Congenital Multiple Arthrogryposis: Clinical Guidelines

List of Abbreviations

AMC — arthrogryposis multiplex congenita.

DA — distal arthrogryposis.

SMA — spinal muscular atrophy.

EMG — electromyography.

ENMG — electroneuromyography.

CT — computed tomography.

MRI — magnetic resonance imaging.

PT — physical therapy.

US — ultrasound examination.

CTG — cardiotocography.

ECG — electrocardiography.

CNS — central nervous system.

IPRA — individual rehabilitation and habilitation program.

AR — autosomal recessive.

AD — autosomal dominant.

LoE — levels of evidence.

GoR — grades of recommendation.

POO — prosthetics and orthotics.

ATD — assistive technology devices.

Terms and Definitions

Akinesia — inability to perform voluntary movements or alteration in their strength, range, or speed.

Amyoplasia — the most common form of arthrogryposis multiplex congenita (AMC).

Embryogenesis — the formation and development of the embryo.

Genotype — the set of genes of a given organism.

Phenotype — the set of characteristics exhibited by an individual at a specific stage of development.

Contracture — limitation of passive movement in a joint.

Mutation (nucleotide sequence variant) — a permanent change in the nucleotide sequence of the genome.

Inversion — a change in the orientation of chromosome segments.

Reciprocal translocation — transfer of a chromosomal segment to a non-homologous chromosome.

Chromosomal aberrations — anomalies in the structure or number of chromosomes.

Deletion — loss of genetic material from one or more chromosomes.

Duplication — doubling of a part of the genetic material of one or more chromosomes.

ICD-10 — International Classification of Diseases, Tenth Revision.

Intrauterine growth restriction — a condition in which a fetus fails to achieve its optimal growth potential during pregnancy.

Myopathies — chronically progressive neuromuscular disorders characterized by primary muscle involvement.

Assistive technology devices — devices containing technical solutions, including special ones, used to compensate for or eliminate permanent restrictions on the daily activities of a person with a disability.

Prosthetic and orthotic devices are technical rehabilitation means used to compensate for or eliminate persistent disabilities.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Congenital multiple arthrogryposis (CMA) is a term used to describe a group of disorders characterized by congenital joint contractures in two or more body parts [1].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The occurrence of arthrogryposis is associated with restricted fetal movement (fetal akinesia), with a correlation between the severity of contractures and the duration of restricted fetal motor activity: the longer this duration, the more severe the contractures. Loss of fetal muscle function leads to fetal akinesia and, secondarily, to joint contractures. At the same time, restriction of joint movement secondarily leads to muscle atrophy and the formation of contractures [2]. Fixation of the joint in a forced position is associated with excessive proliferation of connective tissue in the joint capsule, which occurs compensatorily due to the lack of fetal movement [3]. A possible cause of fetal akinesia is ischemia of the anterior horn cells of the spinal cord due to vascular disorders and impaired muscle tissue development [2]. In most cases, joint formation is not impaired during embryogenesis; however, the lack of movement secondarily leads to joint deformity and changes in periarticular tissues [1, 4]. The main causes of CMA are:

1. genetic factors (currently, over 400 genes associated with this pathology have been identified; resulting mutations lead to damage to the motor neurons of the anterior horns of the spinal cord, muscle cells, impaired neuromuscular transmission, etc.).

2. maternal diseases (myasthenia gravis, arterial hypotension, diabetes);

3. environmental factors, including bacterial and viral infections (Zika virus, cytomegalovirus infection, rubella virus, etc.), substance use (cocaine, etc.), etc.;

4. mechanical factors limiting fetal movement (oligohydramnios, uterine malformations (bicornuate uterus), uterine myoma (fibroid), multiple pregnancy, presence of amniotic bands, etc.) [1-2, 5-6].

Amyoplasia occurs sporadically as a result of vascular disorders arising during embryogenesis, whereas distal forms are often classified as hereditary diseases [7].

1.3 Epidemiology of the Disease or Condition

According to R.B. Lowry et al. (2010), the incidence of arthrogryposis is 1 case per 3,000–5,000 live births [8]. The most common type of arthrogryposis is amyoplasia, which is a sporadic, non-progressive disorder occurring at a rate of 1 case per 10,000 live births [4].

1.4 Features of Coding the Disease or Condition

Q74.3 – Congenital multiple arthrogryposis

Q74.8 – Other specified congenital malformations of limb(s)

1.5 Classification of the disease or condition

M. Bamshad et al. (1996) subdivide arthrogryposis into three groups: amyoplasia; distal forms of arthrogryposis; and congenital multiple contractures that are symptoms of syndromes caused by central nervous system damage, as well as various neuromuscular disorders [9].

According to Hall's classification, 3 types of CMA are distinguished:

• Type I - amyoplasia (the most common type of CMA) is characterized by limb involvement only;

• Type II - limb involvement combined with anomalies of other systems;

• Type III - damage to the neuromuscular apparatus combined with central nervous system dysfunction or intellectual disability [10].

In type II CMA, anomalies of the cardiovascular system, respiratory system, gastrointestinal tract, urogenital system, visual organs, and ENT organs are noted [11].

Distal arthrogryposes are a group of genetic disorders predominantly with an autosomal dominant inheritance pattern, characterized by involvement of the distal limbs (hands and feet). Depending on the type of disease, typical facial anomalies and varying degrees of involvement of other body parts are characteristic [4].

M. Bamshad et al. (1996) revised and expanded the classification of the most common types of distal arthrogryposis proposed by J. Hall in 1982, identifying 9 types [9]. M. Bamshad's classification (2009) presents 10 types of distal arthrogryposis [12]. Currently, more than 12 different types have already been described (Table 1).

Table 1 Classification of distal arthrogryposis types

Phenotypic series of distal arthrogryposis are presented in the OMIM database [13]. The absolute majority of distal arthrogryposises are inherited in an autosomal dominant manner, with only two types—DA5D (ECEL1) and DA12 (ADAMTS15)—being inherited in an autosomal recessive manner.

Distal arthrogryposis type 1, digitotalar dysmorphism (OMIM 108120). There are 3 genetic variants: type 1A includes cases associated with mutations in the TPM2 gene (9p13.3) encoding β-tropomyosin; type 1B includes mutations in the MYBPC1 gene (12q23.2), whose protein product is myosin-binding protein C; and type 1C includes mutations in the MYL11 gene (MYLPF) encoding the fast-twitch skeletal muscle regulatory light chain. Inheritance pattern: autosomal dominant, with autosomal recessive patients described for DA1C. Distinctive features: camptodactyly, foot deformity. Contractures of the distal limbs—hands (camptodactyly, ulnar deviation of the wrists, flexion contracture of the thumb, poorly defined palmar creases, absence of interphalangeal creases) and feet (clubfoot—25%, pes planovalgus—33%) of varying severity. Involvement of proximal joints (shoulders and hips) is an inconsistent feature. Facial dysmorphisms, micrognathia, and limitation of mouth opening may be present. Other organs and systems are usually unaffected. Intrafamilial variability of clinical manifestations is characteristic.

Distal arthrogryposis type 2A, Freeman-Sheldon syndrome, craniocarpotarsal dysplasia (OMIM 193700). Most cases are caused by mutations in the MYH3 gene located in segment 17p13.1, encoding one of the heavy chain isoforms of myosin. Inheritance pattern: autosomal dominant. Distinctive features: contractures of the orofacial muscles lead to the formation of a phenotype resembling a "whistling face": a wide prominent forehead, a mask-like face, and a small mouth with lips pursed as if whistling; in addition, ulnar deviation of the fingers, camptodactyly, and foot deformity are characteristic. Signs of facial dysmorphism: prominent forehead and superciliary arches, mask-like flat face, long philtrum, H- or V-shaped chin dimple, hypertelorism, deep-set eyes, blepharophimosis, ptosis, downslanting palpebral fissures, epicanthus, strabismus, alar hypoplasia, short nose and wide nasal bridge, prominent nasolabial folds, microstomia, and "pursed" lips. Other: small tongue and jaw, high palate, swallowing difficulties, speech problems (nasal voice). Signs of skeletal involvement: short neck, kyphoscoliosis (84%), hip dislocation, shoulder and knee joint contractures (73%), camptodactyly (88%), ulnar deviation of the fingers (91%), thumb flexion contracture, severe pes planovalgus ("rocker-bottom foot") or clubfoot (59%).

Distal arthrogryposis type 2B, Sheldon-Hall syndrome (OMIM 601680). Sheldon-Hall syndrome is caused by mutations in the TNNI2 (type 2B1) and TNNT3 (type 2B2) genes localized in segment 11p15.5 and encoding troponin I and troponin T isoforms, respectively. In some cases, type 2B is caused by mutations in the MYH3 gene (type 2B3) (segment 17p13.1) encoding embryonic myosin heavy chain 3, and the TPM2 gene (type 2B4) (segment 9p13.3) encoding β-tropomyosin (it is an allelic disorder to DA 1). Inheritance pattern: autosomal dominant. Distinctive features: characteristic facial dysmorphisms—triangular face with prominent nasolabial folds, downslanting palpebral fissures, microstomia, and a prominent chin; camptodactyly, ulnar deviation of the fingers, foot deformity. Signs of facial dysmorphism: triangular face, long philtrum, prominent nasolabial folds, microstomia, temporomandibular joint contracture (type 2B3), small prominent chin, micrognathia, downslanting palpebral fissures, wide nasal bridge, fused earlobe. Signs of skeletal involvement: neck skin folds, scoliosis (type 2B3), hip dislocation (type 2B2), wrist extension contracture, severe camptodactyly, ulnar deviation of the fingers, thumb flexion contracture, absence of skin creases over the interphalangeal joints of the fingers, foot deformity: types 2B1 and 2B3—clubfoot, type 2B2—severe pes planovalgus ("rocker-bottom foot").

Distal arthrogryposis type 3, Gordon syndrome (OMIM 114300). The syndrome is caused by heterozygous mutations in the PIEZO2 gene, which is localized to the 18p11 segment. Inheritance pattern: autosomal dominant. Distinctive features: short stature, short neck, cleft palate, camptodactyly, clubfoot. Signs of facial dysmorphism: micrognathia, slight facial asymmetry, ptosis, epicanthus, ophthalmoplegia (rare), cleft palate or high-arched palate. Signs of skeletal involvement: short stature, short neck, cervical skin folds, low hairline, sloping shoulders, pectus excavatum, kyphoscoliosis, lumbar hyperlordosis, congenital hip dislocation, knee flexion contractures, short fingers, camptodactyly, cutaneous syndactyly, clubfoot. Signs of muscle involvement: diffuse hypotrophy with predominant involvement of the leg muscles. Other: Chiari malformation type I, mild intellectual disability, cryptorchidism.

Distal arthrogryposis type 4, with severe scoliosis (OMIM 609128). Inheritance pattern: autosomal dominant. The gene has not been identified. Distinctive features: scoliosis that progresses with age. Signs of facial dysmorphism: frontal hypoplasia, low anterior and posterior hairlines, nystagmus, depressed nasal bridge. Signs of skeletal involvement: craniosynostosis/skull asymmetry, torticollis (bony forms), camptodactyly, syndactyly, ulnar deviation of the hands, clubfoot, plano-valgus foot deformity.

Distal arthrogryposis type 5, with ocular motor abnormalities and retinopathy (OMIM 108145). The etiological factor is heterozygous mutations in the PIEZO2 gene, localized to the 18p11 region. Inheritance pattern: autosomal dominant. Distinctive features: blepharophimosis, ophthalmoplegia, retinopathy, ptosis, camptodactyly, clubfoot, restrictive lung disease. Signs of facial dysmorphism: triangular expressionless face, ophthalmoplegia, deep-set eyes, epicanthus, blepharophimosis, ptosis, hyperopia (rare), retinitis pigmentosa, Duane syndrome, strabismus, astigmatism, keratoglobus or keratoconus, limitation of mouth opening. Signs of skeletal involvement: pectus excavatum, scoliosis (rare), restriction of forearm rotation and wrist extension, camptodactyly, long fingers, clinodactyly, clubfoot, signs of muscle involvement (decreased muscle mass, firm muscles). Poorly formed palmar creases, dimples over major joints, restrictive lung disease.

Distal arthrogryposis type 5D (OMIM 615065). The development of the syndrome is associated with biallelic variants in the ECEL1 gene (chromosomal segment 2q37.1), whose protein product is endothelin-converting enzyme 1, necessary for proper intramuscular branching of motor neuron axons in skeletal muscles during embryogenesis. Inheritance pattern: autosomal recessive. Distinctive features: round face, arched eyebrows, unilateral or asymmetric ptosis, micrognathia, congenital hip dislocation, knee extension contractures, severe camptodactyly, clubfoot. Signs of facial dysmorphism: round, expressionless face, micrognathia, arched eyebrows, unilateral ptosis or more prominent on one side, bulbous nose, cleft palate. Signs of skeletal involvement: short neck, mild to severe scoliosis (rare), bilateral hip dislocation (rare), contractures of the shoulder, elbow, wrist, and knee (extension) joints, severe camptodactyly, adduction of the thumb, flat-valgus foot, clubfoot (rare). Signs of muscle involvement: muscle mass hypotrophy (predominantly in the lower extremities).

Distal arthrogryposis type 6, with sensorineural hearing loss (OMIM 108200). Inheritance pattern: autosomal dominant. The etiological gene for this type remains unidentified. Distinctive features: sensorineural hearing loss, upper limb contractures. Signs of skeletal involvement: microcephaly, camptodactyly.

Distal arthrogryposis type 7, trismus-pseudocamptodactyly syndrome, Hecht syndrome (OMIM 158300). Caused by a recurrent variant in the MYH8 gene located on chromosome 17p13.1, which encodes the perinatal myosin heavy chain 8. Inheritance pattern: autosomal dominant. Distinctive features: trismus, pseudocamptodactyly (limited extension in the interphalangeal joints of the hand only upon dorsal extension), hip dislocation, clubfoot. Facial dysmorphism features: micrognathia, long chin (rare), ptosis, limited mouth opening (trismus). Skeletal involvement features: hip dislocation, limited forearm supination, pseudocamptodactyly, clubfoot or metatarsus adductus, pes planovalgus. Muscle involvement features: shortening of the flexor digitorum profundus, shortening of the gastrocnemius muscle.

Distal arthrogryposis type 8, multiple pterygium syndrome (OMIM 178110). Caused by a mutation in the MYH3 gene (segment 9p13.3) encoding the embryonic myosin heavy chain 3. Inheritance pattern: most commonly autosomal recessive, autosomal dominant also occurs. Distinctive features: multiple joint contractures with pterygia: cervical, elbow, popliteal, axillary pterygium; camptodactyly, minor facial anomalies. Facial dysmorphism features: micrognathia, long philtrum, antimongoloid slant of the eyes, epicanthus, ptosis, low-set ears, cleft palate, and downturned corners of the mouth. Skeletal involvement features: short stature, multiple joint contractures with pterygia, kyphoscoliosis and vertebral fusion (frequently), rib fusion, hip dislocation, absence of the patella. Males may present with cryptorchidism and a small penis, females with hypoplastic labia majora.

Distal arthrogryposis type 9, Beals syndrome, congenital contractural arachnodactyly (OMIM 121050). The syndrome is caused by mutations in the FBN2 gene (5q23) encoding the glycoprotein fibrillin-2, a key regulator of elastic fiber assembly during early embryogenesis, which is essential for the proper formation and function of connective tissue elastic fibers. Inheritance pattern: autosomal dominant. Distinctive features: Marfanoid phenotype, arachnodactyly, camptodactyly, deformed auricles, joint contractures, kyphoscoliosis, foot deformities, osteopenia. Facial dysmorphism features: micrognathia (27%), prominent frontal eminences, " crumpled" ear (76%): prominent crus of the helix, helical folds; lens ectopia, myopia, high-arched palate (28%), relatively short neck. Skeletal involvement features: cranial deformation (scaphocephaly, brachycephaly, or dolichocephaly), dolichostenomelia, congenital kyphoscoliosis (45%), contractures of the hip (25%), elbow (86%), and knee (81%) joints, patellar subluxation, arachnodactyly, camptodactyly, ulnar deviation of the fingers, metatarsus adductus or clubfoot (32%). Joint contractures frequently tend to resolve spontaneously with age. Additionally, osteopenia, gastrocnemius muscle hypoplasia, aortic aneurysm in approximately 15–20% of cases, lens subluxation, variable degrees of myopia, and congenital heart defects (atrial and ventricular septal defects, aortic root dilatation, mitral valve regurgitation) are observed.

Distal arthrogryposis type 10, with equinus contracture (OMIM 187370). The causative gene has not been identified. Inheritance pattern: autosomal dominant. Distinctive features: equinus or equinovarus foot deformity, causing children to walk on tiptoe. Skeletal involvement features: camptodactyly, knee, elbow, and wrist contractures are rare and mild.

Distal arthrogryposis type 11, with camptodactyly, absence of skin creases over the interphalangeal joints of the fingers, and limited forearm supination (OMIM 620019). Caused by mutations in the MET gene, which belongs to the receptor protein kinase family. Inheritance pattern: autosomal dominant. Distinctive features: isolated involvement of the upper extremities, absence of flexion creases, limited forearm supination. Skeletal involvement features: camptodactyly, limited forearm supination, wrist contractures. Facial, spinal, and lower extremity involvement is absent [14].

Distal arthrogryposis type 12, with spinal rigidity, scoliosis, and orthodontic anomalies (OMIM 620542). The syndrome is associated with biallelic variants in the ADAMTS15 gene (chromosomal segment 11q24.3), whose protein product belongs to the metalloproteinase family, which plays an important role in connective tissue homeostasis. Inheritance pattern: autosomal recessive. Distinctive features: hypoplasia or absence of flexion creases of the distal fingers, kyphoscoliosis and/or spinal rigidity, microstomia, dental crowding, tooth agenesis. Facial dysmorphism features: micrognathia, microstomia, high-arched palate, dental crowding, or tooth agenesis. Skeletal involvement features: contractures of the interphalangeal joints of the fingers and toes, clinodactyly of the fifth finger, knee and ankle contractures, spinal involvement manifesting as kyphoscoliosis and spinal rigidity. Central nervous system or other organ involvement is absent [15].

E. Kimber's classification (2012) divides all types of distal arthrogryposis into groups based on their pathogenesis:

1. Syndromes caused by muscle contractile protein dysfunction resulting from mutations in the TPM2, TNNI2, TNNT3, MYH8, MYH3 genes: distal arthrogryposis types 1, 2A, 2B, 7, and 8. In addition, distal arthrogryposis types 4, 6, and 10 share clinical features similar to the aforementioned types.

2. Syndromes caused by connective tissue protein dysfunction resulting from mutations in the fibrillin FBN2 gene: distal arthrogryposis type 9.

3. Syndromes caused by somatosensory neuron ion channel protein dysfunction resulting from mutations in the PIEZO2 gene: distal arthrogryposis types 3 and 5. There is a clinically similar entity to PIEZO2-related disorders, namely distal arthrogryposis type 5D, associated with a mutation in the ECEL1 gene [16].

1.6 Clinical presentation of the disease or condition

Signs and symptoms characteristic of CMA:

- multiple congenital contractures of two or more joints in non-contiguous body parts;

- contractures do not progress over the course of life;

- contractures do not develop in previously unaffected joints;

- muscle hypotonia;

- spinal deformities (present at birth or developing over time);

- possible combined involvement of the central nervous system, respiratory system, gastrointestinal tract, and urogenital system;

- intelligence is preserved (may be reduced in case of central nervous system involvement);

- sensitivity is preserved;

- ability to walk and perform self-care varies [1].

Amyoplasia is the most common form of CMA, presenting with characteristic clinical manifestations:

- internal rotation contractures of the shoulders;

- extension contractures of the elbows;

- flexion contractures of the wrists with ulnar deviation, flexion contractures of the fingers, flexion-adduction contracture of the thumb;

- contractures and dislocations of the hips;

- flexion or extension contractures of the knees;

- foot deformities (most commonly clubfoot) [1].

In amyoplasia, all four limbs are involved in 63% of cases (i.e., upper and lower extremity joint contractures are typically symmetrical); three limb involvement is observed in 5% of cases, upper limb involvement in 17%, and lower limb involvement only in 15% [17]. Gastroschisis is observed in 9% of patients with amyoplasia, hand and foot malformations in 12%, and limb/finger constriction rings in 4.3% [18].

DA comprises a group of syndromes characterized by specific phenotypes [12]. Individuals with DA primarily exhibit hand and foot joint contractures, along with other anomalies specific to each syndrome [18].

1.6.1 Differential Diagnosis

There are over 400 diseases and syndromes characterized by contractures involving two or more joint levels.

First and foremost, it is necessary to differentiate from neuromuscular disorders accompanied by congenital joint contractures resulting from neuromuscular apparatus dysfunction. Important criteria for differential diagnosis include the clinical picture, changes in creatine kinase (CK) levels, and the results of ENMG (needle electromyography of a single muscle, stimulation electroneuromyography of a single nerve, needle electroneuromyography of a single nerve).

Congenital muscular dystrophies — a clinically and genetically heterogeneous group of disorders characterized by specific pathomorphological changes in skeletal muscles. In most cases, the disease begins after birth or in early childhood with marked muscle hypotonia ("floppy infant") and muscle weakness, accompanied by primary myopathic changes in muscle fibers. In some cases, respiratory muscle weakness is observed. Children show significant delays in motor development compared to their peers; deep tendon reflexes are frequently reduced or absent. Patients often present with scoliosis, flatfoot with valgus deformity, and hip dislocations. Elevated creatine kinase (CK) levels and a primary myopathic pattern on electroneuromyography (ENMG) may be observed [19, 20].

Spinal muscular atrophy (SMA) — a genetically heterogeneous neuromuscular disorder affecting the anterior horns of the spinal cord and motor nuclei of the brainstem, leading to progressive muscle atrophy and weakness. The development of congenital contractures is caused by impaired intrauterine muscle denervation. Although 5q-SMA is the most common form of SMA, congenital contractures occur in type 0 5q-SMA. If ENMG reveals spinal motor neuron involvement and SMN1 gene variants are absent, differential diagnosis should be pursued with other forms of SMA (X-linked SMA, autosomal recessive distal SMA, etc.) [21].

Differential diagnosis should also be performed with a group of hereditary skeletal dysplasias accompanied by congenital joint contractures:

Diastrophic dysplasia — a type of skeletal dysplasia characterized by impaired formation of certain types of cartilage tissue and associated hindered endochondral bone formation. The disease is caused by pathogenic variants in the SLC26A2 gene located on the long arm of chromosome 5 and is inherited in an autosomal recessive manner. Symptoms appear at birth: reduced birth length, flexion contractures of the hip and knee joints, scoliosis, stiffness of the interphalangeal joints, short fingers, and clubfoot (equinovarus deformity). Other early postnatal manifestations include inflammation of the auricular cartilage developing in the first months of life, subsequently leading to auricular deformity. Patients have short stature [4, 22].

Epiphyseal dysplasias — a genetically heterogeneous group of severe hereditary systemic skeletal disorders based on impaired endochondral ossification with predominant involvement of the epiphyses of long tubular bones (delayed ossification, deformation [flattening], tendency toward aseptic necrosis) and vertebrae (delayed ossification, platyspondyly, degenerative changes in intervertebral discs). These changes lead to the early development of osteoarthritis in large joints and spinal osteochondrosis. Clinically, patients exhibit contractures of the knee, elbow, and hip joints, scoliosis, and below-average height [4, 22].

Larsen syndrome is manifested by multiple dislocations of large joints combined with signs of facial dysmorphism (hypertelorism, flat facies, prominent forehead, depressed nasal bridge, etc.) and cylindrical fingers. The classic form of the syndrome is caused by pathogenic variants in the FLNB gene and is inherited in an autosomal dominant manner; more severe recessive variants have also been described. According to most researchers, recessive forms of Larsen syndrome are most commonly associated with congenital anomalies (choanal atresia, aplasia of the right kidney and gallbladder, agenesis of the corpus callosum, and congenital heart defects). Lethal forms of the syndrome reveal marked chest hypoplasia leading to secondary pulmonary hypoplasia [4, 22].

Metatropic dysplasia — a rare spondyloepimetaphyseal dysplasia whose classic variant is characterized by changing body proportions with age: newborns exhibit rhizomelic limb shortening with a relatively normal trunk length, but as the child grows, due to vertebral involvement and progressive kyphoscoliosis, trunk shortening becomes more pronounced, resulting in a severely disproportionate short stature. In newborns, the chest is narrow and elongated, later becoming barrel-shaped and pectus carinatum; progressive kyphoscoliosis, flexion contractures of large joints combined with small joint hypermobility, and brachydactyly are typical, along with characteristic radiological changes (pronounced platyspondyly, dumbbell-shaped deformation of long tubular bones, "halberd-shaped" iliac wings) [4, 22].

Marfan syndrome — an inherited connective tissue disorder with an autosomal dominant inheritance pattern, caused by pathogenic variants in the FBN1 gene encoding the glycoprotein fibrillin-1. The disease is characterized by high but incomplete penetrance and marked variability of clinical expression. In classic cases, tall stature, limb elongation (dolichostenomelia), elongated fingers and toes (arachnodactyly), and a deficiency of subcutaneous adipose tissue are observed. Musculoskeletal features include elongation of the skeletal tubular bones, chest deformities, scoliosis, joint hypermobility, and a tendency toward dislocations. The most significant visceral manifestations include progressive aortic root dilation and/or aortic aneurysm, as well as ectopia lentis [4, 22].

Bruck syndrome — a combination of congenital multiple arthrogryposis and osteogenesis imperfecta. Clinically characterized by congenital contractures of large joints and multiple bone fractures starting in infancy or early childhood. Additional features include postnatal short stature due to limb contractures and deformities, pterygium, and progressive scoliosis. Intellect, vision, and hearing are preserved. There are two types of Bruck syndrome: type I, caused by biallelic pathogenic variants in the FKBP10 gene, and type II, associated with biallelic variants in the PLOD2 gene [18, 23].

Differential diagnosis with other, less frequent disorders phenotypically similar to congenital muscular dystrophies is presented in Table 2 [4, 13].

Table 2. Differential diagnosis of congenital muscular dystrophies

2. Diagnostics, medical indications and contraindications for diagnostic methods

Currently, there is no single "gold standard" diagnostic method for AMC. The primary sign of the disease is the presence in a newborn of multiple contractures in two or more non-adjacent joint areas, which do not progress over the course of life.

Main criteria for establishing the diagnosis/condition:                    

based on pathognomonic findings:

1) anamnesis (family history is absent in amyoplasia and positive in syndromic forms of AMC; absence of contracture progression during the patient's life);

2) physical examination (presence of multiple congenital contractures of two or more non-adjacent joint areas).

2.1 Complaints and Anamnesis

Medical specialists consulted by children with joint contractures should consider this diagnosis in all cases involving congenital contractures.

Signs and symptoms that warrant suspected AMC — see subsection 1.6.

2.2 Physical Examination

Comments: genealogical data analysis in patients with congenital contractures to identify the hereditary nature of the disease, though it should be kept in mind that de novo mutations are possible (parents are not carriers).

Comments: upon patient examination, it is necessary to pay attention to the localization, extent, and nature of joint contractures; assess muscle strength and tone; and note the presence or absence of other clinical signs characteristic of AMC: skin dimples over the joints; deformities of the limbs, spine, skull, and maxillofacial region; presence of a hemangioma in the glabella and forehead region; and delayed motor development of the child (clinical manifestations depend on age).

Comment: the frequency and nature of the examination depend on the existing pathology (medical indications).

2.3 Laboratory Diagnostics

Comments: high CK activity (more than 10-fold) is observed in muscular dystrophies combined with congenital limb joint contractures [33].

Comments: the presence of maternal anti-acetylcholine receptor antibodies in an infant may indicate transient neonatal myasthenia gravis.

2.4 Instrumental Diagnostics

Comment: this study allows for the detection of bone deformities and developmental anomalies (e.g., synostoses), joint abnormalities (contractures, ankyloses), and bone deformations.

Comment: this study allows for the detection of spinal developmental anomalies and scoliosis, as well as dynamic assessment of its progression.

Level of certainty of recommendations C (evidence level of reliability 5)

stimulatory electromyography (stimulatory electroneuromyography of a single nerve), needle electromyography (single muscle), and surface electromyography (single anatomical region) to assess the state of muscles and peripheral nerves [30-32, 40-43].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comment: this study helps determine the level of nervous system lesion, assess the condition of the neuromuscular apparatus, and monitor treatment dynamics.

Comment: this study is non-invasive and allows for the detection of abnormal electrical activity in the brain.

Comment: this study is invasive. It enables the differential diagnosis of AMC from progressive neuromuscular disorders when no other means of diagnosing a neuromuscular disease are available.

2.5 Other Procedures

2.5.1 Prenatal Diagnosis

2.5.1.1 Ultrasound Examination

Comment: A non-invasive procedure with minimal health risk to the unborn child and mother. Assessment includes measuring the length and shape of the long tubular bones, ribs, and spine, checking for deformities, and evaluating whether bone length corresponds to gestational age. The main diagnostic signs at 12 weeks of pregnancy include: decreased size of the fetal nuchal translucency, restricted motor activity or akinesia, and limb and skeletal deformities. The lethal form of arthrogryposis at this gestational age is characterized by such signs as fetal akinesia, decreased fetal nuchal translucency, cystic hygroma, pulmonary hypoplasia, hydrops, and edema, which are poor prognostic signs. By 16–18 weeks of gestation, limb and whole-skeletal deformities are diagnosed, and slowed fetal movements are recorded. In the third trimester of pregnancy, polyhydramnios, clubfoot, joint contractures, pleuritis, micrognathia, ventriculomegaly, hydronephrosis, and gastric paresis are revealed [25–27, 45, 48–51]. Early ultrasound diagnosis of arthrogryposis is difficult. Prior to 24 weeks of gestation, this condition is diagnosed in only 25% of cases [28]. Most commonly, congenital multiple arthrogryposis is diagnosed in the late second to third trimester of pregnancy [26, 48]. The presence of neck edema, hydrops, scoliosis, and flexion contractures of the knee joints prior to 20 weeks is a prognostically unfavorable sign [52], which should be considered when making a decision on continuing the pregnancy [25].

Comment: The presence of cervical spine hyperextension, especially when combined with fetal breech presentation, is an indication for cesarean section due to the high risk of cervical spine injury [28].

Comment: The most informative sign is the assessment of the pattern and quality of fetal movements. The duration of the study should be at least 45 minutes, allowing for a comprehensive evaluation of fetal movements. Follow-up dynamic assessment is recommended. If congenital multiple arthrogryposis is detected in the fetus during pregnancy, measures aimed at enhancing its motor activity should be implemented, including maternal physical exercise, breathing exercises, and caffeine intake [25].

2.5.2.2 Fetal Cardiotocography

Comment: A characteristic sign is the absence of rapid fetal movements while slow movements—manifested as displacement of the head and trunk—are preserved. Slow fetal movements are usually not felt by the woman, which is why the characteristic complaint is the absence of fetal movements [24].

2.5.2.3 Fetal Magnetic Resonance Imaging (MRI)

Comment: This study is not the primary method and is prescribed in addition to fetal ultrasound. It allows for the diagnosis of developmental anomalies of the central nervous system, lungs, and skeletal muscles, including their atrophy and fatty degeneration [24, 26–28, 45, 48, 53].

2.5.2.4 Molecular Genetic Testing

Comment: The choice of procedure is determined by the gestational age, the condition of the pregnant woman, and the availability of technical resources. They are performed to obtain fetal cells and determine the genetic status of the fetus. In the first trimester of pregnancy, chorionic villus sampling is most commonly performed; in the second trimester, amniocentesis, placental biopsy, and cordocentesis are used [57].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

Comment: Provided the somatic condition of the child with arthrogryposis is stable, conservative treatment can be initiated as early as the first week of life in a hospital or home setting [31, 64]. The goal of treatment is to improve passive and active joint range of motion and eliminate limb deformities.

Comments: Parents of a patient with arthrogryposis are trained in therapeutic physical education for joint injuries and diseases (corrective exercises and positioning aimed at eliminating deformities and contractures of the upper and lower limb joints); sessions should be conducted at least 4 times a day for 30 minutes.

Comments: A rapid improvement in the range of motion in affected joints is a favorable prognostic factor for the recovery of the patient's motor activity. If there is no positive dynamic from conservative treatment within 1 month, the chances for further improvement are low. Improvement in the condition of the lower extremities during the first year of life helps determine the child's ability to sit, stand, and walk. Conservative treatment is most effective up to the age of 3–6 months.

Comment: Custom-made pillows are used for this purpose.

Comment: In children under 3 months of age, splints are used for up to 20 hours a day, whereas in older children they are used only during daytime and nighttime sleep.

Comment: the presence of hip dislocation in a patient with arthrogryposis is an indication for surgery. Closed hip reduction methods in most cases fail to achieve reduction and frequently lead to avascular necrosis of the femoral head. When correcting flexion-adduction contractures of the hip joints, positioning the patient prone (to eliminate the flexion component) and in the supine position with lower limb abduction (to eliminate the adduction component) is indicated. In cases of external rotation-abduction contractures of the hips, the lower limbs are rotated and adducted to a neutral position and fixed in this position using elastic bandages.

Comment: for casting feet, it is more rational to use long leg casts with the knee flexed at 90° to eliminate rotational movements in the knee joint and prevent the circular cast from slipping down.

Comment: to unlock the subtalar joint in children with arthrogryposis, an early achillotomy is performed after applying 1–3 circular casts once the cavus component of the deformity has been corrected. In some cases, when correcting equinus in the abducted position with pronounced tension of the achilles tendon, a repeat achillotomy is required. However, this frequently fails to achieve the necessary ankle dorsiflexion, as equinus is often caused not only by Achilles tendon shortening but also by retraction of the capsular and ligamentous structures along the posterior aspect of the ankle joint, necessitating surgical treatment.

Comment: in severe pes planovalgus ("rocker-bottom foot"), serial cast correction aims to stretch the neurovascular bundles along the dorsolateral aspect of the foot, the retracted foot extensor tendons, and the peroneal muscle tendons, serving as a preparatory phase for surgery to prevent postoperative vascular complications and soft tissue necrosis. Initially, serial casting up to the upper third of the leg is performed in maximum possible plantar flexion, supination, and forefoot adduction. Subsequently, once the forefoot and midfoot are brought into a neutral position, the child is fitted with ankle-foot orthoses until surgical intervention takes place.

Comment: for knee flexion contractures, serial application of circular casts and splints to the lower extremity is performed.

If contracture correction is incomplete and interferes with the child's subsequent ability to walk, surgical treatment is indicated.

Comments: the use of prosthetic and orthotic devices helps prevent deformity recurrence, while assistive rehabilitation devices ensure patient mobility and prevent the development of osteoporosis.

3.2 Surgical Treatment

3.2.1 Surgical Treatment of Upper Extremity Deformities

Comment: during preoperative planning, it is necessary to assess the patient's rehabilitation potential and establish primary goals for surgical treatment. Treatment must be personalized [78]. The key joint determining the sequence and order of upper extremity surgeries is the elbow joint [30, 79].

Comment: the optimal age for this surgery is under 1 year [79].

Comment: the latissimus dorsi muscle, pectoralis major muscle, gracilis muscle, and long head of the triceps brachii muscle are most commonly used as donor muscles to restore active elbow flexion [32, 40-43, 78, 80-82].

Comment: there are isolated studies on musculocutaneous nerve neurotization in infants in the first months of life with arthrogryposis to restore active forearm flexion; however, this technique has not gained widespread use [83-84].

Comment: in cases where correction is feasible, tendon-muscle plasty is performed (division of the flexor carpi ulnaris, transposition of the flexor carpi radialis to the extensor carpi radialis brevis, and fasciotomy of the flexor aspect of the forearm). If passive correction of the wrist contracture to a neutral position is not possible, midcarpal joint resection combined with partial excision of the proximal and distal carpal rows is performed along with tendon-muscle plasty (division of the flexor carpi ulnaris, transposition of the flexor carpi radialis to the extensor carpi radialis brevis, and fasciotomy of the flexor aspect of the forearm).

Comment: in case of instability of the thumb metacarpophalangeal joint, chondrodesis is performed.

Comment: this procedure places the hand in a functionally advantageous position relative to the face without improving the range of motion in the shoulder joint. Common complications include periprosthetic fractures and recurrences of intraoral contractures [78, 78]. Currently, no surgical procedures have been developed to improve the range of active and passive motion in the shoulder joint [78, 80, 87, 88].

3.2.2 Surgical Treatment of Lower Extremity Deformities

Comment: it is necessary to assess the patient's functional capabilities, the severity of lower extremity joint lesions, and the muscular system. The choice of the key joint depends on the age at which treatment is initiated.

Comment: in children over 2 years of age with recurrent deformities and the impossibility of single-stage correction, contracture correction is performed by applying external fixation devices using a compression-distraction external fixation device on the lower leg and foot [31].

Comment: for rigid foot deformities and relapses after serial casting according to the Dobbs method, a peritalar release with open reduction of the talus is performed at the age of 6 months to 3 years [31, 93].

Comment: the optimal age for open hip reduction is 5–12 months. Both anterolateral and medial approaches are used for open reduction [91, 93-96]. Joint stability can be enhanced using the ligamentum teres femoris [91]. However, the Watson-Jones anterolateral approach is preferred for patients with AMC, as achieving concentric reduction of the femoral head requires the elimination of external rotation contracture, which is achieved by tenotomy of the m. triceps coxa, and in more severe cases, a posterior capsulotomy is additionally performed [97].

Comment: in hip flexion contractures, percutaneous tenotomies of the subspinal muscles, tensor fasciae latae, and sartorius tendon significantly improve hip extension in children under 3 years of age [91].

Comment: temporary hemiepiphysiodesis is a minimally invasive and safe method compared to other techniques. However, when choosing this treatment method, it is necessary to assess the severity of functional impairments and rule out the need for immediate contracture correction, given the low rate of correction (~1.4° per month).

Comment: supracondylar extension femoral osteotomy for complete single-stage correction of a knee flexion contracture can only be performed in children with closed growth plates, as the effect is neutralized at a rate of 1° per month [89, 101].

Comment: knee extension contractures are more functionally advantageous for patient locomotion, but they limit sitting and transportation in older children. Minimally invasive subcutaneous partial myotomy of the rectus femoris can be performed in patients under 1 year of age. In older children, quadricepsplasty is performed in combination with shortening femoral osteotomy [91].

Comment: talectomy is currently not performed, as it leads to secondary deformities and ankylosis of the tibiocalcaneal joint in older children [91].

Comment: arthrodesis procedures on the feet in children are performed at the end of growth at 14-15 years of age. However, children with arthrogryposis exhibit spontaneous ankylosis at the level of the Chopart, subtalar, and ankle joints in a malpositioned attitude already at 9-10 years of age in recurrent deformities, which is why triple arthrodesis may be performed in them as early as 10-12 years of age [31].

3.3 Other Treatment

Comments: the use of exoskeletons allows some patients to partially improve upper limb function; however, they are largely inaccessible to the majority of patients due to their high cost and lack of mass industrial production [78, 80, 102, 103]. Developing treatment methods utilizing cell technologies have not yet found clinical application [104].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comment: the home exercise program should be performed by the family or caregivers daily, under the regular supervision of specialists (1-2 times a month). Measures aimed at improving joint mobility and stimulating the development of fine and gross motor skills and hand functions should complement each other and be performed in parallel. In the presence of torticollis, special stretching exercises should be performed. Parent training is key to supporting parent-child interaction and ensuring safe and regular performance of exercises at home and in various settings (e.g., kindergarten). Demonstration of exercise technique and practice with physical therapy specialists are important to ensure proper understanding of the recommended stretching exercises and the home exercise program. Children with AMC may not always achieve all expected developmental milestones, and these may be achieved at different ages. The use of biofeedback and computer technologies in the rehabilitation of children with arthrogryposis is advisable from the age of 3-4 years.

Comment: this technique is performed percutaneously in children, is non-invasive, and helps improve the child's motor activity as a result of stimulating motor neurons in the anterior horns of the spinal cord.

Comment: in the presence of joint contracture, the use of orthoses in children should be considered from the first weeks/months of life. The wear schedule (e.g., day/night) and type of orthotic devices should be determined according to the orthosis prescription and treatment goal. Orthoses used to improve or maintain range of motion should be started in the first year of life, continued throughout the growth period, and used predominantly at night. Orthoses used for functional support should be used during the day. When choosing orthotic devices, cost, insurance coverage, access to orthotic services, and resource availability should be considered, which may vary depending on geographic location [31, 112].

Comment: mobility, starting from the first year of life, should be encouraged by improving coordination, muscle strength, development of motor skills and balance, and developed in accordance with the child's individual capabilities, functional needs, and environmental requirements (e.g., at home, school, community). Standing should begin at approximately 1 year of age (this may vary depending on the child's capabilities), using mobility aids if necessary (e.g., standers, gait trainers, walkers, push toys), and should be encouraged daily. Wheeled mobility devices, such as adapted toy cars, can be used earlier to encourage the child to explore the environment while practicing independent mobility where possible. It is important to continue working on maximizing the ability to stand and/or walk, even if a wheelchair is used, taking into account the family's individual preferences and capabilities. When independent manual wheelchair propulsion is difficult due to limited upper extremity function, powered mobility should be considered.

Comment: introduction to self-care tasks begins at an early age with independent feeding. In school age, the need for independence increases in tasks such as dressing, grooming, and school-related activities (e.g., writing, cutting, etc.). For adolescents, toileting and personal hygiene become very important as they affect community participation and self-esteem. The choice of activity depends on the child's age and/or developmental stage, needs, and interests. Functional goals should be determined by the rehabilitation team with the participation of the child and parents to ensure that goals are realistic and aligned with the child's priorities. If necessary, children with arthrogryposis should be taught compensatory strategies, such as using external surfaces or other body parts for passive movement of the upper extremity, which they can use, for example, for independent feeding, self-care, etc.

5. Prevention and Dispensary Observation

For patients with arthrogryposis, it is advisable to use a comprehensive approach during treatment, including: conservative and surgical treatment of contractures and musculoskeletal deformities (to correct functionally unfavorable limb positions for self-care), rehabilitation, including social and vocational rehabilitation (to develop movements in the joints of the upper and lower extremities, teach self-care skills, and integrate them into daily life), as well as individual selection of orthoses (both to correct joint mobility and to prevent recurrent deformities) [115, 120-121].

5.1 Pregnancy and Childbirth in Patients with AMC

6. Organization of Medical Care

At any stage of medical care delivery to patients with AMC, a number of principles must be observed.

1) The patient and their representatives must receive complete information about the disease, including etiology, pathogenesis, course, prognosis, modern treatment methods, and potential complications.

2) A diagnosis of AMC implies the provision of primary, specialized, and palliative care.

3) Upon diagnosis of AMC, the family should be referred to a specialist with experience working with AMC patients, possessing up-to-date information about the disease, practical experience in its treatment, and the opportunity to participate in clinical trials (of new drugs and/or medical devices). It is also important to inform families about existing public organizations working with AMC patients and their families.

4) A multidisciplinary team of specialists should be involved in monitoring an AMC patient, consisting of: a pediatrician, general practitioner (therapist), geneticist, trauma surgeon (orthopedist), neurologist, medical psychologist, physical therapy physician, physiotherapist, social educator, and prosthetic-orthotic technician. Primary follow-up of AMC patients is carried out by the trauma surgeon (orthopedist). The duties of the trauma surgeon (orthopedist) include: examination and diagnosis, informing the family about the disease, drawing up a treatment plan, conservative treatment of the patient, dynamic follow-up and timely referral for surgical treatment, prescription of orthoses and prosthetic-orthotic devices (POD) and assistive technology (AT), as well as monitoring the replacement of POD and AT as the child grows. Other specialists should be involved as needed if the patient has concomitant pathology [6, 44].

5) In accordance with Order of the Ministry of Health of the Russian Federation No. 1122n dated December 6, 2021, "On Approval of the National Schedule of Preventive Vaccinations and the Schedule of Preventive Vaccinations by Epidemiological Indications and the Procedure for Conducting Preventive Vaccinations", vaccination in AMC patients in the absence of severe concomitant pathology is carried out according to the National Vaccination Schedule [122].

6.1 Indications for Planned Hospitalization

• Complex rehabilitation treatment (exercise therapy, mechanotherapy, robotic mechanotherapy, therapeutic exercise with biofeedback for joint diseases and injuries, general medical massage, drug electrophoresis for joint diseases, drug electrophoresis for central nervous system and brain diseases, paraffin-ozokerite applications, muscle electrical stimulation). Staged correction of joint contractures and limb deformities by applying circular plaster casts.

• Staged surgical treatment.

6.2 Indications for Discharge from the Inpatient Facility

• Improvement of motor activity and/or patient self-care after a course of complex rehabilitation treatment. Completion of the correction of contractures and limb deformities by applying circular plaster casts.

• Implementation of staged surgical treatment, stable patient condition, absence of postoperative complications.

Table 3. Organizational and technical conditions for the provision of medical care.

7. Additional Information

In accordance with the Order of the Russian Ministry of Health No. 747 dated December 19, 2025, "On the Approval of the Rules for the Provision of Medical Care in the Profile 'Obstetrics and Gynecology'", parents of children with AMC, when planning subsequent pregnancies, as well as when planning a pregnancy in a family where one of the parents has arthrogryposis, should be referred for a geneticist consultation to minimize the risk of having an affected child.

Women are referred to a medical genetic counseling clinic for an appointment (examination, consultation) with a geneticist to determine the risk of having an affected child. The geneticist determines the risk of this pathology developing in the fetus, and the couple is given recommendations on pregnancy planning. If there is data on a verified mutation in genes responsible for the development of arthrogryposis in close relatives of the proband and/or the proband themselves who have congenital multiple contractures, it is recommended to search for the same mutation variant in the fetal DNA [57].

If fetal pathology is detected in the first and second trimesters of pregnancy, or in the presence of a burdened hereditary history, diagnostic tests such as chorionic villus sampling, amniocentesis, placental biopsy, or cordocentesis are performed to detect severe congenital diseases [57].

If congenital malformations (malformations of development), chromosomal or other hereditary diseases are detected in the fetus, pregnancy management tactics are determined based on a medical board (consilium) conclusion [57]. The board must include a geneticist, an ultrasound diagnostician, an obstetrician-gynecologist, and a trauma surgeon (orthopedist). During the board meeting, the pregnant woman and her family members are informed about the nature of the fetal lesion, possible pregnancy outcomes, and the prognosis for the child's life and health. If indications are present, recommendations on pregnancy termination are given. It is necessary to explain to the parents the full severity of the disease and the prospects for the child's treatment, and if they decide to continue the pregnancy, to psychologically prepare them for treatment immediately after the child's birth, which helps improve treatment outcomes [28, 123].

7.1 Outcomes and prognosis

The prognosis for an AMC patient depends on the form of the disease, the nature of the deformities, their severity, and the presence of concomitant pathology, and can range from life-threatening to minimal orthopedic impairments. 10% of children are born dead, 27% die within the first months of life [28]. 7% of patients have very severe forms of the disease [18]. 30–40% of patients have feeding difficulties, 4% have respiratory disorders, which usually resolve over time. When the patient reaches the age of 3–4 months, the outcomes of further treatment can usually be predicted. The prognosis is determined by the presence of concomitant pathology, including central nervous system involvement, the child's intellectual development, and the timing and results of conservative and surgical treatment. Most AMC patients have significant potential for walking and independence in everyday life in adulthood. Prerequisites for independent walking are: absence of severe scoliosis, hip flexion contracture less than 20°, knee flexion contracture less than 15°, and active movements in the hip and knee joints [22, 124]. When predicting the possibility of self-care, one should focus on the level of the segmental spinal cord lesion. Patients with a C5–C6 lesion level are completely independent in everyday life, those with C5–C7 partially need assistance and often use compensatory-adaptive mechanisms to perform basic daily skills, while with a C5–Th1 lesion, patients' self-care is minimal and they largely or completely require outside help [125].

All children with AMC experience delayed motor development due to limb involvement; however, by the age of 5 years, 85% of patients are able to walk. The majority of children with AMC experience mild to moderate difficulties with mobility, self-care (e.g., showering), and performance of daily activities. Prognostically unfavorable indicators that worsen the quality of life in patients with this pathology include: low birth weight, prolonged hospital stay in early childhood, multiple orthopedic surgeries, and the use of a wheelchair [126]. The ability to walk independently or with assistive devices in adult patients with AMC ranges from 49% to 88%. However, a number of patients eventually lose the ability to walk, which in some cases is associated with weight gain in adulthood [114, 115, 120, 124, 125, 127–129]. Between 48% and 86% drive cars independently [115, 127]. Between 15% and 50% of adult patients with good upper extremity function are completely independent in daily life [114, 115, 124]. Surgical interventions in childhood are performed in the majority of patients (95–98%), averaging 7–10 surgeries, though in some patients the lifetime number reaches 45–70 surgeries [121, 127]. The primary issue impairing the quality of life in adult patients with AMC is pain (75–91%), predominantly localized to the feet, knees, spine, and upper extremities, which frequently limits their physical activity [114, 120, 127–128, 130–131]. Patients are most troubled by pain in the lumbosacral spine as well as the lower extremities, which is often chronic in nature, thereby hindering their ability to achieve verticalization and walking [131–132]. Assessment of the patients' social status is also noteworthy: 83% are employed in adulthood (of whom 48% have a higher education degree), 58% start their own families, and 52% have children [124].

Criteria for Evaluating the Quality of Medical Care

Criteria for assessing the quality of primary health care

References

Appendix A1. Working Group Composition

Agranovich O.E. – Doctor of Medical Sciences, Head of the Arthrogryposis Department, The Turner National Medical Research Center for Children's Orthopedics and Trauma Surgery of the Russian Ministry of Health.

Petrova E.V. – Candidate of Medical Sciences, Senior Researcher at the Arthrogryposis Department, The Turner National Medical Research Center for Children's Orthopedics and Trauma Surgery of the Russian Ministry of Health.

Buklaev D.S. – Candidate of Medical Sciences, Head of the Arthrogryposis Department, The Turner National Medical Research Center for Children's Orthopedics and Trauma Surgery of the Russian Ministry of Health.

Trofimova S.I. – Candidate of Medical Sciences, Researcher at the Arthrogryposis Department, The Turner National Medical Research Center for Children's Orthopedics and Trauma Surgery of the Russian Ministry of Health.

Kochenova E.A. – Candidate of Medical Sciences, Physician at the Arthrogryposis Department, The Turner National Medical Research Center for Children's Orthopedics and Trauma Surgery of the Russian Ministry of Health.

Batkin S.F. – Candidate of Medical Sciences, Physician at the Arthrogryposis Department, The Turner National Medical Research Center for Children's Orthopedics and Trauma Surgery of the Russian Ministry of Health.

Savenkova A.A. – Functional Rehabilitation Physician, Exercise Therapy Physician, Physical Therapy Physician, The Turner National Medical Research Center for Children's Orthopedics and Trauma Surgery of the Russian Ministry of Health.

Ochurenko A.A. – Doctor of Medical Sciences, Professor, Head of the Department for the Implementation of National Medical Research Center Functions, Priorov National Medical Research Center of Traumatology and Orthopedics of the Russian Ministry of Health.

Melnik E.A. – Candidate of Medical Sciences, Leading Researcher at the Scientific Advisory Department, Neurologist, Geneticist at the Advisory Department, Research Centre for Medical Genetics named after Academician N.P. Bochkov.

Merkurieva E.S. – Candidate of Medical Sciences, Senior Researcher at the Scientific Advisory Department, Geneticist at the Advisory Department, Research Centre for Medical Genetics named after Academician N.P. Bochkov.

Markova T.V. – Doctor of Medical Sciences, Chief Researcher, Head of the Scientific Advisory Department, Geneticist at the Advisory Department, Research Centre for Medical Genetics named after Academician N.P. Bochkov.

Dadali E.L. – Doctor of Medical Sciences, Chief Researcher at the Scientific Advisory Department, Geneticist at the Advisory Department, Research Centre for Medical Genetics named after Academician N.P. Bochkov.

Nikitin S.S. – Doctor of Medical Sciences, Head of the Department of Genetics of Neurological Diseases, Institute of Higher and Additional Professional Education, Research Centre for Medical Genetics named after Academician N.P. Bochkov.

The authors declare no financial support or conflicts of interest that need to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

These clinical guidelines are based on current international clinical guidelines for the diagnosis, treatment, and management of patients with CMA.

Target audience for these clinical guidelines:

• Neonatologists

• Pediatricians

• General practitioners (family physicians)

• Medical geneticists

• Orthopedic traumatologists

• Pediatric surgeons

• Neurologists

• Radiologists

• Physicians in physical therapy (or physical and rehabilitation medicine physicians, or physiotherapists, or specialists with higher (non-medical) education (exercise therapy instructor-methods specialists), or specialists with secondary vocational (medical) education (exercise therapy instructors, medical massage nurses, physiotherapy nurses)).

• Functional diagnostics physicians

• Medical students

• Residents and postgraduate students

Methods used for evidence collection/selection:

electronic database searching.

Description of methods used for evidence collection/selection:

The evidence base for the recommendations consists of publications included in the Cochrane Library, EMBASE, and MEDLINE databases. The search depth was 30 years due to the rare occurrence of this pathology.

Methods used to assess the quality and strength of evidence:

• Expert consensus;

• Evaluation of significance according to the rating scheme.

1. Scale for assessing levels of evidence reliability (LER) for diagnostic methods (diagnostic interventions)

2. Scale for assessing levels of evidence reliability (LER) for prevention, treatment, and medical rehabilitation methods, including those based on the use of natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)

3. Scale for assessing levels of recommendation persuasiveness (LRP) for methods of prevention, diagnostics, treatment, and medical rehabilitation, including those based on the use of natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Methods used for evidence analysis:

• Reviews of published meta-analyses;

• Systematic reviews with evidence tables.

Description of methods used for evidence analysis:

When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its validity. The result of this examination affects the level of evidence assigned to the publication, which in turn affects the strength of the recommendations derived from it.

The subjective factor can undoubtedly influence the assessment process. To minimize potential errors, each study was evaluated independently, i.e., by at least two independent members of the working group. Any discrepancies in assessments were discussed by the full working group. If consensus could not be reached, an independent expert was involved.

Evidence tables:

Evidence tables were completed by the members of the working group.

Methods used to formulate the recommendations:

Expert consensus.

Economic analysis:

Cost analysis was not performed, and pharmacoeconomic publications were not analyzed.

Method of recommendation validation:

• External peer review;

• Internal peer review.

Description of the guideline validation method:

The preliminary version of these guidelines was reviewed by independent experts, who were asked to comment primarily on how accessible the interpretation of the evidence underlying the recommendations is for understanding.

Comments were received from primary care physicians regarding the clarity of the presentation of the recommendations and their assessment of the importance of the recommendations as a working tool in daily practice.

The preliminary version was also sent to a non-medical reviewer for comments from the patients' perspective.

Comments received from experts were carefully systematized and discussed by the chair and members of the working group. Each point was discussed, and the resulting changes made to the recommendations were logged. If no changes were made, the reasons for refusing to make changes were logged.

Consultation and peer review:

The draft guidelines were reviewed by independent experts, who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

Working Group:

For the final revision and quality control, the recommendations were re-evaluated by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account and the risk of bias in the development of the recommendations was minimized.

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A3.1 Regulatory legal acts used in the development of the clinical practice guideline

1. Federal Law No. 489-FZ of December 25, 2018, "On Amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'The Fundamentals of Healthcare Protection in the Russian Federation' Regarding Clinical Practice Guidelines."

2. Order of the Russian Ministry of Health No. 103n dated February 28, 2019 (as amended on September 28, 2023) "On Approval of the Procedure and Timelines for the Development and Revision of Clinical Practice Guidelines, Their Standard Form, and Requirements for Their Structure, Composition, and Scientific Validity of Information Included Therein."

3. Order of the Russian Ministry of Health No. 804n dated October 13, 2017 (as amended on September 24, 2020) "On Approval of the Nomenclature of Medical Services."

4. Order of the Ministry of Labor of Russia No. 687n dated December 10, 2024, "On Approval of the List of Indications and Contraindications for Providing Persons with Disabilities with Rehabilitation Equipment."

5. Order of the Russian Ministry of Health No. 747 dated December 19, 2025, "On Approval of the Procedure for Providing Medical Care in the Field of 'Obstetrics and Gynecology'."

6. Order of the Ministry of Health and Social Development of the Russian Federation No. 366n dated April 16, 2012 (as amended on February 21, 2020) "On Approval of the Procedure for Providing Pediatric Care."

7. Order of the Ministry of Health of the Russian Federation No. 274n dated April 21, 2022, "On Approval of the Procedure for Providing Medical Care to Patients with Congenital and (or) Hereditary Diseases."

8. Order of the Ministry of Health of the Russian Federation No. 1122n dated December 6, 2021 (as amended on December 12, 2023) "On Approval of the National Schedule of Preventive Vaccinations and the Schedule of Preventive Vaccinations by Epidemiological Indications." 

Main regulatory legal acts governing the provision of palliative medical care

1. Federal Law "On Amendments to the Federal Law 'The Fundamentals of Healthcare Legislation in the Russian Federation' Regarding the Provision of Palliative Medical Care" No. 18-FZ dated March 6, 2019.

2. Order of the Russian Ministry of Health No. 208n and the Ministry of Labor of Russia No. 243n dated April 14, 2025, "On Approval of the Regulations on the Organization of Palliative Medical Care, Including the Procedure for Interaction Between Medical Organizations, Social Service Organizations, Public Associations, and Other Non-Profit Organizations Operating in the Healthcare Sector."

3. Order of the Russian Ministry of Health No. 398n dated July 9, 2025, "On Approval of the List of Medical Devices Intended to Support Human Organs and Body Systems Provided for Home Use."

4. Order of the Russian Ministry of Health No. 505n dated July 10, 2019, "On approval of the Procedure for the transfer by a medical organization to a patient (their legal representative) of medical devices intended to maintain the functions of human organs and body systems for home use in the provision of palliative medical care."

Appendix A3.2 Medical services used by specialists for medical rehabilitation measures in patients with AMA

A21.01.001 General medical massage

A21.30.004 Massage for musculoskeletal disorders in infants

A17.02.001 Muscle electrical stimulation

A17.04.001 Drug electrophoresis in joint diseases

A17.23.001 Drug electrophoresis in central nervous system and brain diseases

A17.23.003 Spinal cord electroneurostimulation

A20.30.036 Paraffin-ozokerite application

A19.30.003 Therapeutic gymnastics for musculoskeletal disorders in children

A19.04.001 Exercise therapy for joint diseases and injuries

A19.30.006 Mechanotherapy

A19.30.006.001 Robotic mechanotherapy

A19.04.001.012 Exercise therapy with biofeedback for joint diseases and injuries

A19.04.001.023 Exercise therapy using equipment and exercise machines for joint diseases and injuries

A19.23.003 Correction of motor function impairment using biofeedback

A19.23.004 Correction of motor function impairment using computer technologies

A19.30.007 Exercise therapy using an exercise machine

A19.30.009 Exercise therapy in the pool

A21.30.006 Occupational therapy

A13.30.001 Self-care training

A14.30.015 Training family members of the patient in techniques for moving and/or positioning in bed

A14.30.016 Patient self-help training for transfer in bed and/or wheelchair

A14.30.018 Patient self-help training for transfer using an additional support

A23.30.013 Use of games in rehabilitation programs

A23.30.015 Use of sports elements in rehabilitation programs

A23.30.017 Postural correction

Appendix B. Physician Action Algorithms

Patient with suspected arthrogryposis multiplex congenita

Treatment algorithm for congenital upper limb deformities in AMA

Treatment algorithm for congenital foot deformities in AMA

** - CDA - compression-distraction apparatus

Treatment algorithm for knee contractures in AMA

Treatment algorithm for hip joint pathology in AMA

Appendix C. Patient Information

Arthrogryposis multiplex congenita (AMC) is a term used to describe a group of congenital disorders characterized by congenital joint contractures in two or more body segments. The term "contracture" refers to a limitation of the range of motion in a joint.

Currently, more than 400 causes of this disease have been identified: viral and bacterial infections, physical factors, chemical agents, medications, intrauterine crowding (uterine shape anomalies), placental insufficiency, polyhydramnios, etc. Maternal history may include various diseases, pregnancy toxicosis, miscarriages, abortions, etc.

There is no definitive consensus on the pathogenesis of arthrogryposis. The impact of a teratogenic factor in early pregnancy (weeks 5–6) disrupts the development of muscle fibers and joints, or leads to primary spinal cord injury, which in turn causes secondary muscle changes and impaired fetal motor activity. Variants of AMC include amyoplasia, distal arthrogryposis, and syndromes whose clinical symptom is multiple contractures.

In amyoplasia, involvement of the shoulder, elbow, wrist, hip, and knee joints, hand and foot deformities, and potential spinal deformities are observed. Muscle tissue is characteristically replaced by fibrous or fatty tissue, resulting in the absence of active joint movement. In amyoplasia, all four limbs are involved in 63% of cases (i.e., upper and lower limb contractures, typically symmetrical); involvement of three limbs is observed in 5% of cases, upper limbs in 17%, and lower limbs exclusively in 15%.

Distal arthrogryposis is characterized predominantly by hand and foot deformities, which in some cases are combined with pathology of large limb joints and maxillofacial anomalies.

In the vast majority of cases, deformities are symmetrical and do not progress during the child's life.

Internal organ involvement is rare. The intelligence of patients is preserved in the vast majority of cases.

Amyoplasia is not hereditary; at the same time, distal forms, as well as syndromic forms of AMC, are classified as hereditary diseases.

The key to successful treatment of patients with arthrogryposis is the early initiation of conservative treatment (from the first week of life) aimed at eliminating contractures and improving active joint motion.

Timely initiation of conservative treatment allows for complete elimination of contractures or a significant reduction in their severity in a number of cases.

If limb deformities persist after conservative treatment, surgical treatment is indicated starting from the child's age of 3–4 months.

The prescription of orthotic and prosthetic devices (OPDs) plays an important role in preventing the recurrence of contractures.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Rating scales, questionnaires, and other assessment tools for the patient's condition are not provided in the clinical practice guidelines.