et al. (1995) Bilateral middle fossae (2/2) AR Glutaric aciduria type-1 (231670) GCDH
Martínez-Lage et al. (1994) Bilateral middle fossae (2/2) AR Glutaric aciduria type-1 (231670) GCDH
Zhang et al. (2017) Bilateral temporal lobe (1/1) AR Glutaric aciduria type-1 (231670) GCDH
Doherty et al. (2012) Intracranial (8/8) AR Chudley–McCullough syndrome (604213) GPSM2
Koenigstein et al. (2016) Interhemispheric (1/2); interhemispheric and right CPA angle (1/2) AR Chudley–McCullough syndrome (604213) GPSM2
McNiven et al. (2019) Intracranial (2/2) AD Dandy-Walker malformation and occipital cephalocele (609222) NID1
Bogliş et al. (2020) Intracranial (2/2) XLR intellectual disability (300486) OPHN1
Jadeja et al. (2003) Left middle fossa (2/2) AD oculopharyngeal muscular dystrophy (164300) PAPB2
Alehan et al. (2002) Posterior fossa (2/2) AD polycystic kidney disease (173900) PKD1
Wang et al. (2018) Intracranial (2/2) Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (616975) RERE
Orlacchio et al. (2004) Cerebellopontine angle (16/16) AD Spastic paraplegia type 4 (182601) SPG4
Furey et al. (2017) Bilateral middle fossae (2/2) Xp22.2
Hendriks et al. (1999) Between lateral ventricles (1/2); quadrigeminal cistern (1/2) Bilateral sensorineural deafness, partial agenesis of corpus callosum
Tolmie et al. (1997) Left middle fossa (2/2) Cerebral dysplasia, mild mental handicap
Cuny et al. (2017) Posterior fossa (2/2) Cognitive and visual-motor impairments
Bergland et al. (1968) Spinal (3/3) Distichiasis
Ferlini et al. (1995) Posterior fossa (4/4) Hydrocephalus, skeletal anomalies, mental disturbances
Suzuki et al. (2002) Posterior fossa (2/2) Mental retardation, undescended testis
Wilson et al. (1987) Posterior left hemisphere (2/2) Microcephaly, developmental delay
Guzel et al. (2007) Left middle fossa (1/3); left frontotemporal, right temporal, and posterior fossae (1/3), both middle cranial fossae and posterior fossae (1/3) Pachygyria, mental retardation, seizure
Aarabi et al. (1979) Spinal (2/2)
Aiba et al. (1995) Right middle fossae (2/3)
Chynn et al. (1967) Spinal (2/2)
Handa et al. (1981) Bilateral middle fossae (2/2)
Helland et al. (2007, 2007b) Left cerebellopontine angle (1/2); right cerebellopontine angle (1/2)
Menezes et al. (2017) Spinal (2/2)
Pomeranz et al. (1991) Bilateral temporoparietal convexity (1/3); Left hemispheric cerebral cyst (1/3); ambient cistern (1/3)
Sinha et al. (2004) Posterior fossa (2/2)
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Table 2.

Mendelian syndromes with increased frequency of ACs.

Authors and year Location Directly reported or associated syndromes (OMIM) OMIM associated gene/loci
Thyen et al. (1992) Intracranial Acrocallosal syndrome (200990) KIF7
McNiven et al. (2019) Intracranial AD Dandy–Walker malformation and occipital cephalocele (609222) NID1
Ogura et al. (2013) Spinal AD lymphedema–distichiasis syndrome (153400) FOXC2
Ogura et al. (2015) Spinal AD lymphedema–distichiasis syndrome (153400) FOXC2
Ogura et al. (2018) Spinal AD lymphedema–distichiasis syndrome (153400) FOXC2
Sánchez-Carpintero et al. (2010) Spinal AD lymphedema–distichiasis syndrome (153400) FOXC2
Schwartz et al. (1980) Spinal AD lymphedema–distichiasis syndrome (153400) FOXC2
Yabuki et al. (2007) Spinal AD lymphedema–distichiasis syndrome (153400) FOXC2
Di Lazzaro et al. (2007) Spinal Marfan syndrome (154700) FBN1
Hoshino et al. (2005) Spinal Marfan syndrome (154700) FBN1
Rousseaux et al. (1983) Spinal Neurofibromatosis type 1 (162200) NF1
Shehu and Hassan (2009) Spinal Neurofibromatosis type 1 (162200) NF1
Jadeja et al. (2003) Intracranial AD oculopharyngeal muscular dystrophy (164300) PAPB2
Alehan et al. (2002) Intracranial AD polycystic kidney disease (173900) PKD1
Schievink et al. (1995) Intracranial AD polycystic kidney disease (173900) PKD1
Orlacchio et al. (2004) Intracranial AD spastic paraplegia type 4 (182601) SPG4
Boronat et al. (2014), Boronat and Barber (2018) Intracranial AD Tuberous sclerosis complex (191100, 613254) TSC1, TSC2
Aicardi (2005) Intracranial Aicardi syndrome (304050) Xp22
Blauen et al. (2021) Intracranial AR Chudley–McCullough syndrome (604213) GPSM2
Doherty et al. (2012) Intracranial AR Chudley–McCullough syndrome (604213) GPSM2
Koenigstein et al. (2016) Intracranial AR Chudley–McCullough syndrome (604213) GPSM2
Robson et al. (2020) Intracranial AR ciliary dyskinesia, primary, 42 (618695) MCIDAS
Jamjoom et al. (1995) Intracranial AR glutaric aciduria type-1 (231670) GCDH
Martínez-Lage et al. (1994) Intracranial AR glutaric aciduria type-1 (231670) GCDH
Zhang et al. (2017) Intracranial AR glutaric aciduria type-1 (231670) GCDH
Zeegers et al. (2006) Intracranial Autism developmental delay disorders
Gripp et al. (2016) Intracranial Coffin–Siris syndrome 1 (135900) ARID1B
Kosho et al. (2013) Intracranial Coffin–Siris syndrome 2 (614607) ARID1A
Shang et al. (2015) Intracranial Coffin–Siris syndrome 6 (617808) ARID2
Pearlson et al. (1998) Intracranial Down syndrome (190685) 21q22.3
Kurt et al. (2016) Intracranial Friedreich ataxia, Friedreich ataxia with retained reflexes (229300) FXN
Sleven et al. (2017) Intracranial Hypotonia, ataxia, and delayed development syndrome (617330) EBF3
Takenouchi et al. (2019) Intracranial Kosaki overgrowth syndrome (616592), basal ganglia calcification, idiopathic, 4 (615007) PDGFRB
Lee et al. (1993) Intracranial Mucopolysaccharidosis (IH-607014, II-309900, IIIA-252900) IH-IDUA, II-DS, IIIA-SGSH
Petitti et al. (1997) Intracranial Mucopolysaccharidosis IIIB (252920) NAGLU
Schoch et al. (2017) Intracranial Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination (610672) NACC1
Wang et al. (2018) Intracranial Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (616975) RERE
Winczewska-Wiktor et al. (2016) Intracranial Neurodevelopmental disorder with spastic diplegia and visual defects (615075) CTNNB1
Wadsby et al. (1989) Intracranial Neurofibromatosis (162200, 101000) NF1, NF2
Gripp et al. (2016) Intracranial Noonan syndrome-like disorder with loose anagen hair 2 (617506) PPP1CB
Hung et al. (2018) Intracranial Schizencephaly (269160) SIX3, SHH, EMX2
Sener et al. (1997) Intracranial Schizencephaly (269160) SIX3, SHH, EMX2
Yang and Yang (2020) Intracranial Zhu–Tokita–Takenouchi–Kim syndrome (617140) SON
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Pedigrees with multiple affected family members in which ACs are the predominant phenotype

Although some cases of sporadic AC have been described in the literature, most existing reports focus on familial cases with or without comorbidity. Orlacchio et al. reported one of the first large, familial IAC cases, noting that 16 of 36 members of an Italian family presented with cerebellopontine angle ACs and a variant form of autosomal dominant hereditary spastic paraplegia (HSP). Brain MRI exclusively found uncomplicated ACs with no focal neurologic deficits. However, 37.5% (6/16) had intellectual disability and 12.5% (2/16) had significant dementia. Another 18.75% (3/16) had epilepsy, urinary issues, or sudden bilateral hearing loss. Targeted sequencing revealed a novel missense mutation, p.T614I, in exon 17 of SPG4 in all affected family members. Mutations in SPG4 (spastin) have been linked with autosomal dominant HSP and are suspected of causing focal cortical dysgenesis and neurodegeneration of motor neurons in the corticospinal tract (Errico et al. 2002; Orlacchio et al. 2004). Spastin is an AAA protein involved in microtubule dynamics. Consequently, Orlacchio et al. questioned whether this was the pathologic mechanism for their mutation and suggested a locus for autosomal dominant AC may neighbor the SPG4 locus.

Furey et al. (2017) reported the only known case of familial IAC with an X-linked inheritance pattern. Like Orlacchio et al., they found altered expression in microtubule-associated protein. However, they also noted differential expression in several other proteins. The study presents a case of familial isolated IAC in 4 family members across 2 generations, all of whom presented with large, bilateral, symmetric middle fossa cysts with no other symptoms or disorders. Array comparative genomic hybridization analysis was performed and found a maternally inherited 720-kb duplication of Xp22.2 that segregated with the disease status was not present in unaffected family members. This mutation, in turn, caused duplications in HCCS and AMELX and interruptions likely indicative of loss of function in MID1 and ARHGAP6 (Furey et al. 2017). HCCS encodes holocytochrome c-type synthase, a crucial component of the mitochondrial respiratory chain (Indrieri et al. 2013); AMELX encodes amelogenin, a component of enamel (Gibson et al. 2001); MID1 encodes midin, a microtubule-associated protein that influences microtubule dynamics in cell growth and development (Aranda-Orgillés et al. 2008); and ARHGAP6 is a Rho GTPase-activating protein that also promotes actin remodeling (Schaefer et al. 1997). Deletions or loss-of-function mutations in MID1 have already been shown to cause type 1 Optiz/BBB syndrome, which presents with ocular hypertelorism, something that interestingly affected all 4 patients in this study. A larger 9-Mb duplication of Xp22.2 has also been reported in a family presenting with developmental delay, intellectual disability, and hypotonia but without AC (Furey et al. 2017).

Regarding familial reports of SEDAC, one of the largest cases was reported by Yabuki et al. (2007), who discovered 10 family members across 2 generations presenting with lymphedema–distichiasis syndrome. Lymphedema–distichiasis syndrome (Schoch et al. 2017) (OMIM no. 153400) is a rare familial syndrome usually characterized by lower limb lymphedema and supernumerary eyelashes (Sánchez-Carpintero et al. 2010). In this case, 7 of the 10 LDS-affected family members also had SEDACs. Although molecular analyses were not performed, given that LDS has been associated with FOXC2 mutations, Yabuki et al. suspected that a mutation in FOXC2 caused the LDS and associated SEDACs.

Three years later, Sánchez-Carpintero et al. (2010) would support this suspicion in their report describing 12 family members over 3 generations with LDS, 7 of whom also had SEDACs. Upon molecular analysis, all 12 LDS-affected family members had a nonsense truncating mutation, p.Q100X, in exon 1 of FOXC2. FOXC2 is a transcription factor in the forkhead/winged-helix family important in various developmental pathways. Its role in the development of mesenchymal structures, including the spinal arachnoid, may explain its association with SEDAC formation (Fang et al. 2000).

Mendelian syndromes in which ACs are more commonly represented than the general population

An increased prevalence of ACs has been noted in several syndromes to date. Chudley–McCullough syndrome (CMS) (OMIM no. 604213) is a rare autosomal recessive disorder characterized by early-onset sensorineural deafness and a highly distinctive combination of brain malformations, including ventriculomegaly, partial agenesis of the corpus callosum, cerebellar dysplasia, gray matter heterotopia, frontal polymicrogyria, and AC (Blauen et al. 2021). It is due to pathogenic mutations in the G-protein signaling modulator 2 (GPSM2) gene, which encodes for a protein involved in mitotic spindle orientation during cell division in multiple tissues (Doherty et al. 2012). More specifically, GPSM2 regulates actin cytoskeleton polymerization in neuronal cells and at the apical surface of hair cells during early embryogenesis (Mauriac et al. 2017). Impaired asymmetric cell division in neuroblasts, in turn, causes dysfunctional neuronal migration and differentiation resulting in the characteristic brain malformations of CMS. Interestingly, a significant percentage of CMS patients present with AC. According to Koenigstein et al. (2016), 48% of CMS cases reported in the literature found interhemispheric cysts, with AC being the most common. Consequently, we suggest that the prevalence of AC in CMS indicates that mutations in neuronal cell division and migration may cause AC. In a broader sense, the presence of AC in GPSM2-related CMS suggests mutations may not be limited to the arachnoid layer but can impact neuronal cells throughout the brain (Koenigstein et al. 2016).

Acrocallosal syndrome (ACLS) (OMIM no. 200990) is another rare autosomal recessive disorder. It is characterized by a pattern of craniofacial, brain, limb, and neurodevelopmental abnormalities, including facial dysmorphia, agenesis of the corpus callosum, hypotonia, seizures, mental retardation, and polydactyly of the hands and feet (Thyen et al. 1992). ACLS may also present with anencephaly, Dandy–Walker malformation, and cystic malformations, including AC (Thyen et al. 1992). Putoux et al. (2011) discovered that homozygous mutations in KIF7, a cilia-associated protein with a major role in Sonic hedgehog (Shh) transduction, were responsible for ACLS. Both KIF7 and its Hedgehog (Hh) target gene are involved in brain development (Putoux et al. 2011). KIF7 knockout mice developed exencephaly and polydactyly, similar to ACLS. Due to their findings, ACLS has been defined as a ciliopathy, and the group would go on to find KFI mutations in various other ciliopathies. This distinction is critical, indicating that ACs and other brain malformations characteristic of ACLS are a direct consequence of dysfunctional cilia in the developing brain. On a more nuanced level, Putoux et al.’s findings suggest that AC pathogenesis may involve defects in the Shh signaling pathway leading to reduced cilia function during brain development. Other proteins in the Shh pathway may thus serve as valuable targets for further investigation (Putoux et al. 2011).

A third disorder linked with AC and characterized by defects in motile cilia function is autosomal recessive primary ciliary dyskinesia (PCD) (OMIM no. 618695). In PCD, impaired ciliary clearance commonly results in lung, heart, and sinonasal diseases and less commonly in hydrocephalus and/or infertility (Robson et al. 2020; Diab et al. 2021a). Primary ciliary dyskinesia-42 (PCD-42) is an autosomal recessive subset of PCD caused by mutation of the multiciliate differentiation and DNA synthesis associated cell cycle protein (MCIDAS) gene, a protein involved in ependymal ciliogenesis by stimulating the production of multiple centrioles in epithelial cells that form the basal bodies of motile cilia (Stubbs et al. 2012). Robson et al. (2020) found choroid plexus hyperplasia in PCD patients with MCIDAS mutations. CPH is characterized by enlarged but morphologically normal choroid plexus, causing CSF overproduction and hydrocephalus. Consequently, it is suggested that ependymal cilia may regulate CSF production by influencing choroid plexus ependymal cells and facilitating CSF flow. Mutations in cilia function in turn may cause CPH and hydrocephalus (Robson et al. 2020; Robert et al. 2021; Kundishora et al. 2021b; Allington et al. 2022). Interestingly, PCD-42 also has a high incidence of AC in addition to hydrocephalus and CPH (Kundishora et al. 2021b). MCIDAS mutations may result in ACs due to tears in the arachnoid layer caused by abnormal CSF flow or adhesions from impaired clearance of CSF debris. MCIDAS-associated PCD also demonstrates how defects in ependymal cilia and their effects on CSF production may cause ACs.

Various other syndromes and disorders have been further associated with AC (Table 2). In particular, IACs have been reported in multiple developmental and neurological disorders, including autism spectrum disorder (Helsmoortel et al. 2014), Down syndrome (OMIM no. 190685) (Pearlson et al. 1998), Noonan syndrome (OMIM no. 163950) (Gripp et al. 2016), Friedreich ataxia (OMIM no. 229300) (Kurt et al. 2016), autosomal dominant tuberous sclerosis (OMIM no. 191100) (Boronat et al. 2014; Boronat and Barber 2018), and neurofibromatosis (OMIM no. 162200) (Wadsby et al. 1989). This is consistent with the high rates of cognitive impairment, seizure, hypotonia, and other neurological symptoms reported with AC. It also suggests that neurological symptoms in AC patients may often be caused by a deeper neurological pathology. AC has also been found at higher rates in cystic disorders such as autosomal dominant polycystic kidney disease (OMIM no. 173900) (Schievink et al. 1995; Alehan et al. 2002) as well as other non-neurologic disorders, including mucopolysaccharidosis (Lee et al. 1993; Petitti et al. 1997) and autosomal recessive glutaric aciduria type-1 (OMIM no. 231670) (Martínez-Lage et al. 1994; Jamjoom et al. 1995; Zhang and Luo 2017).

Spinal ACs, in particular, have been found in various disorders associated with dural ectasia and impaired dural formation including Marfan syndrome (MF) (OMIM no. 154700) (Hoshino et al. 2005; Di Lazzaro et al. 2007) and neurofibromatosis type 1 (OMIM no. 162200) (Rousseaux et al. 1983; Shehu and Hassan 2009). Dural ectasia is a widening of the dural sac often causing erosion of surrounding vertebrae and compression of neural structures. Dural ectasias are extremely common in MF (Shirley and Sponseller 2009) and, while not definitively known, it has been theorized that the deficiency in fibrillin-1 causes weakening of connective tissue structures including the dural sac which consequently expands from CSF hydrostatic pressure (Fattori et al. 1999; Foran et al. 2005). Similarly, in NF it is believed that neurofibromas infiltrate the dura and cause weakening of the dural sac with subsequent ectasia (Polster et al. 2020). The increased incidence of both spinal ACs and other dural pathologies suggests that a similar pathomechanism may be involved.

Case reports of ACs with genetic findings

There are relatively few case reports describing familial or sporadic AC in general. Of these, very few have genetic data available. Here we present 3 of the most salient cases with genetic data suggesting unique mechanisms of pathogenesis.

Xiong et al. discovered a de novo heterozygous mutation, c.1069C>G, p.H357D, in exon 1 of ZIC2 in a 9-month-old presenting with mild microcephaly, semi-lobar holoprosencephaly (HPE), and AC (Xiong et al. 2019). ZIC2 is a zinc finger protein and transcription factor with an essential role in embryonic brain development and one of the most commonly mutated genes in HPE (Solomon et al. 2010). Given that ZIC2a2b knockdown in zebrafish was found to cause reduced expression of HOXD4a, a gene associated with arachnoid development and SEDACs, this case suggests that transcriptional dysregulation during embryonic brain development may cause AC formation (Xiong et al. 2019).

Using targeted sequencing, Kantaputra et al. (2019) discovered a homozygous single base pair duplication c.859dupC (p.H287P*30) in WNT1 in a baby presenting with a rare form of osteogenesis imperfecta (OI), left cerebellar hypoplasia, atrophic frontal lobes, compressed left midbrain and pons, and ACs in the posterior fossa and right anterior temporal surface. His parents were consanguineous and heterozygous for the mutation. WNT1 is a key protein in the Wnt signaling pathway, which maintains En1 expression in the developing brain (Alves dos Santos and Smidt 2011). En1 is a transcription factor essential for the midbrain and cerebellar formation (Alves dos Santos and Smidt 2011). Abnormal expression of En1 in mouse models during development leads to cystic malformations in the cerebellum, indicating that impaired WNT1 regulation of En1 expression may cause abnormal cerebellar development and thus AC (Alves dos Santos and Smidt 2011).

Winczewska-Wiktor et al. reported a heterozygous de novo nonsense mutation, c.C232T (p.Q78X), in exon 3 of CTNNB1 (beta-catenin) in an 11-year-old presenting with microcephaly, intellectual disability, hyperekplexia, and an AC in the posterior fossa (Winczewska-Wiktor et al. 2016). Mutations in CTNNB1 have previously been associated with neurodevelopmental symptoms, including intellectual disability, motor delay, distal hypertonia, speech impairment, behavioral anomalies, microcephaly, and dysmorphic facial features (Winczewska-Wiktor et al. 2016). In WNT signaling, beta-catenin binds TCF/LEF transcription factors to regulate the gene expression involved in neuron excitation (Narasipura et al. 2012), which might explain this patient’s hyperekplexia. CTNNB1 also plays a critical role in dendritic morphogenesis and axonal growth, which could have caused this patient’s intellectual disability and AC (Yu and Malenka 2004). This case is a clear example of how common symptoms associated with AC, including seizure and intellectual disability, can present alongside AC but actually result from a deeper neurologic pathology.

Future directions: AC genetics as a tool

ACs have a heterogeneous and complex clinical presentation that has historically been managed with an overly simplistic treatment approach (Jafrani et al. 2019; Ichinose et al. 2020). Although neurosurgical interventions have been performed for ACs causing clear signs of mass effect, increased intracranial pressure, or hydrocephalus, it remains unclear whether surgery would benefit patients presenting with only cognitive or neurodevelopmental deficits. A deeper understanding of the pathogenic mechanisms underlying AC and neurodevelopmental phenotypes in these patients is needed to provide intelligent surgical management.

Investigating AC human genetics is critical to obtaining a better understanding of AC pathogenesis. Familial reports of AC and reports of increased AC frequency in various Mendelian syndromes suggest a strong genetic component. However, traditional genetic approaches are limited in their ability to identify AC-associated genes, given that ACs are rare, often sporadic, and genetically heterogeneous with incomplete penetrance and variable expressivity. Our review of familial and syndromic AC cases suggests that genes involved in microtubule dynamics, transcription regulation, and various signaling pathways may also contribute to sporadic AC. While some genetic variants have been reported from small case reports, no large GWAS or next-generation sequencing studies have been done to date.

To date, there are various competing theories regarding the mechanism of AC expansion. Multiple signaling pathways, developmental processes, and cellular functions exist and are suspected to play a role in AC pathogenesis. Current literature suggests that ACs are multigenic malformation, resulting from a dysfunction in early embryonic and fetal development (Aarhus et al. 2010; Xiong et al. 2019) and involving dysregulated neuronal growth or migration (Kantaputra et al. 2019). A deeper understanding of the underlying molecular mechanisms involved will require superior genetic techniques.

GWAS, an approach that aims to evaluate the association between (typically millions of) common single nucleotide polymorphisms and a trait of interest, have successfully mapped tens of thousands of loci associated with complex traits (Visscher et al. 2017; Buniello et al. 2019). Although the effect sizes associated with the most significant variants from GWAS were typically small, it is a powerful tool to identify putative genetic modifiers that can influence penetrance and/or expressivity (Timberlake et al. 2016; Deming et al. 2019) and to quantify the genetic predisposition to disease risk for an individual using the polygenic risk prediction model (Chatterjee et al. 2016). More recently, whole-exome sequencing and whole-genome sequencing technologies have dramatically expanded our ability to evaluate the consequence of rare coding single nucleotide variants, cis- and trans-regulatory elements, transposable elements, and complex structural variants underlying rare and complex diseases (Levy and Myers 2016; Wang et al. 2022). Notably, the trio-based study design makes it possible to distinguish between de novo variants and transmitted variants (Diab et al. 2021b), enabling the identification of monogenic causes of other brain malformations (Bilgüvar et al. 2010; de Ligt et al. 2012; Mishra-Gorur et al. 2014; Jin et al. 2020b; Kundishora et al. 2021a), congenital heart diseases (Jin et al. 2017; Richter et al. 2020; Diab et al. 2021a), congenital hydrocephalus (Furey et al. 2018; Jin et al. 2020a; Kundishora et al. 2021b; Allington et al. 2022), and other genetically heterogeneous neurodevelopmental disorders, including autism and epilepsy (Neale et al. 2012; Allen et al. 2013). Therefore, we speculate that in the near future WES or WGS in a large, well-phenotyped AC cohort coupled with other integrative functional genomics and clinical phenomic techniques will begin to reveal novel genetic etiologies and biological pathways, link genotype to phenotype, and reveal temporal, regional, sex, and cell type-specific dynamics underlying AC pathogenesis.

Acknowledgments

We would like to thank the children and families with ACs that were involved in the many studies reported in this paper. Our work was made possible due to their contributions and sacrifice.

Contributor Information

Hanya M Qureshi, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, United States.

Kedous Y Mekbib, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, United States; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States.

Garrett Allington, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States; Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, United States.

Aladine A Elsamadicy, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, United States.

Phan Q Duy, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, United States.

Adam J Kundishora, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, United States.

Sheng Chih Jin, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States.

Kristopher T Kahle, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, United States; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States; Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA 02115, United States; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, United States; Department of Neurology, Harvard Medical School, Boston, MA 02115, United States; Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States.

Funding

This work was supported by Leon Rosenberg, MD, Medical Student Research Fund in Genetics; G. D. Hsiung, PhD, Student Research Fellowship Fund (KYM); the Gruber Science Fellowship (GA); and the Rudi Schulte Research Institute (KTK). SCJ is supported by a K99/R00 Pathway to Independence Award (K99HL143036 and R00HL143036-02), the Hydrocephalus Association Innovator Award, the Clinical & Translational Research Funding Program award (CTSA1405), and the Children’s Discovery Institute Faculty Scholar award (CDI-FR-2021-926).

Conflict of interest statement: None declared.

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