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Abstract：
Dysosteosclerosis (DSS), the term coined in 1968 for ultrarare dysplasia of the skeleton featuring platyspondyly with focal appendicular osteosclerosis, has become generic by encompassing the genetic heterogeneity recently reported for this phenotype. We studied four unrelated Turkish patients with DSS to advance understanding of the new nosology. Patient 1 suffered femur fractures beginning at age 1 year. DSS was suspected from marked metaphyseal osteosclerosis in early childhood and subsequently platyspondyly accompanying patchy osteosclerosis of her appendicular skeleton. She harbored in SLC29A3, in 2012 the first gene associated with DSS, a unique homozygous duplication (c.303_320dup, p.102_107dupYFESYL). Patient 2 presented similarly with fractures and metaphyseal osteosclerosis but with no platyspondyly at age 2 months. She was homozygous for a novel nonsense mutation in SLC29A3 (c.1284C>G, p.Tyr428*). Patient 3 had ocular disease at age 2 years, presented for short stature at age 11 years, and did not begin to fracture until age 16 years. Radiographs showed mild platyspondyly and focal metaphyseal and femoral osteosclerosis. She was homozygous for a unique splice site mutation in TNFRSF11A (c.616+3A>G). Patient 4 at age 2 years manifested developmental delay and frequent infections but did not fracture. He had unique metadiaphyseal splaying and osteosclerosis, vertebral end-plate osteosclerosis, and cortical thinning of long bones but no mutation was detected of SLC29A3, TNFRSF11A, TCIRG1, LRRK1, or CSF1R associated with DSS. We find that DSS from defective SLC29A3 presents earliest and with fractures. DSS from compromised TNFRSF11A can lead to optic atrophy as an early finding. Negative mutation analysis in patient 4 suggests further genetic heterogeneity underlying the skeletal phenotype of DSS. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
摘要：
强肌硬化(DSS),该术语于1968年创造，用于描述骨骼的异常发育不良，其特征是伴有局灶性阑尾骨硬化，通过涵盖最近报道的这种表型的遗传异质性，已经变得普遍。我们研究了四名与DSS无关的土耳其患者，以增进对新疾病的了解。患者1在1岁时开始遭受股骨骨折。怀疑DSS在儿童早期因明显的干phy端骨硬化而出现，随后伴有附肢骨骼的斑片状骨硬化。2012年，她在SLC29A3中拥有第一个与DSS相关的基因，一个独特的纯合重复(c.303_320dup，p.102_107dupYFESYL)。患者2在2个月大时表现为类似的骨折和干phy端骨质硬化，但没有颅骨畸形。她是SLC29A3中一种新的无义突变的纯合子（c.128C>G，p.Tyr428*)。患者3在2岁时患有眼部疾病，在11岁时因身材矮小而被提出，直到16岁才开始骨折。X线照片显示轻度颈椎病和局灶性干phy端和股骨骨硬化。她对于TNFRSF11A中的独特剪接位点突变是纯合的(c.616+3A>G)。患者4在2岁时表现出发育延迟和频繁感染,但没有骨折。他有独特的骨折后骨折和骨硬化，椎体终板骨硬化，和长骨皮质变薄，但未检测到SLC29A3，TNFRSF11A的突变，与DSS关联的TCIRG1、LRRK1或CSF1R。我们发现来自有缺陷的SLC29A3的DSS出现最早且具有骨折。作为早期发现，来自受损TNFRSF11A的DSS可导致视神经萎缩。4例患者的阴性突变分析提示DSS骨骼表型的进一步遗传异质性。©2022作者JBMRPlus由WileyPeriodicalsLLC代表美国骨骼和矿物研究学会出版。
