Arthrogryposis Clinical Presentation

Family history

Review the history of children with arthrogryposis and other affected family members. Look for the presence of hyperextensibility, dislocated joints, dislocated hips, and clubfeet in other family members. Inquire about increased incidence of congenital contractures in second-degree and third-degree relatives.

Consanguinity increases the chance that both parents carry the same disease gene. Consanguinity is more common in families with rare recessive diseases than in those with common recessive diseases.

Some chromosomal abnormalities dramatically increase with maternal age, and single-gene dominant mutations can increase with paternal age.

Look for marked intrafamilial variability; the parent may be very mildly affected or may have had contractures early in infancy. Review previous miscarriages or stillbirths.

Pregnancy history

Infants born to mothers affected with myotonic dystrophy, myasthenia gravis, or multiple sclerosis are at risk. A mother with congenital myotonic dystrophy may have a child who inherits the gene and is severely affected with resistant contractures. A mother with myasthenia gravis or multiple sclerosis can have children with congenital contractures.

Maternal infections (rubella, rubeola, coxsackievirus, enterovirus) can lead to CNS or peripheral nerve destruction with secondary congenital contractures. Protracted or severe nausea may suggest maternal viral infection or encephalitis.

Maternal fever of more than 39°C for an extended period or maternal hyperthermia can cause contractures due to abnormal nerve growth or migration. This can be caused by prolonged soaking in hot tubs or hot baths.

Exposure to teratogens, such as drugs, alcohol, curare, methocarbamol, and phenytoin, may lead to decreased fetal movement.

Oligohydramnios or chronic amniotic fluid leakage may cause fetal constraint and secondary deformational contractures. Polyhydramnios may suggest fetal compromise (ie, defect in swallowing) and is a poor prognostic sign if associated with fetal hydrops.

Ask about uterine abnormalities such as bicornuate uterus with a septum or uterine fibroid.

Ask if the mother had large fibroids or other tumors, severe hypotension at a critical time, or severe hypoxia (eg, carbon monoxide poisoning) during pregnancy.

Review abnormal fetal movements such as decreased fetal movements, fetal kicking in one place, and decreased rolling.

Other complications that may be related to contractures include bleeding, abnormal fetal lies, threatened abortion, attempted termination, and trauma, such as a blow to the abdomen. An abnormal fetal lie may be a clue to intrauterine joint contractures.

Delivery history

Delivery history is usually atypical because of abnormal fetal presentation or difficulty due to the fixed fetal joints.

Breech or transverse fetal position is relatively common. Length of gestation is usually normal, but induction of labor is often prolonged. A limb is fractured during traumatic delivery in about 5-10% of cases.

Check for abnormal placenta, membranes, or cord insertion in cases that involve amniotic bands or vascular compromise. The umbilical cord may be shortened or wrapped around a limb, leading to compression.

Arthrogryposis epidemics have been reported, but whether these are due to chance occurrence, environmental factors, or infectious agents is unclear. Any clustering of children born with congenital contractures should be investigated.

In multiple births or twins, lack of movement due to uterine crowding can cause contractures. The death of one twin may lead to vascular compromise in the remaining twin.

Although joint contractures and associated clinical manifestations vary from case to case, several characteristics are common, including the following:

• Involved extremities are fusiform or cylindrical in shape, with thin subcutaneous tissue and absent skin creases

• Deformities are usually symmetrical, and severity increases distally, with the hands and feet typically the most deformed

• Joint rigidity may be present

• The patient may have joint dislocation, especially the hips and, occasionally, the knees

• Atrophy may be present, and muscles or muscle groups may be absent

• Sensation is usually intact, although deep tendon reflexes may be diminished or absent

A retrospective study by Hansen-Jaumard et al of children with arthrogryposis found less proximal joint involvement in youngsters with distal arthrogryposis than in patients with amyoplasia or in those who were classified as “other.” Contractures of the shoulder and elbow were also less common in distal arthrogryposis. Foot deformities and ankle contractures were quite prevalent in all patient groups, at rates of 91.5% (amyoplasia), 85.7% (distal arthrogryposis), and 83.3% (other). ^[49]

Contractures

Points to consider include the following (see the images below):

• Distal joints are affected more frequently than proximal joints

• Observe flexion versus extension, limitation of movement (fixed vs passive vs active), and characteristic position at rest; note the severity of all limitations. Distinguish between complete fusion or ankylosis and soft-tissue contracture

• Range of motion in the jaw is frequently limited

• Intrinsically derived contractures are frequently associated with polyhydramnios; the contractures are symmetrical and accompanied by taut skin, pterygia across joints, and a lack of flexion creases; recurrence risk and prognosis depend on etiology

• Extrinsically derived contractures are associated with positional limb anomalies, large ears, loose skin, and normal or exaggerated flexion creases; patients have an excellent prognosis and a low recurrence risk

Deformities

Limb deformities include pterygium, shortening, webs, compression (eg, due to cord wrapping), absent patella, dislocated radial heads, and dimples.

Facies deformities include asymmetry, flat nasal bridge, and hemangioma. Jaw deformities include micrognathia and trismus. See the image below.

Other deformities include scoliosis, genital deformities (cryptorchidism, lack of labia, microphallus), and hernia (inguinal, umbilical).

Other features of the fetal akinesia sequence include intrauterine growth retardation, pulmonary hypoplasia, and craniofacial anomalies such as hypertelorism, cleft palate, depressed nasal tip, high nasal bridge, functional short gut with feeding problems, and short umbilical cord.

Absent or distorted crease abnormalities are a result of aberrant form or function in early hand or foot development. See the image below.

Malformations

Craniofacial malformations may involve the CNS (structural malformations, seizures, intellectual disability), skull (craniosynostosis, asymmetry, microencephaly), eyes (small and malformed eyes, corneal opacities, ptosis, strabismus), and palate (high, cleft, submucous cleft).

Respiratory problems include tracheal and laryngeal clefts and stenosis. Hypoplasia, weak muscles, or hypoplastic diaphragm may affect lung function.

Limb malformations include deletion anomalies, radioulnar synostosis, syndactyly, and shortened digits.

Skin vasculature abnormalities may cause hemangiomas and cutis marmorata; distal limbs may be blue and cold.

Cardiac problems include congenital anomalies and cardiomyopathy. The kidneys, ureters, and bladder may have structural anomalies.

Nervous system problems include loss of vigor; lethargy; sluggish, brisk, or absent deep tendon reflexes; and sensory deficits.

Muscle malformations include decreased muscle mass, soft muscle texture, fibrous bands, abnormal tendon attachments, and muscle changes over time.

Connective tissue abnormalities

Skin webs (pterygia) across joints, with limitation of movement, are common. Skin dimples are common over joints where movement is limited.

Skin may be soft, doughy, thick, or extensible. Subcutaneous fat is decreased or increased. Inguinal, umbilical, or diaphragmatic hernias may be present. Thickness in joints, symphalangism, and abnormalities in tendon attachment and length may also be present.

Associated skin defects include scalp defects, amniotic bands on limbs, and nail defects.

Pretibial linear skin indentation may be a sign of autosomal recessive inheritance or at least a sign for an increased risk of recurrence.

Arthrogryposis is presumed to be multifactorial in etiology. ^[8] In most cases, arthrogryposis multiplex congenita (AMC) is not a genetic condition. However, in approximately 30% of cases, a genetic cause can be identified. ^[9]

Arthrogryposis is a physical sign in many specific medical conditions. It can be a component of numerous conditions caused by environmental agents, single gene defects (autosomal dominant, autosomal recessive, X-linked recessive), chromosomal abnormalities, known syndromes, or unknown conditions. The principal cause is persistently decreased fetal movements (fetal akinesia) due to either fetal or maternal abnormalities.

The molecular basis of most genetic causes is not yet determined. However, the following 5 genetic loci associated with autosomal recessive arthrogryposis multiplex congenita have been described to date using a linkage analysis approach ^{[10, 11]} :

• Lethal congenital contracture syndrome (OMIM 253310) (9q34) - This is characterized by early fetal hydrops and akinesia, Pena-Shokeir phenotype, multiple pterygia and fractures, and a specific neuropathology in the spinal cord

• Neurogenic type of arthrogryposis multiplex congenita (OMIM 208100) (5q35) - This is a nonprogressive, nonlethal, multiple joint contracture described in a large Israeli-Arab inbred kindred

• Arthrogryposis-renal dysfunction-cholestasis syndrome (OMIM 208085) (15q26.1) - This is a neurogenic arthrogryposis multiplex congenita with renal tubular dysfunction and neonatal cholestasis, with bile duct hypoplasia and low gamma glumyl transpeptidase activity, leading to death within the first year of life

• Lethal congenital contracture syndrome (LCCS) type 2 (OMIM 607598) (12q13) - This is a lethal arthrogryposis multiplex congenita characterized by multiple joint contractures and micrognathia, normal duration of pregnancy, markedly distended urinary bladder, and lack of hydrops, pterygia, and fractures; it is prevalent in a large inbred Israeli-Bedouin kindred

• A novel autosomal recessive LCCS type 3 - This is similar to LCCS2 but lacks the urogenic bladder defect; the genetic defect leading to this syndrome was mapped to 3.4 Mb on chromosome 19p13, and it was shown that LCCS3 results from a mutation in PIP5K1C (GenBank accession number NM_012398)

Neuropathic abnormalities are the most common cause of arthrogryposis. They may include malformations or malfunctions of the central and peripheral nervous systems. Abnormalities include meningomyelocele, anencephaly, hydranencephaly, holoprosencephaly, spinal muscular atrophy, cerebrooculofacial-skeletal syndrome, and Marden-Walker syndrome.

Muscle abnormalities (malformations or malfunctions) are relatively rare causes of arthrogryposis. Some associated diseases include congenital muscular dystrophies, congenital myopathies, intrauterine myositis, and mitochondrial disorders.

Wallach et al, in a study of 42 children with arthrogryposis, found that in 19.1% of patients, the condition had a neurologic etiology, mainly involving polymicrogyria, while in 9.5% of the group, the disease arose myopathically. ^[12]

A study by Chareyre et al of 82 patients with arthrogryposis found that neuromuscular disorders were the most prevalent cause, at 39%, including involvement of the skeletal muscles (23%), peripheral nerves (13%), or neuromuscular junctions (4%). The cause rates for central nervous system and connective tissue disorders were 23% and 6%, respectively, with 8.5% of cases caused by mixed mechanisms and 22% of cases unable to be classified. ^[50]

Connective tissue abnormalities in tendon, bone, joint, or joint lining may develop in such a way that restricts fetal movements, resulting in congenital contractures. Examples include synostosis, lack of joint development, aberrant fixation of joints (as in diastrophic dysplasia and metatropic dwarfism), aberrant laxity of joints with dislocations (as in Larsen syndrome), and aberrant soft tissue fixations (as in popliteal pterygium syndrome). In some forms of distal arthrogryposis, the tendon develops normally but fails to attach to the appropriate place around the joint or bone. This results in abnormal lack of movement of the joints with secondary contractures at birth.

Limited space for fetal movement inside the uterus may contribute to the development of contractures. Examples include multiple births, uterine structural abnormalities, oligohydramnios in renal agenesis, and early persistent leakage of amniotic fluid.

Intrauterine vascular compromise may result in a loss of function in nerve and muscle with development of fetal akinesia and secondary joint contractures. Examples include severe maternal bleeding during pregnancy and failed attempts at termination of pregnancy.