Department of Pediatrics (Division of Endocrinology and Metabolism), Baylor College of Medicine, Houston, TX, USA.
Mol Genet Metab. 2012 Jun;106(2):237-40. doi: 10.1016/j.ymgme.2012.04.003. Epub 2012 Apr 11.
Noonan syndrome (NS) is a disorder of RAS- mitogen activated protein kinase (MAPK) pathway with clinical features of skeletal dysplasia. This pathway is essential for regulation of cell differentiation and growth including bone homeostasis. Currently, limited information exists regarding bone mineralization in NS.
Using dual-energy X-ray absorptiometry (DXA), bone mineralization was evaluated in 12 subjects (mean age 8.7 years) with clinical features of NS. All subjects underwent genetic testing which showed mutations in PTPN11 gene (N=8) and SOS1 gene (N=1). In a subgroup of subjects with low bone mass, indices of calcium-phosphate metabolism and bone turnover were obtained.
50% of subjects had low bone mass as measured by DXA. Z-scores for bone mineral content (BMC) were calculated based on age, gender, height, and ethnicity. Mean BMC z-score was marginally decreased at -0.89 {95% CI -2.01 to 0.23; p=0.1}. Mean total body bone mineral density (BMD) z-score was significantly reduced at -1.87 {95% CI -2.73 to -1.0; p=0.001}. Mean height percentile was close to - 2 SD for this cohort, thus total body BMD z-scores were recalculated, adjusting for height age. Adjusted mean total body BMD z-score was less reduced but still significant at -0.82 {95% CI -1.39 to -0.25; p=0.009}. Biochemical evaluation for bone turnover was unremarkable except serum IGF-I and IGF-BP3 levels which were low-normal for age.
Children with NS have a significantly lower total body BMD compared to age, gender, ethnicity and height matched controls. In addition, total BMC appears to trend lower in children with NS compared to controls. We conclude that the metabolic bone disease present resulted from a subtle variation in the interplay of osteoclast and osteoblast activity, without clear abnormalities being defined in the metabolism of either. Clinical significance of this finding needs to be validated by larger longitudinal studies. Also, histomorphometric analysis of bone tissue from NS patients and mouse model of NS may further elucidate the relationship between the RAS-MAPK pathway and skeletal homeostasis.
努南综合征（Noonan syndrome，NS）是一种 RAS-丝裂原活化蛋白激酶（mitogen activated protein kinase，MAPK）通路异常的疾病，具有骨骼发育不良的临床特征。该通路对于细胞分化和生长的调节至关重要，包括骨稳态。目前，关于 NS 中的骨矿化的信息有限。
使用双能 X 射线吸收法（dual-energy X-ray absorptiometry，DXA）评估 12 名具有 NS 临床特征的受试者（平均年龄 8.7 岁）的骨矿化情况。所有受试者均接受基因检测，结果显示 PTPN11 基因（N=8）和 SOS1 基因（N=1）突变。在骨量低的受试者亚组中，获得钙磷代谢和骨转换的指标。
50%的受试者通过 DXA 测量存在骨量低。根据年龄、性别、身高和种族计算骨矿物质含量（bone mineral content，BMC）的 Z 分数。平均 BMC Z 分数略有下降，为-0.89（95%CI-2.01 至 0.23；p=0.1）。平均全身骨密度（bone mineral density，BMD）Z 分数显著降低，为-1.87（95%CI-2.73 至-1.0；p=0.001）。该队列的平均身高百分位数接近-2 SD，因此重新计算了全身 BMD Z 分数，以身高年龄为调整因素。调整后的平均全身 BMD Z 分数仍显著降低，但为-0.82（95%CI-1.39 至-0.25；p=0.009）。骨转换的生化评估无明显异常，除血清 IGF-I 和 IGF-BP3 水平为年龄正常低值。
与年龄、性别、种族和身高匹配的对照组相比，患有 NS 的儿童全身 BMD 显著降低。此外，与对照组相比，儿童的全身 BMC 似乎也呈下降趋势。我们得出结论，代谢性骨病是由于破骨细胞和成骨细胞活性的微妙变化所致，而代谢过程中并没有明确的异常。这一发现的临床意义需要通过更大的纵向研究来验证。此外，NS 患者的骨组织组织学分析和 NS 小鼠模型可能进一步阐明 RAS-MAPK 通路与骨骼稳态之间的关系。
