Distal arthrogryposis type 8 (DA8 – also known as multiple pterygium syndrome) is caused by heterozygous mutation in the MYH3 gene. The transmissions is autosomal dominant. Mutations in the same gene can also cause DA2A and DA2B.
Detailed clinical features
Wide variability in severity can be observed among affected subjects. Ptosis and severe scoliosis due to hemivertebrae are present in some. Limb findings can be consistent with hypoplastic flexion creases, camptodactyly, antecubital and popliteal webbing, elbow contractures, limited forearm supination, hip and knee contracture, and feet contractures. Mildest cases may be similar to DA2B, in which joint contractures are associated with ptosis, whereas the most severely affected case may more closely resemble the Escobar variant of multiple pterygium syndrome, also known as pterygium universale, which is autosomal recessively inherited (CHRNG gene mutations). Some patients have a functional palate abnormality producing nasal speech. Other major or subtle minor signs of the disorder include difficulty in opening the mouth widely, scoliosis, pectus excavatum, slight cutaneous syndactyly, malformed carpal bones, downslanting palpebral fissures, long nasal bridge, low-set, posteriorly rotated ears, and an altered metacarpal-phalangeal pattern.
Identified DA8-related MYH3 mutations include 3-bp duplication (c.3214_3216dup, p.Asn1072dup), c.3224A>C (p.Gln1075pro / p.Q1075P), and another 3-bp deletion (c.727_729del, p.Ser243del). The first two locate in exon 25, whereas the third one is exon 8.
Genetic testing stratetgy
Targeted mutation analysis can be done to detect the known DA8 disease-causing mutations in the MYH3 gene. However, since arthrogryposes are genetically and clinically heterogeneous, full MYH3 gene sequencing (EXOME GENE) or panel testing (EXOME PANEL) is recommended.
Panel testing recommended at Breda Genetics for this condition:
Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3. Chong JX, Burrage LC, Beck AE, Marvin CT, McMillin MJ, Shively KM, Harrell TM, Buckingham KJ, Bacino CA, Jain M, Alanay Y, Berry SA, Carey JC, Gibbs RA, Lee BH, Krakow D, Shendure J, Nickerson DA; University of Washington Center for Mendelian Genomics, Bamshad MJ. Am J Hum Genet. 2015 May 7;96(5):841-9. PMID 25957469