Arthrogryposis multiplex congenita: classification, diagnosis, perioperative care, and anesthesia

Abstract

Arthrogryposis multiplex congenita (AMC) is a rare disorder characterized by non-progressive, multiple contractures. In addition to affected extremities, patients may also present microstomia, decreased temporomandibular joint mobility. Although the etiology of AMC is unclear, any factor that decreases fetal movement is responsible for AMC. Thus, accurate diagnosis and classification are crucial to the appropriate treatment of AMC. The development of ultrasound technology has enabled prenatal diagnosis. Very early treatment is favorable, and multidisciplinary treatment is necessary to improve the function of AMC patients. Most patients require surgery to release contracture and reconstruct joints. However, perioperative care is challenging, and difficult airway is the first concern of anesthesiologists. Postoperative pulmonary complications are common and regional anesthesia is recommended for postoperative analgesia. This review on AMC is intended for anesthesiologists. Thus, we discuss the treatment and perioperative management of patients undergoing surgery, as well as the diagnosis and classification of AMC.

Keywords

arthrogryposis / amyoplasia / distal arthrogryposis / anesthesia

Introduction

Arthrogryposis multiplex congenita (AMC) was first described by Otto as congenital myodystrophy in 1841. AMC is characterized by congenital, non-progressive, and symmetric joint contractures that involve at least two different body areas. Both upper and lower limbs are usually involved [ 1]. AMC is not a homogenous disease, and hundreds of conditions with arthrogryposis have been recognized.

Although the etiology of AMC is unclear, any factor that decreases fetal movement may result in multiple contractures. The lack of joint mobility is associated with the development of extra connective tissue around the joints, which leads to fibrosis and contractures of the affected joints. Neurological diseases, muscular and connective tissue abnormalities, limited intrauterine space, inadequate placental supply, and maternal disease, such as diabetes mellitus, myasthenia gravis, and infections may contribute to fetal akinesia and subsequent AMC. The incidence is approximately 1 in 3000 to 5000 live births with equal gender ratio [ 2– 4]. Lethal arthrogryposis has also been reported [ 5, 6].

The objective of this review is to discuss the classification, diagnostic methods, treatments, and perioperative challenges for AMC patients.

Classification

There are numerous AMC subgroups based on various signs, symptoms, and causes. Thus, classification is important because the different AMC subgroups have different treatments and different responses to therapies. The widely accepted classification of AMC was first published in 2009 by Bamshad [ 7].

The first step is to check whether the patient has normal neurological function. Normal neurological function suggests that AMC is caused by amyoplasia and distal arthrogryposis, a generalized connective tissue disorder or fetal crowding (that is, space restriction in the uterus caused by leiomyoma or oligohydramnios).

Clinical manifestation

Amyoplasia is sporadic and characterized by symmetric contractures. Muscle tissue is atrophy and replaced by fatty and fibrous tissue. Patients with amyoplasia usually have normal intelligence. The typical appearance of amyoplasia is as follows: adducted and internally rotated shoulder, extension contracture of elbow, palmar flexion and flexion contractures of distal interphalangeal joints (Fig. 1), dislocation of hip and extension contractures of knee, and severe equinovarus contractures of the feet.

Distal arthrogryposis (DA) is an autosomal dominant disorder with contractures on the distal parts of the limbs. Ten different types of DA have been described [ 8– 10] and are classified hierarchically from distal arthrogryposis type 1(DA1) to distal arthrogryposis type 10 (DA10).

DA1 (OMIM 108120, (OMIM, Online Mendelian Inheritance in Man)), a prototype of DA, is characterized by camptodactyly and clubfoot. DA2A (OMIM 193700) was first described in 1938 as Freeman‒Sheldon syndrome (FSS)[ 11]. Its typical features include contractures of the toes and fingers, kyphosis, scoliosis, and a characteristic face, which is also called whistling face. DA2B (OMIM 601680) or Sheldon‒Hall syndrome has clinical features similar to those in DA1 and FSS[7]. DA3 (OMIM 114300) or Gordon syndrome is rare and presents low stature and palatoschisis as its main features. DA4 (OMIM 609128) is characterized by contractures and severe scoliosis. DA5 (OMIM 108145) is distinguished by ocular abnormalities, such as limited eye motion, ptosis, and strabismus [ 12, 13]. Chest wall muscle involvement has also been noted, and pulmonary hypertension may develop because of restricted respiratory movement [ 14]. DA6 (OMIM 108200) is very rare and is characterized by sensorineural auditory abnormalities. DA7 (OMIM 158300), also called trismus-pseudocamptodactyly syndrome (TPS), is characterized by trismus and pesudocamptodactyly. Short stature and shortened hamstring muscles have also been observed [ 1, 7]. DA8 (OMIM 178110) is an autosomal-dominant multiple pterygium syndrome. DA9 (OMIM 121050) or Beals syndrome is characterized by congenital contracture arachnodactyly. Patients are phenotypically similar to patients with Marfan’s syndrome, but without cardiovascular abnormalities [ 15, 16]. DA10 (OMIM 187370) is characterized by congenital plantar flexion contracture of the foot.

AMC patients with abnormal neurological function suggest that diminished movement in utero is mainly caused by the abnormal function of central, peripheral nervous system, neuromuscular junction, or muscle. Examples are abnormal development of the forebrain, hydranencephaly, microcephaly, fetal central nervous system infection, including zika virus [ 17], X-linked spinal muscular atrophy, peripheral neuropathies, or congenital myopathies [ 18]. Parturients with myasthenia gravis and autoantibodies that target fetal acetylcholine receptors have also been reported to be associated with arthrogryposis [ 19].

Genetics

AMC usually occurs sporadically. However, gene mutations, chromosomal abnormalities, and mitochondrial defects have been found in patients with AMC. Patterns of inheritance include autosomal recessive, autosomal dominant, X-linked, and maternal inheritance of some mitochondrial disorders. More than 200 genes have been recognized [ 20], and genes which encode muscular components or connective tissue, central or peripheral nerve system, neuromuscular endplate, and ion channels may be responsible for AMC. b-tropomyosin (TPM2) [ 21], troponin I type 2 (TNNI2) [ 22], troponin T type 3 (TNNT3) [ 23], myosin heavy chain 3 (MYH3) [ 24], myosin binding protein C1 (MYBPC1) [ 25], endothelin-converting enzyme-like 1 (ECEL1) [ 26], and sodium leak channel, non-selective protein (NALCN) [ 27] contribute to the etiology of AMC.

Although genes associated with AMC have been identified, the molecular mechanism of AMC is unknown. Moreover, the role of gene mutation in fetal development and in the interaction between abnormal and normal genes during fetal development is still elusive. Thus, further research is necessary to develop a molecular diagnostic approach and gene therapy.

Diagnosis

A comprehensive evaluation is necessary for the specific diagnosis of arthrogryposis, which is important for the corresponding life-long treatment. Evaluation includes history of pregnancy and delivery, family history, physical and neurological examinations, involvement of affected joints, intellectual development, and response to treatment. Laboratory tests, such as electrophysiological studies, pathologic examinations (including muscle and/or nerve biopsy), and gene sequencing may help differential diagnosis.

Moreover, prenatal screening has become more widely available in recent years [ 28]. Lack of mobility and an abnormal position of the joints are typical ultrasound findings. However, 75% of AMC is not diagnosed prior to delivery, and only severe AMC may be discovered by ultrasound screening [ 29]. Fetal movement is not routinely screened because it is time-consuming: an experienced ultrasound technician requires 45 min to examine the movement of each fetal limb. It is also difficult to detect abnormal fetal movement during the first trimester [ 30]. Micrognathia, altered amniotic fluid volume [ 31], increased nuchal edema [ 32], and cystic hygroma [ 33] have also been reported as common sonographic findings in AMC. Given the improved visualization of small anatomical structures, the use of 4D ultrasound enables early diagnosis [ 34].

Treatment

Treatment for AMC is multidisplinary and involves the participation of orthopedics, neurologists, anesthesiologists, physical therapists, and parents/guardians. Surgical procedures include tendon release, lengthening of the extensor, repair of club feet, traction and casting, and distraction osteogenesis to improve upper airway obstruction. Moreover, posterior spinal instrumentation is required to prevent further angular deformity caused by scoliosis. The primary objective is to restore the ability of personal care, mobility, and functional ambulation. Patient-specific therapy and rehabilitation are necessary for positive outcomes. The majority of patients require multiple surgeries to release contractures and correct deformities. It is also important to initiate surgical intervention and rehabilitation as early as possible [ 35]. However, satisfactory correction in AMC patients who need revision surgery is difficult and has a high recurrence rate [ 36].

Perioperative challenges and anesthetic choices

General anesthesia is required in most procedures. Difficult airway is the first concern of anesthesiologists. The incidence of difficult airway is 25%. [ 37]. Limited mouth opening, micrognathia, high-arched palate, limited cervical movement or cervical instability, and abnormal orofacial musculature make direct laryngoscopy or intubation difficult or impossible.. Some AMC patients may have severe airway obstruction, and tracheostomy is usually needed because of abnormal orofacial development [ 38, 39]. Although there have been many reports on successful intubations via fiberoptic bronchoscopy and intubating laryngeal mask airway [ 40– 42], it is recommended that all equipment necessary for the management of pediatric difficult airway must be available in the operating room.

Regional anesthesia has been successfully used in AMC patients [ 43– 45] and is an alternative to general anesthesia. Epidural anesthesia has been effectively used in a parturient with AMC [ 43]. Single-shot spinal anesthesia has been used for emergency surgery for tibial fracture in a pediatric AMC patient [ 46]. It is important to know that these patients may have abnormal cerebrospinal fluid flow dynamics with unpredictable spread of local anesthetics because of spina bifida or sacral agenesis. Complications, including hematoma, dural puncture, and nerve damage have been reported in patients with tethered cord syndrome [ 47, 48]. Ultrasound guidance can increase the success rate of nerve block in AMC patients, and nerve stimulation may be limited in some patients because of joint contracture and immobility [ 37]. Regional anesthesia may be difficult given the abnormalities of the spine and extremities. Moreover, anesthesiologists should always be on the alert for potential nerve complications and conversion to general anesthesia that result from incomplete or failed block.

Intraoperative position is also a problem because of multiple contractures. Appropriate padding to decrease compression pressure is necessary to decrease the risk of damage. Difficult IV access may occur because of tense skin and scanty subcutaneous tissue.

AMC patients are more susceptible to postoperative pulmonary complications because of increased sensitivity to neuromuscular blockers and opioids, as well as restrictive ventilation dysfunction caused by scoliosis or thoracic deformities. Stridor and postoperative atelectasis are common [ 37]. Thus, it is important to monitor postoperative respiratory function and airway patency. Furthermore, regional anesthesia or local infiltration is recommended for postoperative analgesia to decrease the postoperative use of opioids. For example, single-shot nerve block is suggested for upper or lower extremities and caudal block can be used for postoperative analgesia of club-foot repair or hernia repair.

Although there have been several reports of MH-like symptoms in children with AMC [ 37, 49], the association between AMC and MH is unclear. Volatile agents have been safely used in AMC patients [ 50]. Short-acting nondepolarizing neuromuscular blocking agents have been recommended [ 37]. Meanwhile, there is no data supporting the safe use of succinylcholine in AMC.

Conclusions

AMC is an etiopathogenetically heterogeneous disease with variable degrees of severity. Diagnosis of AMC should include clinical features, neurological examination, and genetic testing. Patients with AMC usually require life-long surgical and non-surgical therapies to improve joint function. Thus, it is important for anesthesiologists to understand the pathophysiology of AMC to best manage patients in the perioperative setting.

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