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Last updated: 9/11/2024
Years published: 1988, 1989, 1992, 1997, 1998, 1999, 2006, 2007, 2021, 2024
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, Craig R. Dufresne, MD, FACS, FICFS, and Mikaela I. Poling, BA, for assistance in the preparation of this report.
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Summary
Freeman-Sheldon syndrome (FSS) or โwhistling face syndromeโ is an exceptionally rare disorder present before birth (congenital) that primarily affects muscles of the face and skull (craniofacial muscles) but frequently involves problems with joints of the hands and feet.
Diagnosis requires the presence of an exceptionally small mouth (microstomia), whistling face appearance (pursed lips), โHโ or โVโ shaped chin dimple and very obvious creases from the nostril to the corners of the mouth (nasolabial creases). While some include restricted movement (contractures) in the hands and feet as requirements, these are not specific findings to FSS. In FSS, normal muscle is present but is interspersed or sometimes replaced by tendon-like matter that reduces the musclesโ ability to move well and causes deformities. Signs and symptoms have varying degrees of severity. Some muscles are unaffected, while others may be completely non-functional, causing affected joints, muscles of facial expression and muscles between the ribs (intercostal muscles) to be immobile. The face muscles tend to be most severely affected, with people having an expressionless mask-like appearance. Diagnosis before birth (with genetic testing or sonography) may be possible if a parent has FSS, but diagnosis before birth is not considered definitive.
Males and females and all geographic areas and ethnicities are affected equally, and there is no known link with environmental or parental factors, such as exposure to illnesses, toxins, drugs or harsh substances. FSS can be passed on from a person who has the disorder, but most people with FSS have no family history of the syndrome. People with FSS have normal intelligence, but most children with FSS have developmental delays that are caused by physical deformities.
Introduction
FSS is named for Dr. Ernest Arthur Freeman, an orthopedic surgeon from Wolverhampton, England, UK, and Prof. Fredrick Burian, a plastic surgeon from Prague, Czech Republic. In 1938, Dr. Freeman and Dr. John Howard Sheldon, who described a different but similar appearing condition now known as Sheldon-Hall syndrome (SHS), published the first description of FSS, which they called โcranio-carpo-tarsal dystrophyโ. In 1962, Prof. Burian independently verified the existence of FSS, coining the term โwhistling face syndromeโ and giving the first complete description of classic FSS.
Freeman-Sheldon syndrome (FSS) has certain specific symptoms that are always present. Everyone with FSS has the following characteristics:
Other common symptoms include the following:
Airway management is difficult because protecting the airway during unconsciousness is difficult due to head and neck deformities. Healthcare providers may struggle to access blood vessels for tests or treatment, complicating anesthesia and surgery planning.
Freeman-Sheldon Syndrome (FSS) is caused by a change (pathogenic variant) in the embryonic myosin heavy chain (MYH3) gene, which is located on band 13.1 of the short arm (p) of chromosome 17 (a locus of 17p13.1). The MYH3 gene provides instructions for creating a protein called myosin-3. This protein, along with another called actin, plays a crucial role in forming muscle fibers and enabling muscles to contract, which is essential for muscle movement. Myosin-3 is specifically active in muscle fibers during fetal development, where it is vital for the normal growth and formation of muscles before birth.
Researchers are still working to fully understand how variants in the MYH3 gene lead to the signs and symptoms of Freeman-Sheldon syndrome. It is believed that these variants disrupt the normal function of the myosin-3 protein. Studies suggest that these variants cause muscles to stay contracted for too long and make it difficult for them to relax, which restricts muscle movement. This lack of movement in the muscles and limbs during development likely leads to stiffening of the muscles and surrounding tissues, resulting in the contractures (tightened muscles) that cause the characteristic โwhistling faceโ appearance, as well as deformities in the hands, feet and spine.
The limited muscle movement before birth might also interfere with the normal development of other parts of the body, contributing to the other features associated with Freeman-Sheldon syndrome.
A small number of people with Freeman-Sheldon syndrome do not have variants in the MYH3 gene. In these individuals, the cause of the disorder is unknown.
There is no known link between FSS and environmental or parental factors, such as exposure to illnesses, toxins, drugs or harsh substances.
Freeman-Sheldon syndrome is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
In very rare instances, a parent may carry the gene variant only in some or all their sperm or egg cells, a condition known as germline mosaicism. In these cases, the parent does not show any signs or symptoms of Freeman-Sheldon syndrome but can still pass the gene variant to their child.
Freeman-Sheldon Syndrome (FSS) appears to occur in all ethnicities and all geographic regions and affects males and females. FSS is an exceptionally rare disorder. It is estimated that 200-300 individuals worldwide may be affected, but the prevalence is not known.
Freeman-Sheldon Syndrome (FSS) is diagnosed based on signs and symptoms and medical history. Plastic surgeons and anesthesiologists who specialize in treating patients with skull and face problems are the best able to diagnose and evaluate people who may have FSS.
The following signs and symptoms must be present for diagnosis of FSS:
Classically, there also must be two or more body areas with limited movement of joints, frequently the hands or feet and ankles, but FSS may be diagnosed without problems beyond the face.
People with FSS type 2 tend to be the mildest and have the least complications and people with FSS type 1 or โclassicโ tend to be the most seriously affected and more likely to have medical complications. People with FSS type 3 fall between FSS types 1 and 2.
Medical imaging, muscle and nerve function tests and breathing tests, may add more information needed for treatment but not for diagnosis. Diagnosis of FSS before birth (prenatal) may be possible if a parent has FSS, but it is not considered definitive.
If in vitro fertilization is used by a woman with FSS and the gene variant causing FSS is known before pregnancy (before eggs are fertilized) diagnosis can be made by testing polar bodies from eggs, which have the same genetic material as the egg but do not develop.
In vitro fertilization (IVF) is a procedure where a womanโs egg is removed from her ovary, fertilized with sperm in a laboratory dish (โin vitroโ meaning โin glassโ), and then the resulting embryo is transferred back into her uterus to establish a pregnancy; itโs a common method used to treat infertility issues when other methods are not successful.
Freeman-Sheldon Syndrome (FSS) treatment is focused on addressing specific functional problems. Since FSS primarily affects the face and skull (craniofacial areas) itโs important that a craniofacial surgeon coordinates overall care. Patients with FSS who are treated by doctors in other specialties may not have as good outcomes, as those doctors might not fully understand how craniofacial issues can impact general health and emotional well-being.
Physical, occupational and speech therapies are essential for managing FSS. These therapies aim to improve muscle function, mobility and communication skills.
Surgery is used selectively, mainly for dental and mouth problems (oral-maxillofacial surgery) and for issues with the face, head and hands (plastic surgery). Surgery can help extend the benefits of therapy, but abnormal muscle function in FSS can limit surgical options and lead to mixed results. Itโs common for surgeries to be repeated over time to release tight muscles and improve movement.
For the best results, any reconstructive surgery on the face and skull should ideally be done before the child starts school. Early surgery can improve speech, breathing through the nose, access to dental care and facial appearance. If facial deformities arenโt addressed early, they can significantly impact the childโs social interactions and emotional well-being throughout life. If the eyelids obstruct vision, delaying surgery could lead to blindness. However, while surgery can improve facial appearance, there are limits to how much improvement is possible.
Physical therapy is the best approach for treating hand, foot and spine deformities. Braces and splints can help maintain the progress made through therapy. Itโs important to start physical therapy for the hands soon after birth and during early childhood, though some benefits can still be achieved in early adulthood.
Surgery on the feet is generally not recommended for people with FSS because of the high risk of complications. Failed foot surgery can result in non-functional feet or even lead to the loss of one or both feet. If foot deformities canโt be corrected with therapy and braces, prosthetics can be used to help the person walk comfortably without requiring amputation.
With early diagnosis, aggressive physical therapy, and a healthy, active lifestyle, most people with FSS can have a good quality of life. Proper therapy, along with carefully planned surgeries, can greatly improve outcomes and reduce the impact of physical challenges on development.
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: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
The Office of Craig R. Dufresne, MD, FACS, FICFS, is seeking participants for two studies to: (1) survey and review medical records for information about specific treatments and major problems in patientsโ medical history, quality of life, and mental health issues relating to FSS; and (2) medically evaluate healthy persons and patients to compare their bodiesโ functioning at rest and during exercise. These studies are each designed to provide a stronger evidence base for improving the standard of care and developing new treatments. Patients will receive any new information learned about them during the studies. Persons with Freeman-Sheldon syndrome, Sheldon-Hall syndrome, distal arthrogryposis type 1, or distal arthrogryposis type 3 are eligible for all studies. For more information, please contact:
Office of Craig R. Dufresne, MD, FACS, FICFS
8501 Arlington Boulevard
Suite 420
Fairfax, VA 22031
USA
Office Telephone: 703-207-3065
Home page: https://www.duplastics.com/research
Email: [email protected]
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JOURNAL ARTICLES
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Systematic Reviews
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Poling MI, Dufresne CR, Chamberlain RL. Findings, phenotypes, diagnostic accuracy, and treatment in Freeman-Burian syndrome: a patient-level data meta-analysis of unstructured observational clinical studies. J Craniofac Surg. 2020;31(4):1063-1069.
Poling MI, Dufresne CR, McCormick RJ. Identification and recent approaches for evaluation and management of rehabilitation concerns for patients with Freeman-Burian Syndrome: principles for global treatment. J Ped Genet. 2020;09(03):158-163.
Poling MI, Dufresne CR, Portillo AL. Identification and recent approaches for evaluation, operative counseling, and management in patients with Freeman-Burian syndrome: principles for global treatment. J Craniofac Surg. 2019;30(8):2502โ2508.
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Letters
Poling MI, Dufresne CR. Accuracy of Facts About Freeman-Sheldon syndrome. Clin Exp Obstet Gynecol. 15 Oct 2021. [In Press]
Poling MI, Dufresne CR. Head First, Not Feet First: Freeman-Sheldon Syndrome as Primarily a Craniofacial Condition. Cleft Palate Craniofac J. 2018;55(5):787-788.
Poling MI, Dufresne CR. Revisiting the many names of Freeman-Sheldon syndrome. J Craniofac Surg. 2018;29(8):2176โ2178.
Poling MI, Dufresne CR. Letter: Precise Pulmonary Function Evaluation and Management of a Patient With Freeman-Sheldon Syndrome Associated With Recurrent Pneumonia and Chronic Respiratory Insufficiency (Ann Rehabil Med 2020;44:165-70). Ann Rehabil Med. 2020;44(5):409-410.
Poling MI, Dufresne CR. Letter. AANA J. 2020;88(5):54.
Clinical Practice Guidelines
Poling MI, Dufresne CR. Freeman-Burian syndrome. Anรคsth Intensivmed. 2019;60(1):S8-S17. doi: 10.19224/ai2019.S008
INTERNET
Poling MI, Dufresne CR. Anaesthesia recommendations for Freeman-Burian syndrome. Orphan Anesthesia. 27 Sept 2018. Available at: https://www.orphananesthesia.eu/de/erkrankungen/handlungsempfehlungen/freeman-burian-syndrom/467-freeman-burian-syndrome-1/file.html#:~:text=Lidocaine%20with%20or%20without%20epinephrine,epidural%20anaesthesia%20may%20be%20used. Accessed Sept 11, 2024.
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Poling MI, Morales Corado JA. Findings, phenotypes, and outcomes in Freeman-Sheldon and Sheldon-Hall syndromes, and distal arthrogryposis types 1 and 3: Protocol for systematic review and patient-level data meta-analysis. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339949/ Accessed Sept 11, 2024.
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NORD strives to open new assistance programs as funding allows. If we donโt have a program for you now, please continue to check back with us.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORDโs mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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