The MLL gene is a site of frequent rearrangement in acute leukemia with multiple fusion partners, but MLL-SEPT6 rearrangement is rare in clinical leukemia practice, and only 13 cases have been reported. We describe the case of an acute myelogenous leukemia child with MLL-SEPT6 rearrangement whose age of onset and accompanying gene mutations differs from previous reports. Considering the poor prognosis of leukemia children with MLL-SEPT6 rearrangement and the unsatisfactory results of existing treatments, the study of this case may provide new theories for diagnosis and treatment of MLL-SEPT6-associated childhood acute leukemia.

Extensive limb lengthening (ELL) was completed in 75 patients: 66 achondroplasia and 9 hypochondroplasia. The average lengthening was 27cm for achondroplasia (12-40cm) and 17cm for hypochondroplasia (range 10-25cm). There were 48 females and 27 males. Lengthening was done either by 2-segment (14 patients; both tibias and/or both femurs) or by serial 4-segment lengthenings (64 patients; both femurs and tibias same time). Most patients also had bilateral humeral lengthening. Lengthenings were either juvenile-onset (31), adolescent-onset (38) or adult-onset (6). The average age at final follow-up was 26 years old (range 17-43 years). There were few permanent sequelae of complications. The most serious was one paraparesis. All patients returned to activities of normal living and only one was made worse by the surgery (paraparesis). This is the first study to show that ELL can lead to increase of height into the normal height range. Previous studies showed mean increases of height of up to 20cm, while this study consistently showed an average increase of 30 cm (range 15-40cm) for juvenile-onset and increase of 26cm (range 15-30cm) for adolescent-onset. This results in lower normal height at skeletal maturity for males and females. The adult-onset had a mean increase of 16.8 (range 12-22cm). This long-term follow-up study shows ELL can be done safely even with large lengthenings and that 4-segment lengthening may offer advantages over 2-segment lengthening. While the majority of cases were performed using external fixation, implantable limb lengthening promises to be an excellent alternative and perhaps an improvement.

Advanced paternal age increases the risk of transmitting de novo germline mutations, particularly missense mutations activating the receptor tyrosine kinase (RTK) signaling pathway, exemplified by the FGFR3 mutation linked to achondroplasia (ACH). This risk is attributed to the expansion of spermatogonial stem cells carrying the mutation, forming sub-clonal clusters in the ageing testis, thereby increasing the frequency of mutant sperm and the number of affected offspring from older fathers. While prior studies proposed a correlation between sub-clonal cluster expansion in the testis and elevated mutant sperm production in older donors, limited data exist on the universality of this phenomenon. Our study addresses this gap by examining the testis expansion patterns, as well as increases of mutations in sperm for two FGFR3 variants: c.1138G>A (p.G380R) and c.1948A>G (p.K650E)- associated with ACH or thanatophoric dysplasia (TDII), respectively. Unlike the ACH mutation, which showed sub-clonal expansion events in an aged testis and a significant increase of mutant sperm with the donor’s age, the TDII mutation formed sub-clonal clusters, but exhibited reduced transmission into sperm and no significant age-related increase. The mechanism behind this divergence remains unclear, suggesting potential pleiotropic effects of aberrant RTK signaling in the male germline, possibly hindering differentiation requiring meiosis. This study provides further insights into transmission risks of micro-mosaics associated with advanced paternal age in the male germline.