Patient cohort and recruitment

The human sample included 288 European and North American children from 0 to 18 years old recruited for photographic sessions at schools, research centers, Down syndrome OPTIONS and family congresses between 2009 and 2017 (Table ​(Table22 and Table ^S1). All protocols were approved by ethics committees: Comité Ético de Investigación Clínica-Parc de Salut MAR, Nº 2012/4849/I; modificación 24/07/2015; University Central Florida Institutional Review Board approval SBE-15-11524). To photograph the children and to obtain relevant clinical information, we obtained informed consent from their parents or legal guardians. All methods were carried out in accordance with relevant guidelines and regulations.

Human faces were digitalized using non-invasive photogrammetry techniques. The facial images of each individual were acquired in an upright position with neutral facial expression using either a 3dMD Face system (3dMD, Atlanta, GA) or self-built photographic rigs, as described elsewhere ⁴². Each system acquired 5–10 images simultaneously of an individual’s face and used photogrammetry to merge separate two-dimensional (2D) images into a single three-dimensional (3D) model that accurately represents facial shape. The software used for obtaining the 3D reconstructions was 3dMD (3dMD, Atlanta, GA), PhotoModeler (v 1.1.1546, Eos Systems, Inc. Canada), and AgiSoft PhotoScan Standard (v 1.3.2). All data was collected with high precision and accuracy based on the same principles of stereo photogrammetry. Scale differences from the different acquisition systems were accounted for in the subsequent analyses by transforming pixel sizes to their corresponding mm measures.

We measured and recorded 3D coordinates of 21 facial landmarks from each individual’s 3D image following published protocols ⁴² (Fig. ^S1B and Table ^S2). Measurement error was within the range of previous studies (0.26 mm along the x-dimension, 0.30 mm along the y-dimension, and 0.31 mm along the z-dimension) ² and thus considered negligible. Following inspection of landmark coordinates for gross error, anatomical landmark coordinates were used to conduct morphometric analyses.

In this observational study, the cohort included cases of children with Down syndrome whose parents had administered them commercially available green tea extracts containing EGCG obtained over-the-counter. GTE-EGCG supplementation was variable for onset and duration of treatment, dosage and brand, as specified for each individual in Table ^S1.