Myostatin-related muscle hypertrophy (MRMH) develops because of pathological mutations in the MSTN gene on the long arm of chromosome 2 [1] [2]. MRMH has a strong familial component but can also occur sporadically [3]. Heterozygotic carriers of MRMH-associated mutations present with a milder MRMH phenotype than homozygotes, suggesting an incomplete autosomal dominant mode of inheritance [4].

Myostatin - also called growth/differentiation factor 8 (GDF-8) - downregulates muscle growth in mammals. Loss of myostatin function leads to MRMH, while myostatin overexpression is associated with muscle wasting syndromes [5] [6]. Skeletal muscle overgrowth in MRMH can lead to an effective doubling of muscle tissue volume with a concomitant loss of subcutaneous fat [7] [8]. Additionally, infant MRMH patients can also show increased tendon reflexes and congenital stimulus-induced myoclonus, which should resolve spontaneously after a few months [1].

The effect MRMH-associated muscle growth is still under dispute. While MRMH cases in humans seem to suggest increased physical strength in children [1], detailed histopathological investigations of myostatin-deficient skeletal muscles have revealed a strong predominance of type IIb muscle fibers with tubular aggregates together with a loss of oxidative capacity due to mitochondrial depletion [9].

Hence, MRMH should result in faster muscle contraction and relaxation combined with conserved maximum tetanic force generation but also in impaired long-term intramuscular energy production [9].

• Weakness

  Muscle disorders can cause weakness, pain or even paralysis. [medlineplus.gov]

  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 [ncbi.nlm.nih.gov]

  The strong survive and the weak die. Will China make a super army and take over the world? My imagination could keep going but I will stop here! [strengthathletes.com]

  Muscle-liver-brain-eye nanism Muscle phosphoglycerate mutase deficiency Muscular atrophy-ataxia-retinitis pigmentosa-diabetes mellitus syndrome Muscular channelopathy Muscular dystrophy Muscular dystrophy, Selcen type Muscular dystrophy with progressive weakness [orpha.net]

  Missense; c.T2276C Polymorphism (Rs905938): Associated with height DCST2 protein Transmembrane Glycoprotein Expression Skeletal muscle & ubiquitous Type 1 2 muscle fibers Sarcoplasmic reticulum Clinical Strength Early: Above average Disease progression: Weakness [neuromuscular.wustl.edu]

• Swelling

  Onset Age: 1st decade Swellings: Warm & Tender Course Progressive or Regress Calcification (Progressive heterotopic endochondral ossification (HEO)) Forms qualitatively normal bone Between muscles, Across joints Common locations Early: Dorsal, Axial [neuromuscular.wustl.edu]

• Lactose Intolerance

  He also had eczema, enlarged kidneys, was lactose intolerant and had severe stomach reflux that made him vomit several times each day, his mother said. [trulyhuge.com]

• Regurgitation

  1,271 satisfied customers My 77 yr old dad recently had an echocardiogram that showed my 77 yr old dad recently had an echocardiogram that showed moderate to severe concentric left ventricular hypertrophy with some aortic valve scherosis, mild valve regurgitation [justanswer.com]

  […] mechanism Mitochondrial protein import disorder Mitochondrial pyruvate carrier deficiency Mitochondrial spinocerebellar ataxia with epilepsy Mitochondrial substrate carrier disorder Mitochondrial trifunctional protein deficiency Mitral atresia Mitral regurgitation-deafness-skeletal [orpha.net]

• Increased Muscle Mass

  Heterozygotes may have increased muscle mass. [ncbi.nlm.nih.gov]

  People with a mutation in both copies of the gene in each cell (homozygotes) have significantly increased muscle mass and strength. [en.wikipedia.org]

  People with a mutation in both copies of the MSTN gene in each cell (homozygotes) have significantly increased muscle mass and strength. [ghr.nlm.nih.gov]

• Long Arm

  Myostatin-related muscle hypertrophy (MRMH) develops because of pathological mutations in the MSTN gene on the long arm of chromosome 2. MRMH has a strong familial component but can also occur sporadically. [symptoma.com]

• Muscle Weakness

  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 [ncbi.nlm.nih.gov]

• Myoclonus

  He initially displayed stimulus-induced myoclonus that subsided after two months. The relationship between myoclonus and the MSTN causative variant is not clear. [ncbi.nlm.nih.gov]

  Additionally, infant MRMH patients can also show increased tendon reflexes and congenital stimulus-induced myoclonus, which should resolve spontaneously after a few months. The effect MRMH-associated muscle growth is still under dispute. [symptoma.com]

  […] ataxia-deafness syndrome Myoclonus-dystonia syndrome Myoclonus epilepsy and ataxia due to potassium channel mutation Myoclonus epilepsy associated with ragged-red fibres Myoclonus epilepsy in non-progressive encephalopathies Myoclonus-nephropathy syndrome [orpha.net]

  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. [tetongravity.com]

• Dystonia

  Extraordinary Humans: Muscles NGC investigates the science of muscle by taking us on a journey inside the bodies of two remarkable humans with startling genetic conditions. 31-year old Jason Dunn lives with Dystonia, a... [webtalya.com]

  […] chronic progressive external ophthalmoplegia Maternally-inherited CPEO Maternally-inherited diabetes and deafness Maternally-inherited infantile subacute necrotizing encephalopathy Maternally-inherited Leigh disease Maternally-inherited mitochondrial dystonia [orpha.net]

  Home, Search, Index, Links, Pathology, Molecules, Syndromes, Muscle, NMJ, Nerve, Spinal, Ataxia, Antibody & Biopsy, Patient Info LARGE OR PROMINENT MUSCLES Overusage Neural Myokymia / Neuromyotonia Isaac's Syndrome Schwartz-Jampel Dystonia & Athetosis [neuromuscular.wustl.edu]

• Headache

  He's a real headache and a half. So - per the child of the original post - I don't feel sorry for the kid. I feel sorry for the kids parents! Talk about a kid who can really give a headache. [theringlord.org]

• Paresis

  Clinical Muscle hyperplasia 1st branchial arch: Includes muscles of facial expression & orbicularis oculi 2nd branchial arch: Includes muscles of mastication No evidence of hyperplasia of bone or other organ systems on side of the face Facial nerve: Paresis [neuromuscular.wustl.edu]

Diagnosis of MRMH rests on a thorough analysis of the family history, clinical findings, imaging techniques, and genetic testing for MSTN mutations as well as genetic counseling [10].

These discussions should explain the hereditary nature of MRMH to the parents of the infant patient and recommend genetic tests not only for their progeny but also for themselves. Parent testing allows a distinction between a hereditary or sporadic occurrence. In case of a parent mutation carrier, further genetic tests of the patient's siblings should be performed [10].

Clinical findings in MRMH are evident at birth because functional myostatin restrains perinatal skeletal muscle growth. Significant muscle overgrowth on thighs and upper arms, insufficient fat pads, and increased tendon reflexes are hallmark signs in infants [1] [11].

Muscle hypertrophy can be visualized with imaging techniques like ultrasonography, magnetic resonance imaging (MRI) or dual energy X-ray absorptiometry (DXA). On the other hand, loss of subcutaneous fat can be revealed with MRI or simply with a caliper [1] [10].

Long-term prophylactic monitoring of cardiac function may be advisable [1].

Genetic testing is required to support the clinical diagnosis. Mutations in the MSTN gene can be shown with polymerase-chain-reaction (PCR) - assisted restriction analysis [1].

1. Schuelke M, Wagner KR, Stolz LE, et al. Myostatin Mutation Associated with Gross Muscle Hypertrophy in a Child. N Engl J Med. 2004; 350:2682-2688.
2. McPherron AC, Lee SJ. Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci USA. 1997;94(23):12457-12461.
3. Szabo G, Dallmann G, Muller G, Patthy L, Soller M, Varga L. A deletion in the myostatin gene causes the compact (Cmpt) hypermuscular mutation in mice. Mamm Genome. 1998;9(8):671-672.
4. Amthor H, Huang R, McKinnell I, et al. The regulation and action of myostatin as a negative regulator of muscle development during avian embryogenesis. Dev Biol. 2002;251(2):241-257.
5. Zimmers TA, Davies MV, Koniaris LG, et al. Induction of cachexia in mice by systemically administered myostatin. Science. 2002;296(5572):1486-1488.
6. Gonzalez-Cadavid NF, Taylor WE, Yarasheski K, et al. Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting. Proc Natl Acad Sci USA. 1998; 95(25): 14938-14943.
7. Grobet L, Martin LJR, Poncelet D, et al. A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nat Genet. 1997;17(1):71-74.
8. Lin J, Arnold HB, Della-Fera MA, Azain MJ, Hartzell DL, Baile CA. Myostatin knockout in mice increases myogenesis and decreases adipogenesis. Biochem Biophys Res Commun. 2002;291(3):701-706
9. Amthor H, Macharia R, Navarrete R, et al. Lack of myostatin results in excessive muscle growth but impaired force generation. Proc Nat Acad Sci USA. 2007;104(6):1835-1840.
10. Wagner KR, Cohen JS. Myostatin-Related Muscle Hypertrophy. 2005. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. Seattle, WA: University of Washington, Seattle; 1993-2017. https://www.ncbi.nlm.nih.gov/books/NBK1498/?report=reader. Accessed Nov 7th, 2017.
11. McPherron AC, Lee SJ. Suppression of body fat accumulation in myostatin-deficient mice. J Clin Invest. 2002;109(5):595-601.