Freeman-Sheldon syndrome
Encyclopedia
Freeman-Sheldon syndrome (FSS), also termed distal arthrogryposis type 2A (DA2A), craniocarpotarsal dysplasia (or dystrophy), Cranio-carpo-tarsal syndrome, Windmill-Vane-Hand syndrome, or Whistling-face syndrome, was originally described by Freeman and Sheldon in 1938. Freeman-Sheldon syndrome is a rare form of multiple congenital contracture (MCC) syndrome
s (arthrogryposes
) and is the most severe form of distal arthrogryposis (DA).
, related to distal arthrogryposis type 1 (DA1). In 1996, more strict criteria for the diagnosis of Freeman-Sheldon syndrome were drawn up, assigning Freeman-Sheldon syndrome as distal arthrogryposis type 2A (DA2A).
On the whole, DA1 is the least severe; DA2B is more severe with additional features that respond less favourably to therapy. DA2A (Freeman-Sheldon syndrome) is the most severe of the three, with more abnormalities and greater resistance to therapy.
Freeman-Sheldon syndrome has been described as a type of congenital myopathy
.
In March 2006, Stevenson et al. published strict diagnostic criteria for distal arthrogryposis type 2A (DA2A) or Freeman-Sheldon syndrome. These included two or more features of distal arthrogryposis: microstomia
, whistling-face, nasolabial creases, and 'H-shaped' chin dimple.
, a syndrome very similar in phenotypic expression to classic FSS, to 11p15.5-pter. Other mutation
s have been found as well. --> In FSS, inheritance may be either autosomal dominant, most often demonstrated. or autosomal recessive (MIM 277720). Alves and Azevedo (1977) note most reported cases of DA2A have been identified as new allelic variation. Toydemir et al. (2006) showed that mutations in embryonic myosin heavy chain 3 (MYH3; MIM *160270), at 17p-13.1-pter, caused classic FSS phenotype, in their screening of 28 (21 sporadic and 7 familial) proband
s with distal arthrogryposis type 2A. In 20 patients (12 and 8 probands, respectively), missense mutations (R672H; MIM *160270.0001 and R672C; MIM *160270.0002) caused substitution of arg672, an embryonic myosin residue retained post-embryonically. Of the remaining 6 patients in whom they found mutations, 3 had missense private de novo (E498G; MIM *160270.0006 and Y583S) or familial mutations (V825D; MIM *160270.0004); 3 other patients with sporadic expression had de novo mutations (T178I; MIM *160270.0003), which was also found in DA2B; 2 patients had no recognized mutations.
and orthopaedic surgeon
s, when craniofacial, clubfoot, or hand correction is indicated to improve function or aesthetics. Operative measures should be pursued cautiously, with avoidance of radical measures and careful consideration of the abnormal muscle physiology in Freeman-Sheldon syndrome. Unfortunately, many surgical procedures have suboptimal outcomes, secondary to the myopathy
of the syndrome.
When operative measures are to be undertaken, they should be planned for as early in life as is feasible, in consideration of the tendency for fragile health. Early interventions hold the possibility to minimise developmental delays and negate the necessity of relearning basic functions.
Due to the abnormal muscle
physiology
in Freeman-Sheldon syndrome, therapeutic measures may have unfavourable outcomes. Difficult endotracheal intubation
s and vein access complicate operative decisions in many DA2A patients, and malignant hyperthermia
(MH) may affect individuals with FSS, as well. Cruickshanks et al. (1999) reports uneventful use of non-MH-triggering agents. Reports have been published about spina bifida occulta in anaesthesia management and cervical
kyphoscoliosis
in intubations.
, which should include marriage counselling. Mitigation of lasting psychological problems, including depression
secondary to chronic
illness and posttraumatic stress disorder (PTSD), can be very successfully addressed with early interventions. This care may come from the family physician, or other attending physician
, whoever is more appropriate; specialist care is generally not required. Lewis and Vitulano (2003) note several studies suggesting predisposal for psychopathology in paediatric patients with chronic illness. Esch (2002) advocates preventive psychiatry supports to facilitate balance of positive and negative stressors associated with chronic physical pathology. Patients with FSS should have pre-emptive and ongoing mixed cognitive therapy-psychodynamic psychotherapy
for patients with FSS and cognitive-behavioural therapy (CBT), if begun after onset of obvious pathology.
Adler (1995) cautioned the failure of modern medicine to implement the biopsychosocial model
, which incorporates all aspects of a patient’s experience in a scientific approach into the clinical picture, often results in chronically-ill patients deferring to non-traditional and alternative forms of therapy, seeking to be understood as a whole, not a part, which may be problematic among patients with FSS.
Furthermore, neuropsychiatry, physiological, and imaging studies have shown PTSD and depression to be physical syndromes, in many respects, as they are psychiatric ones in demonstrating limbic system physiological and anatomy disturbances. Attendant PTSD hyperarousal symptoms, which additionally increase physiological stress
, may play a part in leading to frequent MH-like hyperpyrexia and speculate on its influence on underlying myopathology of FSS in other ways. PTSD may also bring about developmental delays or developmental stagnation, especially in paediatric patients.
With psychodynamic psychotherapy, psychopharmacotherapy may need to be considered. Electroconvulsive therapy
(ECT
) is advised against, in light of abnormal myophysiology, with predisposal to MH.
s because the musculoskeletal abnormalities make recovery from routine infections much more difficult in FSS. Pneumonitis
and bronchitis
often follow seemingly mild upper respiratory tract infection
s. Though respiratory challenges and complications faced by a patient with FSS can be numerous, the syndrome’s primary involvement is limited to the musculoskeletal systems, and satisfactory quality and length of life can be expected with proper care.
involvement or respiratory complications. Several syndromes are related to the Freeman-Sheldon syndrome spectrum, but more information is required before undertaking such nosological delineation.
in FSS. Such knowledge would benefit possible surgical candidates and the anaesthesiology and surgical teams who would care for them. MH may also be triggered by stress in patients with muscular dystrophies. Much more research is warranted to evaluate this apparent relationship of idiopathic
hyperpyrexia, MH, and stress. Further research is wanted to determine epidemiology
of psychopathology in FSS and refine therapy protocols.
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...
s (arthrogryposes
Arthrogryposis
Arthrogryposis, also known as Arthrogryposis Multiplex Congenita, is a rare congenital disorder that is characterized by multiple joint contractures and can include muscle weakness and fibrosis. It is a non-progressive disease...
) and is the most severe form of distal arthrogryposis (DA).
Signs and symptoms
The symptoms of Freeman-Sheldon syndrome include drooping of the upper eyelids, strabismus, low-set ears, a long philtrum, gradual hearing loss, scoliosis, and walking difficulties. Gastroesophageal reflux has been noted during infancy, but usually improves with age. The tongue may be small, and the limited movement of the soft palate may cause nasal speech. Often there is an H- or Y-shaped dimpling of the skin over the chin.Diagnosis
Freeman-Sheldon syndrome is a type of distal arthrogryposisArthrogryposis
Arthrogryposis, also known as Arthrogryposis Multiplex Congenita, is a rare congenital disorder that is characterized by multiple joint contractures and can include muscle weakness and fibrosis. It is a non-progressive disease...
, related to distal arthrogryposis type 1 (DA1). In 1996, more strict criteria for the diagnosis of Freeman-Sheldon syndrome were drawn up, assigning Freeman-Sheldon syndrome as distal arthrogryposis type 2A (DA2A).
On the whole, DA1 is the least severe; DA2B is more severe with additional features that respond less favourably to therapy. DA2A (Freeman-Sheldon syndrome) is the most severe of the three, with more abnormalities and greater resistance to therapy.
Freeman-Sheldon syndrome has been described as a type of congenital myopathy
Myopathy
In medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...
.
In March 2006, Stevenson et al. published strict diagnostic criteria for distal arthrogryposis type 2A (DA2A) or Freeman-Sheldon syndrome. These included two or more features of distal arthrogryposis: microstomia
Microstomia
Microstomia is a clinical feature of many craniofacial syndromes, including Freeman-Sheldon syndrome and Sheldon-Hall syndromes . It may present with whistling-face feature, as well, as in Freeman-Sheldon syndrome...
, whistling-face, nasolabial creases, and 'H-shaped' chin dimple.
Cause
FSS is caused by genetic changes. Krakowiak et al. (1998) mapped the distal arthrogryposis multiplex congenita (DA2B; MIM #601680) geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
, a syndrome very similar in phenotypic expression to classic FSS, to 11p15.5-pter. Other mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s have been found as well. --> In FSS, inheritance may be either autosomal dominant, most often demonstrated. or autosomal recessive (MIM 277720). Alves and Azevedo (1977) note most reported cases of DA2A have been identified as new allelic variation. Toydemir et al. (2006) showed that mutations in embryonic myosin heavy chain 3 (MYH3; MIM *160270), at 17p-13.1-pter, caused classic FSS phenotype, in their screening of 28 (21 sporadic and 7 familial) proband
Proband
Proband, or propositus, is a term used most often in medical genetics and other medical fields to denote a particular subject being studied or reported on. On pedigrees, the proband is noted with an arrow and the box or circle shaded accordingly...
s with distal arthrogryposis type 2A. In 20 patients (12 and 8 probands, respectively), missense mutations (R672H; MIM *160270.0001 and R672C; MIM *160270.0002) caused substitution of arg672, an embryonic myosin residue retained post-embryonically. Of the remaining 6 patients in whom they found mutations, 3 had missense private de novo (E498G; MIM *160270.0006 and Y583S) or familial mutations (V825D; MIM *160270.0004); 3 other patients with sporadic expression had de novo mutations (T178I; MIM *160270.0003), which was also found in DA2B; 2 patients had no recognized mutations.
Surgical and anaesthetic considerations
Patients must have early consultation with craniofacialCraniofacial
Craniofacial may be used to describe certain congenital malformations, injuries, surgeons who subspecialize in this area, multi-disciplinary medical-surgical teams that treat and do research on disorders affecting this region, and organizations with interest in...
and orthopaedic surgeon
Surgeon
In medicine, a surgeon is a specialist in surgery. Surgery is a broad category of invasive medical treatment that involves the cutting of a body, whether human or animal, for a specific reason such as the removal of diseased tissue or to repair a tear or breakage...
s, when craniofacial, clubfoot, or hand correction is indicated to improve function or aesthetics. Operative measures should be pursued cautiously, with avoidance of radical measures and careful consideration of the abnormal muscle physiology in Freeman-Sheldon syndrome. Unfortunately, many surgical procedures have suboptimal outcomes, secondary to the myopathy
Myopathy
In medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...
of the syndrome.
When operative measures are to be undertaken, they should be planned for as early in life as is feasible, in consideration of the tendency for fragile health. Early interventions hold the possibility to minimise developmental delays and negate the necessity of relearning basic functions.
Due to the abnormal muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
physiology
Physiology
Physiology is the science of the function of living systems. This includes how organisms, organ systems, organs, cells, and bio-molecules carry out the chemical or physical functions that exist in a living system. The highest honor awarded in physiology is the Nobel Prize in Physiology or...
in Freeman-Sheldon syndrome, therapeutic measures may have unfavourable outcomes. Difficult endotracheal intubation
Intubation
Tracheal intubation, usually simply referred to as intubation, is the placement of a flexible plastic or rubber tube into the trachea to maintain an open airway or to serve as a conduit through which to administer certain drugs...
s and vein access complicate operative decisions in many DA2A patients, and malignant hyperthermia
Malignant hyperthermia
Malignant hyperthermia or malignant hyperpyrexia is a rare life-threatening condition that is usually triggered by exposure to certain drugs used for general anesthesia; specifically, the volatile anesthetic agents and the neuromuscular blocking agent, succinylcholine...
(MH) may affect individuals with FSS, as well. Cruickshanks et al. (1999) reports uneventful use of non-MH-triggering agents. Reports have been published about spina bifida occulta in anaesthesia management and cervical
Cervical vertebrae
In vertebrates, cervical vertebrae are those vertebrae immediately inferior to the skull.Thoracic vertebrae in all mammalian species are defined as those vertebrae that also carry a pair of ribs, and lie caudal to the cervical vertebrae. Further caudally follow the lumbar vertebrae, which also...
kyphoscoliosis
Kyphoscoliosis
Kyphoscoliosis describes an abnormal curvature of the spine in both a coronal and sagittal plane. It is a combination of kyphosis and scoliosis. Kyphoscoliosis is a musculoskeletal disorder causing chronic underventilation of the lungs and may be one of the major causes of pulmonary hypertension...
in intubations.
Psychiatric considerations
Patients and their parents must receive psychotherapyPsychotherapy
Psychotherapy is a general term referring to any form of therapeutic interaction or treatment contracted between a trained professional and a client or patient; family, couple or group...
, which should include marriage counselling. Mitigation of lasting psychological problems, including depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
secondary to chronic
Chronic (medicine)
A chronic disease is a disease or other human health condition that is persistent or long-lasting in nature. The term chronic is usually applied when the course of the disease lasts for more than three months. Common chronic diseases include asthma, cancer, diabetes and HIV/AIDS.In medicine, the...
illness and posttraumatic stress disorder (PTSD), can be very successfully addressed with early interventions. This care may come from the family physician, or other attending physician
Attending physician
In the United States, an attending physician is a physician who has completed residency and practices medicine in a clinic or hospital, in the specialty learned during residency. An attending physician can supervise fellows, residents, and medical students...
, whoever is more appropriate; specialist care is generally not required. Lewis and Vitulano (2003) note several studies suggesting predisposal for psychopathology in paediatric patients with chronic illness. Esch (2002) advocates preventive psychiatry supports to facilitate balance of positive and negative stressors associated with chronic physical pathology. Patients with FSS should have pre-emptive and ongoing mixed cognitive therapy-psychodynamic psychotherapy
Psychodynamic psychotherapy
Psychodynamic psychotherapy is a form of depth psychology, the primary focus of which is to reveal the unconscious content of a client's psyche in an effort to alleviate psychic tension. In this way, it is similar to psychoanalysis. It also relies on the interpersonal relationship between client...
for patients with FSS and cognitive-behavioural therapy (CBT), if begun after onset of obvious pathology.
Adler (1995) cautioned the failure of modern medicine to implement the biopsychosocial model
Biopsychosocial model
The biopsychosocial model is a general model or approach that posits that biological, psychological , and social factors, all play a significant role in human functioning in the context of disease or illness...
, which incorporates all aspects of a patient’s experience in a scientific approach into the clinical picture, often results in chronically-ill patients deferring to non-traditional and alternative forms of therapy, seeking to be understood as a whole, not a part, which may be problematic among patients with FSS.
Furthermore, neuropsychiatry, physiological, and imaging studies have shown PTSD and depression to be physical syndromes, in many respects, as they are psychiatric ones in demonstrating limbic system physiological and anatomy disturbances. Attendant PTSD hyperarousal symptoms, which additionally increase physiological stress
Stress (medicine)
Stress is a term in psychology and biology, borrowed from physics and engineering and first used in the biological context in the 1930s, which has in more recent decades become commonly used in popular parlance...
, may play a part in leading to frequent MH-like hyperpyrexia and speculate on its influence on underlying myopathology of FSS in other ways. PTSD may also bring about developmental delays or developmental stagnation, especially in paediatric patients.
With psychodynamic psychotherapy, psychopharmacotherapy may need to be considered. Electroconvulsive therapy
Electroconvulsive therapy
Electroconvulsive therapy , formerly known as electroshock, is a psychiatric treatment in which seizures are electrically induced in anesthetized patients for therapeutic effect. Its mode of action is unknown...
(ECT
ECT
-Automotive:* Electronically controlled transmission, found in premium automobiles* Engine coolant temperature-Industry & Technology:* Eddy-current testing, a nondestructive testing technique for metal objects...
) is advised against, in light of abnormal myophysiology, with predisposal to MH.
Medical emphasis
General health maintenance should be the therapeutic emphasis in Freeman-Sheldon syndrome. The focus is on limiting exposure to infectious diseaseInfectious disease
Infectious diseases, also known as communicable diseases, contagious diseases or transmissible diseases comprise clinically evident illness resulting from the infection, presence and growth of pathogenic biological agents in an individual host organism...
s because the musculoskeletal abnormalities make recovery from routine infections much more difficult in FSS. Pneumonitis
Pneumonitis
Pneumonitis or pulmonitis is a general term that refers to inflammation of lung tissue.Pneumonia is pneumonitis combined with consolidation and exudation...
and bronchitis
Bronchitis
Acute bronchitis is an inflammation of the large bronchi in the lungs that is usually caused by viruses or bacteria and may last several days or weeks. Characteristic symptoms include cough, sputum production, and shortness of breath and wheezing related to the obstruction of the inflamed airways...
often follow seemingly mild upper respiratory tract infection
Upper respiratory tract infection
Upper respiratory tract infections are the illnesses caused by an acute infection which involves the upper respiratory tract: nose, sinuses, pharynx or larynx...
s. Though respiratory challenges and complications faced by a patient with FSS can be numerous, the syndrome’s primary involvement is limited to the musculoskeletal systems, and satisfactory quality and length of life can be expected with proper care.
Prognosis
There are little data on prognosis. Rarely, some patients have died in infancy from respiratory failure; otherwise, life expectancy is considered to be normal.Epidemiology
As of 1990, 65 patients had been reported in the literature, with no sex or ethnic preference notable. Some individuals present with minimal malformation; rarely patients have died during infancy as a result of severe central nervous systemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
involvement or respiratory complications. Several syndromes are related to the Freeman-Sheldon syndrome spectrum, but more information is required before undertaking such nosological delineation.
Research directions
One research priority is to determine the role and nature of malignant hyperthermiaMalignant hyperthermia
Malignant hyperthermia or malignant hyperpyrexia is a rare life-threatening condition that is usually triggered by exposure to certain drugs used for general anesthesia; specifically, the volatile anesthetic agents and the neuromuscular blocking agent, succinylcholine...
in FSS. Such knowledge would benefit possible surgical candidates and the anaesthesiology and surgical teams who would care for them. MH may also be triggered by stress in patients with muscular dystrophies. Much more research is warranted to evaluate this apparent relationship of idiopathic
Idiopathic
Idiopathic is an adjective used primarily in medicine meaning arising spontaneously or from an obscure or unknown cause. From Greek ἴδιος, idios + πάθος, pathos , it means approximately "a disease of its own kind". It is technically a term from nosology, the classification of disease...
hyperpyrexia, MH, and stress. Further research is wanted to determine epidemiology
Epidemiology
Epidemiology is the study of health-event, health-characteristic, or health-determinant patterns in a population. It is the cornerstone method of public health research, and helps inform policy decisions and evidence-based medicine by identifying risk factors for disease and targets for preventive...
of psychopathology in FSS and refine therapy protocols.
External links
- http://clinmedsurgcranio.blogspot.com from the Freeman-Sheldon Research Group, Inc. (FSRG) The Freeman-Sheldon Parent Support Group dissolved in Jan. 2011, after 29 years of operation. Records and services were transferred to the FSRG.