NPR2 – tall stature-scoliosis-macrodactyly of the great toes syndrome

Natriuretic peptide receptor B (NPR2) gain-of-function variants cause an autosomal dominant overgrowth syndrome characterized by uniformly increased linear growth, scoliosis, and macrodactyly of the great toes (MONDO:0014401). Patients present with height Z-scores of +2.0 to +3.0 and progressive vertebral curvature.

Multiple heterozygous NPR2 variants have been implicated. A missense variant c.1462G>C (p.Ala488Pro) was identified in a four-generation family with co-segregation in four affected relatives (PMID:24259409). An in-frame deletion c.1444_1449del (p.Met482_Leu483del) was found in a mother and two daughters exhibiting scoliosis and macrodactyly (PMID:32282051). The recurrent missense variant c.2647G>A (p.Val883Met) has also been reported to cause fully penetrant overgrowth with similar phalangeal enlargement (PMID:23827346).

Functional assays demonstrate that these gain-of-function variants markedly increase receptor activity and cGMP production. Cells expressing p.Ala488Pro and p.Met482_Leu483del exhibit elevated baseline and CNP-stimulated guanylyl cyclase activity, indicating enhanced ligand-independent and ligand-dependent signaling ([PMID:24259409]; [PMID:32282051]). The p.Val883Met mutation increases maximal enzyme velocity and abolishes normal desensitization ([PMID:23827346]).

In vivo, chondrocyte-specific expression of the p.Val883Met mutant in mice recapitulates skeletal overgrowth with thickened hypertrophic zones, persistent CREB phosphorylation, and continued chondrocyte proliferation, supporting a gain-of-function mechanism (PMID:30544148).

Overall, autosomal dominant gain-of-function NPR2 variants define a clinically recognizable overgrowth syndrome with scoliosis and macrodactyly of the great toes. NPR2 genetic testing should be considered in patients with unexplained tall stature and phalangeal enlargement to guide diagnosis and potential cGMP-targeted interventions.

Key Take-home: Dominant NPR2 gain-of-function variants cause a distinctive overgrowth syndrome with macrodactyly and scoliosis via hyperactive cGMP signaling, supporting genetic testing for targeted therapeutic strategies.

References

• American journal of medical genetics. Part A | 2014 | Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene. PMID:24259409
• The Journal of clinical endocrinology and metabolism | 2020 | An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature. PMID:32282051
• Bone | 2013 | A human skeletal overgrowth mutation increases maximal velocity and blocks desensitization of guanylyl cyclase-B. PMID:23827346
• Human molecular genetics | 2019 | CREB activation in hypertrophic chondrocytes is involved in the skeletal overgrowth in epiphyseal chondrodysplasia Miura type caused by activating mutations of natriuretic peptide receptor B. PMID:30544148

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