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Acrania

Acrania is a rare and lethal congenital malformation characterized by the complete or partial absence of the calvaria—the dome-shaped vault of the —above the orbits and supraciliary ridge, resulting in direct exposure of the developing tissue to the . This condition typically arises during the fourth week of embryonic development due to disturbances in mesenchymal migration and closure, distinguishing it from classic neural tube defects while often serving as a precursor in the acrania-exencephaly-anencephaly sequence (AEAS). The incidence of acrania is estimated at 3.68 to 5.4 cases per 10,000 live births, with a recurrence risk of 2–5% in subsequent pregnancies. Etiologically, it involves a combination of genetic factors, such as mutations in genes like MTHFR and VANGL1, and environmental influences including maternal , (with an of 1.62), , and exposure to certain medications like antiepileptic drugs or . Although folic acid supplementation can prevent many defects, its efficacy specifically for acrania remains under study due to the condition's complex origins beyond simple failure. Diagnosis is primarily achieved through prenatal , often after the first-trimester routine scan (11–14 weeks ), where key findings include the absence of cranial , a distorted "" appearance of the head due to bulging cerebral hemispheres, and the "beret sign" indicating exposed brain tissue. Three-dimensional and fetal can provide confirmatory details, while differential diagnoses include , amniotic band syndrome, and craniorachischisis. Postnatally, confirms the lack of calvarial bones, , and associated muscles, though survival beyond delivery is exceedingly rare, with approximately 65% of cases resulting in intrauterine fetal demise and the remainder succumbing shortly after birth. Management typically involves counseling on elective termination of , as no curative interventions exist.

Definition and Characteristics

Anatomical Features

Acrania is defined by the partial or complete absence of the calvaria, which comprises the flat membranous bones of the situated above the orbits and supraciliary ridge. This defect spares the , resulting in the preservation of the facial bones, including the orbits, , and . Consequently, the lacks its protective bony enclosure and , with neural tissue covered only by a thin translucent membrane derived from the or thickened leptomeninges, leading to partial exposure to . In affected fetuses, the cerebral hemispheres initially develop to a relatively normal volume—often at least one-third of the expected size—but protrude outward in a condition known as exencephaly, where the tissue becomes distorted due to mechanical pressure and chemical exposure from . The exposed is typically covered only by a thin, translucent membrane derived from the or thickened leptomeninges, which offers minimal protection and contributes to progressive degeneration over . Early in , the , , and exhibit normal formation, though the supratentorial structures undergo secondary and disorganization without support. Soft tissue anomalies accompany the skeletal defect, notably the absence of scalp covering the cranial vault from the browline upward, replaced instead by the aforementioned membranous layer. The thoracic and abdominal cavities remain uninvolved in uncomplicated cases of acrania, distinguishing it from more extensive neural tube disruptions. This configuration may progress to anencephaly in later stages through ongoing brain tissue breakdown.

Relation to Neural Tube Defects

Although classified among neural tube defects, acrania is distinguished from classic neural tube defects by its specific involvement of cranial vault formation rather than direct failure of neural tube closure alone, while often serving as a precursor in the acrania-exencephaly-anencephaly sequence (AEAS). It arises during the fourth week of (around day 25), when disturbances in mesenchymal migration disrupt normal cranial development. This places acrania within the broader spectrum of cranial dysraphism. Unlike more common NTDs, acrania invariably progresses to lethal outcomes due to the unprotected exposure of developing neural tissue to and mechanical stresses. The condition follows a well-documented developmental progression known as the acrania-exencephaly- (AEAS) sequence, where initial acrania leads to exencephaly, characterized by exposed and distorted brain tissue, and subsequently to , marked by degeneration and collapse of the cerebral hemispheres. This sequence was first empirically observed in human fetuses through serial ultrasound imaging in the early , building on embryological studies from the that established the in models and early human cases. The AEAS pathway underscores acrania's role as the foundational stage, with the absence of the calvaria—as noted in anatomical descriptions—enabling progressive neural tissue damage without intervention. In contrast to other NTDs such as , which involves incomplete posterior closure in the spinal region and can allow survival with surgical repair, or , featuring herniation of brain tissue through a localized defect, acrania entails a diffuse failure of membranous bone formation in the without associated herniation. This specific anterior cranial involvement renders the AEAS sequence uniformly fatal, typically resulting in or neonatal death, unlike the variable prognoses of posterior or focal cranial NTDs.

Etiology

Genetic Factors

Acrania is primarily a sporadic condition, occurring without a clear pattern of inheritance in most cases, with a low recurrence risk estimated at 2-5% for subsequent siblings. This pattern aligns with the multifactorial inheritance characteristic of many defects (NTDs), where multiple genetic susceptibility loci interact with environmental influences to disrupt cell migration and differentiation during early embryogenesis. Neural crest cells are critical for proper cranial development, and perturbations in their migration genes contribute to the failure of skull vault formation in acrania. Genetic associations with acrania and related NTDs include polymorphisms in folate metabolism pathways, notably the methylenetetrahydrofolate reductase (MTHFR) gene, where variants such as C677T reduce enzyme activity, elevate homocysteine levels, and impair neural tube closure. Similarly, genes involved in neural tube closure and signaling, such as PAX3 (essential for neural crest survival and migration) and TCF7L2 (linked to Wnt pathway regulation and increased risk in maternal obesity contexts), show associations with NTD susceptibility. Mutations in VANGL1, which regulates planar cell polarity signaling essential for neural tube closure, are also implicated. Chromosomal abnormalities are rare in isolated acrania cases but occur in approximately 5-10% of open NTDs overall, with 13 and being the most commonly reported aneuploidies in associated cases. These can often be detected prenatally through karyotyping or chromosomal microarray analysis, highlighting the importance of in affected pregnancies. Maternal genetic factors contribute significantly, as a family history of NTDs in prior pregnancies elevates the recurrence risk to 2-5%, compared to the general incidence of about 0.1%. This underscores the heritable component, particularly through shared polygenic risk profiles in folate-related and developmental pathways.

Non-Genetic Causes

Maternal is a well-established environmental for defects (NTDs), including acrania; inadequate periconceptional folic acid intake is associated with a higher risk of NTDs, and supplementation with 400–800 mcg daily can prevent a substantial proportion (50–70%) of these cases by supporting proper closure during early embryogenesis. Other maternal health conditions contribute to elevated risks of acrania through metabolic and physiological disruptions. Pregestational diabetes mellitus is associated with a 3- to 4-fold increased risk of NTDs, likely due to hyperglycemia-induced and impaired folate metabolism in the . Maternal (body mass index ≥30 kg/m²) similarly raises the risk approximately 2-fold, potentially via chronic inflammation and altered nutrient transport across the . , such as from febrile illnesses or excessive heat exposure in early pregnancy, and use of anticonvulsants like valproic acid further heighten susceptibility, with valproic acid exposure conferring a 1–2% absolute risk of NTDs, far exceeding the general population rate of 0.1%. Teratogenic exposures during early , including and consumption, have been linked to acrania and other NTDs, although the evidence is less robust and often confounded by other factors. Maternal in the periconceptional period may increase NTD risk through vascular effects and toxin-induced cellular damage, with some studies reporting modest associations (odds ratios around 1.3–1.5). intake, particularly , shows weaker and inconsistent correlations specific to acrania, but overall contributes to disrupted embryogenesis in susceptible cases. Vascular disruption theories propose that non-genetic events, such as early embryonic ischemia, can impair mesenchymal migration and formation, leading to acrania independently of inherited factors. This mechanism involves transient reductions in blood flow during critical developmental windows (around 3–4 weeks ), potentially triggered by maternal or thrombotic events, resulting in localized and failure of precursors.

Pathophysiology

Developmental Mechanism

Acrania arises from a primary defect in the embryological development of the during early , specifically involving the failure of -derived mesenchymal cells to properly migrate and differentiate into the precursors of calvarial bones. These cells, originating from the cephalic , normally migrate beneath the surface around the fourth week of development to form the mesenchymal condensations essential for of the flat bones comprising the vault, such as the frontal and parietal bones. This migration occurs concurrently with or shortly after anterior neuropore closure, and its disruption prevents the formation of the membranous , leaving the developing unprotected. The abnormal ectodermal-mesenchymal interactions in acrania impair the inductive signals required for of the , resulting in the absence of formation while sparing the of the base, including structures like the sphenoid and temporal bones, which derive primarily from paraxial . This selective failure leads to a persistent membranous covering (desmocranium) over the rather than rigid bony protection, disrupting normal regulation that typically supports cerebral expansion and folding. The timeline of this process begins with a potential defect in anterior neuropore closure around embryonic days 24-26, which may contribute to inadequate mesenchymal infiltration and subsequent calvarial during weeks 5-7, when osteoprogenitor intensifies. Without the calvarial barrier, the exposed neural tissue is vulnerable to progressive degeneration from direct contact with , involving pressure from fetal movements and chemical that erode astroglial coverings and neuronal structures over subsequent weeks. This exacerbates malformation by preventing proper gyration and hemispheric separation, leading to a flattened, disorganized while lower structures like the remain relatively preserved. Although amniotic band syndrome can mimic these effects through extrinsic disruption, the intrinsic embryological failure in acrania is characterized by these cellular and deficits independent of such bands.

Role of Amniotic Band Syndrome

Amniotic band syndrome () represents a disruptive in a subset of acrania cases, arising from early rupture of the amniotic membrane that forms fibrous mesodermal strands or bands capable of encircling and constricting fetal structures. These bands can adhere to the developing cranium during the critical period of calvarial , typically between 6 and 10 weeks of , thereby preventing normal migration and formation of the flat bones or inducing focal disruptions. For instance, in a review of 13 acrania cases, approximately 15% were attributed to amniotic bands. The mechanism in ABS-related acrania involves mechanical interference rather than intrinsic cellular errors, leading to irregular or asymmetric skull defects that contrast with the symmetric, midline involvement seen in primary defects. Bands may cause localized ischemia or tissue amputation in the cranial region, resulting in partial or complete absence of the without uniform progression to ; the base of the is often preserved, and degeneration of exposed neural tissue may be less extensive due to the focal nature of the disruption. This extrinsic mechanical etiology differs from intrinsic developmental failures in calvarial formation. Pathognomonic features of in acrania include concomitant limb anomalies, such as amputations, constrictions, or pseudosyndactyly, and body wall defects like asymmetric clefts or abdominal eventrations, which occur in a substantial proportion of affected cases—extremity involvement is reported in up to 70% of ABS presentations overall. These associated malformations underscore the syndromic nature of ABS-related acrania, facilitating differentiation from isolated defects through the presence of non-midline, disruptive anomalies.

Clinical Presentation

Prenatal Findings

Acrania is typically detected during routine first-trimester scans between 11 and 14 weeks of , when the absence of cranial becomes apparent. At this stage, characteristic sonographic signs include the "" sign, representing the separated frontal lobes without overlying vault, and the "" sign, indicating a flattened of the exposed brain tissue. As progresses, typically by 16 weeks, the exposed undergoes distortion and degeneration, leading to exencephaly with herniation of neural into the amniotic . This exposure often results in due to impaired fetal . Associated anomalies occur in approximately 12-25% of cases, including cleft lip and palate, limb defects particularly when amniotic band syndrome is involved, and cardiac malformations. Fetal movements are initially normal and coordinated in early but may become reduced later due to progressive exposure and degeneration.

Postnatal Appearance

Newborns with acrania typically present with a complete or near-complete absence of the , resulting in exposed and flattened cerebral hemispheres that give the head a distinctive "frog-like" , while the facial structures, including the orbits, remain preserved and normally formed. The eyes often appear prominent and bulging due to the lack of overlying support. This severe cranial defect creates an open expanse where the bones fail to form, extending posteriorly from the supraorbital ridges and to the occiput, with the tissue directly vulnerable to external factors. The exposed neural tissue, which may initially appear as disorganized cerebral remnants in early postnatal stages, undergoes rapid degeneration due to exposure during , transforming into a spongy, vascular mass primarily composed of hindbrain elements such as the and . This degenerated mass is often covered by a thin, transparent resembling the arachnoid, though in some cases, it may be directly exposed without such protection, increasing susceptibility to mechanical damage. The large, irregular fontanelle-like openings associated with the absent calvaria frequently extend laterally toward the orbits, further emphasizing the profound malformation. Additional postnatal features include a short and potential for immediate complications such as minor hemorrhage from the friable or secondary infections arising from the unprotected neural structures. to term is rare, with most affected infants exhibiting only rudimentary brainstem-mediated reflexes, such as brief spontaneous respirations or responses to stimuli, but lacking any higher functions like or ; death typically occurs within hours to a few days after birth.

Diagnosis

Ultrasound Imaging

Ultrasound imaging plays a crucial role in the prenatal diagnosis of acrania, enabling early detection through visualization of the absent cranial vault during routine scans. In the first trimester, between 11 and 13+6 weeks of gestation, two-dimensional (2D) and three-dimensional (3D) ultrasound techniques are employed, particularly using transvaginal approaches for enhanced resolution. Key findings include the absence of the normally ossified skull bones, such as the frontal and parietal bones, with the brain appearing distorted or exposed directly to the amniotic fluid, often described as exencephaly in early stages. This method achieves high detection rates in experienced centers with transvaginal views, due to the clear contrast between the fetal face and the unprotected cerebral tissue. Confirmation in the second , typically at 18-20 weeks, involves detailed neurosonography to assess the progression of the defect. Characteristic features encompass with bulging, resembling a "Mickey Mouse" appearance on sagittal views, orbital measurements that reveal prominent, shallow-set eyes with normal biparietal dimensions but widened interorbital distances. These scans provide higher resolution for evaluating the extent of cranial absence and associated changes, aiding in distinguishing acrania from similar defects like . Advanced ultrasound modalities enhance diagnostic accuracy when standard 2D is inconclusive. Three-dimensional ultrasound with techniques offers multiplanar and surface of the defect, vividly illustrating the irregular contours of the exposed and absent calvaria for better parental counseling. If ultrasound findings remain ambiguous, fetal (MRI) is recommended for detailed soft tissue assessment, confirming the lack of membranous bone and evaluating integrity. Screening protocols for acrania are integrated into combined first-trimester testing, combining evaluation of nuchal translucency with maternal markers such as free β-hCG and PAPP-A to assess overall risk, during which the is routinely inspected. This approach facilitates simultaneous screening for and structural anomalies, with acrania often identified incidentally during nuchal translucency measurement.

Differential Diagnosis

Acrania must be differentiated from other cranial and neural tube defects that present with abnormal skull development on prenatal ultrasound. Key conditions include anencephaly, which represents an advanced stage of the acrania-exencephaly-anencephaly sequence characterized by the absence of calvarial bones and overlying brain tissue, resulting in a flattened "frog-like" cranial appearance; in early gestation, acrania can be distinguished by the presence of distorted but preserved neural tissue exposed due to the isolated calvarial defect. Encephalocele, another neural tube defect, involves a localized skull defect with herniation of meninges and brain tissue, often through a midline or occipital opening, whereas acrania features a complete absence of the cranial vault with diffuse brain exposure and no focal herniation. Amniotic band disruptions may mimic acrania through craniofacial involvement but are typically asymmetric, with associated limb constrictions or amputations, contrasting the symmetric calvarial absence in isolated acrania. Rare mimics include skeletal dysplasias such as and , which may show delayed or absent calvarial ossification but are ruled out by the presence of some orbital or facial bone remnants and additional skeletal abnormalities like limb fractures on imaging. Following presumptive diagnosis, for karyotyping is recommended if is suspected based on associated anomalies, with chromosomal abnormalities identified in approximately 5-10% of fetuses with open defects including acrania.

Management and Treatment

Prenatal Counseling

Upon prenatal of acrania, a multidisciplinary team comprising perinatologists, genetic counselors, and ethicists provides comprehensive guidance to expectant parents, confirming the diagnosis with high accuracy exceeding 99% through advanced imaging. This collaborative approach ensures that families receive balanced, evidence-based information tailored to their circumstances, facilitating informed without . Counseling addresses key management options, including pregnancy termination where legally available—often up to 24 weeks in many jurisdictions—continuation of the pregnancy with planning for perinatal , or consideration of experimental interventions, though none are currently curative for acrania. For families opting to continue, discussions emphasize comfort-focused strategies to support the infant's limited survival expectancy, typically hours to days postnatally. The recurrence risk for acrania or related in future pregnancies is low, estimated at 2-5%, and parents are advised to initiate preconception folic acid supplementation at 4 mg daily to mitigate this risk. may be recommended to rule out familial factors, but most cases are sporadic. Emotional support forms a cornerstone of counseling, with professionals addressing parental , anxiety, and guilt through empathetic dialogue and referrals to neural tube defect support groups such as those offered by the Fetal Health Foundation. This holistic process empowers families to navigate their choices while prioritizing psychological well-being and long-term .

Perinatal Care

Perinatal care for infants with acrania emphasizes supportive measures to ensure maternal safety and newborn comfort, given the condition's lethality and absence of viable curative options. typically favors vaginal birth at (around 37 weeks ) unless obstetric complications such as polyhydramnios-induced preterm labor or fetal malpresentation necessitate . Cesarean is reserved for standard maternal indications, such as or prior uterine surgery, rather than fetal benefit, with a multidisciplinary neonatal team present to facilitate immediate transition to . Intrapartum fetal monitoring may be deferred if it aligns with family preferences, prioritizing maternal over routine fetal . Postnatally, management centers on comfort care protocols, including via oral or intravenous routes, pain relief through non-pharmacologic methods like or pharmacologic agents if distress is evident, and preventive measures against such as gentle cleansing of exposed neural tissue. Surgical reconstruction of the is not pursued due to its futility in altering the fatal , as the lack of cerebral development precludes meaningful neurological function. Instead, care focuses on symptom alleviation, such as positioning to minimize pressure on exposed areas and respiratory support only if it enhances comfort without prolonging suffering. Family involvement is integral, with opportunities for skin-to-skin contact, holding, and bonding immediately after birth to foster emotional closure, often in a private setting to accommodate . Referral to perinatal services is standard for ongoing support, including guidance on end-of-life decisions and bereavement resources, ensuring parents' preferences guide care duration—typically hours to days. Brief monitoring for associated anomalies, such as cardiac defects, occurs to inform comfort measures but does not extend to aggressive interventions, maintaining emphasis on over survival prolongation. This approach builds on prior prenatal counseling to align care with family values.

Prognosis and Outcomes

Survival Expectations

Acrania is a uniformly lethal condition, with approximately 65% of affected fetuses experiencing or intrauterine demise, while the remaining 35% result in live births where is limited to minutes to hours postnatally. Short-term extending to 1-2 days has been documented in rare instances with intensive supportive care, though such cases remain exceptional. The absence of the leads to severe exposure and degeneration, rendering long-term viability impossible due to the lack of protective structures and functional development. Factors influencing survival patterns include the timing of prenatal , where earlier detection often correlates with higher rates of in-utero loss owing to the progressive nature of the defect and associated imbalances. In cases of acrania associated with (), survival may be slightly prolonged if brain involvement is less extensive and does not fully develop, though outcomes remain fatal. Historical data indicate no verified long-term survivors beyond infancy, with case reports from the 1980s and earlier confirming postnatal lifespans of hours at most, attributable to the irreversible neurological deficits. Emphasis in care prioritizes a dignified over life prolongation, as average postnatal survival for liveborn infants is under 24 hours, with associated complications such as potentially hastening demise.

Associated Complications

One of the primary complications associated with acrania is the progressive degeneration of exposed tissue due to direct contact with . This exposure leads to mechanical disruption and chemical toxicity, causing the neural tissue to break down over time and often progressing to . In rare cases where live birth occurs, this degeneration can manifest as severe neurological impairments, including seizures and episodes of apnea, which further compromise respiratory function and survival. Polyhydramnios, an excess of , occurs in approximately 25% to 50% of acrania cases, primarily due to impaired fetal secondary to the cranial defect. This condition can result in maternal discomfort from uterine overdistension and increases the risk of preterm labor, potentially necessitating early delivery interventions. In severe instances, may also contribute to obstetrical complications such as postpartum hemorrhage, though these are relatively uncommon. Acrania frequently co-occurs with other congenital anomalies in 20% to 50% of cases, exacerbating fetal distress and overall . Limb defects, often linked to amniotic band syndrome (ABS), are particularly common and may include amputations or constrictions of the extremities, arising from disruptive fibrous bands in the amniotic cavity. Renal anomalies, such as or , can also accompany acrania, typically within broader multiple malformation patterns, leading to additional risks of or impaired fetal function. Maternal psychological risks are significant following an acrania diagnosis, with parents often experiencing intense , including symptoms of post-traumatic and that may persist long-term. This emotional burden often stems from the prenatal awareness of the lethal outcome, prompting needs for specialized counseling. While rare, associated obstetrical risks like hemorrhage during can compound maternal physical recovery challenges.

Epidemiology

Incidence Rates

Acrania, as the initial manifestation of the acrania-exencephaly-anencephaly , has an estimated global incidence of 3.68 to 5.4 cases per 10,000 live births. However, prenatal screening reveals a higher of approximately 1 in 1,000 pregnancies at 12 weeks' , reflecting significant early embryonic and fetal losses that reduce the number reaching term. The condition exhibits regional variations, with higher rates observed in areas of low dietary intake prior to widespread programs; for instance, pre-fortification incidence in parts of reached up to 5.4 per 10,000 live births for the associated sequence. Following the implementation of mandatory folic acid in the 1990s in various countries, incidence has declined by 30-50%, as evidenced by reductions in rates including , attributable to improved maternal status. The acrania-exencephaly- sequence accounts for about 25-35% of defects, showing a predominance with a of approximately 3:1. Historical trends indicate a decline from 3.6-5.4 per 10,000 live births in the 1980s to rates as low as 1-2 per 10,000 in regions with fortification programs as of the 2020s, driven by nutritional interventions and prenatal detection.

Risk Factors

Advanced maternal age is a recognized risk factor for acrania, with women over 35 years of age experiencing approximately a 1.3-fold increased risk (RR 1.31) compared to younger mothers. This association has been observed in population-based studies analyzing neural tube defects, including acrania and related conditions like anencephaly. Socioeconomic factors significantly contribute to the likelihood of acrania, particularly in low-income communities where access to adequate nutrition is limited. Poor nutritional status, often linked to lower socioeconomic environments, correlates with higher rates of neural tube defects, including acrania, due to associated deficiencies in essential nutrients. Ethnic disparities also play a role, with higher incidences noted among populations prior to widespread folic acid fortification programs; for instance, pre-fortification rates among were 50-200% higher than in non-Hispanic white populations. A history of a previous pregnancy affected by a neural tube defect markedly elevates the risk for acrania in subsequent pregnancies, with recurrence rates estimated at 2-5% without preventive interventions. Geographic variations further highlight disparities, with elevated prevalence of acrania and other neural tube defects in regions lacking mandatory folic acid fortification, such as parts of Asia and Africa, where rates can reach up to 10-12 per 10,000 births or higher (up to 21 per 10,000 in some studies). These areas often face challenges related to nutritional and healthcare access, contributing to the higher burden.