medwireNews: Research from the Netherlands suggests that the majority of children heterozygous for pathogenic alterations to the NPR2 gene, resulting in mild skeletal dysplasia, respond to growth hormone (GH) therapy.
Judith Renes (Dutch Growth Research Foundation, Rotterdam) and co-workers explain that the natriuretic peptide receptor-B protein encoded by NPR2 “plays a critical role in the human growth plate” by stimulating chondrocyte proliferation and bone matrix synthesis.
The team determined the impact of GH therapy in 27 children aged at least 4 years with a confirmed or probable pathological heterozygous NPR2 variant and a predicted height below –2.5 standard deviation score (SDS) who were eligible for GH therapy 1.4 mg/m2 per day, as per Dutch national guidelines.
The 18 boys and nine girls included in the study came from 23 different families and showed 18 distinct NPR2 variants, 11 of which were novel alterations, the team reports in the Journal of Clinical Endocrinology & Metabolism.
In particular, 39% of variants occurred in the ligand binding domain of NPR2, 33% in the protein kinase homology domain, 17% in the nucleotide cyclase domain and 11% in the dimerization region. There were 11 non-truncating variants, five truncating variants and two splice site variants.
Median birth length and weight were within the normal range for the 27 children, although five were born small-for-gestational age and five were preterm. Median height at GH initiation was –2.9 SDS; bone age was delayed in 12 children but not advanced in any child.
Of note, the children with an NPR2 protein kinase homology domain alteration were significantly shorter than their peers with NPR2 mutations to other regions (median –3.2 vs –2.5 SDS), as were patients with a truncating variant versus a non-truncating alteration (–3.3 vs –2.5 SDS).
Twenty-one of the children had dysmorphic hand features, most commonly brachydactyly, 14 children had a sitting height to height ratio of 1.0 SDS or more, and six children had an arm span that was at least 3 cm shorter than their standing height. Three children had no known features associated with NPR2 alterations.
Radiology revealed abnormalities of the hand or wrist in 11 children, such as premature closing of the epiphysis leading to shortening of the middle or distal phalanx, and when considering both physical and radiological findings, the researchers conclude that there was a “trend toward generalized brachydactyly in almost all patients.”
Twelve boys and three girls began GH therapy before puberty at an average age of 6.3 years and a height SDS of –3.2. After 1 year of treatment, these children experienced a significant median increase in height SDS of 0.7, and 1.2 after 2 years of GH.
Renes et al note that six of these children were given a lower than recommended dose of GH, most commonly because of insulin-like growth factor (IGF)-1 levels greater than 2 SDS, but the change in height SDS was not significantly affected by dosage. Nor did the location and truncation status of a child’s NPR2 variant affect change in height SDS. One child had a suboptimal response to GH in their first year, but home support led to improved treatment adherence and a better height SDS response in year 2.
The remaining six girls and six boys began GH therapy during puberty at an average age of 12.9 years and a height SDS of –2.4. These children had a significant median change in height SDS of 0.5 in their first year and again in their second year of GH therapy.
The researchers note that for six pubertal patients the GH dose was not adjusted for body surface area or the dose was reduced because of elevated IGF-1, while two patients received a gonadotropin-releasing hormone agonist (GnRHa) and four patients received an aromatase inhibitor (AI) during GH therapy. However, the change in height SDS for the subgroup was not significantly affected after adjusting for these factors.
Renes and co-authors observe that there was a significant difference in height SDS by NPR2 variant location in the pubertal subgroup that was mostly attributed to a patient with a protein kinase homology domain variant, who had an “exceptionally good response to GH” that resulted in a 1.2 SDS height gain after 2 years of treatment.
Six study participants reached near adult height after beginning GH during puberty, of whom three had a height greater than –2.0 SDS and two had a higher height SDS than their affected parent. The height SDS was between –2.2 and –2.5 SDS for patients given only GH, and between –1.5 and –2.3 SDS for those also using an AI, two of whom had received GnRHa before beginning GH and AI therapy.
“Overall, GH treatment was well tolerated”, the researchers say. Four prepubertal and six pubertal patients treated with GH at 1.4 mg/m2 per day experienced a 2.0 SDS or greater increase in IGF-1 but these elevations normalised without dose reduction or intervention.
None of the children developed intracranial hypertension, scoliosis or slipped capital femoral epiphysis during GH therapy, they add.
The authors acknowledge that the understanding of the benefits of GH in the current study is limited by the small group of children with NPR2 variants whose parents instigated genetic testing and GH therapy, some of whom also received GnRHa and AI therapy.
“However, since the majority of these children were able to maintain a growth velocity above average, while being co-treated with a GnRHa or AI, [this] does suggest a clinically significant growth response”, they comment.
The study authors add that “[c]areful examination, especially of the hands, can be helpful in identifying which children to test for an NPR2 variant” and note that “children who are pubertal at the time of diagnosis may still benefit from GH.”
By Lynda Williams
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