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Neurosurg Clin N Am. Author manuscript; available in PMC 2023 January 01.
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Published in final edited form as:

Neurosurg Clin N Am. 2022 January ; 33(1): 67–79. doi:10.1016/j.nec.2021.09.006.

Syndromic Hydrocephalus
Kaamya Varagur, BA, MPhil1 [Medical student], Sai Anusha Sanka, BA, MPH1 [Medical
Student], Jennifer M. Strahle, MD1 [Associate Professor, Department of Neurosurgery,
Washington University School of Medicine, Washington University in St. Louis, St. Louis,
Missouri, USA]
1.Department of Neurosurgery, Washington University School of Medicine, St Louis, Missouri,
USA
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Keywords
hydrocephalus; syndromic hydrocephalus; hydrocephalus genetics

Introduction
Hydrocephalus is characterized by abnormal accumulation, and impaired circulation and
clearance, of cerebrospinal fluid (CSF). CSF accumulation results in distention of the
ventricular system, leading to accelerated head growth and increased intracranial pressure,
and often requires surgical intervention1,2. Syndromic hydrocephalus encompasses a diverse
group of disorders and genetic variants in which hydrocephalus is a symptom, due to
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congenital structural malformations, or a range of emerging pathology associated with

recently described genetic variants3. In this review we discuss several of the major
syndromic causes of hydrocephalus, as well as emerging research on the genetic basis for
congenital hydrocephalus as part of recently described genetic mutations (Table 1).

L1 Syndrome, and X-Linked Hydrocephalus

X-linked hydrocephalus comprises 5% of all cases of congenital hydrocephalus (Table
1)1.X-linked hydrocephalus, associated with stenosis of the aqueduct of Sylvius (cerebral
aqueduct), is the most severe phenotype associated with L1 syndrome, an X-linked recessive
disorder (Fig. 1)4. Other phenotypes of L1 syndrome include MASA (mental retardation,
aphasia, spastic paraplegia, adducted thumbs) and X-linked complicated corpus callosum
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and/or pyramidal tract agenesis3,5. Many of these phenotypic features commonly co-occur
with X-linked hydrocephalus, especially intellectual disability6.

CORRESPONDING AUTHOR: Washington University in Saint Louis, 660 South Euclid Avenue, Campus Box 8057, St. Louis, MO
63110 USA, Jennifer M. Strahle, [email protected].
DISCLOSURE STATEMENT
The Authors have nothing to disclose.
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 Varagur et al. Page 2

This syndrome results from mutations in L1CAM on chromosome region Xq28, affecting
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the locus of a gene coding for the neural cell adhesion molecule L1. Mutations in this gene
are associated with disordered neuronal migration which is considered a key mechanism
in the pathogenesis of this syndrome7. Knockout rat models of the disease have revealed
early pathologic changes of periventricular white matter tracts following the development
of hydrocephalus, evidenced by reductions in fractional anisotropy and axial diffusivity on
DTI in the corpus callosum, external capsule, and internal capsule. Histology also revealed
hypomyelination and increased extracellular fluid in the corpus callosum, yielding some
insight into how mutations of L1CAM contribute not only to hydrocephalus, but also to the
developmental delays and intellectual deficits observed in this condition8.

Point mutations at branch points in introns of L1CAM, causing abnormal splicing, were
among the first mutations implicated in the disease. Recently, duplication affecting the
intracellular domain, frameshift mutations affecting translation of fibronectin type-III of
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L1CAM, and novel nonsense mutations affecting ependymal cilia have also been implicated
in this syndrome9,10,11,12,13.

Beyond L1CAM, other X-linked mutations have recently been associated with
syndromic hydrocephalus including missense mutations in OTUD5 resulting in severe
neurodevelopmental delay, hydrocephalus, and early lethality14. Duplications of Xp22.33
also lead to an L1-like phenotype of hydrocephalus associated with stenosis of the cerebral
aqueduct, and dysgenesis of the corpus callosum15. Modern sequencing techniques may
reveal other X linked mutations associated with L1-like syndromic hydrocephalus, though
L1CAM remains the most common and thoroughly explored locus causing this condition.

Once an L1CAM pathogenic variant has been identified in a family, carrier testing,
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prenatal testing, and preimplantation genetic testing are available to patients and families.
Treatment of individuals with X-linked hydrocephalus may vary depending on the timing
of presentation; however, because many of these patients present with symptomatic
hydrocephalus at birth, treatment often involves ventriculoperitoneal shunting (VPS), as
the efficacy of endoscopic third ventriculostomy (ETV) with choroid plexus catheterization
(CPC) in young infants is variable4.

Syndromic Craniosynostosis
Syndromic craniosynostosis is associated with an increased incidence of hydrocephalus16.
Hydrocephalus is more common in syndromic compared to non-syndromic or isolated
craniosynostosis, and is seen in Crouzon’s and Pfeiffer’s syndromes17. Mechanisms
underlying hydrocephalus in this group of syndromes relate to primary cerebral
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maldevelopment and residual structural outflow obstruction, not significantly ameliorated

by posterior vault distraction strip craniectomy or cranial vault reconstruction commonly
utilized in the treatment of craniosynostosis16,18. Conversely, early shunting (or over-
shunting) can cause iatrogenic premature fusion of the cranial sutures in patients without
craniosynostosis19. Treatment of hydrocephalus in patients with syndromic craniosynostosis
includes VP shunt and ETV +/− CPC and is usually influenced by future need for cranial

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vault reconstruction; therefore, location of shunt placement may vary to accommodate future
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planned surgeries.

Pfeiffer Syndrome
Of the syndromes associated with craniosynostosis, Pfeiffer syndrome is most frequently
associated with hydrocephalus, with up to 60–80% of patients requiring ventriculoperitoneal
shunt insertion or other treatment for hydrocephalus20,21. This syndrome is also associated
with speech, language, hearing and feeding issues related to mutations in FGFR221,22.

Crouzon Syndrome
Crouzon syndrome, related to mutations in FGFR223, can be associated with a small
foramen magnum and outlet obstruction associated with hydrocephalus.[24] Because of the
structural predisposition to developing hydrocephalus in this form of craniosynostosis, up to
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40% of patients with Crouzon’s can present with or develop ventricular dilation25. While
ventriculomegaly is common, a smaller number will ultimately require surgical treatment of
hydrocephalus26.

Apert Syndrome
Apert syndrome, also related to mutations in FGFR2, is characterized by multi-suture
craniosynostosis, midface retrusion, syndactyly of the hands, fusion of the second through
fourth nails, and nonprogressive ventriculomegaly27,28. Fewer patients with Apert syndrome
have true or progressive hydrocephalus29. Rates of ventriculoperitoneal shunt placement in
one study of a cohort of patients with Apert syndrome was 24.3%, lower that that seen in
Crouzon or Pfeiffer syndromes30.
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Muenke Syndrome
Muenke syndrome is an autosomal dominant syndrome associated with mutations in FGFR3
characterized by coronal craniosynostosis and variable extracranial anomalies31. Though this
syndrome is not regularly associated with hydrocephalus, there has been a rare familial
variant of this syndrome (p.Pro250Arg) with hydrocephalus, without craniosynostosis32.

Achondroplasia
Achondroplasia is an autosomal dominant skeletal dysplasia caused by a gain of
function G380R mutation in FGFR3 on chromosome 433,34. This mutation alters
bone growth resulting in obstruction or stenosis of the cranial skull base foramina.
Increases in venous pressure secondary to stenosis of the jugular foramen can result in
macrocephaly, ventriculomegaly and hydrocephalus33,34,35. The etiology of hydrocephalus
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in achondroplasia is likely multifactorial, with contributions from alterations in CSF flow

at the foramen magnum, venous outflow alterations, and potentially decreased CSF egress
along cranial nerve sheaths due to narrowing of their respective foramina 34,36,37.

Many patients with achondroplasia have some degree of ventriculomegaly which stabilizes
overtime 37,38. As the natural history of this ventriculomegaly and the contributions from
stenosis at the foramen magnum and cervical medullary junction is better understood, there

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are far fewer patients who receive treatment with ventriculoperitoneal shunting, which in the
past was associated with significant complications39. Some patients are successfully treated
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with cervicomedullary decompression, which is associated with decreased need for shunting
and stabilization of both ventriculomegaly and intracranial pressure40,37.

NF 1 and NF 2
Neurofibromatosis 1 (NF1), also known as von Recklinghausen’s disease, is an autosomal
dominant disorder caused by mutations on chromosome 17q11.2 that affect neurofibromin
production41,42. NF 1 has variable expression and predisposes individuals to several tumors
and hamartomas in the central and peripheral nervous system, including optic pathway
gliomas (OPG) and gliomas outside the optic pathway, which in some cases can lead
to obstructive hydrocephalus (Fig. 2) 43,44,45,46. Hydrocephalus in NF-1 can occur from
alterations in CSF circulation that results from OPGs, as well as periaqueductal gliosis,
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aqueductal webs, nontumor hamartomatous changes, and tectal and midbrain tumors causing
obstruction or narrowing of the ventricular system, particularly at the level of the cerebral
aqueduct.45,47. Treatment may involve the tumor directly, or in some cases, surgical
treatment for symptomatic hydrocephalus. 42,47. Direct treatment of a tumor may involve
surgical removal or treatment with chemotherapy including BRAF/MEK inhibitors 47.
Finally, treatment of NF-1 associated hydrocephalus with ETV can be successful regardless
of the type or level of obstruction48.

Neurofibromatosis 2 (NF2), another autosomal dominant disorder, is caused by deletions

or loss of function of the tumor suppressor gene on chromosome 22q12 that encodes
the protein Merlin49,50. Compared to NF1 with a prevalence of 1 in 4,000–5,000 births,
NF2 is more rare with an incidence of 1 in 40,000 births43,51. Patients with NF2 can
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develop bilateral vestibular schwannomas or other intracranial tumors that can rarely cause
hydrocephalus through obstruction of CSF circulation50,52.

Down Syndrome
There have been several case reports of hydrocephalus in patients with Down syndrome.
Two early reports from the 1970s describe children with Down syndrome and
hydrocephalus, aqueductal stenosis, and partial agenesis of the corpus callosum53,54. A
more recent case report describes a patient with hydrocephalus detected during pregnancy
who required treatment with ventriculoperitoneal shunt55. Two additional case reports
describe two patients with Down syndrome and normal pressure hydrocephalus, both of
whom were treated with ventriculoperitoneal shunts56. The second report describes a patient
with tetraventricular hydrocephalus caused by obstruction of the foramina of Luschka and
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Magendie treated using ETV57.

Although Down syndrome is not associated with hydrocephalus, mouse models have
demonstrated ventriculomegaly related to the genetic abnormalities in Down syndrome.
The Ts1Rhr mouse model, with a shorter trisomic segment than previous models, exhibits
PcP4-dependent ciliopathy sufficient to trigger ventricular enlargement58. Thus, it is
possible that despite their varying presentations and treatment, some of the reported human

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hydrocephalus cases may be related to trisomy 21 itself rather than non-syndromic findings.
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Finally, there is an increased prevalence of ventriculomegaly in very low birthweight

(VLBW) infants with Down syndrome compared to other VLBW infants, suggesting that
some Down Syndrome-related pathologic process may contribute to the development of
hydrocephalus or ventriculomegaly in a subset of patients with this condition59.

Tuberous Sclerosis
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic syndrome with
dysfunction of the mTOR pathway resulting in cortical and subcortical tubers,
subependymal nodules along the lateral ventricles, and subependymal giant cell
astrocytomas (SEGAs) 60,61. SEGAs are associated with obstructive hydrocephalus in the
first two decades of life, and are monitored for growth using frequent, serial imaging
in patients with TSC60,61. Though they grow slowly, SEGAs can cause obstructive
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hydrocephalus secondary to blockage of CSF circulation at the Foramen of Monro.62.

Management of hydrocephalus in these cases depends on management of the SEGAs

themselves. Treatment strategies include surgical resection or mTOR inhibition. Early
surgical resection was once the standard for management of SEGAs that showed growth
on serial imaging, and surgery was curative for small lesions, with low complication
rates63. However for larger or bilateral lesions, complication rates were higher, and in many
patients with both SEGA and hydrocephalus, VPS was still necessary63,64. More recently,
medical management using mTOR inhibitors has been used alone or in combination with
surgical resection, though some concerns remain about its long-term safety considering
effects on linear growth, puberty, and immunosuppression65,66,67,68. In patients with SEGA
and asymptomatic obstructive hydrocephalus, mTOR inhibition is effective in treating
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hydrocephalus even in the setting of acute, symptomatic increases in intracranial pressure,

though surgery is often still considered in these cases66,69. Endoscopic tumor removal, laser
interstitial thermal therapy (LITT), and biologics targeting of the MAPK/ERK pathway, may
also be utilized in the treatment of SEGA and associated hydrocephalus in TSC patients70,71.

Walker-Warburg Syndrome/ Brain-muscle-eye disease

Walker-Warburg Syndrome (WWS), the most severe congenital muscular disorder, is
caused by an autosomal recessive mutation that leads to type II Lissencephaly and
severe hydrocephalus (Fig. 3)72,73. WWS is characterized by defective O-glycosylation of
α-dextroglycan but the disease is highly heterogenous, as hypoglycosylation can occur in
the Protein O-Mannosyltransferase 1 (POMT1) gene, present in 10–20% of patients, as well
as in the POMT2, POMGNT1, FKTN, FKRP, LARGE, ISPD or other genes associated with
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dystroglycanopathy phenotypes73,74,75.

While the incidence of WWS is rare, estimated at 1.2 per 100,000 births, many
cases of WWS are complicated by hydrocephalus76,77,78. Similar to the clinical and
genetic variability of WWS, the nature of the concurrent hydrocephalus is also variable.
Hydrocephalus can be associated with tectal enlargement resulting in aqueductal stenosis
as well as cobblestone cortex79. One patient with WWS presented with ventriculomegaly

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and a bulging third ventricle along with progressive hydrocephalus, while another WWS
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patient presented with macrocephaly, triventricular enlargement, hypoplasia of the corpus

collosum, and obstructive hydrocephalus; both were treated with VP shunts77. Other case
studies reported prenatal findings of posterior fossa anomalies and associated hydrocephalus
with a POMT2 mutation confirming WWS, and three affected siblings with varying levels
of fetal and congenital hydrocephalus, all with fatal prognosis 76,78. ETV-CPC was used to
treat a patient with cobblestone lissencephaly, increased bulging of the anterior fontanelle
and sutural separation, with a POMT1 mutation80.

It is important to note that the etiology of hydrocephalus in WWS is likely due to stenosis
of the aqueduct secondary to altered brain development and an enlarged tectum. This
differs from an aqueductal web, in which the brain stem is otherwise normal. Given the
rates of hydrocephalus and abnormal brain development in WWS, close monitoring for
hydrocephalus is warranted, although many patients present at birth with symptomatic
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hydrocephalus requiring treatment76. Given the early presentation, although many patients
do have aqueductal stenosis, VP shunting may be more efficacious than ETV or ETV-CPC
due to the young age at presentation.

Primary Ciliary Dyskinesia/Kartagener’s

Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous syndrome associated
with defects in cilia and flagella motility81,82. Many of the mutations associated with PCD
affect the dynein axonemal heavy chain 5 or dynein axonemal intermediate chain 1 genes
which encode the outer dynein arms of cilia83,84,85. PCD has a worldwide prevalence of 1 in
16,000 children86. Common manifestations include Kartagener’s syndrome (bronchiectasis,
situs inversus, and chronic sinusitis), as well as neonatal respiratory distress, and male
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infertility86. While hydrocephalus is infrequently seen in humans with PCD, mouse

models of this disease frequently develop severe symptomatic hydrocephalus82. Insertional
mutations in the mouse axonemal dynein heavy chain gene, Mdnah5, cause loss of axonemal
outer arms, and reproduce most of the classic features of PCD such as recurrent respiratory
infections, situs inversus, and ciliary immobility87. In these mice, the mutation also causes
hydrocephalus and death in the perinatal period and this mouse model suggest that the
degree of ciliary dysfunction caused by the mutation is causally related to the severity of
PCD and the development of hydrocephalus87. In both human and mouse models, functional
loss of the Ccdc151 gene has also been associated with PCD, as this gene is expressed
by ependymal cells and affects the ciliary axoneme. This mutation, too, is associated with
hydrocephalus and perinatal death in mouse models88. The exact role of ciliary motion in the
development of hydrocephalus has yet to be determined, including whether cilia are capable
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of producing or maintaining bulk flow of CSF throughout the ventricular system.

While there are case reports of hydrocephalus in Kartagener’s syndrome or PCD, in humans
hydrocephalus is relatively infrequent 82,89,90,91,92. One case of PCD and hydrocephalus was
associated with aqueductal stenosis and abnormal ultrastructure of the respiratory epithelium
cilia93. Another report of autosomal recessively inherited PCD and intellectual disability
in 3 generations of a Jordanian family notes that 4 of 9 affected individuals also had
hydrocephalus94. Mutations in the multicilin gene (MCIDAS) are associated with choroid

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plexus hyperplasia and hydrocephalus in humans, possibly related to reduced generation

of motile cilia95. Finally, mutations in FOXJ1, encoding a transcription factor involved
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in ciliogenesis, are associated with an autosomal dominant motile ciliopathy like PCD,
with obstructive hydrocephalus in all reported cases. Hydrocephalus in these cases was
associated with the inability to maintain patency, and resulting stenosis, of the aqueduct
and/or foramina of Luschka/Magendie due to insufficient motile ciliary function96. In
all affected individuals, pathological specimens showed mis-localized basal bodies and
incorrect localization of adhesion proteins, leading to deficits in ciliary function and
inadequate fluid flow96. Overall, while PCD is not consistently linked with hydrocephalus
in humans, findings from mouse models and several human reports suggest that severe
dysfunction of ciliary motility may contribute to hydrocephalus in some cases of PCD and
related ciliopathies. Possible mechanisms for symptomatic hydrocephalus include stenosis
of the aqueduct due to decreased flow of fluid across this channel or from collapse of the
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ependymal walls around the aqueduct due to changes in the integrity of the ependyma.
Finally, as in other syndromes, the concurrent altered brain development may play a role in
the development of hydrocephalus.

Osteogenesis Imperfecta
Osteogenesis Imperfecta (OI) is a group of disorders of connective tissue that affects bone
growth and fragility, caused by defective COL1A1 and COL1A2 genes and is grouped into
four types— Type II, type III, type IV and type I — ordered from most to least severe97,98.
OI can be associated with macrocephaly, hydrocephalus, basilar invagination and cerebral
atrophy99. Concurrent basilar invagination can lead to obstructive hydrocephalus. While the
true incidence of hydrocephalus in OI is not well known, several studies and case reports
have documented OI with associated hydrocephalus99,100.
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In one study, OI was associated with sulcal prominence and hydrocephalus with no clear
intraventricular obstruction in 22% of patients99. In another study of 5 neonates with OI,
4 had hydrocephalus associated with foramen magnum stenosis, cerebral parenchymal and
intraventricular hemorrhage, and occipital-bone fractures101. All 4 infants died soon after
birth101. One other case reported a patient that presented with a novel mutation of the
COL1A2 gene and was diagnosed with type II OI with obstructive hydrocephalus; in this
case the patient was treated with ETV98.

Emerging Genetic Syndromes

Through the use of next generation sequencing, novel genetic mutations associated with
hydrocephalus have been identified, accounting for many cases previously classified as
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sporadic or as “congenital hydrocephalus”3,102,103. It is unclear in all cases how these

genetic alterations directly lead to hydrocephalus, however mechanisms beyond disruptions
to CSF dynamics or structural barriers to CSF flow such as abnormal neuronal proliferation,
differentiation, and maintenance may be involved in hydrocephalus102.

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Pettigrew Syndrome
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Pettigrew syndrome is an X-linked disorder, characterized by mutations in the AP1S2 gene

that encodes a subunit of the AP1 adaptin protein essential in regulating lysosomal protein
sorting104. Mutations lead to intellectual disabilities, iron and calcium deposition, and
hydrocephalus3. The related Lethal giant larva (Lgl) protein is involved in maintaining cell
polarity in mice. Loss of this protein in Lgl1−/− mice pups leads to severe hydrocephalus
and neonatal death105.

RASopathies
Various RASopathies, through mutations in the RAS-MAPK pathway, have been associated
with hydrocephalus; among these disorders are NF1, discussed previously, Costello
syndrome, Noonan syndrome and cardio-facio-cutaneous (CFC) syndrome, all with
autosomal dominant inheritance3. Noonan syndrome is associated with mutations in CBL
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(regulators of activated TRKs), KRAS, NRAS (RAS proteins), PTPN11, SOS1, SHOC2
(modulators of RAS function) and RAF1 (downstream signal transducers); it is also
associated with hydrocephalus in addition to hindbrain herniation and syringomyelia106,107.
Costello syndrome is caused by mutations in the HRAS protooncogene that lead to failure-
to-thrive, along with macrocephaly, posterior fossa crowding, low cerebellar tonsil position
and hydrocephalus108. CFC syndrome is most frequently caused by mutations in BRAF, but
can occur due to mutations in MEK1, KRAS and MEK2 as well. This can lead to cervical
stenosis, torticollis, Chiari malformation, and hydrocephalus109.

RAS has a multifaceted role in CNS development. Through its involvement in the RAS-
ERK pathway, it is involved in the regulation and maintenance of neural stem cells, as
well as in the regulation of oligodendrocyte differentiation110,111. Through its regulation of
the PI3K-AKT pathway, RAS is also involved in synaptic plasticity112,113. Despite these
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interactions with CNS cell growth, differentiation, and maintenance, the role of RAS in CSF
clearance and flow is not well characterized, and it is possible that structural deficits due to
defective neurogenesis and differentiation contribute to hydrocephalus in these cases rather
than direct effects on CSF flow.

PI3K-AKT-mTOR pathway
Four different mutations of genes in the PI3K-AKT-mTOR pathway, involved in cell
proliferation, growth and function, have been shown to cause megalencephaly-associated
symptoms, leading to hydrocephalus3. Mutations in the AKT3, CCND2 and PIK3R2
genes cause different types of Megalencephaly-polymicrogyria-polydactyly-hydrocephalus
(MPPH), while mutations in the PIK3CA gene causes Megalencephaly-capillary-
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malformations (MCAP). Both MPPH and MCAP cause megalencephaly, polymicrogyria

and ventriculomegaly that can lead to hydrocephalus114. PI3K pathway genes, including
PIK3CA, PTEN, and MTOR contribute to neural stem cell growth, proliferation, and
differentiation, especially in the developing ventricular zone, and mutations in these genes
predispose patients to tumorigenesis and overgrowth syndromes115,103. As these syndromes
have only recently been characterized, it remains to be seen whether therapeutics targeting
affected molecular pathways will eventually aid in the treatment of hydrocephalus in these
cases.

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Discussion
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Hydrocephalus occurs in the setting of many well-characterized syndromes of childhood.

Treatment involves a combination of treating the primary pathology (e.g. tumors that
cause outflow obstruction) and treatment for hydrocephalus with VPS and/or ETV +/−
CPC. Next-generation sequencing has allowed for the characterization of novel genetic
syndromes associated with hydrocephalus and the identification of mutations in sporadic
cases of hydrocephalus. These mutations shed light on how alterations to development and
proliferation of neurons and neural stem cells contribute to sporadic hydrocephalus, and may
eventually contribute to our understanding of novel syndromic causes of hydrocephalus.

Four genes regulating neural stem cell fate have recently been described in congenital
hydrocephalus102. TRIM71 loss is associated with defective neural tube closure, and
decreased proliferation of neural progenitor cells (NPCs) in mouse models116. SMARCC1
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encodes a subunit of a chromatin remodeling complex important to the survival of NPCs

and transcriptional control of telencephalon development, and knockouts are associated
with hydrocephalus and aqueductal stenosis117. PTCH1 is involved in the mechanism by
which primary cilia in neuroepithelial cells sense and respond to SHH gradients, which
is important in NPC differentiation and fate118. SHH encodes the ligand responsible for
NPC migration along the dorsal-ventral axis of the neural tube119. TRIM71 mutations are
associated with communicating hydrocephalus, while SMARCC1 and PTCH1 mutations
are more likely to be associated with aqueductal stenosis. These mutations highlight that
abnormal neurogenesis or brain development likely play a role in the development of
hydrocephalus, beyond deficits in CSF accumulation or clearance102. In a follow-up study,
mutations in the PI3K pathway genes previously discussed, as well as FOXJ1, FMN2,
and FXYD2 were present in up to 22% of sporadic congenital hydrocephalus cases.
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Their involvement is likely related to their role in supporting embryonic neurogenesis103.

These findings highlight that the dysregulation of neurogenesis, proliferation, or migration,
especially in the ventricular zone, are emerging areas of interest that may contribute to CSF
accumulation or disordered circulation in some cases of hydrocephalus.

Summary
Hydrocephalus is a common phenotype in various syndromes of childhood with
diverse genetic etiologies. The mechanisms behind these disorders include structural
deficits, mutations affecting neuronal adhesion, vesicle trafficking, growth factors, PI3K-
AKT-mTOR pathway and Dystroglycanopathies, Ciliopathies and RASopathies3. The
pathophysiology of syndromic hydrocephalus is multifactorial, and treatment is often
multimodal, addressing both the underlying condition and the associated hydrocephalus.
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While the incidence or the underlying pathogenesis of hydrocephalus in certain conditions is

not fully known, next generation genetic sequencing has begun to shed light on the complex
underlying pathways affecting development of the brain which result in hydrocephalus.

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KEY POINTS
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• Hydrocephalus is a phenotypic feature associated with a diverse set of genetic

syndromes in childhood

• Pathogenesis and accompanying phenotypic features,as well as inheritance

patterns,vary between and within syndromes

• Next-generation sequencing studies now identify underlying genetic causes of

hydrocephalus, previously categorized as “congenital hydrocephalus”.
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SYNOPSIS
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Hydrocephalus, the abnormal accumulation and impaired circulation/clearance of

cerebrospinal fluid, occurs as a common phenotypic feature of a diverse group of
genetic syndromes. In this review we outline the genetic mutations, pathogenesis,
and accompanying symptoms underlying syndromic hydrocephalus in the context
of: L1 syndrome, syndromic craniosynostoses, achondroplasia, NF 1/2, Down’s
syndrome, tuberous sclerosis, Walker-Warburg syndrome, primary ciliary dyskinesia, and
osteogenesis imperfecta. Further, we discuss emerging genetic variants associated with
syndromic hydrocephalus.
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CLINICS CARE POINTS

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• Management of syndromic hydrocephalus may require direct surgical

treatment with VPS or ETV (±CPC) and/or treatment of associated pathology
resulting in hydrocephalus such as tumors obstructing CSF flow.

• Treatment options vary depending on a variety of patient- and syndrome-

specific factors.

• In sporadic cases of congenital hydrocephalus, genetic screening for recently

described variants may eventually influence treatment decisions, though at
this stage few pathway-specific therapeutics are available
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Figure 1.
1-day-old with L1 syndrome resulting in hydrocephalus and aqueductal stenosis treated on
day-of-life 1 with a VP shunt. T2-weighted MRI (A) sagittal and (B) axial views.
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Figure 2.
14-month-old with NF-1 presented with enlarged ventricles, transependymal CSF, and low
tonsil position. Patient underwent Chiari decompression and subsequent treatment with ETV.
T2-weighted MRI (A) sagittal and (B) axial views
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Figure 3.
1 day old with POMT-1 P273L Walker-Warburg syndrome, born at 35 weeks gestation.
MRI A) sagittal (T1) and B) axial (T2) views showing hydrocephalus with tectal dysplasia
contributing to aqueductal stenosis. This patient was treated with a VP shunt on day of life 4
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Table 1.

Genetic Basis of Syndromes Associated with Hydrocephalus

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Syndrome Type of Disorder Mode of Inheritance Genetic Locus

L1 Syndrome, and X-Linked

Neuronal Adhesion X-linked L1CAM
Hydrocephalus
FGFR1 (Pfeiffer), FGFR2
Syndromic Craniosynostoses (Pfeiffer,
Primary cerebral maldevelopment Heterogeneous (Crouzon; Apert; Pfeiffer), FGFR3
Crouzon, Apert, Muenke)
(Muenke)

Achondroplasia Growth Factor Autosomal Dominant FGFR3

NF 1 RASopathy Autosomal Dominant NF1 (17q11.2)

NF 2 RASopathy Autosomal Dominant NF2 (22q12)

Down’s Syndrome Trisomy Non-disjunction Chromosome 21

DNAH5, DAIC1, CCDC151,

Tuberous Sclerosis mTOR related Autosomal Dominant
MCIDAS, FOXJ1
POMT1, POMT2, POMGNT1,
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Walker-Warburg Syndrome/ Brain-

Dystroglycanopathies Autosomal Recessive
muscle-eye disease FKTN, FKRP, LARGE, ISPD
Primary Ciliary Dyskinesia Ciliopathy Heterogeneous DNAH5, MCIDAS, FOXJ1

Osteogenesis Imperfecta Connective tissue Autosomal Dominant COL1A1 and COL1A2

Pettigrew Syndrome Vesicle trafficking X-linked AP1S2

Costello Syndrome RASopathy Autosomal Dominant HRAS

CBL, KRAS, NRAS, PTPN11,

Noonon Syndrome RASopathy Autosomal Dominant
SOS1, SHOC2 and RAF1

Cardio-facio-cutaneous (CFC)
RASopathy Autosomal Dominant BRAF, MEK1, KRAS and MEK2
syndrome

Megalencephaly-polymicrogyria-
PI3K-AKT-mTOR pathway Autosomal Dominant AKT3, CCND2 and PIK3R2
polydactyly-hydrocephalus (MPPH)

Megalencephaly-capillary-
PI3K-AKT-mTOR pathway N/A PIK3CA
malformation (MCAP)
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