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Freeman-Sheldon Syndrome

Whistling Face Syndrome

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.


Presentation

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]
Pneumonia
  • This patient also presented severe hypertonicity, multiple episodes of pneumonia, difficulty in swallowing, and poor weight gain, which are characteristic of the most severe cases of FSS. A brain CT scan showed cerebellar and brainstem atrophy.[ncbi.nlm.nih.gov]
  • Aspiration pneumonia and respiratory difficulties are the main causes of early mortality. In Taiwan, only a few cases have been reported before.[ncbi.nlm.nih.gov]
  • The infant died two months later from pneumonia. Upon construction of a standard mouth length chart, it was found that the fetal lip width in this case of FSS was well below the 5th centile. Here we present a standard chart for fetal lip width.[ncbi.nlm.nih.gov]
  • Aspiration pneumonia and respiratory difficulties are the main causes of early mortality (9). Long-term outcomes have been satisfactory in the majority of children.[czytelniamedyczna.pl]
Pharyngitis
  • He did not show anatomical or histopathological abnormalities in the pharyngeal, laryngeal or tracheal regions. We assume that the only explanation of the repeated obstructive episodes is a functional muscular obstruction.[ncbi.nlm.nih.gov]
  • He did not show anatomical or histopathological abnormalities in the pharyngeal, laryngeal or tracheal regions. We assume that the only explanation of the repeated obstructive episodes is a functional muscular obstruction. 2002 S.[karger.com]
  • A cuffed tracheal tube would have been better in our case as it offers better airway seal than a pharyngeal pack.[omicsonline.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]
  • 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]
  • 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]
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]
Chin Dimples
  • FSS is considered a type of myopathic distal arthrogryposis; diagnosis requires the following: microstomia, whistling-face appearance, H-shaped chin dimpling, nasolabial folds, and multiple contractures of the hands and feet.[ncbi.nlm.nih.gov]
  • FSS is described as a myopathic distal arthrogryposis; diagnosis requires the following: microstomia, whistling face appearance, H-shaped chin dimpling, nasolabial folds, and multiple hand and foot contractures.[ncbi.nlm.nih.gov]
  • 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]
  • 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]
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]
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]

Workup

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].

Treatment

  • Oral commissure contraction treatments vary from patient education to complicated surgical and/or prosthetic treatments, but recurrence is often described.[ncbi.nlm.nih.gov]
  • Herein, we describe dental problems of a child with Freeman-Sheldon syndrome and the treatment procedures performed.[ncbi.nlm.nih.gov]
  • It incurs the need for dental and oral treatment.[ncbi.nlm.nih.gov]
  • Orthodontic treatment improved the patient's Class II malocclusion, which was accompanied by crowding and a deep bite.[ncbi.nlm.nih.gov]
  • Dental treatment was carried out successfully under local anaesthetic for a young child with Freeman-Sheldon syndrome. A novel coloured compomer material was helpful in the management of the case.[ncbi.nlm.nih.gov]

Prognosis

  • 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]

Etiology

  • (Etiology) Freeman Sheldon Syndrome is caused by a genetic mutation defect.[dovemed.com]
  • Chamberlain Systematic Reviews (2017) Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases Asaf Vivante , Hadas Ityel , Ben Pode-Shakked , Jing Chen , Shirlee Shril , Amelie T. van der Ven , Nina[nature.com]
  • Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases Asaf Vivante , Hadas Ityel , Ben Pode-Shakked , Jing Chen , Shirlee Shril , Amelie T. van der Ven , Nina Mann , Johanna Magdalena Schmidt , Reeval[nature.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]

Epidemiology

  • 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]
  • Further research is wanted to determine epidemiology of psychopathology in FSS and refine therapy protocols.[en.wikipedia.org]
  • Epidemiology The prevalence of arthrogryposis is about 1/3000 [ 3 ].[ojrd.biomedcentral.com]
  • Further research is indicated to determine epidemiology of psychopathology in FSS and refine therapy protocols. References 1.0 1.1 Freeman, EA (1938). "Cranio-carpo-tarsal dystrophy: undescribed congenital malformation".[wikidoc.org]
Sex distribution
Age distribution

Pathophysiology

  • The pathophysiology and anaesthetic problems encountered are discussed.[ncbi.nlm.nih.gov]
  • […] 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.[en.wikipedia.org]

Prevention

  • 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]
  • 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]
  • Emphasis needs to be on preventive or limiting contact to communicable diseases due to the abnormalities to the musculoskeletal system making recovery from even routine infections more problematic in FSS.[syndrome.org]
  • Current medical research have not indicated effective preventive measures for Freeman Sheldon Syndrome occurrence Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy[dovemed.com]

References

Article

  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.

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Last updated: 2019-06-28 10:25