medwireNews: Children with familial short stature (FSS) who have mutations in their C-type natriuretic peptide receptor (NPR2) gene may respond well to growth hormone (GH) therapy, preliminary study findings indicate.
Stepanka Pruhova, from Charles University in Prague, Czech Republic, and co-workers identified 87 patients attending a clinic with FSS, defined as a pretreatment life-minimum height of –2 standard deviations (SD) or greater in both the child and their shorter parent in the absence of a known genetic marker.
Next-generation sequencing revealed NPR2 variations in five (5.7%) children aged a median of 11 years at the time of last follow-up; the known pathogenic mutation lle558Thr in two siblings and the “likely pathogenic” p.Arg205*, Ser603Thr and p.Arg557His variants in three patients, the researchers say.
And the shorter parents all carried the same NPR2 variant as their children, the team reports in The Journal of Clinical Endocrinology & Metabolism.
Three children had GH deficiency but all had a normal pituitary gland on imaging and normal levels of other pituitary hormones. Two patients had disproportionate short stature, including one patient with dysplastic middle phalanx of the fifth finger, while three had no evidence of bone dysplasia.
GH therapy was initiated before puberty, between age 3 and 10 years – albeit one patient began puberty a year after starting GH – and four of the children completed at least 5 years of GH therapy beginning at an initial dose of 21–45 µg/kg per day.
Height before treatment was a median of –3.7 SD and their shorter parent’s height was –2.4 SD. GH therapy achieved a growth acceleration of 3.6–4.2 cm/year in the first year of treatment with an increase in height by the end of the first, second and fifth years of treatment of 0.33–0.79, 0.43–1.34 and 1.2–1.8 SD, respectively.
Pruhova and co-workers believe their patient outcomes are comparable to those reported for children with the GH-indicated growth plate disorder SHOX-D, with an acceleration of 4.8–8.7 cm/year for the first year of treatment and a height SD score increase of 1.2 after 2 years.
“Thus, although no data on final height are available, GH treatment of short stature caused by NPR2 gene variants seems to be promising”, they write.
However, the researchers highlight the possibility of legal barriers affecting access to GH therapy in children with pathogenic NPR2 variants, noting that only three of the five children met the small for gestational age criteria for treatment. This included just one of the two siblings, despite both being successfully treated with GH.
“Clarifying the genetic disorder specific reactions to GH treatment that would lead to further refinement of indications for GH therapy poses one of the important current challenges of pediatric endocrinology”, they remark.
By Lynda Williams
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J Clin Endocrinol Metab 2020; doi:10.1210/clinem/dgaa037