Lauffer P, Miranda-Laferte E, van Duyvenvoorde HA, et al. - In view of critical involvement of C-type natriuretic peptide (CNP) in endochondral bone growth and monogenic growth disorders in correlation with variants in the genes encoding CNP or its cGMP-forming receptor (natriuretic peptide receptor-B (NPR-B), gene NPR2), researchers sought to describe a novel gain-of-function variant of NPR-B linked with tall stature and macrodactyly of the great toes (epiphyseal chondrodysplasia, Miura type). They gathered history and clinical characteristics of three family members and selected NPR2 for sequencing. Mother’s height was +2.77 SDS and her two daughters' heights were +1.96 SDS at 7 years and +1.30 SDS at 4 years of age. Macrodactyly of the great toes and pseudo-epiphyses of the mid- and proximal phalanges were identified in skeletal surveys. A novel heterozygous variant c.1444_1449delATGCTG was identified in exon-8 of NPR2 via sequencing, that was considered resulting in deletion of two amino acids Met482-Leu483 within the sub-membrane region of NPR-B. Markedly increase in basal cGMP levels and CNP-stimulated cGMP production were noted in proband´s skin fibroblasts vs controls. Consistently, assays with transfected HEK-293 cells displayed significantly raised baseline and ligand-dependent activity of mutant NPR-B. This study thus inscribed the second activating variant within the intracellular sub-membrane region of NPR-B that resulted in tall stature and macrodactyly. This domain appeared to have a critical role in the baseline conformation and ligand-dependent structural rearrangement of NPR-B required for cGMP production.