Freeman-Sheldon syndrome (FSS), also known as distal arthrogryposis type 2A, whistling-face syndrome, or windmill vane hand syndrome, is a rare genetic disorder which has been reported with both autosomal dominant and autosomal recessive inheritance patterns. Most cases, however, occur sporadically as a consequence of de novo mutations in the MYH3 gene. Some features of FSS are obvious at birth and primarily affect the face and both upper and lower limbs. Patients require numerous surgical procedures throughout their lives to correct for FSS-associated deformities. FSS patients may suffer from hearing loss or speech problems as a consequence of these deformities but are usually not intellectually impaired.
Freeman-Sheldon syndrome (FSS), originally termed craniocarpotarsal dystrophy by Freeman and Sheldon in their first description of the disease in 1938 [1], is a rare genetic disease caused primarily by either inherited or spontaneous mutations in the MYH3 gene, which codes for the skeletal muscle myosin heavy chain 3 protein [2]. These mutations may disturb fetal muscle development and lead to characteristic contractures of both upper and lower limbs.
FSS is characterized by a "mask-like" face with a prominent forehead, hypertelorism, microstomia with pouting lips resembling a whistling mouth, midface hypoplasia, blepharophimosis, ptosis, a long philtrum, pronounced nasolabial folds, full cheeks, deep-set eyes, down-slanting palpebral fissures, strabismus, and an "H" or "V" shaped chin dimple. Patients may also present with microglossia, micrognathia, and a high-arched palate. The combination of these manifestations leads to an increased susceptibility to dental crowding, dysphagia, failure to thrive, and impaired speech [3]. FSS can present only with orofacial features [4].
Most frequent limb-associated deformities are camptodactyly, a "windmill vane hand" in which all of the fingers are angled outward toward the fifth finger, and talipes eqinovarus. Affected individuals may also suffer from scoliosis. Speech and motor development are delayed [5].
Building an FSS diagnosis requires a multidisciplinary approach. Prenatal ultrasonography can raise the first suspicion if the test reveals joint deformities. In such a case, parents should be prepared for the special requirements of their child. Postnatal diagnosis requires a thorough clinical examination with a special focus on a potential misdiagnosis for Sheldon-Hall syndrome (SHS), which shares significant phenotypical overlap with FSS [6]. FSS can be distinguished from SHS by the presence of pouting lips, prominent nasolabial folds, and the characteristic chin dimple [7]. Genetic testing is required to confirm the provisional FSS diagnosis.
Newborns affected by FSS will most likely suffer from feeding difficulties. CT imaging may be used to determine the severity of orofacial disorders. Electromyography (EMG) can be used to prove muscle hypoplasia and a muscle biopsy will reveal accumulated fibrous connective tissue [5] [8].
FSS patients require numerous corrective surgeries to correct FSS-associated malformations, some of which should be carried out in early life, e.g. commissurotomy to overcome feeding problems [7]. A frequent complication apart from difficult intubation in these necessary procedures is malignant hyperthermia initiated by the use of volatile anesthetics, which affects about 16% of FSS patients and can lead to acute renal failure and death [7] [9] [10].