Segmental undergrowth is associated with pathogenic variants in vascular malformation genes: A retrospective case-series study

Segmental overgrowth has been widely described in patients with congenital vascular anomalies. However, segmental undergrowth has been poorly characterized, and no large series of patients have been published. We present the clinical and molecular characteristics a cohort of 37 patients with vascular malformations and segmental undergrowth. True undergrowth was only considered when the musculoskeletal system was involved to avoid confusion with other causes of segmental reduction, as in lipodystrophy or the long-term osteopenia seen in patients with Servelle-Martorell syndrome. Deep high-throughput sequencing was performed in tissue samples from 20 patients using a custom panel. We identified three groups: undergrowth associated with (1) venous, (2) capillary-venous, and (3) lymphatic-capillary-venous malformations. Congenital or early childhood onset undergrowth can occur with or without associated overgrowth. Different likely pathogenic or pathogenic variants were detected in 13 of 20 (65%) tissue samples in the PIK3CA, TEK, GNAQ, or GNA11 genes. In conclusion, the eponymous Servelle-Martorell syndrome should not be used as a synonym for undergrowth. Segmental undergrowth should be considered a characteristic associated with vascular malformations. Patients with PIK3CA variants show all different combinations of overgrowth and undergrowth. Thus, the term PROS (PIK3CA-related overgrowth spectrum) does not cover the entire spectrum.