Summary
NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE.
Clinical characteristics.
Myostatin-related muscle hypertrophy is characterized by reduced subcutaneous fat pad thickness and increased muscle size in individuals with normal or increased muscle strength. Both heterozygotes and homozygotes for a causative variant in MSTN encoding the protein growth differentiation factor 8 (myostatin) can exhibit muscle hypertrophy. Clinical manifestations depend on the amount of myostatin protein present. An infant homozygous for an MSTN causative variant had muscle mass twice that of sex- and age-matched controls; intellect and cardiac function were normal. He displayed stimulus-induced myoclonus that subsided after two months. Heterozygotes may have increased muscle bulk and strength, but to a lesser degree.
Diagnosis/testing.
Skeletal muscle size in an individual with myostatin-related muscle hypertrophy is measured by ultrasound examination, DEXA, or MRI. Subcutaneous fat pad thickness is measured by ultrasound or with a caliper. MSTN is the only gene in which mutation is known to cause myostatin-related muscle hypertrophy.
Management.
Myostatin-related muscle hypertrophy is not known to cause medical complications.
Genetic counseling.
The phenotypes associated with myostatin-related muscle hypertrophy are inherited in an incomplete autosomal dominant manner. At conception, the sibs of a child with homozygous myostatin-related muscle hypertrophy have a 25% chance of having homozygous myostatin-related muscle hypertrophy, a 50% chance of having one MSTN causative variant with or without increased muscle mass, and a 25% chance of having normal muscle mass and no MSTN causative variants. Heterozygotes may have increased muscle mass. Individuals diagnosed with heterozygous myostatin-related muscle hypertrophy may have a parent with the MSTN causative variant who may have increased muscle mass, or the proband may have the condition as the result of a de novo variant. The proportion of cases caused by a de novo variant is unknown. The chance that sibs of a proband with heterozygous myostatin-related muscle hypertrophy will inherit the MSTN variant is 50% if a parent has increased muscle mass or has an MSTN causative variant. Each child of an individual with heterozygous myostatin-related muscle hypertrophy has a 50% chance of inheriting the MSTN causative variant.
Diagnosis
Clinical Diagnosis
The diagnosis of myostatin-related muscle hypertrophy is established by clinical findings of reduced subcutaneous fat pad thickness and increased muscle size in individuals with normal or increased muscle strength and an MSTN causative variant identified on molecular genetic testing.
Testing
Skeletal muscle size can be measured by ultrasound, DEXA, or MRI. It is expected to be several deviations above normal for age- and sex-matched controls.
Subcutaneous fat pad thickness can be measured by ultrasound or with a caliper at various standard locations for which normal values exist.
Creatine kinase (CK) serum concentration is expected to be normal.
Molecular Genetic Testing
Gene.
MSTN, which encodes the protein growth differentiation factor 8 (also known as myostatin) is the only gene in which variants are known to cause myostatin-related muscle hypertrophy.
Table 1.
Molecular Genetic Testing Used in Myostatin-Related Muscle Hypertrophy
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| Gene 1 | Method | Variants Detected 2 | Variant Detection Frequency by Method 3 |
|---|
|
MSTN
| Sequence analysis 4 | Sequence variants including c.506+5G>A 5 | Unknown |
- 1.
- 2.
- 3.
The ability of the test method used to detect a variant that is present in the indicated gene
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
The only MSTN causative variant related to myostatin-related muscle hypertrophy that has been reported [Schuelke et al 2004]
Testing Strategy
To confirm/establish the diagnosis in a proband
Clinical Characteristics
Clinical Description
Clinical manifestations of myostatin-related muscle hypertrophy appear to be dependent on the amount of myostatin protein present. Therefore both heterozygotes and homozygotes can exhibit muscle hypertrophy.
Homozygotes. A homozygous loss-of-function myostatin variant was identified in a hypermuscular infant with muscle mass approximately twice that of sex- and age-matched controls [Schuelke et al 2004]. At age 4.5 years, he continued to have increased muscle bulk and strength with normal intellect and normal cardiac function by echocardiography and electrocardiography.
He initially displayed stimulus-induced myoclonus that subsided after two months. The relationship between myoclonus and the MSTN causative variant is not clear.
Ultrasonography revealed normal muscle echogenicity and cross-sectional diameter of quadriceps muscle 7.2 SD above the mean.
Heterozygotes. Heterozygotes may have increased muscle bulk and strength. The mother of the child identified to be homozygous for the c.506+5G>A variant was a former professional athlete with large calf muscles [Schuelke et al 2004]. See also Genotype-Phenotype Correlations.
Genotype-Phenotype Correlations
No information is currently available as only one myostatin-related muscle hypertrophy-causing variant in MSTN has been identified.
In a multigenerational family segregating a 3.4-Mb deletion of chromosome 2q32.1q32.3 including MSTN, four of seven individuals with the deletion available for examination were reported to have increased muscle strength and increased size of the gastrocnemius and soleus muscles, whereas the other three individuals with the deletion did not have increased muscle strength or size [Meienberg et al 2010].
Penetrance
Penetrance is unknown.
Anticipation
Anticipation is not known to occur.
Prevalence
Prevalence is unknown.
Differential Diagnosis
The MSTN causative variant does not appear to be associated with myopathy or muscle weakness, thus allowing differentiation of myostatin-related muscle hypertrophy from muscular dystrophies with muscle hypertrophy, including:
Limb-girdle muscular dystrophy 1C (caveolinopathy)
Limb-girdle muscular dystrophies 2C, 2D, 2E (sarcoglycanopthies)
Channelopathies such as
myotonia congenita, a chloride channelopathy resulting from pathogenic variants in
CLCN1
The MSTN causative variant also causes decreased adipose tissue and needs to be distinguished from familial partial lipodystrophy, Dunnigan type (FPLD2), caused by pathogenic variants in LMNA, in which increased muscle mass is not seen [Schmidt et al 2001].
Management
Treatment of Manifestations
Myostatin-related muscle hypertrophy is not currently known to cause any medical complications.
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Mode of Inheritance
The phenotypes associated with myostatin-related muscle hypertrophy are inherited in an incomplete autosomal dominant manner.
Risk to Family Members
Parents of a proband who is homozygous for myostatin-related muscle hypertrophy
Sibs of a proband
At conception, each sib of a child with homozygous myostatin-related muscle hypertrophy has a 25% chance of having homozygous myostatin-related muscle hypertrophy, a 50% chance of having one MSTN causative variant with or without increased muscle mass, and a 25% chance of having normal muscle mass and no MSTN causative variants.
Heterozygotes may have increased muscle mass.
Offspring of a proband. The offspring of an individual with homozygous myostatin-related muscle hypertrophy are obligate heterozygotes for a causative variant in MSTN and may have increased muscle mass.
Other family members of a proband. Each sib of the proband's parents has a 50% chance of having one MSTN causative variant and may have increased muscle mass.
Parents of a proband
who is heterozygous for myostatin-related muscle hypertrophy
Individuals diagnosed with heterozygous myostatin-related muscle hypertrophy may have a parent with an MSTN causative variant who may have increased muscle mass or may have the condition as the result of a de novo variant. The proportion of cases caused by a de novo variant is unknown.
Recommendations for the evaluation of parents of a proband with an apparent de novo variant include clinical evaluation for evidence of muscle hypertrophy.
Note: Although individuals diagnosed with heterozygous myostatin-related muscle hypertrophy may have a parent with increased muscle mass, the family history may appear to be negative because of incomplete penetrance or failure to recognize the condition in family members.
Sibs of a proband
The chance that the sibs of the proband will inherit the MSTN causative variant depends on the genetic status of the proband's parents.
If a parent of the proband has increased muscle mass, the chance that the sibs will inherit the MSTN causative variant is 50%.
Offspring of a proband. Each child of an individual with heterozygous myostatin-related muscle hypertrophy has a 50% chance of inheriting the MSTN causative variant.
Other family members of a proband. The chance that other family members will be affected depends on the status of the proband's parents: if a parent has increased muscle mass, his or her family members may be affected.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella
support organizations and/or registries for the benefit of individuals with this disorder
and their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click here.
No specific resources for Myostatin-Related Muscle Hypertrophy have been identified by GeneReviews staff.
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A.
Myostatin-Related Muscle Hypertrophy: Genes and Databases
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Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Benign variants. Five missense substitutions in conserved amino acid residues have been identified [Ferrell et al 1999]. Two of these, p.Ala55Thr in exon 1 and p.Lys153Arg in exon 2, are polymorphic benign variants in the general population (see Table 2).
Pathogenic variants. Only one muscle hypertrophy-causing MSTN variant has been reported to date; c.506+5G>A results in misspliced mRNA [Schuelke et al 2004] (see Table 2; for more information, see Table A). In a multiplex family, a heterozygous contiguous gene deletion including the entire MSTN gene was reported. Some of the individuals in this family who had the heterozygous contiguous gene deletion had increased muscle strength and size [Meienberg et al 2010].
Table 2.
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| Variant Classification | DNA Nucleotide Change
(Alias 1) | Predicted Protein Change | Reference
Sequences |
|---|
|
Benign
| c.163G>A | p.Ala55Thr |
NM_005259.2
NP_005250.1
|
| c.458A>G | p.Lys153Arg |
|
Pathogenic
| c.506+5G>A
(IVS1+5G>A) | -- |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Variant designation that does not conform to current naming conventions
Normal gene product. Myostatin, composed of 375 amino acids, is also known as growth differentiation factor 8 and belongs to the transforming growth factor β superfamily. Myostatin is a negative regulator of muscle growth expressed almost exclusively in developing and adult skeletal muscle [McPherron et al 1997].
Abnormal gene product. The only known causative variant results in no detectable myostatin production. Loss or inhibition of myostatin is associated with increased skeletal muscle growth by muscle fiber hyperplasia and hypertrophy [McPherron et al 1997].
References
Literature Cited
Ferrell RE, Conte V, Lawrence EC, Roth SM, Hagberg JM, Hurley BF. Frequent sequence variation in the human myostatin (GDF8) gene as a marker for analysis of muscle-related phenotypes.
Genomics. 1999;62:203–7. [
PubMed: 10610713]
Grobet L, Martin LJ, Poncelet D, Pirottin D, Brouwers B, Riquet J, Schoeberlein A, Dunner S, Ménissier F, Massabanda J, Fries R, Hanset R, Georges M. A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle.
Nat Genet. 1997;17:71–4. [
PubMed: 9288100]
Kambadur R, Sharma M, Smith TP, Bass JJ. Mutations in myostatin (GDF8) in double-muscled Belgian Blue and Piedmontese cattle.
Genome Res. 1997;7:910–6. [
PubMed: 9314496]
McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member.
Nature. 1997;387:83–90. [
PubMed: 9139826]
Meienberg J, Rohrbach M, Neuenschwander S, Spanaus K, Giunta C, Alonso S, Arnold E, Henggeler C, Regenass S, Patrignani A, Azzarello-Burri S, Steiner B, Nygren AO, Carrel T, Steinmann B, Mátyás G. Hemizygous deletion of COL3A1, COL5A2, and MSTN causes a complex phenotype with aortic dissection: a lesson for and from true haploinsufficiency.
Eur J Hum Genet. 2010;18:1315–21. [
PMC free article: PMC3002852] [
PubMed: 20648054]
Schmidt HH, Genschel J, Baier P, Schmidt M, Ockenga J, Tietge UJ, Pröpsting M, Büttner C, Manns MP, Lochs H, Brabant G. Dyslipemia in familial partial lipodystrophy caused by an R482W mutation in the LMNA gene.
J Clin Endocrinol Metab. 2001;86:2289–95. [
PubMed: 11344241]
Schuelke M, Wagner KR, Stolz LE, Hübner C, Riebel T, Kömen W, Braun T, Tobin JF, Lee SJ. Myostatin mutation associated with gross muscle hypertrophy in a child.
N Engl J Med. 2004;350:2682–8. [
PubMed: 15215484]
Chapter Notes
Author History
Julie S Cohen, ScM, CGC (2013-present)
Nicole Johnson, ScM, CGC; Johns Hopkins School of Medicine (2005-2009)
Kathryn R Wagner, MD, PhD (2005-present)
Revision History
18 April 2019 (ma) Chapter retired: extremely rare
3 July 2013 (me) Comprehensive update posted live
30 April 2009 (me) Comprehensive update posted live
4 October 2005 (me) Review posted live
14 February 2005 (kw) Original submission