GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. FSHD is diagnosed by a molecular genetic test that identifies deletion of integral copies of a 3.3-kb DNA repeat motif, D4Z4, which is located in the subtelomeric region of chromosome 4q35. Normal D4Z4 alleles have 11-100 repeat units; those associated with FSHD have between one and ten repeat units. Molecular genetic testing detects approximately 95% of affected individuals and is clinically available.
Management. Treatment of manifestations: low-intensity aerobic exercise; ankle/foot orthoses to improve mobility and prevent falls; surgical fixation of the scapula to the chest wall may improve range of motion of the arms over the short term; standard treatment of sensorineural hearing loss; lubricants to prevent drying of the sclera or taping the eyes shut during sleep to treat exposure keratitis. Surveillance: annual evaluation to assess strength and functional limitations.
Genetic counseling. FSHD is inherited in an autosomal dominant manner. Approximately 70%-90% of individuals have inherited the disease-causing deletion from a parent, and approximately 10%-30% of affected individuals have FSHD as the result of a de novo deletion. Offspring of an affected individual have a 50% chance of inheriting the deletion. Prenatal testing for pregnancies at increased risk is possible if the D4Z4 contraction mutation has been identified in the family.
FSHD is suspected in individuals with the following [Tawil et al 1998, Tawil & Van Der Maarel 2006]:
Weakness that predominantly involves the facial, scapular stabilizer, and foot dorsiflexor muscles without associated ocular or bulbar muscle weakness.
Onset of signs by age 20 years, although more mildly affected individuals show signs at a later age and some remain asymptomatic.
Serum concentration of creatine kinase (CK) is normal to elevated in individuals with FSHD and usually does not exceed three to five times the upper limit of the normal range. Serum concentration of CK over 1500 IU/L suggests an alternate diagnosis.
EMG usually shows mild myopathic changes.
Muscle biopsy most often shows nonspecific chronic myopathic changes. Mononuclear inflammatory reaction is present in muscle biopsies in up to 40% of individuals with FSHD. Rarely, the inflammatory reaction is intense enough to suggest an inflammatory myopathy. Muscle biopsy is now performed only in those individuals in whom FSHD is suspected but not confirmed by molecular genetic testing.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Critical region. Approximately 95% of individuals with FSHD have a contraction mutation of the repeat sequence of the D4Z4 locus in the subtelomeric region of chromosome 4q35. The D4Z4 locus encompasses a hypothetical double homeodomain gene, called DUX4 [Gabriels et al 1999]. Recently transcription analysis showed that DUX4 is indeed transcribed, but other sense, antisense, and small RNA molecules are also transcribed from the D4Z4 region [Dixit et al 2007, Snider et al 2009]. However, studies performed to date have failed to identify FSHD-specific transcription from the D4Z4 locus or the 4q35 region.
Other loci. A repeat sequence almost identical to D4Z4 has been identified on chromosome 10q26 but contractions of this repeat have never been associated with FSHD.
Figure 1. Schematic comparison of the structure of the normal D4Z4 allele and the contracted mutant D4Z4 allele that causes FSHD. The normal D4Z4 allele has between 11 and 100 units of the 3.3-kb repeat sequence (depicted by triangles), while the contracted mutant FSHD-causing D4Z4 allele has contracted to between one to ten units of the 3.3-kb repeat sequence.
).
Unaffected individuals: Both D4Z4 alleles have 11-100 repeat units.
Individuals with FSHD:
Haplotypes telomeric to the D4Z4 region. Haplotypes telomeric to the D4Z4 locus, designated 4A and 4B, contribute to the pathogenicity of a contracted D4Z4 mutant allele [van Geel et al 2002]. 4A and 4B represent at least nine distinct haplotypes (i.e., different combinations of SNPs at one locus that are inherited together) [Lemmers et al 2007].
Contractions of the D4Z4 allele on the haplotype designated 4A161 cause FSHD.
Contractions of the D4Z4 allele on the haplotypes designated 4A166 and 4B are non-pathogenic [Lemmers et al 2004a, Lemmers et al 2007].
Note: In the Caucasian population, approximately 35% of the alleles on chromosome 4 are categorized 4A161, 5% as 4A166, and 50% as 4B.
Clinical testing
Allele sizes. Molecular genetic testing to determine the length or number of repeat units of the D4Z4 locus relies on Southern blot analysis, typically with a probe (e.g., p13E-11) that is localized immediately proximal to the D4Z4 locus. Standard DNA diagnostic testing (linear gel electrophoresis and Southern blot analysis) uses the restriction enzyme EcoRI that recognizes the D4Z4 locus on chromosomes 4 and 10.
Note: Pulsed-field gel electrophoresis and Southern blot analysis requires EcoRI/HindIII double digestion for a better resolution of DNA fragments between 20 and 50 kb. An EcoRI/BlnI double digestion further fragmentizes the chromosome 10 locus and specifically shows the chromosome 4 D4Z4 locus.
Normal alleles. A D4Z4 locus with 11 to 100 repeat units (i.e., fragments of 42 kb or greater using the p13E-11 probe)
Borderline alleles. A D4Z4 locus with 10 or 11 repeat units (i.e., fragments of 38-41 kb using the p13E-11 probe)
Note: (1) To date, it has not been possible to establish a definitive diagnostic cut-off for the number of repeat units of the D4Z4 locus; thus, caution should be exercised in assigning the diagnosis of FSHD to persons whose clinical findings are atypical and whose molecular genetic test results are within this borderline ("gray") zone. (2) Interpretation of the significance of fragments of this length requires correlation with clinical findings: In a study of 39 unrelated individuals having a D4Z4 allele in this size range, Butz et al [2003] identified individuals representing the complete phenotypic spectrum, from typical and atypical FSHD, to facial-sparing FSHD, to non-FSHD myopathy, to healthy without signs or symptoms. We consider 35-40 kb fragments to be FSHD-associated if the person has clinical features of FSHD.
FSHD-associated alleles. A D4Z4 locus with 1-10 repeat units (i.e., fragments of 10-40 kb using the p13E-11 probe) AND on a 4A161 haplotype. When such a fragment is not visible in the DNA sample, the person is said to have tested negative for FSHD.
Mosaicism for FSHD-associated alleles. Approximately half of de novo FSHD cases result from mosaicism. An individual may be mosaic for a contracted D4Z4 mutant allele as a result of a de novo post-zygotic contraction during mitosis, probably occurring early in embryogenesis. In such cases, a proportion of cells have two normal-sized D4Z4 alleles, while the remaining cells have one normal-sized D4Z4 allele and one contracted mutant D4Z4 allele [Lemmers et al 2004b].
Depending on when in embryogenesis the contraction mutation occurs at the D4Z4 locus, individuals with mosaicism can be affected (i.e., have a relatively high proportion of cells with the contracted mutant D4Z4 allele) or asymptomatic (i.e., have a relatively low proportion of cells with the contracted mutant D4Z4 allele). Furthermore, mosaic males are more susceptible to FSHD than mosaic females [van der Maarel et al 2000].
Note: In the other half of de novo FSHD cases, the contraction mutation at the D4Z4 locus occurs within the germline.
Translocated alleles. In approximately 20% of the general population the authors observed either a chromosome 4q35-type D4Z4 allele on chromosome 10q26 or a D4Z4 allele that consists of both 4q35- and 10q26-type sequence repeats on chromosome 4q35 [van Deutekom et al 1996]. Therefore, the finding of a D4Z4 allele that appears to be contracted in an individual that carries these exchanged D4Z4 alleles must be interpreted with caution and reconciled with clinical findings. Note: Although these are commonly known as ‘translocated alleles,’ the mechanism is unknown.
Haplotype analysis. The clinician should know whether the laboratory test can distinguish between contracted mutant D4Z4 alleles that occur on either the pathogenic 4A161 haplotype or the non-pathogenic 4A166 and 4B haplotypes (see Molecular Genetic Testing, Haplotypes telomeric to the D4Z4 region).
Haplotype analysis is important to prevent a false positive diagnosis. Sometimes a D4Z4 allele from chromosome 4 that appears to have a contraction mutation is detected in unaffected control individuals. In such cases, the contracted D4Z4 allele is on the non-pathogenic 4B haplotype and is therefore non-penetrant. Lemmers et al [2002] developed a clinical diagnostic test to discriminate both haplotype variants using HindIII-digested DNA and specific probes for 4qA and 4qB [Lemmers et al 2007]. This test is clinically available.
Note: More specific genotyping to distinguish different 4A haplotypes has not yet been implemented in the molecular diagnostics of FSHD.
Deletion alleles. The approximately 3% of Caucasian families with FSHD that do not have a contraction mutation at the D4Z4 locus require additional testing to resolve the size of the allele as they might have a deletion that encompasses the region of the molecular diagnostic probe p13E-11 [Lemmers et al 2003, Ehrlich et al 2007].
Research testing
D4Z4 hypomethylation. Epigenetic DNA analysis of persons with FSHD revealed that the contracted mutant D4Z4 allele has a significantly lower level of CpG methylation than normal-sized repeats. This implies that hypomethylation of D4Z4 may play a role in its pathogenicity. Further analysis showed that the fewer than 5% of persons with FSHD who do not have a contracted mutant D4Z4 allele do show DNA hypomethylation on both normal D4Z4 alleles [van Overveld et al 2003].
Table 1. Molecular Genetic Testing Used in Facioscapulohumeral Muscular Dystrophy
| Test Method | Mutation Detected | Mutation Detection Frequency | Test Availability |
|---|---|---|---|
| Deletion testing | Contraction mutation of D4Z4 locus | 95% | Clinical
 |
| Haplotype analysis | Analysis to confirm that the D4Z4 contraction mutation occurred on the pathogenic 4qA161 haplotype | >95% |
Interpretation of test results
Molecular genetic test results should always be interpreted within the context of clinical findings.
Detection of the contracted mutation of the D4Z4 locus by Southern blot analysis requires a high DNA quality; in some cases a false negative test result can be caused by poor quality DNA which has been sheared into small segments.
Confirming the diagnosis in a proband. Molecular genetic testing is the preferred method of diagnosis.
Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in the family.
No other phenotypes are associated with the contraction mutation of the D4Z4 locus in the subtelomeric region of chromosome 4q.
Facioscapulohumeral muscular dystrophy (FSHD) is characterized by progressive muscle weakness involving the face, scapular stabilizers, upper arm, lower leg (peroneal muscles), and hip girdle [Tawil et al 1998]. Asymmetry of limb and/or shoulder weakness is common [Kilmer et al 1995]. Typically, individuals with FSHD become symptomatic in their teens, but age of onset is variable. More than 90% of affected individuals demonstrate findings by age 20 years. Individuals with severe infantile FSHD have muscle weakness at birth. In contrast, some individuals remain asymptomatic throughout their lives. Progression is usually slow and continuous; however, many affected individuals describe a stuttering course with periods of disease inactivity followed by periods of rapid deterioration. Eventually 20% of affected individuals require a wheelchair.
Scapular winging is the most common initial finding; preferential weakness of the lower trapezius muscle results in characteristic upward movement of the scapula when attempting to flex or abduct the arms. The shoulders tend to slope forward with straight clavicles and pectoral muscle atrophy.
Affected individuals show facial weakness, more in the lower facial muscles than the upper. Some affected individuals recall having facial weakness before the onset of shoulder weakness. Earliest signs are often difficulty whistling or sleeping with eyes partially open in childhood. They are unable to purse their lips, turn up the corners of their mouth when smiling, or bury their eyelashes when attempting to close their eyelids tightly. Extraocular, eyelid, and bulbar muscles are spared.
The deltoids remain minimally affected until late in the disease; however, the biceps and triceps are selectively involved, resulting in atrophy of the upper arm and sparing of the forearm muscles. The latter results in the appearance of ‘Popeye arms.’
Abdominal muscle weakness results in protuberance of the abdomen and exaggerated lumbar lordosis. The lower abdominal muscles are selectively involved, resulting in Beevor's sign, which is upward displacement of the umbilicus upon flexion of the neck in a supine position.
The legs are variably involved, with peroneal muscle weakness with or without weakness of the hip girdle muscles, resulting in foot drop.
Sensation is preserved; reflexes are often diminished.
Respiratory function is usually normal [Tawil & Griggs 1997] but occasionally compromised [Kilmer et al 1995].
Other manifestations. Retinal vasculopathy consisting of telangiectasia and microaneurysms can be demonstrated by fluorescein angiography in 40%-60% of affected individuals [Padberg et al 1995]. Vision is usually unaffected; however, Coats disease has been described. Bindoff et al [2006] reported two sisters with infantile onset FSHD who had tortuous retinal vessels, small aneurysms, and yellow exudates.
Approximately 60% of individuals with FSHD have an abnormal audiogram with high-tone sensorineural hearing loss [Brouwer et al 1991, Padberg et al 1995].
A predilection for atrial tachyarrhythmias has been reported in about 5% of cases, but symptoms are rarely observed [Laforet et al 1998, Galetta et al 2005, Trevisan et al 2006].
Atypical presentations. Clinical variants of typical FSHD in individuals with a contraction mutation of the D4Z4 locus in the subtelomeric region of chromosome 4q35 include the following:
Scapulohumeral dystrophy with facial sparing
Slowly progressive FSHD with progressive external ophthalmoplegia [Krasnianski et al 2003]. This kindred presents a departure from previously described atypical FSHD kindreds. Given the complexity of interpreting FSHD molecular genetic test results, more comprehensive molecular testing of this kindred is necessary before progressive external ophthalmoplegia can be included with certainty in the clinical spectrum of FSHD.
Infantile onset with severe rapidly progressive disease and a large contraction mutation of D4Z4 (D4Z4 fragments in the 9-21 kb range) was observed in 4% of individuals studied [Klinge et al 2006]. Felice et al [2005] and Bindoff et al [2006] have also reported cases with infantile onset. Mild to moderate cognitive deficiency and possible epilepsy have been reported in early-onset cases often with associated deafness and retinopathy [Bindoff et al 2006, Hobson-Webb & Caress 2006, Quarantelli et al 2006].The affected parent often had mild disease and was mosaic for a contraction mutation of the D4Z4 locus.
Pregnancy. Outcome of 105 pregnancies in 38 women with FSHD was generally favorable [Ciafaloni et al 2006]. However, rates for low birth weight and total operative deliveries were higher than for the general population. Worsening of weakness occured in 24% of the pregnancies.
A correlation has been reported between the degree of the contraction mutation of the D4Z4 locus and the age at onset of symptoms [Zatz et al 1995], age at loss of ambulation [Lunt et al 1995], and muscle strength as measured by quantitative isometric myometry [Tawil et al 1996], particularly in affected females [Tonini et al 2004a]. Individuals with a large contraction of the D4Z4 locus tend to have earlier-onset disease and more rapid progression than those with smaller contractions of the D4Z4 locus [Bindoff et al 2006, Hobson-Webb & Caress 2006, Klinge et al 2006]. However, others have not been able to confirm a correlation between disease severity and degree of D4Z4 contraction mutations [Butz et al 2003].
De novo mutations are associated with larger contraction mutations of D4Z4 (on average) compared to the degree of D4Z4 contraction mutations observed segregating in families; hence, individuals with de novo mutations tend to have findings at the more severe end of the phenotypic spectrum.
Zatz et al [1998] have reported reduced penetrance in females with large contraction mutations of D4Z4, compared to the penetrance in males with similar-sized contraction mutations; these results support their previous findings (see Penetrance).
Mosaicism. The phenotypic severity of individuals with mosaicism, which is typically less than that of individuals without mosaicism, may reflect the proportion of cells carrying the contracted mutated D4Z4 locus in addition to the degree of the contraction of the D4Z4 locus in those cells.
Compound heterozygosity. Two unrelated affected individuals homozygous for a D4Z4 contraction mutation were reported by Wohlgemuth et al [2003], suggesting that the presence of two FSHD-associated alleles can be compatible with life. However, both families demonstrated reduced penetrance for FSHD, leaving open the possibility that in other genetic/environmental settings, compound heterozygosity might be a lethal condition. In support of this possibility, the authors report a phenotypic dosage effect in both of the compound heterozygotes in comparison to other family members.
Homozygosity. Tonini et al [2004b] reported an individual homozygous for the contraction on two 4qA alleles whose clinical phenotype is not more severe than those of some of his heterozygous relatives. Within the same family, the authors also observed a large number of asymptomatic or minimally affected heterozygotes, reflecting the wide range of clinical variability that can occur in a given kindred.
In one study, penetrance of FSHD was found to vary by age and gender; it was 83% by age 30 years, but significantly greater for males (95%) than for females (69%) [Zatz et al 1998]. This finding was confirmed by Tonini et al [2004a]. The sex difference in penetrance is unexplained [Zatz et al 1998].
Tonini et al [2004a] suggest that non-penetrance may cluster in families, with other genetic factors contributing to the severity of clinical presentation. Goto et al [2004] drew similar conclusions in an analysis of penetrance in 85 kindreds.
The existence and putative mechanism for anticipation in FSHD remains controversial. Anticipation in FSHD was originally suggested by Zatz et al [1995] based on the observation in multigenerational families that parents were frequently less affected than their offspring. Substantiation for this idea can be found in the reports of Lunt et al [1995] and Tawil et al [1996].
More recently, data suggest that this apparent anticipation may be the result of the gender differences in penetrance described above [Zatz et al 1998]. Thus, affected male offspring of affected mothers are likely to be more severely affected as a function of gender difference rather than anticipation.
It has also been suggested that late ascertainment bias among maternal relatives contributed to the apparent anticipation.
Absence of anticipation in large multigenerational families has also been reported [Flanigan et al 2001].
The term Landouzy-Dejerine muscular dystrophy used in the past for a syndrome similar or identical to FSHD is no longer in use.
Persons with FSHD are sometimes included under the descriptive terms of scapulo-humeral or scapulo-peroneal syndromes.
The estimated prevalence of FSHD is between four and ten per 100,000 population. Sposito et al [2005] found a prevalence in central Italy of 4.6 per 100,000, a much higher prevalence than found in a previous study from the same region done in the pre-molecular diagnosis era (1981).
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Disorders that are similar clinically to facioscapulohumeral muscular dystrophy (FSHD) but easily differentiated by their distinct muscle histopathology include the following:
Myofibrillar myopathy (previously called desmin-storage myopathy)
Inclusion body myositis including inclusion body myopathy 2 (IBM2)
Congenital myopathies (see Congenital Muscular Dystrophy Overview)
Polymyositis
More troublesome are the following disorders in which the distribution of weakness and pathologic findings can be difficult to distinguish easily from FSHD:
The limb girdle muscular dystrophies (see Limb-Girdle Muscular Dystrophy Overview)
Scapuloperoneal muscular dystrophy syndromes, including myotonic dystrophy type 1 and myotonic dystrophy type 2 (also known as PROMM), that have mild facial weakness and nonspecific histopathologic changes that cannot be differentiated from FSHD. Molecular genetic testing allows definitive diagnosis of these two conditions.
To establish the extent of disease in an individual diagnosed with facioscapulohumeral muscular dystrophy (FSHD), the following evaluations are recommended:
Physical examination to assess strength and functional limitations
Evaluation for physical therapy and need for assistive devices
Assessment of hearing if the individual has symptomatic hearing loss
Ophthalmologic evaluation for the presence of retinal telangiectasias
Ankle/foot orthoses can improve mobility and prevent falls in individuals with foot drop.
Surgical fixation of the scapula to the chest wall often improves range of motion of the arms, although this gain can be short-lived in individuals with rapidly progressive disease [Diab et al 2005, Krishnan et al 2005, Giannini et al 2006]. Evaluation of such individuals prior to surgery is warranted to assure a functional and sustained benefit.
Low-intensity aerobic exercise improved maximum oxygen uptake and workload with no signs of muscle damage [Olsen et al 2005]. A Cochran Review of strength training is available [van der Kooi et al 2005].
Sensorineural hearing loss, when present, is treated in a standard manner (see Hereditary Deafness and Hearing Loss Overview).
Exposure keratitis may occur in individuals who sleep with their eyes partially open. Use of lubricants to prevent drying of the sclera or in more severe cases taping the eyes shut during sleep may be required.
Annual physical evaluation to assess strength and functional limitations is appropriate.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Myostatin is an inhibitor of muscle growth. Although a treatment trial using a neutralizing antibody to myostatin (MYO-029) in several muscular dystrophies including FSH showed that it was safe, there was no improvement in muscle strength or function [Wagner et al 2008].
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
A 24-week trial Dilitazem did not improve findings in individuals with FSHD [Elsheikh et al 2007].
Steroids, albuterol, and creatine have not proven effective [Tawil & van der Maarel 2006].
Two controlled studies of oral albuterol in FSHD [Kissel et al 2001, van der Kooi et al 2004] did not show significant global improvement in strength despite a modest increase in muscle mass. A Cochrane review concluded that further study of albuterol in FSHD is needed [Rose & Tawil 2004].
Corticosteroids have been used in individuals who have evidence of inflammation on muscle biopsy. Although transient improvement in strength has been reported, a natural-history-controlled study in eight individuals with FSHD revealed no improvement after 12 weeks of treatment with prednisone [Tawil et al 1997].
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Facioscapulohumeral muscular dystrophy (FSHD) is inherited in an autosomal dominant manner.
Parents of a proband
Most individuals diagnosed with FSHD have a parent with clinical findings of FSHD and one D4Z4 allele with a contraction mutation (70%-90% of individuals with FSHD).
However, approximately 10%-30% of probands with FSHD have the disorder as the result of a D4Z4 with a de novo contraction mutation [Bakker et al 1996, Kohler et al 1996].
It is appropriate to evaluate the parents of a proband clinically and with molecular genetic testing.
Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
Note: The family history may appear to be "negative" because of failure to recognize the disorder in family members, an asymptomatic parent who has a deletion of the region subtelomeric to the D4Z4 locus where the probe hybridizes (and is therefore probe negative), early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. (2) If the parent is the individual in whom the mutation first occurred s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.
Sibs of a proband
The risk to the sibs of a proband depends on the genetic status of the parents.
If a parent of the proband is affected, the risk to the sibs of inheriting the D4Z4 contraction mutation is 50%.
When neither parent has the D4Z4 contraction mutation, the risk to the sibs of a proband appears to be low.
If neither parent of the proband has a detectable D4Z4 contraction mutation, two possible explanations are germline mosaicism in a parent or a de novo D4Z4 contraction mutation in the proband. The incidence of germline mosaicism is unknown.
Offspring of a proband. Each offspring of an affected individual has a 50% chance of inheriting the D4Z4 contraction mutation.
Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected and/or has a D4Z4 contraction mutation, his or her family members are at risk.
Testing of at-risk individuals. Molecular genetic testing for asymptomatic at-risk adult family members is available. The testing of unaffected at-risk children under age 18 years is discouraged because no treatment is available. Testing of at-risk individuals who are under age 18 years is always appropriate when symptoms are present. See also the National Society of Genetic Counselors resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents (pdf; Genetic Testing).
Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.
Family planning
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Prenatal testing is available for pregnancies at 50% risk for FSHD [Bakker et al 1996] by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The D4Z4 contraction mutation of the affected parent must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Requests for prenatal diagnosis of (typically) adult-onset diseases (such as FSHD) that do not usually affect intellect or life span are uncommon. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Critical Region | Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|---|
| D4Z4 | Unknown | 4q35 | Unknown |
| 158900 | FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 1A; FSHMD1A |
| 158901 | FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 1B; FSHMD1B |
| 601278 | FSHD GENE 1; FRG1 |
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page
The authors would like to acknowledge their colleagues in the FSH-Dystrophy Group, based at the University of Rochester and Ohio State University. Our research is funded in part by grants from the MDA-USA; NIH; NYS Department of Education; and FSH Society, Inc.
Denise A Figlewicz, PhD; University of Michigan Medical School (1998-2009)
Richard JLF Lemmers, PhD (2009-present)
Rabi Tawil, MD; University of Rochester Medical School (1998-2009)
Silvere M van der Maarel, MD (2009-present)
9 July 2009 (me) Comprehensive update posted live
17 March 2005 (me) Comprehensive update posted to live Web site
18 March 2003 (me) Comprehensive update posted to live Web site
8 March 1999 (pb) Review posted to live Web site
10 July 1998 (df) Original submission
