Division of Pediatric Endocrinology, MCCD 3044A, D820, 1601 NW 12th Avenue, Miami, Florida 33136.
J Clin Endocrinol Metab. 2011 Sep;96(9):E1507-11. doi: 10.1210/jc.2011-1411. Epub 2011 Jul 13.
Pseudohypoparathyroidism (PHP) types 1a and 1b are distinguished by clinical, biochemical, and molecular features. We report extended kindred with PHP 1b in which many affected members also had growth plate defects, including brachydactyly and a Madelung-like deformity.
Analyses included clinical examination, assessment of mineral metabolism, thyroid function, skeletal radiography, and analysis of the GNAS and STX16 genes.
Patients were studied in an academic medical center.
We studied 37 members of a family in which PHP 1b occurred in 23 individuals. Ten of 17 affected patients who were examined had brachydactyly E, including two subjects with Madelung-like defects. Five of 16 subjects had subclinical hypothyroidism; no subject showed sc ossification or short stature. None of the unaffected members had brachydactyly or an elevated serum level of PTH or TSH. Levels of immunoactive erythrocyte Gα(s) were normal in two affected subjects tested. Linkage analysis indicated linkage between PTH resistance and the GNAS gene locus; however, no mutations were identified in GNAS exons 1-13. Methylation analysis of genomic DNA from affected subjects showed loss of maternal epigenotype in exon 1A with normal methylation of the differentially methylated regions for XLGαs and NESP55, and PCR demonstrated heterozygosity for a 3.0-kb deletion in the STX16 gene.
The segregation of brachydactyly with PHP 1b in this family indicates that an imprinting defect in GNAS can lead to growth plate defects, including brachydactyly and Madelung deformity. These features suggest that GNAS signaling plays a more extensive role in chondrocyte maturation than previously thought.
假性甲状旁腺功能减退症（PHP）1a 型和 1b 型通过临床、生化和分子特征进行区分。我们报告了一个 PHP 1b 扩展家族，其中许多受影响的成员也有生长板缺陷，包括短指畸形和马德隆样畸形。
分析包括临床检查、矿物质代谢评估、甲状腺功能、骨骼放射照相以及 GNAS 和 STX16 基因分析。
患者在学术医疗中心接受研究。
我们研究了一个家族的 37 名成员，其中 23 名患有 PHP 1b。在接受检查的 17 名受影响患者中，有 10 名患有短指畸形 E，其中 2 名患者有马德隆样畸形。5 名受影响的患者中有亚临床甲状腺功能减退症；没有患者出现骨化不全或身材矮小。所有未受影响的成员均无短指畸形或甲状旁腺素或促甲状腺激素血清水平升高。在接受检测的 2 名受影响患者中，免疫活性红细胞 Gα(s)水平正常。连锁分析表明 PTH 抵抗与 GNAS 基因座之间存在连锁关系；然而，在 GNAS 外显子 1-13 中未发现突变。对受影响个体的基因组 DNA 进行甲基化分析显示，1A 外显子中母系表型缺失，XLGαs 和 NESP55 的差异甲基化区域正常甲基化，PCR 显示 STX16 基因 3.0kb 缺失杂合性。
在这个家族中，短指畸形与 PHP 1b 的分离表明 GNAS 的印迹缺陷可导致生长板缺陷，包括短指畸形和马德隆畸形。这些特征表明，GNAS 信号在软骨细胞成熟中的作用比以前认为的更为广泛。
