Supplementary Material for: Two Patients with Severe Short Stature due to a FBN1 Mutation (p.Ala1728Val) with a Mild Form of Acromicric Dysplasia

<b><i>Background:</i></b> Acromicric dysplasia (AD) and geleophysic dysplasia 2 (GD2) belong to the category of acromelic dysplasia syndromes, consisting of severe short stature, short hands and feet and skin thickening. Both can result from missense mutations in the transforming growth factor beta 5 domain of the fibrillin-1 gene <i>(FBN1)</i>. <b><i>Methods:</i></b> Two patients (P1 age 10, and P2 age 7) from unrelated families presented to their endocrinologist with severe short stature (approx. -4 SDS). They were otherwise asymptomatic and only had mild facial dysmorphisms. Extensive endocrine work-up did not reveal an underlying etiology. Exome sequencing was performed in each family. <b><i>Results:</i></b> Exome sequencing identified the presence of the same heterozygous missense variant c.C5183T (p.Ala1728Val) in the <i>FBN1</i> gene in both P1 and P2. This variant was previously reported in a patient with GD2 and associated cardiac valvulopathy and hepatomegaly. Detailed clinical re-examination, cardiac and skeletal imaging did not reveal any abnormalities in P1 or P2 other than mild hip dysplasia. <b><i>Conclusion:</i></b> This report broadens the phenotypic spectrum of growth disorders associated with <i>FBN1</i> mutations. Identical mutations give rise to a wide phenotypic spectrum, ranging from isolated short stature to a more classic picture of GD2 with cardiac involvement, distinct facial dysmorphisms and various skeletal anomalies.

背景：肢端小骨发育不良（Acromicric dysplasia, AD）与骨骺发育不良2型（Geleophysic dysplasia 2, GD2）均属于肢端发育不良综合征范畴，典型临床特征包括重度身材矮小、手足短小及皮肤增厚。二者均由原纤维蛋白1基因（fibrillin-1 gene, *FBN1*）的转化生长因子β5结构域错义突变引发。方法：本研究纳入2名来自无关家系的患者（P1，10岁；P2，7岁），二人因重度身材矮小（约-4标准差评分（Standard Deviation Score, SDS））就诊于内分泌专科。除上述表现外，二人无其他明显不适，仅存在轻度面部形态异常。全面的内分泌功能检查未明确其发病潜在病因，研究团队对两个家系分别开展了外显子组测序。结果：外显子组测序显示，P1与P2的*FBN1*基因中均存在同一杂合错义变异c.C5183T（p.Ala1728Val）。该变异此前曾在1例合并心脏瓣膜病及肝大的GD2患者中被报道。对二人进行详细临床复查、心脏及骨骼影像学检查后，仅发现轻度髋关节发育不良，未检出其他异常。结论：本研究拓展了与*FBN1*突变相关的生长障碍表型谱。相同的致病突变可引发广泛的表型差异，涵盖从单纯性身材矮小，到伴心脏受累、特征性面部形态异常及多种骨骼异常的经典GD2表型等一系列表型。