背景:进行性骨异型增生(POH)是一种罕见的,以皮肤和肌肉异位骨化为特征的衰弱性疾病,导致关节挛缩和功能逐渐丧失。虽然60-70%的POH患者具有父系遗传,在GNAS中灭活致病变异,其余的30-40%没有已知的病因。FAM111B致病变异,位于染色体11q12.1上,导致POIKTMP(遗传性纤维性真皮病伴肌腱挛缩,肌病,和肺纤维化),一个非常罕见的,具有高频率从头错义致病变异的常染色体显性疾病,影响多个组织和器官,导致广泛的纤维化和肌肉脂肪,虽然确切的机制是未知的。据我们所知,没有FAM111B与POH相关的报告。我们描述了与FAM111B中的新型从头移码致病变体相关的POH表型的第一例,并对这种基因组破坏引起的蛋白质结构和功能进行了分析。
方法:一名15岁的非裔美国男性,表现为全身性钙化结节,进行性挛缩,肌肉无力导致不活动,从6岁开始。皮肤检查显示广泛的硬结节,从小到斑块状溃疡爆发的皮肤病变。生化评估显示25(OH)维生素D不足(20ng/mL),和正常水平的甲状旁腺激素,FGF-23,碱性磷酸酶,钙,和磷。胸部的骨骼检查射线照片和计算机断层扫描(CT),腹部,和骨盆显示广泛的软组织和肌肉异位骨化累及肩部,腋窝,树干,腹部,骨盆,上肢和下肢,成团的,肌肉内的砾岩分布,皮下脂肪,在一些延伸到皮肤的区域。胸部CT未见肺纤维化。临床和影像学检查结果与POH最一致。三临床外显子组测序显示FAM111B(OMIM#615584)中存在从头杂合的可能致病变异(c.1462delT[p.Cys488Valfs*21])。外显子4中产生的移码变化用21个替代氨基酸替换了C末端区域。多个,先前报道的疾病相关变体似乎位于该变体发生的胰蛋白酶样半胱氨酸/丝氨酸肽酶结构域内,支持该地区的功能意义,尽管以前没有报道与POH表型相关。我们的3D蛋白质建模显示了预测的蛋白质折叠和结构的消除,消除锌结合域,可能严重影响蛋白质功能。
结论:这是FAM111B中与新的从头致病性移码变异相关的POH表型的首例病例。FAM111B的移码变化是否预测POH尚不清楚。进一步的评估对于充分阐明这一发现以及FAM111B变体促成POH表型的潜在作用和机制是必要的。
Progressive osseous heteroplasia (POH) is a rare, debilitating disorder characterized by heterotopic ossification in the skin and muscles, resulting in contractures of the joints and progressive loss of function. While 60-70% of the POH patients have paternally inherited, inactivating pathogenic variants in GNAS, the remaining 30-40% have no known etiology. FAM111B pathogenic variants, located on chromosome 11q12.1, cause POIKTMP (hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis), a very rare, autosomal-dominant disorder with high frequency of de novo missense pathogenic variants, which affects multiple tissues and organs, causing extensive fibrosis and muscle adiposis, though the exact mechanism is unknown. To our knowledge, there are no reports of FAM111B associated with POH. We describe the first case of POH phenotype associated with a novel de novo frameshift pathogenic variant in the FAM111B and present an analysis of the protein structure and function caused by this genomic disruption.
A 15-year-old African-American male presented with generalized calcific nodules, progressive contractures, and muscle weakness leading to immobility, beginning at 6 years of age. Cutaneous examination showed generalized hard nodules varying from small to plaque-like ulcerated erupted skin lesions. Biochemical evaluation revealed 25(OH) vitamin D insufficiency (20 ng/mL), and normal levels of parathyroid hormone, FGF-23, alkaline phosphatase, calcium, and phosphorus. Skeletal survey radiographs and computed tomography (CT) of the chest, abdomen, and pelvis showed extensive soft tissue and muscle heterotopic ossifications involving shoulders, axillae, trunk, abdomen, pelvis, upper and lower extremities, in a clumped, conglomerate distribution within muscle, subcutaneous fat, and in some areas extending to the skin. There was no pulmonary fibrosis on the chest CT. The clinical and radiographic findings were most consistent with POH. A trio-clinical exome sequencing revealed a de novo heterozygous likely pathogenic variant in the FAM111B (OMIM # 615584) (c.1462delT [p.Cys488Valfs*21]). The resulted frameshift change in exon 4 replaced C-terminal region with 21 alternative amino acids. Multiple, previously reported disease-associated variants appear to localize within the trypsin-like cysteine/serine peptidase domain in which this variant occurs, supporting the functional significance of this region, though none have been previously reported to be associated with POH phenotype. Our 3D protein modeling showed obliteration of predicted protein folding and structure, and elimination of the zinc-binding domain, likely severely affecting protein function.
This is the first case of POH phenotype associated with a novel de novo pathogenic frameshift variant in FAM111B. Whether the frameshift change in FAM111B predicts POH remains unclear. Further evaluations are necessary to fully elucidate this finding and the potential role and mechanism by which the FAM111B variants contributes to POH phenotype.