Fetal Akinesia Deformation Sequence

GENESIS

Fetal movement is essential to normal joint morphogenesis. Joints develop secondarily within the condensed mesenchyme of the developing bones, and chronic lack of movement leads to joint contractures. Fetal akinesia is associated with a specific combination of clinical findings that was previously called the Pena-Shokeir phenotype because these signs were first described as part of Pena-Shokeir syndrome. These findings include fetal growth retardation, congenital contractures with underdeveloped limbs, polyhydramnios, pulmonary hypoplasia, short umbilical cord, and craniofacial alterations such as micrognathia, occasional cleft palate, hypertelorism, and short neck ( Fig. 47.1 ), and they are usually autosomal recessive and detectable through prenatal diagnosis. Prenatal diagnosis of fetal akinesia may reveal cystic hygroma, increased nuchal translucency, nuchal edema, hydrops fetalis, arthrogryposis, pterygia, and other structural abnormalities. Genetic evaluation should include a differential diagnosis of neuromuscular junction disorders with genetic analysis for mutations in neuromuscular junction genes such as CHRNA1 , CHRND , CHRNG , CNTN1 , DOK7 , RAPSN , and SYNE1 . Genomic evaluation may unveil the pathogenetic cause of fetal akinesia deformation sequence (FADS) and multiple pterygium syndrome, which is helpful for genetic counseling and clinical management.

Hall emphasized the causal heterogeneity of this condition, and Moessinger demonstrated that rat fetuses paralyzed by daily transuterine injections of curare from day 18 of gestation until term on day 21 demonstrated a consistent pattern of abnormalities that he termed the fetal akinesia deformation sequence . In a dramatic human example, the mother of an infant born with multiple joint contractures (arthrogryposis) had received tubocurarine for 19 days in early pregnancy for the treatment of tetanus. This phenotype represents an etiologically heterogeneous deformation sequence that can result from neuropathy, myopathy, restrictive dermopathy, teratogens, or intrauterine constraint caused by prolonged oligohydramnios, which results in congenital contractures owing to extrinsic fetal immobilization. Among 30 cases of arthrogryposis associated with long-standing oligohydramnios (representing 1.2% of 2500 cases of arthrogryposis), none had renal agenesis or renal disease, 73% had a history of known rupture of membranes, and 50% had pulmonary hypoplasia, but only 2 died (7%), whereas 60% had multiple congenital contractures owing to the long-standing oligohydramnios and they responded well to physical therapy.

Pena-Shokeir syndrome was first described in 1974 as an autosomal recessive type of fetal akinesia (see the affected brothers in Fig. 47.1 ), and since that time multiple cases have been reported with a wide variety of associated findings, which suggest causal heterogeneity and warrant use of the more general term FADS. It is very important to distinguish extrinsic factors that limit fetal movement (e.g., oligohydramnios or fetal crowding) from intrinsic factors owing to neuromuscular abnormalities ( Fig. 47.2 ). Both types of problems can lead to abnormal fetal presentation, hence the association between breech presentation and fetal abnormalities. Fetal immobilization during late gestation can also give rise to transient joint limitation in normal newborns. Both FADS and oligohydramnios sequence share phenotypic manifestations such as arthrogryposis, short umbilical cord, and lung hypoplasia, caused by decreased intrauterine fetal motility. Other characteristic manifestations found in oligohydramnios sequence, such as Potter facies and redundant skin, are produced by fetal compression. On the other hand, growth retardation, craniofacial anomalies, micrognathia, long bone hypoplasia, and polyhydramnios are found in FADS and related to intrauterine muscular weakness.

There is ample evidence in both experimental animals and humans that fetal akinesia owing to a variety of causes can lead to multiple joint contractures and other manifestations of FADS. The fetal akinesia phenotype occurs in Pena-Shokeir syndrome (see Fig. 47.1 ), an autosomal recessive disorder, and also in a number of other genetic fetal malformation syndromes. Myotonic dystrophy can produce this phenotype ( Fig. 47.2B ), and similar effects have been noted in infants born to mothers with myasthenia gravis ( Fig. 47.3 ). Among 176 births by 79 mothers with myasthenia gravis, 4 (2.2%) newborns (including one pair of twins) were born with severe lethal skeletal anomalies (3 with arthrogryposis multiplex congenita and 1 with FADS). The mother of the child with fetal akinesia had previously given birth to a child with neonatal myasthenia gravis, and the mother of the twins with arthrogryposis later gave birth to a child with neonatal myasthenia gravis, suggesting a genetic basis independent of the mother’s clinical state.

Congenital myasthenic syndromes are a heterogeneous group of disorders caused by genetic defects affecting neuromuscular transmission and leading to muscle weakness accentuated by exertion. Disease-causing genes coding for proteins that have a key role at the neuromuscular junction have been identified, such as CHAT , CHRNA1 , CHRNB1 , CHRND , CHRNE , COLQ , RAPSN , SCN4A , MUSK , DOK7 , LAMB2 , and AGRN ; however, for half of congenital myasthenia patients, the genes underlying their disease have not yet been identified.

The manifestations and severity of FADS depend on the timing, duration, and degree of fetal akinesia, with multiple pterygia and increased nuchal translucency resulting from early prolonged fetal akinesia ( Fig. 47.4 ). Prolonged neuromuscular akinesia limits bone growth, which affects subperiosteal growth in bone breadth much more severely than linear growth. This leads to the development of thin bones that are susceptible to fractures. The size of a muscle relates to the magnitude and frequency of forces it brings to bear across a joint, and with diminished function, muscles tend to atrophy. Thus prolonged fetal akinesia results in low birth weight. Absence of flexion creases implies that the joint has never functioned, and, because most joints flex by the early second trimester, this implies an early cessation of fetal movement. Polyhydramnios is a relatively late manifestation of fetal akinesia sequence, which is usually associated with micrognathia caused by diminished fetal swallowing. Fetal lung movements are necessary for normal pulmonary growth and maturation, and deficient diaphragmatic function can lead to pulmonary hypoplasia. The importance of fetal respiratory movements in normal lung morphogenesis was highlighted by a case report that described an infant with pulmonary hypoplasia caused by phrenic nerve agenesis and diaphragmatic amyoplasia. In an experimental fetal rabbit model, destruction of the fetal cervical spinal cord in the C4 to C6 region caused complete atrophy of the diaphragm in addition to cutting off motor pathways from the respiratory center. Higher lesions at C1 to C3 preserved the phrenic nerve supply and hence allowed normal diaphragmatic growth but prevented any coordinated fetal respiratory activity. Each operation, when performed at 23 days of gestation during the late pseudoglandular phase of lung development, resulted in severe lung hypoplasia. Consequently, with severe fetal akinesia that inhibits fetal swallowing and fetal lung movements, the fetus is usually born with micrognathia, polyhydramnios, and respiratory insufficiency from pulmonary hypoplasia.

The association of a shortened umbilical cord implies that fetal akinesia began during or prior to the second trimester. Umbilical cord growth is influenced by tensile forces and depends on both fetal motion and the amount of space available for fetal movement. This has been demonstrated in both humans and rats. Oligohydramnios can severely limit fetal movement during the last half of gestation, and there is overlap between oligohydramnios sequence and FADS, but oligohydramnios does not limit fetal long bone growth to the same extent seen with neuromuscular akinesia, which also results in thin, fragile bones. Compression of skin in oligohydramnios sequence leads to skin redundancy, whereas fetal akinesia is associated with thin, tight skin with few flexion creases.

Restrictive dermopathy is a rare, lethal, autosomal recessive disorder characterized by extreme tautness of the skin causing restricted intrauterine movement and FADS with characteristic facial features (e.g., large anterior fontanelle; hypertelorism; a short, narrow, upturned nose; blepharophimosis with swollen lids and exophthalmos; a small, open mouth; and micrognathia). Dermatopathology findings include thin dermis consisting of compactly arranged collagen fibers, scant elastic fibers, and poorly developed skin appendages. The epidermal rete ridges are flattened and the dermal-hypodermal border is remarkably straight. LMNA and ZMPSTE24 have been identified as causative genes, offering an opportunity for prenatal genetic diagnosis. Exome sequencing of two siblings with lethal multiple pterygium syndrome revealed GBE1 mutations, which results in glycogen storage disease type IV, which was confirmed biochemically, and muscle pathology revealed storage material.

When foot deformations are associated with polyhydramnios, this usually implies an intrinsic neuromuscular abnormality, whereas foot deformations associated with oligohydramnios suggest extrinsic constraint. In a study of 30 fetuses with FADS, detailed neuropathologic studies that included the brain, spinal cord, and muscles allowed a specific diagnosis to be made in 16 cases (53%). Of these 16 cases, 9 had central nervous system abnormalities, 1 had spinal cord abnormality (spinal muscular atrophy I), 3 had a primary myopathy (nemaline myopathy and myotonic dystrophy), and 3 had a recognizable syndrome. In 10 other cases, neuromuscular pathology was evident but no specific diagnosis could be established. Only four patients had normal neuromuscular findings with no apparent etiology for FADS. Most importantly, recurrences in subsequent pregnancies were noted among all three groups (specific diagnosis, nonspecific neuromuscular pathology, and normal neuromuscular pathology). Subsequently other autopsy studies have revealed different novel causes for FADS, such as loss/absence of Purkinje cells in the cerebellum in siblings. A female fetus with hypoplasia of the cerebellum, corpus callosum, and optic nerves had nuclear cataracts and widespread axonal spheroids throughout the central and peripheral nervous systems with normal PLA2G6 sequencing, ruling out infantile neuroaxonal dystrophy and related disorders. Other postmortem case reports revealed evidence for a hypoxic-ischemic cause of FADS.

Pathological examination of female fetuses with severe FADS, multiple pterygia, and muscular hypoplasia showed massive cystic dilatation of the cerebral ventricles (hydranencephaly) with calcification of the basal ganglion and brainstem, and a proliferative vasculopathy throughout the central nervous system. These findings in two female siblings suggested autosomal recessive inheritance of the Fowler type of hydranencephaly. Mutations in FLVCR2 were associated with this proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (Fowler syndrome) in other cases.