Corsi Alessandro, Cherman Natasha, Donaldson David L, Robey Pamela G, Collins Michael T, Riminucci Mara
Department of Molecular Medicine Sapienza University Rome Italy.
Skeletal Biology Section National Institute of Dental and Craniofacial Research National Institutes of Health Bethesda MD USA.
JBMR Plus. 2019 Jan 15;3(8):e10134. doi: 10.1002/jbm4.10134. eCollection 2019 Aug.
Somatic gain-of-function mutations of cause a spectrum of clinical phenotypes, ranging from McCune-Albright syndrome (MAS) to isolated disease of bone, endocrine glands, and more rarely, other organs. In MAS, a syndrome classically characterized by polyostotic fibrous dysplasia (FD), café-au-lait (CAL) skin spots, and precocious puberty, the heterogenity of organ involvement, age of onset, and clinical severity of the disease are thought to reflect the variable size and the random distribution of the mutated cell clone arising from the postzygotic mutation. We report a case of neonatal MAS with hypercortisolism and cholestatic hepatobiliary dysfunction in which bone changes indirectly emanating from the disease genotype, and distinct from FD, led to a fatal outcome. Pulmonary embolism of marrow and bone fragments secondary to rib fractures was the immediate cause of death. Ribs, and all other skeletal segments, were free of changes of typical FD and fractures appeared to be the result of a mild-to-moderate degree of osteopenia. The mutated allele was abundant in the adrenal glands and liver, but not in skin, muscle, and fractured ribs, where it could only be demonstrated using a much more sensitive PNA hybridization probe-based FRET (Förster resonance energy transfer) technique. Histologically, bilateral adrenal hyperplasia and cholestatic disease matched the abundant disease genotype in the adrenals and liver. Based on this case and other sporadic reports, it appears that gain-of-function mutations of underlie a unique syndromic profile in neonates characterized by CAL skin spots, hypercortisolism, hyperthyroidism, hepatic and cardiac dysfunction, and an absence (or latency) of FD, often with a lethal outcome. Taken together, our and previous cases highlight the phenotypic severity and the diagnostic and therapeutic challenges of MAS in neonates. Furthermore, our case specifically points out how secondary bone changes, unrelated to the direct impact of the mutation, may contribute to the unfavorable outcome of very early-onset MAS.
[基因名称]的体细胞功能获得性突变会引发一系列临床表型,从McCune-Albright综合征(MAS)到孤立性骨病、内分泌腺疾病,较少见的还有其他器官疾病。在MAS中,该综合征的典型特征为多骨型纤维发育不良(FD)、牛奶咖啡斑(CAL)皮肤斑和性早熟,疾病累及器官的异质性、发病年龄和临床严重程度被认为反映了合子后突变产生的突变细胞克隆的大小差异和随机分布。我们报告一例新生儿MAS,伴有皮质醇增多症和胆汁淤积性肝胆功能障碍,其中由疾病基因型间接引发且不同于FD的骨骼变化导致了致命结局。肋骨骨折继发的骨髓和骨碎片肺栓塞是直接死因。肋骨以及所有其他骨骼部位均无典型FD的变化,骨折似乎是轻度至中度骨质减少的结果。突变等位基因在肾上腺和肝脏中丰富,但在皮肤、肌肉和骨折的肋骨中不存在,在后者中只能使用基于肽核酸(PNA)杂交探针的更灵敏的荧光共振能量转移(FRET)技术才能检测到。组织学上,双侧肾上腺增生和胆汁淤积性疾病与肾上腺和肝脏中丰富的疾病基因型相符。基于该病例及其他散发病例报告,似乎[基因名称]的功能获得性突变构成了新生儿独特的综合征特征,其特点为CAL皮肤斑、皮质醇增多症、甲状腺功能亢进、肝脏和心脏功能障碍以及FD缺失(或隐匿),通常伴有致命结局。综合我们的病例和既往病例,突出了新生儿MAS的表型严重性以及诊断和治疗挑战。此外,我们的病例特别指出了与突变的直接影响无关的继发性骨骼变化可能如何导致极早发型MAS的不良结局。