Molecular Genetic Analysis and Growth Hormone Treatment in a Three-Generation Chinese Family with Tricho-Rhino-Phalangeal Syndrome I.

Introduction: Tricho-rhino-phalangeal syndrome (TRPS) is a rare genetic disorder characterized by craniofacial and skeletal abnormalities, which is caused by variants in the TRPS1 gene.

Methods: Clinical information and follow-up data were collected. Whole-exome sequencing (WES) was performed for variants and validated by Sanger sequencing. Bioinformatic analysis was performed to predict the pathogenicity of the identified variant. Moreover, wild-type and mutated TRPS1 vectors were constructed and transfected into human embryonic kidney (HEK) 293T cells. Immunofluorescence experiments were performed to assess the localization and expression of the mutated protein. Western blot analysis and RT-qPCR were used to detect the expression of downstream genes.

Results: The affected family members had typical craniofacial phenotype including sparse lateral eyebrows, pear-shaped nasal tip, and large prominent ears, plus skeletal abnormalities including short stature and brachydactyly. WES and Sanger sequencing identified the TRPS1 c.880_882delAAG variant in affected family members. In vitro functional studies showed that the TRPS1 variant did not affect the cellular localization and the expression of TRPS1, but the transcriptional repression effect of the TRPS1 on the RUNX2 and STAT3 was disturbed. The proband and his brother have been treated with growth hormone (GH) for 2 years until now, and we have observed the improvement of the linear growth in both.

Conclusions: The variant of c.880_882delAAG in TRPS1 was responsible for the pathogenesis of the Chinese family with TRPS I. The treatment of GH could be beneficial for the height outcome in TRPS I patients, and earlier initiation and longer duration of the therapy in prepubertal or early pubertal stage could be associated with better height outcomes.