Arthrogryposis, distal, type 3 (DA3)

Summary

DA3, or Gordon syndrome, is distinguished from other distal arthrogryposes by short stature and cleft palate. The syndrome is caused by mutationsin the PIEZO2 gene, which also causes DA5 (oculomelic amyoplasia) and Marden-Walker syndrome (MWKS). DA5 and MWKS are very similar to DA3 and are distinguished by ocular abnormalities and mental retardation, respectively (it has also been suggested that the three disorders represent variable expressivity of the same condition).

Detailed clinical description

DA3 is characterized by clinical variability and reduced penetrance (especially in females), also within the same family. Clubfoot and camptodactyly are typical.  Holes in the palate, bifid uvula, short stature, ptosis, cleft palate, pterygium colli, ophthalmoplegia, deep-set eyes, prominent ears, pectus excavatum, triangular face, and vertebral anomalies can be seen in PIEZO2-related disorders. Similarity between Gordon syndrome and Aase-Smith syndrome has been reported and should be kept in mind for the differential diagnosis.

Molecular genetics

Gordon syndrome mutations detected in the PIEZO2 gene are c.8238_8245delGACTAGAG (p.Trp2746Terfs) and c.8057G>A (p.Arg2686His). The presence of cleft palate is significantly associated with c.8057G>A.

Genetic testing

Targeted mutation analysis can be done to detect the known DA3-related mutations in PIEZO2. However, since DA3 and all arthrogryposes in general are genetically and clinically heterogeneous, full PIEZO2 gene sequencing (EXOME GENE) or panel testing (EXOME PANEL) is recommended.

Recommended panel testing at Breda Genetics for this condition:

References:

OMIM: 114300

Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5. McMillin MJ, Beck AE, Chong JX, Shively KM, Buckingham KJ, Gildersleeve HI, Aracena MI, Aylsworth AS, Bitoun P, Carey JC, Clericuzio CL, Crow YJ, Curry CJ, Devriendt K, Everman DB, Fryer A, Gibson K, Giovannucci Uzielli ML, Graham JM Jr, Hall JG, Hecht JT, Heidenreich RA, Hurst JA, Irani S, Krapels IP, Leroy JG, Mowat D, Plant GT, Robertson SP, Schorry EK, Scott RH, Seaver LH, Sherr E, Splitt M, Stewart H, Stumpel C, Temel SG, Weaver DD, Whiteford M, Williams MS, Tabor HK, Smith JD, Shendure J, Nickerson DA; University of Washington Center for Mendelian Genomics, Bamshad MJ. Am J Hum Genet. 2014 May 1;94(5):734-44. PMID 24726473.