Noncoding RET variants explain the strong association with Hirschsprung disease in patients without rare coding sequence variant

The pathogenesis of Hirschsprung disease is complex. Although the RET proto-oncogene is the most frequently affected gene in Hirschsprung disease, rare coding sequence variants explain only a small part of Hirschsprung disease cases. We aimed to assess the genetic background of Hirschsprung disease using a genome-wide association analysis combined with sequencing all RET exons in samples from 105 Hirschsprung disease cases (30 familial and 75 sporadic) and 386 controls.As expected, variants in or near RET showed the strongest overall association with Hirschsprung disease and the most statistically significant association was observed when using a recessive genetic model (rs2435357, NC_000010.10:g.43582056T?>?C; genotype TT, OR?=?17.31, P?=?1.462?×?10^?21). Previously published associations in variants in SEMA (rs11766001, NC_000007.13:g.84145202A?>?C; allele C, OR?=?2.268, P?=?0.009533) and NRG1 (rs4541858, NC_000008.10:g.32410309A?>?G; allele G, OR?=?1.567, P?=?0.015; rs7835688, NC_000008.10:g.32411499G?>?C; allele C, OR?=?1.567, P?=?0.015) were also replicated in the genome-wide association analysis. Sequencing revealed a total of 12 exonic RET rare variants. Of these, eight amino acid changing rare variants and two frameshift variants caused or possibly caused Hirschsprung disease.Only a minority of the Hirschsprung disease cases (9/30 familial; 7/75 sporadic) carried one of the rare variants. Excluding the rare variant carriers from the genome-wide association analysis did not appreciably change the association of rs2435357 with Hirschsprung disease. We estimate that approximately two thirds of the sporadic cases may be statistically attributed to the recessive action of the common non-coding RET variants. Thus, even though most cases do not carry rare RET variants, combinations of rare variants and the common non-coding RET variant cause the majority of the cases in our population.     

游离血管化髂骨瓣：26例回顾分析

该文对应用游离髂骨瓣修复颌骨缺损的病例进行回顾研究，并分析手术并发症。作者共用26块髂骨肌瓣、1块髂骨肌皮瓣修复18例下颌骨和8例上颌骨缺损。1例因微血管再灌注问题而导致手术失败：3例术后行组织瓣抢救，其中2例吻合口血栓形成，重新吻合血管后抢救成功；10例术后出现股外侧皮神经支配区皮肤麻木，3例并发切口疝，1例供区创口裂开，2例并发口鼻瘘，1例颈部创口感染，     

Pituitary Gonadotrophic Hormone Synthesis,Secretion, Subunit Gene Expression and Cell Structure in Normal and Follicle‐Stimulating Hormone β Knockout,Follicle‐Stimulating Hormone Receptor Knockout,Luteinising Hormone Receptor Knockout,Hypogonadal and Ovariectomised Female Mice

To investigate the relationship between gonadotroph function and ultrastructure, we have compared, in parallel in female mice, the effects of several different mutations that perturb the hypothalamic‐pituitary‐gonadal axis. Specifically, serum and pituitary gonadotrophin concentrations, gonadotrophin gene expression, gonadotroph structure and number were measured. Follicle‐stimulating hormone β knockout (FSHβKO), follicle‐stimulating hormone receptor knockout (FSHRKO), luteinising hormone receptor knockout (LuRKO), hypogonadal (hpg) and ovariectomised mice were compared with control wild‐type or heterozygote female mice. Serum levels of LH were elevated in FSHβKO and FSHRKO compared to heterozygote females, reflecting the likely decreased oestrogen production in KO females, as demonstrated by the threadlike uteri and acyclicity. As expected, there was no detectable FSH in the serum or pituitary and an absence of expression of the FSHβ subunit gene in FSHβKO mice. However, there was a significant increase in expression of the FSHβ and LHβ subunit genes in FSHRKO female mice. The morphology of FSHβKO and FSHRKO gonadotrophs was not significantly different from the control, except that secretory granules in FSHRKO gonadotrophs were larger in diameter. In LuRKO and ovariectomised mice, stimulation of LHβ and FSHβ mRNA, as well as serum protein concentrations, were reflected in subcellular changes in gonadotroph morphology, including more dilated rough endoplasmic reticula and fewer, larger secretory granules. In the gonadotophin‐releasing hormone deficient hpg mouse, gonadotrophin mRNA and protein levels were significantly lower than in control mice and gonadotrophs were correspondingly smaller with less abundant endoplasmic reticula and reduced numbers of secretory granules. In summary, major differences in pituitary content and serum concentrations of the gonadotrophins LH and FSH were found between control and mutant female mice. These changes were associated with changes in expression of the gonadotrophin subunit genes and were reflected in the cellular structure and secretory granule appearance within the gonadotroph cells.