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Freeman-Sheldon syndrome (FSS), also termed distal arthrogryposis type 2A (DA2A), craniocarpotarsal dysplasia (or dystrophy), or whistling-face syndrome, was originally described by Freeman and Sheldon in 1938.[1] Freeman-Sheldon syndrome is a rare form of multiple congenital contracture (MCC) syndromes (arthrogryposes) and is the most severe form of distal arthrogryposis (DA).[2][3][4]
The symptoms of Freeman-Sheldon syndrome include drooping of the upper eyelids, strabismus, low-set ears, a long philtrum, gradual hearing loss, scoliosis, and walking difficulties. Gastroesophageal reflux has been noted during infancy, but usually improve with age. The tongue may be small, and the limited movement of the soft palate may cause nasal speech. Often there is an H- or Y-shaped dimpling of the skin over the chin. There is no laboratory test that can diagnose Freeman-Sheldon syndrome– research continues. Chromosome tests are usually normal.
Freeman-Sheldon syndrome is a type of distal arthrogryposis, related to distal arthrogryposis type 1 (DA1).[5] In 1996, more strict criteria for the diagnosis of Freeman-Sheldon syndrome were drawn up, assigning Freeman-Sheldon syndrome as distal arthrogryposis type 2A (DA2A).[4]
On the whole, DA1 is the least severe; DA2B is more severe with additional features that respond less favourably to therapy. DA2A (Freeman-Sheldon syndrome) is the most severe of the three, with more abnormalities and greater resistance to therapy.[4]
Freeman-Sheldon syndrome has been described as a type of congenital myopathy.[6]
In March 2006, Stevenson et al. published strict diagnostic criteria for distal arthrogryposis type 2A (DA2A) or Freeman-Sheldon syndrome. These included two or more features of distal arthrogryposis: microstomia, whistling-face, nasolabial creases, and ‘H-shaped’ chin dimple.[3]
FSS is caused by genetic changes. Krakowiak et al (1998) mapped the distal arthrogryposis multiplex congenita (DA2B; MIM #601680) gene, a syndrome very similar in phenotypic expression to classic FSS, to 11p15.5-pter.[7][8] Other mutations have been found as well.[9][10] In FSS, inheritance may be either autosomal dominant, most often demonstrated.[11][12][13] or autosomal recessive (MIM 277720).[14][15][16][17] Alves and Azevedo (1977) note most reported cases of DA2A have been identified as new allelic variation.[18] Toydemir et al (2006) showed that mutations in embryonic myosin heavy chain 3 (MYH3; MIM *160270), at 17p-13.1-pter, caused classic FSS phenotype, in their screening of 28 (21 sporadic and 7 familial) probands with distal arthrogryposis type 2A.[19][20] In 20 patients (12 and 8 probands, respectively), missense mutations (R672H; MIM *160270.0001 and R672C; MIM *160270.0002) caused substitution of arg672, an embryonic myosin residue retained post-embryonically.[19][20][20] Of the remaining 6 patients in whom they found mutations, 3 had missense private de novo (E498G; MIM *160270.0006 and Y583S) or familial mutations (V825D; MIM *160270.0004); 3 other patients with sporadic expression had de novo mutations (T178I; MIM *160270.0003), which was also found in DA2B; 2 patients had no recognized mutations.[19][20]
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