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Exencephaly-anencephaly Sequence

Published:November 07, 2020DOI:https://doi.org/10.1016/j.ajog.2020.08.176

      Introduction

      The most common neural tube defect (NTD) is anencephaly.
      • Parker S.E.
      • Mai C.T.
      • Canfield M.A.
      • et al.
      Updated National Birth Prevalence estimates for selected birth defects in the United States, 2004-2006.
      Overall, the estimated prevalence of anencephaly is 3 per 10,000 births,
      • Williams J.
      • Mai C.T.
      • Mulinare J.
      • et al.
      Updated estimates of neural tube defects prevented by mandatory folic acid fortification - United States, 1995-2011.
      although the incidence varies among different geographic regions, ethnic groups, and environmental exposures.
      • Williams J.
      • Mai C.T.
      • Mulinare J.
      • et al.
      Updated estimates of neural tube defects prevented by mandatory folic acid fortification - United States, 1995-2011.
      ,
      Committee on Practice Bulletins-Obstetrics
      Practice Bulletin no. 187: neural tube defects.
      This malformation is also referred to as acrania.
      Exencephaly-anencephaly sequence is a multifactorial malformation in which both environmental and genetic factors play a role.
      • Greene N.D.
      • Copp A.J.
      Neural tube defects.
      This complex developmental sequence begins with failure of the anterior neural groove to close at approximately 10 to 20 postovulatory days (dysraphia). As development continues, a relatively normal-appearing brain forms that lacks a covering skull/calvarium and meninges (exencephaly). Mechanical and chemical influences of the amniotic fluid on the exposed brain subsequently causes it to disintegrate, and the skull and cerebral hemispheres fail to develop (anencephaly).
      • Timor-Tritsch I.E.
      • Greenebaum E.
      • Monteagudo A.
      • Baxi L.
      Exencephaly-anencephaly sequence: proof by ultrasound imaging and amniotic fluid cytology.
      • Limb C.J.
      • Holmes L.B.
      Anencephaly: changes in prenatal detection and birth status, 1972 through 1990.
      • Cunningham M.E.
      • Walls W.J.
      Ultrasound in the evaluation of anencephaly.
      • Icenogle D.A.
      • Kaplan A.M.
      A review of congenital neurologic malformations.
      • Deak K.L.
      • Siegel D.G.
      • George T.M.
      • et al.
      Further evidence for a maternal genetic effect and a sex-influenced effect contributing to risk for human neural tube defects.
      • Marín-Padilla M.
      Cephalic axial skeletal-neural dysraphic disorders: embryology and pathology.
      This degenerative process has been well documented using ultrasonography and is the cause of the echogenic amniotic fluid characteristic of exencephaly-anencephaly sequence. The cytologic evaluation of amniotic fluid in cases of exencephaly-anencephaly sequence showing the presence of neural cells supports this theory.
      • Timor-Tritsch I.E.
      • Greenebaum E.
      • Monteagudo A.
      • Baxi L.
      Exencephaly-anencephaly sequence: proof by ultrasound imaging and amniotic fluid cytology.
      In the past, screening for anencephaly and other NTDs has been performed using maternal serum alpha fetoprotein measurement between 15 and 22 weeks of gestation. Improvements in ultrasonography have resulted in reported rates of ultrasonographic diagnosis for anencephaly during the first and second trimesters of pregnancy that approach 100%.
      • Edwards L.
      • Hui L.
      First and second trimester screening for fetal structural anomalies.

      Definition

      Exencephaly, a precursor of anencephaly, is defined as the presence of a relatively normal-appearing embryonic or fetal brain that is not encased in the calvarium. Anencephaly is defined as the complete or partial absence of the cranium. The bony structures of the base of the skull and face and facial features are preserved. The cerebrum, cerebellum, and basal ganglia are missing, although the brainstem remains.

      Ultrasound Findings

      Exencephaly is readily detected during the first trimester of pregnancy. Currently, many cases are diagnosed at the time of nuchal translucency screening. The ultrasonographic signs of exencephaly include a wide and irregularly shaped head that lacks the echogenic calvarium surrounding the brain and the brain landmarks appropriate for gestational age. In well-dated pregnancies, a size or date discrepancy can often be seen. In the sagittal plane, the head appears flat and irregular, and the commonly seen intracranial features are missing. In the coronal plane, the exposed cerebellar hemispheres may be seen falling to the side of the head, resulting in the typical bilobed or “Mickey Mouse”–shaped head (Figure 1).
      Figure thumbnail gr6
      Figure 1Exencephaly-anencephaly in a fetus at 11 6/7 weeks of gestation
      A, Sagittal view showing an irregularly shaped head. B, In this coronal section, the cerebellar hemisphere (CH) are seen splayed apart; there is no calvarium present. C, Three-dimensional reconstruction of a fetus with exencephaly-anencephaly sequence.
      SMFM. SMFM Anomalies Consult Series #3. Am J Obstet Gynecol 2020.
      Anencephaly is typically detected in the first and second trimesters of pregnancy. In anencephaly, the brightly echogenic calvarium encasing the brain is absent beyond the area of the forehead. Normal-appearing orbits and facial features are retained. A variable amount of disorganized brain tissue, mostly the brainstem, remains on top of the head; this is called the “area cerebrovasculosa” (Figure 2). Polyhydramnios is present in up to 50% of cases during the latter half of the second trimester and in the third trimester of pregnancy. The echogenic amniotic fluid is best seen when scanning transvaginally or when the overall gain is increased; its appearance is in contrast to the anechoic extra-embryonic space or the sac of a normal co-twin (Figure 3).
      Figure thumbnail gr7
      Figure 2Exencephaly-anencephaly sequence in a fetus at 14 1/7 weeks of gestation
      A, Sagittal section shows a relatively normal profile; no calvarium is seen covering the brain. B and C, Coronal sections demonstrate the orbits and the bony components of the face.
      SMFM. SMFM Anomalies Consult Series #3. Am J Obstet Gynecol 2020.
      Figure thumbnail gr8
      Figure 3Echogenic amniotic fluid characteristic of anencephaly
      A, In a twin pregnancy, the amniotic fluid within the sac of the normal co-twin appears anechoic, whereas the amniotic fluid in the sac of the fetus with anencephaly is echogenic. B, The fetus with anencephaly is seen within the echogenic amniotic fluid, whereas the extra-embryonic space appears anechoic.
      SMFM. SMFM Anomalies Consult Series #3. Am J Obstet Gynecol 2020.

      Associated Abnormalities

      Exencephaly-anencephaly sequence has been associated with several congenital anomalies affecting multiple body systems. Among these anomalies, the most common are central nervous system (CNS) abnormalities, such as open spina bifida (craniorachischisis). Open spina bifida can be seen in the cervical region; it can also extend to include the entire length of the spine (lumbar and sacral regions). In the face, cleft lip and palate may be present. Other malformations that have been described include congenital heart defects; diaphragmatic hernia; abdominal wall defects; and renal, skeletal, and gastrointestinal anomalies. Aneuploidy has been reported in about 2% of cases, including the common trisomies (21, 18, and 13), triploidy, and some genetic deletions and duplications.
      Committee on Practice Bulletins-Obstetrics
      Practice Bulletin no. 187: neural tube defects.

      Differential Diagnosis

      The main differential diagnoses are amniotic bands and severe microcephaly. In amniotic band sequence, the most common defects are those involving the fetal extremities that can result in constrictions and amputations. However, severe craniofacial defects, such as anencephaly, have been reported in approximately one-third of cases of amniotic bands.
      • Menekse G.
      • Mert M.K.
      • Olmaz B.
      • Celik T.
      • Celik U.S.
      • Okten A.I.
      Placento-cranial adhesions in amniotic band syndrome and the role of surgery in their management: an unusual case presentation and systematic literature review.
      ,
      • Seeds J.W.
      • Cefalo R.C.
      • Herbert W.N.
      Amniotic band syndrome.
      The malformations caused by amniotic banding do not follow any specific pattern and are nonembryologic.
      • Padmanabhan L.D.
      • Hamza Z.V.
      • Thampi M.V.
      • Nampoothiri S.
      Prenatal diagnosis of amniotic band syndrome.
      Placentocranial adhesions result in serious abnormalities and are associated with a poor outcome.
      In cases of severe microcephaly, the fetal head may be so small that it can be confused with anencephaly. However, in contrast to anencephaly, the echogenic calvarium will be seen surrounding the fetal head.

      Genetic Evaluation

      Chromosomal abnormalities have been reported in 2.5% to 10.3% of fetal and newborn patients with common NTDs.
      • Chen C.P.
      Chromosomal abnormalities associated with neural tube defects (I): full aneuploidy.
      Chromosomal abnormalities that have been associated with anencephaly include trisomies 2, 9, 13, 18, and 21; trisomy 11 mosaicism; and triploidy. There was 1 case described of a family with a variant in the TRIM36 gene on chromosome 5q22 thought to have caused anencephaly.
      • Singh N.
      • Kumble Bhat V.
      • Tiwari A.
      • et al.
      A homozygous mutation in TRIM36 causes autosomal recessive anencephaly in an Indian family.
      Given the lethal nature of this disorder, genetic testing results do not predict prognosis. However, diagnostic testing (amniocentesis or chorionic villus sampling) with chromosomal microarray analysis (CMA) should be offered when an NTD, including exencephaly-anencephaly sequence, is detected as results of this testing informs recurrence risk and prenatal diagnosis recommendations in a future pregnancy. It is reasonable to initially perform karyotype analysis, with reflex to CMA if these test results are normal. If there are additional anomalies, consanguinity, or a family history of a specific condition, gene panel testing or exome sequencing is sometimes useful because CMA does not detect single-gene (Mendelian) disorders. If exome sequencing is pursued, appropriate pretest and posttest genetic counseling by a provider experienced in the complexities of genomic sequencing is recommended.
      For patients who decline prenatal diagnostic evaluation, diagnostic testing after delivery or termination is more useful than cell-free DNA screening.

      Pregnancy and Delivery Management

      In general, pregnancy termination is an option that should be offered to patients when a major fetal anomaly, including anencephaly, is detected. For patients who continue the pregnancy, routine prenatal care should be offered. Although polyhydramnios develops in 25% to 50% of cases of anencephaly, it does not typically affect management unless maternal symptoms develop.
      • Obeidi N.
      • Russell N.
      • Higgins J.R.
      • O’Donoghue K.
      The natural history of anencephaly.

      Prognosis

      Anencephaly should be considered to be a lethal abnormality. In a recent series of 26 pregnancies complicated by anencephaly, 42% of the fetuses were born alive. Overall, stillbirth occurred in 58% of the cases; of these, 23% were in utero deaths, and 35% were intrapartum fetal deaths. Among the live births, most neonates died within the first day of life; however, some neonates survived for up to 1 week.
      • Obeidi N.
      • Russell N.
      • Higgins J.R.
      • O’Donoghue K.
      The natural history of anencephaly.
      Neonates with anencephaly should be given palliative care, and family members should be offered support.

      Summary

      In exencephaly, the cranium that normally covers the brain is absent. It is typically detected during the first trimester of pregnancy. As the exposed brain disintegrates, features of anencephaly become apparent. Anencephaly is a lethal NTD in which there is a complete or partial absence of the cranium, cerebrum, cerebellum, and basal ganglia. Anencephaly is most commonly diagnosed during the first or second trimester of pregnancy using ultrasound, which can detect almost all cases of anencephaly. This malformation can be associated with other CNS anomalies and anomalies involving other systems. Aneuploidy has been reported in a small number of cases of anencephaly; therefore, genetic counseling and diagnostic testing are recommended. Pregnancy termination should be offered. In those who continue the pregnancy, intrauterine fetal demise occurs in most cases. Among liveborn neonates, demise typically occurs within the first few days of life. To decrease the risk of recurrence of NTDs, 4 mg of folate should be recommended in prepregnancy.
      MRC Vitamin Study Research Group
      Prevention of neural tube defects: results of the Medical Research Council Vitamin Study.

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