GENETICS/BASIC DEFECTS Acardia

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Acardia is a bizarre fetal malformation occurring only in twins or triplets. It is also called acardius acephalus, acardiac twinning, or twin reversed arterial perfusion (TRAP) syndrome or sequence. This condition is very rare and occurs 1 in 35,000 deliveries, 1 in 100 monozygotic twins, rarely in triplet pregnancy, and even in quintuplet gestations.

GENETICS/BASIC DEFECTS

1. Etiology

a. Rare complication of monochorionic twinning, pre- sumably resulting from the fused placentation of monochorionic twins

b. Represents manifestation of abnormal embryonic and fetal blood flow rather than a primary defect of cardiac formation

c. Heterogeneous chromosomal abnormalities are present in nearly 50% of the cases, although chromosome errors are not underlying pathogenesis of the acardiac anomaly.

i. 45,XX,t(4;21)del(4p) ii. 46,X,i(Xp)

iii. 47,XX,+2 iv. 47,XX,+11

v. 47,XY,+G vi. 47,XXY vii. 69,XXX viii. 70,XXX,+15

ix. 94,XXXXYY

2. Pathogenesis: reversal of fetal arterial perfusion a. First hypothesis

i. A primary defect in the development of the heart ii. Survival of the acardiac twin as a result of the

compensatory anastomoses that develop b. Second hypothesis

i. The acardiac twin beginning life as a normal fetus ii. The reversal of the arterial blood flow resulting in atrophy of the heart and the tributary organs 3. Classification of TRAP sequence (syndrome)

a. Classification according to the status of the heart of the acardiac twin

i. Hemiacardius (with incompletely formed heart) ii. Holoacardius (with completely absent heart) b. Morphologic classification of the acardiac twin

i. Acardius amorphous

a) The least differentiated form; no resem- blance to classical human form

b) Anatomical features: presence of only bones, cartilage, muscles, fat, blood vessels, and stroma

ii. Acardius myelacephalus

a) Resembles the amorphous type, except for the presence of rudimentary limb formation

b) Presence of rudimentary nerve tissue in addition to anatomical features in acardius amorphous

iii. Acardius acephalus

a) The most common type

b) Missing head, part of the thorax, and upper extremities

c) May have additional malformations in the remaining organs

iv. Acardius anceps

a) Presence of a partially developed fetal head, a thorax, abdominal organs, and extremities b) Lacks even a rudimentary heart

v. Acardius acormus a) The rarest type b) Lacks thorax

c) Presence of a rudimentary head only d) The umbilical cord inserts in the head and

connects directly to the placenta 4. The acardia

a. Characterized by the absence of a normally function- ing heart

b. Acardia as a recipient of twin transfusion sequence i. Reversal of blood flow in various types of acar-

dia, hence the term “twin reversed arterial perfusion (TRAP) sequence” has been proposed ii. Receiving the deoxygenated blood from an

umbilical artery of its co-twin through the single umbilical artery of the acardiac twin and returning to its umbilical vein. Therefore, the circulation is entirely opposite to the normal direction

c. Usually the severe reduction anomalies occur in the upper part of the body

d. May develop various structural malformations i. Growth retardation

ii. Anencephaly iii. Holoprosencephaly

iv. Facial defects

v. Absent or malformed limbs vi. Gastrointestinal atresias

vii. Other abnormalities of abdominal organs 5. The co-twin

a. Also known as the “pump twin or donor twin”

b. The donor “pump” twin perfuses itself and its recipient acardiac twin through abnormal arterial anastomosis in the fused placenta

c. Increased cardiac workload often leads to cardiac failure and causes further poor perfusion and oxygena- tion of the acardiac co-twin

d. May develop various malformations (about 10%)

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CLINICAL FEATURES

1. Perinatal problems associated with acardiac twinning a. Pump-twin congestive heart failure

b. In utero fetal death of the pump fetus c. Maternal polyhydramnios

d. Premature rupture of membrane e. Preterm delivery

f. Spontaneous abortions g. Soft tissue dystocia h. Uterine rupture

i. Postpartum hemorrhage

j. Increased rate of cesarean section, up to 50%

2. Majority of acardiac twins and their normal twin counter- parts are females

3. Nonviable 4. Gross features

a. Severe reduction anomalies, particularly of the upper body

b. Characteristic subcutaneous edema c. Internal organs: invariably missing

d. Absent or rudimentary cardiac development: the key diagnostic feature

i. Pseudoacardia (rudimentary heart tissue) ii. Holoacardia (completely lacking a heart) 5. Growth abnormality

6. Cranial vault a. Absent b. Partial c. Intact 7. Brain

a. Absent b. Necrotic

c. Open cranial vault d. Holoprosencephaly 8. Facial features

a. Absent facial features b. Rudimentary facial features c. Present with defects

d. Anophthalmia/microphthalmia e. Cleft lip/palate

9. Upper limbs a. Absent b. Rudimentary c. Radial aplasia

d. Syndactyly/oligodactyly 10. Lower limbs

a. Absent

b. Rudimentary/reduced c. Syndactyly/oligodactyly d. Talipes equinovarus 11. Thorax

a. Absent b. Reduced

c. Diaphragmatic defect 12. Lungs

a. Absent

b. Necrotic or rudimentary c. Single midline lobe

13. Cardiac

a. Absent heart tissue b. Unfolded heart tube

c. Folded heart with common chamber 14. Gastrointestinal

a. Esophageal atresia b. Short intestine c. Interrupted intestine d. Omphalocele

e. Incomplete rotation of the gut f. Imperforated anus

g. Ascites 15. Liver

a. Absent b. Reduced 16. Kidney

a. Absent (bilateral)

b. Hypoplastic and/or lobulated 17. Other viscera

a. Absent gallbladder b. Absent spleen

c. Absent-to-reduced pancreas d. Absent adrenal

e. Absent-to-hypoplastic gonads f. Exstrophy of the cloaca

g. Skin with myxedematous thickening 18. Umbilical cord vessels

a. Two vessels b. Three vessels

19. Severe obstetrical complications a. Maternal polyhydramnios b. Preterm labor

c. Cord accidents d. Dystocia e. Uterine rupture

20. Severe neonatal complications a. Hydrops

b. Intrauterine demise c. Prematurity d. Heart failure e. Anemia

f. Twin-to-twin transfusion syndrome

21. Outcome for the normal sib in an acardiac twin pregnancy a. Unsatisfactory

i. Adapting to the increasing circulatory load, resulting in the following situations:

a) Intrauterine growth retardation b) Hydrops

c) Ascites

d) Pleural effusion

e) Hypertrophy of the right ventricle f) Hepatosplenomegaly

g) Severe heart failure resulting in pericardial effusion and/or tricuspid insufficiency ii. Stillbirth

iii. Prematurity iv. Neonatal death

b. Mortality for the normal twin reported as high as 50%

without intervention

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DIAGNOSTIC INVESTIGATIONS

1. Radiography

a. Absent or rudimentary skull b. Absent or rudimentary thorax c. Absent or rudimentary heart d. Vertebral anomalies

e. Rib anomalies

f. Limb defects, especially upper limbs 2. Pathology

a. Microcephaly

b. Severely rudimentary brain

c. Developmental arrest of brain at the prosencephalic stage (holoprosencephaly)

d. Hypoxic damage to the holospheric brain mantle with cystic change (hydranencephaly)

GENETIC COUNSELING

1. Recurrence risk

a. Patient’s sib: overall recurrence risk of about 1 in 10,000 (The recurrence risk is for monoamniotic twinning [1% for couples who have had one set of monozygotic twins] times the frequency of the occur- rence of TRAP sequence with near-term survival [about 1% of monozygotic twin sets])

b. Patient’s offspring: not applicable (a lethal condition) 2. Prenatal ultrasonography

a. Monochorionic placenta with a single umbilical artery in 2/3 of cases

b. Acardiac fetus

i. Unrecognizable head or upper trunk

ii. Without a recognizable heart or a partially formed heart

iii. A variety of other malformations

iv. Reversal of blood flow in the umbilical artery with flow going from the placenta toward the acardiac fetus (reversed arterial perfusion). Such a reversal of the blood flow in the recipient twin can be demonstrated in utero by transvaginal Doppler ultrasound as early as 12 weeks of gestation

v. Early diagnosis by transvaginal sonography on the following signs:

a) Monozygotic twin gestation (absence of the lambda sign)

b) Biometric discordance between the twins c) Diffuse subcutaneous edema or morpho-

logic anomalies of one of the twins, or both

d) Detection of reversed umbilical cord flow;

cardiac activity likely to disappear as the pregnancy progresses

e) Absence of cardiac activity, although hemi- cardia or pseudocardia may be present c. The donor fetus

i. Hydrops

ii. Cardiac failure (cardiomegaly, pericardial effusion, and tricuspid regurgitation)

2. Amniocentesis to diagnose associated chromosome abnormalities (about 10% of pump twins)

3. Management of pregnancies complicated by an acardiac fetus

a. Conservative treatment

i. Monitor pregnancy by serial ultrasonography ii. Conservative approach as long as there is no evi-

dence of cardiac circulatory decompensation in the donor twin

b. Termination of pregnancies

c. Treatment and prevention of preterm labor by tocolytics i. Magnesium sulphate

ii. Beta-Sympathomimetics iii. Indomethacin

d. Treatment of pump fetus heart failure involving maternal digitalization

e. Treatment of polyhydramnios by therapeutic repeated amniocentesis

f. Selective termination of the acardiac twin

i. To occlude the umbilical artery of the acardiac twin in order to stop umbilical flow through the anastomosis

a) Intrafunicular injection and mechanical occlusion of the umbilical artery

b) Embolization by steel or platinum coil, alco- hol-soaked suture material, or ethanol c) Hysterotomy and delivery of acardiac twin d) Ligation of the umbilical cord

e) Hysterotomy and umbilical cord ligation ii. Fetal surgery: best available treatment for acar-

diac twinning

a) Endoscopic laser coagulation of the umbilical vessels at or before 24 weeks of gestation b) Endoscopic or sonographic guided umbilical

cord ligation after 24 weeks of gestation iii. Summary of acardiac twins treated with invasive

procedures reported in the literature a) Mortality of the pump twin (13.6%) b) Preterm delivery (50.3%)

c) Delivery before 30-weeks gestation (27.2%) d) Perinatal mortality, if untreated, is at least 50%

REFERENCES

Aggarwal N, Suri V, Saxena SV, et al.: Acardiac acephalus twins: a case report and review of literature. Acta Obstet Gynecol Scand 81:983–984, 2002.

Alderman B: Foetus acardius amorphous. Postgrad Med J 49:102–105, 1973.

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Donnenfeld AE, Van de Woestijne J, Craparo F, et al.: The normal fetus of an acardiac twin pregnancy: perinatal management based on echocardio- graphic and sonographic evaluation. Prenat Diagn 11:235–244, 1991.

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Fig. 1. Ventral view of an acardiac acephalus fetus (upper photo) shows a large abdominal defect, gastroschisis (arrow), through which small rudiments of gastrointestinal tract are seen. Dorsal view (lower photo) shows a very underdeveloped cephalic end and relatively well- developed lower limbs. The co-twin had major malformations consist- ing of a large omphalocele, ectopia cordis, and absent pericardium, incompatible with life.

Fig. 2. Radiographs of the above acardiac fetus showing a missing head, cervical vertebrae and part of upper thoracic vertebrae, rudimen- tal lower ribs, malformed lower thoracic and lumbar vertebrae, and relatively well-formed lower limbs.

Fig. 3. The head and part of the thorax of this acardiac fetus are com- pletely missing with relatively well-formed lower limbs.

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Fig. 4. Another acardiac fetus with a missing head and part of the upper thorax. Radiograph shows missing head, and cervical and part of thoracic vertebrae and ribs. Pelvis and lower limbs are well formed.

Fig. 5. Acardius (second twin, 36-weeks gestation) showing spherical body with a small amorphous mass of leptomeningeal and glial tissue at the cephalic end. There were one deformed lower extremity and a small arm appendage. Small intestinal loops, nodules of adrenal glands, and testicles were present in the body. There was no heart or lungs. The placenta was nonoamniotic monochorionic with velamen- tous insertion of the umbilical cord. The other identical twin was free of birth defects. Radiograph of acardius twin shows a short segment of the spine, a femur, a tibia, and a fibula.