Anencephaly

Complex MONDO:0000819 Pathograph 19 Show in embeddings browser Neural Tube Defect

Anencephaly is the most severe and one of the most common open neural tube defects, characterized by absence of a major portion of the brain, skull (calvaria), and scalp. It results from failure of the rostral (cranial) neuropore to close during the fourth week of embryogenesis (around days 24-26 post-conception), leaving the developing forebrain exposed to amniotic fluid and progressively destroyed (area cerebrovasculosa). The condition lies on a continuum with exencephaly (an earlier developmental stage) and craniorachischisis. Anencephaly is uniformly lethal: affected pregnancies end in spontaneous abortion or stillbirth, and liveborn infants survive only hours to days. It is multifactorial, with periconceptional folate status the major modifiable determinant; maternal folic acid supplementation and food fortification prevent a large fraction of cases.

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1
Inheritance
4
Pathophys.
5
Phenotypes
2
Gaps
19
Pathograph
5
Genes
2
Medical Actions
3
Differentials
2
Models
2
References
1
Deep Research
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Classifications

Harrison's Part
NEUROLOGIC GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Multifactorial / polygenic with oligogenic contributions HP:0010982
Most nonsyndromic anencephaly is sporadic and multifactorial, arising from polygenic susceptibility (folate one-carbon metabolism and planar cell polarity pathway variants) combined with environmental exposures; targeted sequencing supports an additional oligogenic contribution in some cases.
Polygenic inheritance
Show evidence (1 reference)
PMID:29205322 SUPPORT Human Clinical
"Together with evidence for oligogenic inheritance, this study provides new information on the possible genetic causation of anencephaly"
Rare damaging variants across multiple candidate genes support an oligogenic/polygenic model of anencephaly causation.
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Discussions and Knowledge Gaps

2
Which human in-vitro neurulation readouts predict anencephaly specifically, rather than neural-tube defects collectively?
HUMAN MODEL MISMATCH OPEN anencephaly_human_model_specificity_gap
Attached to
pathophysiology#Failure of Cranial Neuropore Closure
Current human brain-organoid systems reproduce lumen expansion and apical-constriction defects after genetic or teratogenic perturbation, but the reported SOSRS system lacks developmental-axis context and reports an NTD-like rather than an anencephaly-specific phenotype. Translational specificity to human anencephaly therefore remains unresolved.
Show evidence (1 reference)
PMID:37443734 SUPPORT In Vitro
"Our system allows the rapid identification of NTD-like phenotypes for both compounds and genetic variants"
The authors explicitly describe the readout as NTD-like, supporting the open question of whether it is specific to anencephaly.
Which genetic and exposure combinations explain anencephaly that occurs despite adequate periconceptional folic acid?
KNOWLEDGE GAP OPEN anencephaly_residual_folate_resistant_risk_gap
Attached to
pathophysiology#Disrupted Folate One-Carbon Metabolism pathophysiology#Convergent Extension and Neural Plate Morphogenesis Defect
Folic acid prevents many but not all neural-tube defects, while sequencing implicates heterogeneous and often oligogenic closure pathways. The relative contribution and interaction of folate-resistant mechanisms remain poorly quantified in human anencephaly cohorts.
Show evidence (1 reference)
PMID:1677062 SUPPORT Human Clinical
"27 of these had a known neural tube defect, 6 in the folic acid groups and 21 in the two other groups, a 72% protective effect (relative risk 0.28, 95% confidence interval 0.12-0.71)."
The randomized recurrence trial demonstrates substantial but incomplete prevention across neural-tube defects; PARTIAL because it was not powered for anencephaly-specific residual mechanisms.
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Pathophysiology

4
Disrupted Folate One-Carbon Metabolism
Periconceptional folate status is the strongest modifiable determinant of successful neural tube closure. Folate one-carbon metabolism supplies the methyl groups and nucleotide precursors required by the rapidly proliferating cranial neuroepithelium; reduced 5,10-methylenetetrahydrofolate reductase (MTHFR) activity and inadequate folate availability compromise this supply and increase the risk that the cranial neuropore fails to close.
MTHFR hgnc:7436 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MTHFR (hgnc:7436). hgnc:7436 is a gene from the HUGO Gene Nomenclature Committee.
tetrahydrofolate interconversion GO:0035999 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased tetrahydrofolate interconversion (GO:0035999). GO:0035999 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Failure of Cranial Neuropore Closure Impaired folate one-carbon metabolism compromises the neuroepithelial methylation and nucleotide supply required for timely cranial neuropore closure; the precise molecular link between folate status and closure remains unresolved.
Show evidence (1 reference)
PMID:25808073 SUPPORT Human Clinical
"a significant correlation between MTHFR C677T polymorphism and NTD risk was found in NTD patients and in their mother"
Meta-analysis links reduced MTHFR-dependent folate one-carbon metabolism to increased neural tube defect risk in affected individuals and their mothers.
Failure of Cranial Neuropore Closure
Primary neurulation requires the flat neural plate to bend, elevate its neural folds, and fuse dorsally to form the closed neural tube, a process that proceeds by multiple closure initiation sites and zips both rostrally and caudally. Anencephaly arises specifically from failure of closure of the rostral (anterior/cranial) neuropore, which normally seals by approximately embryonic day 24-26. When the cranial neural folds fail to appose and fuse, the forebrain neuroepithelium remains open and the future cranial vault does not form over it.
neuroepithelial cell CL:0000710 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuroepithelial cell, annotated with neurecto-epithelial cell (CL:0000710). CL:0000710 is a cell type from the Cell Ontology.
PAX3 hgnc:8617 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PAX3 (hgnc:8617). hgnc:8617 is a gene from the HUGO Gene Nomenclature Committee. PDGFRA hgnc:8803 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PDGFRA (hgnc:8803). hgnc:8803 is a gene from the HUGO Gene Nomenclature Committee.
neural tube closure GO:0001843 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neural tube closure (GO:0001843). GO:0001843 is a biological process from the Gene Ontology. ↓ DECREASED apical constriction driving neural fold bending GO:0003383 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves apical constriction driving neural fold bending, annotated with apical constriction (GO:0003383). GO:0003383 is a biological process from the Gene Ontology.
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Exencephaly The unclosed cranial neural tube remains open, producing exencephaly — the exposed, disorganized brain precursor lesion.
Exposure and Degeneration of Exposed Neural Tissue Failure of closure leaves the forebrain neuroepithelium exposed to the amniotic cavity, initiating its progressive mechanical and chemical degeneration.
Show evidence (1 reference)
PMID:23790957 SUPPORT Other
"human brain formation is achieved by neurulation progressing directly between Closures 1 and 3, with completion of a single cranial (rostral) neuropore"
Human cranial neurulation completes at a single rostral neuropore; failure of its closure produces anencephaly.
Convergent Extension and Neural Plate Morphogenesis Defect
Convergent extension movements, governed by the non-canonical Wnt/planar cell polarity (PCP) pathway, narrow and lengthen the neural plate and are required to bring the neural folds close enough to fuse. Disruption of PCP signaling (e.g. VANGL1/VANGL2, CELSR1, SCRIB) broadens the neural plate and prevents fold apposition, producing severe open neural tube defects including anencephaly and craniorachischisis in model organisms and humans.
VANGL1 hgnc:15512 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves VANGL1 (hgnc:15512). hgnc:15512 is a gene from the HUGO Gene Nomenclature Committee. VANGL2 hgnc:15511 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves VANGL2 (hgnc:15511). hgnc:15511 is a gene from the HUGO Gene Nomenclature Committee.
convergent extension in neural plate elongation GO:0022007 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased convergent extension in neural plate elongation, annotated with convergent extension involved in neural plate elongation (GO:0022007). GO:0022007 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Failure of Cranial Neuropore Closure Defective convergent extension leaves the neural plate too broad for the cranial neural folds to appose and fuse, causing failure of rostral neuropore closure.
Show evidence (1 reference)
PMID:23790957 SUPPORT Other
"convergent extension cell movements are dependent on non-canonical Wnt signalling: the planar cell polarity (PCP) pathway"
Neural plate narrowing/elongation (convergent extension) is driven by PCP signaling; its disruption prevents neural fold apposition and closure.
Exposure and Degeneration of Exposed Neural Tissue
Following failed closure, the exposed forebrain (initially exencephaly) undergoes progressive mechanical and chemical degeneration on contact with amniotic fluid, leaving a hemorrhagic, poorly differentiated vascular mass (area cerebrovasculosa) in place of the cerebral hemispheres. The absence of a normal brain also disrupts induction of the overlying skull and scalp.
forebrain development GO:0030900 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal forebrain development (GO:0030900). GO:0030900 is a biological process from the Gene Ontology. ⚠ ABNORMAL
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology. cranium UBERON:0003128 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cranium (UBERON:0003128). UBERON:0003128 is an anatomical location from the Uberon multi-species anatomy ontology. scalp UBERON:0000403 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in scalp (UBERON:0000403). UBERON:0000403 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Anencephaly Progressive destruction of the exposed forebrain leaves the area cerebrovasculosa in place of the cerebral hemispheres — anencephaly.
Absent Calvaria Absence of the underlying brain and failure of the overlying cranial vault to form produce acrania (absent calvaria).
Adrenal Hypoplasia Loss of the forebrain and hypothalamic-pituitary axis removes trophic ACTH drive to the fetal adrenal cortex, producing adrenal hypoplasia.
Polyhydramnios Loss of the forebrain and higher neurological control of the swallowing reflex impairs fetal swallowing of amniotic fluid, producing polyhydramnios. (The brainstem is typically at least partly preserved in anencephaly, so this reflects loss of suprabulbar control rather than brainstem absence.)
Show evidence (1 reference)
PMID:23790957 SUPPORT Other
"presenting NTDs as separate open lesions of the cranial neural tube (exencephaly, progressing to anencephaly)"
Anencephaly develops when the open cranial neural tube (exencephaly) degenerates, confirming the exencephaly-to-anencephaly progression.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Anencephaly Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

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Prenatal and Birth 1
Polyhydramnios OCCASIONAL HP:0001561 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polyhydramnios (HP:0001561). HP:0001561 is a phenotype from the Human Phenotype Ontology.
Frequency band derived from PMID:16827827 (56/211, 26%). That cohort is self-selected — parents who declined termination, recruited via a parent website — so 26% is a lower bound for continued/liveborn pregnancies rather than a population estimate, and it sits at the upper edge of the OCCASIONAL band.
Show evidence (1 reference)
PMID:16827827 SUPPORT Human Clinical
"polyhydramnios was a feature in 56 (26%) pregnancies"
In a cohort of 211 continued anencephalic pregnancies, polyhydramnios complicated 26% — quantifying the frequently reported association.
Other 4
Anencephaly OBLIGATE HP:0002323 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anencephaly (HP:0002323). HP:0002323 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17409324 SUPPORT Human Clinical
"Neural-tube defects such as anencephaly and spina bifida constitute a group of common congenital malformations caused by complex genetic and environmental factors."
Establishes anencephaly as a common open neural tube defect of multifactorial (genetic and environmental) origin.
Exencephaly HP:0030769 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exencephaly (HP:0030769). HP:0030769 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23790957 SUPPORT Other
"embryos complete Closure 1 but fail in later neurulation, presenting NTDs as separate open lesions of the cranial neural tube (exencephaly, progressing to anencephaly)"
Exencephaly is the open cranial-neural-tube precursor lesion that progresses to anencephaly.
Absent Calvaria OBLIGATE Acrania HP:0030716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acrania (absent calvaria), annotated with Acrania (HP:0030716). HP:0030716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27429697 SUPPORT Human Clinical
"In diagnosing fetal anencephaly using POCUS, a very important finding is absence of the fetal calvarium"
Absence of the fetal calvarium (acrania) is a defining sonographic feature of anencephaly.
Adrenal Hypoplasia HP:0000835 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Adrenal hypoplasia (HP:0000835). HP:0000835 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:2625322 SUPPORT Human Clinical
"decreased cortical thickness in the anencephalic group represented cellular hypoplasia"
Anencephalic fetal adrenals show cellular hypoplasia and fail to gain weight, consistent with loss of ACTH-dependent adrenal development.
🧬

Genetic Associations

5
MTHFR
Gene: MTHFR hgnc:7436 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MTHFR (hgnc:7436). hgnc:7436 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (1 reference)
PMID:25808073 SUPPORT Human Clinical
"a significant correlation between MTHFR C677T polymorphism and NTD risk was found in NTD patients and in their mother"
Meta-analysis showing the MTHFR C677T polymorphism is associated with NTD risk in affected individuals and their mothers.
VANGL1
Gene: VANGL1 hgnc:15512 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is VANGL1 (hgnc:15512). hgnc:15512 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (1 reference)
PMID:17409324 SUPPORT Human Clinical
"These findings implicate VANGL1 as a risk factor in human neural-tube defects."
Identifies VANGL1 (a PCP-pathway gene) missense mutations in patients with familial and sporadic neural tube defects.
VANGL2
Gene: VANGL2 hgnc:15511 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is VANGL2 (hgnc:15511). hgnc:15511 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (1 reference)
PMID:23790957 SUPPORT Model Organism
"Analysis of the mouse mutant loop-tail (Vangl2 gene) has shown that craniorachischisis, the most severe NTD, results from failure of Closure 1"
The Vangl2 loop-tail mouse links PCP-gene disruption to failure of neural tube closure and the most severe NTDs.
PAX3
Gene: PAX3 hgnc:8617 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PAX3 (hgnc:8617). hgnc:8617 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (1 reference)
PMID:23790957 SUPPORT Model Organism
"The frequency of cranial NTDs is exacerbated by maternal folate deficiency in mutant splotch (Pax3) embryos, whereas wild-type littermates are never affected by NTDs"
Splotch (Pax3) mutant embryos develop folate-sensitive cranial NTDs, implicating PAX3 in cranial neural tube closure.
PDGFRA
Gene: PDGFRA hgnc:8803 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PDGFRA (hgnc:8803). hgnc:8803 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (1 reference)
PMID:29205322 SUPPORT Human Clinical
"This included 1 frameshift (PDGFRA)"
A 191-gene panel in 90 cranial NTD (85 anencephaly) patients identified a rare damaging PDGFRA frameshift variant among candidate anencephaly genes.
💊

Medical Actions

2
Periconceptional Folic Acid Supplementation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: folic acid CHEBI:27470 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses folic acid (CHEBI:27470). CHEBI:27470 is a therapeutic agent from Chemical Entities of Biological Interest.
Primary prevention: daily periconceptional folic acid (typically 0.4 mg for average risk, up to 4 mg for high-risk/prior-NTD pregnancies) markedly reduces the occurrence and recurrence of neural tube defects. This is preventive, not curative — anencephaly itself has no treatment.
Show evidence (2 references)
PMID:1307234 SUPPORT Human Clinical
"Periconceptional vitamin use decreases the incidence of a first occurrence of neural-tube defects."
Randomized trial demonstrating periconceptional folic-acid-containing supplementation prevents first-occurrence NTDs.
PMID:1677062 SUPPORT Human Clinical
"Folic acid supplementation starting before pregnancy can now be firmly recommended for all women who have had an affected pregnancy"
The MRC Vitamin Study established a 72% reduction in NTD recurrence with periconceptional folic acid.
Palliative and Supportive Care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Anencephaly is uniformly lethal and has no curative therapy; management is comfort/palliative care for liveborn neonates and supportive counseling for families, including reproductive counseling.
Show evidence (1 reference)
PMID:29205322 SUPPORT Human Clinical
"Neural tube defects (NTDs) affecting the brain (anencephaly) are lethal before or at birth"
Anencephaly is uniformly lethal before or at birth, so management is limited to palliative and supportive care rather than curative therapy.
🌍

Environmental Factors

5
Maternal Folate Deficiency
low maternal folic acid exposure ECTO:9000123 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is decreased low maternal folic acid exposure, annotated with exposure to folic acid (ECTO:9000123). ECTO:9000123 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Inadequate periconceptional folate is the strongest modifiable risk factor for neural tube defects; folic acid supplementation and food fortification substantially reduce anencephaly incidence.
Show evidence (1 reference)
PMID:1677062 SUPPORT Human Clinical
"supplementation with folic acid (one of the vitamins in the B group) or a mixture of seven other vitamins (A,D,B1,B2,B6,C and nicotinamide) around the time of conception can prevent neural tube defects (anencephaly, spina bifida, encephalocele)"
The randomized MRC Vitamin Study established that periconceptional folic acid prevents NTDs, implicating folate status as the key modifiable determinant.
Mechanism Target:
TRIGGERS Disrupted Folate One-Carbon Metabolism — Inadequate maternal folate directly limits the one-carbon pool this node depends on. The link is direct because the exposure and the metabolic deficit are the same thing viewed from outside and inside the mother.
Show evidence (1 reference)
PMID:1677062 SUPPORT Human Clinical
"supplementation with folic acid (one of the vitamins in the B group) or a mixture of seven other vitamins (A,D,B1,B2,B6,C and nicotinamide) around the time of conception can prevent neural tube defects (anencephaly, spina bifida, encephalocele)"
Periconceptional folic acid supplementation reduced neural tube defect recurrence, establishing maternal folate status as causally relevant to the defect rather than merely correlated with it.
Maternal Valproate Exposure
gestational maternal valproate exposure XCO:0001598 Experimental Conditions Ontology (XCO) Relation: this environmental factor is this exposure This environmental factor is gestational maternal valproate exposure, annotated with gestational maternal exposure to valproate (XCO:0001598). XCO:0001598 is an exposure from the Experimental Conditions Ontology.
Periconceptional exposure to the antiepileptic valproic acid interferes with folate metabolism and histone deacetylation and increases the risk of neural tube defects.
Show evidence (1 reference)
PMID:16639967 SUPPORT Human Clinical
"It has now become evident that valproic acid might cause more than just neural tube defects (NTDs)."
Systematic review of cohort studies confirms valproic acid is a teratogen causing neural tube defects and other major malformations.
Mechanism Target:
TRIGGERS Failure of Cranial Neuropore Closure — Valproate is an established human teratogen for neural tube defects, so it initiates rather than merely raises the risk of failed closure. It is marked indirect because the responsible step is unsettled between folate antagonism and histone deacetylase inhibition.
Show evidence (1 reference)
PMID:16639967 SUPPORT Other
"It has now become evident that valproic acid might cause more than just neural tube defects (NTDs)."
Identifies valproic acid as a cause of neural tube defects. Support is PARTIAL and the source is OTHER because this is a hedged statement in a clinical question-and-answer column rather than a primary study, and the defect it names is the neural tube generally rather than the cranial neuropore specifically.
Maternal Pregestational Diabetes
Poorly controlled maternal diabetes mellitus is an established risk factor for neural tube defects including anencephaly.
Show evidence (1 reference)
PMID:23790957 SUPPORT Other
"factors implicated in the aetiology of NTDs include maternal diabetes"
Maternal diabetes is an established environmental risk factor for neural tube defects.
Mechanism Target:
PREDISPOSES Failure of Cranial Neuropore Closure — Maternal diabetes raises the probability of failed closure without being sufficient to cause it, and the intervening steps between maternal hyperglycaemia and the neuroepithelium are not established here.
Show evidence (1 reference)
PMID:23790957 SUPPORT Other
"factors implicated in the aetiology of NTDs include maternal diabetes"
Lists maternal diabetes among the factors implicated in the aetiology of neural tube defects, a risk-factor attribution rather than a demonstrated mechanism.
Maternal Obesity
Maternal obesity is a reported risk factor for anencephaly and other neural tube defects. Its contribution is recorded as an association rather than a sufficient cause in this multifactorial disorder.
Show evidence (1 reference)
PMID:33544785 SUPPORT Other
"various maternal-related environmental and genetic risk factors have been reported, which include diabetes, obesity, exposure to different drugs or toxins"
The disease-specific review lists maternal obesity among reported environmental risk factors for anencephaly.
Mechanism Target:
PREDISPOSES Failure of Cranial Neuropore Closure — Obesity appears alongside diabetes as a maternal metabolic risk factor. Whether it acts through the same hyperglycaemic route or independently is not resolved by the cited source.
Show evidence (1 reference)
PMID:33544785 SUPPORT Other
"various maternal-related environmental and genetic risk factors have been reported, which include diabetes, obesity, exposure to different drugs or toxins"
Lists obesity among the reported maternal risk factors for the malformation, without identifying a mediating step.
Maternal Hyperthermia
maternal exposure to increased temperature ECTO:4000001 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is maternal exposure to increased temperature, annotated with exposure to increased temperature (ECTO:4000001). ECTO:4000001 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
First-trimester maternal hyperthermia (febrile illness, hot tub/sauna) is associated with an increased risk of neural tube defects.
Show evidence (1 reference)
PMID:15703536 SUPPORT Human Clinical
"Maternal hyperthermia in early pregnancy is associated with increased risk for neural tube defects and may be a human teratogen."
Meta-analysis reporting an ~1.9-fold increased NTD risk with maternal hyperthermia in early pregnancy.
Mechanism Target:
PREDISPOSES Failure of Cranial Neuropore Closure — Elevated core temperature in early pregnancy raises neural tube defect risk. Recorded as predisposing rather than triggering because the cited source states the association firmly but stops short of calling hyperthermia an established human teratogen.
Show evidence (1 reference)
PMID:15703536 SUPPORT Human Clinical
"Maternal hyperthermia in early pregnancy is associated with increased risk for neural tube defects and may be a human teratogen."
Reports early-pregnancy maternal hyperthermia as associated with increased neural tube defect risk and only possibly a human teratogen, which is why this is graded as predisposing.
🔬

Diagnosis

1
Prenatal Screening and Imaging
Anencephaly is detected by elevated maternal serum alpha-fetoprotein, elevated amniotic fluid AFP and acetylcholinesterase, and prenatal ultrasound demonstrating absence of the cranial vault and cerebral hemispheres (often from the late first trimester onward).
Show evidence (2 references)
PMID:23790957 SUPPORT Other
"diagnosis was based on measurement of alphafetoprotein (AFP) concentration in the amniotic fluid and maternal blood 8,9, but later technological improvements enabled ultrasound to replace AFP measurement as the mainstay of prenatal diagnosis"
Prenatal diagnosis of open neural tube defects historically relied on amniotic-fluid and maternal-serum AFP and is now performed principally by ultrasound.
PMID:33544785 SUPPORT Other
"Screening tests include maternal serum alpha-fetoprotein level and ultrasound (US) examination."
Disease-specific review confirms the principal biochemical screening and imaging modalities for anencephaly.
🩻

Imaging Findings

1
Acrania-exencephaly-anencephaly sequence on prenatal ultrasound
Prenatal ultrasound demonstrates the acrania-exencephaly-anencephaly sequence through loss of the normal cranial contour and progressive abnormality or absence of cranial tissue. Quantitative cranial ratios can support recognition before 11 weeks, but very early findings require confirmation after 11 weeks.
Ultrasound Diagnostic
Absent cranial vault with abnormal or absent cerebral tissue brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Anencephaly HP:0002323 Human Phenotype Ontology (HP)
Show evidence (1 reference)
PMID:41267385 SUPPORT Human Clinical
"When combined with cranial ultrasound morphological changes, it can accurately diagnose the acrania-exencephaly-anencephaly sequence before 11 weeks of gestation. However, diagnosis at this stage still requires reconfirmation after 11 weeks"
Multicenter human evidence supports early ultrasonographic detection while preserving the authors' explicit requirement for later confirmation.
📊

Prevalence

2
Worldwide
Birth Prevalence 51.0 per 100,000 (47.0–55.0) 1–9 per 10,000
Global meta-analysis estimate of 5.1 per 10,000 births (95% CI 4.7-5.5), normalized to cases per 100,000. This pooled estimate is higher than the 3.7 per 10,000 live-birth prevalence reported by Metropolitan Atlanta population surveillance. The sources use different geography, eras, and pregnancy-outcome ascertainment, so the pooled figure should not be interpreted as a uniform country-specific live-birth rate.
Show evidence (1 reference)
PMID:36253858 SUPPORT Human Clinical
"Overall estimate of the prevalence, incidence and attenuation of anencephaly worldwide were 5.1 per ten thousand births (95% confidence interval 4.7-5.5 per ten thousand births)"
Directly supports the disease-specific worldwide rate and interval, replacing an inference from a combined neural-tube-defect prevalence.
Metropolitan Atlanta, United States
Birth Prevalence 37.0 per 100,000 1–9 per 10,000
Population-based surveillance estimate of 3.7 per 10,000 live births for 1968-2002. This outcome-restricted estimate is presented alongside the higher global pooled estimate because national US surveillance found that live births represented only 34% of ascertained anencephaly cases and warned that live-birth-only surveillance severely underestimates cases.
Show evidence (2 references)
PMID:16950981 SUPPORT Human Clinical
"Prevalence rates of encephalocele (n = 167), spina bifida (n = 650), and anencephaly (n = 431) were 1.4, 5.5, and 3.7 per 10 000 live births, respectively."
Directly supports the anencephaly live-birth surveillance rate used for comparison with the global pooled estimate.
PMID:31580536 SUPPORT Human Clinical
"Live birth cases contributed to only 34% of the anencephaly cases"
Supports the explicit caveat that live-birth prevalence omits most anencephaly cases captured through broader pregnancy-outcome surveillance.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Anencephaly:

Encephalocele Not Yet Curated MONDO:0016057
Overlapping Features Herniation of meninges, with or without brain tissue, through a skull opening rather than a persistently open cranial neural tube.
Distinguishing Features
  • Focal herniation through a pathological skull opening
  • Brain or meningeal tissue is exteriorized rather than broadly exposed
Show evidence (1 reference)
PMID:24009034 SUPPORT Other
"'Herniation' NTDs are those in which meninges, with or without brain or spinal cord tissue, become exteriorized through a pathological opening in the skull or vertebral column (e.g., encephalocele and meningocele)."
Defines the focal herniation morphology that distinguishes encephalocele from an open cranial neural-tube defect.
Iniencephaly Not Yet Curated MONDO:0018968
Overlapping Features Lethal neural-tube defect dominated by an occipital/cervical defect and extreme fixed retroflexion rather than absence of the calvarium and brain.
Distinguishing Features
  • Extreme retroflexion of the head and short malformed spine
  • Occipital and cervical vertebral defect rather than isolated cranial-vault absence
Show evidence (1 reference)
PMID:9688130 SUPPORT Human Clinical
"Iniencephaly is a rare congenital anomaly characterized by spina bifida of the cervical vertebrae, fixed retroflexion of the head on the cervical spine, and occipital bone defect."
Directly supports the occipital, cervical, and fixed-retroflexion features that distinguish iniencephaly.
Craniorachischisis Not Yet Curated MONDO:0018969
Overlapping Features Continuous failure of closure involving both the cranial and spinal neural tube, distinguished from anencephaly without a contiguous open spinal defect.
Distinguishing Features
  • Cranial defect continues caudally as rachischisis/open spine
  • Involves failure of multiple closure sites rather than the cranial site alone
Show evidence (1 reference)
PMID:38846167 SUPPORT Human Clinical
"Craniorachischisis is characterized by anencephaly and an open defect extending from the brain to the spine and is the most severe and fatal type of neural tube defect."
Directly distinguishes the contiguous craniospinal open defect from an isolated cranial defect.
🧫

Experimental Models

2
Human SOSRS brain organoid model of NTD-like apical-constriction failure
Self-organizing single-rosette spheroids provide a human in-vitro system in which valproate exposure or SHROOM3 knockout enlarges the apical lumen and cell surface through reduced apical constriction. The model captures a closure-relevant cellular readout, but it lacks developmental-axis context and does not establish an anencephaly-specific phenotype.
Publication
PMID:37443734
Show evidence (2 references)
PMID:37443734 SUPPORT In Vitro
"The increased lumen sizes were caused by reduced cell apical constriction suggesting that impingement of this process is a shared mechanism for VPA treatment and SHROOM3-KO, two well-known causes of NTDs."
Demonstrates a convergent cellular mechanism for a teratogenic exposure and genetic perturbation in a human organoid system.
PMID:37090564 SUPPORT In Vitro
"our current SOSRS methodology has no developmental axis patterning such as dorsal-ventral or rostral-caudal."
This is the preprint version of PMID:37443734, not an independent study; it is cited only because its accessible full text directly documents the published model's missing developmental-axis context.
Surface-ectoderm Rac1 conditional-knockout mouse
Conditional Rac1 loss in mouse surface ectoderm yields a spectrum including open spina bifida, exencephaly/anencephaly, and localized encephalocele. It is useful for separating failed-closure phenotypes from post-neurulation herniation, but it is not a model of common nonsyndromic human anencephaly.
Publication
PMID:31628096
Show evidence (1 reference)
PMID:31628096 SUPPORT Model Organism
"Most mutant fetuses have open spina bifida, and some also exhibit exencephaly/anencephaly."
Supports the model's open-NTD phenotype spectrum; classified PARTIAL because the experiment was designed primarily as an encephalocele model.
{ }

Source YAML

click to show 
name: Anencephaly
creation_date: '2026-07-31T00:00:00Z'
category: Complex
description: >-
  Anencephaly is the most severe and one of the most common open neural tube
  defects, characterized by absence of a major portion of the brain, skull
  (calvaria), and scalp. It results from failure of the rostral (cranial)
  neuropore to close during the fourth week of embryogenesis (around days
  24-26 post-conception), leaving the developing forebrain exposed to amniotic
  fluid and progressively destroyed (area cerebrovasculosa). The condition lies
  on a continuum with exencephaly (an earlier developmental stage) and
  craniorachischisis. Anencephaly is uniformly lethal: affected pregnancies end
  in spontaneous abortion or stillbirth, and liveborn infants survive only hours
  to days. It is multifactorial, with periconceptional folate status the major
  modifiable determinant; maternal folic acid supplementation and food
  fortification prevent a large fraction of cases.
disease_term:
  preferred_term: anencephaly
  term:
    id: MONDO:0000819
    label: anencephaly
synonyms:
- anencephalus
parents:
- Neural Tube Defect
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      Congenital malformation of the central nervous system (open cranial neural
      tube defect).
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      Multifactorial disorder of development with polygenic/oligogenic
      susceptibility (folate one-carbon metabolism and planar cell polarity
      pathways) interacting with environmental exposures.
references:
- reference: PMID:23790957
  title: 'Neural tube defects: recent advances, unsolved questions, and controversies.'
  findings:
  - statement: >-
      Authoritative review of neural tube defect embryology, genetics (folate
      one-carbon metabolism and planar cell polarity), and prevention.
    evidence:
    - reference: PMID:23790957
      reference_title: "Neural tube defects: recent advances, unsolved questions, and controversies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        folate one-carbon metabolism is a key mechanism in the development of
        NTDs that is affected by, and interacts with, both genetic and
        environmental factors
      explanation: >-
        Review establishes folate one-carbon metabolism as central to NTD
        pathogenesis, interacting with genetic and environmental factors.
- reference: PMID:33544785
  title: 'The etiopathogenic and morphological spectrum of anencephaly: a comprehensive review of literature.'
  findings:
  - statement: >-
      Disease-specific review defining the morphology, lethality, reported
      genetic and maternal risk factors, and prenatal screening approach.
    evidence:
    - reference: PMID:33544785
      reference_title: "The etiopathogenic and morphological spectrum of anencephaly: a comprehensive review of literature."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Anencephaly is a severe malformation of the central nervous system (CNS), being
        one of the most common types of neural tube defects. It is defined as total or
        partial absence of the calvarium, with absence of the brain.
      explanation: >-
        Provides an anencephaly-specific definition rather than extrapolating
        the disease identity from literature about neural tube defects broadly.
inheritance:
- name: Multifactorial / polygenic with oligogenic contributions
  inheritance_term:
    preferred_term: Polygenic inheritance
    term:
      id: HP:0010982
      label: Polygenic inheritance
  description: >-
    Most nonsyndromic anencephaly is sporadic and multifactorial, arising from
    polygenic susceptibility (folate one-carbon metabolism and planar cell
    polarity pathway variants) combined with environmental exposures; targeted
    sequencing supports an additional oligogenic contribution in some cases.
  evidence:
  - reference: PMID:29205322
    reference_title: "A targeted sequencing panel identifies rare damaging variants in multiple genes in the cranial neural tube defect, anencephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Together with evidence for oligogenic inheritance, this study provides new
      information on the possible genetic causation of anencephaly
    explanation: >-
      Rare damaging variants across multiple candidate genes support an
      oligogenic/polygenic model of anencephaly causation.
pathophysiology:
- name: Disrupted Folate One-Carbon Metabolism
  biological_scale: MOLECULAR
  description: >-
    Periconceptional folate status is the strongest modifiable determinant of
    successful neural tube closure. Folate one-carbon metabolism supplies the
    methyl groups and nucleotide precursors required by the rapidly
    proliferating cranial neuroepithelium; reduced
    5,10-methylenetetrahydrofolate reductase (MTHFR) activity and inadequate
    folate availability compromise this supply and increase the risk that the
    cranial neuropore fails to close.
  genes:
  - preferred_term: MTHFR
    term:
      id: hgnc:7436
      label: MTHFR
  biological_processes:
  - preferred_term: tetrahydrofolate interconversion
    term:
      id: GO:0035999
      label: tetrahydrofolate interconversion
    modifier: DECREASED
  evidence:
  - reference: PMID:25808073
    reference_title: "Association between MTHFR C677T polymorphism and neural tube defect risks: A comprehensive evaluation in three groups of NTD patients, mothers, and fathers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a significant correlation between MTHFR C677T polymorphism and NTD risk was
      found in NTD patients and in their mother
    explanation: >-
      Meta-analysis links reduced MTHFR-dependent folate one-carbon metabolism to
      increased neural tube defect risk in affected individuals and their mothers.
  downstream:
  - target: Failure of Cranial Neuropore Closure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired folate one-carbon metabolism compromises the neuroepithelial
      methylation and nucleotide supply required for timely cranial neuropore
      closure; the precise molecular link between folate status and closure
      remains unresolved.
- name: Failure of Cranial Neuropore Closure
  biological_scale: TISSUE
  description: >-
    Primary neurulation requires the flat neural plate to bend, elevate its
    neural folds, and fuse dorsally to form the closed neural tube, a process
    that proceeds by multiple closure initiation sites and zips both rostrally
    and caudally. Anencephaly arises specifically from failure of closure of
    the rostral (anterior/cranial) neuropore, which normally seals by
    approximately embryonic day 24-26. When the cranial neural folds fail to
    appose and fuse, the forebrain neuroepithelium remains open and the future
    cranial vault does not form over it.
  genes:
  - preferred_term: PAX3
    term:
      id: hgnc:8617
      label: PAX3
  - preferred_term: PDGFRA
    term:
      id: hgnc:8803
      label: PDGFRA
  cell_types:
  - preferred_term: neuroepithelial cell
    term:
      id: CL:0000710
      label: neurecto-epithelial cell
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  biological_processes:
  - preferred_term: neural tube closure
    term:
      id: GO:0001843
      label: neural tube closure
    modifier: DECREASED
  - preferred_term: apical constriction driving neural fold bending
    term:
      id: GO:0003383
      label: apical constriction
  evidence:
  - reference: PMID:23790957
    reference_title: "Neural tube defects: recent advances, unsolved questions, and controversies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      human brain formation is achieved by neurulation progressing directly
      between Closures 1 and 3, with completion of a single cranial (rostral)
      neuropore
    explanation: >-
      Human cranial neurulation completes at a single rostral neuropore; failure
      of its closure produces anencephaly.
  downstream:
  - target: Exencephaly
    causal_link_type: DIRECT
    description: >-
      The unclosed cranial neural tube remains open, producing exencephaly — the
      exposed, disorganized brain precursor lesion.
    evidence:
    - reference: PMID:23790957
      reference_title: "Neural tube defects: recent advances, unsolved questions, and controversies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        presenting NTDs as separate open lesions of the cranial neural tube
        (exencephaly, progressing to anencephaly)
      explanation: >-
        Failure of cranial neural tube closure leaves the cranial neural tube
        open as exencephaly.
  - target: Exposure and Degeneration of Exposed Neural Tissue
    causal_link_type: DIRECT
    description: >-
      Failure of closure leaves the forebrain neuroepithelium exposed to the
      amniotic cavity, initiating its progressive mechanical and chemical
      degeneration.
- name: Convergent Extension and Neural Plate Morphogenesis Defect
  biological_scale: CELLULAR
  description: >-
    Convergent extension movements, governed by the non-canonical Wnt/planar
    cell polarity (PCP) pathway, narrow and lengthen the neural plate and are
    required to bring the neural folds close enough to fuse. Disruption of PCP
    signaling (e.g. VANGL1/VANGL2, CELSR1, SCRIB) broadens the neural plate and
    prevents fold apposition, producing severe open neural tube defects
    including anencephaly and craniorachischisis in model organisms and humans.
  genes:
  - preferred_term: VANGL1
    term:
      id: hgnc:15512
      label: VANGL1
  - preferred_term: VANGL2
    term:
      id: hgnc:15511
      label: VANGL2
  biological_processes:
  - preferred_term: convergent extension in neural plate elongation
    term:
      id: GO:0022007
      label: convergent extension involved in neural plate elongation
    modifier: DECREASED
  evidence:
  - reference: PMID:23790957
    reference_title: "Neural tube defects: recent advances, unsolved questions, and controversies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      convergent extension cell movements are dependent on non-canonical Wnt
      signalling: the planar cell polarity (PCP) pathway
    explanation: >-
      Neural plate narrowing/elongation (convergent extension) is driven by PCP
      signaling; its disruption prevents neural fold apposition and closure.
  downstream:
  - target: Failure of Cranial Neuropore Closure
    causal_link_type: DIRECT
    description: >-
      Defective convergent extension leaves the neural plate too broad for the
      cranial neural folds to appose and fuse, causing failure of rostral
      neuropore closure.
- name: Exposure and Degeneration of Exposed Neural Tissue
  biological_scale: TISSUE
  description: >-
    Following failed closure, the exposed forebrain (initially exencephaly)
    undergoes progressive mechanical and chemical degeneration on contact with
    amniotic fluid, leaving a hemorrhagic, poorly differentiated vascular mass
    (area cerebrovasculosa) in place of the cerebral hemispheres. The absence of
    a normal brain also disrupts induction of the overlying skull and scalp.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  - preferred_term: cranium
    term:
      id: UBERON:0003128
      label: cranium
  - preferred_term: scalp
    term:
      id: UBERON:0000403
      label: scalp
  biological_processes:
  - preferred_term: forebrain development
    term:
      id: GO:0030900
      label: forebrain development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:23790957
    reference_title: "Neural tube defects: recent advances, unsolved questions, and controversies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      presenting NTDs as separate open lesions of the cranial neural tube
      (exencephaly, progressing to anencephaly)
    explanation: >-
      Anencephaly develops when the open cranial neural tube (exencephaly)
      degenerates, confirming the exencephaly-to-anencephaly progression.
  downstream:
  - target: Anencephaly
    causal_link_type: DIRECT
    description: >-
      Progressive destruction of the exposed forebrain leaves the area
      cerebrovasculosa in place of the cerebral hemispheres — anencephaly.
    evidence:
    - reference: PMID:23790957
      reference_title: "Neural tube defects: recent advances, unsolved questions, and controversies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        presenting NTDs as separate open lesions of the cranial neural tube
        (exencephaly, progressing to anencephaly)
      explanation: >-
        The exposed cranial neural tube (exencephaly) degenerates to produce
        anencephaly.
  - target: Absent Calvaria
    causal_link_type: DIRECT
    description: >-
      Absence of the underlying brain and failure of the overlying cranial vault
      to form produce acrania (absent calvaria).
  - target: Adrenal Hypoplasia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Loss of the forebrain and hypothalamic-pituitary axis removes trophic ACTH
      drive to the fetal adrenal cortex, producing adrenal hypoplasia.
  - target: Polyhydramnios
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Loss of the forebrain and higher neurological control of the swallowing
      reflex impairs fetal swallowing of amniotic fluid, producing
      polyhydramnios. (The brainstem is typically at least partly preserved in
      anencephaly, so this reflects loss of suprabulbar control rather than
      brainstem absence.)
phenotypes:
- name: Anencephaly
  category: Phenotypic abnormality
  description: >-
    Absence of the major portion of the brain, skull, and scalp, the defining
    feature of the disorder.
  phenotype_term:
    preferred_term: Anencephaly
    term:
      id: HP:0002323
      label: Anencephaly
  frequency: OBLIGATE
  evidence:
  - reference: PMID:17409324
    reference_title: "Mutations in VANGL1 associated with neural-tube defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neural-tube defects such as anencephaly and spina bifida constitute a
      group of common congenital malformations caused by complex genetic and
      environmental factors.
    explanation: >-
      Establishes anencephaly as a common open neural tube defect of
      multifactorial (genetic and environmental) origin.
- name: Exencephaly
  category: Phenotypic abnormality
  description: >-
    The earlier developmental precursor lesion, in which the disorganized brain
    is exposed but not yet destroyed; it degenerates into anencephaly.
  phenotype_term:
    preferred_term: Exencephaly
    term:
      id: HP:0030769
      label: Exencephaly
  evidence:
  - reference: PMID:23790957
    reference_title: "Neural tube defects: recent advances, unsolved questions, and controversies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      embryos complete Closure 1 but fail in later neurulation, presenting NTDs
      as separate open lesions of the cranial neural tube (exencephaly,
      progressing to anencephaly)
    explanation: >-
      Exencephaly is the open cranial-neural-tube precursor lesion that
      progresses to anencephaly.
- name: Absent Calvaria
  category: Phenotypic abnormality
  description: >-
    Absence of the cranial vault (acrania), leaving the brain uncovered.
  phenotype_term:
    preferred_term: Acrania (absent calvaria)
    term:
      id: HP:0030716
      label: Acrania
  frequency: OBLIGATE
  evidence:
  - reference: PMID:27429697
    reference_title: "Check the Head: Emergency Ultrasound Diagnosis of Fetal Anencephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In diagnosing fetal anencephaly using POCUS, a very important finding is
      absence of the fetal calvarium
    explanation: >-
      Absence of the fetal calvarium (acrania) is a defining sonographic feature
      of anencephaly.
- name: Polyhydramnios
  category: Phenotypic abnormality
  description: >-
    Excess amniotic fluid, attributed to impaired fetal swallowing, frequently
    complicates anencephalic pregnancies.
  phenotype_term:
    preferred_term: Polyhydramnios
    term:
      id: HP:0001561
      label: Polyhydramnios
  frequency: OCCASIONAL
  notes: >-
    Frequency band derived from PMID:16827827 (56/211, 26%). That cohort is
    self-selected — parents who declined termination, recruited via a parent
    website — so 26% is a lower bound for continued/liveborn pregnancies rather
    than a population estimate, and it sits at the upper edge of the OCCASIONAL
    band.
  evidence:
  - reference: PMID:16827827
    reference_title: "Spontaneous pregnancy outcome after prenatal diagnosis of anencephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      polyhydramnios was a feature in 56 (26%) pregnancies
    explanation: >-
      In a cohort of 211 continued anencephalic pregnancies, polyhydramnios
      complicated 26% — quantifying the frequently reported association.
- name: Adrenal Hypoplasia
  category: Phenotypic abnormality
  description: >-
    Fetal adrenal hypoplasia occurs secondary to absent hypothalamic-pituitary
    drive (absent forebrain/pituitary axis).
  phenotype_term:
    preferred_term: Adrenal hypoplasia
    term:
      id: HP:0000835
      label: Adrenal hypoplasia
  evidence:
  - reference: PMID:2625322
    reference_title: "Relationship between fetal adrenal morphology and anterior pituitary function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      decreased cortical thickness in the anencephalic group represented
      cellular hypoplasia
    explanation: >-
      Anencephalic fetal adrenals show cellular hypoplasia and fail to gain
      weight, consistent with loss of ACTH-dependent adrenal development.
genetic:
- name: MTHFR
  notes: >-
    The MTHFR c.677C>T (p.Ala222Val) thermolabile polymorphism reduces
    5,10-methylenetetrahydrofolate reductase activity and is a folate-dependent
    maternal/fetal risk factor for neural tube defects including anencephaly.
  gene_term:
    preferred_term: MTHFR
    term:
      id: hgnc:7436
      label: MTHFR
  relationship_type: SUSCEPTIBILITY
  evidence:
  - reference: PMID:25808073
    reference_title: "Association between MTHFR C677T polymorphism and neural tube defect risks: A comprehensive evaluation in three groups of NTD patients, mothers, and fathers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a significant correlation between MTHFR C677T polymorphism and NTD risk was
      found in NTD patients and in their mother
    explanation: >-
      Meta-analysis showing the MTHFR C677T polymorphism is associated with NTD
      risk in affected individuals and their mothers.
- name: VANGL1
  notes: >-
    VANGL1 encodes a core planar cell polarity protein; rare missense variants
    have been identified in patients with neural tube defects, implicating the
    PCP/convergent-extension pathway in human anencephaly.
  gene_term:
    preferred_term: VANGL1
    term:
      id: hgnc:15512
      label: VANGL1
  relationship_type: SUSCEPTIBILITY
  evidence:
  - reference: PMID:17409324
    reference_title: "Mutations in VANGL1 associated with neural-tube defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings implicate VANGL1 as a risk factor in human neural-tube
      defects.
    explanation: >-
      Identifies VANGL1 (a PCP-pathway gene) missense mutations in patients with
      familial and sporadic neural tube defects.
- name: VANGL2
  notes: >-
    VANGL2, another core PCP gene, causes severe neural tube defects including
    craniorachischisis and exencephaly/anencephaly in mutant mice. Its role in
    human anencephaly is inferred from this model-organism evidence and the
    established human relevance of the PCP pathway (e.g. VANGL1); direct human
    genetic evidence for VANGL2 is not yet established here.
  gene_term:
    preferred_term: VANGL2
    term:
      id: hgnc:15511
      label: VANGL2
  relationship_type: SUSCEPTIBILITY
  evidence:
  - reference: PMID:23790957
    reference_title: "Neural tube defects: recent advances, unsolved questions, and controversies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Analysis of the mouse mutant loop-tail (Vangl2 gene) has shown that
      craniorachischisis, the most severe NTD, results from failure of Closure 1
    explanation: >-
      The Vangl2 loop-tail mouse links PCP-gene disruption to failure of neural
      tube closure and the most severe NTDs.
- name: PAX3
  notes: >-
    PAX3 is required for neural tube and neural crest development; Pax3 mutant
    (Splotch) mice develop cranial NTDs, especially under folate deficiency.
    The link to human anencephaly rests on this model-organism evidence; direct
    human genetic evidence for PAX3 in anencephaly is not yet established here.
  gene_term:
    preferred_term: PAX3
    term:
      id: hgnc:8617
      label: PAX3
  relationship_type: SUSCEPTIBILITY
  evidence:
  - reference: PMID:23790957
    reference_title: "Neural tube defects: recent advances, unsolved questions, and controversies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The frequency of cranial NTDs is exacerbated by maternal folate deficiency
      in mutant splotch (Pax3) embryos, whereas wild-type littermates are never
      affected by NTDs
    explanation: >-
      Splotch (Pax3) mutant embryos develop folate-sensitive cranial NTDs,
      implicating PAX3 in cranial neural tube closure.
- name: PDGFRA
  notes: >-
    Targeted exome sequencing of cranial NTD (predominantly anencephaly) cohorts
    has identified rare damaging variants, including a PDGFRA frameshift,
    supporting an oligogenic contribution to anencephaly.
  gene_term:
    preferred_term: PDGFRA
    term:
      id: hgnc:8803
      label: PDGFRA
  relationship_type: SUSCEPTIBILITY
  evidence:
  - reference: PMID:29205322
    reference_title: "A targeted sequencing panel identifies rare damaging variants in multiple genes in the cranial neural tube defect, anencephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This included 1 frameshift (PDGFRA)
    explanation: >-
      A 191-gene panel in 90 cranial NTD (85 anencephaly) patients identified a
      rare damaging PDGFRA frameshift variant among candidate anencephaly genes.
environmental:
- name: Maternal Folate Deficiency
  exposure_term:
    preferred_term: low maternal folic acid exposure
    modifier: DECREASED
    term:
      id: ECTO:9000123
      label: exposure to folic acid
  influences_mechanisms:
  - target: Disrupted Folate One-Carbon Metabolism
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Inadequate maternal folate directly limits the one-carbon pool this node
      depends on. The link is direct because the exposure and the metabolic
      deficit are the same thing viewed from outside and inside the mother.
    evidence:
    - reference: PMID:1677062
      reference_title: "Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "supplementation with folic acid (one of the vitamins in the B group) or a mixture of seven other vitamins (A,D,B1,B2,B6,C and nicotinamide) around the time of conception can prevent neural tube defects (anencephaly, spina bifida, encephalocele)"
      explanation: >-
        Periconceptional folic acid supplementation reduced neural tube defect
        recurrence, establishing maternal folate status as causally relevant
        to the defect rather than merely correlated with it.
  description: >-
    Inadequate periconceptional folate is the strongest modifiable risk factor
    for neural tube defects; folic acid supplementation and food fortification
    substantially reduce anencephaly incidence.
  evidence:
  - reference: PMID:1677062
    reference_title: "Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      supplementation with folic acid (one of the vitamins in the B group) or a
      mixture of seven other vitamins (A,D,B1,B2,B6,C and nicotinamide) around
      the time of conception can prevent neural tube defects (anencephaly, spina
      bifida, encephalocele)
    explanation: >-
      The randomized MRC Vitamin Study established that periconceptional folic
      acid prevents NTDs, implicating folate status as the key modifiable
      determinant.
- name: Maternal Valproate Exposure
  exposure_term:
    preferred_term: gestational maternal valproate exposure
    term:
      id: XCO:0001598
      label: gestational maternal exposure to valproate
  influences_mechanisms:
  - target: Failure of Cranial Neuropore Closure
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Valproate is an established human teratogen for neural tube defects, so
      it initiates rather than merely raises the risk of failed closure. It is
      marked indirect because the responsible step is unsettled between folate
      antagonism and histone deacetylase inhibition.
    evidence:
    - reference: PMID:16639967
      reference_title: "Major malformations with valproic acid."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "It has now become evident that valproic acid might cause more than just neural tube defects (NTDs)."
      explanation: >-
        Identifies valproic acid as a cause of neural tube defects. Support is
        PARTIAL and the source is OTHER because this is a hedged statement in a
        clinical question-and-answer column rather than a primary study, and
        the defect it names is the neural tube generally rather than the
        cranial neuropore specifically.
  description: >-
    Periconceptional exposure to the antiepileptic valproic acid interferes with
    folate metabolism and histone deacetylation and increases the risk of neural
    tube defects.
  evidence:
  - reference: PMID:16639967
    reference_title: "Major malformations with valproic acid."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It has now become evident that valproic acid might cause more than just
      neural tube defects (NTDs).
    explanation: >-
      Systematic review of cohort studies confirms valproic acid is a teratogen
      causing neural tube defects and other major malformations.
- name: Maternal Pregestational Diabetes
  influences_mechanisms:
  - target: Failure of Cranial Neuropore Closure
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Maternal diabetes raises the probability of failed closure without being
      sufficient to cause it, and the intervening steps between maternal
      hyperglycaemia and the neuroepithelium are not established here.
    evidence:
    - reference: PMID:23790957
      reference_title: "Neural tube defects: recent advances, unsolved questions, and controversies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "factors implicated in the aetiology of NTDs include maternal diabetes"
      explanation: >-
        Lists maternal diabetes among the factors implicated in the aetiology
        of neural tube defects, a risk-factor attribution rather than a
        demonstrated mechanism.
  description: >-
    Poorly controlled maternal diabetes mellitus is an established risk factor
    for neural tube defects including anencephaly.
  evidence:
  - reference: PMID:23790957
    reference_title: "Neural tube defects: recent advances, unsolved questions, and controversies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      factors implicated in the aetiology of NTDs include maternal diabetes
    explanation: >-
      Maternal diabetes is an established environmental risk factor for neural
      tube defects.
- name: Maternal Obesity
  influences_mechanisms:
  - target: Failure of Cranial Neuropore Closure
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Obesity appears alongside diabetes as a maternal metabolic risk factor.
      Whether it acts through the same hyperglycaemic route or independently
      is not resolved by the cited source.
    evidence:
    - reference: PMID:33544785
      reference_title: "The etiopathogenic and morphological spectrum of anencephaly: a comprehensive review of literature."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "various maternal-related environmental and genetic risk factors have been reported, which include diabetes, obesity, exposure to different drugs or toxins"
      explanation: >-
        Lists obesity among the reported maternal risk factors for the
        malformation, without identifying a mediating step.
  description: >-
    Maternal obesity is a reported risk factor for anencephaly and other neural
    tube defects. Its contribution is recorded as an association rather than a
    sufficient cause in this multifactorial disorder.
  evidence:
  - reference: PMID:33544785
    reference_title: "The etiopathogenic and morphological spectrum of anencephaly: a comprehensive review of literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      various maternal-related environmental and genetic risk factors have been reported, which include diabetes, obesity, exposure to different drugs or toxins
    explanation: >-
      The disease-specific review lists maternal obesity among reported
      environmental risk factors for anencephaly.
- name: Maternal Hyperthermia
  exposure_term:
    preferred_term: maternal exposure to increased temperature
    term:
      id: ECTO:4000001
      label: exposure to increased temperature
  influences_mechanisms:
  - target: Failure of Cranial Neuropore Closure
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Elevated core temperature in early pregnancy raises neural tube defect
      risk. Recorded as predisposing rather than triggering because the cited
      source states the association firmly but stops short of calling
      hyperthermia an established human teratogen.
    evidence:
    - reference: PMID:15703536
      reference_title: "Maternal hyperthermia and the risk for neural tube defects in offspring: systematic review and meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Maternal hyperthermia in early pregnancy is associated with increased risk for neural tube defects and may be a human teratogen."
      explanation: >-
        Reports early-pregnancy maternal hyperthermia as associated with
        increased neural tube defect risk and only possibly a human teratogen,
        which is why this is graded as predisposing.
  description: >-
    First-trimester maternal hyperthermia (febrile illness, hot tub/sauna) is
    associated with an increased risk of neural tube defects.
  evidence:
  - reference: PMID:15703536
    reference_title: "Maternal hyperthermia and the risk for neural tube defects in offspring: systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Maternal hyperthermia in early pregnancy is associated with increased risk
      for neural tube defects and may be a human teratogen.
    explanation: >-
      Meta-analysis reporting an ~1.9-fold increased NTD risk with maternal
      hyperthermia in early pregnancy.
treatments:
- name: Periconceptional Folic Acid Supplementation
  description: >-
    Primary prevention: daily periconceptional folic acid (typically 0.4 mg for
    average risk, up to 4 mg for high-risk/prior-NTD pregnancies) markedly
    reduces the occurrence and recurrence of neural tube defects. This is
    preventive, not curative — anencephaly itself has no treatment.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: folic acid
      term:
        id: CHEBI:27470
        label: folic acid
  evidence:
  - reference: PMID:1307234
    reference_title: "Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Periconceptional vitamin use decreases the incidence of a first
      occurrence of neural-tube defects.
    explanation: >-
      Randomized trial demonstrating periconceptional folic-acid-containing
      supplementation prevents first-occurrence NTDs.
  - reference: PMID:1677062
    reference_title: "Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Folic acid supplementation starting before pregnancy can now be firmly
      recommended for all women who have had an affected pregnancy
    explanation: >-
      The MRC Vitamin Study established a 72% reduction in NTD recurrence with
      periconceptional folic acid.
- name: Palliative and Supportive Care
  description: >-
    Anencephaly is uniformly lethal and has no curative therapy; management is
    comfort/palliative care for liveborn neonates and supportive counseling for
    families, including reproductive counseling.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:29205322
    reference_title: "A targeted sequencing panel identifies rare damaging variants in multiple genes in the cranial neural tube defect, anencephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neural tube defects (NTDs) affecting the brain (anencephaly) are lethal
      before or at birth
    explanation: >-
      Anencephaly is uniformly lethal before or at birth, so management is
      limited to palliative and supportive care rather than curative therapy.
prevalence:
- population: Worldwide
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 51.0
  rate_low: 47.0
  rate_high: 55.0
  notes: >-
    Global meta-analysis estimate of 5.1 per 10,000 births (95% CI 4.7-5.5),
    normalized to cases per 100,000. This pooled estimate is higher than the
    3.7 per 10,000 live-birth prevalence reported by Metropolitan Atlanta
    population surveillance. The sources use different geography, eras, and
    pregnancy-outcome ascertainment, so the pooled figure should not be
    interpreted as a uniform country-specific live-birth rate.
  evidence:
  - reference: PMID:36253858
    reference_title: "Global prevalence of congenital anencephaly: a comprehensive systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall estimate of the prevalence, incidence and attenuation of
      anencephaly worldwide were 5.1 per ten thousand births (95% confidence interval
      4.7-5.5 per ten thousand births)
    explanation: >-
      Directly supports the disease-specific worldwide rate and interval,
      replacing an inference from a combined neural-tube-defect prevalence.
- population: Metropolitan Atlanta, United States
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 37.0
  notes: >-
    Population-based surveillance estimate of 3.7 per 10,000 live births for
    1968-2002. This outcome-restricted estimate is presented alongside the
    higher global pooled estimate because national US surveillance found that
    live births represented only 34% of ascertained anencephaly cases and
    warned that live-birth-only surveillance severely underestimates cases.
  evidence:
  - reference: PMID:16950981
    reference_title: "Are encephaloceles neural tube defects?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prevalence rates of encephalocele (n = 167), spina bifida (n = 650), and
      anencephaly (n = 431) were 1.4, 5.5, and 3.7 per 10 000 live births,
      respectively.
    explanation: >-
      Directly supports the anencephaly live-birth surveillance rate used for
      comparison with the global pooled estimate.
  - reference: PMID:31580536
    reference_title: "National population-based estimates for major birth defects, 2010-2014."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Live birth cases contributed to only 34% of the anencephaly cases
    explanation: >-
      Supports the explicit caveat that live-birth prevalence omits most
      anencephaly cases captured through broader pregnancy-outcome surveillance.
imaging_findings:
- name: Acrania-exencephaly-anencephaly sequence on prenatal ultrasound
  modality: ULTRASOUND
  imaging_finding_term:
    preferred_term: Absent cranial vault with abnormal or absent cerebral tissue
  located_in:
    preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  phenotype_term:
    preferred_term: Anencephaly
    term:
      id: HP:0002323
      label: Anencephaly
  diagnostic: true
  description: >-
    Prenatal ultrasound demonstrates the acrania-exencephaly-anencephaly
    sequence through loss of the normal cranial contour and progressive
    abnormality or absence of cranial tissue. Quantitative cranial ratios can
    support recognition before 11 weeks, but very early findings require
    confirmation after 11 weeks.
  evidence:
  - reference: PMID:41267385
    reference_title: "Study of Ultrasound Diagnosis of Acrania-Exencephaly-Anencephaly Sequence in Middle First Trimester: A Multicenter Center, Retrospective Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      When combined with cranial ultrasound morphological changes, it can accurately diagnose the
      acrania-exencephaly-anencephaly sequence before 11 weeks of gestation. However,
      diagnosis at this stage still requires reconfirmation after 11 weeks
    explanation: >-
      Multicenter human evidence supports early ultrasonographic detection while
      preserving the authors' explicit requirement for later confirmation.
diagnosis:
- name: Prenatal Screening and Imaging
  description: >-
    Anencephaly is detected by elevated maternal serum alpha-fetoprotein,
    elevated amniotic fluid AFP and acetylcholinesterase, and prenatal
    ultrasound demonstrating absence of the cranial vault and cerebral
    hemispheres (often from the late first trimester onward).
  evidence:
  - reference: PMID:23790957
    reference_title: "Neural tube defects: recent advances, unsolved questions, and controversies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      diagnosis was based on measurement of alphafetoprotein (AFP) concentration
      in the amniotic fluid and maternal blood 8,9, but later technological
      improvements enabled ultrasound to replace AFP measurement as the mainstay
      of prenatal diagnosis
    explanation: >-
      Prenatal diagnosis of open neural tube defects historically relied on
      amniotic-fluid and maternal-serum AFP and is now performed principally by
      ultrasound.
  - reference: PMID:33544785
    reference_title: "The etiopathogenic and morphological spectrum of anencephaly: a comprehensive review of literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Screening tests include maternal serum alpha-fetoprotein level and ultrasound (US) examination.
    explanation: >-
      Disease-specific review confirms the principal biochemical screening and
      imaging modalities for anencephaly.
differential_diagnoses:
- name: Encephalocele
  description: >-
    Herniation of meninges, with or without brain tissue, through a skull
    opening rather than a persistently open cranial neural tube.
  distinguishing_features:
  - Focal herniation through a pathological skull opening
  - Brain or meningeal tissue is exteriorized rather than broadly exposed
  disease_term:
    preferred_term: isolated encephalocele
    term:
      id: MONDO:0016057
      label: isolated encephalocele
  evidence:
  - reference: PMID:24009034
    reference_title: "Neural tube defects--disorders of neurulation and related embryonic processes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      'Herniation' NTDs are those in which meninges, with or without brain or spinal
      cord tissue, become exteriorized through a pathological opening in the skull or
      vertebral column (e.g., encephalocele and meningocele).
    explanation: >-
      Defines the focal herniation morphology that distinguishes encephalocele
      from an open cranial neural-tube defect.
- name: Iniencephaly
  description: >-
    Lethal neural-tube defect dominated by an occipital/cervical defect and
    extreme fixed retroflexion rather than absence of the calvarium and brain.
  distinguishing_features:
  - Extreme retroflexion of the head and short malformed spine
  - Occipital and cervical vertebral defect rather than isolated cranial-vault absence
  disease_term:
    preferred_term: iniencephaly
    term:
      id: MONDO:0018968
      label: iniencephaly
  evidence:
  - reference: PMID:9688130
    reference_title: "Iniencephaly: neuroradiological and surgical features. Case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Iniencephaly is a rare congenital anomaly characterized by spina bifida of
      the cervical vertebrae, fixed retroflexion of the head on the cervical spine,
      and occipital bone defect.
    explanation: >-
      Directly supports the occipital, cervical, and fixed-retroflexion features
      that distinguish iniencephaly.
- name: Craniorachischisis
  description: >-
    Continuous failure of closure involving both the cranial and spinal neural
    tube, distinguished from anencephaly without a contiguous open spinal defect.
  distinguishing_features:
  - Cranial defect continues caudally as rachischisis/open spine
  - Involves failure of multiple closure sites rather than the cranial site alone
  disease_term:
    preferred_term: craniorachischisis
    term:
      id: MONDO:0018969
      label: craniorachischisis
  evidence:
  - reference: PMID:38846167
    reference_title: "Craniorachischisis in a 33-week-old Female Fetus: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Craniorachischisis is characterized by anencephaly and an open defect
      extending from the brain to the spine and is the most severe and fatal type
      of neural tube defect.
    explanation: >-
      Directly distinguishes the contiguous craniospinal open defect from an
      isolated cranial defect.
experimental_models:
- name: Human SOSRS brain organoid model of NTD-like apical-constriction failure
  description: >-
    Self-organizing single-rosette spheroids provide a human in-vitro system in
    which valproate exposure or SHROOM3 knockout enlarges the apical lumen and
    cell surface through reduced apical constriction. The model captures a
    closure-relevant cellular readout, but it lacks developmental-axis context
    and does not establish an anencephaly-specific phenotype.
  publication: PMID:37443734
  evidence:
  - reference: PMID:37443734
    reference_title: "A Shared Pathogenic Mechanism for Valproic Acid and SHROOM3 Knockout in a Brain Organoid Model of Neural Tube Defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The increased lumen sizes were caused by reduced cell apical constriction suggesting that
      impingement of this process is a shared mechanism for VPA treatment and
      SHROOM3-KO, two well-known causes of NTDs.
    explanation: >-
      Demonstrates a convergent cellular mechanism for a teratogenic exposure
      and genetic perturbation in a human organoid system.
  - reference: PMID:37090564
    reference_title: "A Shared Pathogenic Mechanism for Valproic Acid and SHROOM3 Knockout in a Brain Organoid Model of Neural Tube Defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      our current SOSRS methodology has no developmental axis patterning such as
      dorsal-ventral or rostral-caudal.
    explanation: >-
      This is the preprint version of PMID:37443734, not an independent study;
      it is cited only because its accessible full text directly documents the
      published model's missing developmental-axis context.
- name: Surface-ectoderm Rac1 conditional-knockout mouse
  description: >-
    Conditional Rac1 loss in mouse surface ectoderm yields a spectrum including
    open spina bifida, exencephaly/anencephaly, and localized encephalocele. It
    is useful for separating failed-closure phenotypes from post-neurulation
    herniation, but it is not a model of common nonsyndromic human anencephaly.
  publication: PMID:31628096
  evidence:
  - reference: PMID:31628096
    reference_title: "Novel mouse model of encephalocele: post-neurulation origin and relationship to open neural tube defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Most mutant fetuses have open
      spina bifida, and some also exhibit exencephaly/anencephaly.
    explanation: >-
      Supports the model's open-NTD phenotype spectrum; classified PARTIAL
      because the experiment was designed primarily as an encephalocele model.
clinical_trials: []
discussions:
- discussion_id: anencephaly_human_model_specificity_gap
  prompt: >-
    Which human in-vitro neurulation readouts predict anencephaly specifically,
    rather than neural-tube defects collectively?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Failure of Cranial Neuropore Closure
  rationale: >-
    Current human brain-organoid systems reproduce lumen expansion and
    apical-constriction defects after genetic or teratogenic perturbation, but
    the reported SOSRS system lacks developmental-axis context and reports an
    NTD-like rather than an anencephaly-specific phenotype. Translational
    specificity to human anencephaly therefore remains unresolved.
  evidence:
  - reference: PMID:37443734
    reference_title: "A Shared Pathogenic Mechanism for Valproic Acid and SHROOM3 Knockout in a Brain Organoid Model of Neural Tube Defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our system allows the rapid
      identification of NTD-like phenotypes for both compounds and genetic variants
    explanation: >-
      The authors explicitly describe the readout as NTD-like, supporting the
      open question of whether it is specific to anencephaly.
- discussion_id: anencephaly_residual_folate_resistant_risk_gap
  prompt: >-
    Which genetic and exposure combinations explain anencephaly that occurs
    despite adequate periconceptional folic acid?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Disrupted Folate One-Carbon Metabolism
  - pathophysiology#Convergent Extension and Neural Plate Morphogenesis Defect
  rationale: >-
    Folic acid prevents many but not all neural-tube defects, while sequencing
    implicates heterogeneous and often oligogenic closure pathways. The relative
    contribution and interaction of folate-resistant mechanisms remain poorly
    quantified in human anencephaly cohorts.
  evidence:
  - reference: PMID:1677062
    reference_title: "Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      27 of these had a known neural tube defect, 6 in the folic
      acid groups and 21 in the two other groups, a 72% protective effect (relative
      risk 0.28, 95% confidence interval 0.12-0.71).
    explanation: >-
      The randomized recurrence trial demonstrates substantial but incomplete
      prevention across neural-tube defects; PARTIAL because it was not powered
      for anencephaly-specific residual mechanisms.
📚

References & Deep Research

References

2
PMID:23790957
Neural tube defects: recent advances, unsolved questions, and controversies.
1 finding
Authoritative review of neural tube defect embryology, genetics (folate one-carbon metabolism and planar cell polarity), and prevention.
Show evidence (1 reference)
PMID:23790957 SUPPORT Other
"folate one-carbon metabolism is a key mechanism in the development of NTDs that is affected by, and interacts with, both genetic and environmental factors"
Review establishes folate one-carbon metabolism as central to NTD pathogenesis, interacting with genetic and environmental factors.
PMID:33544785
The etiopathogenic and morphological spectrum of anencephaly: a comprehensive review of literature.
1 finding
Disease-specific review defining the morphology, lethality, reported genetic and maternal risk factors, and prenatal screening approach.
Show evidence (1 reference)
PMID:33544785 SUPPORT Other
"Anencephaly is a severe malformation of the central nervous system (CNS), being one of the most common types of neural tube defects. It is defined as total or partial absence of the calvarium, with absence of the brain."
Provides an anencephaly-specific definition rather than extrapolating the disease identity from literature about neural tube defects broadly.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 24 citations 2026-07-31T23:38:30.075260

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Anencephaly
  • MONDO ID: (if available)
  • Category: Complex

Research Objectives

Please provide a comprehensive research report on Anencephaly covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Anencephaly: comprehensive disease-characteristics report

Executive summary and evidence scope

Anencephaly is a congenital, open cranial neural-tube defect caused by failure of cranial neurulation during the first month after fertilization. It is characterized by partial or complete absence of the calvarium and destruction or absence of most of the brain. It is not compatible with prolonged survival: death occurs prenatally or usually within hours to days after birth. Most nonsyndromic cases are sporadic and multifactorial rather than attributable to one diagnostic gene. The best-supported model combines polygenic or oligogenic susceptibility with maternal nutrition, metabolic disease, medications, hyperthermia, and other environmental exposures. Human sequencing has implicated several pathways, especially non-canonical Wnt/planar-cell-polarity (PCP) signaling, but most reported variants remain susceptibility alleles or variants requiring additional evidence rather than universally causal mutations. (munteanu2020theetiopathogenicand pages 1-2, munteanu2020theetiopathogenicand pages 2-3, ishida2018atargetedsequencing pages 1-5)

The most effective intervention is primary prevention before neural-tube closure, especially periconceptional folic acid and population food fortification. Prenatal ultrasound permits early diagnosis but does not alter the malformation. There is no curative fetal surgery, pharmacotherapy, gene therapy, or postnatal repair for anencephaly. Much modern mechanistic and prevention literature reports neural-tube defects (NTDs) collectively; such findings should not automatically be encoded as anencephaly-specific.

1. Disease information

Definition and classification

Anencephaly is defined morphologically by total or partial absence of the cranial vault and brain. Brainstem, cerebellar, and diencephalic remnants may persist; therefore, “complete absence of all neural tissue” is not required. Morphologic subdivisions include meroacrania (partial cranial defect), holoacrania (extensive cranial defect), and holoacrania with rachischisis/craniorachischisis. It belongs to the open NTD spectrum but must be distinguished from acalvaria, in which calvarial bones are absent while cerebral tissue is relatively preserved. (munteanu2020theetiopathogenicand pages 1-2)

A disease-specific review’s abstract states directly: “Anencephaly is a severe malformation of the central nervous system … defined as total or partial absence of the calvarium, with absence of the brain.” Published August 2020; DOI: 10.47162/rjme.61.2.03. (munteanu2020theetiopathogenicand pages 1-2)

Identifiers and synonyms

  • MONDO: Anencephaly; the exact current MONDO identifier should be verified against the live MONDO release before ingestion.
  • ICD-10-CM: Q00.0, anencephaly.
  • ICD-10 category: Q00, anencephaly and similar malformations.
  • ICD-11, Orphanet, OMIM, and MeSH: use the current entries titled Anencephaly; exact release-specific identifiers were not established by the retrieved literature and should be verified directly rather than inferred.
  • Common terms: anencephalus, anencephalic fetus, congenital absence of brain and skull, cranial open neural-tube defect. Exencephaly is the earlier exposed-brain phenotype that can undergo degeneration and become anencephaly; the terms are developmentally related but not exactly synonymous.

The report primarily summarizes aggregated disease-level resources, reviews, population studies, and research cohorts, not individual EHR records. The sequencing study comprised 85 anencephaly and five craniorachischisis cases. (ishida2018atargetedsequencing pages 1-5)

Domain Recommended identifier/ontology term Meaning/use Evidence caveat
Disease MONDO: verify in source ontology Preferred disease ontology anchor for anencephaly in cross-resource integration Exact MONDO ID not confirmed from retrieved context; verify before database ingestion (munteanu2020theetiopathogenicand pages 1-2)
Disease Orphanet: anencephaly — verify in source ontology Rare-disease registry identifier for disease-level aggregation Exact Orphanet code not confirmed in retrieved context; verify in Orphanet (munteanu2020theetiopathogenicand pages 1-2)
Disease ICD-10: Q00.0 Anencephaly Billing/classification code for congenital CNS malformation Commonly used code; not directly confirmed in retrieved context, so verify against current ICD release (munteanu2020theetiopathogenicand pages 1-2)
Disease ICD-11: verify in source ontology International classification term for contemporary coding/interoperability Exact ICD-11 stem code not confirmed from retrieved context; verify in WHO browser (munteanu2020theetiopathogenicand pages 1-2)
Disease MeSH: Anencephaly (verify descriptor ID) Literature indexing term for PubMed/biomedical retrieval Descriptor name is standard; exact MeSH unique ID not confirmed here (munteanu2020theetiopathogenicand pages 1-2)
Disease concept Open neural tube defect High-level grouping used for etiologic and mechanistic aggregation Much mechanistic evidence is NTD-wide rather than anencephaly-specific (avagliano2019overviewonneural pages 1-2, rai2023aquestfor pages 2-3)
Phenotype (HPO) HP:0002323 Anencephaly Core phenotype/disease-defining cranial neural tube closure defect Primary phenotype; use as top phenotype assertion (munteanu2020theetiopathogenicand pages 1-2, ishida2018atargetedsequencing pages 1-5)
Phenotype (HPO) HP:0000248 Microcephaly or verify more specific cranial-abnormality term Differential/related cranial size abnormality in prenatal imaging/pathology context Mentioned mainly for differential diagnosis; exact best-fit term should be curated (munteanu2020theetiopathogenicand pages 7-8)
Phenotype (HPO) HP:0001363 Craniorachischisis Associated severe open NTD phenotype/subclassification when present Not present in all cases; use only where explicitly documented (munteanu2020theetiopathogenicand pages 1-2, ishida2018atargetedsequencing pages 1-5)
Phenotype (HPO) HP:0000238 Hydrocephalus / verify relevance Potential associated CNS phenotype in broader NTD contexts Association is broader NTD-wide; not core to isolated anencephaly (avagliano2019overviewonneural pages 1-2)
Prenatal imaging sign “Mickey Mouse” sign — verify ontology mapping Useful prenatal ultrasound annotation for first-trimester detection Imaging descriptor, not a standard disease ontology term (munteanu2020theetiopathogenicand pages 8-9)
Anatomy (UBERON) UBERON:0000955 brain Primary malformed/absent organ structure Central anatomic entity for disease localization (munteanu2020theetiopathogenicand pages 1-2)
Anatomy (UBERON) UBERON:0003129 calvaria Absent/partially absent calvarium is part of defining morphology Verify exact UBERON term label/version in target pipeline (munteanu2020theetiopathogenicand pages 1-2)
Anatomy (UBERON) UBERON:0001049 neural tube Embryonic structure whose cranial closure failure causes disease Core developmental anatomy term (munteanu2020theetiopathogenicand pages 2-3, ishida2018atargetedsequencing pages 1-5)
Anatomy (UBERON) UBERON:0001891 surface ectoderm / verify Relevant tissue in neurulation and some model mechanisms Stronger support from model systems than direct human pathology (avagliano2019overviewonneural pages 1-2)
Cell type (CL) CL:0000031 neuroepithelial cell / verify Principal embryonic cell population participating in neurulation Exact CL mapping should be checked in target ontology version (avagliano2019overviewonneural pages 1-2, rai2023aquestfor pages 2-3)
Cell type (CL) Neural fold cells — verify CL term Developmentally relevant cells for cranial neural tube elevation/fusion Often described anatomically/developmentally rather than by stable CL code (munteanu2020theetiopathogenicand pages 2-3, avagliano2019overviewonneural pages 1-2)
Biological process (GO) GO:0001841 neural tube formation Broad developmental process disrupted in anencephaly High-confidence process-level annotation (munteanu2020theetiopathogenicand pages 2-3, avagliano2019overviewonneural pages 1-2)
Biological process (GO) GO:0001838 embryonic epithelial tube formation / verify specificity Supports morphogenetic framing of neurulation failure Use if broader developmental annotation is desired; may be less specific (avagliano2019overviewonneural pages 1-2)
Biological process (GO) GO:0035252 planar cell polarity pathway involved in neural tube closure / verify Mechanistically relevant pathway implicated by human and animal studies Exact GO child term should be verified; evidence mostly NTD-wide (munteanu2020theetiopathogenicand pages 2-3, rai2023aquestfor pages 2-3)
Biological process (GO) Convergent extension — verify GO term Key morphogenetic mechanism downstream of PCP/Wnt signaling Strong mechanistic support, but usually broader NTD rather than isolated anencephaly (rai2023aquestfor pages 2-3)
Pathway Non-canonical Wnt/planar cell polarity signaling Important pathway for neurulation genes such as VANGL/CELSR Pathway evidence is robust but not specific to every anencephaly case (munteanu2020theetiopathogenicand pages 2-3, rai2023aquestfor pages 2-3)
Gene-level annotation MTHFR Folate metabolism susceptibility gene frequently discussed in risk/prevention context Association often based on polymorphism/risk studies, not monogenic causation (munteanu2020theetiopathogenicand pages 1-2, munteanu2020theetiopathogenicand pages 2-3)
Gene-level annotation PDGFRA Candidate/causal-susceptibility gene with rare damaging variants reported in anencephaly Variant evidence comes from sequencing cohorts and likely oligogenic models (ishida2018atargetedsequencing pages 1-5)
Gene-level annotation VANGL1 / VANGL2 / CELSR1 PCP pathway genes implicated in neurulation defects Often stronger in NTD-wide aggregation and model systems than isolated anencephaly-only cohorts (munteanu2020theetiopathogenicand pages 1-2, munteanu2020theetiopathogenicand pages 2-3, rai2023aquestfor pages 2-3)
Chemical (CHEBI) CHEBI:27470 folic acid Prevention exposure/intervention and nutrient ontology anchor Central preventive chemical entity; exact CHEBI version should be checked (samaniegovaesken2024supplementationwithfolic pages 2-4, samaniegovaesken2024supplementationwithfolic pages 1-2)
Chemical (CHEBI) folate / tetrahydrofolate derivatives — verify CHEBI term Nutrient class for one-carbon metabolism annotations Multiple related CHEBI entities exist; choose level appropriate to data model (samaniegovaesken2024supplementationwithfolic pages 2-4, samaniegovaesken2024supplementationwithfolic pages 1-2)
Chemical (CHEBI) 5-methyltetrahydrofolate (5-MTHF) — verify CHEBI term Alternative supplemental folate form discussed in recent literature Evidence for equivalence to folic acid in prevention remains insufficient (samaniegovaesken2024supplementationwithfolic pages 2-4, samaniegovaesken2024supplementationwithfolic pages 1-2)
Exposure/risk Valproic acid — map to CHEBI/Drug ontology in implementation Major teratogenic exposure/risk factor to capture in exposure model Evidence is NTD-wide; not unique to anencephaly (munteanu2020theetiopathogenicand pages 2-3, rai2023aquestfor pages 2-3)
Exposure/risk Maternal diabetes / obesity / hyperthermia Key maternal risk factor concepts for epidemiology and prevention annotations These are clinical exposure concepts rather than disease ontology IDs here (munteanu2020theetiopathogenicand pages 2-3, rai2023aquestfor pages 2-3)
Intervention (NCIT) NCIT: folic acid supplementation — verify exact NCIT code Primary prevention intervention for at-risk or general reproductive-age populations Exact NCIT code not confirmed; term should be checked in NCIt browser (samaniegovaesken2024supplementationwithfolic pages 2-4, samaniegovaesken2024supplementationwithfolic pages 1-2)
Intervention (NCIT) Prenatal ultrasonography — verify exact NCIT code Main diagnostic/screening intervention, especially first trimester Exact NCIT code not confirmed; disease detection evidence strong (munteanu2020theetiopathogenicand pages 1-2, munteanu2020theetiopathogenicand pages 7-8)
Intervention (NCIT) Maternal serum alpha-fetoprotein measurement — verify exact NCIT code Ancillary prenatal screening biomarker test Less specific than ultrasound; exact NCIT code should be verified (munteanu2020theetiopathogenicand pages 1-2)
Intervention (NCIT) Pregnancy termination counseling/management — verify exact NCIT concept Real-world management consequence after prenatal diagnosis of lethal anomaly Sensitive management domain; terminology should follow local governance and ontology policy (munteanu2020theetiopathogenicand pages 7-8)
Public health Mandatory folic acid food fortification Population-level primary prevention implementation concept Strong NTD-prevention evidence, but policy effect is usually reported for combined spina bifida/anencephaly burden (munteanu2020theetiopathogenicand pages 2-3, samaniegovaesken2024supplementationwithfolic pages 2-4)
Data provenance Aggregated disease-level resource Most current information comes from literature reviews, sequencing cohorts, and public-health studies rather than individual-patient EHR data Distinguish curated disease knowledge from case-level records in KB design (munteanu2020theetiopathogenicand pages 1-2, ishida2018atargetedsequencing pages 1-5, samaniegovaesken2024supplementationwithfolic pages 2-4)

Table: This table provides a compact, database-oriented set of recommended identifiers and ontology terms for representing anencephaly across disease, phenotype, anatomy, mechanism, exposure, and intervention domains. It also flags where exact codes should be verified rather than assumed, which is important for safe knowledge-base population.

2. Etiology, risks, protection, and gene–environment interaction

Overall causal architecture

Nonsyndromic anencephaly is a complex multifactorial threshold disorder. Familial aggregation and heritability estimates as high as approximately 70% support substantial genetic contribution, but most cases are sporadic and molecular diagnosis is uncommon. A prior affected pregnancy raises recurrence risk to approximately 2–10%, compared with a much lower background risk; the wide range reflects population, ascertainment, folate exposure, and whether all NTDs or anencephaly alone were counted. (munteanu2020theetiopathogenicand pages 2-3, ishida2018atargetedsequencing pages 1-5)

Genetic risk factors

Human evidence supports candidate genes in several functional groups:

  • PCP/convergent extension: VANGL1, VANGL2, CELSR1 and other non-canonical Wnt components. Disrupted PCP impairs mediolateral cell intercalation and neural-plate narrowing/elongation, preventing cranial folds from apposing.
  • Growth-factor/cytoskeletal and closure biology: PDGFRA, TRIM36, CFL1, PRKCA, PRKCB, CITED2.
  • Transcription/developmental regulation: PAX3, ZIC1, ZIC2, ZIC3.
  • Redox, DNA-damage, apoptosis, and proliferation: TXN2, TP53, BRCA1, NOS2.
  • Metabolic candidates: MTHFR, MAT1A and related one-carbon genes.
  • Hippo–YAP signaling: biallelic loss-of-function in NUAK2 has been reported in severe NTD/anencephaly families, but this represents a rare cause rather than the usual architecture. (munteanu2020theetiopathogenicand pages 2-3, rai2023aquestfor pages 2-3, isakovic2022overviewofneural pages 24-25)

The strongest anencephaly-focused sequencing evidence comes from Ishida et al., published February 2018, DOI 10.1111/cge.13189. A 191-gene panel in 90 cranial-NTD cases found 397 variants with MAF <1%, including 21 previously unreported variants predicted damaging: one PDGFRA frameshift, stop-gained variants in MAT1A and NOS2, and 18 missense variants. The findings support an oligogenic model but do not establish every variant as ACMG pathogenic. (ishida2018atargetedsequencing pages 1-5)

Variant-curation caution: no single recurrent germline variant explains most anencephaly. Candidate variants should be stored with the original laboratory classification, segregation, functional data, and population frequency. Predicted damaging does not equal ClinVar pathogenic. Somatic mutation, repeat expansion, mitochondrial inheritance, anticipation, and a characteristic founder mutation are not established general features.

Chromosomal abnormalities

Most isolated cases have a normal karyotype. Chromosomal abnormalities are reported in only a minority—approximately 1–5% in one review, with broader NTD estimates under 10%. Trisomy 18 is a recognized association, particularly when additional malformations are present. Karyotype or chromosomal microarray is therefore most informative in non-isolated cases. (munteanu2020theetiopathogenicand pages 1-2, munteanu2020theetiopathogenicand pages 2-3, avagliano2019overviewonneural pages 1-2)

Maternal and environmental risks

Supported or repeatedly reported NTD risks include:

  • low periconceptional folate status and vitamin B12 insufficiency;
  • pregestational diabetes and poor glycemic control;
  • maternal obesity;
  • valproate and some other antiseizure drugs;
  • fever, sauna/hot-tub exposure, or other hyperthermia during the neurulation window;
  • occupational organic solvents and epidemiologic associations with pesticides, arsenic, and polycyclic aromatic hydrocarbons;
  • restrictive diets, malabsorption, drug–nutrient interactions, and cooking-related folate loss.

Some studies report associations with frequent sprouted-potato consumption, but this is much weaker evidence than folate deficiency, diabetes, obesity, valproate, or hyperthermia and may reflect glycoalkaloid exposure or confounding. No infectious organism is an established cause, and anencephaly is neither communicable nor zoonotic. (munteanu2020theetiopathogenicand pages 2-3, munteanu2020theetiopathogenicand pages 7-8, rai2023aquestfor pages 2-3, samaniegovaesken2024supplementationwithfolic pages 2-4)

Protective factors and gene–environment interaction

Folic acid is the best-established protective exposure. Randomized evidence for recurrent NTD prevention indicates approximately 50–70% risk reduction with high-dose folic acid; broader estimates state that up to 70% of NTDs may be folic-acid preventable. Not all cases are folate responsive. (ishida2018atargetedsequencing pages 1-5, rai2023aquestfor pages 2-3)

Gene–environment interaction is biologically credible because folate supplies one-carbon units for nucleotide synthesis and methylation, while closure genes govern morphogenesis. Low folate may expose susceptibility produced by variants such as PAX3 or folate-pathway alleles. The common MTHFR c.677C>T polymorphism reduces enzyme activity, particularly under low-folate conditions, but it is a modest susceptibility factor—not a deterministic diagnostic mutation. Maternal metabolic or teratogenic stress can similarly shift a genetically susceptible embryo beyond the closure-failure threshold. (munteanu2020theetiopathogenicand pages 1-2, rai2023aquestfor pages 2-3)

3. Phenotypes and quality-of-life consequences

Phenotype Type, timing, course, and frequency Suggested HPO term
Absent/partially absent calvarium Defining physical sign; congenital, severe, stable structural defect Anencephaly, HP:0002323; abnormality of skull ossification—verify precise child term
Absent/destructed cerebral hemispheres Defining CNS malformation; begins after failed cranial closure and exposure/degeneration Anencephaly; abnormal cerebral morphology
Exposed vascular neural tissue Prenatal physical/pathologic sign of open cranial NTD; progressively degenerates Open neural-tube defect—verify HPO code
Protruding orbits/absent frontal bones Common craniofacial appearance; “frog-eye” or first-trimester “Mickey Mouse” imaging appearance Abnormality of orbit/skull—select granular terms per case
Polyhydramnios Variable prenatal complication, related partly to impaired fetal swallowing Polyhydramnios, HP:0001561
Adrenal hypoplasia and growth restriction Variable downstream endocrine/organ findings; impaired hypothalamic–pituitary–adrenal function has been described Adrenal hypoplasia; intrauterine growth retardation, HP:0001511
Craniorachischisis Severe associated extension through spine; not present in isolated anencephaly Craniorachischisis, HP:0001363
Additional congenital anomalies Approximately 12–25% in one review; examine heart, kidneys, gastrointestinal tract, limbs, and face Code each observed anomaly separately

Onset is embryonic, not neonatal: cranial neurulation occurs around postfertilization days 17–28, with neuropore closure expected around days 25–28. Severity is uniformly profound. There is no remission or recovery. Conventional patient-reported quality-of-life instruments are inapplicable because sustained consciousness and long-term survival are absent. The principal quality-of-life burden falls on the pregnant patient and family through grief, complex reproductive decisions, delivery planning, and recurrence anxiety. (munteanu2020theetiopathogenicand pages 2-3, avagliano2019overviewonneural pages 1-2)

4. Genetic, molecular, epigenetic, and omics information

There is no single “anencephaly gene,” no clinically complete gene panel, and no meaningful population carrier frequency for nonsyndromic disease. Most implicated alleles are germline rare variants or common susceptibility polymorphisms with incomplete penetrance and variable expression across the NTD spectrum. Oligogenic inheritance is plausible; dominant, recessive, and digenic mechanisms can occur in rare families. (ishida2018atargetedsequencing pages 1-5)

Epigenetically, folate-dependent S-adenosylmethionine production links maternal nutrition to DNA and histone methylation. Experimental studies identify altered methylation or expression of developmental regulators such as GATA4, CDX2, PAX6, and NES, while arsenic may perturb DNA methylation. These findings are mechanistically informative but are not validated diagnostic methylation signatures for human anencephaly. (rai2023aquestfor pages 2-3)

Human disease-level transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, and multi-omic classifiers remain investigational. Tissue availability, gestational heterogeneity, postmortem degeneration, and mixed etiologies complicate interpretation. Maternal serum alpha-fetoprotein is a clinical screening analyte, not a disease-specific molecular subtype marker.

5. Environmental and lifestyle information

The critical exposure window is before many pregnancies are recognized. Prevention should therefore target all who may become pregnant rather than begin after the first prenatal visit. Clinically actionable measures are adequate folic acid, diabetes optimization, healthy preconception weight, medication review—especially avoiding valproate when a safe effective alternative exists—and prompt management of fever/avoidance of sustained extreme heat early in pregnancy. Smoking and alcohol are undesirable in pregnancy generally, but neither is as specifically established for anencephaly as folate deficiency, diabetes, obesity, valproate, and hyperthermia.

Environmental chemical associations are often observational and NTD-wide. They should be recorded as risk evidence with exposure timing and confidence, not as individually sufficient causes. There is no recognized bacterial, viral, fungal, or parasitic trigger. (munteanu2020theetiopathogenicand pages 2-3, rai2023aquestfor pages 2-3)

6. Mechanism and pathophysiology

Causal chain

  1. Upstream susceptibility/exposure: closure-gene variants, inadequate one-carbon nutrition, maternal diabetes/obesity, valproate, hyperthermia, or toxicant exposure.
  2. Molecular/cellular disruption: altered PCP/Wnt signaling and convergent extension; disturbed cytoskeletal dynamics and cell adhesion; imbalanced proliferation/apoptosis; oxidative stress; impaired nucleotide synthesis and methylation.
  3. Morphogenetic failure: cranial neural folds fail to elevate, converge, adhere, and fuse during weeks 3–4.
  4. Open neuroepithelium/exencephaly: the developing brain remains exposed to amniotic fluid and mechanical injury.
  5. Secondary tissue degeneration: exposed cerebral tissue undergoes progressive destruction, yielding the characteristic absent brain and calvarium.
  6. Clinical outcome: endocrine/autonomic dysfunction, impaired swallowing and polyhydramnios, fetal loss, stillbirth, or death soon after delivery.

The PCP pathway is especially relevant: defective non-canonical Wnt signaling impairs convergent extension, a morphogenetic process required to narrow and lengthen the neural plate so the folds can meet. This mechanism is strongly supported across vertebrate models and by rare human variants, but the proportion of human anencephaly attributable to PCP dysfunction remains uncertain. (munteanu2020theetiopathogenicand pages 2-3, rai2023aquestfor pages 2-3)

Suggested annotations include GO:0001841 neural tube formation, neural-tube closure, convergent extension, canonical/non-canonical Wnt signaling, epithelial cell migration, actin-cytoskeleton organization, cell–cell adhesion, one-carbon metabolism, DNA methylation, oxidative-stress response, cell proliferation, and apoptotic process. Relevant cells include neuroepithelial cells (CL:0000031; verify release), neural-fold cells, surface ectoderm, cranial mesenchyme, and neural crest. No single protein-misfolding, lysosomal, ion-channel, immune, or autoimmune mechanism defines the disease.

7. Anatomical structures affected

The primary site is the cranial neural tube and its derivatives: forebrain, midbrain, hindbrain, overlying meninges, cranial mesenchyme, and calvarial bones. Brainstem, cerebellum, and diencephalic tissue may be partly retained. The skull base and facial bones are less severely affected than the cranial vault. In craniorachischisis, the open defect extends caudally into spinal neural tube and vertebral arches. (munteanu2020theetiopathogenicand pages 1-2, ishida2018atargetedsequencing pages 1-5)

Suggested anatomy mappings are neural tube (UBERON:0001049), brain (UBERON:0000955), neuroepithelium, forebrain, midbrain, hindbrain, cranial meninges, calvaria, skull, cranial mesenchyme, surface ectoderm, and—when present—spinal cord and vertebral column. The lesion is a midline developmental defect, not a unilateral disorder. Relevant subcellular structures include nucleus/chromatin, actin cytoskeleton, adherens junctions, and mitochondria/redox systems; these are pathway-level annotations, not universal histologic abnormalities.

8. Temporal development and natural history

  • Initiation: embryonic days 17–28 after fertilization.
  • Primary lesion: failure of cranial neuropore closure by approximately day 25.
  • Evolution: exposed brain initially resembles exencephaly and degenerates during gestation.
  • Prenatal course: miscarriage, stillbirth, or continued pregnancy with possible polyhydramnios and atypical gestational duration.
  • Postnatal course: irreversible and rapidly fatal; rare longer survival does not constitute recovery.

There are no conventional early/intermediate/end-stage categories, relapses, remission, or chronic survivorship. The only effective biological intervention window is before closure, explaining why postdiagnosis folate cannot repair an established lesion. (munteanu2020theetiopathogenicand pages 1-2, munteanu2020theetiopathogenicand pages 2-3)

9. Inheritance and population epidemiology

Published rates vary sharply with whether spontaneous losses and terminations are included. A disease review cited 1–5 per 1,000 births and approximately 1 in 4,600 births in the United States, while NTD-wide global prevalence estimates are around 18.6–19 per 10,000 births. These measures are not interchangeable. Birth prevalence underestimates conceptions because prenatal diagnosis and termination are common. (munteanu2020theetiopathogenicand pages 1-2)

Higher historical rates have been reported in parts of northern China, Mexico, Turkey, the British Isles, and some low-resource settings. Food fortification, supplementation, ascertainment, pregnancy termination, maternal nutrition, diabetes/obesity prevalence, and ancestry all contribute. Anencephaly shows a consistent female excess, unlike many spinal NTD series, but its mechanism is unresolved. (munteanu2020theetiopathogenicand pages 2-3, avagliano2019overviewonneural pages 1-2, ishida2018atargetedsequencing pages 1-5)

Inheritance is best encoded as multifactorial/polygenic with occasional oligogenic or rare Mendelian forms. Penetrance is incomplete and exposure dependent; expressivity may span anencephaly, craniorachischisis, encephalocele, or spinal NTD in a family. Anticipation is not established. Consanguinity may enrich rare recessive causes but is not a general prerequisite. “Carrier frequency” is not meaningful for common nonsyndromic anencephaly.

10. Diagnostics and screening

Prenatal diagnosis

First-trimester ultrasonography is the principal diagnostic method. Findings include absent cranial ossification above the orbits, absent or abnormal cerebral tissue, exposed disorganized tissue, and characteristic coronal appearances. The 2020 review reports detection of essentially all cases in contemporary first-trimester screening, although real-world sensitivity depends on gestational age, operator skill, equipment, and access. Three-dimensional ultrasound refines anatomic definition. Fetal MRI is rarely needed when ultrasound is definitive. (munteanu2020theetiopathogenicand pages 1-2, munteanu2020theetiopathogenicand pages 7-8)

Maternal serum alpha-fetoprotein is typically markedly elevated because fetal tissue is openly exposed, but AFP is a screening test and is not specific. Amniotic-fluid AFP/acetylcholinesterase can support diagnosis when imaging is uncertain. There is no role for EEG, EMG, biopsy, liquid biopsy, or newborn biochemical screening.

Differential diagnosis

Distinguish:

  • acrania/exencephaly/anencephaly sequence: related developmental stages;
  • acalvaria: absent skull vault with preserved brain and skin;
  • encephalocele: herniated brain/meninges through a localized skull defect;
  • iniencephaly: occipital/cervical defect with extreme retroflexion;
  • craniorachischisis: cranial defect continuous with open spine;
  • severe microcephaly: small but present skull and brain;
  • amniotic-band disruption: asymmetric craniofacial defects and constriction/amputation findings. (munteanu2020theetiopathogenicand pages 7-8)

Genetic testing approach

After confirmation, perform a detailed anatomic survey. Offer karyotype or chromosomal microarray, especially for non-isolated disease. Trio exome/genome sequencing may be considered in recurrent, familial, consanguineous, or syndromic cases, but diagnostic yield for isolated anencephaly is uncertain. Research NTD panels may include PCP, folate, cytoskeletal, ciliary, and developmental genes, but no panel excludes multifactorial recurrence. Mitochondrial sequencing, repeat-expansion testing, FISH, and single-gene testing are not routine unless another phenotype directs them. (ishida2018atargetedsequencing pages 1-5)

11. Outcome and prognosis

Prognosis is uniformly lethal: the disease-specific review reports 100% mortality in utero or within hours or days after birth. There are no meaningful 5- or 10-year survival rates. Associated anomalies occur in approximately 12–25%, but prognosis is driven by the cranial defect itself. (munteanu2020theetiopathogenicand pages 1-2)

A Japanese dataset covering more than 311,000 pregnancies in 2014–2015 reported pregnancy termination in approximately 80% of diagnosed cases; another cited estimate exceeded 83%. Such proportions are jurisdiction- and ascertainment-dependent and should not be interpreted as a biological outcome. (munteanu2020theetiopathogenicand pages 1-2, munteanu2020theetiopathogenicand pages 7-8)

For continuing pregnancies, planning should address polyhydramnios, malpresentation, labor, neonatal comfort care, family presence, memory-making, and bereavement. Aggressive neonatal resuscitation does not reverse the underlying condition. Long-term disability and rehabilitation metrics are not applicable.

12. Treatment and current applications

There is no disease-modifying treatment. Open-spina-bifida fetal surgery must not be extrapolated to anencephaly because the essential brain and cranial structures cannot be reconstructed. Likewise, no pharmacotherapy, gene therapy, cell therapy, RNA therapy, immunotherapy, organ transplantation, or genotype-guided therapy has demonstrated benefit.

Current real-world management consists of:

  1. confirmatory high-quality ultrasound and assessment for additional anomalies;
  2. nondirective counseling regarding prognosis and legally available pregnancy options;
  3. maternal–fetal medicine, clinical genetics, neonatology/palliative-care, and psychosocial support;
  4. if pregnancy continues, individualized delivery and neonatal comfort-care planning;
  5. post-pregnancy pathology/genetic evaluation when consented and recurrence-prevention counseling.

Relevant NCIt concepts include prenatal ultrasonography, genetic counseling, palliative care, folic-acid supplementation, and pregnancy management; exact current NCIt codes should be verified before ingestion.

The trial search identified observational NTD genetics and exposure studies, but no credible disease-modifying anencephaly intervention. Fetoscopic repair trials concern myelomeningocele and are not treatments for anencephaly.

13. Prevention

Primary prevention

For average-risk people capable of pregnancy, authoritative organizations converge on 400 µg (0.4 mg) folic acid daily, beginning at least one month before conception and continuing through the first trimester; many prenatal preparations continue it throughout pregnancy. Dietary folate has approximately 50% bioavailability, fortified-food folic acid about 85%, and supplements taken fasting approximately 100%. Published September 2024; DOI: 10.3390/nu16183154. (samaniegovaesken2024supplementationwithfolic pages 2-4, samaniegovaesken2024supplementationwithfolic pages 1-2)

For a previous folate-sensitive NTD pregnancy or selected very-high-risk circumstances, guidelines commonly recommend 4 mg/day, started before conception and continued through early pregnancy under clinical supervision. This exceeds the general adult tolerable upper intake level of 1 mg/day and therefore should not be self-prescribed or obtained by multiplying prenatal multivitamins. Randomized evidence indicates approximately 50–70% recurrent-NTD reduction. (rai2023aquestfor pages 2-3, samaniegovaesken2024supplementationwithfolic pages 1-2)

Mandatory fortification is a proven, cost-effective population strategy because the neural tube closes before many pregnancies are recognized. The United States fortification program has been credited with preventing roughly 1,300 NTD cases annually. The 2024 review notes implementation in the United States, Canada, and Chile, contrasted with incomplete fortification coverage elsewhere. (munteanu2020theetiopathogenicand pages 2-3, samaniegovaesken2024supplementationwithfolic pages 2-4)

A recent nutritional survey cited mean folate intake of only 156.3 µg/day in Spain, with merely 3.0% of women meeting adequate intake, illustrating the adherence gap where mandatory fortification is absent. (samaniegovaesken2024supplementationwithfolic pages 2-4)

5-MTHF: although biologically plausible and commercially available, the September 2024 review concludes that clinical evidence is insufficient to establish equivalence to folic acid for NTD prevention, including optimal dose, timing, efficacy, and safety. Folic acid remains the evidence-based standard. (samaniegovaesken2024supplementationwithfolic pages 1-2)

Additional prevention comprises preconception diabetes control, weight optimization, vitamin B12 assessment where indicated, medication review, avoiding valproate when clinically feasible, and avoiding sustained hyperthermia. Medication changes must be supervised because uncontrolled epilepsy also endangers parent and fetus.

Secondary and tertiary prevention

Secondary prevention means early prenatal ultrasound and informed reproductive care; it detects but does not prevent or treat the defect. Tertiary prevention is limited to avoiding maternal complications and providing proportionate palliative care. There is no vaccine or infectious prophylaxis.

14. Other species and natural disease

Congenital cranial NTDs, including anencephaly-like/acrania–exencephaly phenotypes, occur naturally in domestic mammals and livestock, but the retrieved evidence does not support a single common breed-specific Mendelian anencephaly syndrome suitable for confident VBO annotation. Veterinary cases are rare, usually lethal, and may involve genetic, nutritional, toxic, or sporadic developmental causes. There is no transmission or zoonotic potential.

Mechanisms are evolutionarily conserved across vertebrates: neural-fold morphogenesis, PCP signaling, cytoskeletal remodeling, folate/one-carbon biology, proliferation, and apoptosis. Species terminology matters—exencephaly in mouse embryos is often the experimental counterpart of human anencephaly because exposed mouse brain may still be present when embryos are examined.

15. Model organisms and advanced technologies

Mouse

Mouse is the dominant mammalian model. Hundreds of genes can produce NTDs, and more than 400 closure-related genes have been identified in animal models. PCP mutants, cytoskeletal mutants, folate-pathway perturbations, maternal diabetes, hyperthermia, and valproate exposure model different causal routes. Models reproduce closure failure and exposed cranial neuroepithelium well, enable timed perturbation and rescue experiments, and support oligogenic/G×E testing. Limitations include strain-dependent penetrance, species-specific closure sites, placentation/metabolism differences, and examination at exencephaly rather than later degenerative anencephaly. (avagliano2019overviewonneural pages 1-2, rai2023aquestfor pages 2-3)

Other vertebrates

Zebrafish and amphibian embryos permit live imaging and rapid manipulation of PCP, convergent extension, cell polarity, and folate-responsive development. Their neurulation morphology and cranial anatomy differ from mammals, so they are pathway models rather than complete anencephaly replicas.

Human cellular models and organoids

Human pluripotent-stem-cell neural-tube organoids and neuruloids can model neural induction, epithelial polarization, lumen formation, closure-like morphogenesis, and genotype/exposure effects. They are valuable because direct experimental observation of human neurulation in vivo is ethically impossible. The organoid review describes them as an emerging system for cellular and molecular investigation of NTDs. Published April 2021; DOI: 10.1096/fj.202002348R. Their limitations are absence of complete extraembryonic tissues, maternal metabolism, vasculature, biomechanical context, and whole-embryo anterior–posterior patterning. They are research tools, not validated diagnostics or treatment platforms.

Current interpretation and knowledge gaps

The authoritative interpretation is that anencephaly is a developmental endpoint shared by heterogeneous causes, not one molecular disease. The strongest actionable evidence concerns prevention and prenatal diagnosis; gene discovery has not yet produced routine precision therapy. Priorities include ancestrally diverse trio WGS, rigorous functional classification of rare variants, integrated maternal–fetal exposure data, human neuruloid validation, and quantification of residual folate-resistant risk.

The most important 2023–2024 development is not a curative therapy but renewed emphasis on universal fortification and closing global prevention gaps, alongside recognition that 5-MTHF lacks the outcome evidence supporting folic acid. Exact ontology and coding identifiers should be checked against current live releases before database ingestion, and every mechanistic assertion should retain an evidence tag—human anencephaly cohort, broader human NTD study, model organism, in vitro/organoid, or computational prediction.

References

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