Discussion:
In this report, we described a case of NS that developed during follow-up for AA with monosomy 7 without HSCT. We performed a literature review of cases with both diseases, and analyzed genetic factors that may predispose to their onset.
Previous studies have reported that clonal evolution is a major complication for AA treated with IST2), 3). Patel et al. reported that in a large cohort of 666 adult subjects with severe AA treated with IST, monosomy 7 appeared in 38 subjects, and 33 of the 38 subjects developed it within 5 years of starting IST4).
NS has been described as a clinical form of chronic GVHD, but only a limited number of cases have been reported1). Kim et al. reported that a 13-year-old Asian boy developed NS 22 months after allogeneic HSCT for severe AA possibly due to the effects of chronic GVHD5). Our case developed NS during IST alone without HSCT for AA, and to the best of our knowledge, there has been only one report of a case with a similar course in the past. Abrams et al. reported a case of 9-year-old boy who presented NS that was pathologically diagnosed as minimal change NS, and that gradually progressed to concurrent idiopathic AA6). Prior to the diagnosis of AA, he had frequent relapses of NS. However, after the start of IST for AA, the NS remained in remission. Unfortunately, no information about monosomy 7 was presented in this report.
Recently, several groups have reported germlineSAMD9/9Lmut in addition to somaticGATA2mut as a predisposing factor for cytopenia, bone marrow failure, and myelodysplastic syndrome with non-random monosomy 7 or deletion of 7q7). Sahoo et al. reported that almost half of the myelodysplastic syndrome patients with monosomy 7 or del(7q) carried mutations in eitherSAMD9/9Lmut (21%) orGATA2mut mutations (30%)8). They reported that the prevalence of GATA2mutincreased with age, whereas SAMD9/9Lmut were found at similar frequencies across all age groups. Recently, there was a case report of a girl with myelodysplasia, infection, growth restriction, adrenal hypoplasia, genital phenotypes, and enteropathy (MIRAGE) syndrome caused by a gain-of-function mutation in theSAMD9 gene on chromosome 7 who developed steroid-resistant NS9).
Based on this background, we examined the case for such genetic abnormalities, but there were no somatic/germline gene mutations inSAMD9/9Lmut orGATA2mut in our case. The genetic factors associated with hematopoietic failure and NS are currently unknown, but it is possible that some common genetic factors exist, because the patient developed NS when the proportion of cells with monosomy 7 was increased. The prognosis of the patient appears favorable at this point, but it will be necessary to carefully monitor the rate of IST tapering, in the future, including consideration of hematopoiesis and the proportion of cells with monosomy7.
In conclusion, this is the first detailed report of NS associated with AA that was treated without HSCT. Some common immunological and genetic factors might be involved in the development of both AA and NS. Identification of these factors is expected in the future with the accumulation of data from more cases of AA and NS.