Myostatin-related muscle hypertrophy (MRMH) is a rare genetic disorder with an incomplete autosomal dominant mode of inheritance. It is caused by deletions in the intron of the MSTN gene located on chromosome 2q32.2.
Causative mutations lead to a loss of myostatin function which results in significant skeletal muscle growth accompanied by loss of subcutaneous fat tissue. Characteristic MRMH symptoms are evident at birth. Increased muscle mass in MRMH does not necessarily entail augmented physical strength.
Diagnosis is based on clinical findings and supported by genetic tests. Genetic counseling is advisable due to the familial nature of MRMH.
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].
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].