Fetal akinesia sequence refers to the condition of decreased intrauterine fetal movement and its consequent manifestations of multiple joint contractures, pulmonary hypoplasia, and abnormal face present at birth. The incidence is estimated to be 1 in 12,000, reflecting causal heterogeneity
GENETICS/BASIC DEFECTS
1. Genetics
a. Sporadic in majority of cases b. Familial cases
i. Autosomal recessive inheritance ii. Possible X-linked recessive inheritance 2. Heterogeneous causes
a. Inadequacy of the intrauterine fetal environment i. Etiologic factors
a) Ovarian cyst b) Bicornuate uterus c) Umbilical cord wrapping d) Twins
e) Extra-uterine pregnancy f) Insufficient placental circulation g) Maternal tetanus, drug treatment h) Amniotic bands
ii. Oligohydramnios sequence
a) Facial deformities (Potter’s facies) b) Arthrogryposis
c) Lung hypoplasia
iii. Types of defects determined by the timing of constraint
a) Early in pregnancy leading to limb reduction defects, syndactyly and polydactyly b) Later in pregnancy (3rd trimester) leading to
genu recurvatum, dislocated hips and deviated wrists
c) Various developmental defects occurring earlier in the upper than in the lower limbs d) Embryonic onset of immobility interferes
with limb development and results in joint fixation and pterygium formation, in con- trast to fetal-onset immobility, which causes joint contractures alone
b. Pena-Shokeir phenotype or sequence i. Pena-Shokeir syndrome
a) Originally described by Pena and Shokeir in 1974
b) Syndrome consisting of camptodactyly, multiple ankyloses, facial anomalies, pul- monary hypoplasia, and lethal outcome ii. Curarization of fetal rats during pregnancy (study
by Moessinger, 1983) resulted in better under- standing of fetal akinesia deformation sequence with the following features almost identical with those described in the Pena-Shokeir syndrome:
a) Multiple contractures or arthrogryposis b) Pulmonary hypoplasia
c) Craniofacial anomalies d) Polyhydramnios
e) Intrauterine growth retardation f) Short umbilical cord
iii. Currently the term “Pena-Shokeir phenotype or sequence” is recommended instead of “Pena- Shokeir syndrome”
3. Fetal akinesia not associated with primary malformations a. Mechanical causes
i. Oligohydramnios ii. Polyhydramnios
iii. Premature rupture of the membrane iv. Chorioamnionitis
b. Congenital infections i. Rubella
ii. CMV
iii. Toxoplasmosis c. Physical or chemical agents
i. Toxic agents ii. Drugs iii. X-rays
iv. Hyperthermia d. Fetal hypoxia
i. Fetal anemia a) Blood loss b) Hemolysis
ii. Compression of umbilical cord iii. Placental insufficiency
iv. Severe toxemia e. Maternal myasthenia gravis
4. Role of fetal akinesia in heterogeneous syndromes and conditions
a. Cerebro-oculo-facio-skeletal (COFS) syndrome b. Potter sequence
c. Neu-Laxova syndrome
d. Syndrome described by Herva et al. (1985) e. Osteochondrodysplasias
i. Thanatophoric dysplasia ii. Achondrogenesis iii. Diastrophic dysplasia
f. Lethal multiple pterygium syndrome g. CNS anomalies
i. Hydranencephaly
ii. Dandy-Walker malformation with hydro- cephalus
iii. Schizencephaly
iv. Olivo-ponto-cerebellar degeneration h. Skin/connective tissue disorders
i. Restrictive dermopathy ii. Epidermolysis bullosa iii. Congenital ichthyosis 398
i. Metabolic disorders
i. Lysosomal storage disorders
ii. Generalized gangliosidosis syndrome type I iii. Glycogenosis type VII
j. Neuromuscular disorders
i. Congenital muscular dystrophy ii. Congenital myotonic dystrophy iii. Congenital spinal muscular atrophy
iv. Central core disease v. Nemaline myopathy
k. Other disorders causing restrictive fetal akinesia i. Loss of anterior horn cells
ii. Radical disease iii. Peripheral neuropathy
iv. Congenital myasthenia gravis v. Amyoplasia congenita vi. Prader-Willi syndrome vii. Cohen syndrome viii. Angelman syndrome
ix. Neurofibromatosis I x. Moebius syndrome
xi. Bilateral dislocation of the hips xii. Exstrophy of cloaca and bladder xiii. Chromosome abnormalities
a) Fetal triploidy
b) Trisomies 4p, 9, 9q, 9p, 10q, 11q, proximal 14, proximal 15, and 18
c) Monosomies 4p and 13q xiv. Miscellaneous
a) Cornelia de Lange syndrome b) Catel-Manzke syndrome c) Opitz-Frias syndrome d) Bowen-Conradi syndrome e) Marden-Walker syndrome
5. Pathogenesis of fetal akinesia sequence (Hageman et al., 1987)
a. Spinal cord lesions observed most often (28%) b. Brain lesions (19%)
c. Miscellaneous or connective tissue disorders (11%) d. Combined brain and spinal cord lesions (9%) e. Mechanical restriction (7%)
f. Muscle disorders (5%)
g. Peripheral neuropathy and myasthenia gravis (1%) h. No underlying defect observed in 14% of cases
CLINICAL FEATURES
1. Pregnancy history
a. Feeble fetal movement b. Polyhydramnios c. Oligohydramnios
d. Craniofacial abnormalities i. Ocular hypertelorism ii. Micrognathia iii. Low-set ears
iv. Depressed nasal tip v. Short neck
e. Limb anomalies
i. Lack of normal growth ii. Limitation of joint movement iii. Abnormal shape
iv. Abnormal position
v. Decreased bone calcification 2. Phenotype present at birth
a. Multiple joint contractures b. Limb pterygia
c. Craniofacial abnormalities d. Pulmonary hypoplasia e. Short umbilical cord
f. Growth retardation
3. Lethal outcome with pulmonary hypoplasia
DIAGNOSTIC INVESTIGATIONS
1. Radiography
a. Thin tubular bones b. Gracile ribs
c. Multiple fractures possible at mid-diaphyses of humeri, distal diaphyses of femora, proximal diaphyses of tibiae and fibulae
d. Camptodactyly
2. Histopathologic and other laboratory studies
a. Trophoblastic inclusions in the chorionic villi of placenta:
i. Triploidy
ii. Lethal multiple pterygium syndrome b. Lung hypoplasia
c. Bones
i. Unremarkable resting cartilage
ii. Normal cartilage cell columns at the chondro- osseous junctions
iii. Marrow bony spicules often unusually thin and underossified
iv. Irregular and focal areas of extreme diaphyseal thinning: a consistent finding
d. CNS, muscles, and other organ systems
e. Biochemical studies for lysosomal storage disease f. Analysis for chromosome abnormality
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. Autosomal recessive inheritance: 25%
ii. A recurrence risk of 10–15% suggested in the nonfamilial sporadic cases
b. Patient’s offspring: a lethal entity not surviving to reproductive age
2. Prenatal diagnosis by ultrasonography in high-risk pregnan- cies after the birth of a previous child with a heritable (most- ly autosomal recessive) form of fetal akinesia sequence a. Marked decreased fetal activity
i. Restricted limb movements ii. Decreased fetal chest movements b. Hydramnios/oligohydramnios c. Intrauterine growth retardation
d. Other echographic abnormalities associated with fetal akinesia
i. Brain
a) Microcephaly b) Holoprosencephaly c) Hydranencephaly
d) Meningomyelocele e) Lissencephaly
f) Dilated ventricles
g) Absence of septum pellucidum ii. Spinal cord: sacrococcygeal agenesis iii. Gastrointestinal tract
a) Omphalocele b) Gastroschisis iv. Renal
a) Bilateral renal agenesis b) Renal malformations v. Craniofacial
a) Hypertelorism b) Hypotelorism c) Micrognathia d) Cleft palate vi. Limbs
a) Contractures (arthrogryposis) b) Camptodactyly
c) Webbing d) Syndactyly e) Polydactyly
f) Overlapping fingers and toes g) Abnormal position
h) Clubfoot
i) Partial absence or shortness vii. Cardiopulmonary
a) Pulmonary hypoplasia b) Cardiac defects
3. Management: no effective treatment for pulmonary hypoplasia
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Fig. 1. A neonate with fetal akinesia sequence showing micro/retrog- nathia, short neck, narrow thorax, flexion contractures of hips, fixed extension of the right knee, and inverted and rotated feet. The radi- ograph showed gracile ribs, thin long bones with multiple fractures at mid-diaphyses of humeri, distal diaphysis of femora, and proximal diaphyses of both tibiae and left fibula, and club hands.
Fig. 2. A neonate with fetal akinesia sequence showing micrognathia and multiple contractures. The radiograph showed gracile ribs and fractures at mid-diaphyses of humeri.
Fig. 3. A neonate with Pena-Shokeir sequence showing hypertelorism, a short nose with depressed nasal bridge, a small and recessed jaw, low-set malformed ears, a short neck, multiple contractures at the hip, elbows, knees, and ankles. The infant had scalp edema and pulmonary hypoplasia. Prenatal ultrasonography showed hydramnios, retrog- nathia, low-set ears, scalp edema, and flexion contractures at the elbows and knees.
