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].

• Failure to Thrive in Infancy

  But swallowing difficulties as well as vomiting can lead to failure to thrive during infancy and in some cases retarded growth can occur. Surgical treatment can improve any facial appearances and functioning of feet and hands. [syndrome.org]

• Failure to Thrive

  The combination of these manifestations leads to an increased susceptibility to dental crowding, dysphagia, failure to thrive, and impaired speech. FSS can present only with orofacial features. [symptoma.com]

  […] to thrive, normal IQ, short stature, scoliosis, camptodactyly with ulnar deviation—‘windmill hands’—talipes equinovarus or clubfoot Freeman, Ernest A., English orthopedic surgeon, 1900-1975. [medical-dictionary.thefreedictionary.com]

  Children with Freeman-Sheldon syndrome may also exhibit speech impairment; swallowing and eating difficulties; vomiting; failure to grow and gain weight at the expected rate (failure to thrive); and/or respiratory problems that may result in life-threatening [courageousfacesfoundation.org]

  But swallowing difficulties as well as vomiting can lead to failure to thrive during infancy and in some cases retarded growth can occur. Surgical treatment can improve any facial appearances and functioning of feet and hands. [syndrome.org]

  Children affected by Freeman Sheldon syndrome generally suffer from feeding problems and failure to thrive and meet normal developmental milestones. Feeding and respiratory problems are aggravated due to the underdeveloped jaw and pursed mouth. [skinsheen.com]

• Small Palpebral Fissures

  Freeman-Sheldon syndrome is defined as a combination of microstomia, deep set eyes, small palpebral fissures, arthrogryposis with ulnar deviation of the hand, talipes equinovarus and generalized muscular hypertension. [ncbi.nlm.nih.gov]

  Article / Publication Details First-Page Preview Abstract Freeman-Sheldon syndrome is defined as a combination of microstomia, deep set eyes, small palpebral fissures, arthrogryposis with ulnar deviation of the hand, talipes equinovarus and generalized [karger.com]

• Skeletal Dysplasia

  dysplasia Microtubules Kinesin Charcot–Marie–Tooth disease 2A Hereditary spastic paraplegia 10 Dynein Primary ciliary dyskinesia Short rib-polydactyly syndrome 3 Asphyxiating thoracic dysplasia 3 Other Tauopathy Cavernous venous malformation Membrane [en.wikipedia.org]

• Distractibility

  Bilateral mandibular osteotomies were performed and bilateral internal mandibular distracters were placed. She was distracted a total of 3 cm over 15 days without event and successfully extubated on the postoperative day 16. [ncbi.nlm.nih.gov]

• Short Neck

  Persons with FSS may also have a short neck that doesn't move well and has extra skin giving a 'webbed' appearance. Persons may also have trouble with dislocations in different joints, such as knees and hips. [fsrgroup.org]

  She also has short neck (Figure 1). There is contracture of both knees. Flexion contractures of both hands and toes of the right foot are found (Figure 2). Anaemia, jaundice, cyanosis, clubbing and edema are absent. [elynsgroup.com]

  T: B.’s hands drift to the outside, low muscle tone in his upper body, a small mouth, smaller than normal airways [which affect his breathing], a short neck…he had bilateral club feet. [brighthubeducation.com]

  neck Webbed neck Facial manifestations Among the facial characteristics of SHS the most common finding is a narrow face that is pointed at the chin giving the face a triangular appearance. [ojrd.biomedcentral.com]

• Mask-like Facies

  A six-day-old girl, born to normal non-consanguineous parents presented with mask like facies with a small mouth giving a 'whistling' appearance. [ncbi.nlm.nih.gov]

  […] mən shel′dən] Etymology: Ernest Arthur Freeman, British orthopedic surgeon, 1900-1975; Joseph Harold Sheldon, British physician, 1920-1964 An autosomal dominant [MIM 193700] or less commonly, or autosomal recessive [MIM 277720] condition with atypical mask-like [medical-dictionary.thefreedictionary.com]

  She has dysmorphic mask like facies which has whistling appearance and other features include deep set eyes, broad nasal bridge, short neck, hypoplasia of the ala nasai, long philtrum, small tongue, high arched palate with “H” shaped dimple on chin. [elynsgroup.com]

• Broad Nasal Bridge

  Other dysmorphic features include deep set eyes, broad nasal bridge, long philtrum and 'H' shaped cutaneous dimple on the chin. There was congenital windmill vane hand position and severe talipes equinovarus deformity. [ncbi.nlm.nih.gov]

  She has dysmorphic mask like facies which has whistling appearance and other features include deep set eyes, broad nasal bridge, short neck, hypoplasia of the ala nasai, long philtrum, small tongue, high arched palate with “H” shaped dimple on chin. [elynsgroup.com]

  A more complete list of symptoms and signs referred to in various resources on FSS includes the symptoms below: Full forehead Small mouth Mask-like face Broad nasal bridge Deep-set eyes Strabismus Telecanthus Epicanthal folds Blepharophimosis Small nose [syndrome.org]

• Mid-Face Hypoplasia

  Children with Freeman Sheldon syndrome may have: Distinctive facial appearance, including: - microstomia (a small mouth) with pursed lips - giving the appearance of a 'whistling face' - prominent forehead and brow ridges - mid-face hypoplasia (a sunken [cafamily.org.uk]

• Loss of Speech

  FSS patients may suffer from hearing loss or speech problems as a consequence of these deformities but are usually not intellectually impaired. [symptoma.com]

• Incontinence

  We report the case of a 7-year-old girl who presented with the appearance of scarred lips with difficulties in closing her mouth, a speech impediment and oral incontinence. [ncbi.nlm.nih.gov]

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].

1. Freeman EA, Sheldon JH. Cranio-carpo-tarsal dystrophy: undescribed congenital malformation. Arch Dis Child. 1938;13(75):277–283.
2. Zauner S, Ramoni A, Strobl I, Navarro-Psihas S, Pototschnig C. Freeman-Sheldon-Syndrom – Kasuistik. Geburtshilfe Frauenheilkd. 2010; 70 - P39.
3. Toydemir RM, Rutherford A, Whitby FG, Jorde LB, Carey JC, Bamshad MJ. Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome. Nat Genet. 2006;38(5):561–565.
4. Toydemir PB, Toydemir R, Bokesoy I. Whistling face phenotype without limb abnormalities. Am J Med Genet. 1999;86(1):86–87.
5. Ali AM, Mbwasi RM, Kinabo G, Kamsteeg EJ, Hamel BC, Dekker MCJ. Freeman–Sheldon Syndrome: First Molecularly Confirmed Case from Sub-Saharan Africa. Case Rep Genet. 2017; 2017: 9327169.
6. Tajsharghi H, Kimber E, Holmgren D, Tulinius M, Oldfors A. Distal arthrogryposis and muscle weakness associated with a β-tropomyosin mutation. Neurology. 2007;68(10):772–775.
7. Stevenson DA, Carey JC, Palumbos J, Rutherford A, Dolcourt J, Bamshad MJ. Clinical characteristics and natural history of Freeman-Sheldon syndrome. Pediatrics. 2006;117(3):754–762.
8. Sauk JJ Jr, Delaney JR, Reaume C, Brandjord R, Witkop CJ Jr. Electromyography of oral-facial musculature in craniocarpaltarsal dysplasia. Clin Genet. 1974;6(2):132-137.
9. Jones R, Dolcourt JL. Muscle rigidity following halothane anesthesia in two patients with Freeman-Sheldon Syndrome. Anesthesiology. 1992;77(3):599–600.
10. Sobrado CG, Ribera M, Marti M, Erdocia J, Rodríguez R. Freeman-Sheldon syndrome: generalized muscular rigidity after anesthetic induction. Rev Espan Anestes Y Reani. 1994;41(3):182–184.