Freeman Sheldon Syndrome

Freeman Sheldon Syndrome

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Freeman Sheldon Syndrome is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • Craniocarpotarsal dystrophy (dysplasia)
  • FSS
  • Whistling face syndrome
  • Whistling face-windmill vane hand syndrome
  • Distal arthrogryposis type 2A
  • DA2A

Disorder Subdivisions

  • None

General Discussion

Freeman-Sheldon syndrome is a rare inherited disorder characterized by multiple contractures (i.e., restricted movement around two or more body areas) at birth (congenital), abnormalities of the head and face (craniofacial) area, defects of the hands and feet, and skeletal malformations. Craniofacial abnormalities may consist of characteristic facial features that cause the individual to appear to be whistling. These features include an extremely small puckered mouth (microstomia); a "full" forehead appearance, unusually prominent cheeks; and thin, pursed lips. Affected infants may also have an unusually flat middle portion of the face, a high roof of the mouth (palate), an unusually small jaw (micrognathia), an abnormally small tongue (microglossia), and/or a raised, scar-like mark in the shape of an "H" or a "V" extending from the lower lip to the chin. Affected infants often have abnormalities affecting the eyes including widely-spaced deep-set eyes, crossed eyes (strabismus), and/or downslanting eyelid folds (palpebral fissures). Malformations of the hands and feet are also characteristic of Freeman-Sheldon syndrome. 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 complications. Freeman-Sheldon syndrome can be inherited as an autosomal dominant genetic trait. However, most cases occur randomly with no apparent cause (sporadically).

Symptoms

Freeman-Sheldon syndrome is characterized by abnormalities of the head and face (craniofacial) area, defects of the hands and feet, and skeletal malformations. Symptoms and physical findings associated with this disorder are usually present at birth (congenital) and may vary greatly from case to case.



Infants with Freeman-Sheldon syndrome exhibit various abnormalities of the head and face (craniofacial) area including an unusually small puckered mouth (microstomia) that appears as if the infants are attempting to whistle. Affected infants have an unusually flat middle portion of the face, a "masking" or immobile facial appearance, full cheeks, a high roof of the mouth (palate), an unusually small jaw (micrognathia), improperly aligned teeth (malocclusion), abnormal crowding of the teeth, and/or an abnormally small tongue (microglossia). In some cases, infants with Freeman-Sheldon syndrome have a raised scar-like mark in the shape of an "H" or a "Y" extending from the lower lip to the bottom of the chin. In addition, affected children may have a nasal quality to their voice (nasal speech) due to limited movement of the soft palate. Malformations of the mouth and jaw may cause several other complications including a poor or diminished ability to suck; speech abnormalities; vomiting; difficulty swallowing (dysphagia) and eating, resulting in failure to grow and gain weight at the expected rate (failure to thrive); and/or respiratory problems that, in some cases, may lead to life-threatening complications. In addition, swallowing and feeding difficulties may cause foreign material (e.g., food or vomit) to be inhaled (aspirated) into the lungs, which may result in severe lung infections (aspiration pneumonia).



Several abnormalities of the eyes may be present in individuals with Freeman-Sheldon syndrome. In most cases, affected infants have widely spaced eyes (ocular hypertelorism) that are deeply-set and/or crossed (strabismus). In some cases, affected infants may also have abnormal folds of skin between the upper eyelid and the nose (epicanthal folds), downslanting eyelid folds (palpebral fissures), and/or droopy upper eyelids (ptosis). In addition, the space between the upper and lower eyelids may be unusually narrow (blepharophimosis).



Other characteristic facial features associated with Freeman-Sheldon syndrome may include malformations of the nose. The nose may be unusually small with narrow, underdeveloped nostrils (nasi alae). In addition, the bridge of the nose may be abnormally broad and there may be an unusually long vertical gap between the upper lip (philtrum) and the nose.



Several malformations affecting the hands and feet may be present in infants with Freeman-Sheldon syndrome. Certain fingers may be permanently flexed (camptodactyly) outward away from the thumb (ulnar deviation). In contrast, the thumbs may be flexed inward toward the palm (adducted). Flexion of the fingers and thumbs may be caused by permanent fixation (contracture) of the joints between the fingers and the palms (metacarpophalangeal joints). These permanently flexed fingers are known as the "windmill vane position." In addition, some affected infants may have abnormally thick skin and underlying tissue (subcutaneous) on the surface of the hands.



Infants with Freeman-Sheldon syndrome also exhibit deformities of the feet, including a form of club foot where the heel of the foot may be turned inward toward the body while the rest of the foot is bent downward and inward (talipes equinovarus). In most cases, this deformity affects both feet (bilateral), although in some cases it affects only one foot (unilateral). Club foot may cause walking difficulties.



Infants with Freeman-Sheldon syndrome often have skeletal abnormalities including progressive and often severe front-to-back and side-to-side curvature of the spine (kyphoscoliosis); contractures of the knees, shoulders, and/or hips, resulting in limited movement of these areas; and/or dislocation of the hips and the head of one of the forearm bones (radius). In some cases, degeneration (atrophy) of the muscles in the forearms and lower legs may also occur.



In some cases, infants with Freeman-Sheldon syndrome experience delayed growth after birth (postnatal growth deficiency). Intelligence and cognition are typically unaffected in children with Freeman-Sheldon syndrome. In some cases, there may be slight delays in attaining motor milestones (e.g., head control, rolling over). Additional findings that are sometimes associated with this disorder may include incomplete closure of bones in the spinal column surrounding the spinal cord (spina bifida occulta), protrusion of a portion of the intestine through an abnormal opening in the muscular wall of the abdomen into the groin area (inguinal hernia), epileptic seizures, hearing loss, and/or webbing of the neck or shoulders (pterygium colli or axilla). (See spina bifida in the "related disorders" section of this report.)



Additionally, some types of anesthesia administered to people with Freeman-Sheldon syndrome may trigger malignant hyperthermia which can be an acute life threatening condition. It is therefore important for surgeons and dentists to be aware that certain types of anesthesia should be avoided in individuals with Freeman-Sheldon syndrome.



Malignant hyperthermia is a disorder in which a person does not react appropriately to certain drugs due to a genetic abnormality. Affected individuals develop a rapid, high fever after the administration of general anesthesia or certain muscle relaxants. Drugs that could cause this response include halothane, cyclopropane, or succinylcholine. People with Freeman-Sheldon Syndrome are especially prone to malignant hyperthermia. (For more information on this disorder, choose "malignant hyperthermia" as your search term in the Rare Disease Database.)

Causes

In most cases, Freeman-Sheldon syndrome occurs randomly, with no apparent cause (sporadically). Other cases are inherited as an autosomal dominant trait. In rare cases, autosomal recessive or X-linked recessive inheritance has been suggested.



Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.



Investigators have determined that Freeman-Sheldon syndrome can be caused by disruptions or changes (mutations) to the embryonic myosin heavy chain (MYH3) gene located on the short arm of chromosome 17 (17p13.1). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 17p13.1" refers to band 13.1 on the short arm of chromosome 17. The numbered bands specify the location of the thousands of genes that are present on each chromosome.



In some rare cases, a clinically indistinguishable form of Freeman-Sheldon syndrome is inherited as an autosomal recessive trait. In a few of these cases, parents of several individuals with the disorder have been closely related by blood (consanguineous). If both parents carry the same disease gene, then there is a higher than normal risk that their children may inherit the two disease genes for this disorder.



Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.



Some findings associated with Freeman-Sheldon syndrome suggest the disorder may be a form of muscle disease known as myopathic arthrogryposis, a condition in which an underlying disease of the muscles (myopathy) results in permanent fixation of the joints of the fingers and toes (distal arthrogryposis).

Affected Populations

Freeman-Sheldon syndrome is a rare disorder that affects males and females in equal numbers. Approximately 100 cases have been reported in the medical literature since the disorder was first described in 1938 by Drs. Freeman and Sheldon. Some cases occurred within families (kindreds) over several generations. Some symptoms and physical findings associated with the disorder are apparent at birth (congenital). Freeman-Sheldon syndrome is one of a group of disorders that are associated with multiple congenital contractures (MCCs). MCCs occur in approximately 1 in 3,000 children. Because the disorder shares features with other congenital contracture syndromes it sometimes is misdiagnosed making it difficult to determine its true frequency in the general population.

Standard Therapies

Diagnosis

The diagnosis of Freeman-Sheldon syndrome may be confirmed based upon a thorough clinical evaluation, the identification of characteristic physical findings, a detailed patient history, and specialized testing such as advanced imaging techniques. In some cases, the disorder may be diagnosed before birth (prenatally) using fetal ultrasonography to identify characteristic physical abnormalities. In fetal ultrasonography, an image of the developing fetus is created using sound waves.



Most of the physical abnormalities associated with this disorder may be obvious at birth. However, physical findings and symptoms are highly variable and characteristic facial features and malformations of the hands and feet may not be present in all cases. Computed tomography (CT) scanning may be used to determine the presence and/or severity of specific craniofacial and dental symptoms. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. X-ray studies may also reveal an abnormally steep depression in the (occipital) bone of the lower rear portion of the skull (anterior cerebral fossa).



In addition, electromyography may reveal the underdevelopment (hypoplasia) of certain muscles in the hands, feet and upper jaw. In electromyography, special equipment is used to measure the response of certain muscles to stimulation by electrical currents. In some cases, surgical removal and microscopic examination of small samples of muscle tissue (biopsy) may reveal abnormal accumulation of fibrous connective tissue.



Treatment

The treatment of Freeman-Sheldon syndrome is directed toward specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists including pediatricians, orthopedic surgeons, dental specialists, speech pathologists, physicians who specialize in the diagnosis and treatment of disorders of the muscles, and other health care professionals. These medical specialists systematically and comprehensively plan an affected child's treatment.



Specific therapies for the treatment of Freeman-Sheldon syndrome are symptomatic and supportive. An unusually small mouth (microstomia) may be treated by surgery or by using a special device that expands the mouth for a few hours each day. This treatment is essential since the mouth may be too small to permit orthodontic treatment that may be necessary to correct dental abnormalities such as malocclusion.



Swallowing difficulty (dysphagia) may be treated with a device that maintains tension on the neck (halo traction) and special procedures that can correct the stiffness of the neck muscles (posterior occipital-cervical decompression and fusion). Speech therapy may prove beneficial in improving tongue movement for speech and swallowing.



Surgery may be performed to correct additional physical abnormalities, such as club feet, abnormalities of the hands, craniofacial abnormalities, and contractures of the knees and elbows. Physical therapy in combination with surgical and supportive measures may improve an affected individual's ability to walk and perform other movements independently. Ulnar deviation usually improves with age and does not require corrective surgery.



Some individuals with Freeman-Sheldon syndrome may be at risk for a malignant hyperthermia-like response when exposed to certain anesthesia or muscle relaxants (e.g., halothane). This risk must be taken into consideration by surgeons, anesthesiologists, dentists, and other health care workers when making decisions concerning potential surgery and use of particular anesthetics. It must also be considered by primary care physicians when prescribing certain medications.



Early intervention is important to ensure that children with Freeman-Sheldon syndrome reach their potential. Special services that may be beneficial to affected children include special educational and occupational therapy as well as other medical, social, and/or vocational services. Genetic counseling will be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



The University of Virginia's Department of Plastic Surgery is reviewing surgical procedures for FSS. For more information, contact :



Craniofacial Abnormalities

Dept. of Plastic and Maxillofacial Surgery

University of Virginia Medical Center

Box 376

Charlotteville, VA 22908

Phone: (804) 924-5801



Investigators from the Intermountain Unit of Shriners Hospitals for Children, the University of Utah Department of Pediatrics, and the Eccles Institute of Human Genetics are collaborating on a project to map and characterize genes causing multiple congenital contracture disorders and limb deficiency/duplication syndromes. The disorders being studied are: autosomal dominant clubfoot, distal arthrogryposis type I, Gordon syndrome, Freeman-Sheldon syndrome, trismus-pseudocamptodactyly, autosomal dominant multiple pterygium syndrome, autosomal ulnar hypoplasia ectrodactyly disorders, ulnar mammary syndrome, Holt-Oram syndrome, and fibular hypoplasia. For more information, please contact:



Michael Bamshad, M.D.

Eccles Institute of Human Genetics

Building 533, Room 2100

University of Utah Medical Center

Salt Lake City, UT 84112

Tel: (801) 585-3384 (office)

Tel: (801) 585-3385 (lab)

Fax: (801) 581-7796

E-mail: mike@thor.med.utah.edu

References

TEXTBOOKS

Birth Defects Encyclopedia: Mary Louise Buyse, Editor-In-Chief; Blackwell Scientific Publications, 1990. Pp. 456-57.



Smith's Recognizable Patterns of Human Malformation, 5th Ed.: Kenneth L. Jones, Editor; W. B. Saunders Co., 1997. P. 214.



Syndromes of the Head and Neck, 3rd Ed.: Robert J. Gorlin, M. Michael Cohen, Jr., and L. Stephan Levin, Editors; Oxford University Press, 1990. Pp. 634-36.



Nelson Textbook of Pediatrics, 15th Ed.: Richard E. Behrman, Editor; W.B. Saunders Company, 1996. Pp. 1953-54.



JOURNAL ARTICLES

Toydemir RM, Rutherford A, Whitby FG, et al. Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome. Nat Genet. 2006;38:561-5.



Stevenson DA, Carey JC, Palumbos J, et al. Clinical characteristics and natural history of Freeman-Sheldon syndrome. Pediatrics. 2006;117:754-62.



Krakowiak PA, Bohnsack JF, Carey JC, Bamshad M. Clinical analysis of a variant of Freeman-Sheldon syndrome. Am J Med Genet. 1998;76:93-8.



Krakowiak PA, O'Quinn JR, Bohnsack JF, et al. A variant of Freeman-Sheldon syndrome maps to 11p15.5-pter. Am J Med Genet. 1997;60:426-32.



Ohyama K, Susami T, Kato Y, Amano H, Kuroda T. Freeman-Sheldon syndrome: case management from age 6 to 16 years. Cleft Palate Craniofac J. 1997;34:151-3.



Munro HM, Butler PJ, Washington EJ. Freeman-Sheldon (whistling face) syndrome. Anaesthetic and airway management. Paediatr Anaesth. 1997;7:345-8.



Bamshad M, Jorde LB, Carey JC. A revised and extended classification of the distal arthrogryposes. Am J Med Genet. 1996;65:277-81.



Song HR, Sarwark JF, Sauntry F, Grant J. Freeman-Sheldon syndrome (whistling face syndrome) and cranio-vertebral junction malformation producing dysphagia and weight loss. Pediatr Neurosurg. 1996;24:272-4.



Zampino G, Conti G, Balducci F, et al. Severe form of Freeman-Sheldon syndrome associated with brain anomalies and hearing loss. Am J Med Genet. 1996;62:293-6.



Robbins-Furman P. Prenatal diagnosis of freeman-sheldon syndrome (whistling face). Prenat Diagn. 1995;15:179-82.



Ferreira LM Minami M, Andrews Jde M. Freeman-Sheldon syndrome: surgical correction of microstomia. Br J Plast Surg. 1994;47:201-2.



Bamshad M, Watkins WS, Zenger RK, et al. A gene for distal arthrogryposis type 1 maps to the pericentromeric region of chromosome 9. Am J Med Genet. 1994;55:1153-58.



Mayhew JF. Anesthesia for children with freeman-sheldon syndrome to the editor. Anesthesiology. 1993;78:408.



Sackey A, Coulter B, Fryer A, Van Velzen D. Epilepsy in the Freeman Sheldon syndrome. J of Child Neurology. 1995;10:335-7.



Marasovich WA, Mazaheri M, Stool SE. Otolaryngologic findings in whistling face syndrome. Arch Otolaryngol Head Neck Surg. 1989;115:1373-80.



Vanek J, Janda J, Amblerova V, Losan F. Freeman-Sheldon syndrome: a disorder of congenital myopathic origin? J Med Genet. 1986;23:231-6.



Hall JG, Reed SD, Greene G. The distal arthrogryposes: delineation of new entities - review and nosologic discussion. Am J Med Genet. 1982;11:185-239.



FROM THE INTERNET

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:193700; Last Update:05/02/2006. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=193700 Accessed on: August 24, 2006.



McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:277720; Last Update:03/03/2005. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=277720 Accessed on: August 24, 2006.



McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:601680; Last Update:05/02/2006. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601680 Accessed on: August 24, 2006.

Resources

Freeman-Sheldon Research Group, Inc.

1701 Hamill Avenue

Clarksburg, WV 26301

Tel: (304)624-1436

Email: phaberbosch@aol.com

Internet: http://clinmedsurgcranio.blogspot.com/ & http://www.fspsg.org



March of Dimes Birth Defects Foundation

1275 Mamaroneck Avenue

White Plains, NY 10605

Tel: (914)997-4488

Fax: (914)997-4763

Tel: (888)663-4637

Email: Askus@marchofdimes.com

Internet: http://www.marchofdimes.com



FACES: The National Craniofacial Association

PO Box 11082

Chattanooga, TN 37401

Tel: (423)266-1632

Fax: (423)267-3124

Tel: (800)332-2373

Email: faces@faces-cranio.org

Internet: http://www.faces-cranio.org



Malignant Hyperthermia Association of the United States

1 North Main St

PO Box 1069

Sherburne, NY 13460

USA

Tel: (607)674-7901

Fax: (607)674-7910

Email: info@mhaus.org

Internet: http://www.mhaus.org



AmeriFace

P.O. Box 751112

Limekiln, PA 19535

USA

Tel: (702)769-9264

Fax: (702)341-5351

Tel: (888)486-1209

Email: info@ameriface.org

Internet: http://www.ameriface.org



NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases

Information Clearinghouse

One AMS Circle

Bethesda, MD 20892-3675

USA

Tel: (301)495-4484

Fax: (301)718-6366

Tel: (877)226-4267

TDD: (301)565-2966

Email: NIAMSinfo@mail.nih.gov

Internet: http://www.niams.nih.gov/



Craniofacial Foundation of America

975 East Third Street

Chattanooga, TN 37403

Tel: (423)778-9176

Fax: (423)778-8172

Tel: (800)418-3223

Email: terry.smyth@erlanger.org

Internet: http://www.craniofacialfoundation.org



Shine

42 Park Road

Peterborough, PE1 2UQ

United Kingdom

Tel: 01733555988

Fax: 08454507755

Email: info@shinecharity.org.uk

Internet: http://www.shinecharity.org.uk/



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Madisons Foundation

PO Box 241956

Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.org



For a Complete Report

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