Distal arthrogryposis type 1 (ORPHA:1146)
A form of arthrogryposis characterized by contractures of the distal regions of the hands and feet in the absence of a primary neurological and/or muscle disease affecting limb function. Facial involvement is limited to a small mouth and impaired mouth opening. No additional anomalies are reported.
Epidemiology
Epidemiological data is limited regarding Distal arthrogryposis type 1 (DA1). The prevalence of arthrogryposis overall is estimated between 1/4,300-5,100 live births and the birth prevalence of distal arthrogryposis (DA) has been suggested at 1/20,000. DA1 is the second most frequent type of DA, after DA2B (Sheldon-Hall syndrome). However, the overlap between the two conditions favors a similar frequency of the two forms.
Clinical description
In 25% of cases DA1 is suspected prior to delivery, due to joint contractures (camptodactyly and/or clubfoot) and reduce fetal movements, in particular in familial cases. In the newborn a consistent pattern of hand and foot involvement, limited involvement of proximal joints and variable expressivity can be seen. Camptodactyly and clubfoot are largely present. Hypoplasia and/or absence of some interphalangeal creases is common. The shoulders and hips are less frequently affected. While the pattern of affected joints is consistent, the degree to which the joints are affected is highly variable, with equinovarus deformities ranging from mild to severe and hand involvement ranging from isolated hypoplasia of the distal interphalangeal crease of the fifth digit, to severely clenched fist and ulnar deviation of the wrist. In the mildest form of DA1, affected individuals have only hypoplasia of the gastrocnemius. Short stature, small mouth with limited opening and mild microretrognathia are frequently seen. A linear vertical crease along the anterior tibia, usually bilaterally, is described in some patients. Intelligence is normal.
Etiology
DA1 is caused by a heterozygous mutation in a gene encoding sarcomeric components of skeletal muscle fibers (TNNI2, 11p15.5; TNNT3, 11p15.5 ; TPM2, 9p13.3; MYH3, 17p13.1; MYBPC1, 12q23.2). The same genes are also responsible for DA2B. Recently, variants in MYLPF (16p11.2), encoding light chains of skeletal muscle myosin, have been described and appears to be more frequently associated with short stature and proximal joint contractures (ie, elbows, hips, knees).
Diagnostic methods
Diagnosis is based on clinical examination and molecular studies. Instrumental investigations generally do not show any significant alterations.
Differential diagnosis
The principal differential diagnosis includes a different type of DA (in particular DA2B), congenital amyoplasia and situations with limitation of fetal joint mobility (neurological/neuromuscular diseases, metabolic disturbances, skeletal dysplasias/connective tissue abnormalities, maternal illness or exposures, space limitation in utero, and intrauterine vascular compromise).
Antenatal diagnosis
Some cases can be detected prenatally by ultrasonography. Detection of a known pathogenic mutation by chorionic villus sampling and amniocentesis should be discussed with couples at risk.
Genetic counseling
Transmission is autosomal dominant, with a 50% recurrence risk for the offspring of affected individuals. Reduced penetrance and variable expressivity are reported, and some relatives with the mutation are asymptomatic. Some de novo mutations are reported, with a recurrence risk for sibs of approximately 1%. MYLPF variants can be autosomal dominant (50% recurrence risk) or autosomal recessive (25% recurrence risk).
Management and treatment
Long-term orthopedic management and physiotherapy is required. Physiotherapy soon after birth is helpful in mobilizing joints and preventing disuse atrophy. Sometimes surgical procedures are required.
Prognosis
Life expectancy is normal. The course of the disease is non-progressive. Significant improvements are achieved with physical and orthopedic therapy. Autonomy is generally unlimited.

                            Last update: 
                            December 2020


                            - Expert reviewer(s): 
                            Dr Livia GARAVELLI | ITHACA* - Dr Marzia POLLAZZON | ITHACA*


                                * European Reference Network