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].

• Short Stature

  stature, scoliosis, camptodactyly with ulnar deviation—‘windmill hands’—talipes equinovarus or clubfoot Segen's Medical Dictionary. © 2012 Farlex, Inc. [medical-dictionary.thefreedictionary.com]

  Minor diagnostic criteria include a triangular face, downslanting palpebral fissures, attached ear lobules, a small mouth, a small mandible, an arched palate, cervical webbing and short stature. [ojrd.biomedcentral.com]

  […] ears are set lower, upper eyelids droop, dimpled chin (‘H’ or ‘Y’ shaped), small jaw, and tongue with restricted movement Feet and hands are contracted at birth, with multiple bent fingers; feet may be bent downwards or inwards Sideways curving spine Short [dovemed.com]

• 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]

• Nasal Voice

  Abnormally small tongue Deformities related to the mouth and jaw, limited activity of the soft palate, causing nasal voice, difficulty speaking, continuous vomiting, difficulty swallowing, breathing difficulties. [vinmec.com]

  Speech problems (dysphasia), which typically include both a nasal voice (hyponasality) and articulation problems, are caused by multiple structural and functional problems, specifically problems with regional muscles; a very small tongue (microglossia [rarediseases.org]

• Failure to Thrive

  Failure to thrive Weight faltering, Postnatal failure to thrive, Undergrowth, Poor weight gain [more] Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm. [rarediseases.oscar.ncsu.edu]

  […] to thrive, normal IQ, short stature, scoliosis, camptodactyly with ulnar deviation—‘windmill hands’—talipes equinovarus or clubfoot Segen's Medical Dictionary. © 2012 Farlex, Inc. [medical-dictionary.thefreedictionary.com]

  Evaluate physical status: failure to thrive is common as a result of vomiting and swallowing difficulties. Muscle rigidity following halothane anesthesia has been reported, suggesting the presence of an underlying myopathy. [accesspediatrics.mhmedical.com]

  Affected children may also experience: – a failure to gain weight and grow at the expected rate (failure to thrive) – speech problems – hearing loss. [contact.org.uk]

• Microstomia

  Homepage Rare diseases Search Search for a rare disease Freeman-Sheldon syndrome Disease definition Freeman-Sheldon syndrome (FSS) is a very rare, multiple congenital contractures syndrome characterized by a microstomia with a whistling appearance of [orpha.net]

  The majority of these patients have microstomia and dental crowding, making oral hygiene difficult and increasing the risk of caries. [unboundmedicine.com]

• Malocclusion

  Orthodontic treatment improved the patient's Class II malocclusion, which was accompanied by crowding and a deep bite. [ncbi.nlm.nih.gov]

  Dental problems were microsomia(whistling mouth) & micrognathia, perioral muscle contracture, restricted mouth opening, poor oral hygiene & care, generalized dental caries, high palatal vault, severe malocclusion & crowding. [journal.kapd.org]

  There may be malocclusion (misalignment) of the teeth and orthodontic treatment of this may be required. Opening the mouth fully for dental treatment may be difficult. [cafamily.org.uk]

  Conclusion Orthodontic treatment improved the patient's Class II malocclusion, which was accompanied by crowding and a deep bite. References Antley, R.M., Uga, N., Burzynski, N.J.. Diagnostic criteria for the whistling face syndrome. [journals.sagepub.com]

  Small puckered mouth (microstomia) Sunken or flat appearance of the middle face (midface hypoplasia) Small tongue (microglossia) Small jaw (micrognathia) Misaligned teeth (malocclusion) Widely spaced eyes (ocular hypertelorism), deep set, or crossed eyes [craniofacialteamtexas.com]

• Strabismus

  Corresponding Author:[email protected] Author Profile Craig R Dufresne Virginia Commonwealth University, Craig R Dufresne, MD, PC Author Profile Abstract In Freeman-Burian syndrome (formerly, Freeman-Sheldon syndrome), correcting visual obstruction and strabismus [authorea.com]

  The clinical spectrum includes cranio-facial: long philtrum mouth puckering microstomia H-shaped chin dimple orbital features hypotelorism 8 : drooping of the upper eyelids : strabismus : low-set ears gradual hearing loss microcephaly musculoskeletal: [radiopaedia.org]

  […] and toes equinovarus feet kyphosis scoliosis epicanthic fold strabismus arthrogryposis talipes equinovarus kyphosis scoliosis [gpnotebook.com]

  In Case 1, deep-set eyes, epicanthus, blepharophimosis, right lid ptosis, strabismus, anti mongoloid slant, small mouth, mask-like face, high-arched palate, nasal speech, dysphagia, kyphosis and minimal scoliosis were noted, while Case 2 displayed blepharophimosis [ncbi.nlm.nih.gov]

• Low Set Ears

  The clinical spectrum includes cranio-facial: long philtrum mouth puckering microstomia H-shaped chin dimple orbital features hypotelorism 8 : drooping of the upper eyelids : strabismus : low-set ears gradual hearing loss microcephaly musculoskeletal: [radiopaedia.org]

  Signs and symptoms 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. [owlapps.net]

  Clinical description Facial features include prominent forehead and eyebrow ridges, hypertelorism, epicanthus, telecanthus, down-slanting palpebral fissures, deep-set eyes, full cheeks, low-set ears, midface hypoplasia, a short nose and long philtrum, [orpha.net]

• Hearing Impairment

  Speech problems or hearing impairment can also occur in people with this disorder. [medlineplus.gov]

  When present, the combination of severely abnormal curves of the backbone and non-functional muscles between the ribs (intercostal muscles) may result in chronic lung problems (reduced intrathoracic volume, impaired thoracic cage compliance, impaired [rarediseases.org]

• Hypertelorism

  Freeman-Sheldon syndrome (FSS); it involves certain skeletal malformations with some facial characteristics; skeletal malformations include camptodactyly with ulnar deviation, talipes equinovarus, while the facial characteristics include deep-sunken eyes with hypertelorism [ncbi.nlm.nih.gov]

  […] cra·ni·o·car·po·tar·sal dys·tro·phy [MIM*193700] a syndrome characterized by specific facial features with sunken eyes, hypertelorism, long philtrum, small nose, and small mouth with pursing of lips as in whistling, and skeletal malformations with ulnar [medical-dictionary.thefreedictionary.com]

  […] authors. ...read moreread less Abstract: IN 1938, Freeman, an orthopedic surgeon, and Sheldon, a pediatrician, described two children with microsomia, increased philtrum length, small nose and nostrils, flattening of facial bones, deep set eyes, ocular hypertelorism [typeset.io]

  Hypertelorism Increased distance between eye sockets, Increased distance between eyes, Increased interpupillary distance, Widely spaced eyes, Excessive orbital separation, Widened interpupillary distance, Ocular hypertelorism, Wide-set eyes [more] Interpupillary [rarediseases.oscar.ncsu.edu]

• Chin Dimples

  The clinical spectrum includes cranio-facial: long philtrum mouth puckering microstomia H-shaped chin dimple orbital features hypotelorism 8 : drooping of the upper eyelids : strabismus : low-set ears gradual hearing loss microcephaly musculoskeletal: [radiopaedia.org]

  Clinical diagnosis requires microstomia, whistling-face appearance (pursed lips), H-shaped chin dimpling, nasolabial folds, and two or more contractures of hands and feet. [ncbi.nlm.nih.gov]

• Short Nose

  Other facial features may include a prominent forehead and brow ridges, a short nose and area between the nose and mouth, widely spaced eyes (hypertelorism), a narrowing of the eye opening (blepharophimosis), droopy eyelids ( ptosis ), and a small tongue [rarediseases.info.nih.gov]

  nose, and a long philtrum (area between the nose and mouth) – hypoglossia (unusually small tongue) – micrognathia (small jaw) – a high arch in the roof of the mouth (high-arched palate). [contact.org.uk]

  The disease-specific oral and dental findings include prominent supraorbital ridge, sunken eyes, telecanthus, short nose, colobomata of the nostrils, long philtrum [Figure 1]a, b, high narrow palate [Figure 2], and marked microsomia and microglossia [ [jisppd.com]

  Other facial features may include a prominent forehead and brow ridges, a short nose and area between the nose and mouth, widely spaced eyes (hypertelorism), a narrowing of the eye opening (blepharophimosis), droopy eyelids (ptosis), and a small tongue [rareguru.com]

• 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]

  […] deep, creased nasal bridge; small, upturned nose with hypoplastic alae and narrow nares; microstomia with pursed lips; glossoptosis; micrognathia; 2 deep vertical chin creases; short neck with excess nuchal skin; inverted and wide spaced nipples; clenched [gimjournal.org]

• 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]

  Farlex Partner Medical Dictionary © Farlex 2012 An autosomal dominant [MIM 193700] or less commonly, or autosomal recessive [MIM 277720] condition with atypical mask-like facies—small ‘pursed’ lips, deep-set/sunken eyes, epicanthus, hypoplastic nasal [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]

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].

The material is in no way intended to replace professional medical care by a qualified specialist and should not be used as a basis for diagnosis or treatment. [orpha.net]

Herein, we describe dental problems of a child with Freeman-Sheldon syndrome and the treatment procedures performed. [unboundmedicine.com]

Treatment Currently, doctors have not found a cure for Freeman-Sheldon syndrome. The goal of treatment is to control symptoms and help the person live a better life. [vinmec.com]

Prognosis There are little data on prognosis. Rarely, some patients have died in infancy from respiratory failure; otherwise, life expectancy is considered to be normal. [owlapps.net]

Freeman Sheldon Syndrome Prognosis There is scarce data on prognosis of FSS. There are rare cases of patients dying during infancy from respiratory failure. [syndrome.org]

The prognosis or natural history in these children is feeding difficulty, vomiting and dysphagia leading to failure to thrive. Most of the features are secondary to increased muscle tone. [elynsgroup.com]

Darin N, Kimber E, Kroksmark AK, Tulinius M: Multiple congenital contractures: Birth prevalence, etiology and outcome. J Pediatr 2002; 140(1): 61-7. [medigraphic.com]

Arthrogryposis in children: Etiological assessments and preparation of a protocol for etiological investigations. Arch Pediatr. 2018 Jun 15. [Medline]. Hall JG. [medscape.com]

The etiology remains unknown. Ultrasonographic evaluation (revealing abnormalities of the extremities and mouth) may be useful for prenatal diagnosis. Due to the clinical variability and rarity of FSS, there is no standard management protocol. [wiki.romse.org]

Etiology FSS is caused by homozygous mutations in MYH3, encoding for embryonic myosin heavy chain 3, a primary component of fetal myotubules; this protein has a central role during fetal muscular development, while postnatally it is progressively replaced [orpha.net]

Arthrogryposis (Multiple Congenital Contractures): Diagnostic Approach to Etiology, Classification, Genetics, and General Principles. Eur J Med Genet 2014;57:464-472. Filges I, Hall JG. [rarediseases.org]

Further research is wanted to determine epidemiology of psychopathology in FSS and refine therapy protocols. [owlapps.net]

FSS No mutation detected – risk for FSS reduced but not eliminated Differential Diagnosis Sheldon-Hall syndrome Distal arthrogryposis type 1 Trismus-pseudocamptodactyly syndrome Congenital contractual arachnodactyly (Beals-Hecht syndrome) Background Epidemiology [arupconsult.com]

Summary Epidemiology Approximately 100 cases of Freeman-Sheldon syndrome (FSS) have been reported to date; no gender predominance is reported and the distribution is worldwide. [orpha.net]

Condition or disease Intervention/treatment Arthrogryposis Craniofacial Abnormalities Posttraumatic Stress Disorder Depressive Disorder Other: PTSD Checklist-Specific Other: Modified Flanagan Quality of Life Scale Other: Center for Epidemiologic Studies [clinicaltrials.gov]

Further research is wanted to determine epidemiology of psychopathology in FSS and refine therapy protocols. References ^ Freeman, EA; Sheldon JH (1938). "Cranio-carpo-tarsal dystrophy: undescribed congenital malformation". [dictionnaire.sensagent.leparisien.fr]

The pathophysiology and anaesthetic problems encountered are discussed. [ncbi.nlm.nih.gov]

While fulfilling Stevenson's 2006 diagnostic criteria, the patient described presented with several previously unreported and rare findings that may serve as 'missing links' in the effort to better appreciate pathophysiology in FSS. [hilarispublisher.com]

Pathophysiology Unknown, but it is thought to involve fibrous replacement of muscles fibers. Diagnosis Facial features and malformations of limbs are typical. [accesspediatrics.mhmedical.com]

[…] inheritance – ~70% of cases represent new mutations Mutations in MYH3 gene – 93% of cases 2 common missense mutations occur in exon 17 of MYH3 – 72% of FSS cases c.2014C>T (p.R672C) c.2015G>A (p.R672H) No other FSS-associated genes identified to date Pathophysiology [arupconsult.com]

"Persistent elevations of cerebrospinal fluid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early-life stressors: implications for the pathophysiology of mood and anxiety disorders". Proc. Natl. Acad. Sci. [dictionnaire.sensagent.leparisien.fr]

The dentist should henceforth instruct preventive modalities for such patients. A 7-year-old male child reported to the Department of Pedodontics and Preventive Dentistry with a chief complaint of carious teeth and difficulty in mouth opening. [jisppd.com]

Flexion contractures of fingers were so severe as to prevent their extension. Previously reported patients with similar hand anomalies had only mild to moderate limitation of extension. [ncbi.nlm.nih.gov]

It includes the prevention of Taravana syndrome and prevents hemoptysis. Traitement à long terme du retard de croissance associé au syndrome de Turner. Long-term treatment of growth failure associated with Turner syndrome. [context.reverso.net]

This paper reports a case of tracheostomy in a newborn baby suffering from the Freeman-Sheldon syndrome, contributing with information that can help health professionals to improve the respiratory condition in such cases and to prevent future complications [neurores.org]

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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.
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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.