Department of Paediatrics, Beijing Jishuitan Hospital, No. 31 of Xinjiekou Dongjie Street, Xi Cheng District, Beijing, 100035, People's Republic of China.
Department of Radiology, Beijing Jishuitan Hospital, No. 31 of Xinjiekou Dongjie Street, Xi Cheng District, Beijing, 100035, People's Republic of China.
BMC Med Genomics. 2021 Nov 5;14(1):261. doi: 10.1186/s12920-021-01113-8.
Syndromic short stature is a genetic and phenotypic heterogeneous disorder with multiple causes. This study aims to identify genetic causes in patients with syndromic short stature of unknown cause and evaluate the efficacy of the growth hormone response.
Trio-whole-exome sequencing was applied to identify pathogenic gene mutations in seven patents with short stature, multiple malformations, and/or intellectual disability. Whole-genome low-coverage sequencing was also performed to identify copy number variants in three patients with concurrent intellectual disability. Recombinant human growth hormone was administered to improve height in patients with an identified cause of syndromic short stature.
Of the seven patients, three pathogenic/likely pathogenic gene mutations, including one FGFR3 mutation (c.1620C>A p.N540K), one novel GNAS mutation (c.2288C>T p.A763V), and one novel TRPS1 mutation (c.2527_c.2528dupTA p.S843fsX72), were identified in three patients. No copy number variants were identified in the three patients with concurrent intellectual disability. The proband with an FGFR3 mutation, a female 4 and 3/12 years of age, was diagnosed with hypochondroplasia. Long-acting growth hormone improved her height from 85.8 cm [- 5.05 standard deviation (SD)] to 100.4 cm (- 4.02 SD), and her increased height SD score (SDS) was 1.03 after 25 months of treatment. The proband with a GNAS mutation, a female 12 and 9/12 years of age, was diagnosed with pseudohypoparathyroidism Ia. After 14 months of treatment with short-acting growth hormone, her height improved from 139.3 cm (- 2.69 SD) to 145.0 cm (- 2.36 SD), and her increased height SDS was 0.33.
Trio-whole-exome sequencing was an important approach to confirm genetic disorders in patients with syndromic short stature of unknown etiology. Short-term growth hormone was effective in improving height in patients with hypochondroplasia and pseudohypoparathyroidism Ia.
综合征性身材矮小是一种遗传和表型异质性疾病，有多种病因。本研究旨在确定病因不明的综合征性身材矮小患者的遗传病因，并评估生长激素反应的疗效。
对 7 名身材矮小、多发畸形和/或智力障碍的患者进行三核苷酸全外显子组测序，以鉴定致病性基因突变。对 3 名伴有智力障碍的患者进行全基因组低覆盖测序，以鉴定拷贝数变异。对有明确综合征性身材矮小病因的患者给予重组人生长激素以改善身高。
在 7 名患者中，3 名患者发现了 3 个致病性/可能致病性基因突变，包括 1 个 FGFR3 突变（c.1620C>A p.N540K）、1 个新的 GNAS 突变（c.2288C>T p.A763V）和 1 个新的 TRPS1 突变（c.2527_c.2528dupTA p.S843fsX72）。3 名伴有智力障碍的患者未发现拷贝数变异。携带 FGFR3 突变的先证者为 4 岁 3/12 岁女性，诊断为软骨发育不全症。长效生长激素治疗 25 个月后，她的身高从 85.8cm（-5.05 标准差）增加到 100.4cm（-4.02 SD），身高 SDS 增加 1.03。携带 GNAS 突变的先证者为 12 岁 9/12 岁女性，诊断为假性甲状旁腺功能减退症 Ia。短期生长激素治疗 14 个月后，她的身高从 139.3cm（-2.69 SD）增加到 145.0cm（-2.36 SD），身高 SDS 增加 0.33。
三核苷酸全外显子组测序是确定病因不明的综合征性身材矮小患者遗传疾病的重要方法。短期生长激素对软骨发育不全症和假性甲状旁腺功能减退症 Ia 患者的身高增长有效。
