BACKGROUND The calcium-selective channel TRPV6 (transient receptor potential cation channel subfamily V member 6) is crucial for maternal-fetal calcium transport across the placenta. TRPV6 mutations have recently been associated with an antenatally severe under-mineralising skeletal dysplasia accompanied by postnatal biochemical abnormalities. This is the first post-mortem report in a patient with TRPV6 skeletal dysplasia. CASE PRESENTATION The female infant had severe antenatal and postnatal skeletal abnormalities by 20 weeks gestation and was ventilator-dependent from birth. These skeletal abnormalities were apparent at an earlier gestational age than in previous reported cases and a more severe clinical course ensued. Biochemical and skeletal abnormalities, including bone density, improved postnatally but cardiac arrest at 4 months of age led to withdrawal of intensive care. Compound heterozygous TRPV6 variants (c.1978G > C p.(Gly660Arg) and c.1528C > T p.(Arg510Ter)) were identified on exome sequencing. Post-mortem identified skeletal abnormalities but no specific abnormalities in other organ systems. No placental pathology was found, multi-organ histological features reflected prolonged intensive care only. Post-mortem macroscopic examination indicated reduced thoracic size and short, pale and pliable ribs. Histological examination identified reduced number of trabeculae in the diaphyses (away from the growth plates), whereas metaphyses showed adequate mineralisation and normal number of trabeculae, but with slightly enlarged reactive chondrocytes, indicating post-natal skeletal growth recovery. Post-mortem radiological findings demonstrated improved bone density, improved rib width, healed fractures, although ribs were still shorter than normal. Long bones (especially humerus and femur) had improved from initial poorly defined metaphyses and reduced bone density to sharply defined metaphyses, prominent growth restart lines in distal diaphyses and bone-in-bone appearance along diaphyses. CONCLUSIONS This case provide bone histological confirmation that human skeletal development is compromised in the presence of TRPV6 pathogenic variants. Post-mortem findings were consistent with abnormal in utero skeletal mineralisation due to severe calcium deficit from compromised placental calcium transfer, followed by subsequent phenotypic improvement with adequate postnatal calcium availability. Significant skeletal recovery occurs in the early weeks of postnatal life in TRPV6 skeletal dysplasia.

中文翻译：

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矿物质化骨骼发育不良中瞬时受体电位阳离子通道亚家族V成员6（TRPV6）的验尸组织学提示出生后骨骼恢复：一例。

背景技术钙选择性通道TRPV6（瞬时受体电位阳离子通道亚家族V成员6）对于跨胎盘的母胎钙运输至关重要。最近，TRPV6突变与产前严重矿化不足的骨骼发育异常有关，并伴有产后生化异常。这是TRPV6骨骼发育异常患者的首次尸检报告。病例介绍该女婴在妊娠20周时有严重的产前和产后骨骼异常，并且从出生起就依赖呼吸机。与以前报道的病例相比，这些骨骼异常在更早的胎龄中就很明显，并且随之而来的是更严重的临床过程。生化和骨骼异常，包括骨密度，产后情况有所改善，但4个月大时心脏骤停导致重症监护的撤出。在外显子组测序中鉴定出复合杂合的TRPV6变体（c.1978G> C p。（Gly660Arg）和c.1528C> T p。（Arg510Ter））。验尸确定了骨骼异常，但在其他器官系统中未发现特定异常。没有发现胎盘病理，多器官组织学特征仅反映了长期的重症监护。验尸后的宏观检查显示胸廓缩小，肋骨短，苍白，柔韧。组织学检查发现，干骨中小梁的数量减少了（远离生长板），而干showed端显示出足够的矿化和小梁的正常数量，但反应性软骨细胞略微增大，表明出生后骨骼生长恢复。尸体放射学检查结果显示，尽管肋骨比正常人还短，但骨密度有所改善，肋骨宽度有所改善，骨折已愈合。长骨（特别是肱骨和股骨）已从最初定义不清的干phy端和降低的骨密度改善为清晰定义的干phy端，远侧干phy端明显的生长重新开始线以及沿干dia端的骨中出现。结论该病例提供了骨组织学证实，在存在TRPV6致病性变异的情况下人的骨骼发育受到损害。尸检结果与胎盘钙转移受损引起的严重钙缺乏引起的子宫内骨骼矿化异常一致，随后表型改善，且产后钙供应充足。