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Hidden in plain sight: Satoyoshi syndrome

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By Warren R. Heymann, MD
Feb. 19, 2018

I was inspired by the conclusion of a report detailing an 11 year-old boy from India diagnosed Satoyoshi syndrome: "We present this case to emphasize the importance of recognizing Satoyoshi syndrome, which could go unnoticed if not suspected." (1)

I have never suspected Satoyoshi syndrome (SS) because I never heard of it. The purpose of this commentary is to become familiar with this rare condition (approximately 60 cases have been reported since it was first described). Although a prior post discussed when to screen patients with alopecia areata for autoimmune thyroid disease (“Adjusting the Screen Door: Developing a Rational Approach to Assessing for Thyroid Disease in Patients with Alopecia Areata”, January 11, 2018), it should be remembered that there are other associated autoimmune diseases that may be associated with alopecia areata — SS is one.

According to Montanaro et al, Eijiro Satoyoshi and Kaneo Yamada first described SS in Tokyo in 1967. SS is also known as Komuragaeri disease (which translates to calf spasm), and it usually has a progressive course. SS is characterized by painful muscle spasms, alopecia [usually alopecia totalis or universalis], diarrhea, secondary bone deformities and various endocrine abnormalities. Orthopedic issues (such as acro-osteolysis, early osteoarthrosis, bone fragmentation at tendinous insertions, fatigue fractures, and residual joint deformity) and endocrine disorders are more common in children. (2)

SS has now been described worldwide. Most patients display the first signs and symptoms in the first or second decade of life, although adult onset may occur. Characteristically, alopecia appears first, although in 10% of patients, muscle spasm precedes hair loss.

Rudnicka et al have proposed diagnostic criteria for SS. The obligatory criterion is severe hair loss such as alopecia totalis. At least two of the following are necessary to establish the diagnosis: a) intermittent painful muscle spasms; b) diarrhea; c) positive antinuclear antibodies (ANA).

The muscle spasms have been described as “myokymia”, which are involuntary, spontaneous, localized fasciculations of a few muscles, or bundles within a muscle, but are insufficient to move a joint. In most cases these spasms are limited to the lower extremities, although they may involve all muscle groups; they usually last 30 seconds to a few minutes, occurring 5 to 15 times a day. (3) Electrophysiological studies suggest that these “spasms” may be secondary to peripheral nerve hyperexcitability. (4)

Diarrhea occurs in approximately two-thirds of patients, resulting in nutritional deficiency and growth retardation. Skeletal abnormalities occur in a similar number of patients, although not in adults. Multiple autoimmune diseases, including, but not limited to myasthenia gravis or idiopathic thrombocytopenia, may be associated. Rucnicka et al suggest that two subtypes of SS be considered: ANA-positive SS, that generally responds to steroid therapy, and ANA-negative SS with a less favorable prognosis. (3)

Corticosteroids remain the mainstay of treatment, with adjuvants including cyclosporine [and other immunosuppressive agents], phenytoin, diazepam, dantrolene sodium [a muscle relaxant], and plasmapheresis also reported as effective in the reduction of diarrhea and neuromuscular symptoms. Significant improvement in alopecia, diarrhea, and the frequency of muscle spasms has been noted in all ANA-positive patients treated with corticosteroids. However, only 50% of ANA-negative patients responded to this line of treatment. Neuromuscular symptoms reportedly respond within 2-4 weeks and hair regrowth is seen after 3-4 months. (1)

The etiology of SS is unknown. Although considered a sporadic autoimmune disease, rare autosomal recessive cases have been reported. Solera et al performed exome sequencing on a 28 year-old woman with SS and her parents. They identified a missense variant in the ZNF808 gene is located in the long arm of chromosome 19 long arm, encoding a 903 amino acid zinc finger with 24 zinc finger motifs and one Kruppel associated box domain (KRAB). This finding connects ZNF proteins with the immune system and suggests an impairment in function compatible with autoimmune diseases such as SS. (5)

When assessing patients with severe alopecia areata, I usually inquire about a personal or family history of autoimmune diseases such as thyroid disease and diabetes. In my directed review of systems, muscle spasms and diarrhea will now be added to the list.

1. Mani V, George R. Satoyoshi syndrome — A case report from India. Pediatr Dermatol 2017; 34: e296-8.
2. Montanaro VV, et al. Adult-onset Satoyoshi syndrome in a young male. Neuromuscul Disord 2017; 27: 382-4.
3. Rudnicka L, et al. Alopecia areata. How not to miss Satoyoshi syndrome? J Dermatol 2014; 41: 951-6.
4. Aghoram R. Adult-onset Satoyoshi syndrome and response to plasmapheresis. Ann Indian Acad Neurol 2016; 19: 131-3.
5. Solera J, et al. A newly homozygous variant in ZNF808: A possible candidate gene for Satoyoshi syndrome. J Neurol Sci 2017; 379: 226-8.

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