Freeman–Sheldon syndrome (FSS) is a very rare form of multiple congenital contracture (MCC)

syndrome A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease or disorder. The word derives from the Greek language, Greek σύνδρομον, meaning "concurrence". When a sy ...

s ( arthrogryposes) and is the most severe form of distal arthrogryposis (DA). It was originally described by Ernest Arthur Freeman and Joseph Harold Sheldon in 1938.James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. . As of 2007, only about 100 cases had been reported in medical literature.

Signs and symptoms

The symptoms of Freeman–Sheldon syndrome include drooping of the upper eyelids,

strabismus Strabismus is an eye disorder in which the eyes do not properly align with each other when looking at an object. The eye that is pointed at an object can alternate. The condition may be present occasionally or constantly. If present during a ...

, 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.

Cause

FSS is caused by genetic changes. Krakowiak et al. (1998) mapped the distal arthrogryposis multiplex congenita (DA2B; MIM #601680)

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

, a syndrome very similar in phenotypic expression to classic FSS, to 11p15.5-pter. Other

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

s have been found as well. In FSS, inheritance may be either

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

, most often demonstrated. or

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

(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 In medical genetics and other medical fields, a proband, propositus (male proband), or proposita (female proband) is a particular subject (human or other animal) being studied or reported on. On pedigrees, the proband is noted with a square (male) ...

s with distal arthrogryposis type 2A.
b .0001 c .0002 d .0004 e .0006, .0003 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.

Diagnosis

Freeman–Sheldon syndrome is a type of distal

arthrogryposis Arthrogryposis (AMC) describes congenital joint contracture in two or more areas of the body. It derives its name from Greek, literally meaning 'curving of joints' (', 'joint'; ', late Latin form of late Greek ', 'hooking'). Children born with one ...

, 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 Congenital myopathy is a very broad term for any muscle disorder present at birth. This defect primarily affects skeletal muscle fibres and causes muscular weakness and/or hypotonia. Congenital myopathies account for one of the top neuromuscular di ...

. 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.

Management

Surgical and anesthetic considerations

Patients must have early consultation with

craniofacial Craniofacial surgery is a surgical subspecialty that deals with congenital and acquired deformities of the head, skull, face, neck, jaws and associated structures. Although craniofacial treatment often involves manipulation of bone, craniofacial ...

and

orthopaedic Orthopedic surgery or orthopedics ( alternative spelling orthopaedics) is the branch of surgery concerned with conditions involving the musculoskeletal system. Orthopedic surgeons use both surgical and nonsurgical means to treat musculoskeletal ...

surgeon In medicine, a surgeon is a medical doctor who performs surgery. Even though there are different traditions in different times and places, a modern surgeon is a licensed physician and received the same medical training as physicians before spec ...

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 In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. ''Myopathy'' means muscle disease ( Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meaning implies that the primary defec ...

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 is a soft tissue, one of the four basic types of animal tissue. There are three types of muscle tissue in vertebrates: skeletal muscle, cardiac muscle, and smooth muscle. Muscle tissue gives skeletal muscles the ability to muscle contra ...

physiology Physiology (; ) is the science, scientific study of function (biology), functions and mechanism (biology), mechanisms in a life, living system. As a branches of science, subdiscipline of biology, physiology focuses on how organisms, organ syst ...

in Freeman–Sheldon syndrome, therapeutic measures may have unfavourable outcomes. Difficult endotracheal

intubation Intubation (sometimes entubation) is a medical procedure involving the insertion of a tube into the body. Most commonly, intubation refers to tracheal intubation, a procedure during which an endotracheal tube is inserted into the trachea to supp ...

s and

vein Veins () are blood vessels in the circulatory system of humans and most other animals that carry blood towards the heart. Most veins carry deoxygenated blood from the tissues back to the heart; exceptions are those of the pulmonary and feta ...

access complicate operative decisions in many DA2A patients, and

malignant hyperthermia Malignant hyperthermia (MH) is a type of severe reaction that occurs in response to particular medications used during general anesthesia, among those who are susceptible. Symptoms include muscle rigidity, fever, and a fast heart rate. Complica ...

(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 Anesthesia (American English) or anaesthesia (British English) is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prev ...

management and cervical kyphoscoliosis in intubations.

Medical emphasis

General health maintenance should be the therapeutic emphasis in Freeman–Sheldon syndrome. The focus is on limiting exposure to

infectious disease An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmis ...

s because the musculoskeletal abnormalities make recovery from routine infections much more difficult in FSS.

Pneumonitis Pneumonitis describes general inflammation of lung tissue. Possible causative agents include radiation therapy of the chest, exposure to medications used during chemo-therapy, the inhalation of debris (e.g., animal dander), aspiration, herbicide ...

and

bronchitis Bronchitis is inflammation of the bronchi (large and medium-sized airways) in the lungs that causes coughing. Bronchitis usually begins as an infection in the nose, ears, throat, or sinuses. The infection then makes its way down to the bronchi. ...

often follow seemingly mild

upper respiratory tract infection An upper respiratory tract infection (URTI) is an illness caused by an acute infection, which involves the upper respiratory tract, including the nose, sinuses, pharynx, larynx or trachea. This commonly includes nasal obstruction, sore throat ...

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

By 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 system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

involvement or respiratory complications. Several syndromes are related to the Freeman–Sheldon syndrome spectrum, but more information is required before undertaking such

nosological Nosology () is the branch of medical science that deals with the Medical classification, classification of diseases. Fully classifying a medical condition requires knowing its cause (and that there is only one cause), the effects it has on the ...

delineation.

Research directions

One research priority is to determine the role and nature of

in FSS. Such knowledge would benefit possible surgical candidates and the

anaesthesiology Anesthesiology, anaesthesiology or anaesthesia is the medical specialty concerned with the total perioperative care of patients before, during and after surgery. It encompasses anesthesia, intensive care medicine, critical emergency medicine, ...

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 An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin. For some medical conditions, one or more causes are somewhat understood, but in a certain percentage of people with the condition, the cause ...

hyperpyrexia, MH, and stress. Further research is wanted to determine

epidemiology Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and Risk factor (epidemiology), determinants of health and disease conditions in a defined population, and application of this knowledge to prevent dise ...

of psychopathology in FSS and refine therapy protocols.

Eponym

It is named for British orthopaedic surgeon Ernest Arthur Freeman (1900–1975) and British physician Joseph Harold Sheldon (1893–1972), who first described it in 1938.

Notable individuals

Melissa Blake (writer) is a writer and disability advocate with Freeman-Sheldon syndrome.

References

External links

{{DEFAULTSORT:Freeman-Sheldon syndrome Syndromes affecting the tongue Genodermatoses Rare syndromes Syndromes with scoliosis Syndromes affecting the eye Syndromes with craniofacial abnormalities