Cephaloceles (including Occipital Cephalocele and Knobloch Syndrome)

Congenital herniation of meninges, with or without brain tissue, through a bony defect of the skull; an anatomical finding with chromosomal, monogenic, disruptive, teratogenic and multifactorial causes, among them Meckel-Gruber syndrome, Knobloch syndrome and the dystroglycanopathies.

Literature and regulatory information updated: 29 October 2026.

0. Initial Reference Table

Cephalocele is a morphological finding rather than a single disease, which is why the table distinguishes the malformation itself, its topographic subtypes and the monogenic syndromes in which cephalocele is a cardinal sign. Meckel-Gruber syndrome and Joubert syndrome appear here only as differential diagnoses.

0.1. Syndromes with cephalocele and related entities

1. Introduction

1.1. Definition and terminology

Cephalocele is the extracranial protrusion of intracranial structures through a defect of the skull and dura mater; the resulting mass is usually covered by skin or by a thin membrane and resembles a sac [1]. The term is generic and encompasses variants defined by the contents of the sac: the meningoencephalocele contains cerebrospinal fluid (CSF), meninges and brain tissue; the cranial meningocele contains only meninges and CSF; the gliocele is a glia-lined cyst filled with CSF; the atretic cephalocele is a small lesion made up of dura mater, fibrous tissue and degenerated brain tissue [1]. In clinical practice, “encephalocele” is used as a synonym for cephalocele, although strictly speaking it refers to lesions containing brain tissue. These lesions together with their minimal bony forms are sometimes described as cranium bifidum, a term that includes cranium bifidum occultum, without herniation [2].

Orphanet organises the cephaloceles into a clinical group (ORPHA:268817) with subtypes defined by location: occipital, parietal, frontal, nasal and basal; isolated encephalocele (ORPHA:199647) is defined as a rare neural tube defect with sac-like protrusions of brain and meninges, which may lie at any point of the skull, mainly in the occipital region, and which, depending on size and location, is accompanied by intellectual disability, epileptic seizures, visual impairment, ataxia and hydrocephalus [5, 11]. The International Classification of Diseases (ICD-10) codes encephalocele under Q01, with Q01.0 frontal, Q01.1 nasofrontal, Q01.2 occipital and Q01.8 other sites; ICD-11 groups them all under LA01 [5, 6, 8, 9].

1.2. Topographic classification

The most widely used anatomical classification distinguishes cephaloceles of the vault (occipital, parietal and, rarely, temporal), sincipital or frontoethmoidal cephaloceles, visible on the face, and basal cephaloceles, hidden in the skull base [2, 5]. Occipital cephalocele lies in the midline of the occipital bone, between the lambda and the foramen magnum, and is subdivided into supratorcular and infratorcular according to its relationship with the torcula; the sac may contain meninges, occipital lobes, ventricles and, less often, cerebellum, brainstem or the torcula itself, and the bony defect may extend to the posterior lip of the foramen magnum and to the posterior arch of the atlas [1]. When the occipitocervical herniation contains cerebellum, the lesion is classified as Chiari type III malformation [1, 41]. The term giant cephalocele applies when the sac exceeds the size of the newborn's head [1].

Frontoethmoidal cephaloceles emerge through the foramen caecum and are subdivided, according to their exit route on the face, into nasofrontal, nasoethmoidal and naso-orbital; in a Cambodian series of 257 patients, the nasoethmoidal type accounted for 69% of cases [42]. A later alphanumeric classification (FEEM classification) combines facial deformity, external bony defect, herniation route and brain malformation, and describes forms without an underlying external bony defect and masses separated from the defect (“sequestered cephalocele”) [43]. Orphanet's nasal encephalocele corresponds to herniation into the fonticulus frontalis, with widening of the nasal root and a compressible, bluish, pulsatile mass that enlarges with crying or jugular compression, or to an intranasal mass arising from the cribriform plate that may obstruct the airway [9]. Basal cephaloceles (transethmoidal, sphenoethmoidal, transsphenoidal and spheno-orbital) are not externally visible; Orphanet treats them as a separate subtype (ORPHA:268829), and one of their syndromic associations, frontonasal dysplasia with optic disc anomalies, includes diabetes insipidus and pituitary deficiency [10, 38].

1.3. Historical perspective

Occipital encephalocele was described as a component of the syndrome described by Meckel in 1822 and redescribed by Gruber in 1934, whose autosomal recessive nature and spectrum were delineated in the 20th century [33]. The work of Fraser and Lytwyn in 1981, with 38 secondarily ascertained cases, showed that cystic renal dysplasia was constant in this syndrome, but that encephalocele occurred in 63% and that 18% had no brain malformation, which ruled out cephalocele as a mandatory criterion [14, 33]. In 1971, Knobloch and Layer described the association of high myopia, retinal detachment and occipital encephalocele that now bears their name [44]; the COL18A1 gene was identified in 2000 in a consanguineous Brazilian family [12], and a second, dominant form caused by PAK2 was characterised in 2021 [4]. The observation that frontoethmoidal cephaloceles predominate in South-East Asia, in rural populations, and that they rarely recur in families, steered research towards environmental causes in those regions [42, 45, 46].

1.4. Neural tube defect or post-neurulation malformation

Sources diverge on the primary mechanism. Firth and Hurst's handbook classifies encephalocele among the closed neural tube defects (NTDs), in which the early neural tube is abnormal but there has been no failure of closure, and describes encephalocele as herniation of the already closed neural tube through a bony defect [14]. The Brazilian handbook Síndromes Genéticas: Reconhecer para Tratar and the Orphanet definition describe it as failure of closure of the cephalic end of the neural tube [11, 47]. A mouse model with conditional ablation of Rac1 in the surface ectoderm produced, in the same litter, open spina bifida, exencephaly and occipito-parietal encephalocele; in the latter, the neural tube closed normally and it was the late rupture of the surface ectoderm that allowed herniation, with a large overlying cranial defect [48]. These data support a post-neurulation pathogenesis, compatible with genetic causes shared with open NTDs [48]. For frontoethmoidal forms, a failure of separation between the neural and surface ectoderm at the site of final closure of the rostral neuropore, in the fourth week, has been proposed, with a secondary mesodermal defect at the foramen caecum [49].

Epidemiology supports a close but not identical relationship with the other NTDs. In the Metropolitan Atlanta Congenital Defects Program (1968–2002), encephalocele shared with anencephaly the excess in females and in multiple pregnancies and shared with both open NTDs the annual decline in prevalence (−1.2% for encephalocele, −3.6% for anencephaly and −4.2% for spina bifida), but after mandatory folic acid fortification of cereals in the USA only spina bifida decreased significantly [50]. In Western Australia, promotion of supplements and voluntary fortification were associated with similar reductions in anencephaly (32%), spina bifida (23%) and encephalocele (34%) between 1996–2006 and 1980–1992 [51].

2. Molecular Genetics and Pathophysiology

2.1. Aetiological architecture

Cephalocele results from four broad groups of causes: isolated forms of multifactorial cause, which are the majority; monogenic syndromes; chromosomal anomalies; and disruptive or teratogenic mechanisms [1, 14]. In the Murcia series of 46 children with cranium bifidum, there was parental consanguinity in 7, a family history of central nervous system (CNS) malformation in 8, associated systemic anomalies in 23 and other CNS anomalies in 36 [2]. In the Atlanta registry, 79% of the 83 live births with encephalocele had an isolated defect [52]. In a population-based study from California and Illinois (1985–1987), cited by OMIM, 22.9% (8 of 35) of postnatal encephaloceles had anomalies unrelated to the NTD, compared with 14.9% (45 of 303) of all NTDs, and Meckel-Gruber syndrome was the most frequently identified specific syndrome; the authors concluded that a multifactorial cause should not be presumed in an encephalocele before a complete evaluation [53]. In a series of 35 fetuses diagnosed in the 1st trimester, there were no aneuploidies, but 11% had Meckel-Gruber syndrome, 6% a disruptive syndrome and 3% a skeletal dysplasia [20]. A narrative review cites encephalocele as a component of more than 30 syndromes and lists chromosomal anomalies described with NTDs (monosomy X, trisomies 13, 18 and 21, mosaicism for various trisomies and tetraploidy), but gives internally inconsistent proportions of associated malformations (60% in one paragraph, 15–20% in another), so these figures are not used as an estimate [1].

2.2. Isolated forms: multifactorial susceptibility

In non-syndromic NTDs, recurrence in multigenerational families is rare despite the high frequency, which indicates multifactorial causation with environmental (folate status) and genetic components [14]. The risk variants described belong mainly to the folate pathway and the planar cell polarity pathway: the C677T and A1298C polymorphisms (historical numbering, = NM_005957.5:c.665C>T p.(Ala222Val) and NM_005957.5:c.1286A>C p.(Glu429Ala)) of the methylenetetrahydrofolate reductase gene (MTHFR) are associated with an approximately 1.8-fold higher risk of NTD, an effect observed only in non-Hispanic populations; missense variants have been described in the glycine cleavage system genes (AMT, GLDC) and planar cell polarity genes (CELSR1, VANGL2) in cases and not in controls [14]. Because they have a small effect or are rare, analysis of these genes has no routine clinical utility [14]. For the frontoethmoidal cephaloceles of East Java, one study did not find the MTHFR C677T allele in patients, which reinforces the aetiological heterogeneity between sites [54]. OMIM groups the NTD susceptibility genes in a separate entry (182940), which includes VANGL2 and FUZ.

2.3. Knobloch syndrome type 1 and the COL18A1 gene

The COL18A1 gene (21q22.3; MANE transcript NM_001379500.1) encodes the α1 chain of collagen XVIII, a basement membrane multiplexin whose C-terminal domain, once cleaved, gives rise to endostatin, an inhibitor of endothelial proliferation and of vascular endothelial growth factor A-dependent angiogenesis [39]. The original Brazilian family had a homozygous variant at the splice acceptor site of intron 1, present in all 12 patients and absent from 140 control chromosomes, predicted to create a stop codon in exon 4 and truncation of the short isoform, which is expressed in the adult retina [12]. The mechanism is loss of function: the pathogenic variants described in recent cohorts are mainly truncating and biallelic, and collagen XVIII is required for retinal structure and neural tube closure [12, 21, 55]. There is no circulating biomarker of the deficiency in clinical use [39].

Inheritance is autosomal recessive, with consanguinity in 76% of a multicentre cohort of 34 patients [21]. Molecular confirmation is not always obtained: in a Saudi cohort of 50 patients with a clinical diagnosis, 37 (74%) had molecular confirmation [23], and in a series of 7 families only one variant was identified, in a family with 2 affected members [22]. The gene therefore has two inheritance patterns: in addition to recessive Knobloch syndrome, OMIM lists an autosomal dominant primary angle-closure glaucoma (OMIM 618880), described in a five-generation consanguineous Iranian family with the heterozygous missense variant NM_130444.3:c.550G>A p.(Glu184Lys) (short isoform; described in NM_130444.2; in the MANE transcript NM_001379500.1 it corresponds to the intronic position c.107-12162G>A; NC_000021.9:g.45456080G>A) segregating with the disease [15]. Consistently, acute angle closure has been described in two homozygous siblings with Knobloch syndrome [56]. In a study of 8 patients with Knobloch syndrome, the pathogenic variants found in 5 were all truncating, with deficiency of one or all isoforms of collagen XVIII and of endostatin, and the study of Hungarian and New Zealand families demonstrated genetic heterogeneity [15]. The allelic spectrum extends to phenotypes without encephalocele: four sisters with anterior polymicrogyria, refractory epilepsy with a Lennox-Gastaut phenotype, intellectual disability and complex ocular anomalies were compound heterozygous for truncating variants [57], and four patients evaluated for brain malformations had homozygous frameshift variants [58].

2.4. Knobloch syndrome type 2 and the PAK2 gene

The historical family designated KNO2, a New Zealand family published in 1998 and restudied in 2004 [13], combined intellectual disability, autistic behaviour, retinal degeneration and encephalocele; exome sequencing of the two siblings and their parents identified the PAK2 variant p.(Glu435Lys) (NM_002577.4:c.1303G>A according to OMIM), monoallelic and apparently de novo in both, which suggests germline mosaicism in a parent, not detected in blood by deep sequencing [4]. The PAK2 protein is a p21-activated serine/threonine kinase; the variant lies in the kinase domain and partially reduces activity in HEK293T cells [4]. A second patient, with a de novo variant NM_002577.4:c.1273G>A p.(Asp425Asn) identified by genome sequencing, had global delay, congenital retinal detachment, mild ventriculomegaly, hypotonia, pyloric stenosis and patent ductus arteriosus; the variant had not been reported in an earlier test because the significance of PAK2 was then unknown, which illustrates the value of reanalysis [19]. The notation of this variant was confirmed in VariantValidator (NC_000003.12:g.196820490G>A; MANE transcript NM_002577.4) [59].

2.5. Ciliopathies: Meckel-Gruber syndrome and the Joubert spectrum

The proteins encoded by the Meckel-Gruber syndrome genes localise to the centrosome, the pericentriolar region or the primary cilium, and Smith lists 17 genes (MKS1, TMEM67, TMEM107, TMEM216, TMEM231, CEP290, CC2D2A, RPGRIP1L, B9D1, B9D2, NPHP3, TCTN2, C5orf42/CPLANE1, CSPP1, KIF14, TXNDC15 and CEP55), which account for 50–60% of cases [33]. The same genes cause forms of Joubert syndrome and other ciliopathies, and hypomorphic variants in syndromic encephalocele genes have been associated with Bardet-Biedl syndrome [60, 61]. In patients with atretic occipital cephalocele, MRI may reveal Joubert syndrome associated with Dandy-Walker malformation (“Joubert-plus”); two normocephalic patients without dysmorphism, with a pathogenic variant in CPLANE1, have been described [34]. The OMIM entries for these genes illustrate three points relevant to cephalocele: Meckel syndrome is described as an autosomal recessive fetal disorder whose cardinal signs are occipital meningoencephalocele, cystic renal dysplasia, hepatic fibrosis and polydactyly [62]; there are founder variants, such as the CC2D2A splice variant found in the homozygous state in 11 of 17 unrelated Finnish fetuses with Meckel type 6 [63] or the 1-bp deletion of CEP290 in fetuses from two consanguineous families from Kosovo [64]; and the same genotype can cause Meckel in one fetus and Joubert in a sibling, such as the homozygous TMEM216 variant NM_001173990.3:c.218G>A p.(Arg73His) in two Turkish siblings [65]. The complete genetic architecture, the remaining founder variants and the genotype-phenotype correlations of these ciliopathies are specific to Meckel-Gruber syndrome and Joubert syndrome.

2.6. Dystroglycanopathies

In Walker-Warburg syndrome, biallelic variants affect at least 15 genes involved in O-mannosylation of α-dystroglycan (POMT1, POMT2, POMGNT1, FKTN, FKRP, LARGE1, ISPD/CRPPA), which account for 35–40% of cases; the collagen IV α1 gene (COL4A1), a basement membrane component, is another described mechanism [35]. OMIM groups Walker-Warburg syndrome and muscle-eye-brain disease under congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), autosomal recessive and genetically heterogeneous, and records the designation HARD ± E (hydrocephalus, agyria, retinal dysplasia, with or without encephalocele) [66]. The resulting phenotype combines cobblestone (type II) lissencephaly, retinal dysplasia and congenital muscular dystrophy [35, 67]. The dystroglycanopathy class enters the differential.

2.7. Autosomal dominant Dandy-Walker with occipital cephalocele and NID1

The familial autosomal dominant form of Dandy-Walker malformation with occipital cephalocele (ADDWOC, OMIM 609222) was initially described as autosomal dominant atretic occipital cephalocele in a Vietnamese-American family with 7 affected members over 3 generations, reclassified after MRI of other relatives, which showed posterior fossa and cerebellar changes in 7 individuals without apparent cephalocele; only 2 individuals of the third generation had neurological manifestations [68]. Also described were a non-consanguineous Brazilian family with atretic occipital cephalocele in 6 people over 4 generations and variable expressivity, including two siblings with epilepsy from the 1st year, spastic gait and severe intellectual disability, and an Indian family in which the father of a fetus with cephalocele had only a small occipital lesion with alopecia [68]. This form was mapped to 2q36.1 in the same Vietnamese-American family (multipoint LOD 3.3; 1.1 Mb interval), with no variants in the five genes in the interval; a similar Brazilian family showed no linkage to this locus, which demonstrates heterogeneity [37]. Subsequently, the NID1 variant NM_002508.3:c.1162C>T p.(Gln388Ter) (NC_000001.11:g.236038227G>A, confirmed in VariantValidator) was found in two independent three-generation families, with incomplete penetrance and expressivity ranging from arachnoid cyst to small occipital bony defect and cephalocele; the authors proposed the designation “posterior fossa anomalies with occipital cephaloceles, autosomal dominant” [36, 59]. Nidogen 1, encoded by NID1, is another basement membrane protein, as are collagen XVIII and collagen IV [36]. According to OMIM, the same p.(Gln388Ter) variant was identified by Darbro and colleagues (2013) in 14 affected members of the large three-generation Vietnamese family, the same family as in the linkage analysis, predicted to cause loss of the G2 and G3 domains that include the beta-propeller binding laminin γ1 (LAMC1); OMIM keeps the variant classified as of uncertain significance for ADDWOC, because its contribution is not confirmed, and the title of Darbro's work also attributes the disorder to LAMC1 variants [69]. The relationship between the 2q36.1 locus and NID1, located on chromosome 1, is not clarified in the sources consulted, and the molecular diagnosis of ADDWOC should therefore be interpreted with caution.

2.8. Frontonasal dysplasias and other monogenic forms

The ALX-related frontonasal dysplasias are autosomal recessive: ALX3 causes frontorhiny (FND1), biallelic ALX4 causes FND2 with alopecia and genital anomalies, and ALX1 causes FND3, with extreme microphthalmia and oblique facial clefts, described in two consanguineous families with a homozygous 3.7 Mb deletion or a homozygous splice variant [39]. In the heterozygous state, ALX4 (and MSX2) causes enlarged parietal foramina, symmetrical defects of parietal ossification that are usually asymptomatic [39]. Frontonasal dysplasia was defined by Sedano and colleagues (1970) by the presence of two or more of: true ocular hypertelorism, broadening of the nasal root, median facial cleft of the nose and/or upper lip and palate, unilateral or bilateral clefting of the alae nasi, absent nasal tip, anterior cranium bifidum occultum and V-shaped frontal hairline; anterior cranium bifidum is the point of contact with the frontal cephaloceles [70]. Acromelic frontonasal dysostosis is due to a single heterozygous activating ZSWIM6 variant (NM_020928.2:c.3487C>T p.(Arg1163Trp)), present in all genotyped cases, and is associated with severe intellectual disability [38]. Frontonasal dysplasia with optic disc anomalies, basal encephalocele, agenesis of the corpus callosum, diabetes insipidus and pituitary deficiency has only been described in sporadic cases [38, 71]. Other monogenic disorders in which encephalocele is occasional include Pallister-Hall syndrome (GLI3), Fraser syndrome, Roberts syndrome (frontal encephalocele), Adams-Oliver syndrome, achondrogenesis IA (TRIP11), thanatophoric dysplasia type II (FGFR3; a fetus with occipital encephalocele and the variant NM_000142.5:c.1948A>G p.(Lys650Glu) was described as the second published case [72]), dyssegmental dysplasia, boomerang dysplasia (FLNB) and synostosis with radiohumeral fusions (CYP26B1), which Orphanet calls “lethal occipital encephalocele-skeletal dysplasia syndrome” [73–80]. Encephalocele has also been described, as an occasional finding, in the oculo-auriculo-vertebral spectrum, in the MURCS association (Müllerian aplasia, renal aplasia and cervicothoracic somite dysplasia), in the cloacal exstrophy sequence and in a lethal case of Werner-type mesomelic dysplasia [81–84].

2.9. Environmental and disruptive causes

Diabetic mothers and epileptic mothers treated with sodium valproate have a relative risk of NTD about 10 times higher, and severe maternal obesity before pregnancy about 3 times [14]. In retrospective studies of more than 170 NTD cases, including occipital encephaloceles, about 10% of mothers reported hyperthermia in the week of neural tube closure (days 21 to 28), compared with none of the control mothers [85]. In the frontoethmoidal cephaloceles of Burma, the lower proportion of conceptions in the cold season, the longer interval since the previous pregnancy and the absence of affected first-degree relatives point to an environmental factor [45]. The anterior encephaloceles of the limb-body wall complex, often multiple and sometimes adherent to the amnion, result from a disruptive mechanism different from the amniotic band sequence, to which they were mistakenly attributed [40, 86].

2.10. Variants cited, normalised

The second variant of Corbett and colleagues (NM_030582.3:c.3690G>A) is not compatible with the stated reference sequence (the nucleotide at that position is C), so it could not be normalised as published [57, 59]. The PAK2 variant p.(Glu435Lys) of the KNO2 family is described by OMIM as NM_002577.4:c.1303G>A; the notation matches the MANE transcript, with consequence p.(Glu435Lys) [13]. OMIM classifies the relationship between PAK2 and Knobloch syndrome 2 as provisional [13].

3. Clinical Spectrum and Manifestations by System

3.1. Presentation of occipital cephalocele

Occipital cephalocele presents as a midline swelling of variable size over the occipital bone, covered by intact skin, dysplastic skin or a thin membrane; the bony defect may measure from a few millimetres to more than 20 cm, and in one series cited in Markovic's review 16% of children had lesions larger than 20 cm [1]. The head is often small, and the lesion is more frequent in females, with about 70% girls in the series summarised by the same review [1]. In the Los Angeles series (1994–2012, 70 operated children), 80% of lesions were posterior to the coronal suture, the mean maximum diameter was 4 cm (median 3.1 cm; range 0.5–23 cm), 67% contained neural tissue and 8 newborns had CSF leakage at birth, one of them infected [25]. In the Tunisian series of 40 children treated for occipital cephalocele over 23 years, the male/female ratio was 0.38 and hydrocephalus was the most frequent associated anomaly (40%) [87].

Neurological manifestations depend on the size, location, amount and type of herniated tissue, CSF circulation and associated anomalies; some children have a normal examination, others show delayed developmental milestones, intellectual disability, learning difficulties, growth retardation, epilepsy, visual impairment, ataxia, hydrocephalus, spastic paraparesis or tetraparesis and microcephaly [1, 11]. Epilepsy occurs in at least 15% of cases [1]. Associated intracranial anomalies include Chiari type II or III malformation, Dandy-Walker malformation, holoprosencephaly, aqueductal stenosis, agenesis of the corpus callosum, subependymal heterotopia, craniosynostosis and syringomyelia, and venous MR angiography often shows venous sinuses displaced or stretched into the sac, sometimes with a persistent falcine sinus [1].

3.2. Hydrocephalus

Hydrocephalus is the complication that most determines prognosis. Markovic's review reports hydrocephalus in about 60% of newborns with occipital cephalocele and a risk of 60–70%, especially after repair, attributed to kinking or stenosis of the aqueduct of Sylvius and to altered CSF dynamics after closure of the sac [1]. Recent surgical series give lower figures: in the Los Angeles series, 17 of 70 children (24%) had hydrocephalus, 6 already before surgery and 11 progressively after it, and 15 received a shunt [25]; in Tunis, secondary postoperative hydrocephalus occurred in 37.5% [87]. The presence of neural tissue in the sac was associated with hydrocephalus with borderline significance in multivariate analysis (odds ratio 5.8; 95% confidence interval 0.8–74.0) [25]. The difference between anterior (14%) and posterior (27%) lesions was not significant (p = 0.49) [25].

3.3. Neurodevelopment

In the Los Angeles series, with a mean follow-up of 3.7 years, 40% of children were neurologically normal, 40% had mild to moderate delay and 20% severe delay; none of the 17 children with hydrocephalus had normal development, and hydrocephalus was the only significant factor for neurological deficit in the multivariate model (odds ratio 17.2; confidence interval 1.7–infinity) [25]. In Murcia (46 children, mean follow-up 7 years), 20 of the 29 survivors had no neurological sequelae and 18 had an intellectual level considered competitive; good outcome correlated with normal head circumference at birth, normal initial neurological status, operable lesion and absence of neuronal migration disorder, and intellectual level was related above all to the absence of brain tissue in the sac [2]. In Tunis, 67.6% of children had psychomotor delay and 10% visual agnosia, with preoperative hydrocephalus, herniation of functional brain tissue and late surgery as adverse factors in univariate analysis [87].

3.4. Survival

The Atlanta population cohort (1979–1998) included 83 live births with encephalocele: 76% of deaths occurred on the first day of life, and the probability of survival was 70.8% at one year (confidence interval 60.9–80.7) and 67.3% at 20 years (55.7–78.8) [52]. Survival was 74.3% in isolated cases and 41.2% in cases with multiple defects; low birth weight (<2500 g; relative risk 5.18), multiple defects (relative risk 2.82) and Black ethnicity (relative risk 2.36, confidence interval 0.95–5.85) were associated with higher mortality [52]. These values refer to live births and do not include fetal losses or terminations of pregnancy, so they do not describe the outcome of all diagnosed fetuses. In the Murcia series, overall mortality was 36% (17 of 46), with no operative deaths in 35 repairs [2]; in Tunis, 10% [87]. Markovic's review cites overall morbidity and mortality ranges of 55–83% and a mortality of 2% in selected series that excluded associated malformations, large lesions with much brain tissue and microcephaly, which shows the weight of selection in published figures [1].

3.5. First-trimester diagnosis and fetal course

In a series from four fetal medicine centres, 35 fetuses had cephalocele diagnosed in the 1st trimester: 13 (37%) cranial meningoceles and 22 (63%) encephaloceles; the defect was occipital in 77%, frontal in 9%, parietal in 9% and unclassifiable in 6%, with small, medium and large sizes in similar proportions [20]. There was loss to follow-up in 23%; of the remaining 27, the parents opted for termination of pregnancy in 21, and of the 6 continuing pregnancies there were 4 miscarriages or fetal deaths in the 2nd trimester, one neonatal death and a single survivor, operated on in the neonatal period for an isolated meningocele and with a favourable course [20].

3.6. Frontoethmoidal cephaloceles

Frontoethmoidal cephaloceles present as a mass at the nasal root or at the inner canthus, with hypertelorism and widening of the nasal pyramid; in a prospective series of 30 patients, all had interorbital hypertelorism and a developed nose [49]. In the Cambodian series of 200 operated patients, 46% had associated ophthalmological problems, and the family questionnaire documented relevant social and educational consequences, partly corrected by surgery [42].

3.7. Atretic cephalocele

Atretic cephalocele is a small, nodular or flat lesion in the parietal or occipital midline, without CSF, made up of fibrous tissue, dura mater and remnants of degenerated brain tissue [1, 25]. In the Murcia series it was the most frequent form (26 of 46), which the authors interpreted as geographical variation [2]. The association with brain malformations may not be evident on examination: two patients with a suboccipital swelling, normocephalic and without dysmorphism, had Joubert syndrome with Dandy-Walker and a pathogenic variant in CPLANE1 [34]. Two imaging publications from 2025 and 2026 in general journals documented atretic cephalocele as a cause of cranial swelling in infants [88, 89].

3.8. Knobloch syndrome

In 1971, Knobloch and Layer described a sibship in which 5 of 10 siblings had high myopia, vitreoretinal degeneration with detachment and occipital encephalocele, all with normal intelligence; in the consanguineous Brazilian family of 1994, with 12 patients, the occipital lesion of one of them was a non-cystic extracranial nodule, covered by thin skin, over a 6 mm midline bony defect [90]. Some authors considered that scalp defects with heterotopic neuronal tissue, rather than true encephaloceles, accompany some of the cases [90]. The ocular phenotype defines the syndrome and is present from early childhood. In the Moorfields, Portland and Houston series (12 patients from 7 families, mean age at last assessment 16 years), all had high myopia in at least one eye and very reduced vision; there was absence of iris crypts, iris transillumination, lens subluxation, cataract, collapsed vitreous, macular atrophy and tessellated fundus; the electroretinogram showed cone-rod dysfunction in 8, very reduced or undetectable responses in 2 and asymmetry between eyes in 2; two patients with iris transillumination had glaucoma [22]. Biometry of 12 eyes showed that the myopia is axial (axial length 26.58–30.27 mm, mean 28.16; axial length/corneal radius ratio 3.23–3.77), with spherical equivalents of −10.00 to −18.50 dioptres, corrected acuity usually 20/300 or worse, and optical coherence tomography (OCT) showed absence of choriocapillaris, disorganisation of the outer retina and an absent or rudimentary foveal pit, i.e. a choroidopathy that is part of the phenotype [91]. A child with iris transillumination and an albinotic fundus was initially diagnosed with albinism [55].

Retinal detachment is the defining complication and appears early. It affected 48 of 100 eyes (48%), at a mean age of 6.5 years, in a Saudi cohort of 50 patients (1983–2023) [23]; 50% of 68 eyes, at a median of 2.5 years, in a Turkish and Emirati cohort of 34 patients [21]; and 23 of 72 eyes (31.9%), at a mean age of 6.24 years and with 12 already present at first examination, in a North American cohort of 36 genetically confirmed patients [26]. Detachment associated with a macular hole accounted for 33% of detachments in the Saudi cohort and 57% in the Turkish cohort, at a median of 11 months; the holes are small, flap-like, and may be visible only on OCT, and in infants they manifest only as poor fixation and nystagmus [21, 23, 92].

The occipital defect is variable and may be absent. In the Hull series, 3 patients had encephalocele or meningocele, 4 an occipital bony defect, 2 minor occipital changes and 2 normal imaging, and 5 had cutaneous scalp changes [22]; 44% of the Saudi cohort had a documented occipital bony defect or scalp lesion [23], and 47.2% of the North American cohort had an occipital defect [26]. Intracranial anomalies appeared in 27.8% of the North American cohort (polymicrogyria, cortical dysplasia, encephalomalacia, periventricular heterotopia) [26]; the Hull series recorded learning difficulties, epilepsy and congenital renal anomalies in 8 of 12 patients [22], and a West Virginia series described epilepsy, aplasia cutis congenita, renal anomalies, occipital encephalocele and global delay [93]. The North American cohort also recorded cataracts in 25.0% of eyes, iris defects in 20.0%, optically empty vitreous or vitreous with condensations in 57.1% and macular anomalies in 91.4% [26]. Cases of acute angle closure have been described in homozygous siblings [56].

3.9. Knobloch syndrome type 2

Patients with PAK2 variants described so far combine ocular involvement (retinal degeneration or congenital retinal detachment), intellectual disability or global delay, autistic behaviour in the original family and encephalocele in that family; the second patient had no encephalocele described and presented with hypotonia, faltering growth, pyloric stenosis, patent ductus arteriosus and mild dysmorphism [4, 19]. OMIM describes KNO2 as severe vitreoretinal degeneration with occipital defects ranging from mild encephalocele to abnormally pigmented hair, and mild or severe developmental delay; in the New Zealand family, the two siblings had high myopia, vitreoretinal degeneration, retinal detachment and occipital encephalocele or scalp lesion, and one of them patent ductus arteriosus, single umbilical artery and pyloric stenosis [16]. With only two families, the clinical spectrum is not delineated.

3.10. Other syndromes with cephalocele

In Walker-Warburg syndrome, type II lissencephaly and cerebellar malformation are present in all cases, occipital encephalocele, sometimes small, in 24%, Dandy-Walker malformation in 53%, hydrocephalus in 53%, anterior chamber malformation in 91%, retinal changes in all and congenital muscular dystrophy in all; most die in the first year and 5–10% survive beyond 5 years [35]. In Meckel-Gruber syndrome, occipital encephalocele coexists with cystic renal dysplasia, hepatic fibrosis and postaxial polydactyly, and survival rarely exceeds days or weeks [33]. In a compilation of published cases cited by OMIM, 57% had the triad of encephalocele, polycystic kidneys and polydactyly, and 16% only encephalocele and polycystic kidneys [53]. In ADDWOC, McNiven and colleagues describe usually normal neurological development [36], but expressivity is variable: in the Vietnamese family only 2 of several affected members had neurological manifestations, and in a Brazilian family two siblings had epilepsy, spasticity and severe intellectual disability [68]. In the Lucknow series, the association of Dandy-Walker malformation with occipital encephalocele occurred in 5 of 128 patients with Dandy-Walker (3.9%), with giant encephaloceles in 4 and adequate later development in 2 [94].

4. Clinical Recognition and Warning Signs

4.1. Prenatal period

Cephalocele is visible from the end of the 1st trimester; ISUOG (International Society of Ultrasound in Obstetrics and Gynecology) states that defects of dorsal and rhombencephalic induction can be recognised at this stage and that assessment at 12–15 weeks benefits from the reduced thickness of the bones [95]. In Sepulveda's series, the diagnosis was made while observing the cranial contour in the axial (biparietal diameter) and sagittal (nuchal translucency) planes of the aneuploidy screening scan [20]. In the 2nd trimester, the CNS screening examination should include head shape and the spine [95]. Findings that should point to a syndrome are enlarged and hyperechogenic or cystic kidneys, polydactyly, oligohydramnios (Meckel-Gruber), ventriculomegaly and posterior fossa anomalies (Joubert, Meckel, Dandy-Walker), microphthalmia, cataract or retinal dysplasia (Walker-Warburg, Knobloch), facial clefts, limb or abdominal wall defects (limb-body wall complex) and limb shortening (skeletal dysplasias) [40, 44, 60, 96, 97].

4.2. Newborn and infant

In the newborn, the skin covering the lesion determines urgency: a lesion without skin cover, with CSF leakage or at risk of rupture should be operated on as early as possible, whereas a well-covered lesion allows surgery to be planned [1, 25]. Warning signs during follow-up are rapid growth of head circumference, a tense fontanelle, irritability or vomiting (hydrocephalus), epileptic seizures and fever (meningitis) [25, 87]. Nasal encephalocele is suspected in the presence of a bluish, pulsatile, compressible mass at the nasal root that enlarges with crying or jugular compression, or of an intranasal mass arising from the cribriform plate causing nasal obstruction or respiratory difficulty [9]. A review in the Brazilian handbook lists congenital frontonasal masses (dermoid cyst, glial heterotopia and encephalocele) as an imaging differential diagnosis [47].

4.3. Child with early high myopia

A child with nystagmus, high myopia, tessellated fundus and macular atrophy, especially with an occipital scalp lesion, aplasia cutis or cephalocele, should be assessed for Knobloch syndrome, even if brain imaging is normal [22, 93]. In a child with the diagnosis, any sudden change in fixation, new nystagmus or change in visual behaviour is a possible retinal detachment and requires urgent examination [39, 92].

4.4. Family context

The family history should cover three generations, stillbirths and neonatal deaths, consanguinity, diabetes (including gestational), exposure to anticonvulsants and folate antagonists and use of folic acid before conception [14]. The finding of small occipital bony defects or arachnoid cysts in other relatives suggests ADDWOC [36], and that of high myopia with retinal detachment in the sibship suggests Knobloch syndrome [21].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no formal criteria for isolated cephalocele beyond imaging demonstration of the bony and dural defect with herniated contents; aetiological diagnosis is based on characterisation of the contents, the search for associated anomalies and targeted genetic investigation [1, 14]. For Knobloch syndrome there are no consensus criteria or scientific society guidelines; the ocular phenotype is described as often pathognomonic, but confirmation is molecular [21, 39].

5.2. Prenatal imaging

Ultrasound demonstrates the bony defect in about 80% of fetuses with occipital cephalocele, according to Markovic's review, with limitations due to maternal habitus, fetal position and amniotic fluid volume [1]. ISUOG recommends that, when a CNS anomaly is suspected at the screening scan or at the nuchal translucency scan, the pregnant woman should be referred for targeted neurosonography, a multiplanar examination performed by an experienced operator; the indications also include a family history of hereditary CNS malformation, a previous affected pregnancy, exposure to teratogens and a copy-number variant of uncertain significance on microarray [95, 98]. Fetal MRI should be requested by the expert after neurosonography and not directly from a suspicious screening scan (good practice point), because requests outside this pathway increased false positives and overestimated the yield of MRI [95]. Part 2 of the guideline, which describes how to perform targeted neurosonography, reinforces this pathway: fetal MRI is complementary and answers specific questions from the neurosonographer; when neurosonography is performed by an experienced operator according to the technical criteria of the guideline, MRI is needed in only 7–15% of cases; and it only replaces neurosonography as a second-line examination when the latter is unavailable or inadequate, provided that the MRI operator has training in fetal neuroimaging (good practice point) [98].

The recommended technique has useful details for occipital cephalocele [98]. The transvaginal route is preferred whenever the fetus is in cephalic presentation; when it is not feasible (breech presentation, twin pregnancy), the abdominal route is used with high-frequency linear or microconvex probes (emission up to 8–9 MHz), the transfundal approach in breech presentation and, until the start of the 3rd trimester, gentle external version when technically possible (good practice points). The systematic examination includes four coronal planes (transfrontal, transcaudate, transthalamic and transcerebellar) and three sagittal planes, with the same measurements as the basic examination (biparietal diameter, head circumference, atrial width and transverse cerebellar diameter); the anteroposterior diameter of the cisterna magna is measured only if mega cisterna magna is suspected. The posterior midsagittal plane, obtained through the posterior fontanelle or the sagittal suture, is the best for the posterior fossa (vermis with fastigium and primary fissure, 4th ventricle, cisterna magna, tentorium and brainstem), but the acoustic shadow of the occipital bone may limit or prevent interpretation, and the transcerebellar coronal plane is the only one obtained through the posterior fontanelle. Three-dimensional ultrasound is recommended, especially when two-dimensional imaging is difficult, for the multiplanar correlation of the three orthogonal planes and the better contrast of thick slices; in the spine, visualisation of the conus medullaris close to the ventral side of the canal, normally at L2–L3 after 20 weeks, supports normality of the lumbosacral spine, which is relevant when looking for associated dysraphism (Meckel-Gruber syndrome) [98].

Between 13 and 17 weeks, the guideline recommends the transvaginal route with 6–12 MHz probes; the high-frequency abdominal route may suffice with a maternal body mass index ≤25 kg/m² and if the focus is not the posterior fossa [98]. At 13–14 weeks the examination combines the transventricular and transthalamic axial planes with the midsagittal and posterior coronal planes reconstructed from 3D volumes, and assessment of cystic posterior fossa anomalies at this age should be cautious because of the risk of false positives; for most CNS anomalies detected at 13–17 weeks a follow-up neurosonography after 20 weeks is indicated, except for lethal or near-lethal anomalies with an unequivocal diagnosis, among which the guideline includes exencephaly-anencephaly, large cephalocele and holoprosencephaly [98]. Fetal MRI defines the contents of the sac, the posterior fossa and associated cortical anomalies; in the Toronto prenatal Knobloch case, it showed rotation and dysplasia of the vermis, a membrane between the 4th ventricle and the bony defect, elongated eyeballs and frontal polymicrogyria [44]. Computed tomography (CT) is not used in the fetus [1].

Maternal serum alpha-fetoprotein, with a threshold of 2.5 multiples of the median at 16 weeks, detects 82% of spina bifida with 1.9% false positives, but does not detect skin-covered closed NTDs, which include most cephaloceles; biochemical screening therefore does not replace ultrasound [14]. For NTDs, the sensitivity of ultrasound in an unselected population was 98% for anencephaly and 75% for spina bifida (Boyd and colleagues, according to Firth and Hurst), and amniocentesis is rarely used solely for the diagnosis of NTD [14].

5.3. Postnatal imaging

MRI is the examination of choice after birth: on T1- and T2-weighted sequences it shows the defect, the extent of herniated tissue and associated anomalies (Chiari, holoprosencephaly, Dandy-Walker complex, aqueductal stenosis, agenesis of the corpus callosum), and MR venography and MR angiography show the relationship of the sac to the torcula and transverse sinuses, information needed for surgical planning [1]. CT better characterises the bony defect and, with water-soluble contrast (cisternography), demonstrates communication with the subarachnoid space [1]. In Knobloch syndrome, neuroimaging documents the occipital spectrum and cortical malformations and should be performed even in the absence of encephalocele [26, 58].

5.4. Clinical and genetic assessment

Firth and Hurst propose examining the affected individual or obtaining the autopsy report to confirm the type of NTD and check whether it is isolated; additional anomalies are present in more than 20% of cases and should prompt reconsideration of a syndrome or chromosomal anomaly, and there is an association with congenital heart disease, diaphragmatic aplasia and oesophageal atresia [14]. If the NTD is the only anomaly, karyotyping is not routine; in the presence of syndromic or chromosomal features, chromosomal microarray, gene panel, exome or genome is indicated [14]. The American College of Medical Genetics and Genomics (ACMG) recommends considering exome or genome sequencing as a first- or second-tier test in children with congenital anomalies with onset before 1 year of age or with developmental delay or intellectual disability, because of the higher yield than conventional tests [24]. Searches of Europe PMC did not identify a cohort measuring exome yield specifically in isolated cephalocele; the available data are case reports and syndrome series [19, 36, 44].

In practice, investigation of a fetus or newborn with cephalocele follows four steps: complete imaging (neurosonography, MRI, renal ultrasound, postnatal ophthalmological assessment); dysmorphological examination and autopsy when there is fetal loss or termination, with DNA storage [99]; quantitative fluorescent polymerase chain reaction (QF-PCR) and microarray; and exome or genome, preferably as a trio, when there are associated anomalies, consanguinity, family recurrence or ocular, renal or cortical findings [14, 24, 44]. In assessing the parents, examination of the occiput, scalp and lumbosacral region and, if there are signs, imaging identify dominant forms with minimal expression (ADDWOC) or occult dysraphism [14, 36].

5.5. Tests in Knobloch syndrome

Assessment includes cycloplegic refraction, biometry, dilated fundoscopy (under anaesthesia in young children), macular OCT, electroretinogram, intraocular pressure measurement and angle assessment, neuroimaging, electroencephalogram if there are seizures, and renal ultrasound [22, 39, 91]. Sequencing of COL18A1 confirms the diagnosis; a negative result or one with a single variant in a patient with typical vitreoretinopathy should prompt a search for the second allele (CNV, non-coding regions) and consideration of PAK2 and locus heterogeneity, given that 26% of the Saudi cohort lacked molecular confirmation [4, 22, 23].

5.6. Test limitations and report content

Microarray does not detect point variants; exome has limited coverage of deep intronic regions, structural variants and low-level mosaicism, and a negative result does not exclude a genetic cause, especially in an isolated cephalocele of probable multifactorial cause [24]. The report should state the gene, the transcript with version (preferably MANE), the HGVS notation at DNA and protein level, zygosity, parental origin when testing as a trio and the class according to the ACMG/AMP criteria; in the Toronto case, the two COL18A1 variants were classified as pathogenic with criteria PVS1, PM3 and PP4 (plus PM2 for one of them) and confirmed by Sanger [44]. Periodic reanalysis of negative exomes can change the diagnosis, as in the patient with PAK2 whose variant had not been reported [19].

5.7. Algorithm

6. Differential Diagnosis

6.1. Aetiological differential

6.2. Morphological differential

Some lesions mimic a cephalocele. In the frontonasal region, dermoid cyst and glial heterotopia (“nasal glioma”) present as congenital midline masses, and MRI distinguishes them by the absence of intracranial communication [47]. In the occipital region, rare tumours such as mature teratoma have been described as mimicking encephalocele in infants [110]. Enlarged parietal foramina are bony defects without herniated contents [39]. Iniencephaly, a severe defect of the cervical spine with retroflexion of the head, often coexists with occipital encephalocele and should be identified because it changes the prognosis [14]. Acquired cephaloceles of adults (spontaneous temporal and sphenoidal cephaloceles, associated with idiopathic intracranial hypertension or epilepsy, and post-traumatic ones) do not belong to this article and are distinguished by age at presentation and context.

6.3. Practical points

The combination of occipital cephalocele and enlarged, hyperechogenic kidneys in the fetus points to Meckel-Gruber syndrome; that of cephalocele, ventriculomegaly and ocular anomalies points to Walker-Warburg syndrome; that of a small cephalocele, polymicrogyria, vermis dysplasia and elongated eyeballs points to Knobloch syndrome [33, 35, 44]. A cephalocele in a child with normal development and relatives with minimal occipital defects suggests ADDWOC [36]. Multiple, asymmetrical, anterior encephaloceles with body wall defects suggest a disruptive mechanism with a low recurrence risk [40].

7. Treatments and Risk Management Strategies

7.1. Principles

There is no pharmacological treatment for cephalocele or for any of the syndromes in this article; management is neurosurgical, craniofacial, ophthalmological and rehabilitative, and the sources consulted did not identify a scientific society guideline dedicated to cephalocele or Knobloch syndrome, so the recommendations rest on case series and retrospective cohorts [1, 25, 39]. Decisions depend on the amount of brain tissue in the sac, the state of the CSF pathways, the neurological deficit and associated malformations [1].

7.2. Care in the neonatal period

In general, the Brazilian handbook advocates cardiorespiratory stabilisation of the newborn, frequent measurement of head circumference before and after surgery, ventriculoperitoneal shunting if there is hydrocephalus and treatment of comorbidities by a multidisciplinary team [47]. The same handbook indicates elective caesarean section for NTDs in general [47]; for open spina bifida, the neurological advantage of caesarean section was advocated and later disputed, according to Firth and Hurst, and the sources consulted provide no specific data on the mode of delivery in cephalocele [14]. A lesion without skin cover, with CSF leakage or at risk of rupture is protected and operated on as a priority, because infection of the sac and meningitis are recognised complications: in the Los Angeles series, one of the eight newborns with CSF leakage at birth had an infection [1, 25].

7.3. Neurosurgical repair of occipital and parietal cephalocele

Markovic's review places the preferred surgical window between birth and 4 months; if skin covers the lesion, surgery can be deferred for a few months, but without skin cover it should be done as early as possible [1]. Indications include risk of rupture, CSF leakage, meningitis, presence of brain tissue, a venous sinus in the sac, hydrocephalus, associated anomalies and cosmetic reasons [1]. The aims are to reposition viable brain tissue, meninges and CSF inside the skull without causing deficit, to close the dura mater and to reconstruct the skull; dysplastic, gliotic and non-functional tissue is excised, preserving essential vascular and brain structures, and injury to the torcula can cause deep venous thrombosis [1]. Cranioplasty is not always necessary, because of the osteogenic capacity of the dura, and in giant lesions with microcephaly expansion cranioplasty may be used [1]. Surgery does not recover congenital neurological deficits [1]. In the Los Angeles series, the median age at surgery was 2 months and there were 2 postoperative CSF leaks, one infected [25]; in Tunis, with a median of 11.8 months, postoperative meningitis occurred in 12.5% and mortality was 10%, and late surgery was associated with worse development [87]. In a Nigerian series of 12 children, with a mean age of 29.8 days at surgery, all those with hydrocephalus received CSF shunting at the same operation and there were no deaths at 30 days [111].

7.4. Hydrocephalus

Hydrocephalus is treated with ventriculoperitoneal shunting, and follow-up after repair is necessary because most cases appear after surgery [1, 25]. In the Lucknow systematic review of the association of Dandy-Walker with occipital encephalocele (79 cases from the literature and 5 of their own), patients with ventriculoperitoneal or cystoperitoneal shunting, with or without repair, had a better course than those undergoing repair alone (p = 0.03) [94].

7.5. Giant cephaloceles and decisions to limit treatment

Giant cephaloceles with cerebrum, cerebellum and brainstem in the sac and microcephaly have a poor prognosis even with surgery, and repair may nonetheless facilitate care and feeding [1]. In the Los Angeles series, a newborn with massive CNS disorganisation was not operated on, by agreement with the parents, and died; another, initially untreated, survived and was operated on at 6 months with ventriculoperitoneal shunting [25]. A Rotterdam case of giant parieto-occipital cephalocele, containing part of the occipital and parietal lobes and the cerebellum and with venous hypoplasia, initially directed towards palliative care, was reconstructed at 4 weeks and at 4 years showed language and motor progress; the authors stress the need to reassess expectations case by case [112].

7.6. Frontoethmoidal cephaloceles

Repair combines a neurosurgical stage (closure of the dura and the anterior skull base) and facial reconstruction (correction of hypertelorism and of the nose); in the Cambodian series of 200 patients, a neurosurgical approach avoided a facial incision in 42 cases, the most frequent complications were transient CSF fistula (12%) and infection (14%), there were 3 surgery-related deaths and the cosmetic result was good in 145, fair in 27, poor in 7 and worse than before in 6 [42]. The series also showed that trained local surgeons can treat these lesions with limited resources [42]. Single-stage extracranial repair techniques were developed in Thai centres [113]. In the frontonasal dysplasias, craniofacial surgery is staged (facial bipartition, box osteotomies, fronto-orbital advancement, nasal reconstruction, cleft repair) [39].

7.7. Ocular management in Knobloch syndrome

Treatment of retinal detachment is surgical, by pars plana vitrectomy, with or without scleral buckling and silicone oil tamponade. In the Saudi cohort, single-surgery success was 36% and final anatomical success 70% (58% in macular hole detachments), and vitrectomy with buckling and silicone oil had the highest single-surgery success (62.2%); mean acuity was 20/320 before and 20/500 after successful repair [23]. In the Turkish cohort, success was 54% after the first surgery and 69% after reoperation, and Tenon's capsule or amniotic membrane grafts in macular holes increased reattachment from 40% to 82% [21]. In the North American cohort, 20 of the 23 eyes with detachment were operated on (laser, buckling, vitrectomy or a combination), with 60% single-surgery success and 85% final success [26]. In a series of 9 eyes of 5 children (2 months to 5 years) with macular hole detachment, reattachment with hole closure was achieved in 5 of the 7 operated eyes, with improved fixation [92].

Prophylaxis of detachment is the open therapeutic question. In the North American cohort, 21 of 72 eyes (29.2%) received prophylactic laser or buckling and only 2 detached; in an age-adjusted model, prophylaxis was associated with a lower probability of detachment (odds ratio 0.20; p = 0.022), with no significant difference in fellow eyes (0.42; p = 0.41) [26]. The study is retrospective and non-randomised, and a case published in 2026 described bilateral detachment 7 days after bilateral prophylactic laser in a single session in an 8-year-old girl, treated with sequential scleral buckling and with recovery of baseline acuity; the authors conclude that the evidence in favour of prophylactic laser is limited and that the decision should be individualised [114]. The remaining ocular care includes optical correction of myopia, amblyopia treatment and low-vision support, surgery for cataract and lens subluxation with attention to zonular weakness, and monitoring of intraocular pressure; acute angle closure in two siblings was controlled with cyclophotocoagulation [39, 56]. Non-ocular management includes repair of the cephalocele when present, treatment of epilepsy, which may be refractory when polymicrogyria is present, developmental support and renal imaging [39, 57].

7.8. Regulatory status

7.9. Intervention studies and recent developments

None of these studies is randomised. The fetal surgery series has 6 patients, no comparison group and 12 months of follow-up, and was published online in June 2026; the selection criteria excluded syndromic forms, and the results do not allow benefit or maternal risk to be estimated, so the intervention is experimental [115]. The MOMS trial of fetal surgery for myelomeningocele, cited by Firth and Hurst, does not apply to cephalocele [14]. In Knobloch syndrome, the comparison between eyes with and without prophylaxis is subject to selection bias, and the case of detachment after laser shows that the intervention carries risk [26, 114]. In 2025 and 2026, the first description of Knobloch syndrome diagnosed prenatally by trio exome [44], the second family with a PAK2 variant [19] and neuroimaging series of Knobloch syndrome in childhood [116] were also published.

7.10. Exposures to avoid, pregnancy and transition

Prevention in women of childbearing age includes periconceptional folic acid, review of antiepileptic therapy before conception (valproate is the drug with the highest risk of NTD, and carbamazepine, phenytoin, phenobarbital and primidone have also been implicated), attention to folate antagonists (sulfasalazine, triamterene, trimethoprim), control of diabetes and obesity and prevention of hyperthermia in the 1st month, with a limit of 15 minutes of immersion at 39 °C and 10 minutes at 40 °C according to Smith [14, 47, 85]. Adolescents with repaired cephalocele, a ventriculoperitoneal shunt or Knobloch syndrome need organised transition to adult neurosurgery, neurology and ophthalmology, because shunt dysfunction, epilepsy and retinal detachment remain risks [25, 26].

7.11. Guideline recommendations and consensus documents

Sources diverge on the folic acid dose to recommend after an affected child: 5 mg/day according to the British practice described by Firth and Hurst, in women planning pregnancy, from at least 1 month before conception until the 12th week, and 4 mg/day according to the Brazilian handbook, the same dose as used in the Medical Research Council (MRC) trial, which prevented about 70% of recurrences [14, 47]. No maximum dose is defined in the sources; Firth and Hurst record no adverse effects at 5 mg/day [14]. The North American guideline consulted addresses only the general population [27].

8. Reproductive Options and Family Counselling

8.1. Principle: the risk depends on the cause

The recurrence risk of a cephalocele depends on its aetiology, and the first task of counselling is to distinguish an isolated form from a syndromic, chromosomal, disruptive or teratogenic form [14, 47]. Complete aetiological investigation, including autopsy and DNA storage when there is fetal loss or termination of pregnancy, is what allows a precise risk to be offered and, if there is a molecular diagnosis, prenatal or preimplantation diagnosis [44, 99].

8.2. Isolated cephalocele

For isolated forms the empirical NTD risks apply, which Firth and Hurst tabulate for anencephaly and spina bifida without folate supplementation; in non-syndromic NTDs, the site of the defect does not tend to repeat in subsequent pregnancies, which justifies using the same values for an isolated encephalocele [14].

Source: Firth and Hurst, table 3.31, values without folate supplementation [14]. The Brazilian handbook gives, with folic acid use, a population incidence of 1/2000, a risk of 1/100 (1%) after one affected child, of 1/4 after three affected offspring and up to 1/25 when several 2nd- and 3rd-degree relatives are affected, a situation in which X-linked inheritance should be considered [47]. The evidence that folic acid prevents encephalocele is less direct than for spina bifida: mandatory fortification in the USA did not significantly reduce encephalocele in Atlanta, whereas in Western Australia promotion of supplements and voluntary fortification were associated with a 34% reduction [50, 51].

8.3. Prevention of recurrence with folic acid

To prevent the first occurrence of NTD, Firth and Hurst indicate 400 μg of folic acid per day from at least one month before conception until the 12th week, and the USPSTF (US Preventive Services Task Force) recommends 0.4–0.8 mg per day for all people planning or capable of pregnancy [14, 27]. After a child with an NTD, the dose recommended by Firth and Hurst is 5 mg per day, over the same period; in the MRC trial, 4 mg per day prevented about 70% of recurrences [14]. The 5 mg per day dose is also indicated when a parent has spinal dysraphism (hair tuft or abnormal lumbosacral skin with two or more incomplete vertebral arches), when the mother remains on antiepileptic therapy, is diabetic, has coeliac disease or other malabsorption or sickle cell disease, and in 2nd-degree relatives, in whom the high dose would reduce an absolute risk of 1–2% by about 85% (compared with about 36% with 400 μg) [14]. The authors know of no adverse effects at 5 mg and no contraindications, but recommend reviewing antiepileptic therapy [14]. The Brazilian handbook indicates 4 mg per day, despite fortification of wheat, maize and cassava flours [47]. If recurrence occurs on the high dose, a syndromic cause should be reconsidered; the practice of the British authors is to maintain the high dose, with an estimated recurrence risk of 10% [14]. Inositol has been studied in a randomised pilot trial as an adjuvant in folate-resistant NTDs, according to the same authors [14].

8.4. Monogenic forms

In autosomal recessive forms (Meckel-Gruber syndrome, Knobloch syndrome 1, dystroglycanopathies, ALX frontonasal dysplasias), the risk for each pregnancy of the same parents is 25%, unaffected siblings have a two-thirds probability of being carriers and, once the variants are known, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are possible [12, 33, 35, 44]. Consanguinity is frequent in Knobloch syndrome (76% in the Turkish cohort), which justifies offering carrier testing to the couple and the extended family [21]. In NID1-associated ADDWOC, autosomal dominant with incomplete penetrance, each child of a carrier has a 50% probability of inheriting the variant, but expression ranges from none to cephalocele, and apparently healthy relatives may be carriers with small bony defects or arachnoid cysts [36]. In Knobloch syndrome 2, the PAK2 variant arose de novo in two siblings, which indicates parental germline mosaicism and a recurrence risk above the population risk even with parents negative in blood [4]. Offering an ophthalmological examination with angle assessment to relatives of patients with Knobloch syndrome is recommended, given the proposed association between heterozygous COL18A1 variants and angle closure [39, 56].

8.5. Prenatal diagnosis in a subsequent pregnancy

After a pregnancy with cephalocele, ISUOG includes a previous affected pregnancy and a family history of hereditary CNS malformation among the indications for targeted neurosonography, which can begin at the end of the 1st trimester [95]. The Brazilian handbook advises prenatal diagnostic examinations for all pregnant women with a previous affected child [47]. Alpha-fetoprotein does not detect skin-covered lesions [14]. Legislation on termination of pregnancy varies between countries; the Brazilian handbook states that Brazilian law permits it in anencephaly [47], and in the Canadian Knobloch case termination after 24 weeks required institutional ethics review [44].

8.6. Minors and relatives

In Knobloch syndrome, siblings with nystagmus, poor fixation or high myopia should have an ophthalmological assessment and diagnostic testing without delay, because macular hole detachment can appear in the first year of life [21, 92]. Carrier testing of asymptomatic siblings has no medical consequence for them in childhood and is a genetic counselling decision.

9. Special Considerations: Population Diversity and Epidemiology

9.1. United States

Data from the National Birth Defects Prevention Network (NBDPN), which pooled 13 population-based programmes with 4,141,961 live births between 2016 and 2020 (22% of births in the country), recorded 432 cases of encephalocele, with a prevalence of 1.04 per 10,000 live births (confidence interval 0.95–1.15) [17]. Prevalence was 0.87 in children of non-Hispanic White mothers, 1.54 in children of non-Hispanic Black mothers (the highest), 0.97 in children of Hispanic mothers, 0.45 in children of Asian or Pacific Islander mothers (the lowest) and 0.66 in children of American Indian or Alaska Native mothers, and it was higher in mothers under 20 years of age [17]. The adjusted national prevalence remained stable between 1999–2001 (0.93) and 2016–2020 (0.95 per 10,000), which corresponds to about 1 in 10,365 live births and about 354 cases per year [17]. In Texas (1999–2002, 125 cases without chromosomal anomaly in 1,449,943 live births), children of Hispanic mothers had a prevalence 1.91 times higher than children of White mothers, and those of mothers aged 20–24 years 1.52 times higher than those of mothers aged 25–29 years [117]. In Atlanta (1968–2002), prevalence was 1.4 per 10,000 live births [50]. The NBDPN figures refer to live births and do not measure total frequency, which includes fetal losses and terminations.

9.2. Europe, Portugal and Brazil

In the EUROCAT network (European Surveillance of Congenital Anomalies), 28 registries in 19 countries with about 12.5 million births between 1991 and 2011 recorded 11,353 non-chromosomal NTDs, of which 1415 were encephaloceles, 4162 anencephalies and 5776 spina bifida; the total prevalence of NTDs (live births, fetal deaths from 20 weeks and terminations) was 9.1 per 10,000 births, with no downward trend over the period, in the absence of mandatory fortification [18]. The southern Portugal registry (1991–2010, 316,853 births) had a total NTD prevalence of 4.73 per 10,000, with anencephaly at 1.96 and spina bifida at 2.40; the article does not break down encephalocele by registry [18]. Firth and Hurst cite an NTD prevalence of 0.94 per 1000 in Europe, 1.3 in Australia, 2.0 in Peru and 4.5 in China, and estimate encephalocele at about 1 per 10,000 established pregnancies [14]. The Brazilian handbook gives an NTD prevalence of 1–5 per 1000 live births, more frequent in females and in children of mothers aged 20–24 years, and mentions Brazilian studies on the effect of flour fortification; the sources consulted do not give the prevalence of encephalocele in Brazil [47]. The family in which COL18A1 was identified and one of the families with ADDWOC are Brazilian [12, 37].

9.3. South-East Asia and other regions

Frontoethmoidal cephaloceles are frequent in South-East Asia, where Firth and Hurst record high frequencies and Richards describes them as a common and severe anomaly [14, 46]. In Cambodia, among 257 patients seen at a single centre over 5 years, 87% of parents were rice farmers and there was only one familial case [42]. In Burma, frontal encephalomeningoceles predominated, with no affected 1st-degree relatives [45]. In Western Australia, Aboriginal children had higher rates of all NTDs and did not show the decline observed in the others (prevalence ratio 0.90 versus 0.70) [51]. In a Nigerian series, no mother had taken folic acid before conception [111].

9.4. Rare syndromes and populations with consanguinity

Knobloch syndrome has a prevalence of less than 1 per million, with 119 cases or families described according to Orphanet; most cohorts come from Saudi Arabia and Turkey, with high consanguinity, and a North American cohort of 36 patients was published in 2026 [3, 21, 23, 26]. In a US inherited retinal dystrophy centre, the syndrome accounted for 0.64% of 627 patients [93].

9.5. Networks and associations

ERN ITHACA (rare malformation syndromes and neurodevelopmental disorders) is the European reference network for syndromic forms; ERN CRANIO covers craniofacial anomalies and ERN-EYE rare eye diseases, including Knobloch syndrome [28, 29, 32]. Patient associations include the International Federation for Spina Bifida and Hydrocephalus (IF SBH), the Associação Spina Bífida e Hidrocefalia de Portugal (ASBIHP) and the British association SHINE [14, 30, 31].

10. Illustrative Clinical Case

Carmant and colleagues described, in 2025, the first Knobloch syndrome diagnosed in the prenatal period [44]. A 36-year-old pregnant woman, G3P1A1, was referred at 23 weeks and 4 days because of non-visualisation of the cavum septi pellucidi and a Blake's pouch cyst on the anomaly scan; 1st-trimester screening, with nuchal translucency at 12 weeks, had been normal. Targeted neurosonography showed a small occipital cephalocele, vermian dysplasia and diffuse bilateral polymicrogyria, predominantly frontal, and amniocentesis was performed on the same day. Fetal MRI, performed at 27 weeks and 4 days because of the woman's ambivalence and the distance from the centre, confirmed hypoplasia and dysplasia of the vermis with cephalic rotation, an enlarged posterior fossa, a membrane from the 4th ventricle to a midline occipital bony defect with fluid in the subcutaneous tissue, elongated eyeballs and symmetrical frontal polymicrogyria. QF-PCR and microarray were normal (male fetus). Trio exome identified two truncating COL18A1 variants in compound heterozygosity, NM_130445.2:c.3024_3042del p.(Pro1009LeufsTer13), of maternal origin, and NM_130445.2:c.2823dup p.(Gly942ArgfsTer142), of paternal origin, both classified as pathogenic; in the MANE transcript, the first corresponds to NM_001379500.1:c.3033_3051del p.(Pro1012LeufsTer13) [44, 59]. After counselling by maternal-fetal medicine, paediatrics and genetics, the parents opted for termination of pregnancy, approved after ethics review because 24 weeks had been exceeded, and performed at 28 weeks and 2 days; there was no autopsy, and external examination showed only the occipital mass [44]. Figure 1 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC12254427/figure/pd6838-fig-0001/) brings together the ultrasound images at 23+4 and 27+4 weeks and the T2-weighted MRI images with the bony defect, the elongated eyeballs and the polymicrogyria. The authors conclude that the prenatal association of occipital cephalocele, polymicrogyria and vermian anomaly should lead to consideration of Knobloch syndrome and a request for exome sequencing [44]. The case illustrates the sequence of examinations in section 5; the reproductive decision taken belongs to the Canadian legal and institutional context and does not represent routine practice.

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

The prognosis of isolated cephalocele depends mainly on hydrocephalus, brain tissue in the sac, lesion size, microcephaly and associated anomalies [1, 2, 25]. Among operated children, about 40% have normal development in the Los Angeles series, and none with hydrocephalus did [25]; in Tunis, 67.6% had psychomotor delay [87]. Survival of live births was 70.8% at one year and 67.3% at 20 years in Atlanta, with 74.3% in isolated cases and 41.2% with multiple defects [52]. Fetuses diagnosed in the 1st trimester have a worse course, because of the frequency of syndromes and fetal losses [20]. In syndromic forms, the prognosis is that of the syndrome: lethal in Meckel-Gruber, death in the 1st year in most patients with Walker-Warburg, usually normal development in ADDWOC, with familial exceptions, and reduced vision with a risk of blindness from detachment in Knobloch [23, 33, 35, 36].

11.2. Surveillance

The sources consulted do not define surveillance intervals for repaired cephalocele or for Knobloch syndrome; the intervals depend on the centre and on the clinical course [1, 39].

12. Summary and Final Considerations

Cephalocele is the herniation of meninges, with or without brain tissue, through a defect of the skull; the occipital form accounts for 77–90% of cases in the series consulted, and frontoethmoidal forms predominate in South-East Asia. Birth prevalence is about 1 per 10,000 live births in the USA and of a similar order in Europe. Although classified among the NTDs and sharing risk factors and, probably, genetic causes with them, the pathogenesis of occipital forms appears to follow neural tube closure, and protection by folic acid is less well demonstrated than in spina bifida. Most isolated cephaloceles are multifactorial, but a fraction is syndromic, and cephalocele may be the sign that leads to Meckel-Gruber syndrome, Joubert syndrome, the dystroglycanopathies, the frontonasal dysplasias, NID1-related ADDWOC and Knobloch syndrome. Investigation combines neurosonography, MRI, dysmorphological and ophthalmological examination, microarray and exome or genome, and autopsy with DNA storage when there is fetal loss. Treatment is surgical, with early repair and surveillance of hydrocephalus, which is the main determinant of development. In Knobloch syndrome, retinal surveillance from childhood, with macular OCT, and experienced vitreoretinal surgery are the interventions that preserve vision; prophylaxis of detachment was associated with fewer detachments in a retrospective cohort and remains under discussion. Counselling depends on the aetiological diagnosis: empirical NTD risks and high-dose folic acid in isolated forms, 25% in recessive forms and risk related to incomplete penetrance or germline mosaicism in dominant forms. Fetal surgery for isolated occipital encephalocele has been described in a series of six fetuses and remains experimental.

13. References

1. Markovic I, Bosnjakovic P, Milenkovic Z. Occipital Encephalocele: Cause, Incidence, Neuroimaging and Surgical Management. Curr Pediatr Rev. 2020;16(3):200-205. https://doi.org/10.2174/1573396315666191018161535
2. Martínez-Lage JF, Poza M, Sola J, Soler CL, Montalvo CG, Domingo R, et al. The child with a cephalocele: etiology, neuroimaging, and outcome. Childs Nerv Syst. 1996;12(9):540-50. https://doi.org/10.1007/BF00261608
3. Orphanet. Knobloch syndrome (ORPHA:1571). Available from: https://www.orpha.net/en/disease/detail/1571
4. Antonarakis SE, Holoubek A, Rapti M, Rademaker J, Meylan J, Iwaszkiewicz J, et al. Dominant monoallelic variant in the PAK2 gene causes Knobloch syndrome type 2. Hum Mol Genet. 2021;31(1):1-9. https://doi.org/10.1093/hmg/ddab026
5. Orphanet. Cephalocele (ORPHA:268817). Available from: https://www.orpha.net/en/disease/detail/268817
6. Orphanet. Occipital encephalocele (ORPHA:268823). Available from: https://www.orpha.net/en/disease/detail/268823
7. Orphanet. Parietal encephalocele (ORPHA:268826). Available from: https://www.orpha.net/en/disease/detail/268826
8. Orphanet. Frontal encephalocele (ORPHA:1931). Available from: https://www.orpha.net/en/disease/detail/1931
9. Orphanet. Nasal encephalocele (ORPHA:141118). Available from: https://www.orpha.net/en/disease/detail/141118
10. Orphanet. Basal encephalocele (ORPHA:268829). Available from: https://www.orpha.net/en/disease/detail/268829
11. Orphanet. Isolated encephalocele (ORPHA:199647). Available from: https://www.orpha.net/en/disease/detail/199647
12. Sertié AL, Sossi V, Camargo AA, Zatz M, Brahe C, Passos-Bueno MR. Collagen XVIII, containing an endogenous inhibitor of angiogenesis and tumor growth, plays a critical role in the maintenance of retinal structure and in neural tube closure (Knobloch syndrome). Hum Mol Genet. 2000;9(13):2051-8. https://doi.org/10.1093/hmg/9.13.2051
13. Online Mendelian Inheritance in Man, OMIM®. *605022 p21 protein-activated kinase 2; PAK2. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/605022
14. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 500–504 (Neural tube defects).
15. Online Mendelian Inheritance in Man, OMIM®. *120328 Collagen, type XVIII, alpha-1; COL18A1. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/120328
16. Online Mendelian Inheritance in Man, OMIM®. #618458 Knobloch syndrome 2; KNO2. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/618458
17. Stallings EB, Isenburg JL, Rutkowski RE, Kirby RS, Nembhard WN, Sandidge T, et al. National population-based estimates for major birth defects, 2016-2020. Birth Defects Res. 2024;116(1):e2301. https://doi.org/10.1002/bdr2.2301
18. Khoshnood B, Loane M, de Walle H, Arriola L, Addor MC, Barisic I, et al. Long term trends in prevalence of neural tube defects in Europe: population based study. BMJ. 2015;351:h5949. https://doi.org/10.1136/bmj.h5949
19. Werren EA, Kalsner L, Ewald JM, Peracchio M, King C, Vats P, et al. Phenotypic Expansion of Knobloch Syndrome Type 2 in an Individual With a De Novo PAK2 Variant. Am J Med Genet A. 2025;197(6):e64006. https://doi.org/10.1002/ajmg.a.64006
20. Sepulveda W, Wong AE, Andreeva E, Odegova N, Martinez-Ten P, Meagher S. Sonographic spectrum of first-trimester fetal cephalocele: review of 35 cases. Ultrasound Obstet Gynecol. 2015;46(1):29-33. https://doi.org/10.1002/uog.14661
21. Ozdek S, Ozdemir Zeydanli E, Kayhan G, Yalcin E, Ozdemir HB, Ergun MA, et al. Ophthalmological and Genetic Profile in Knobloch Syndrome. Am J Ophthalmol. 2025;277:87-95. https://doi.org/10.1016/j.ajo.2025.05.003
22. Hull S, Arno G, Ku CA, Ge Z, Waseem N, Chandra A, et al. Molecular and Clinical Findings in Patients With Knobloch Syndrome. JAMA Ophthalmol. 2016;134(7):753-62. https://doi.org/10.1001/jamaophthalmol.2016.1073
23. Alzaben KA, Mousa A, Al-Abdi L, Alkuraya FS, Alsulaiman SM. Surgical Outcomes of Retinal Detachment in Knobloch Syndrome. Ophthalmol Retina. 2024;8(9):898-904. https://doi.org/10.1016/j.oret.2024.03.020
24. Manickam K, McClain MR, Demmer LA, Biswas S, Kearney HM, Malinowski J, et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23(11):2029-2037. https://doi.org/10.1038/s41436-021-01242-6
25. Da Silva SL, Jeelani Y, Dang H, Krieger MD, McComb JG. Risk factors for hydrocephalus and neurological deficit in children born with an encephalocele. J Neurosurg Pediatr. 2015;15(4):392-8. https://doi.org/10.3171/2014.10.PEDS14192
26. Rao P, Chang E, Spoth E, da Cruz NFS, Berrocal A, Quiram P, et al. Clinical Features, Retinal Detachment Rates, and Retinal Detachment Prophylaxis in Patients with Genetically Confirmed Knobloch Syndrome: A US-Based Multicenter Study. Ophthalmol Retina. 2026. https://doi.org/10.1016/j.oret.2026.09.002
27. US Preventive Services Task Force; Barry MJ, Nicholson WK, Silverstein M, Chelmow D, Coker TR, Davis EM, et al. Folic Acid Supplementation to Prevent Neural Tube Defects: US Preventive Services Task Force Reaffirmation Recommendation Statement. JAMA. 2023;330(5):454-459. https://doi.org/10.1001/jama.2023.12876
28. ERN ITHACA — European Reference Network on Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders. Available from: https://ern-ithaca.eu
29. ERN CRANIO — European Reference Network for rare and/or complex craniofacial anomalies and ENT disorders. Available from: https://www.ern-cranio.eu
30. International Federation for Spina Bifida and Hydrocephalus (IF SBH). Available from: https://www.ifglobal.org
31. Associação Spina Bífida e Hidrocefalia de Portugal (ASBIHP). Available from: https://www.asbihp.pt
32. ERN-EYE — European Reference Network for rare eye diseases. Available from: https://www.ern-eye.eu
33. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 246–247 (Meckel-Gruber syndrome).
34. Babiker AI, Alkabbani H, AlMaraghi S, Al Sulaiti N, Abbas O, Al Serhan AAA, et al. Suboccipital Atretic Cephalocele as a Marker for Joubert-Plus Syndrome: An Extended Phenotype of the CPLANE1 Gene Mutation. Cureus. 2025;17(12):e99416. https://doi.org/10.7759/cureus.99416
35. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 256–257 (Walker-Warburg syndrome).
36. McNiven V, Ito YA, Hartley T, Kernohan K, Miller E, Armour CM. NID1 variant associated with occipital cephaloceles in a family expressing a spectrum of phenotypes. Am J Med Genet A. 2019;179(5):837-841. https://doi.org/10.1002/ajmg.a.61095
37. Jalali A, Aldinger KA, Chary A, McLone DG, Bowman RM, Le LC, et al. Linkage to chromosome 2q36.1 in autosomal dominant Dandy-Walker malformation with occipital cephalocele and evidence for genetic heterogeneity. Hum Genet. 2008;123(3):237-45. https://doi.org/10.1007/s00439-008-0467-y
38. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 342–343 (Frontonasal dysplasia sequence).
39. GeneGuidance. Curated gene records for COL18A1, ALX1, ALX3, ALX4. Version of 2026-09-26.
40. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 902–903 (Limb–body wall complex).
41. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 92–95 (Cerebellar anomalies).
42. Oucheng N, Lauwers F, Gollogly J, Draper L, Joly B, Roux FE. Frontoethmoidal meningoencephalocele: appraisal of 200 operated cases. J Neurosurg Pediatr. 2010;6(6):541-9. https://doi.org/10.3171/2010.9.PEDS1043
43. Rojvachiranonda N, David DJ, Moore MH, Cole J. Frontoethmoidal encephalomeningocele: new morphological findings and a new classification. J Craniofac Surg. 2003;14(6):847-58. https://doi.org/10.1097/00001665-200311000-00006
44. Carmant LS, Miller E, Chitayat D, Hedges S, McGivern B, Harris K, et al. Occipital Cephalocele, Polymicrogyria, Ocular Anomaly and Vermian Dysplasia: Prenatal Markers for Knobloch Syndrome. Prenat Diagn. 2025;45(8):1074-1077. https://doi.org/10.1002/pd.6838
45. Aung Thu, Hta Kyu. Epidemiology of frontoethmoidal encephalomeningocoele in Burma. J Epidemiol Community Health. 1984;38(2):89-98. https://doi.org/10.1136/jech.38.2.89
46. Richards CG. Frontoethmoidal meningoencephalocele: a common and severe congenital abnormality in South East Asia. Arch Dis Child. 1992;67(6):717-9. https://doi.org/10.1136/adc.67.6.717
47. Banhos MEH, Barbosa MA, Ribeiro EM. Defeitos do fechamento do tubo neural. In: Ribeiro EM, coord. Síndromes Genéticas: Reconhecer para Tratar. Fortaleza: EdUnichristus; 2021. p. 160–162.
48. Rolo A, Galea GL, Savery D, Greene NDE, Copp AJ. Novel mouse model of encephalocele: post-neurulation origin and relationship to open neural tube defects. Dis Model Mech. 2019;12(11). https://doi.org/10.1242/dmm.040683
49. Hoving EW, Vermeij-Keers C. Frontoethmoidal encephaloceles, a study of their pathogenesis. Pediatr Neurosurg. 1997;27(5):246-56. https://doi.org/10.1159/000121262
50. Rowland CA, Correa A, Cragan JD, Alverson CJ. Are encephaloceles neural tube defects? Pediatrics. 2006;118(3):916-23. https://doi.org/10.1542/peds.2005-1739
51. Bower C, D'Antoine H, Stanley FJ. Neural tube defects in Australia: trends in encephaloceles and other neural tube defects before and after promotion of folic acid supplementation and voluntary food fortification. Birth Defects Res A Clin Mol Teratol. 2009;85(4):269-73. https://doi.org/10.1002/bdra.20536
52. Siffel C, Wong LY, Olney RS, Correa A. Survival of infants diagnosed with encephalocele in Atlanta, 1979-98. Paediatr Perinat Epidemiol. 2003;17(1):40-8. https://doi.org/10.1046/j.1365-3016.2003.00471.x
53. Online Mendelian Inheritance in Man, OMIM®. #249000 Meckel syndrome, type 1; MKS1. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/249000
54. Sadewa AH, Sutomo R, Istiadjid M, Nishiyama K, Shirakawa T, Matsuo M, et al. C677T mutation in the MTHFR gene was not found in patients with frontoethmoidal encephalocele in East Java, Indonesia. Pediatr Int. 2004;46(4):409-14. https://doi.org/10.1111/j.1442-200x.2004.01927.x
55. Levinger N, Hendler K, Banin E, Hanany M, Kimchi A, Mechoulam H, et al. Variable phenotype of Knobloch syndrome due to biallelic COL18A1 mutations in children. Eur J Ophthalmol. 2021;31(6):3349-3354. https://doi.org/10.1177/1120672120977343
56. Wawrzynski J, Than J, Gillam M, Foster PJ. Acute Angle Closure in Knobloch Syndrome. J Glaucoma. 2021;30(5):e265-e268. https://doi.org/10.1097/IJG.0000000000001781
57. Corbett MA, Turner SJ, Gardner A, Silver J, Stankovich J, Leventer RJ, et al. Familial epilepsy with anterior polymicrogyria as a presentation of COL18A1 mutations. Eur J Med Genet. 2017;60(8):437-443. https://doi.org/10.1016/j.ejmg.2017.06.002
58. Caglayan AO, Baranoski JF, Aktar F, Han W, Tuysuz B, Guzel A, et al. Brain malformations associated with Knobloch syndrome--review of literature, expanding clinical spectrum, and identification of novel mutations. Pediatr Neurol. 2014;51(6):806-813.e8. https://doi.org/10.1016/j.pediatrneurol.2014.08.025
59. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-8. https://doi.org/10.1002/humu.23348
60. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 366–368 (Ciliopathies).
61. Leitch CC, Zaghloul NA, Davis EE, Stoetzel C, Diaz-Font A, Rix S, et al. Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nat Genet. 2008;40(4):443-8. https://doi.org/10.1038/ng.97
62. Online Mendelian Inheritance in Man, OMIM®. *609883 MKS1 gene. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/609883
63. Online Mendelian Inheritance in Man, OMIM®. *612013 CC2D2A gene. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/612013
64. Online Mendelian Inheritance in Man, OMIM®. *610142 CEP290 gene. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/610142
65. Online Mendelian Inheritance in Man, OMIM®. *613277 TMEM216 gene. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/613277
66. Online Mendelian Inheritance in Man, OMIM®. #236670 Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 1; MDDGA1. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/236670
67. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 172–175 (Hydrocephalus).
68. Online Mendelian Inheritance in Man, OMIM®. %609222 Dandy-Walker malformation with occipital cephalocele, autosomal dominant; ADDWOC. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/609222
69. Online Mendelian Inheritance in Man, OMIM®. *131390 Nidogen 1; NID1. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/131390
70. Online Mendelian Inheritance in Man, OMIM®. #136760 Frontonasal dysplasia 1; FND1. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/136760
71. Richieri-Costa A, Guion-Almeida ML. The Syndrome of Frontonasal Dysplasia, Callosal Agenesis, Basal Encephalocele, and Eye Anomalies - Phenotypic and Aetiological Considerations. Int J Med Sci. 2004;1(1):34-42. https://doi.org/10.7150/ijms.1.34
72. Online Mendelian Inheritance in Man, OMIM®. #187601 Thanatophoric dysplasia, type II; TD2. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/187601
73. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 248–249 (Pallister-Hall syndrome).
74. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 348–349 (Fraser syndrome).
75. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 424–425 (Roberts syndrome).
76. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 444–445 (Adams-Oliver syndrome).
77. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 460–461 (Achondrogenesis types IA and IB).
78. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 478–479 (Thanatophoric dysplasia).
79. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 194–197 (Dyssegmental dysplasia).
80. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 331–333 (Boomerang dysplasia).
81. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 904–907 (Oculo-auriculo-vertebral spectrum).
82. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 926–927 (MURCS association).
83. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 888–889 (Exstrophy of cloaca sequence).
84. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 427–429 (Mesomelic dysplasia, Werner type).
85. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 808–811 (Hyperthermia-induced spectrum of defects).
86. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 898–901 (Amnion rupture sequence).
87. Bounemra M, Abderrahmen K, Slimane A, Chaouch N, Belhaj A, Bouali S, et al. Occipital encephalocele: prognostic factors of psychomotor delay and visual agnosia. Childs Nerv Syst. 2026;42(1):2. https://doi.org/10.1007/s00381-025-07097-5
88. Ottenhausen M, Ringel F, Lollert A. Atretic Cephalocele as the Cause of Swelling on the Head of an Infant. Dtsch Arztebl Int. 2025;122(1):29. https://doi.org/10.3238/arztebl.m2024.0171
89. Ralph J, Browne F. Atretic Cephalocele. N Engl J Med. 2026;394(2):177. https://doi.org/10.1056/NEJMicm2507483
90. Online Mendelian Inheritance in Man, OMIM®. #267750 Knobloch syndrome 1; KNO1. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/267750
91. AlBakri A, Ghazi NG, Khan AO. Biometry, optical coherence tomography, and further clinical observations in Knobloch syndrome. Ophthalmic Genet. 2017;38(2):138-142. https://doi.org/10.3109/13816810.2016.1164197
92. Alsulaiman SM, Al-Abdullah AA, Alakeely A, Aldhibi H, Engelbrecht L, Ghazi NG, et al. Macular Hole-Related Retinal Detachment in Children with Knobloch Syndrome. Ophthalmol Retina. 2020;4(5):498-503. https://doi.org/10.1016/j.oret.2019.12.004
93. Sadat OA, Shi M, Mahmud H, Bradford G, Odom JV, Leys M. Clinical and Genetic Features in Knobloch Syndrome: A Case Series Reporting Two Previously Unreported COL18A1 Variants. Children (Basel). 2026;13(8). https://doi.org/10.3390/children13081014
94. Datta A, Vardhan MV, Srivastava C, Ojha BK. Dandy Walker malformation with occipital encephalocele - personal series and updated literature review. Childs Nerv Syst. 2025;41(1):417. https://doi.org/10.1007/s00381-025-07061-3
95. Malinger G, Paladini D, Haratz KK, Monteagudo A, Pilu GL, Timor-Tritsch IE. ISUOG Practice Guidelines (updated): sonographic examination of the fetal central nervous system. Part 1: performance of screening examination and indications for targeted neurosonography. Ultrasound Obstet Gynecol. 2020;56(3):476-484. https://doi.org/10.1002/uog.22145
96. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 300–301 (Retinal dysplasia).
97. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 776–777 (Posterior fossa malformations).
98. Paladini D, Malinger G, Birnbaum R, Monteagudo A, Pilu G, Salomon LJ, et al. ISUOG Practice Guidelines (updated): sonographic examination of the fetal central nervous system. Part 2: performance of targeted neurosonography. Ultrasound Obstet Gynecol. 2021;57(4):661-671. https://doi.org/10.1002/uog.23616
99. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 802–805 (Ventriculomegaly).
100. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 258–259 (Ocular hypertelorism).
101. Online Mendelian Inheritance in Man, OMIM®. 229400 Frontofacionasal dysplasia. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/229400
102. Online Mendelian Inheritance in Man, OMIM®. 612916 Zechi-Ceide syndrome. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/612916
103. Online Mendelian Inheritance in Man, OMIM®. #614416 Radiohumeral fusions with other skeletal and craniofacial anomalies; RHFCA. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/614416
104. Online Mendelian Inheritance in Man, OMIM®. 607132 Laryngeal atresia, encephalocele, and limb deformities; LEL. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/607132
105. Online Mendelian Inheritance in Man, OMIM®. 223340 DK phocomelia syndrome. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/223340
106. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 242–245 (Nasal anomalies).
107. Online Mendelian Inheritance in Man, OMIM®. #304110 Craniofrontonasal syndrome; CFNS. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/304110
108. Online Mendelian Inheritance in Man, OMIM®. #236680 Hydrolethalus syndrome 1; HLS1. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/236680
109. Online Mendelian Inheritance in Man, OMIM®. 217100 Constricting bands, congenital. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/217100
110. Haile H, Adapa AR, Korben VA, Faust PL, Canoll P, Feldstein NA. Case Report: Occipital Mature Teratoma Mimicking Encephalocele in an Infant. Pediatr Neurosurg. 2026:1-7. https://doi.org/10.1159/000552835
111. Adekunle OO, Odebode OT, Adeleke NA, Adegboye OM, Enaworu O, Yeqeen HA, et al. Clinicopathological profile, management and outcome of patients with congenital encephalocele: a Nigerian tertiary centre experience. Childs Nerv Syst. 2026;42(1):52. https://doi.org/10.1007/s00381-026-07143-w
112. Dronkers WJ, Mathijssen IMJ, Go A, Volovici V, Spoor JKH. Giant parieto-occipital encephaloceles: always a dismal prognosis? A case report and review of the literature. Childs Nerv Syst. 2026;42(1). https://doi.org/10.1007/s00381-026-07212-0
113. Mahatumarat C, Rojvachiranonda N, Taecholarn C. Frontoethmoidal encephalomeningocele: surgical correction by the Chula technique. Plast Reconstr Surg. 2003;111(2):556-65; discussion 566-7. https://doi.org/10.1097/01.PRS.0000040523.57406.94
114. Silva CA, Frasson M, Lima JS, Nunes BF, Nehemy MB. Bilateral Retinal Detachment after prophylactic laser therapy in Knobloch Syndrome. Retin Cases Brief Rep. 2026. https://doi.org/10.1097/ICB.0000000000002005
115. Cruz-Martínez R, Pavón-Gómez N, Dávila-Escamilla I, Cantarero C, Chavelas-Ochoa F, Martínez S, et al. Open Fetal Microneurosurgery for Intrauterine Correction of Encephalocele: A Prospective 1-Year Follow-Up Study. Fetal Diagn Ther. 2026:1-8. https://doi.org/10.1159/000553013
116. Kravutske Y, Esmeraldo MA, Chambers S, Dahmoush HM, Halverson MR, Geraldo AF, et al. Knobloch Syndrome in Childhood: Neuroradiologic Findings and Clinical Correlation. J Child Neurol. 2026:8830738261444228. https://doi.org/10.1177/08830738261444228
117. Wen S, Ethen M, Langlois PH, Mitchell LE. Prevalence of encephalocele in Texas, 1999-2002. Am J Med Genet A. 2007;143A(18):2150-5. https://doi.org/10.1002/ajmg.a.31907