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A congenital contracture is broadly defined as a limitation of
movement of a body area because of a musculoskeletal abnormality.
This abnormality may be caused by a primary or secondary defect
of muscle, bone, tendon, or skin, or it may be secondary to impaired
neurologic function that causes reduced movement, weakness, and/or
hypotonia. Congenital contractures can roughly be distinguished
into isolated congenital contractures that affect only a single
body area (eg, unilateral or bilateral clubfoot) and multiple congenital
contractures that affect two or more different body areas. Individuals with
multiple congenital contractures are often diagnosed with arthrogryposis,
the literal meaning of which is “twisted joint.” However,
arthrogryposis is a description of physical findings and does not
imply that the etiology or pathogenesis is similar among affected
individuals.
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The most common congenital contracture is idiopathic talipes
equinovarus (ITEV), or clubfoot, which occurs in 1 in every 200
to 500 live births. Multiple congenital contractures are about 10-fold
less common, occurring in about 1 in 3000 to 5000 live births. Worldwide,
more than 100,000 children are born each year with a congenital
contracture, and it is estimated that more than 5,000,000 people
live with congenital contractures. Accordingly, congenital contractures
are a substantial source of morbidity.
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Most congenital contractures are complex traits, with susceptibility
influenced by a heterogenous combination of genetic and environmental
factors. Any factor that diminishes movement can, in principle,
cause congenital contractures. Examples of such factors include uterine
crowding as a result of multiple gestation, oligohydramnios, myotonic
dystrophy, and trisomy 18. Indeed, multiple congenital contractures
have been observed in more than 300 different conditions.
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About 30% of children with multiple congenital contractures
are diagnosed with amyoplasia, a phenotype characterized by symmetric
reduced muscle bulk of all four limbs and a specific positioning
of the limbs with the arms extended and the hips and knees held
in flexion. A midfacial capillary hemangioma is also commonly observed.
About 10% of affected children have other anomalies, such
as gastroschisis or bowel atresia. Most cases are sporadic, but rare
families with either multiple affected siblings or an affected parent
and child have been reported. The etiology of amyoplasia is unknown
but likely to be heterogenous.
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Most cases of multiple congenital contractures are sporadic,
although autosomal dominant, autosomal recessive, and X-linked inheritance
is well documented. The most common of the heritable multiple congenital
contracture disorders is a group of about a dozen conditions known
as the distal arthrogryposis (DA) syndromes—so called because
they predominantly affect the more “distal” joints
of the limbs. Features shared among all DAs include a consistent
pattern of hand and foot involvement (eg, camptodactyly or flexion
contractures of the digits, clubfoot, vertical talus), limited proximal
joint involvement, an autosomal dominant inheritance pattern, and
variable expressivity.
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The most common of the DAs are Freeman-Sheldon syndrome (FSS),
Sheldon-Hall syndrome, trismus-pseudocamptodactyly syndrome, and
distal arthrogryposis with ophthalmoplegia. In addition to limb
contractures, each of these ...