Tall Stature and Scoliosis Associated With a Novel Homozygous Loss‐of‐Function Missense Variant in <i>NPR3</i>

NPR3-related tall stature is characterized by tall stature, elongated big toes, and additional epiphyses in hand and foot bones. The condition is caused by biallelic loss-of-function variants affecting natriuretic peptide receptor 3 (NPR3). Five individuals from four different families have been reported. Here we describe three siblings with NPR3-related tall stature who were tall (height z-scores between +2.9 and + 4.9) and had markedly elongated proximal and middle phalanges. Two siblings had additional epiphyses in phalangeal and metacarpal bones. All three siblings developed scoliosis, requiring spinal fusion surgery in one individual. Lumbar spine bone mineral density appeared low considering the tall stature. Sequencing of a skeletal disorders gene panel in one sibling revealed a homozygous missense variant in NPR3 (NM_001204375.2; c.382C>T; p.Pro128Ser). Sanger sequencing demonstrated the same homozygous variant in the other siblings. In vitro functional testing in MC3T3-E1 preosteoblastic cells showed that NPR3 carrying the p.Pro128Ser variant was expressed but was retained in the endoplasmic reticulum, leading to loss of NPR3 function. In conclusion, the novel homozygous p.Pro128Ser loss-of-function variant in NPR3 led to the typical features of NPR3-related tall stature and, in addition, was associated with scoliosis. These observations expand the genotypic and phenotypic spectrum of NPR3-related tall stature.