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

Abstract

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.

Mosaic pathogenic variants in AKT3 cause capillary malformation and undergrowth

“…In contrast, capillary malformations may be associated with undergrowth of the musculoskeletal system and dermal atrophy. In the largest retrospective study of 37 participants with vascular malformations with undergrowth, almost all participants had muscle undergrowth (92%) (Martinez‐Glez et al, 2022). Bone undergrowth was more common than subcutaneous hypoplasia (68% compared to 24%) (Martinez‐Glez et al, 2022).…”

“…Pathogenic variants in several genes have been implicated in CM with undergrowth. Undergrowth with vascular lesions was observed in patients who had somatic pathogenic variants in PIK3CA, TEK, GNAQ, and GNA11 (Cubir o et al, 2020;Martinez-Glez et al, 2022).…”

“…Pathogenic variants in several genes have been implicated in CM with undergrowth. Undergrowth with vascular lesions was observed in patients who had somatic pathogenic variants in PIK3CA , TEK , GNAQ , and GNA11 (Cubiró et al, 2020; Martinez‐Glez et al, 2022). Interestingly, somatic pathogenic variants in PIK3CA more commonly cause overgrowth (Cubiró et al, 2020; Lee et al, 2013).…”

“…In the largest retrospective study of 37 participants with vascular malformations with undergrowth, almost all participants had muscle undergrowth (92%) (Martinez‐Glez et al, 2022). Bone undergrowth was more common than subcutaneous hypoplasia (68% compared to 24%) (Martinez‐Glez et al, 2022). In our patient, MRI at 2 years of age demonstrated undergrowth of bones, musculature, and subcutaneous fat.…”

“…Few studies have evaluated genetic causes of capillary malformations with undergrowth. Somatic pathogenic variants associated with undergrowth in vascular lesions have been previously reported in PIK3CA , TEK , GNAQ , and GNA11 (Martinez‐Glez et al, 2022). The association of mosaic variants in PIK3CA with capillary malformations with undergrowth was confirmed by another group (Cubiró et al, 2020).…”