Arthrogryposis refers to multiple congenital joint contractures and resulting restriction of movements. It is a clinical feature that occurs as part of >300 different disorders. Distal arthrogryposes are a specific type of arthrogryposis disorders that involve contractures in ≥2 distal parts of the limbs and the absence of neurological/muscle disease. Pathogenic variants in >10 genes (TPM2, MYBPC1, MYH3, TNNT3, TNNI2, MYH8, FBN2, PIEZO2, ECEL1, DOK7, RAPSN) that encode proteins important for the myofibers contractile functions, can cause distal arthrogryposis. 1, 2
Major clinical symptoms for arthrogryposis include the following 1, 2:
- Upper limbs:
- camptodactyly (permanent banding of one or more fingers)
- hypoplastic and/or absent flexion creases
- overriding fingers
- ulnar deviation at the wrist
- Lower limbs:
- talipes equinovarus (clubfoot)
- vertical talus (rocker bottom feet)
- other foot deformities (calcaneovalgus talipes, metatarsus varus)
- ≥2 above major symptoms in an individual
- ≥1 of the major symptoms in an individual with an affected family member (with ≥2 symptoms)
- Known pathogenic variant in one of the following genes: TPM2, MYBPC1, MYH3, TNNT3, TNNI2, MYH8, FBN2, PIEZO2, ECEL1, DOK7, RAPSN
There is no cure for arthrogryposis but different management and interventions can relieve symptoms 1, 2
- Surgical correction of the contractures
- Complex multi-disciplinary treatment involving pediatricians, physiotherapists, geneticists, orthopedic surgeons, and orthotic specialists.
- Holt-Oram syndrome
- Tuberous sclerosis
- Otopalatodigital syndrome
- Nemaline myopathy
- Oculodentodigital syndrome
- Ophthalmomandibulomelic dysplasia
To confirm/establish the diagnosis, CENTOGENE offers the following tests:
- Arthrogryposis NGS Panel which includes sequencing of the genes TPM2, MYBPC1, MYH3, TNNT3, TNNI2, MYH8, FBN2, PIEZO2, ECEL1, DOK7, RAPSN
- Arthrogryposis NGS Panel + CNV which includes sequencing and additionally detection of large deletions and duplications from the NGS data
- Individuals with a positive family history of distal arthrogryposis.
- Individuals that meet the diagnostic criteria for distal arthrogryposis (regardless of family history).
Why is this test good for the patient?
Confirmation of a clinical diagnosis through genetic testing of Arthrogryposis can allow for genetic counseling and may direct medical management.
Table 1. Overview of genes included in Arthrogryposis panel:
|Gene||OMIM (Gene)||Associated diseases (OMIM)||Inheritance||CentoMD® exclusive variant numbers (++)|
|DOK7||610285||congenital myasthenic syndrome type 10||AR||32|
|ECEL1||605896||distal arthrogryposis type 5D||AR||17|
|FBN2||612570||congenital contractural arachnodactyly; early-onset macular degeneration||AD||47|
|MYBPC1||160794||Arthrogryposis, distal, type 1B; Lethal congenital contracture syndrome 4||AD, AR||47|
|MYH3||160720||distal arthrogryposis type 2A||AD, AR||56|
|MYH8||160741||distal arthrogryposis type 7; Carney complex variant||AD||23|
|PIEZO2||613629||Arthrogryposis, distal, type 5; Marden-Walker syndrome; Arthrogryposis, distal, with impaired proprioception and touch||AD, AR||50|
|RAPSN||601592||congenital myasthenic syndrome, type 11, associated with acetylcholine receptor deficiency||AR||13|
|TNNI2||191043||distal arthrogryposis type 2B||AD||9|
|TPM2||190990||Nemaline myopathy type 4, autosomal dominant||AD||15|
Abbreviations for Table 1: DA-Distal arthrogryposis, FSS-Freeman Sheldon syndrome; SHS-Sheldon-Hall syndrome; FADS-Fetal akinesia syndrome; CMS-Congenital myoasthenic syndrome.
There is no definitive treatment for arthrogryposis, however proper management can prolong survival and improve the quality of life. Physical therapy and prevention of disease-induced complications is of great benefit for patients.