Muscle & peripheral nerve nontumor

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Contributed by Chunyu Cai, M.D., Ph.D.

Case 1: 70 year old man with genetically confirmed FSHD1 (8 D4Z4 repeats on a 4qA haplotype)



Case 2: 63 year old woman with genetically confirmed FSHD1 (2 D4Z4 repeats on a 4qA haplotype)


Case 3: 66 year old man with heterozygous pathogenic mutation of SMCHD1 and a FSHD phenotype, consistent with FSHD2

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A 63 year old woman presented with progressive weakness over the last 10 years. She initially presented with stooped posture that progressed to head drop followed by proximal arm and leg weakness. No significant distal weakness. She had been treated with steroid therapy for the past few years with no significant improvement. Laboratory study showed mildly elevated creatine kinase (CK, 350 IU). Myositis panel, HMG CoA autoantibody, myasthenia gravis panel were all negative. A muscle biopsy shows a chronic myopathy with inflammation (figure 1) and prominent lobulated myofiber architecture (figure 2). Which of the following is the most likely diagnosis?

1. Facioscapulohumeral muscular dystrophy
2. Immune mediated necrotizing myopathy
3. Mitochondria myopathy
4. Neurogenic atrophy
5. Sporadic inclusion body myositis

A. Facioscapulohumeral muscular dystrophy (FSHD). This case illustrates a typical presentation and muscle pathology of a FSHD patient. Answer E is incorrect because sporadic inclusion body myositis (sIBM) patients usually have both proximal and distal weakness. The inflammation on muscle biopsy is usually endomysial predominant, not perimysial / perivascular. Answer B is incorrect because these patients usually have high CK and positive HMG CoA or SRP antibodies. Also, muscle usually shows a necrotizing myopathy. These patients usually respond to steroid therapy. Answer D is incorrect because neurogenic atrophy usually does not show dystrophic changes and widespread lobulated changes in myofibers. Answer C is incorrect because patients with mitochondria abnormality usually present with exercise intolerance or rhabdomyolysis. Muscle pathology is characterized by ragged red fibers on Gomori trichrome and COX deficient fibers on COX / SDH stains but usually no dystrophic changes.

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Reference: Facioscapulohumeral muscular dystrophy

A 63 year old woman presented with progressive weakness over the last 10 years. She initially presented with stooped posture that progressed to head drop followed by proximal arm and leg weakness. No significant distal weakness. She had been treated with steroid therapy for the past few years with no significant improvement. Laboratory study showed mildly elevated creatine kinase (CK, 350 IU). Myositis panel, HMG CoA autoantibody, myasthenia gravis panel were all negative. A muscle biopsy shows a chronic myopathy with inflammation (figure 1) and prominent lobulated myofiber architecture (figure 2). What is the next step to confirm the diagnosis?

1. Muscle MRI
2. Muscular dystrophy immunostaining panel
3. Neuromuscular next generation sequencing (NGS) panel
4. Specific FSHD gene testing

D. Specific FSHD gene testing. Diagnosis of FSHD requires a specific genetic test that usually involves restriction enzyme digestion and Southern blot analysis that interrogates the size of the D4Z4 domain. Answer B is incorrect because the FSHD protein abnormality (DUX4 aberrant expression) is of very low amount and cannot be detected by immunohistochemistry. Answer C is incorrect because most neuromuscular NGS panels cannot detect D4Z4 domain retraction and thus fail to detect FSHD. Answer A is incorrect because muscle MRI can only be used to monitor fatty replacement and disease progression once the diagnosis has been confirmed. The MRI finding itself is not specific enough to definitively diagnose FSHD.

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Reference: Facioscapulohumeral muscular dystrophy