Arthrogryposis multiplex congenita refers to a syndrome, apparent at birth, characterized by fixed positions of multiple joints and an associated limitation of movement. The term arthrogryposis is derived from the Greek and literally means bent joint . Arthrogryposis multiplex congenita is a syndrome, not a disease entity, and is discussed in this section because, albeit frequently syndromic, it can also be a manifestation of many nonsyndromic fetal and neonatal disorders of the motor system. Indeed, disturbances at each of the major levels of the nervous system listed in Box 30.1 have been associated with arthrogryposis. Overall, arthrogryposis multiplex congenita is not rare; the incidence is generally approximately 1 in 3000 live births. The intrauterine frequency may be higher because multiple congenital contractures are common among spontaneous abortions and stillbirths.
Clinical Features
The essential clinical features of this syndrome are fixed position and limitation of movement of the affected joints. Distal joints are more frequently and more severely affected than proximal joints. Most common manifestations are talipes equinovarus and flexion deformities of the wrists ( Fig. 31.1 ), but involvement of more proximal joints is also frequent. Both the upper and lower extremities are most commonly affected; lower extremities only, slightly less commonly; and upper extremities only, least commonly. Webbing of affected joints, especially the knee, may be present, and congenital dislocations of the hips are also common.
Muscles are usually atrophic, thus giving a fusiform appearance to the joints. Hypotonia and weakness of the preserved movement occur. Tendon reflexes are depressed and often absent. Elicitation of tendon reflexes is often hindered by the joint contractures.
At least half of patients with arthrogryposis multiplex congenita exhibit congenital anomalies of other organs, craniofacial structures, other parts of the musculoskeletal system, or the central nervous system. Indeed, more than 150 syndromes are known in which arthrogryposis is a predominant sign. Some of the associated extraneural anomalies are relatively minor (e.g., clinodactyly and undescended testes), whereas others are lethal (e.g., pulmonary hypoplasia and renal agenesis). Certain of the abnormalities of the jaw (micrognathia), tongue, and palate may underlie the approximately 60% incidence of subsequent feeding disturbances. Some of the constellations of anomalies (severe arthrogryposis, camptodactyly, pulmonary hypoplasia) have been designated eponymically (e.g., Pena-Shokeir phenotype). Banker has emphasized particularly the strong relation among the congenital anomalies usually observed with arthrogryposis multiplex congenita and their nearly consistent pathogenetic basis as a disturbance of intrauterine movement rather than a primary disturbance of development ( Table 31.1 ).
| ANOMALY a | LIKELY PATHOGENESIS |
|---|---|
| Micrognathia | Impaired facial and masticatory movements |
| Retrognathia | Impaired masticatory movements |
| High-arched or cleft palate | Impaired tongue movement and micrognathia |
| Wide flat nose | Impaired head and facial movements (?) |
| Low-set ears | Impaired head movements (?) |
| Short neck | Impaired neck movements |
| Pulmonary hypoplasia | Impaired breathing movements |
| Clinodactyly, camptodactyly | Impaired finger movements |
| Polyhydramnios | Impaired swallowing |
a Anomalies present in approximately 10%–40% cases of arthrogryposis multiplex congenita studied at autopsy by Banker BQ. Arthrogryposis multiplex congenita: spectrum of pathologic changes. Hum Pathol . 1986;17:656–672.
Pathogenesis
Relation to Impaired Intrauterine Motility
In arthrogryposis, the joints themselves are usually normal, but the lack of fetal movements results in the development of extra connective tissue around the joints. Thus the development of fixed joints with limitation of movement in most cases is secondary to impaired intrauterine motility, almost invariably the result of muscle weakness . The postural deformities are caused by contractures of muscle with fibrous (not bony) ankylosis of the joints. The time of onset of the paralytic process determines in part the severity of the arthrogryposis; onset in the first trimester may be associated with pterygium formation at the neck and elbows. The positions of the deformities are related in large part to muscle imbalance around the joints involved; neuropathological data support this notion. The intrauterine position of the fetus may also play a role in determining the configuration of the deformities.
The basic concept that impaired motility secondary to muscle weakness is the critical common denominator is supported by experiments with developing chicks and with fetal rats, in which infusion of the neuromuscular blocker curare either into incubating eggs or into the fetal animals resulted in fixed postures of the neck and limbs that corresponded to intrauterine position. Pulmonary hypoplasia, micrognathia, polyhydramnios, short umbilical cord, and fetal growth retardation were documented in the fetal rats as in the human —findings further supporting the notion that intrauterine impairments of movement underlie most of the congenital anomalies often observed with arthrogryposis (see Table 31.1 ). An illustrative example is the Pena-Shokeir syndrome ( Box 31.1 ), characterized by (1) arthrogryposis, (2) polyhydramnios, (3) pulmonary hypoplasia, (4) short umbilical cord, (5) intrauterine growth restriction, (6) osteoporosis, and (7) craniofacial abnormalities. Pena-Shokeir syndrome is lethal because, as a result of the fetal akinesia, the lungs are hypoplastic, thus leading to respiratory failure and death after birth. However, because the causes of the Pena-Shokeir phenotype are multiple, the designation of such a syndrome appears to serve little clear purpose.
Craniofacial abnormalities (hypertelorism, low-set malformed ears, depressed tip of the nose)
Arthrogryposis (hip and ankle ankyloses, club feet, camptodactyly)
Pulmonary hypoplasia
Polyhydramnios
Short umbilical cord
Intrauterine growth restriction
Osteoporosis
Other supporting clinical data linking reduced fetal movement to arthrogryposis include the usual association of the disorder with neuromuscular diseases of intrauterine onset (see following discussion) as well as the occurrence of the disorder after the administration of drugs to a pregnant woman that cause diminished motor activity. Disturbance of intrauterine movement is also presumed to be the cause of those unusual cases of arthrogryposis multiplex congenita occurring with intrauterine mechanical restrictions, such as amniotic band, small or malformed maternal pelvis or uterus, or oligohydramnios.
Two Major Subgroups—Genetic and Nongenetic
Arthrogryposis multiplex congenita can be subdivided into two major subgroups, genetic and nongenetic . The vast majority of the disorders have a genetic basis . Genetic disorders include single gene defects (autosomal recessive, autosomal dominant, and X-linked recessive), chromosomal disorders (e.g., trisomy 18, chromosomal mosaicism), and mitochondrial defects. Autosomal recessive disorders are frequently associated with central nervous system dysfunction and severe fetal akinesia sequence (see earlier), whereas autosomal dominant inheritance is frequent in the distal arthrogryposes. Amyoplasia appears to be predominantly sporadic (see later). The sites of involvement of the motor system among familial cases of arthrogryposis are diverse, although the lower motor neuron is most commonly affected. a
a References .
Distal Arthrogryposes
The distal arthrogryposes are a heterogeneous group of genetic disorders in which the joint contractures primarily involve the distal limbs ( Table 31.2 ). Distal arthrogryposis type 1 is an autosomal condition due to mutations in various sarcolemmal proteins (troponin I [TNNI2] gene; troponin T3, fast skeletal type [TNNT3] gene; myosin binding protein C, slow type [MYBPC1] gene; and tropomyosin 2, beta [TPM2] gene). Common clinical features include medially overlapping fingers, clenched fists, ulnar deviation of the fingers when extended, contractures of the fingers (camptodactyly), and foot contractures ( Fig. 31.2 ). These deformities appear to be due to misplaced tendons. Mutation in piezo-type mechanosensitive ion channel component 2 (PIEZO2) gene causes distal arthrogryposis type 3 (Gordon syndrome), an autosomal dominant condition characterized by distal arthrogryposes of hands and feet, short stature, and cleft palate. Distal arthrogryposis type 5 is heterogeneous and can have both dominant and recessive inheritance. In addition to arthrogryposis, these patients have ocular abnormalities (ptosis, ophthalmoplegia, and/or strabismus). Some may have pulmonary hypertension as a result of restrictive lung disease. Distal arthrogryposis type 6 is similar to types 3 and 4 but very rare and associated with deafness. It is caused by a mutation of the fibroblast growth factor receptor 3 (FGFR3) gene. Distal arthrogryposis type 7 is characterized by trismus, pseudocamptodactyly, palmar flexion at the wrists, extension at the metacarpophalangeal joints, short stature, and flexion contractures at the knees. It is caused by a mutation of the myosin heavy chain 8 (MHY8) gene. Distal arthrogryposis type 8 is described as autosomal dominant multiple pterygium syndrome. Distal arthrogryposis type 9 (Beals syndrome) causes contractural arachnodactyly (see later).
| BAMSHAD CLASSIFICATION | CLINICAL MANIFESTATIONS | KNOWN GENE MUTATIONS |
| Type 1 | Medially overlapping fingers, clenched fists, ulnar deviation of the fingers when extended, camptodactyly, foot contractures | TPM2, MYBPC1, TNN12, TNNT3 |
| Type 2A (Freeman-Sheldon syndrome) | Whistling face syndrome (see later) | MYH3 |
| Type 2B (Sheldon-Hall syndrome) | Clinical features of type 1 and some features of type 2A | TNNT3, TNN12, MYH3, TPM2 |
| Type 3 (Gordon syndrome) | Autosomal dominant condition; distal arthrogryposes of hands and feet, short stature, cleft palate | PIEZO2 |
| Type 4 | Contractures with severe scoliosis | |
| Type 5 | Dominant and recessive inheritance; arthrogryposis, ocular abnormalities (ptosis, ophthalmoplegia, and/or strabismus), occasional pulmonary hypertension due to restrictive lung disease | PIEZO2 (AD) ECEL1 (AR) |
| Type 6 | Deafness, camptodactyly | FGFR3 |
| Type 7 | Trismus, pseudocamptodactyly | MYH8 |
| Type 8 | Autosomal dominant multiple pterygium syndrome | |
| Type 9 (Beals syndrome) | Contractural arachnodactyly, phenotypically resembles Marfan syndrome but without cardiovascular and ocular abnormalities | Fibrillin 2 |
Pathology
The basis for the weakness that leads to arthrogryposis multiplex congenita can reside at every major level of the motor system. However, many cases of arthrogryposis, such as those related to mutations in connective tissue genes, do not have a neural basis; thus weakness is not always the mechanism for restricted joint movements ( Table 31.3 ).
| SITE OF MAJOR PATHOLOGICAL FINDINGS | DISORDER |
|---|---|
| Cerebrum–brain stem | Microcephaly; migrational disorders: lissencephaly-pachygyria (e.g., Zellweger syndrome), schizencephaly, polymicrogyria, agenesis of corpus callosum; fetal alcohol syndrome; cytomegalovirus infection; pontocerebellar hypoplasia (type I); dentato-olivary dysplasia; leptomeningeal angiomatosis; encephaloclastic processes: neuronal destruction, porencephalies, hydranencephaly, multicystic encephalomalacia; hydrocephalus |
| Anterior horn cell | Developmental agenesis–hypoplasia–dysgenesis (amyoplasia congenita); destructive disorders (apparent intrauterine ischemic events); degenerative disorders (severe Werdnig-Hoffmann disease [SMA type 0 or IA], lethal congenital contracture syndrome, spinal muscular atrophy with pontocerebellar hypoplasia, spinal muscular atrophy with respiratory distress, X-linked infantile spinal muscular atrophy, early-onset non-5q spinal muscular atrophy); Möbius syndrome; cervical spinal atrophy; lumbar spinal atrophy; lumbosacral meningomyelocele; sacral agenesis; other |
| Peripheral nerve or root | Hypomyelinative polyneuropathy; axonal polyneuropathy; neurofibromatosis |
| Neuromuscular junction | Infant of myasthenic mother; congenital myasthenic syndromes; multiple pterygium syndrome (Escobar type); infant of mother with multiple sclerosis (?) |
| Muscle | Congenital muscular dystrophy (merosin-positive and merosin-negative); congenital myotonic dystrophy; myotubular myopathy; central core disease; nemaline myopathy; congenital myopathy due to sodium channel mutation; congenital polymyositis; congenital fiber-type disproportion; glycogen storage myopathy (muscle phosphorylase deficiency, phosphofructokinase deficiency); mitochondrial myopathy; Freeman-Sheldon syndrome |
| Primary disorder of joint or connective tissue | Marfan syndrome; contractural arachnodactyly; other disorders of connective tissue; intrauterine periarticular inflammation |
| Intrauterine mechanical obstruction | Uterine abnormality; amniotic bands; oligohydramnios; twin pregnancy; extrauterine pregnancy |
Cerebrum or Brain Stem
Major intrauterine disorders of the cerebrum, brain stem, or both have resulted in arthrogryposis multiplex congenita (see Table 31.3 ). a
a References .
The proportion of cases with exclusive involvement of cerebrum or brain stem (and not also of the spinal cord) is approximately 10% to 35%. When the spinal cord is evaluated, particularly postmortem but also by electromyography (EMG) in vivo, concomitant involvement of anterior horn cells is often discovered to accompany the more conspicuous central disorders. bb References .
This combination of findings is apparent particularly with pontocerebellar hypoplasia type I, characterized by atrophy of neurons of the pons, cerebellum, and anterior horn cells (see Chapter 32 ). Although dysgenetic anomalies account for the majority of this category of cases, encephaloclastic lesions (e.g., ischemic or infectious in origin) and intrauterine hydrocephalus have also been causative. Severity of the disturbance of the motor system has been marked in the infants with central disorders; thus, not unexpectedly (see earlier discussion), the resulting severe arthrogryposis with pulmonary hypoplasia has often led to the designation of Pena-Shokeir syndrome in this group. In a series of 15 infants with arthrogryposis multiplex congenita and ventilator dependence in the neonatal period, 9 had severe disease of cerebrum, brain stem, or both. In a carefully studied series of 68 infants identified retrospectively, 23 (34%) had cerebral lesions.Anterior Horn Cell
Disease of the anterior horn cell has been demonstrated many times (see Table 31.3 ); this may be the most common single site of disease in arthrogryposis multiplex congenita (Jones HR, personal communication, 1993). a
a References .
This diverse group of disorders appears to account for at least 20% to 25% of cases of arthrogryposis multiplex congenita (Jones HR, personal communication, 1993). The proportion increases considerably when anterior horn cell disturbances occurring in association with abnormalities at higher levels of the central nervous system are included. The basic abnormalities of anterior horn cell are dysgenetic, destructive, or degenerative. Dysgenetic abnormalities , which are associated with disturbances of number or migration of neurons of the anterior horns, predominate ( Fig. 31.3 ). A likely example of this category is amyoplasia congenita (see later). Destructive disorders consist primarily of apparent intrauterine ischemic events. The association of arthrogryposis with maternal misoprostol exposure (oral or vaginal) may relate to ischemic injury to anterior horn cells. Degenerative disorders include anterior horn cell degenerations with anatomical features often similar to those of Werdnig-Hoffmann disease (spinal muscular atrophy [SMA] type 1) (see Chapter 32 ). However, with one exception (SMA type 0 or 1A) (see Chapter 32 ), when involvement of chromosome 5q in arthrogryposis multiplex congenita has been sought specifically, no relationship with the gene locus of SMA has been found (see later). aa References .
Autosomal recessive, X-linked recessive, or autosomal dominant syndromes involving the anterior horn cells (non-5q SMA) have been identified with arthrogryposis ( Table 31.4 ). a
a References .
Lethal congenital contracture syndrome (LCCS) is an autosomal recessive form of arthrogryposis associated with intrauterine hydrops, growth retardation, and fetal death; severe neuronal loss in the anterior horns and extreme atrophy of skeletal muscle are present. LCCS is genetically heterogeneous with mutations in six genes identified to date (see Table 31.4 ), each of which has a role in the innervation of the contractile apparatus of the skeletal muscles. LCCS1 is caused by mutations in GLE1 , an RNA export mediator (GLE1) gene thought to be involved in the survival of the anterior horn cell neurons. LCCS2 is caused by a mutation of erb-b2 receptor tyrosine kinase 3 (ERBB3) gene, and LCCS3, by a mutation of phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C) gene. Both of these genes are involved in the synthesis of inositol hexaphosphate, which binds with GLE1. LCCS4 is caused by a mutation of the myosin binding protein C, slow type (MYBPC1) gene, and LCCS5, caused by a mutation of the dynamin 2 (DNM2) gene. LCCS6 is due to a mutation of the zinc finger and BTB domain containing the 42 (ZBTB42) gene. Spinal muscular atrophy with pontocerebellar hypoplasia , also known as pontocerebellar hypoplasia type 1 [PCH1]), is caused by a mutation of either the vaccinia-related kinase 1 (VRK1) gene (PCA 1A) or exosome component 3 (EXOSC3) gene (PCA 1B) (see Table 31.4 ). Both genetic forms are characterized by pontocerebellar hypoplasia, infantile spinal muscular atrophy, microcephaly, mental retardation, and early death. An autosomal recessive disorder with severe weakness and hypotonia as well as mild contractures, it is also associated with diaphragmatic paralysis, the need for mechanical ventilation, and a generally lethal course ( often designated SMARD1, for spinal muscular atrophy with respiratory distress ) (see Table 31.4 ). The disorder is genetically distinct from Werdnig-Hoffman disease and is caused by mutation of the gene encoding the immunoglobulin µ-binding protein 2 (IGHMBP2) gene (see Chapter 32 ).| TYPE | CLINICAL MANIFESTATIONS | KNOWN GENE MUTATIONS |
|---|---|---|
| Lethal congenital contracture syndrome (LCCS) | Autosomal recessive, intrauterine hydrops, growth retardation, fetal death | Type 1: GLE1 Type 2: ERBB3 Type 3: PIP5K1C Type 4: MYBPC1 Type 5: DNM2 Type 6: ZBTB42 |
| Spinal muscular atrophy with pontocerebellar hypoplasia (PCH) | Pontocerebellar hypoplasia, infantile spinal muscular atrophy, microcephaly, mental retardation, early death | Type 1A: VRK1 Type 1B: EXOSC3 |
| Spinal muscular atrophy with respiratory distress (SMARD1) | Mild contractures, diaphragmatic paralysis, lethal course | IGHMBP2 |
| X-linked infantile spinal muscular atrophy (SMAX2) | Arthrogryposis, facial weakness, cryptorchidism, bone fractures | UBA1 |
| Early onset non-5q spinal muscular atrophy | Autosomal dominant, primary involvement of the lower limbs | Scapuloperoneal spinal muscular atrophy: TRPV4 . Lower extremity–predominant spinal muscular atrophy-1: DYNC1H . Lower extremity–predominant spinal muscular atrophy-2: BICD2 . |
A severe form of infantile spinal muscular atrophy inherited as an X-linked recessive disorder (SMAX2) is caused by a mutation of the ubiquitin-like modifier activating enzyme 1 (UBA1) gene (see Table 31.4 ). Clinical manifestations include severe hypotonia, areflexia, arthrogryposis, facial weakness, cryptorchidism, and frequently bone fractures.
A group of early-onset non-5q spinal muscular atrophy disorders with primary involvement of the lower limbs have autosomal dominant inheritance (see Table 31.4 ). These are scapuloperoneal spinal muscular atrophy (due to mutation of the transient receptor potential cation channel, subfamily V, member 4 TRPV4 gene), lower extremity–predominant spinal muscular atrophy-1 (due to mutation of the dynein cytoplasmic 1 heavy chain 1 DYNC1H1 gene), and lower extremity–predominant spinal muscular atrophy-2 (due to mutation of the bicaudal D homolog 2 BICD2 gene).
The clinical distinction of the three major categories of anterior horn cell involvement (dysgenetic, destructive, or degenerative) in an infant with arthrogryposis is difficult. The findings of neurological deterioration, fasciculations, and grouped atrophy suggest active degenerative disease rather than a dysgenetic or a completed destructive process. Among probable dysgenetic types , the relatively common clinical entity termed amyoplasia or amyoplasia congenita is perhaps the prototype. This disorder has been said to account for as many as one third of all newborns with arthrogryposis and occurs once in approximately 10,000 live births. In a large series of infants with arthrogryposis, of 16 with anterior horn cell involvement, 14 had amyoplasia. Clinically, these infants are distinctive and exhibit symmetrical involvement of all four limbs, with the upper extremities characteristically in a “waiter’s tip” position ( Fig. 31.4 ). The latter relates to internally rotated, adducted shoulders, extended elbows, pronated forearms, and flexed wrists and fingers. Talipes equinovarus is nearly invariable. Common associations are facial hemangioma as well as abdominal wall and digital defects. The EMG shows a reduced number of motor units but no fasciculations. Muscle biopsy (see later) is nondiagnostic, with affected muscles replaced by fatty and fibrous tissue.
Among the degenerative disorders , the clinical features of various principal genetic disorders involving the anterior horn cell (and genetically distinct from Werdnig-Hoffman disease) were described earlier in relation to the pathological features (see the section on pathology ). Particular note should be made of the relative lack of arthrogryposis in typical Werdnig – Hoffman disease (SMA type 1). Thus only approximately 10% to 20% of infants with typical chromosome 5q–linked Werdnig-Hoffmann disease exhibit contractures, which are mild and usually restricted to distal limbs. In a series of 68 infants with overt arthrogryposis, only 1 infant had Werdnig-Hoffman disease. The reason for the relatively low incidence of joint deformity in such a severe intrauterine disorder of movement is not known definitely, but it may relate to the uniformity of the disturbance of anterior horn cells, unlike the relative preservation of some anterior horn cells in dysgenetic or destructive disorders, and hence the possibility of contracture formation. The important clinical point is that severe generalized arthrogryposis multiplex congenita, even related to anterior horn cell degeneration, is extremely unlikely to represent typical chromosome 5q–linked (survival motor neuron) spinal muscular atrophy (see Chapter 32 ). An exception , as noted earlier, is the small group of very severe chromosomal 5q–linked cases of prenatal onset (SMA type 0 or 1a) described in Chapter 32 .
As many as one third to one half of infants with Möbius syndrome may exhibit arthrogryposis, a finding reflecting involvement of the lower motor neuron in the spinal cord as well as in the brain stem in this disorder. a
a References .
Fixed contractures of the lower limbs are frequent accompaniments of disorders of neural tube development (e.g., lumbosacral meningomyelocele and sacral agenesis). Isolated cervical or lumbar arthrogryposis secondary to nonprogressive anterior horn cell involvement, not defined more clearly, has also been reported. bb References .
Peripheral Nerve
Disorder of the peripheral nerve has been shown to result in arthrogryposis multiplex congenita ( Fig. 31.5 and see Table 31.3 ). c
c References .
However, peripheral neuropathy is relatively rare as the basis for arthrogryposis; in the series of Banker, only 2 of 96 patients with arthrogryposis had peripheral nerve disease. In a series of 15 ventilator-dependent newborns with arthrogryposis, 1 infant had congenital (hypomyelinative) neuropathy. In a well-studied retrospective series of 68 infants, only 1 infant had (hypomyelinative) neuropathy. In virtually all reported cases, the neuropathy was hypomyelinative (see Chapter 32 ).
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