선천성 관절 만곡증 (논문)

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제목 : 선천성 관절 만곡증(Arthrogryposis Multiplex Congenita)
출처 : 국제소아과학(International Pediatrics), Volume 15, Number 4
저자 : Israel Alfonso, MD; Oscar Papazian, MD; Julio Cesar Paez,
MD; John A. I. Grossman, MD
유형 : Review Article
주소: http://www.int-pediatrics.org/newip/volumes/Volume%2015-4/Review/Alfonso/alfonso.htm

요약 :
선천성 관절 만곡증(이하 "만곡증"으로 약함)은 은 출생시 사지에 산발적으로 하나 이상의 관절이 운동하지 않는 증상을 말한다. 관절이 일정 각도로 굳게 되는 것은 태아의 운동능력이 부분적으로 손상되었기 때문이다. 만곡증(AMC)은 신경학적 원인일 수도 아닐 수도 있다. 신경학적으로 관련된 만곡증은 다음과 같은 증상을 포함한다: trisomy 13 and 18, Smith-Lemli-Opitz syndrome, Zellweger syndrome, Walker-Warburg syndrome, Marden-Walker syndrome, spinal cord injury, amyoplasia congenita, infantile spinal muscular atrophy, infantile neuronal degeneration, focal infantile spinal muscular atrophy, Moebious syndrome, congenital hypomyelinating neuropathy, transient congenital myasthenia gravis, infant of mother with multiple sclerosis, congenital myotonic dystrophy, congenital muscular dystrophy myotubular myopathy, and craniocarpotarsal dysplasia. 비 신경학적 원인에 의해 발생하는 만곡증은 연골에 발생하는 이상과 비활성 운동이다. 비 신경학적 원인에 의한 만곡증은 대개 양수과소증에 의할 수 있으며 과 Non-neurological causes of AMC are cartilaginous abnormalities and physical constraint to movement. Neonates with non-neurological causes of AMC usually have signs of oligohydramnios sequence, crumple ears, thin or hyperextensible skin, or pterygium. Neonates with AMC due to cartilaginous abnormalities usually have one of the following syndromes: Beal syndrome, Antley-Bixer syndrome or a condition referred to as distal arthrogryposis. Int Pediatr. 2000;15(4):197-204.

Key words: Arthrogryposis multiplex congenita

Introduction

Arthrogryposis refers to a joint that is in a fixed position. Arthrogryposis multiplex congenita is diagnosed when two or more joints in more than one limb are fixed from birth (Fig 1). A joint becomes fixed in a given position because of unevenly impaired joint motility. Unevenly impaired joint motility results from segmental muscle weakness or hypotonia, or from a sustained asymmetrical posture. Segmental muscle weakness or hypotonia is due to an imbalance between agonistic and antagonistic muscles. Sustained asymmetrical posture results from movement constraints due to reduced uterine volume or when thick skin bands prevent joint movement. Arthrogryposis multiplex congenita (AMC) may be caused by neurological and non-neurological causes. Non-neurological causes of AMC are cartilaginous abnormalities and physical constraint to movement. Neurological causes of AMC include central and peripheral nervous systems abnormalities (Table 1).1-5

Cartilaginous Abnormalities

Cartilaginous abnormalities should be consider the cause of AMC in neonates that are longer that expected for their gestational age, and those with hyperextensible and transparent skin, blue sclera, abnormal ear lobe shape and craniosynostosis.1,2 Intelligence is usually normal in patients with AMC due to cartilaginous abnormalities. Cartilaginous abnormalities produce joint hyperelasticity leading to a symmetrical weakness that when combined with a physical constraint produces arthrogryposis. Arthrogryposis multiplex congenita due to cartilaginous abnormalities improves with time. Neonates with AMC due to cartilaginous abnormalities usually have one of the following syndromes: Beal syndrome, Antley-Bixer syndrome or a condition referred to as distal arthrogryposis.

Beal Syndrome

The characteristic findings of Beal syndrome are: crumpled ears, long slim limbs and fingers, frontal bossing and short neck. They look like patients with Marfan syndrome with arthrogryposis and crumple ears. Arthrogryposis may affect any joint. Beal syndrome is linked to a fibrillin locus on chromosome 5 q 23-31. Beal syndrome is an autosomal dominant disorder.2,5

Antley-Bixer Syndrome

Neonates with Antley-Bixer syndrome have very distinctive facial features. Crouzon syndrome-like appearance and midfacial hypoplasia dominate the facial features(Fig 2). Midfacial hypoplasia manifests by depressed nasal bridge and choanal atresia. Neonates with choanal atresia may present with apnea and require intubation shortly after birth because neonates are obligated nasal breathers. In addition to the facial features patients with Antley-Bixer syndrome often have radio-humeral synostosis, femoral bowing and sacral remnant. Arthrogryposis usually involves the elbows in the upper extremities (Fig 3). There is no confirm‎atory test for Antley-Bixer syndrome. Antley-Bixer syndrome is probably an autosomal recessive disorder.2,5

Distal Arthrogryposis Syndrome

Neonates with distal arthrogryposis syndrome usually do not have any of the characteristic findings that are usually seen in other neonates with AMC due to cartilaginous abnormalities. In a few cases cleft palate, cleft lip, small tongue, trismus, ptosis, and mild epicanthal folds have been described. Facial features are usually normal. The arthrogryposis involves the hands and, to a lesser extent, the feet. Shoulders, elbows, hips and knees are seldom involved. The cartilaginous abnormalities in distal arthrogryposis syndrome are probably restricted to the tendons. Distal arthrogryposis syndrome is an autosomal dominant condition with variable expression‎. The gene for distal arthrogryposis is in the pericentromeric region of chromosome. 2,5,6

Physical Constraint to Movement

Arthrogryposis due to physical constraint occurs when the capacity of the uterus is restricted or when thick cutaneous bands restrict the movement of a joint. The capacity of the uterus may be restricted due to oligohydramnios, anatomic malformations of the uterus, amniotic bands, or uterine tumors. Thick cutaneous bands restricting joint movements occur in Escobar syndrome.4,5

Oligohydramnios Sequence

Oligohydramnios is the most frequent cause of AMC due to physical constraint. A reduce uterine capacity places the fetus at risk for multiple anomalies, in addition to arthrogryposis. The constellation of findings that occur as the result from decreased amniotic fluid is denominated oligohydramnios sequence. The characteristics of oligohydramnios sequence are wrinkled skin, skin fold that extends from the inner canthus to the upper cheek, squashed nose, large-low set and posteriorly rotated ears, short neck and large wrinkled hands. Arthrogryposis usually involves the knees and feet. Oligohydramnios sequence is a clinical diagnosis. The diagnosis is established by the clinical findings. Oligohydramnios is usually due to bilateral renal agenesis.5

Escobar Syndrome

Thick skin folds that produce an usual appearance and keep the joints in a fixed position characterize multiple pterygia syndrome or Escobar syndrome. The skin folds are usually in the neck, axilla, antecubital, popliteal, and digital areas. The thick skin folds reduce joint motility in utero and lead to AMC. Arthrogryposis is especially marked in the hands. Intelligence is normal. Scoliosis often develops by 5 years of age. Escobar syndrome is an autosomal recessive condition. Surgical treatment of the pterygium may be necessary.2,5

Neurological Abnormalities

Neurological disorder should be suspected in any neonate without signs of cartilaginous abnormalities, pterygium or signs suggestive of oligohydramnios sequence. Diseases at the level of the brain, cerebellum, brainstem, spinal cord, motor neuron cell, nerve, myoneural junction and muscle may cause arthrogryposis.

Arthrogryposis due to neurological abnormalities may be symmetrical or asymmetrical, generalized or partial, distal or proximal. The distribution of the arthrogryposis reflects the localization of the neurological involvement. Symmetrical arthrogryposis may occur with brain, brainstem, cerebellar or spinal cord lesions, or with motor neuron, nerve, myoneural junction or muscle diseases. Asymmetrical arthrogryposis, especially with a hemibody involvement suggests unilateral brain, brainstem, cerebellar or spinal lesions. Involvement of the lower extremities only may occur with parasagittal brain lesion, peri-lateral ventricular lesions (the corticospinal fibers destined to innervate the lower extremities are in close proximity to the lateral ventricles) or below the cervical enlargement in the spinal cord. Distal arthrogryposis usually occurs with brain, nerve, myoneural junction and muscle abnormalities. Proximal arthrogryposis occurs with motor neuron disease.

Brain, Cerebellum and Brainstem

The possibility of brain, cerebellum and brainstem abnormalities should be considered in any child with dysmorphic facial features, cranial vault volume or shape abnormalities decrease level of alertness, brainstem release phenomena and seizures. EEG and MRI usually confirm‎ brain, brainstem and cerebellar abnormalities.

Trisomy 18 Syndrome

Trisomy 18 syndrome is characterized by having a narrow bifrontal head diameter with a prominent occiput, epicanthal folds, small mouth, a short upper lip, micrognathia, low-set dysplastic ears, shield chest, short sternum, limited hip abduction, and hand and feet arthrogryposis. The position of the hands is typical in most cases, but not specific since it occurs with other disorders. The hand is clenched with the middle finger partially or complete under the index and fourth finger. Feet anomalies consist of talipes calcaneovalgus, short dorsiflexed big hallux, and prominent heels characterize the feet anomalies. The most frequent central nervous system anomalies are abnormal myelinization, microgyria, cerebellar hypoplasia, agenesis of the corpus callosum, hydrocephalus, and meningomyelocele. Neonates with trisomy 18 syndrome often die during the neonatal period because of apnea. If they survive, they may require respiratory support and nasogastric feedings.

Most neonates with trisomy 18 syndrome phenotype have full trisomy. Full trisomy 18 occurs more frequently in neonates born to older mothers. The risk of recurrence of a trisomy is probably less than 1 percent. Translocation of chromosome 18 material produces a phenotype similar to the trisomy 18. The parents of an infant with translocation should have chromosome studies because they may be asymptomatic carriers of a balance translocation. The chances of recurrence is higher if either parents are carriers of a balance translocation.5

Trisomy 13 Syndrome

Trisomy 13 syndrome is characterized by microcephaly, posterior scalp lesions, microphthalmia, cleft lip, coloboma of the iris, low-set dysplastic ears, deafness, cleft palate, polydactyly, prominent heels, cryptorchidism, abnormal scrotum and distal arthrogryposis. The position of the hands is often similar to the position of the hands in trisomy 18. The most frequent central nervous system anomaly is holoprosencephaly. Trisomy 13 may occur in full and with translocation. Full trisomy 13 occurs more often in neonates born to older mothers. Translocation of chromosome 13 material produces a phenotype similar to the trisomy 13. The parents of an infant with translocation should have chromosomal studies because they may be asymptomatic carriers of a balance translocation. The chance of recurrence is higher if either parent is a carrier of a balance translocation.5

Smith-Lemli-Opitz Syndrome

Smith-Lemli-Opitz syndrome is characterized by microcephaly with a narrow frontal area, slanted or low-set ears, ptosis, anteverted nostrils, cryptorchidism, and hypospadias. The most important distinguishing features in males are cryptorchidism and hypospadias. The diagnosis of this syndrome in females is very difficult because the most characteristic features of this syndrome (cryptorchidism and hypospadia) are not present. Brain and brainstem malformations may be present. Arthrogryposis is more prominent in the hands. Smith-Lemli-Opitz syndrome is due to a severe defect in cholesterol biosynthesis. The defective enzyme is 7-dehydrocholesterol reductase. This defect leads to a high level of the cholesterol precursor 7-dehydrocholesterol and low cholesterol levels. The low cholesterol levels lead to abnormalities of mitochondrial function, hormone synthesis, myelination or bile acid and vitamin D metabolisms. Measuring 7-dehydrocholesterol using chromatographic assay can diagnose smith-Lemli-Opitz syndrome prenatally or postnatally. Most patients with Smith-Lemli-Opitz syndrome die in the neonatal period. Survivors are severely mentally retarded. Smith-Lemli-Opitz syndrome is an autosomal recessive condition.5

Zellweger Syndrome

Severe hypotonia, brachycephaly, widely open fontanels and sutures, hepatomegaly, hypospadias and cryptorchidism in males and clitoral hypertrophy in females characterize Zellweger syndrome. Arthrogryposis is usually distal. Patients with Zellweger syndrome have a prominent forehead, flat occiput, round face, micrognathia, anteverted nares, low-set dysplastic ears, hypertelorism, puffy eyelids, epicanthal folds, glaucoma, cataracts, corneal clouding, and Brushfield spots. Hepatomegaly may not be present at birth but develops during the first month of life. Bone radiograph may reveal calcified stippling of the patella and acetabulum. Magnetic resonance imaging of the brain may show: (1) hypomyelination, (2) perisylvian and perirolandic cortical malformation, and (3) germinolytic cysts.7 Zellweger syndrome is associated with increased serum concentrations of very-long-chain fatty acids in plasma. The diagnosis is established by fibroblast culture or liver biopsy. Their cells do not show peroxisomes when stained for peroxisomal enzymes. But electromicroscopy of the same tissue shows that the peroxisomal membranes are present. This peculiar finding is referred to as "ghost peroxisomes" because the membrane is present but the enzymes are not.7 Genetic defects at 7q11.23 and 1p22-p21 are associated with Zellweger syndrome. Most patients with Zellweger syndrome die during the first year of life. Survivors are mentally retarded Zellweger syndrome has an autosomal recessive inheritance. 5,7,8

Walker-Warburg Syndrome

The acronym HARD +/- E has being used for Walker-Warburg syndrome. The acronym refers to the first letter of the major features of this condition: hydrocephalus, agyria (cerebral and cerebellar), retinal dysplasia, and occasionally encephalocele. In addition to retinal dysplasia, other ocular abnormalities seen in patients with Walker-Warburg syndrome include vitreous abnormalities, retinal detachment, glaucoma, cataracts, and corneal opacities. Neonates with Walker-Warburg syndrome are hypotonic and usually have seizures. Arthrogryposis is usually distal. The brain abnormalities in Walker-Warburg syndrome are probably due to a defect in the external basal lamina of the brain. The external basal lamina of the brain is the boundary that stops the neuronal migrational process. Failure of the external basal lamina to develop causes the neurons to cross over sulci and into the meninges creating a flat brain and engulfing the meninges. Walker-Warburg syndrome is a familial disorder. The familial incidence is most likely due to an autosomal recessive inheritance, but the possibility of a persistent intrauterine viral infection affecting several members in one family has been considered. MRI diagnoses Walker-Warburg syndrome. The MRI shows smooth cerebral and cerebellar surfaces, large lateral ventricles in relation to cerebral mass, and absence of cerebellar vermis. 5,9

Marden-Walker Syndrome

A fixed facial expression‎, blepharophimosis, micrognathia and multiple joint contractors from birth characterize Marden-Walker syndrome. Brain and posterior fossa malformations are frequent. Dandy-Walker abnormality and brainstem hypoplasia may occur. It is an autosomal recessive condition.5

Spinal Cord Injury

The possibility of spinal cord injury producing arthrogryposis should be suspected in any newborn with arthrogryposis of the limbs without jaw involvement and in those neonates with arthrogryposis limited to the lower extremities. Spinal MRI confirm‎s the presence of spinal cord involvement.

Arthrogryposis due to spinal cord involvement is usually due to a development problem. Traumatic spine cord injury usually occurs during delivery, therefore does not produce AMC. Spinal cord arthrogryposis should be suspected if no cause for AMC is present and there are no signs of brain or brainstem involvement. Arthrogryposis multiplex congenita of the lower extremities has been reported with lumbosacral meningocele and with sacral agenesis.10,11

Lower Motor Neuron

The possibility of arthrogryposis due to lower motor neuron involvement should be suspected in all neonates with a neurogenic arthrogryposis without evidence of brain involvement. Several lower motor neuron conditions produce arthrogryposis. They include infantile spinal muscular atrophy, infantile neuronal degeneration, focal spinal muscular atrophy, Moebius syndrome and amyoplasia congenita.

Amyoplasia Congenita

Neonates with amyoplasia congenita are usually full term and of average weight. They appear healthy. They may have a round face, short upturned nostrils, and micrognathia. A midface capillary hemangioma is often present. Neonates with amyoplasia congenita usually have multiple symmetrical fixed joints with typical positions and distribution. The upper extremity position is most characteristic (Fig 4). The shoulders are adducted and medially rotated, elbows are extended or flexed, forearm is pronated, wrists are flexed and have ulnar deviation, and the fingers are flexed. The upper extremity posture, except in neonates with flexed elbows, resembles that which occurs in patients with brachial plexus palsy involving the C5-C6 fibers in the upper trunk. The lower extremities are less frequently involved. When they are involved, the hips are flexed, knees are flexed or extended, and the feet are in equinovarus or calcaneovalgus positions. The limbs are cylindrical and fingers are slender. Cutaneous defects, usually small and round, are present in the proximity of some of the affected joints. Patients with amyoplasia congenita do not have evidence of cardiac, or genitourinary tract abnormality. Bowel atresia and gastroschisis have been reported. The cause of amyoplasia congenita probable is due to anterior horn cell ischemia resulting from fetal hypotension. Amyoplasia congenita is a sporadic condition. This is an important condition to recognize since the chances of recurrence are low and the prognosis is good. Muscle biopsies may show evidence of myopathy and neuropathy. Amyoplasia congenita is the final diagnosis in about one-third of neonates with arthrogryposis multiplex congenita.5,12,13

Infantile Spinal Muscular Atrophy

Arthrogryposis multiplex congenita occurs in 10% to 20% of neonates with infantile spinal muscular atrophy.10 There is no explanations for this selectivity. The electromyographic findings of infantile spine muscular atrophy are characterized by fibrillations and rarely fasciculation at rest. Sometimes spontaneous discharges are present in pairs. These discharges are very characteristic of infantile spinal muscular dystrophy. Muscle contraction produces few motor unit potentials of increased amplitude and duration. Desoxyribonucleic acid studies for infantile spinal muscular atrophy should be performed in neonates with unexplained arthrogryposis. The prognosis of arthrogryposis due to infantile spinal muscular atrophy is poor. Autosomal recessive and X-linked inheritance have been reported.

Infantile Neuronal Degeneration

This entity is clinically indistinguishable from infantile spinal muscular atrophy. The diagnosis is suspected on the basis of electrophysiological findings that demonstrate in addition to the myographic changes characteristic of infantile spinal muscular atrophy a delay in sensory and motor nerve conduction. The diagnosis is confirmed at autopsy. The autopsy findings reveal anterior horn motor neuron atrophy, as it occurs with infantile spinal muscular atrophy, and in addition degenerative changes in the Clarke’s column, corticospinal tracts, spinocerebellar and spinothalamic tracts, Purkinje cell layer, and dentate and ventral thalamic nuclei.13 Desoxyribonucleic acid study for infantile spinal muscular atrophy is normal.

Focal Infantile Spinal Muscular Atrophy

Arthrogryposis multiplex involving only the upper or the lower extremities occurs with congenital focal cervical or lumbar spinal atrophy presumable affecting the lower motor neuron.

Moebius Syndrome

Moebius syndrome consists of bilateral facial weakness due to cranial nerve VII lower motor neuron dysfunction. Arthrogryposis is present in about one-third of patients with Moebius syndrome.

Moebius syndrome is often associated with inability to abduct the eyes as a result of cranial nerve VI lower motor neuron unit involvement and with atrophic changes of the tongue due to cranial nerve XII lower motor neuron involvement. Poland sequence may occur in association with Moebius syndrome. Mental deficiency is present in 15% of cases. Moebius syndrome is usually sporadic. A dominant transmission is present in some cases. 5,11

Peripheral Nerve

Congenital Hypomyelinating Neuropathy

Congenital hypomyelinating neuropathy is a rare cause of arthrogryposis. Neonates are usually hypotonic and weak. Nerve conduction studies reveal a reduced motor conduction in the range of 5 to 8 meters per second. The diagnosis is established by sural nerve biopsy. Sural nerve biopsy shows a small amount or absence of myelin sheaths and occasional onion-bulb formation.14

Myoneural Junction

Transient Congenital Myasthenia Gravis

Neonates with transient myasthenia gravis may have arthrogryposis. The arthrogryposis usually involves the distal limb joints. They also have hypotonia, weakness, and fatigability. Fatigability is the hallmark of myasthenia gravis. The diagnosis is established by eval‎uating the mother. Mothers of neonates with transient congenital myasthenia gravis have a history of myasthenia gravis or have clinical findings of myasthenia gravis. Treatment with neostigmine improves strength.15,16

Infant of Mother with Multiple Sclerosis

Cases of arthrogryposis in infants of mothers with multiple sclerosis have been reported.17

Congenital Myotonic Dystrophy

Neonates with congenital myotonic dystrophy have marked body and facial hypotonia. They usually do not appear alert. Arthrogryposis tends to be more common in the lower than in the upper extremities. The distal joints are more involved than the proximal joints. The only distinguishing facial feature is temporal muscle atrophy but this feature is seldom present at birth. The head is usually large. Magnetic resonance imaging of the brain may show ventricular dilatation. The prognosis is poor. Mental retardation is usually noted as the patients get older. Congenital myotonic dystrophy is diagnosed by demonstrating the presence of myotonia in the mother and is confirmed by DNA testing. The disorder is caused by expansion in the number of trinucleotide repeats at chromosome region 19q13. It is an autosomal dominant disorder, but the neonatal form only occurs if the mother is the affected parent.5,18

Congenital Muscular Dystrophy

Neonates with congenital muscular dystrophy are hypotonic, weak and may have distal arthrogryposis. Serum concentration of creatine kinase may be normal or elevated. Electromyographic findings are consistent with a myopathic process (brief, small and abundant motor unit potentials).18 Muscle biopsy shows variation in fiber size, central nucleus, and replacement of muscle tissue by fibrosis and proliferation of adipose tissue. Merosin deficiency is present in some cases. Every patient with congenital muscular dystrophy should have a MRI of the brain. Fukuyama type congenital muscular dystrophy show migrational errors (polymicrogyria, lissencephaly, and heterotopia) and hypomyelination of the centrum semiovale.5,10

Myotubular Myopathy

Neonates with myotubular myopathy usually present with facial weakness, ptosis, ophthalmoplegia, and generalized weakness and hypotonia. Arthrogryposis may also be present. The malignant form of myotubular myopathy courses with severe respiratory compromise, which may lead to asphyxia. This malignant form occurs in males (X-linked inheritance). Myotubular myopathy is diagnosed based on the muscle biopsy findings. Muscle tissue stained with ATP-ase show muscle fibers with one or more central nucleus, surrounded by a clear halo (area devoid of myofibrils). Chorionic villus biopsy and DNA marker studies of the Xq28 region accomplish prenatal diagnosis of the X-linked recessive form.10

Craniocarpotarsal Dysplasia

Craniocarpotarsal dysplasia, Freeman-Sheldon syndrome, and whistling face syndrome are synonyms. Peculiar facial features characterize Craniocarpotarsal dysplasia (Fig 5). Neonates with craniocarpotarsal dysplasia have an H- or V-shaped groove on the chin. Arthrogryposis is more marked in the upper extremities than in the lower extremities. Feeding problems are frequent. Patients with craniocarpotarsal dysplasia usually have normal intelligence. Craniocarpotarsal dysplasia is usually transmitted as an autosomal dominant disorder but autosomal recessive inheritance occurs in some families. The nature of this disease is not known. Muscle biopsy of the buccinator muscle reveals fibrous connective tissue replacing the muscle bundles.5

Differential Diagnosis

The diagnosis of arthrogryposis multiplex congenita is usually obvious after the initial observation of the patient’s clinical findings. A source of possible confusion is the similar posture that occurs in neonates with bilateral brachial plexus palsy and amyoplasia congenita. The distention between them is established by demonstrating that the abnormal posture in amyoplasia multiplex congenita is at rest and during action whereas the abnormal posture in bilateral brachial plexus palsy is only present during action.

Management

Pivotal to the management of AMC is to determine its cause and to correct the deformities. The cause of AMC determines the prognosis, recurrence rate and to a lesser extent treatment. Efforts to find a cause in the neonatal period should be done baring in mind: (1) that a definite diagnosis may not be possible during the neonatal period, and (2) that in many cases the changes in facial features that result from craniofacial growth will lead to typical findings allowing an etiological or syndromic diagnosis.

The initial approach to a neonate with AMC is to differentiate neurological from non-neurological causes of AMC. Neonates with non-neurological causes of AMC usually have signs of oligohydramnios sequence, crumple ears, thin or hyperextensible skin, or pterygium. In the absence of these finding the possibility of a neurogenic arthrogryposis should be considered. Neuroanatomical localization is the corner stone to the diagnosis of neurogenic AMC. The presence of dysmorphism, associated neurological findings, and the distribution of the arthrogryposis can infer neurological localization.

Neonates with facial and general features that suggest a specific syndrome should be eval‎uated accordingly. Neonates without typical features but with associated neurological findings should be eval‎uated based on the suggested neuroanatomical localization of the deficit and the distribution of the arthrogryposis. Neonates with neurological findings suggestive of brain involvement should have a magnetic resonance imaging (MRI) study of the brain. Brain, brainstem and cerebellum abnormalities will be detected by this test and it may provide a clue as to the possible diagnosis. Chromosome studies are indicated in this group of patients. Neonates with neurological forms of AMC may also benefit from obtaining serum for long chain fatty acid determination (elevated in Zellweger disease), 7-dehydrocholesterol (elevated in Smith-Lemli-Opitz-syndrome), cholesterol (low in Smith-Lemli-Opitz-syndrome). Neonates without neuroogical findings suggestive of a brain lesion and arthrogryposis limited to the lower extremity should have an magnetic resonance imagine of the spine with emphasis in the thoraco-lumbar region. Neonate with arthrogryposis limited to the upper extremities without other features of amyoplasia congenital should have an MRI of the cervical spine. Neonates with arthrogryposis limited to one side of the body should have an MRI of the brain and upper cervical spine.

Neonates without neurological findings suggestive of brain involvement that in addition to arthrogryposis are hypotonic may require DNA studies for spinal muscular atrophy and myotonic dystrophy and a neostigmine test with repetitive nerve stimulation. The order of these tests varies with the clinical setting. Myotonic dystrophy DNA testing should be performed first if there is a family history of myotonia or if the mother has myotonia. Neostigmine test with repetitive nerve stimulation should be performed if there is a history of maternal myasthenia gravis or clinical fatigability is documented. Spinal muscular atrophy DNA testing should be performed in all neonates in this group with unexplained arthrogryposis.

Neonates with no neurological deficit other that the one dictated by the motor limitations of their arthrogryposis, absence of dysmorphism and proximal joint involvement are likely to have amyoplasia congenita. Neonates with no neurological deficit or dysmorphic features, and distal arthrogryposis may have distal arthrogryposis syndrome (a supposed cartilaginous abnormality). The diagnosis of distal arthrogryposis syndrome should be made cautiously. Patients diagnosed distal arthrogryposis syndrome often develop new neurological findings or facial features after the neonatal period that disproves this diagnosis.

Corrections of deformities in the neonatal period are non-surgical. The early goals are to maintain maximum passive joint and encourage active and strength development. This is accomplished through both splitting and physical therapy, including functional electrical stimulation. Serial casting is often valuable when passive motion is decreased. Surgical treatment may be required after the neonatal period. The ultimate goal for the lower limb is to allow ambulation. The ultimate goal for the upper limb is more complex. It demands integration of shoulder, elbow, wrist and hand position and active motion. Release of thumb-in-palm deformity and stabilization of the thumb metacarpals phalangeal joint are paramount for hand use.19 A tendon transfer to restore unilateral elbow flexion is very valuable and considerably aids the child in reaching an independent level of activities of daily living.20 The success of operative treatment often rests on the outcome of early nonoperative therapy. Neonates with myasthenia gravis require neostigmine.

References

Schneider V, Cabrera-Meza Gerardo. Rudolph’s Brief Atlas of the Newborn.1998.
Pope FM, Smith R. Color Atlas of Inherited Connective Tissue Disorders.
Hageman G, Willemse J. Arthrogryposis multiplex congenita. Neuropediatrics. 1983;14:6-11. [MEDLINE]
Hall JG. In utero movement and use of limbs are necessary for normal growth: a study of individuals with arthrogryposis. Progress in Clinical and Biological Research. 1985;200:155-162. [Related articles by HALL]
Jones KL. Smith’s Recognizable Patterns of Human Malformations. Philadelphia, Penn: W B Saunders; 1997.
Hageman G, Jenneckens FGI, Vette JK, et al. The heterogeneity of distal arthrogryposis. Brain Dev. 1984;6:273-183. [MEDLINE]
Barkovich JA, WallaceWP. MR of Zellweger syndrome. Am J Neuroradiol. 1997;18:1163-1170.
Heymans HSA, Wanders RJA, Schutgens RBH. Peroxisomal Disorders. In: Fernandez J, Saudubray JM, Tada K, eds. Inborn Metabolic Diseases. Diagnosis and Treatment. Berlin: Springer-Verlag; 1990:421-433.
Hall JC, Reed SD, Driscoll EP. Amyoplasia: a common sporadic condition with congenital contractures. Am J Med Genet. 1983;15:571-590.
Lyon G. Congenital malformation of the brain. In: Levene MI, Lilford RJ, eds. Fetal and Neonatal Neurology and Neurosurgery. Edinburgh, Britain: Churchill Livingstone; 1994:193-214.
Volpe JJ. Neurology of the Newborn. Philadelphia, Penn: WB Saunders; 1995.
Sarnat HB, Case MF, Graviss R. Sacral agenesis. Neurology and neuropathology features. Neurology. 1976;26:1124-1129. [MEDLINE]
Fenichel GM. Neonatal Neurology. New York, NY: Churchill Livingstone; 1990.
Boylan KB, Ferriero DM, Greco CM, et al. Congenital hypomyelinating neuropathy with arthrogryposis multiplex congenita. Ann Neurol. 1992;31:337-340. [MEDLINE]
Holmes JB, Driscoll SG, Bradley WG. Contracture in a newborn infant of a mother with myasthenia gravis. J Pediatr. 1980;96:1067-1069.
Papazian O. Transient neonatal myasthenia gravis. J Child Neurol. 1997;7:135-141. [MEDLINE]
Livingstone IR, Sack GH. Arthrogryposis multiplex congenita occurring with maternal multiple sclerosis. Arch Neurol. 1984;41:1216-1217. [MEDLINE]
Jones HR Jr, Bolton CF, Harpen CM Jr. Pediatric Clinical Electromyography. Philadelphia, Penn: Lippincott-Raven; 1996.
Cooney WP, Schutt AH. Arthrogryposis multiplex congenital. In Bors FW,ed. The perdiatric upper extremity. Philadelphia, Penn: WB Saunders; 1986
VanHeest A, Walter P, Simmons B. Surgical treatment of arthrogryposis of the elbow. J Hand Surg. 1998;23 A: 1063-1071.

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Arthrogryposis multiplex congenita is diagnosed when two or more joints in more than one limb are fixed from birth. A joint becomes fixed in a given position because of unevenly impaired motility. Arthrogryposis multiplex congenita (AMC) may be caused by neurological and non-neurological causes. Neurological causes of AMC include: trisomy 13 and 18, Smith-Lemli-Opitz syndrome, Zellweger syndrome, Walker-Warburg syndrome, Marden-Walker syndrome, spinal cord injury, amyoplasia congenita, infantile spinal muscular atrophy, infantile neuronal degeneration, focal infantile spinal muscular atrophy, Moebious syndrome, congenital hypomyelinating neuropathy, transient congenital myasthenia gravis, infant of mother with multiple sclerosis, congenital myotonic dystrophy, congenital muscular dystrophy myotubular myopathy, and craniocarpotarsal dysplasia. Non-neurological causes of AMC are cartilaginous abnormalities and physical constraint to movement. Neonates with non-neurological causes of AMC usually have signs of oligohydramnios sequence, crumple ears, thin or hyperextensible skin, or pterygium. Neonates with AMC due to cartilaginous abnormalities usually have one of the following syndromes: Beal syndrome, Antley-Bixer syndrome or a condition referred to as distal arthrogryposis. Int Pediatr. 2000;15(4):197-204.

Key words: Arthrogryposis multiplex congenita

Introduction

Arthrogryposis refers to a joint that is in a fixed position. Arthrogryposis multiplex congenita is diagnosed when two or more joints in more than one limb are fixed from birth (Fig 1). A joint becomes fixed in a given position because of unevenly impaired joint motility. Unevenly impaired joint motility results from segmental muscle weakness or hypotonia, or from a sustained asymmetrical posture. Segmental muscle weakness or hypotonia is due to an imbalance between agonistic and antagonistic muscles. Sustained asymmetrical posture results from movement constraints due to reduced uterine volume or when thick skin bands prevent joint movement. Arthrogryposis multiplex congenita (AMC) may be caused by neurological and non-neurological causes. Non-neurological causes of AMC are cartilaginous abnormalities and physical constraint to movement. Neurological causes of AMC include central and peripheral nervous systems abnormalities (Table 1).1-5

Cartilaginous Abnormalities

Cartilaginous abnormalities should be consider the cause of AMC in neonates that are longer that expected for their gestational age, and those with hyperextensible and transparent skin, blue sclera, abnormal ear lobe shape and craniosynostosis.1,2 Intelligence is usually normal in patients with AMC due to cartilaginous abnormalities. Cartilaginous abnormalities produce joint hyperelasticity leading to a symmetrical weakness that when combined with a physical constraint produces arthrogryposis. Arthrogryposis multiplex congenita due to cartilaginous abnormalities improves with time. Neonates with AMC due to cartilaginous abnormalities usually have one of the following syndromes: Beal syndrome, Antley-Bixer syndrome or a condition referred to as distal arthrogryposis.

Beal Syndrome

The characteristic findings of Beal syndrome are: crumpled ears, long slim limbs and fingers, frontal bossing and short neck. They look like patients with Marfan syndrome with arthrogryposis and crumple ears. Arthrogryposis may affect any joint. Beal syndrome is linked to a fibrillin locus on chromosome 5 q 23-31. Beal syndrome is an autosomal dominant disorder.2,5

Antley-Bixer Syndrome

Neonates with Antley-Bixer syndrome have very distinctive facial features. Crouzon syndrome-like appearance and midfacial hypoplasia dominate the facial features(Fig 2). Midfacial hypoplasia manifests by depressed nasal bridge and choanal atresia. Neonates with choanal atresia may present with apnea and require intubation shortly after birth because neonates are obligated nasal breathers. In addition to the facial features patients with Antley-Bixer syndrome often have radio-humeral synostosis, femoral bowing and sacral remnant. Arthrogryposis usually involves the elbows in the upper extremities (Fig 3). There is no confirm‎atory test for Antley-Bixer syndrome. Antley-Bixer syndrome is probably an autosomal recessive disorder.2,5

Distal Arthrogryposis Syndrome

Neonates with distal arthrogryposis syndrome usually do not have any of the characteristic findings that are usually seen in other neonates with AMC due to cartilaginous abnormalities. In a few cases cleft palate, cleft lip, small tongue, trismus, ptosis, and mild epicanthal folds have been described. Facial features are usually normal. The arthrogryposis involves the hands and, to a lesser extent, the feet. Shoulders, elbows, hips and knees are seldom involved. The cartilaginous abnormalities in distal arthrogryposis syndrome are probably restricted to the tendons. Distal arthrogryposis syndrome is an autosomal dominant condition with variable expression‎. The gene for distal arthrogryposis is in the pericentromeric region of chromosome. 2,5,6

Physical Constraint to Movement

Arthrogryposis due to physical constraint occurs when the capacity of the uterus is restricted or when thick cutaneous bands restrict the movement of a joint. The capacity of the uterus may be restricted due to oligohydramnios, anatomic malformations of the uterus, amniotic bands, or uterine tumors. Thick cutaneous bands restricting joint movements occur in Escobar syndrome.4,5

Oligohydramnios Sequence

Oligohydramnios is the most frequent cause of AMC due to physical constraint. A reduce uterine capacity places the fetus at risk for multiple anomalies, in addition to arthrogryposis. The constellation of findings that occur as the result from decreased amniotic fluid is denominated oligohydramnios sequence. The characteristics of oligohydramnios sequence are wrinkled skin, skin fold that extends from the inner canthus to the upper cheek, squashed nose, large-low set and posteriorly rotated ears, short neck and large wrinkled hands. Arthrogryposis usually involves the knees and feet. Oligohydramnios sequence is a clinical diagnosis. The diagnosis is established by the clinical findings. Oligohydramnios is usually due to bilateral renal agenesis.5

Escobar Syndrome

Thick skin folds that produce an usual appearance and keep the joints in a fixed position characterize multiple pterygia syndrome or Escobar syndrome. The skin folds are usually in the neck, axilla, antecubital, popliteal, and digital areas. The thick skin folds reduce joint motility in utero and lead to AMC. Arthrogryposis is especially marked in the hands. Intelligence is normal. Scoliosis often develops by 5 years of age. Escobar syndrome is an autosomal recessive condition. Surgical treatment of the pterygium may be necessary.2,5

Neurological Abnormalities

Neurological disorder should be suspected in any neonate without signs of cartilaginous abnormalities, pterygium or signs suggestive of oligohydramnios sequence. Diseases at the level of the brain, cerebellum, brainstem, spinal cord, motor neuron cell, nerve, myoneural junction and muscle may cause arthrogryposis.

Arthrogryposis due to neurological abnormalities may be symmetrical or asymmetrical, generalized or partial, distal or proximal. The distribution of the arthrogryposis reflects the localization of the neurological involvement. Symmetrical arthrogryposis may occur with brain, brainstem, cerebellar or spinal cord lesions, or with motor neuron, nerve, myoneural junction or muscle diseases. Asymmetrical arthrogryposis, especially with a hemibody involvement suggests unilateral brain, brainstem, cerebellar or spinal lesions. Involvement of the lower extremities only may occur with parasagittal brain lesion, peri-lateral ventricular lesions (the corticospinal fibers destined to innervate the lower extremities are in close proximity to the lateral ventricles) or below the cervical enlargement in the spinal cord. Distal arthrogryposis usually occurs with brain, nerve, myoneural junction and muscle abnormalities. Proximal arthrogryposis occurs with motor neuron disease.

Brain, Cerebellum and Brainstem

The possibility of brain, cerebellum and brainstem abnormalities should be considered in any child with dysmorphic facial features, cranial vault volume or shape abnormalities decrease level of alertness, brainstem release phenomena and seizures. EEG and MRI usually confirm‎ brain, brainstem and cerebellar abnormalities.

Trisomy 18 Syndrome

Trisomy 18 syndrome is characterized by having a narrow bifrontal head diameter with a prominent occiput, epicanthal folds, small mouth, a short upper lip, micrognathia, low-set dysplastic ears, shield chest, short sternum, limited hip abduction, and hand and feet arthrogryposis. The position of the hands is typical in most cases, but not specific since it occurs with other disorders. The hand is clenched with the middle finger partially or complete under the index and fourth finger. Feet anomalies consist of talipes calcaneovalgus, short dorsiflexed big hallux, and prominent heels characterize the feet anomalies. The most frequent central nervous system anomalies are abnormal myelinization, microgyria, cerebellar hypoplasia, agenesis of the corpus callosum, hydrocephalus, and meningomyelocele. Neonates with trisomy 18 syndrome often die during the neonatal period because of apnea. If they survive, they may require respiratory support and nasogastric feedings.

Most neonates with trisomy 18 syndrome phenotype have full trisomy. Full trisomy 18 occurs more frequently in neonates born to older mothers. The risk of recurrence of a trisomy is probably less than 1 percent. Translocation of chromosome 18 material produces a phenotype similar to the trisomy 18. The parents of an infant with translocation should have chromosome studies because they may be asymptomatic carriers of a balance translocation. The chances of recurrence is higher if either parents are carriers of a balance translocation.5

Trisomy 13 Syndrome

Trisomy 13 syndrome is characterized by microcephaly, posterior scalp lesions, microphthalmia, cleft lip, coloboma of the iris, low-set dysplastic ears, deafness, cleft palate, polydactyly, prominent heels, cryptorchidism, abnormal scrotum and distal arthrogryposis. The position of the hands is often similar to the position of the hands in trisomy 18. The most frequent central nervous system anomaly is holoprosencephaly. Trisomy 13 may occur in full and with translocation. Full trisomy 13 occurs more often in neonates born to older mothers. Translocation of chromosome 13 material produces a phenotype similar to the trisomy 13. The parents of an infant with translocation should have chromosomal studies because they may be asymptomatic carriers of a balance translocation. The chance of recurrence is higher if either parent is a carrier of a balance translocation.5

Smith-Lemli-Opitz Syndrome

Smith-Lemli-Opitz syndrome is characterized by microcephaly with a narrow frontal area, slanted or low-set ears, ptosis, anteverted nostrils, cryptorchidism, and hypospadias. The most important distinguishing features in males are cryptorchidism and hypospadias. The diagnosis of this syndrome in females is very difficult because the most characteristic features of this syndrome (cryptorchidism and hypospadia) are not present. Brain and brainstem malformations may be present. Arthrogryposis is more prominent in the hands. Smith-Lemli-Opitz syndrome is due to a severe defect in cholesterol biosynthesis. The defective enzyme is 7-dehydrocholesterol reductase. This defect leads to a high level of the cholesterol precursor 7-dehydrocholesterol and low cholesterol levels. The low cholesterol levels lead to abnormalities of mitochondrial function, hormone synthesis, myelination or bile acid and vitamin D metabolisms. Measuring 7-dehydrocholesterol using chromatographic assay can diagnose smith-Lemli-Opitz syndrome prenatally or postnatally. Most patients with Smith-Lemli-Opitz syndrome die in the neonatal period. Survivors are severely mentally retarded. Smith-Lemli-Opitz syndrome is an autosomal recessive condition.5

Zellweger Syndrome

Severe hypotonia, brachycephaly, widely open fontanels and sutures, hepatomegaly, hypospadias and cryptorchidism in males and clitoral hypertrophy in females characterize Zellweger syndrome. Arthrogryposis is usually distal. Patients with Zellweger syndrome have a prominent forehead, flat occiput, round face, micrognathia, anteverted nares, low-set dysplastic ears, hypertelorism, puffy eyelids, epicanthal folds, glaucoma, cataracts, corneal clouding, and Brushfield spots. Hepatomegaly may not be present at birth but develops during the first month of life. Bone radiograph may reveal calcified stippling of the patella and acetabulum. Magnetic resonance imaging of the brain may show: (1) hypomyelination, (2) perisylvian and perirolandic cortical malformation, and (3) germinolytic cysts.7 Zellweger syndrome is associated with increased serum concentrations of very-long-chain fatty acids in plasma. The diagnosis is established by fibroblast culture or liver biopsy. Their cells do not show peroxisomes when stained for peroxisomal enzymes. But electromicroscopy of the same tissue shows that the peroxisomal membranes are present. This peculiar finding is referred to as "ghost peroxisomes" because the membrane is present but the enzymes are not.7 Genetic defects at 7q11.23 and 1p22-p21 are associated with Zellweger syndrome. Most patients with Zellweger syndrome die during the first year of life. Survivors are mentally retarded Zellweger syndrome has an autosomal recessive inheritance. 5,7,8

Walker-Warburg Syndrome

The acronym HARD +/- E has being used for Walker-Warburg syndrome. The acronym refers to the first letter of the major features of this condition: hydrocephalus, agyria (cerebral and cerebellar), retinal dysplasia, and occasionally encephalocele. In addition to retinal dysplasia, other ocular abnormalities seen in patients with Walker-Warburg syndrome include vitreous abnormalities, retinal detachment, glaucoma, cataracts, and corneal opacities. Neonates with Walker-Warburg syndrome are hypotonic and usually have seizures. Arthrogryposis is usually distal. The brain abnormalities in Walker-Warburg syndrome are probably due to a defect in the external basal lamina of the brain. The external basal lamina of the brain is the boundary that stops the neuronal migrational process. Failure of the external basal lamina to develop causes the neurons to cross over sulci and into the meninges creating a flat brain and engulfing the meninges. Walker-Warburg syndrome is a familial disorder. The familial incidence is most likely due to an autosomal recessive inheritance, but the possibility of a persistent intrauterine viral infection affecting several members in one family has been considered. MRI diagnoses Walker-Warburg syndrome. The MRI shows smooth cerebral and cerebellar surfaces, large lateral ventricles in relation to cerebral mass, and absence of cerebellar vermis. 5,9

Marden-Walker Syndrome

A fixed facial expression‎, blepharophimosis, micrognathia and multiple joint contractors from birth characterize Marden-Walker syndrome. Brain and posterior fossa malformations are frequent. Dandy-Walker abnormality and brainstem hypoplasia may occur. It is an autosomal recessive condition.5

Spinal Cord Injury

The possibility of spinal cord injury producing arthrogryposis should be suspected in any newborn with arthrogryposis of the limbs without jaw involvement and in those neonates with arthrogryposis limited to the lower extremities. Spinal MRI confirm‎s the presence of spinal cord involvement.

Arthrogryposis due to spinal cord involvement is usually due to a development problem. Traumatic spine cord injury usually occurs during delivery, therefore does not produce AMC. Spinal cord arthrogryposis should be suspected if no cause for AMC is present and there are no signs of brain or brainstem involvement. Arthrogryposis multiplex congenita of the lower extremities has been reported with lumbosacral meningocele and with sacral agenesis.10,11

Lower Motor Neuron

The possibility of arthrogryposis due to lower motor neuron involvement should be suspected in all neonates with a neurogenic arthrogryposis without evidence of brain involvement. Several lower motor neuron conditions produce arthrogryposis. They include infantile spinal muscular atrophy, infantile neuronal degeneration, focal spinal muscular atrophy, Moebius syndrome and amyoplasia congenita.

Amyoplasia Congenita

Neonates with amyoplasia congenita are usually full term and of average weight. They appear healthy. They may have a round face, short upturned nostrils, and micrognathia. A midface capillary hemangioma is often present. Neonates with amyoplasia congenita usually have multiple symmetrical fixed joints with typical positions and distribution. The upper extremity position is most characteristic (Fig 4). The shoulders are adducted and medially rotated, elbows are extended or flexed, forearm is pronated, wrists are flexed and have ulnar deviation, and the fingers are flexed. The upper extremity posture, except in neonates with flexed elbows, resembles that which occurs in patients with brachial plexus palsy involving the C5-C6 fibers in the upper trunk. The lower extremities are less frequently involved. When they are involved, the hips are flexed, knees are flexed or extended, and the feet are in equinovarus or calcaneovalgus positions. The limbs are cylindrical and fingers are slender. Cutaneous defects, usually small and round, are present in the proximity of some of the affected joints. Patients with amyoplasia congenita do not have evidence of cardiac, or genitourinary tract abnormality. Bowel atresia and gastroschisis have been reported. The cause of amyoplasia congenita probable is due to anterior horn cell ischemia resulting from fetal hypotension. Amyoplasia congenita is a sporadic condition. This is an important condition to recognize since the chances of recurrence are low and the prognosis is good. Muscle biopsies may show evidence of myopathy and neuropathy. Amyoplasia congenita is the final diagnosis in about one-third of neonates with arthrogryposis multiplex congenita.5,12,13

Infantile Spinal Muscular Atrophy

Arthrogryposis multiplex congenita occurs in 10% to 20% of neonates with infantile spinal muscular atrophy.10 There is no explanations for this selectivity. The electromyographic findings of infantile spine muscular atrophy are characterized by fibrillations and rarely fasciculation at rest. Sometimes spontaneous discharges are present in pairs. These discharges are very characteristic of infantile spinal muscular dystrophy. Muscle contraction produces few motor unit potentials of increased amplitude and duration. Desoxyribonucleic acid studies for infantile spinal muscular atrophy should be performed in neonates with unexplained arthrogryposis. The prognosis of arthrogryposis due to infantile spinal muscular atrophy is poor. Autosomal recessive and X-linked inheritance have been reported.

Infantile Neuronal Degeneration

This entity is clinically indistinguishable from infantile spinal muscular atrophy. The diagnosis is suspected on the basis of electrophysiological findings that demonstrate in addition to the myographic changes characteristic of infantile spinal muscular atrophy a delay in sensory and motor nerve conduction. The diagnosis is confirmed at autopsy. The autopsy findings reveal anterior horn motor neuron atrophy, as it occurs with infantile spinal muscular atrophy, and in addition degenerative changes in the Clarke’s column, corticospinal tracts, spinocerebellar and spinothalamic tracts, Purkinje cell layer, and dentate and ventral thalamic nuclei.13 Desoxyribonucleic acid study for infantile spinal muscular atrophy is normal.

Focal Infantile Spinal Muscular Atrophy

Arthrogryposis multiplex involving only the upper or the lower extremities occurs with congenital focal cervical or lumbar spinal atrophy presumable affecting the lower motor neuron.

Moebius Syndrome

Moebius syndrome consists of bilateral facial weakness due to cranial nerve VII lower motor neuron dysfunction. Arthrogryposis is present in about one-third of patients with Moebius syndrome.

Moebius syndrome is often associated with inability to abduct the eyes as a result of cranial nerve VI lower motor neuron unit involvement and with atrophic changes of the tongue due to cranial nerve XII lower motor neuron involvement. Poland sequence may occur in association with Moebius syndrome. Mental deficiency is present in 15% of cases. Moebius syndrome is usually sporadic. A dominant transmission is present in some cases. 5,11

Peripheral Nerve

Congenital Hypomyelinating Neuropathy

Congenital hypomyelinating neuropathy is a rare cause of arthrogryposis. Neonates are usually hypotonic and weak. Nerve conduction studies reveal a reduced motor conduction in the range of 5 to 8 meters per second. The diagnosis is established by sural nerve biopsy. Sural nerve biopsy shows a small amount or absence of myelin sheaths and occasional onion-bulb formation.14

Myoneural Junction

Transient Congenital Myasthenia Gravis

Neonates with transient myasthenia gravis may have arthrogryposis. The arthrogryposis usually involves the distal limb joints. They also have hypotonia, weakness, and fatigability. Fatigability is the hallmark of myasthenia gravis. The diagnosis is established by eval‎uating the mother. Mothers of neonates with transient congenital myasthenia gravis have a history of myasthenia gravis or have clinical findings of myasthenia gravis. Treatment with neostigmine improves strength.15,16

Infant of Mother with Multiple Sclerosis

Cases of arthrogryposis in infants of mothers with multiple sclerosis have been reported.17

Congenital Myotonic Dystrophy

Neonates with congenital myotonic dystrophy have marked body and facial hypotonia. They usually do not appear alert. Arthrogryposis tends to be more common in the lower than in the upper extremities. The distal joints are more involved than the proximal joints. The only distinguishing facial feature is temporal muscle atrophy but this feature is seldom present at birth. The head is usually large. Magnetic resonance imaging of the brain may show ventricular dilatation. The prognosis is poor. Mental retardation is usually noted as the patients get older. Congenital myotonic dystrophy is diagnosed by demonstrating the presence of myotonia in the mother and is confirmed by DNA testing. The disorder is caused by expansion in the number of trinucleotide repeats at chromosome region 19q13. It is an autosomal dominant disorder, but the neonatal form only occurs if the mother is the affected parent.5,18

Congenital Muscular Dystrophy

Neonates with congenital muscular dystrophy are hypotonic, weak and may have distal arthrogryposis. Serum concentration of creatine kinase may be normal or elevated. Electromyographic findings are consistent with a myopathic process (brief, small and abundant motor unit potentials).18 Muscle biopsy shows variation in fiber size, central nucleus, and replacement of muscle tissue by fibrosis and proliferation of adipose tissue. Merosin deficiency is present in some cases. Every patient with congenital muscular dystrophy should have a MRI of the brain. Fukuyama type congenital muscular dystrophy show migrational errors (polymicrogyria, lissencephaly, and heterotopia) and hypomyelination of the centrum semiovale.5,10

Myotubular Myopathy

Neonates with myotubular myopathy usually present with facial weakness, ptosis, ophthalmoplegia, and generalized weakness and hypotonia. Arthrogryposis may also be present. The malignant form of myotubular myopathy courses with severe respiratory compromise, which may lead to asphyxia. This malignant form occurs in males (X-linked inheritance). Myotubular myopathy is diagnosed based on the muscle biopsy findings. Muscle tissue stained with ATP-ase show muscle fibers with one or more central nucleus, surrounded by a clear halo (area devoid of myofibrils). Chorionic villus biopsy and DNA marker studies of the Xq28 region accomplish prenatal diagnosis of the X-linked recessive form.10

Craniocarpotarsal Dysplasia

Craniocarpotarsal dysplasia, Freeman-Sheldon syndrome, and whistling face syndrome are synonyms. Peculiar facial features characterize Craniocarpotarsal dysplasia (Fig 5). Neonates with craniocarpotarsal dysplasia have an H- or V-shaped groove on the chin. Arthrogryposis is more marked in the upper extremities than in the lower extremities. Feeding problems are frequent. Patients with craniocarpotarsal dysplasia usually have normal intelligence. Craniocarpotarsal dysplasia is usually transmitted as an autosomal dominant disorder but autosomal recessive inheritance occurs in some families. The nature of this disease is not known. Muscle biopsy of the buccinator muscle reveals fibrous connective tissue replacing the muscle bundles.5

Differential Diagnosis

The diagnosis of arthrogryposis multiplex congenita is usually obvious after the initial observation of the patient’s clinical findings. A source of possible confusion is the similar posture that occurs in neonates with bilateral brachial plexus palsy and amyoplasia congenita. The distention between them is established by demonstrating that the abnormal posture in amyoplasia multiplex congenita is at rest and during action whereas the abnormal posture in bilateral brachial plexus palsy is only present during action.

Management

Pivotal to the management of AMC is to determine its cause and to correct the deformities. The cause of AMC determines the prognosis, recurrence rate and to a lesser extent treatment. Efforts to find a cause in the neonatal period should be done baring in mind: (1) that a definite diagnosis may not be possible during the neonatal period, and (2) that in many cases the changes in facial features that result from craniofacial growth will lead to typical findings allowing an etiological or syndromic diagnosis.

The initial approach to a neonate with AMC is to differentiate neurological from non-neurological causes of AMC. Neonates with non-neurological causes of AMC usually have signs of oligohydramnios sequence, crumple ears, thin or hyperextensible skin, or pterygium. In the absence of these finding the possibility of a neurogenic arthrogryposis should be considered. Neuroanatomical localization is the corner stone to the diagnosis of neurogenic AMC. The presence of dysmorphism, associated neurological findings, and the distribution of the arthrogryposis can infer neurological localization.

Neonates with facial and general features that suggest a specific syndrome should be eval‎uated accordingly. Neonates without typical features but with associated neurological findings should be eval‎uated based on the suggested neuroanatomical localization of the deficit and the distribution of the arthrogryposis. Neonates with neurological findings suggestive of brain involvement should have a magnetic resonance imaging (MRI) study of the brain. Brain, brainstem and cerebellum abnormalities will be detected by this test and it may provide a clue as to the possible diagnosis. Chromosome studies are indicated in this group of patients. Neonates with neurological forms of AMC may also benefit from obtaining serum for long chain fatty acid determination (elevated in Zellweger disease), 7-dehydrocholesterol (elevated in Smith-Lemli-Opitz-syndrome), cholesterol (low in Smith-Lemli-Opitz-syndrome). Neonates without neuroogical findings suggestive of a brain lesion and arthrogryposis limited to the lower extremity should have an magnetic resonance imagine of the spine with emphasis in the thoraco-lumbar region. Neonate with arthrogryposis limited to the upper extremities without other features of amyoplasia congenital should have an MRI of the cervical spine. Neonates with arthrogryposis limited to one side of the body should have an MRI of the brain and upper cervical spine.

Neonates without neurological findings suggestive of brain involvement that in addition to arthrogryposis are hypotonic may require DNA studies for spinal muscular atrophy and myotonic dystrophy and a neostigmine test with repetitive nerve stimulation. The order of these tests varies with the clinical setting. Myotonic dystrophy DNA testing should be performed first if there is a family history of myotonia or if the mother has myotonia. Neostigmine test with repetitive nerve stimulation should be performed if there is a history of maternal myasthenia gravis or clinical fatigability is documented. Spinal muscular atrophy DNA testing should be performed in all neonates in this group with unexplained arthrogryposis.

Neonates with no neurological deficit other that the one dictated by the motor limitations of their arthrogryposis, absence of dysmorphism and proximal joint involvement are likely to have amyoplasia congenita. Neonates with no neurological deficit or dysmorphic features, and distal arthrogryposis may have distal arthrogryposis syndrome (a supposed cartilaginous abnormality). The diagnosis of distal arthrogryposis syndrome should be made cautiously. Patients diagnosed distal arthrogryposis syndrome often develop new neurological findings or facial features after the neonatal period that disproves this diagnosis.

Corrections of deformities in the neonatal period are non-surgical. The early goals are to maintain maximum passive joint and encourage active and strength development. This is accomplished through both splitting and physical therapy, including functional electrical stimulation. Serial casting is often valuable when passive motion is decreased. Surgical treatment may be required after the neonatal period. The ultimate goal for the lower limb is to allow ambulation. The ultimate goal for the upper limb is more complex. It demands integration of shoulder, elbow, wrist and hand position and active motion. Release of thumb-in-palm deformity and stabilization of the thumb metacarpals phalangeal joint are paramount for hand use.19 A tendon transfer to restore unilateral elbow flexion is very valuable and considerably aids the child in reaching an independent level of activities of daily living.20 The success of operative treatment often rests on the outcome of early nonoperative therapy. Neonates with myasthenia gravis require neostigmine.

References

Schneider V, Cabrera-Meza Gerardo. Rudolph’s Brief Atlas of the Newborn.1998.
Pope FM, Smith R. Color Atlas of Inherited Connective Tissue Disorders.
Hageman G, Willemse J. Arthrogryposis multiplex congenita. Neuropediatrics. 1983;14:6-11. [MEDLINE]
Hall JG. In utero movement and use of limbs are necessary for normal growth: a study of individuals with arthrogryposis. Progress in Clinical and Biological Research. 1985;200:155-162. [Related articles by HALL]
Jones KL. Smith’s Recognizable Patterns of Human Malformations. Philadelphia, Penn: W B Saunders; 1997.
Hageman G, Jenneckens FGI, Vette JK, et al. The heterogeneity of distal arthrogryposis. Brain Dev. 1984;6:273-183. [MEDLINE]
Barkovich JA, WallaceWP. MR of Zellweger syndrome. Am J Neuroradiol. 1997;18:1163-1170.
Heymans HSA, Wanders RJA, Schutgens RBH. Peroxisomal Disorders. In: Fernandez J, Saudubray JM, Tada K, eds. Inborn Metabolic Diseases. Diagnosis and Treatment. Berlin: Springer-Verlag; 1990:421-433.
Hall JC, Reed SD, Driscoll EP. Amyoplasia: a common sporadic condition with congenital contractures. Am J Med Genet. 1983;15:571-590.
Lyon G. Congenital malformation of the brain. In: Levene MI, Lilford RJ, eds. Fetal and Neonatal Neurology and Neurosurgery. Edinburgh, Britain: Churchill Livingstone; 1994:193-214.
Volpe JJ. Neurology of the Newborn. Philadelphia, Penn: WB Saunders; 1995.
Sarnat HB, Case MF, Graviss R. Sacral agenesis. Neurology and neuropathology features. Neurology. 1976;26:1124-1129. [MEDLINE]
Fenichel GM. Neonatal Neurology. New York, NY: Churchill Livingstone; 1990.
Boylan KB, Ferriero DM, Greco CM, et al. Congenital hypomyelinating neuropathy with arthrogryposis multiplex congenita. Ann Neurol. 1992;31:337-340. [MEDLINE]
Holmes JB, Driscoll SG, Bradley WG. Contracture in a newborn infant of a mother with myasthenia gravis. J Pediatr. 1980;96:1067-1069.
Papazian O. Transient neonatal myasthenia gravis. J Child Neurol. 1997;7:135-141. [MEDLINE]
Livingstone IR, Sack GH. Arthrogryposis multiplex congenita occurring with maternal multiple sclerosis. Arch Neurol. 1984;41:1216-1217. [MEDLINE]
Jones HR Jr, Bolton CF, Harpen CM Jr. Pediatric Clinical Electromyography. Philadelphia, Penn: Lippincott-Raven; 1996.
Cooney WP, Schutt AH. Arthrogryposis multiplex congenital. In Bors FW,ed. The perdiatric upper extremity. Philadelphia, Penn: WB Saunders; 1986
VanHeest A, Walter P, Simmons B. Surgical treatment of arthrogryposis of the elbow. J Hand Surg. 1998;23 A: 1063-1071.

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