NORD gratefully acknowledges Craig R. Dufresne, MD, FACS, FICFS, and Mikaela I. Poling, BA, for assistance in the preparation of this report.
Freeman-Sheldon syndrome (FSS) or “whistling face syndrome” 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), “H” or “V” shaped chin dimple and very obvious crease 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 muscles’ ability to move well and causes deformities. FSS happens with widely 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 persons 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. Both biologic genders 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 persons with FSS have no family history of the syndrome. Persons with FSS have normal intelligence, but most children with FSS have developmental delays that are caused by physical deformities.
FSS is named for Mr. Ernest Arthur Freeman, an orthopedic surgeon from Wolverhampton, England, UK, and Prof. Fredrick Burian, a plastic surgeon from Prague, Czech Republic. In 1938, Mr. 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 “cranio-carpo-tarsal dystrophy”. In 1962, Prof. Burian independently verified the existence of FSS, coining the term “whistling face syndrome” and giving the first complete description of classic FSS.
Certain problems are required to be present for diagnosis of FSS. All persons with FSS have the following problems: very small mouth (microstomia), whistling-face appearance (pursed lips), “H” or “V” shaped chin dimple and very obvious crease from the nostril to the corners of the mouth (nasolabial creases). Classically, persons also have restricted movement in joints (contractures) of two or more body areas, often hands and feet, with fingers and toes frequently overlapping.
Many additional problems have been associated with FSS, especially problems of the face, including: over-crowded teeth (dental crowding), poorly aligned teeth (class II malocclusion), very high roof of the mouth (vaulted or highly arched palate), extra distance between the nose and upper lip (long philtrum), bulging ridges above the eyes (prominent superciliary ridges or frontal bossing), very small tongue (microglossia), drooping eyelids (blepharoptosis), cross-eyed problem (strabismus), extra inner skin-fold of the eye next to the nose (epicanthal folds), down-slanting eyelid folds (palpebral fissures), very small eyelid opening (blepharophimosis), sunken appearance of eyes (enophthalmos), widely spaced eyes (ocular hypertelorism), low set and tilted ears, mild to moderate hearing impairment, under-developed chin (microgenia), under-developed (micrognathia) and recessed (retrognathia) jaw, wide nasal bridge, small nose, under-developed nostrils (hypoplastic alae nasi), long face and flat mid-face (mid-face hypoplasia). Skull bones may come together too early (craniosynostosis) and a small skull (microcephaly).
Hand or foot deformities may be present on both (bilateral) or only one (unilateral) side. Fingers (phalanges) may be tightly bent (camptodactyly) and pointed outward from the thumb (ulnar deviation or windmill vane appearance). The thumb (pollex) may be tightly bent into the palm (adducted or thumb-in-palm deformity). The wrist often has limited movement and is frequently bent up (dorsoflexed or cock-up deformity). Feet often resemble a golf club (talipes equinovarus or club foot condition) and may have a rocker bottom appearance (vertical talus), with toes (phalanges) tightly bent (camptodactyly) and turned inward (metatarsus varus). Sometimes there is overriding of fingers or toes shortly after birth that improves spontaneously or with mild therapy.
Different deformities of the back, ribs, and chest have been observed. Many persons with FSS have humpback (kyphosis), swayback (lordosis) or sideways (scoliosis) curves in the back bones. If the abnormalities in the curves of the spine and breastbone are significant, they can restrict internal organs of the chest and abdomen and cause gastrointestinal, lung, and heart problems. In people with FSS, the muscles between the ribs (intercostal muscles) often are non-functional, making breathing and coughing difficult (reduced respiratory effort and tussive ability) and rarely causing harm to the lungs (pulmonary hypertension) and heart (right heart strain and cor pulmonale). Not being able to breathe deeply and cough well also can make it difficult to recover from lower respiratory infections. 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 exercise tolerance, reduced ventilation of oxygen, and restrictive pulmonary disease). Notably, there is no evidence of FSS directly causing lung or heart problems. Some of the indirect or secondary lung and heart problems that persons with FSS may experience because of non-functional muscles between the ribs and possibly other areas of the chest can resolve or have improvement with exercise and medical treatment. Less frequently, some people may have deformities of the ribs and breastbone (sternum) cartilage, causing either a sunken (pectus excavatum) or jutted out (pectus carinatum) appearance of the chest. Rarely, persons may have small openings in the spinal bones (spina bifida occulta).
Persons with FSS often have a short neck that does not move well and may have extra skin, giving a “webbed” appearance (pterygium colli). Hips and knees and, less frequently, shoulders and elbows may have limited movement (contractures) and dislocations. The knee cap (patella) may repeatedly partially dislocate (habitual subluxation). Joints with limited or no movement (contractures) may have decreased or absent reflexes (deep tendon reflexes). Some patients have experienced abdominal hernias (inguinal, epigastric).
Under-development of the jaw (micrognathia) may contribute to swallowing (dysphagia) and breathing problems (lower airway obstruction), but typically, patients have a very small tongue (microglossia), preventing breathing problems caused by the tongue that happen in patients with other conditions involving under-development of the jaw. Mouth breathing is caused by very thin (hypoplastic) nasal cartilages and narrowed nasal passages (nasopharynx). Poor coughing (tussive) ability and swallowing problems (dysphagia) may put the person with FSS at greater risk for airway obstruction and inhalation (aspiration) of food, saliva or vomit into the lungs, which may cause lower respiratory infections (bronchitis and pneumonia). Mouth breathing, which causes inhalation of unconditioned air and potentially aerosol droplets from people with contagious respiratory infections, may further complicate the potential respiratory risk for patients with FSS. Upper respiratory infections may progress more often to bronchitis or pneumonia infections, as well. Mouth breathing, swallowing problems (dysphagia), and the not uncommon need for a high calorie diet can also cause persons with FSS to be more at risk for developing dental cavities (caries). Persons may be more at-risk for middle ear infections, which can lead to hearing loss. Persons with FSS may also experience sinus infections and frontal headaches more often because of deformities of the skull.
While severe swallowing problems (dysphagia) may reduce eating efficiency—slowing growth in infancy and childhood, swallowing problems (dysphagia) typically improve spontaneously with age. Rarely, dysphagia may not improve. Persons with FSS typically have difficulty creating a suction with the lips and mouth because of ineffective facial muscles. Persons with FSS are typically short and may be thin into early adulthood, while others are normal weight or overweight as adults. There are some reports of persons with FSS experiencing more chronic constipation, vomiting, and gastroesophageal reflux, suggesting that gut (visceral) muscle may be secondarily affected. A few persons with FSS seem to use energy at higher rates and require high calorie foods, but the cause is unknown.
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); highly arched roof of the mouth (hard palate); very thin (hypoplastic) nasal cartilages; narrowed nasal passages (nasopharynx); and under-developed facial bones (midface hypoplasia).
Except those who have had severe respiratory complications and not enough oxygen reached the brain, persons with FSS have normal intelligence. Most persons have developmental delays that are caused by physical deformities.
Because of head, neck, throat (pharynx) and mouth problems, it is challenging for healthcare providers to protect the airway of persons with FSS who are unconscious. It is also difficult for healthcare providers to access blood vessels to draw blood or give medicine or fluid. These problems seriously complicate anesthesia, sedation and surgery planning for persons with FSS.
There is no known link between FSS and environmental or parental factors, such as exposure to illnesses, toxins, drugs or harsh substances.
Though the cause remains uncertain for a small percentage of people, FSS can be caused by a change (mutation or allelic variation) 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). FSS is believed to impair muscle development in the embryo and disrupt muscle function throughout life by causing the energy [adenosine triphosphate (ATP)] needed for muscles to tense (muscle contraction) and relax properly to have difficulty attaching to the myosin, one of the main parts of muscles fibers. This may happen because of reduced activity of enzymes that break the ATP bonds to the myosin (ATPase) that could be caused by mechanical problems with actin, the other main part of muscle fibers. When muscles cannot function normally, deformities in the bones, joints, and other areas can result.
Most patients with FSS are born to normal healthy parents, and in this situation, FSS is not inherited but arises from a new change in the gene (new mutation). When FSS is inherited, almost all of the time one of the parents has FSS and passes on one copy of the gene to a child (autosomal dominant inheritance). In extremely rare situations, however, a parent may be healthy but have a MYH3 gene variant only in their reproductive cells (germline mosaicism). In this case, still only one copy of the changed gene is needed to cause FSS in a child.
Dominant means that only a single copy of a changed gene is necessary to cause the condition. Autosomal means the changed gene is not located on one of the gender determining chromosomes, and the risk of an affected parent of either biologic gender passing the changed gene in an autosomal dominant condition like FSS to an offspring is 50% for each pregnancy.
Except for women with FSS considering using in vetro fertilization to avoid an FSS pregnancy, determining if there is a change in the MYH3 gene or possibly another gene is not needed for diagnosis and does not affect or improve treatment. Diagnosis is based on the strict criteria of physical findings, which has strong agreement with genetic testing. While FSS severity differs greatly between individuals, each person affected has the same basic types of problems, and treatments have similar outcomes.
FSS appears to occur all ethnicities, both biologic genders and all geographic regions, evenly. FSS is an exceptionally rare disorder. It is estimated that 200-300 individuals worldwide may be affected, but the number of diagnosed and undiagnosed persons with FSS (population prevalence) remains uncertain.
FSS is diagnosed by thorough physical examination and medical history. Plastic surgeons and anesthesiologists who specialize in treating patients with skull and face problems are the best to diagnose and evaluate patients who may have FSS. The following problems must be present for diagnosis of FSS: small mouth (microstomia), whistling-face (pursed lips as in someone trying to whistle), down-slanting crease from the nostril to the corners of the mouth (nasolabial creases), and “H” or “V” shaped chin dimple. Classically, there 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. Patients who have the facial deformities plus two or more body areas with limited movement of joints are considered to have FSS type 1, classic. Patients who have only the facial deformities are considered to have FSS type 2, craniofacial. Patients who have the facial deformities plus one body areas with limited movement of joints are considered to have FSS type 3, mixed (upper or lower extremities). Patients with FSS type 2 tend to be the most mild and have the least complications, and patients with FSS type 1 or “classic” tend to be the most seriously affected and more likely to have medical complications. Patients 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 change causing FSS is known, pre-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.
The underlying cause of the problems in persons with FSS is not fully understood, and treatment targets specific, functional problems. Since FSS is primarily a condition of the face and skull (craniofacial), overall care is best provided and coordinated by a craniofacial surgeon. Patients with FSS who receive overall care from a doctor in another speciality may have poorer outcomes. Doctors from other specialities may not have the training or experience to understand how the patient’s face and skull problems can affect their general health and psychosocial functioning.
Treatment includes physical, occupational, and speech therapy; and limited, specific use of surgery, especially oral-maxillofacial (dental and mouth problems) and plastic surgery (face, head, and hand problems). Surgery may be used to extend benefits gained in physical, occupational, and speech therapy. Abnormal muscle function sometimes limits surgical options and causes unfavorable surgical outcomes. It should be expected that surgeries will need to be repeated periodically because of the abnormalities of the muscle. Follow-up surgeries target the muscles to release the abnormal areas to reduce tension and allow greater movement.
To gain the greatest functional benefit and lessen psychosocial consequences, any face and skull reconstructive surgery deemed feasible should occur before early school years. Failure to operate on the face and skull early in the child’s life reduces treatment options later to improve speech, ability to breathe through the nose, access to the mouth to allow dental care, and facial appearance, as facial deformities can be a significant burden to the child throughout their life, impacting all areas of interpersonal interaction. If the eyelids cause obstruction of vision, failure to operate early can result in blindness. For patients with FSS, the ability to improve the appearance of the face is, however, limited.
Deformities of the hands, feet, and spine are best treated with aggressive physical therapy and without surgery. Braces and splints may be helpful to maintain the corrections gained by physical and occupational therapy. While physical therapy for the hands is best done soon after birth and in early childhood, it may be possible to do some corrective physical therapy into early adulthood. Generally, surgery for deformities of the feet should not be attempted, as the feet present a very poor surgical risk in most patients with FSS. Failure of surgery on the feet can result in non-functional feet or loss of one or both feet. For patients whose foot deformities cannot be corrected with physical therapy and braces, prosthetics (without need for amputation) can be used to transfer the weight-bearing to the knee and leg and allow the person to walk comfortably.
With appropriate therapy, including limited use of surgery, prognosis can be very good for most persons with FSS. Early diagnosis, aggressive physical therapy and maintaining a healthy, active lifestyle is associated with the best outcomes and minimizes the impact of physical problems 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:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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 patients’ medical history, quality of life, and mental health issues relating to FSS; and (2) medically evaluate healthy persons and patients to compare their bodies’ 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
Fairfax, VA 22031
Office Telephone: 703-207-3065
Home page: https://www.duplastics.com/research
Email: [email protected]
Baum VC, O’Flaherty JE. Anesthesia for Genetic, Metabolic, and Dysmorphic Syndromes of Childhood, 2nd ed. Lippincott Williams & Wilkins, 2007. p 394-396.
Baum VC, O’Flaherty JE. Anesthesia for Genetic, Metabolic, and Dysmorphic Syndromes of Childhood, 3rd ed. Lippincott Williams & Wilkins, 2015.
Bergsma D, Liss AR. Birth Defects Compendium, 2nd ed. New York, 1979. 2:270.
Cassidy SB, Allanson JE. Management of Genetic Syndromes, 2nd ed. John Wiley and Sons, 2005. p 63-75.
Castriota-Scanderbeg A, Dallapiccola B. Abnormal Skeletal Phenotypes: From Simple Signs to Complex Diagnoses. Springer Science & Business Media, 2006. p 714-715
Chen H. “Freeman–Sheldon Syndrome” in Atlas of Genetic Diagnosis and Counseling, 2nd ed. Springer Science+Business Media, LLC. 2012. 883-889.
Darras BT, Jones, Jr. Jr. HR, Ryan MM, De Vivo DC. Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach. Elsevier, 2014. p 107-109
Entezami M, Albig M, Gasiorek-Wiens A. Ultrasound Diagnosis of Fetal Anomalies. Thieme, 2011. p 245-246
Goodman RM, Gorlin RJ. Atlas of the Face in Genetic Disorders. Mosby, 1977. p 100-
Gorlin RJ, Cohen MM Jr, Levin LS. Syndromes of the Head and Neck. New York: Oxford University Press. 1990. 634-7.
Hagberg CA. Benumof and Hagberg’s Airway Management. Elsevier Health Sciences, 2012. p 742
Herring JA. Tachdjian’s Pediatric Orthopaedics: From the Texas Scottish Rite Hospital for Children. Elsevier Health Sciences, 2013. p e555-e556
Jones KL, Jones MC, del Campo M. Smith’s Recognizable Patterns of Human Malformation. Elsevier Health Sciences, 2013. p 294-295
Jones KL. Smith’s Recognizable Patterns of Human Malformation, 5th ed. Philadelphia: WB Saunders Company, 1997. p 214-215
Kelly EB. Encyclopedia of Human Genetics and Disease (Vol. 1). ABC-CLIO, 2013. p 284-286
Laing NG. The Sarcomere and Skeletal Muscle Disease. Springer Science & Business Media, 2009. p 82-83
Mason RA, Mason R. Anaesthesia Databook: A Perioperative and Peripartum Manual. Cambridge University Press, 2001. p 199-200
Mundlos S, Horn D. Limb Malformations: An Atlas of Genetic Disorders of Limb Development. Springer, 2014. p 154-155
Reynolds CR, Fletcher-Janzen E. Concise Encyclopedia of Special Education: A Reference for the Education of the Handicapped and Other Exceptional Children and Adults. John Wiley and Sons, 2004. p 409-410
Smith DW, Jones KL. Recognizable Patterns of Human Malformation: Genetic, Embryologic, and Clinical Aspects, 3rd ed. Philadelphia: WB Saunders Company, 1982. p 159-161
Staheli LT. Arthrogryposis: A Text Atlas. Cambridge University Press, 1998. p 10-11
Weaver DD. Catalog of Prenatally Diagnosed Conditions. The Johns Hopkins University Press, 1999. p 205
Wilson G, Cooley WC. Preventive Management of Children with Congenital Anomalies and Syndromes (Vol. 1). Cambridge University Press, 2000. p 403; 404-412
Wynbrandt J, Ludman MD. The Encyclopedia of Genetic Disorders and Birth Defects. Infobase Publishing, 2009. p 390-391
Agritmis A, Unlusoy O, Karaca S. Anesthetic management of a patient with Freeman-Sheldon syndrome. Paediatr Anaesth. 2004;14(10):874-7.
Alonso Calderón JL, Ali Taoube K. [Freeman-Sheldon syndrome: clinical manifestations and anesthetic and surgical management] [Spanish] An Esp Pediatr. 2002;56(2):175-9.
Aren G, Yurdabakan Z, Ozcan I. Freeman-Sheldon syndrome: a case report. Quintessence Int. 2003;34(4):307-10.
Attia A, Suleman M, Al Nwasser AA. Freeman-Sheldon syndrome with respiratory failure: a case report. Respiratory Medicine CME. 2008;1:274-277.
Bekir N, Bayraktaroglu Z, Coskun Y, Karaaslan C. Whistling face (Freeman-Sheldon) syndrome in two siblings. Turk J Pediatr. 1994;36(4):329-32.
Burian F. The “whistling face” characteristic in a compound cranio-facio-corporal syndrome. Br J Plast Surg. 1963;16:140-3.
Call WH, Strickland JW. Functional hand reconstruction in the whistling-face syndrome. J Hand Surg Am. 1981;6(2):148-51.
Cervenka J, Gorlin RJ, Figalova P, Farkasova J. Craniocarpotarsal dysplasia or whistling face syndrome. Arch Otolaryngol. 1970;91(2):183-7.
Chamberlain RL, Poling MI, Portillo AL, Morales A, Ramirez RRT, McCormick RJ. Freeman-Sheldon syndrome in a 29-year-old female presenting with rare and previously undescribed features. BMJ Case Rep. 22 Oct 2015. doi: 10.1136/bcr-2015-212607
Duggar RG Jr, DeMars PD, Bolton VE. Whistling face syndrome: general anesthesia and early postoperative caudal analgesia. Anesth. 1989;70(3):545-7.
Estrada R, Rosenfeld W, Salazar JD, Jhaveri R. Freeman-Sheldon syndrome with unusual hand and foot anomalies. J Natl Med Assoc. 1981;73(7):664-7.
Fitzsimmons JS, Zaldua V, Chrispin AR. Genetic heterogeneity in the Freeman-Sheldon syndrome: two adults with probable autosomal recessive inheritance. J Med Genet. 1984;21(5):364-8.
Fraser FC, Pashayan H, Kadish ME. Cranio-carpo-tarsal dysplasia: report of a case in father and son. JAMA. 1970;211:1374-1376.
Freeman EA, Sheldon JH. Cranio-carpo-tarsal dystrophy: undescribed congenital malformation. Arch Dis Child. 1938;13:277-283.
Gross-Kieselstein E, Abrahamov A, Ben-Hur N. Familial occurrence of the Freeman-Sheldon syndrome: cranio-carpotarsal dysplasia. Pediatr. 1971;47(6):1064-7.
Güven O, Tekin U, Hatipoğlu M. Surgical and prosthodontic rehabilitation in a patient with Freeman-Sheldon syndrome. J Craniofac Surg. 2010;21(5):1571-4.
Guyuron B, Winkler PA. Craniocarpotarsal dysplasia: the whistling face syndrome. Ann Plast Surg. 1988;20(1):86-8.
Hague J, Delon I, Brugger K, Martin H, Abbs S, Park SM. Molecularly proven mosaicism in phenotypically normal parent of a girl with Freeman-Sheldon Syndrome caused by a pathogenic MYH3 mutation. Am J Med Genet A. 2016;170(6):1608-12.
Hegde SS, Shetty MS, Rama Murthy BS. Freeman-Sheldon syndrome—prenatal and postnatal diagnosis. Indian J Pediatr. 2010;77(2):196-7.
Laishley RS, Roy WL. Freeman-Sheldon syndrome: report of three cases and the anaesthetic implications. Can Anaesth Soc J. 1986;33(3 Pt 1):388-93.
MacLeod P, Patriquin H. The whistling face syndrome–cranio-carpo-tarsal dysplasia. Report of a case and a survey of the literature. Clin Pediatr (Phila). 1974;13(2):184-9.
Madi-Jebara S, El-Hajj C, Jawish D, Ayoub E, Kharrat K, Antakly MC. Anesthetic management of a patient with Freeman-Sheldon syndrome: case report. J Clin Anesth. 2007;19(6):460-2.
Marasovich WA, Mazaheri M, Stool SE. Otolaryngologic findings in whistling face syndrome. Arch Otolaryngol Head Neck Surg. 1989;115(11):1373-80.
McCormick RJ, Poling MI, Chamberlain RL. Bilateral patellar tendon-bearing Symes-type prostheses in a severe case of Freeman-Sheldon syndrome in a 21-year-old woman presenting with uncorrectable equinovarus. BMJ Case Rep. 2015. doi: 10.1136/bcr-2015-211338
McCormick RJ, Poling MI, Portillo AL, Chamberlain RL. Preliminary experience with delayed non-operative therapy of multiple hand and wrist contractures in a woman with Freeman-Sheldon syndrome at ages 24 and 28 years. BMJ Case Rep. 2015. doi: 10.1136/bcr-2015-210935
Munro HM, Butler PJ, Washington EJ. Freeman-Sheldon (whistling face) syndrome. Anaesthetic and airway management. Paediatr Anaesth. 1997;7(4):345-8.
Mustacchi Z, Richieri-Costa A, Frota-Pessoa O. The Freeman-Sheldon syndrome. Rev Brazil Genet. 1979;2(4):259-266.
Olkun HK, Poling MI. Nonoperative orthodontic therapy for retrognathia and finding of sella turcica bridging in a 16-year-old girl with Freeman-Burian syndrome. Cleft Palate Cranofac J. 2019;56(8):1107-1114. DOI: 10.1177/1055665619833855
Pahor AL. Whistling-face syndrome. Ear Nose Throat J. 1980;59(5):232-4.
Patel K, Gursale A, Chavan D, Sawant P. Anaesthesia challenges in Freeman-Sheldon syndrome. Indian J Anaesth. 2013;57(6):632-3.
Poling MI, Dufresne CR, Chamberlain RL. Dr Ben Franklin and an unusual modern-day cure for recurrent pleuritis. Br J Gen Pract. 2017;67(654):32-33.
Portillo AL, Poling MI, McCormick RJ. Surgical approach, findings, and 8-year follow-up in a 21-year-old female with Freeman-Sheldon syndrome presenting with blepharophimosis causing near-complete visual obstruction. J Craniofac Surg. 2016;27(5):1273-1276.
Richa FC, Yazbeck PH. Anaesthetic management of a child with Freeman-Sheldon syndrome undergoing spinal surgery. Anaesth Intensive Care. 2008;36(2):249-53.
Rinsky LA, Bleck EE. Freeman-Sheldon (“whistling face”) syndrome. J Bone Joint Surg Am. 1976;58(1):148-50.
Rintala AE. Freeman-Sheldon’s Syndrome, cranio-carpo-tarsal dystrophy. Acta Paediatr Scan. 1968;57:553-6.
Robbins-Furman P, Hecht JT, Rocklin M, Maklad N, Greenhaw G, Wilkins I. Prenatal diagnosis of Freeman-Sheldon syndrome (whistling face). Prenat Diagn. 1995;15(2):179-82.
Salati SA, Hussain M. Freeman-Sheldon syndrome. APSP J Case Rep. 2013;4:7.
Savini R, Gualdrini. Report on two cases of Freeman-Sheldon syndrome (whistling face). Ital J Orthop Traumatol. 1980;1:105-115.
Toydemir PB, Toydemir R, Bökesoy I. Whistling face phenotype without limb abnormalities. Am J Med Genet. 1999;86:86-87.
Vaitiekaitis AS, Hornstein L, Neale HW. A new surgical procedure for correction of lip deformity in cranio-carpo-tarsal dysplasia (whistling face syndrome). J Oral Surg. 1979;37(9):669-72.
Vas L, Naregal P. Anaesthetic management of a patient with Freeman Sheldon syndrome. Paediatr Anaesth. 1998;8(2):175-7.
Weinstein S, Gorlin RJ. Cranio-carop-tarsal dysplasia or the whistling face syndrome. I. Clinical considerations. Am J Dis Child. 1969;117(4):427-33.
Wenner SM, Shalvoy RM. Two-stage correction of thumb adduction contracture in Freeman-Sheldon syndrome (craniocarpotarsal dysplasia). J Hand Surg Am. 1989;14(6):937-40.
Antley RM, Uga N, Burzynski NJ, Baum RS, Bixler D. Diagnostic criteria for the whistling face syndrome. Birth Defects Orig Artic Ser. 1975;11(5):161-8.
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):2502–2508.
Poling MI, Dufresne CR. Identification and recent approaches for evaluation and management of dentofacial and otolaryngologic concerns for patients with Freeman-Burian syndrome: principles for global treatment. J Craniofac Surg. 2020;31(3):787-790.
Poling MI, Morales Corado JA, Chamberlain RL. 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. Syst Rev. 2017;6(1):46. doi: 10.1186/s13643-017-0444-4.
Reviews and Studies
Bamshad M, Jorde LB, Carey JC. A revised and extended classification of the distal arthrogryposes. Am J Med Genet. 1996;11;65(4):277-81.
Beck AE, McMillin MJ, Gildersleeve HI, Shively KM, Tang A, Bamshad MJ. Genotype-phenotype relationships in Freeman-Sheldon syndrome. Am J Med Genet A. 2014;164(11):2808-13.
Bell KM, Huang A, Kronert WA, Bernstein SI, Swank DM. Prolonged myosin binding increases muscle stiffness in Drosophila models of Freeman-Sheldon syndrome. Biophys J. 2021;120(5):844-854. doi:10.1016/j.bpj.2020.12.033
Bell KM, Kronert WA, Guo Y, Rao D, Huang A, Bernstein SI, Swank DM. The muscle mechanical basis of Freeman-Sheldon syndrome. Biophysical J. 2016;110(3):14a. doi: 10.1016/j.bpj.2015.11.134
Boehm S, Limpaphayom N, Alaee F, Sinclair MF, Dobbs MB. Early results of the Ponseti method for the treatment of clubfoot in distal arthrogryposis. J Bone Joint Surg Am. 2008;90(7):1501-7.
Chong JX, McMillin MJ, Shively KM, Beck AE, Marvin CT, Armenteros JR, Buckingham KJ, Nkinsi NT, Boyle EA, Berry MN, et al. De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay. Am J Hum Genet. 2015;96(3):462-73.
Das S, Kumar P, Verma A, Maiti TK, Mathew SJ. Myosin heavy chain mutations that cause Freeman-Sheldon syndrome lead to muscle structural and functional defects in Drosophila. Dev Biol. 2019;449(2):90-98. doi:10.1016/j.ydbio.2019.02.017
Gurnett CA, Alaee F, Desruisseau D, Boehm S, Dobbs MB. Skeletal muscle contractile gene (TNNT3, MYH3, TPM2) mutations not found in vertical talus or clubfoot. Clin Orthop Relat Res. 2009;467(5):1195-200.
Hall JG, Reed SD, Greene G. The distal arthrogryposes: delineation of new entities—review and nosologic discussion. Am J Med Genet. 1982;11(2):185-239.
Poling MI, Dufresne CR, Chamberlain RL. Freeman-Burian syndrome. Orphanet J Rare Dis. 2019;14(1):14. doi: 10.1186/s13023-018-0984-2.
Racca AW, Beck AE, McMillin MJ, Korte FS, Bamshad MJ, Regnier M. The embryonic myosin R672C mutation that underlies Freeman-Sheldon syndrome impairs cross-bridge detachment and cycling in adult skeletal muscle. Hum Mol Genet. 2015;24(12):3348-58.
Stevenson DA, Carey JC, Palumbos J, Rutherford A, Dolcourt J, and Bamshad MJ. Clinical characteristics and natural history of Freeman-Sheldon syndrome. Pediatrics. 2006;117(3):754-762.
Tajsharghi H, Kimber E, Kroksmark AK, Jerre R, Tulinius M, Oldfors A. Embryonic myosin heavy-chain mutations cause distal arthrogryposis and developmental myosin myopathy that persists postnatally. Arch Neurol. 2008;65(8):1083-90. Erratum: Arch Neurol. 2008;65(12):1654.
Tajsharghi H, Oldfors A. Myosinopathies: pathology and mechanisms. Acta Neuropathol. 2013;125(1):3-18.
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):561-5.
Walklate J, Vera C, Bloemink MJ, Geeves MA, Leinwand L. The most prevalent Freeman-Sheldon syndrome mutations in the embryonic myosin motor share functional defects. J Bio Chem. 2016;291(19):10318-10331.
Wynne-Davies R, Gormley J. The prevalence of skeletal dysplasias: an estimate of their minimum frequency and the number of patients requiring orthopaedic care. J Bone Joint Surg Br. 1985;67-B(1):133-137.
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):2176–2178.
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. Anästh Intensivmed. 2019;60(1):S8-S17. doi: 10.19224/ai2019.S008
Poling MI, Dufresne CR. Anaesthesia recommendations for Freeman-Burian syndrome. OrphanAnesthesia. 27 Sept 2018. Available at: https://www.orpha.net/data/patho/Ans/en/Freeman-Burian-syndrome.pdf Accessed August 19, 2021.
Poling MI, Dufresne CR. The epidemiology, prevention, diagnosis, treatment, and outcomes of psychosocial problems in patients and families affected by non-intellectually impairing craniofacial malformation conditions. Available from: https://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018093021&ID=CRD42018093021 Accessed August 19, 2021.
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 August 19, 2021.
Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University, Baltimore, MD. MIM Entry No: 193700: 10/13/2010. URL: http://omim.org/entry/193700 Accessed August 19, 2021.
Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University, Baltimore, MD. MIM Entry No: 277720: 03/03/2005. URL: http://omim.org/entry/277720 Accessed August 19, 2021.
Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University, Baltimore, MD. MIM Entry No: 601680: 03/06/2009. URL: http://omim.org/entry/601680 Accessed August 19, 2021.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100