Information on the following diseases can be found in the Related Disorders section of this report:

• Additional chromosomal disorders may have features similar to those associated with Chromosome 14 Ring. Chromosomal testing is necessary to confirm the specific chromosomal abnormality present. (For further information on such disorders, choose the name of the specific chromosomal disorder in question or use "chromosome" as your search term in the Rare Disease Database.)
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As its name indicates, "facioscapulohumeral" muscular dystrophy (FSHD) typically initially involves weakness of muscles of the face (i.e., "facio"); the shoulder girdle (i.e., "scapulo"), which is the partial arch formed by the shoulder blade (scapula) and the collarbone (clavicle); and the upper arms (i.e., "humeral"). Facial weakness may result in limited movements of the lips, causing difficulties whistling, using a straw, or puckering the lips. Affected individuals may also develop a distinctive "mask-like" facial appearance. Upper facial weakness may also lead to an inability to completely close the eyes during sleep.

FSHD is also typically associated with weakening and wasting (atrophy) of muscles of the neck and shoulder blades (scapulae); muscles at the front and back of the upper arms (biceps and triceps brachii muscles); and the upper portion of the large, triangular muscles that cover the shoulder joints (deltoid muscles). With disease progression, there is a decrease in the ability to flex and rotate the shoulder outward; instability of muscles of the shoulder blades; and "scapular winging," a finding characterized by abnormal prominence of the borders of the shoulder blades. This finding tends to become more obvious when affected individuals attempt to raise their arms to the side (laterally). They often are unable to elevate their arms above the head or, in some cases, to shoulder level due to muscle weakness and an inability to fixate the shoulder blades. In addition, when viewed from the front, the collarbones (clavicles) may appear to sag. Some affected individuals may also develop wrist drop or downward flexion of the wrist due to weakness of certain muscles of the fingers and hands.

In some cases, FSHD may also be characterized by weakness and atrophy of other muscles, including abdominal wall, hip, and thigh muscles. Involvement of the muscle that rotates and moves the thigh outward (gluteus medius) may cause affected individuals to sway or lurch toward the affected side while walking (Trendelenburg gait). There may also be weakness of muscles of the lower legs and feet. In advanced cases, such involvement may lead to a condition known as footdrop, which is characterized by an impaired ability to flex or bend the foot upward. In addition, in some affected individuals, involvement of certain muscles may result in unusually pronounced inward curvature of the lower region of the spine (lordosis) or abnormal front-to-back and sideways spinal curvature (kyphoscoliosis).

For unknown reasons, in most individuals with FSHD, the degree of muscle weakness may differ from one side of the body to the other (asymmetrical). In addition, associated symptoms and disease course may be extremely variable from case to case. Symptom onset usually occurs during the first two decades of life. However, some with very mild involvement may not be aware of symptoms until later during adulthood. In other cases, initial symptoms may become evident as early as infancy.

Those with the disorder may have relatively slow or moderate progression of muscle weakness or, in some cases, apparently nonprogressive involvement of certain muscles. However, evidence suggests that the disease course is most frequently characterized by slow progression with short periods of rapid muscle deterioration. Associated muscle weakness may result in minimal disability or, in other cases, lead to difficulties chewing, swallowing, or speaking; abnormalities in the manner of walking (gait disturbances); and/or an impaired ability to perform certain activities of daily living. In some with the disease, particularly those with infantile onset, disease progression may lead to severe muscle weakness that necessitates the use of a wheelchair or other mobility equipment. Investigators have described affected families (kindreds) in whom disease manifestations ranged from minor facial weakness in a parent to severe infantile onset in an affected child.

In some individuals with FSHD, particularly those with early onset, the disorder may also be associated with hearing impairment and/or abnormalities of blood vessels within the nerve-rich, innermost membrane of the eye (retinal vasculopathy) that may, in rare cases, lead to visual impairment. Other abnormalities have also been reported in rare cases, such as mental retardation.
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Facioscapulohumeral muscular dystrophy (FSHD) is usually inherited as an autosomal dominant trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.

In autosomal dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed "dominating" the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

In approximately 10 to 30 percent of individuals with FSHD, there is no apparent family history of the disorder. In some of these cases, FSHD is thought to be caused by new genetic changes (mutations) that occur spontaneously for unknown reasons (sporadically).

In others without an apparent family history, evidence suggests that the disorder may result from "germline mosaicism" in a seemingly unaffected parent. In germline mosaicism, some of the parent's reproductive cells (germ cells) may carry the mutation whereas others contain a normal cell line ("mosaicism"). As a result, one or more of the parent's children may inherit the mutation, leading to manifestation of the autosomal dominant disorder, whereas the parent may have no apparent symptoms (asymptomatic carrier). Germline mosaicism may be suspected when apparently unaffected parents have more than one child with the same genetic abnormality. In addition, researchers have found "somatic mosaicism" in some affected individuals or seemingly unaffected (asymptomatic) parents. In somatic mosaicism, the mutation occurred in a cell other than a germ cell (i.e., somatic cell) and is passed along with subsequent cellular divisions; as a result, the mutation is not present in all of the body's cells (mosaicism). If the mutation occurred during early embryonic development, a greater number of cells may carry the mutation, potentially affecting disease severity.

In many individuals with FSHD, the genetic change or mutation responsible for the disorder involves lack or "deletion" of part of chromosome 4. More specifically, there is partial deletion of the end (distal) region of the "long arm" of chromosome 4 (4q35), which contains repeated copies of certain DNA instructions, thus resulting in an abnormally reduced number of these repeats. Deoxyribonucleic acid (DNA) is the carrier of the genetic code. Chromosomes, which are present in the nucleus of human cells, carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Chromosomes are further subdivided into bands that are numbered. Therefore, "chromosome 4q35" refers to band 35 on the long arm of chromosome 4.

It remains unknown how such a deletion leads to the muscle abnormalities seen in those with FSHD. However, some researchers have suggested that the deletion serves to change the shape of the chromosome, potentially indirectly affecting the activity of a neighboring gene or genes (position effect variegation). Other investigators indicate that there may be altered expression--or abnormally increased or decreased activity--of multiple "muscle-specific" genes in individuals with FSHD. Such researchers suggest that deletion of the coded instructions at chromosome 4q35 may disrupt the functioning of a particular muscle-specific protein (i.e., transcription factor) that serves to activate or regulate the activity of several other proteins.

Some investigators indicate that there may be an inverse correlation between the size of the fragment containing repeats of coded DNA instructions and the severity of symptoms. In other words, researchers suggest that larger deletions of such repeats may be associated with greater disease severity. In addition, in certain affected families (kindreds), although the inherited fragment size may tend to remain the same, symptoms may appear to develop with increased severity in successive generations, a phenomenon known as genetic anticipation.

Researchers indicate that chromosomal translocations may play some role in causing FSHD in some cases. Translocations occur when regions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material. In some individuals, during the division of certain cells (mitosis), there may be an exchange of chromosomal material between certain regions of chromosome 4q and the distal end of the long arm of chromosome 10 (10qter). According to investigators, translocation of the repeated DNA sequences at 4q35 to chromosome 10q may predispose to somatic mosaicism (see above) for the 4q35 deletion associated with FSHD.

Reports indicate that approximately five to 10 percent of individuals with FSHD may not have deletions or mutations of (i.e., linkage to) chromosome 4q35, suggesting that the disorder may result from changes in different genes on different chromosomes (genetic locus heterogeneity). Further research is needed to learn more about the underlying genetic mechanisms that may play a role in causing FSHD.
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Facioscapulohumeral muscular dystrophy (FSHD) appears to affect males and females in relatively equal numbers. The disorder is thought to have a frequency of approximately one individual per 20,000.
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Symptoms of the following disorders may be similar to those of facioscapulohumeral muscular dystrophy (FSHD). Comparisons may be useful for a differential diagnosis:

There are a number of genetic neuromuscular diseases that may be characterized by muscle weakness of varying severity, muscle wasting (atrophy), and associated symptoms that may be similar to those that may occur with FSHD. However, such disorders typically have characteristic features that may differentiate them from FSHD. (For more information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Diagnosis
Facioscapulohumeral muscular dystrophy (FSHD) may be diagnosed based upon a thorough clinical examination, identification of characteristic physical findings, a complete patient and family history, and various specialized tests. In some affected individuals, laboratory studies may reveal elevated levels of a particular enzyme in the fluid portion of the blood (serum creatine kinase). Tests may also be conducted to record electrical activity in voluntary (skeletal) muscles at rest and during muscle contraction (electromyography [EMG]). In addition, diagnostic evaluation may include surgical removal (biopsy) and microscopic examination of small samples of muscle tissue.

Family members of those diagnosed with FSHD should also receive thorough clinical examinations to help detect any symptoms and signs that may be associated with FSHD.

In addition, DNA testing may be available to help confirm FSHD in some cases in which the diagnosis may be uncertain (e.g., at-risk individuals with asymptomatic or mild disease). Such testing involves analysis of DNA obtained from blood samples; a diagnosis is made based upon confirmation of the chromosome 4q35 deletion. However, as mentioned above, a small percentage of FSHD cases do not have linkage to chromosome 4q35; therefore, absence of such a deletion may not exclude a diagnosis of FSHD. Testing is not yet available for cases in which FSHD is not associated with 4q35 deletion.

DNA testing to detect chromosome 4q35 deletions may only be offered through certain research laboratories. Some of the organizations listed in the "Resources" section of this report below may be able to provide further information on facilities that may offer such testing.

Treatment
The treatment of FSHD is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the treatment of neurological disorders (neurologists); physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); physicians who specialize in physical medicine and rehabilitation (physiatrists); specialists who assess and treat hearing problems (audiologists); and/or other health care professionals.

Disease management may include orthopedic measures and physical therapy to help maintain muscle flexibility. Various physical and adaptive aids may be helpful in performing certain activities. In some cases, severe muscle weakness may necessitate the use of wheelchairs, motorized carts, and other mobility and physical aids.

In addition, speech therapy, use of appropriate assistive devices, and/or other supportive techniques may help to improve speech and communication problems associated with hearing impairment and/or facial weakness.

In some cases, recommended treatment may include surgery to mechanically attach (fixate) the shoulder blades to the chest (thoracic) wall in order to help stabilize the scapulae and improve mobility of the upper arms.

Additional supportive services that may be beneficial for some affected individuals include special education and/or other medical, social, or occupational services. Genetic counseling will also be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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Research is in progress to identify and characterize the nature of the genetic defects responsible for FSHD. For more information, contact:

Jeffrey M. Stajich, M.A., PA-C
Duke University Medical Center
Center for Human Genetics
Durham, NC 27710
Phone: (800) 283-4316
E-mail: stajich@chg.mc.duke.edu

Researchers are investigating the use of the medication albuterol (Proventil) in improving muscle strength for individuals with FSHD. Initial results have shown that albuterol has improved muscle mass and somewhat improved muscle strength in individuals with FSHD. Further research is needed to determine the long-term safety and effectiveness of such therapy for individuals with FSHD. For more information, contact:

University of Rochester Medical Center
Department of Neurology
601 Elmwood Avenue
PO Box 673
Rochester, NY 14642
Lynn Coss, RN
Phone: (716) 275-7680
Fax: (716) 256-1423
E-mail: LCOS@mail.Neurolofy.rochester.edu

or

Cheryl Kacvinsky or Karen Downing
(614) 292-1234

Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 158900; 2/14/00. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?158900.

Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 158901; 5/12/98. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?158901.

TEXTBOOKS
Rowland LP, ed. Merritt's Neurology. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2000:741-742.

Beers MH, et al., eds. The Merck Manual. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:1499.

Behrman RE, et al., eds. Nelson Textbook of Pediatrics. 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:1751-1752.

Buyse ML. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications, Inc.; 1990:1183-1184.

JOURNAL ARTICLES
Kissel JT, et al. Randomized, double-blind, placebo-controlled trial of albuterol in facioscapulohumeral dysptrophy. Neurology. 2001;57:1434-40.

van der Maarel SM, et al. De novo facioscapulohumeral muscular dystrophy: frequent somatic mosaicism, sex-dependent phenotype, and the role of mitotic transchromosomal repeat interaction between chromosomes 4 and 10. Am J Hum Genet. 2000;66:26-35.

van der Maarel SM, et al. A new dosage test for subtelomeric 4;10 translocations improves conventional diagnosis of facioscapulohumeral muscular dystrophy (FSHD). J Med Genet. 1999;36:823-828.

Tupler R, et al. Profound misregulation of muscle-specific gene expression in facioscapulohumeral muscular dystrophy [published erratum appears in Proc Natl Acad Sci U S A. 2000;97:2397]. Proc Natl Acad Sci USA. 1999;96:12650-12654.

Copeland SA, et al. The shoulder in patients with muscular dystrophy. Clin Orthop. 1999;368:80-91.

Kissel JT, et al. Pilot trial of albuterol in facioscapulohumeral muscular dystrophy. Neurology. 1998;50:1402-1406.

Funakoshi M, et al. Epilepsy and mental retardation in a subset of early onset 4q35- facioscapulohumeral muscular dystrophy. Neurology. 1998;50:1791-1794.

The FSH-DY Group. A prospective, quantitative study of the natural history of facioscapulohumeral muscular dystrophy (FSHD): implications for therapeutic trials. Neurology. 1997;48:38-46.

FSH-DY Group. A pilot trial of prednisone in facioscapulohumeral muscular dystrophy. Neurology. 1997;48:46-49.

Tawil R. A pilot trial of prednisone in fasioscapulohumeral muscular dystrophy. Neurology. 1997;48:46-49.

Milanov I, et al. Differential diagnosis of scapuloperoneal syndrome. Electromyogr Clin Neurophysiol. 1997;37:73-78.

Bakker E, et al. Predictive and prenatal testing for facioscapulohumeral muscular dystrophy: diagnostic approach for sporadic and familial cases. J Med Genet. 1996;33: 29-35.

Deidda G, et al. Direct detection of 4q35 rearrangements implicated in facioscapulohumeral muscular dystrophy (FSHD). J Med Genet. 1996;33:361-365.

Kohler J, et al. Germline mosaicism in 4q35 facioscapulohumeral muscular dystrophy (FSHD1A) occuring predominantly in oogenesis. Hum Genet. 1996;98:485-490.

Nakagawa M, et al. Familial facioscapulohumeral muscular dystrophy: phenotypic diversity and genetic abnormality. Acta Neurol Scand. 1996;93:189-192.

Tawil R, et al. Evidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular dystrophy. Ann Neurol. 1996;39:744-748.

Lunt PW, et al. Correlation between fragment size at D4F104S1 and age at onset or at wheelchair use, with a possible generation effect, accounts for much phenotypic variation in 4q35-facioscapulohumeral muscular dystrophy (FSHD). Hum Molec Genet. 1995;4:951-958.

Zatz M, et al. High proportion of new mutations and possible anticipation in Brazilian facioscapulohumeral muscular dystrophy families. Am J Hum Genet. 1995;56:99-105.

Griggs RC, et al. Genetics of facioscapulohumeral muscular dystrophy: new mutations in sporadic cases. Neurology. 1993;43:2369-2372.

Weiffenbach B, et al. Mapping the facioscapulohumeral muscular dystrophy gene is complicated by chromosome 4q35 recombination events. Nature Genet. 1993;4:165-169.

Wijmenga C, et al. Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy. Nature Genet. 1992;2:26-30.

Padberg GW, et al. Retinal vascular disease and sensorineural deafness are part of facioscapulohumeral muscular dystrophy [abstract]. Am J Hum Genet. 1992;51:A104.

Brouwer OF, et al. Hearing loss in facioscapulohumeral muscular dystrophy. Neurology. 1991;41:1878-1881.

Lunt PW, et al. Estimation of age dependent penetrance in facioscapulohumeral muscular dystrophy by minimising ascertainment bias. J Med Genet. 1989;26:755-760.

Fitzsimons RB, et al. Retinal vascular abnormalities in facioscapulohumeral muscular dystrophy: a general association with genetic and therapeutic implications. Brain. 1987;110:631-648.

Matsuzaka T, et al. Facioscapulohumeral dystrophy associated with mental retardation, hearing loss, and tortuosity of retinal arterioles. J Child Neurol. 1986;1:218-223.

Voit T, et al. Hearing loss in facioscapulohumeral dystrophy. Europ J Pediat. 1986;145:280-285.

Taylor DA, et al. Facioscapulohumeral dystrophy associated with hearing loss and Coats syndrome. Ann Neurol. 1982;12:395-398.

Tyler, FH, et al. Studies in disorders of muscle. II. Clinical manifestations and inheritance of facioscapulohumeral dystrophy in a large family. Ann Intern Med. 1950;32:640-660.

INTERNET:
GeneReviews: Facioscapulohumeral Muscular Dystrophy
www.geneclinics.org/profiles/fsh/

Facioscapulohumeral Muscular Dystrophy
eMedicine - Facioscapulohumeral Dystrophy : Author: Naganand Sripathi, MD
www.emedicine.com/neuro/topic133.htm