Alfonso Hisado-Oliva1, Ana I Garre-Vázquez1, Fabiola Santaolalla-Caballero1, Alberta Belinchón1, Ana C Barreda-Bonis1, Gabriela A Vasques1, Joaquin Ramirez1, Cristina Luzuriaga1, Gianni Carlone1, Isabel González-Casado1, Sara Benito-Sanz1, Alexander A Jorge1, Angel Campos-Barros1, Karen E Heath1. 1. Institute of Medical and Molecular Genetics (A.H.-O., A.I.G.-V., F.S.-C., A.B., S.B.-S., A.C.-B., K.E.H.) and Multidisciplinary Skeletal Dysplasia Unit (A.H.-O., A.B., A.C.B.-B., I.G.-C., S.B.-S., K.E.H.), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, 28046 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras Unit 753 (A.H.-O., A.B., S.B.-S., A.C.-B., K.E.H.), Instituto de Salud Carlos III, 28029 Madrid, Spain; Department of Pediatric Endocrinology (A.C.B.-B., I.G.-C.), Hospital Universitario La Paz, Universidad Autónoma de Madrid, 28046 Madrid, Spain; Unidade de Endocrinologia Genetica (G.A.V., A.A.J.), Laboratorio de Endocrinologia Celular and Molecular LIM-25, Universidade de São Paulo, 05508-900 São Paulo, Brazil; Department of Endocrinology and Nutrition (J.R.), Hospital Universitario Príncipe de Asturias, Alcalá de Henares, 28805 Madrid, Spain; Department of Pediatric Endocrinology (C.L.), Hospital Marqués de Valdecilla, 39008 Santander, Spain; and Department of Pediatric Endocrinology (G.C.), Hospital Virgen del Puerto, 10600 Plasencia, Cáceres, Spain.
Abstract
CONTEXT: SHOX mutations have been detected in approximately 70% of Léri-Weill dyschondrosteosis (LWD) and approximately 2.5% of idiopathic short stature (ISS) cases, suggesting the implication of other genes or loci. The recent identification of NPR2 mutations in ISS suggested that NPR2 mutations may also be involved in disproportionate short stature. OBJECTIVE: The objective of the study was to investigate whether NPR2 mutations can account for a proportion of the cases referred for LWD and ISS in whom no SHOX mutation was detected. PATIENTS AND METHODS: We undertook NPR2 mutation screening in 173 individuals referred for suspected LWD and 95 for ISS, with no known defect in SHOX or its enhancers. Intracellular localization and natriuretic peptide precursor C-dependent guanylate cyclase activity were determined for the identified NPR2 variants. RESULTS: Eight NPR2 variants were identified in nine individuals, seven referred for suspected LWD and two for ISS. Six were demonstrated to affect NPR-B cell trafficking and/or its ability to synthesize cyclic GMP (cGMP) under response to natriuretic peptide precursor C/brain natriuretic peptide stimulation. All pathogenic mutations were detected in the suspected LWD referral group (∼3%). Interestingly, one of these patients is currently being treated with recombinant human GH and in contrast to previous reports is showing a positive response to the treatment. CONCLUSIONS: NPR2 mutations account for approximately 3% of patients with disproportionate short stature and/or clinical or radiographic indicators of SHOX deficiency and in whom no SHOX defect has been identified. However, no patient has yet presented with Madelung deformity. Thus, NPR2 should be screened in the SHOX-negative LWD referrals.
CONTEXT: SHOX mutations have been detected in approximately 70% of Léri-Weill dyschondrosteosis (LWD) and approximately 2.5% of idiopathic short stature (ISS) cases, suggesting the implication of other genes or loci. The recent identification of NPR2 mutations in ISS suggested that NPR2 mutations may also be involved in disproportionate short stature. OBJECTIVE: The objective of the study was to investigate whether NPR2 mutations can account for a proportion of the cases referred for LWD and ISS in whom no SHOX mutation was detected. PATIENTS AND METHODS: We undertook NPR2 mutation screening in 173 individuals referred for suspected LWD and 95 for ISS, with no known defect in SHOX or its enhancers. Intracellular localization and natriuretic peptide precursor C-dependent guanylate cyclase activity were determined for the identified NPR2 variants. RESULTS: Eight NPR2 variants were identified in nine individuals, seven referred for suspected LWD and two for ISS. Six were demonstrated to affect NPR-B cell trafficking and/or its ability to synthesize cyclic GMP (cGMP) under response to natriuretic peptide precursor C/brain natriuretic peptide stimulation. All pathogenic mutations were detected in the suspected LWD referral group (∼3%). Interestingly, one of these patients is currently being treated with recombinant human GH and in contrast to previous reports is showing a positive response to the treatment. CONCLUSIONS:NPR2 mutations account for approximately 3% of patients with disproportionate short stature and/or clinical or radiographic indicators of SHOX deficiency and in whom no SHOX defect has been identified. However, no patient has yet presented with Madelung deformity. Thus, NPR2 should be screened in the SHOX-negative LWD referrals.
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