American Journal of Medical Genetics 40284-289 (1991)

Pathogenetic Mechanisms of Fetal Akinesia Deformation Sequence and Oligohydramnios Sequence Jose Ignacio Rodriguez and Jose Palacios Department of Pathology, Hospital La Paz, Madrid, S p a i n

This article briefly reviews the participation of fetal compression,muscularweakness, and fetal akinesia in the genesis of the anomalies found in fetal akinesia deformation sequence (FADS) and oligohydramnios sequence (0s). Both sequences share phenotypic manifestations, such as arthrogryposis, short umbilical cord, and lung hypoplasia, in relation to decreased intrauterine fetal motility. Other characteristic manifestations found in OS, such as Potter face, and redundant skin, are produced by fetal compression. On the other hand, growth retardation,craniofacial anomalies, micrognathia, long bone hypoplasia, and polyhydramnios found in FADS could be related to intrauterine muscular weakness.

KEY WORDS: deformation sequences, fetal akinesia, oligohydramnios

INTRODUCTION Intrauterine movement is now recognized as an essential factor for normal fetal development,but mechanical forces also play an important role in normal fetal morphogenesis. During pregnancy morphogenesis takes place in restricted space. The amniotic fluid protects the developing fetus from uterine wall pressure and allows fetal movements. Deformations are structural defects that represent abnormal morphogenesis caused by mechanical forces [Spranger et al., 19821. They develop when fetal movements are restricted or when an unusual force is applied. Deformations can be divided into 2 groups: those due to an intrinsic problem of the fetus and those in which the deformation is produced by extrinsic mechanical forces acting on a normal fetus

Received for publication May 7, 1990; revision received November 6 , 1990. Address reprint request to Dr. Jose Ig. Rodriguez. Departamento de Anatomia Patolbgica, Hospital La Paz, Paseo de la Castellana 261, E-28046 Madrid, Spain.

0 1991 Wiley-Liss, Inc.

[Jones, 1983; Graham, 19881. Intrinsic or extrinsic factors may cause a single localized deformation, but may also be responsible for a number of deformations (deformation sequence). The term sequence implicates the initiating defect plus its chain of consequences [Spranger et al., 19821. Decreased intrauterine fetal motility of intrinsic origin (caused by a very heterogeneous group of neuromuscular or connective tissue diseases) produces a phenotype characterized by secondary anomalies such as growth retardation, craniofacial alterations, arthrogryposis, pulmonary hypoplasia, short umbilical cord, and polyhydramnios. These anomalies that were previously designated as Pena-Shokeir syndrome [Pena and Shokeir, 1974; Chen et al., 19831are now termed as fetal akinesia/hypokinesia deformation sequence (FADS) [Moessinger, 1983; Hall, 19861 stressing lack of movement as the main pathogenetic mechanism. In addition, muscular weakness must be considered as an important mechanism that produces some ofthe components of this phenotype. Another clinically recognized deformation sequence, the oligohydramnios sequence or tetrad (OS),combined growth deficiency, pulmonary hypoplasia, craniofacial anomalies, limb positioning defects, and short umbilical cord [Graham, 19881. This phenotype has been traditionally related to fetal compression [Thomas and Smith, 19741. Since oligohydramnios is a well-recognized cause of extrinsically reduced fetal motility, fetal akinesia has been proposed as a pathogenetic mechanism in this sequence. Therefore, there may be a striking overlap between the phenotypes of patients with 0s and those with the FADS [Moessinger, 1983; Mease et al., 1976; Davis and Kalousek, 19881.This current point of view is depicted in Figure 1: etiologically heterogeneous conditions, either intrinsic or extrinsic, produce a similar phenotype by means of the same pathogenetic mechanism (fetal akinesia). However, in this approach the role of fetal akinesia in the pathogenesis of both FADS and 0s seem to be overestimated. This article briefly reviews the participation of fetal compression, muscular weakness, and fetal akinesia in the genesis of the anomalies found in these sequences (Fig. 2).

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INTRA - UTERINF. CONSTRAINT

Fig. 1. Diagram of fetal akinesia modified from Moessinger [1983].

INTRINSIC

EXTRINSIC

Neuromuscplar diseases

Oligohydramnios

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I MUSCULAR WEAKNESS

AKINESIA W C O M P R E S S I O N

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Growth retardation Craniofacial anomalies Micrognathia

Redundant skin Lung hypoplasia

Long bone changes Polyhydramnios

Pterygium

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Fig. 2. Different clinical manifestations are related to different pathogenetic mechanisms and causes.

FETAL COMPRESSION The effect of fetal compression in the early and late fetal period secondary to lack of amniotic fluid or uterine malformation has been studied extensively both clinically and experimentally [DeMyer and Baird, 1969; Kennedy and Persaud, 1977;Miller et al., 1979;Graham et al, 1980; Miller et al., 1981al. Constraint may limit the growth of the whole individual and growth retardation is one of the signs of the oligohydramnios tetrad [Thomas and Smith, 19741.However, it is not a constant finding in these patients. In several clinical and autopsy series of OS, less than 25% of newborns showed a ponderal index (weight in grams x 100 +body length in cm) [Miller, 19721 lesser than 10th centile [Curry et al., 1984;Thibeault et al., 1985;Hickok et al., 1989;Palacios and Rodriguez, 19901. Ponderal deficiency is related to the timing and intensity of constraint: the more the constraint the greater is the deceleration of growth [Graham, 19881.

The skin may respond by overgrowth to prolonged external compressive forces [Smith, 19791. Most newborn infants with 0s appear to have an excessive amount of skin, and look as ifthey were dehydrated. The relative overgrowth of skin is evident in the loose folds of skin in the face especially the prominent epicanthal and lower inner folds (Fig. 3). The skin also tends to be loose and redundant elsewhere at sites of unusual forces. Large and flattened ears are also characteristic of Potter face because ear cartilage respond to pressure in a similar fashion to skin [Jones, 19831. Micrognathia has been frequently described in 0s [Moessinger, 1983; Davis and Kalousek, 19881, although this diagnosis appears to be based on subjective criteria. In a recent cephalometric study of newborn infants with 0s due to renal or urinary malformations no alterations were noted in the facial or mandibular growth, indicating that micrognathia is not a major component of 0s (Fig. 4). However, as a consequence of fetal constraint, mandibular asymmetry may occur [Palacios and Rodriguez, 19901. Other major manifestations of OS, such as pulmonary hypoplasia, limb positioning defects, and short umbilical cord, are discussed below.

MUSCULAR WEAKNESS Developmental disorders of muscle are conditions in which striated muscle fails to develop or mature normally because of altered embryological mechanisms, abnormal innervation of neural induction of muscle, or intrinsic metabolic errors which interfere with the maturation process [Sarnat, 19821.Congenital neuromuscular disorders, such as spinal muscular atrophy or congenital myotonic dystrophy [Hall, 1986; Rodriguez et al., 1988a1, and some cerebral lesions [Hageman et al., 19871 that result in muscle fiber atrophy by affecting motor neuron cells of the spinal cord, are conditionsthat produce FADS in newborn infants. In these patients, muscular weakness rather than fetal hypokinesia seems to be the main pathogenetic mechanism which explains some components of this sequence. Weakness of the muscles of the head such as those of

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Fig. 3. Characteristic Potter face in a newborn infant with oligohydramnios sequence (0s).

Fig. 4. Postmortem lateral X-ray of the head of a newborn infant with 0s showing a normal length of the mandible.

the pharynx, palate, and face contributes to abnormal moulding of the craniofacial structures [Sarnat, 19821. Relative macrocephaly, dolichocephaly, high-arched palate, and the characteristic inverted V-shaped upper lip are particularly in some newborn infants with FADS (Fig. 5). Micrognathia is a constant finding in newborn infants with FADS and might be produced by weakness of masticatory muscles because the rate of mandibular growth appears to depend on muscular activity [Moss, 19681. Weakness of ear muscles is probably responsible for the abnormal folding, smallness, and posterior angulation of the ears in these newborn infants [Jones, 19831. Moreover, in these patients lack of swallowing activity produces polyhydramnios [Moessinger, 19831. Thin and elongated long bones have been described

Fig. 5. Inverted V-shaped upper lip and apparent hypertelorism in a newborn infant with fetal akinesia deformation sequence (FADS) secondary to congenital myotonic dystrophy.

in newborn infants who had congenital disorders [Spranger et al., 1980; Rodriguez et al., 1988al. Muscular forces act on bones by means of muscle insertions and lead to stress in bone. Normal bone form will develop and will be maintained only in the presence of normal muscular function, and normal bone mass is similarly dependent on the level of functional activity or mechanical usage. Bone tissue responds to muscular strength by osseous apposition on the periosteal and endosteal surfaces (bone modeling) [Frost, 19871. A morphometric study of long bones in newborn infants with congenital neuromuscular diseases demonstrated a marked reduction of bone mass in those patients who showed a significantly decreased diaphyseal diameter and cortical thickness [Rodriguez et al., 1988bl. Histologically there was a poor periosteal bone apposition with thin cortical bone and periosteum (Fig. 6a,b). All these manifestations clearly indicate a decreased in utero bone modeling secondary to reduced mechanical use of the bone due to weakness. The resulting hypoplastic bones are prone to metaphyseal and diaphyseal fractures during delivery and postnatal handling (Fig. 7). Moreover, there is histological evidence that growth plate fractures may occur in utero [Rodriguez et al., 1988al. Neuromuscular diseases usually produce muscular atrophy or hypotrophy. Since striated muscle is the major tissue component of the mammalian body that contributes between 40 and 50% of its total weight, the reduction of the muscle bulk together with the decreased bone mass are responsible of the nearly constant low birth weight of fetuses with FADS.

FETAL AKINESIA/HYPOKINESIA Clinical, pathological, and experimental evidence supports the hypothesis that active movement of the embryo and fetus is required to assure a normal develop-

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[Drachman and Coulombre, 19621.Arthrogryposis may result from extrinsic or intrinsic immobilization of the joints during embryonic or fetal development. The timing during development almost surely plays a critical role in the severity of the contractures, the positioning of joints, and secondary changes with growth. Once firmly established, ankylosis may persist through development [HaII, 19851. Increased mechanical pressure in oligohydramnios can restrain the movements of the limbs in utero. The limbs so confined become rigidly fixed in the position imposed by external forces. Because extrinsically applied constraint is not uniform on the fetus, it results in marked asymmetry of limb involvement (Fig. 8).In contrast, intrinsically derived congenital contractures tend to be symmetrical in distribution Fig. 6. Cross-sectional histological appearance of the tibia1 di- (Fig. 7), because the conditions that produce them usuaphysis in two 37-week newborn infants: a)normal and b)with congenOverall movement Of the fetus 19831. ital myotonic dystrophy. Note the thinning of the cortical bone (dark) Skin appears to grow passively in response to shape and the scarcity of the osteoblastic cells in the periosteum. Masson, x 140. and size of the underlying tissue. Movement produces a relative redundancy in the skin overlying the joint, allowing unrestricted mobility [Smith, 19791. Lack of movement beginning early in gestation is associated with pterygium or webbing in the skin surrounding the affected joint [Davis and Kalousek, 1988; Hall et al., 19821. The study of Pena-Shokeir syndrome and lethal multiple pterygia has allowed elucidation of the consequences of early and late fetal reduction of movement [Opitz et al., 1985; Chen et al., 1983; 19841. The earlier the insult, the more severe the consequenceswith severe webbing and lethality. In addition, the skin lacks the normal wrinkles and creases that are a function of movement [Jones, 19831.Absence of normal skin creases has been noticed in most patients with FADS; however, it does not occur in 0s because immobilization comes later during gestation. Moreover, in 0s there is an overgrowth of skin due to constraint. The histological study

Fig. 7. Symmetric contractures in a newborn infant with spinal muscular atrophy. Also note the deformities of the upper limbs secondary to multiple fractures, and the severe micrognathia.

ment of joints, skin, umbilical cord, bones, lungs, and gut. Any situation which limits the intrauterine space or movement of the embryo or fetus may give rise to alterations in all these structures. Akinesia may be produced extrinsically by mechanical factors such as oligohydramnios, which produce fetal compression and hinder free movement of the fetus, or may be secondary to intrinsic lesions of the nervous or muscular systems which produce muscular weakness so severe as to paralyze the fetal spontaneous movements. Joint differentiation within the condensed mesenchyme of the developing bones proceeds to a considerable extent in the absence Of but cavity and fine Of the cartilaginous surfaces require normal mechanical action

Fig. 8. Congenital contractures in a newborn infant with 0s. Limb involvement is unusual and asymmetric. Also note the typical Potter face.

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of palmar skin in newborns with FADS showed poorly developed epidermal ridges and dermal papillae, loose connective tissue of the dermis with scarce collagen bundles and almost complete absence of palmar fascia (Fig. 9). Different observations suggest that umbilical cord length relates to stretch placed on the cord by developing embryo and fetus. During the first and second trimesters of pregnancy amniotic fluid volume increases more rapidly than fetal size and provides for increased space for movement and, thus, increases tension on the cord. The rate of cord growth decreases after the 28th to 30th week of gestation since the fetus occupies progressively more of the intrauterine cavity, leaving little space for effective trunk movement [Miller et al., 1981bl. Experimentally, restriction of fetal movements by oligohydramnios leads to short cord. The umbilical cords Fig. 10. Lateral roentgenogram of the lower limb from a 22-week were significantly short in proportion to the duration of infant with gastroschisis. This limb that was immobilized by a time-of-onset of the oligohydramnios [Moessinger e t al., newborn complete pterygium limb shows normal bone development. 19821. The shortest cords observed in human fetuses were found among the patients in whom there was evidence of early amnion rupture with presumed temporary oligohydramnios; lesser degrees of cord shortness were observed in fetuses with renal agenesis and oli- groups, because patients with 0s were immobilized only gohydramnios, for it is not until after the 6th to 7th in late gestation when morphogenesis is almost commonth that urine production begins to play a major role plete. However, these findings also might suggest that in the volume of amniotic fluid [Miller et al., 1981al. muscular strength is the main factor related to fetal Short umbilical cord together with polyhydramnios bone modeling irrespective of fetal movement. This sugwere noted in most human cases of FADS with available gestion is also supported by the observation of normal information. In rats, suppression of fetal movements by bone development in limbs affected by pterygium seccurarization also led to short cord irrespective of amni- ondary to early mechanical immobilization (Fig. 10). Normal fetal lung growth appears to depend on develotic fluid volume [Moessinger et al., 19821. Influence of intrauterine movement in bone mechani- opment of appropriate functional activity. Impairment cal use and bone modeling has not been well established. of lung movement secondary to compression of the thoAs we have previously stated, newborn infants with racic cage in 0s or to muscular weakness in FADS muscular weakness and intrauterine akinesia show a reduces the expansion of pulmonary cavity and lung will reduced bone mass [Rodriguez et al., 1988bl. In contrast, remain hypoplastic and immature [Thomas and Smith, fetuses with akinesia due to oligohydramnios, but pre- 1974; Hall, 19861. served muscle function, had normal bone mass [Palacios and Rodriguez, 19901. The timing, duration, and degree REFERENCES of reduced motility could be important factors to explain these differences observed between both akinetic Chen H, Blumberg B, Immken L, Lachman R, Rightmire D, Bachman

Fig. 9. a) Histological picture of the palmar skin in a normal newborn and b) in a newborn with FADS. Note the discrete thickening of the epidermis which is devoid of their usual ridges. The dermis shows loose connective tissue and poorly organized collagen bundles. The palmar fascia is very thin. Masson, x 35.

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