Lauffer Peter, Boudin Eveline, van der Kaay Daniëlle C M, Koene Saskia, van Haeringen Arie, van Tellingen Vera, Van Hul Wim, Prickett Timothy C R, Mortier Geert, Espiner Eric A, van Duyvenvoorde Hermine A
Department of Pediatric Endocrinology, Emma Children's Hospital, Amsterdam University Medical Center, 1105 AZ Amsterdam, the Netherlands.
Department of Medical Genetics, Antwerp University Hospital and University of Antwerp, 2650 Edegem, Belgium.
J Endocr Soc. 2022 Feb 10;6(4):bvac019. doi: 10.1210/jendso/bvac019. eCollection 2022 Apr 1.
Natriuretic peptide receptor-C (NPR-C, encoded by ) belongs to a family of cell membrane-integral proteins implicated in various physiological processes, including longitudinal bone growth. NPR-C acts as a clearance receptor of natriuretic peptides, including C-type natriuretic peptide (CNP), that stimulate the cGMP-forming guanylyl cyclase-coupled receptors NPR-A and NPR-B. Pathogenic variants in , , and may cause a tall stature phenotype associated with macrodactyly of the halluces and epiphyseal dysplasia.
Here we report on a boy with 2 novel biallelic inactivating variants of .
History and clinical characteristics were collected. Biochemical indices of natriuretic peptide clearance and in vitro cellular localization of NPR-C were studied to investigate causality of the identified variants.
We identified 2 novel compound heterozygous variants c.943G>A p.(Ala315Thr) and c.1294A>T p.(Ile432Phe) in a boy with tall stature and macrodactyly of the halluces. In silico analysis indicated decreased stability of NPR-C, presumably resulting in increased degradation or trafficking defects. Compared to other patients with NPR-C loss-of-function, the phenotype seemed to be milder: pseudo-epiphyses in hands and feet were absent, biochemical features were less severe, and there was some co-localization of p.(Ile432Phe) NPR-C with the cell membrane, as opposed to complete cytoplasmic retention.
With this report on a boy with tall stature and macrodactyly of the halluces we further broaden the genotypic and phenotypic spectrum of NPR-C-related tall stature.
利钠肽受体C（NPR-C，由[具体基因名称]编码）属于一类参与包括纵向骨生长在内的各种生理过程的细胞膜整合蛋白家族。NPR-C作为利钠肽的清除受体，包括C型利钠肽（CNP），后者可刺激形成cGMP的鸟苷酸环化酶偶联受体NPR-A和NPR-B。[相关基因名称]、[相关基因名称]和[相关基因名称]中的致病变异可能导致与拇趾巨趾症和骨骺发育异常相关的高身材表型。
在此，我们报告一名患有[具体基因名称]两个新型双等位基因失活变异的男孩。
收集病史和临床特征。研究利钠肽清除的生化指标以及NPR-C的体外细胞定位，以研究已鉴定变异的因果关系。
我们在一名患有高身材和拇趾巨趾症的男孩中鉴定出两个新型复合杂合变异c.943G>A p.(Ala315Thr)和c.1294A>T p.(Ile432Phe)。计算机分析表明NPR-C的稳定性降低，推测导致降解增加或运输缺陷。与其他NPR-C功能丧失的患者相比，该表型似乎较轻：手足无假骨骺，生化特征不那么严重，并且p.(Ile432Phe) NPR-C与细胞膜有一些共定位，而不是完全保留在细胞质中。
通过对一名患有高身材和拇趾巨趾症男孩的报告，我们进一步拓宽了NPR-C相关高身材的基因型和表型谱。
