Long-term response to growth hormone therapy in a patient with short stature caused by a novel heterozygous mutation in NPR2

• Published in: Journal of Pediatric Endocrinology & Metabolism Vol. 30; no. 1; pp. 111 - 116
• Main Authors: Vasques, Gabriela A., Hisado-Oliva, Alfonso, Funari, Mariana F.A., Lerario, Antonio M., Quedas, Elisangela P.S., Solberg, Paulo, Heath, Karen E., Jorge, Alexander A.L.
• Format: Journal Article
• Language: English
• Published: Germany De Gruyter 01.01.2017; Walter de Gruyter GmbH
• Subjects: Body Height - genetics; C-type natriuretic peptide; Child, Preschool; Dwarfism - drug therapy; Dwarfism - genetics; Female; Genotype; growth; Growth Disorders - drug therapy; Growth Disorders - etiology; growth hormone therapy; Heterozygote; Human Growth Hormone - therapeutic use; Humans; Insulin-Like Growth Factor I - metabolism; Male; Mutation - genetics; Pedigree; Phenotype; Prognosis; Receptors, Atrial Natriuretic Factor - genetics; short stature
• ISSN: 0334-018X; 2191-0251
• DOI: 10.1515/jpem-2016-0280

Heterozygous loss-of-function mutations in the natriuretic peptide receptor B gene (NPR2) are responsible for short stature in patients without a distinct phenotype. Some of these patients have been treated with recombinant human growth hormone (rhGH) therapy with a variable response. The proband was a healthy boy who presented at the age of 5.1 years with familial short stature (height SDS of -3.1). He had a prominent forehead, a depressed nasal bridge, centripetal fat distribution and a high-pitched voice resembling that of children with GH deficiency. His hormonal evaluation showed low insulin-like growth factor-1 (IGF-1) but a normal GH peak at a stimulation test. During the first year of rhGH treatment, his growth velocity increased from 3.4 to 10.4 cm/year (height SDS change of +1.1). At the last visit, he was 8.8 years old and still on treatment, his growth velocity was 6.4 cm/year and height SDS was -1.8. We identified through exome sequencing a novel heterozygous loss-of-function NPR2 mutation (c.2905G>C; p.Val969Leu). Cells cotransfected with the p.Val969Leu mutant showed a significant decrease in cyclic guanosine monophosphate (cGMP) production compared to the wild type (WT), suggesting a dominant negative effect. This case reveals a novel heterozygous loss-of-function NPR2 mutation responsible for familial short stature and the good response of rhGH therapy in this patient.