Clinical characteristics and response to growth hormone treatment in 27 children and adolescents with pathogenic NPR2 variants

Renes Judith S.; Reedijk Ardine M.J.; Hendriks Yvonne M.C.; Boudewijn Bakker; Boot Annemieke M.; van Setten Petra A.; van der Kaay Daniëlle C.M.; Hokken-Koelega Anita C.S.; Monique Losekoot; van Duyvenvoorde Hermine A.; Bruin Christiaan de

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ESPE Abstracts (2024) 98 FC7.1

ESPE2024 Free Communications GH and IGFs (6 abstracts)

Clinical characteristics and response to growth hormone treatment in 27 children and adolescents with pathogenic NPR2 variants

Judith S. Renes ^1,2 , Ardine M.J. Reedijk ¹ , Yvonne M.C. Hendriks ³ , Boudewijn Bakker ^4,5 , Annemieke M. Boot ⁶ , Petra A. van Setten ⁷ , Daniëlle C.M. van der Kaay ⁸ , Anita C.S. Hokken-Koelega ^1,8 , Monique Losekoot ³ , Hermine A. van Duyvenvoorde ³ & Christiaan de Bruin ⁹

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¹Dutch Growth Research Foundation, Rotterdam, Netherlands. ²Albert Schweitzer Hospital, Dordrecht, Netherlands. ³Leiden University Medical Center, Leiden, Netherlands. ⁴University Medical Center Utrecht - Wilhelmina Children's Hospital, Utrecht, Netherlands. ⁵Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands. ⁶University Medical Center Groningen, Groningen, Netherlands. ⁷Radboud University Medical Center, Nijmegen, Netherlands. ⁸Erasmus University Medical Center - Sophia Children’s Hospital, Rotterdam, Netherlands. ⁹Leiden University Medical Center - Willem-Alexander Children’s Hospital, Leiden, Netherlands

Background: The NPR2 gene plays a critical role in the human growth plate. Pathogenic NPR2 variants can result in varying degrees of short stature. The majority of subjects have no specific clinical findings and are likely classified as idiopathic short stature.

Objective: To describe the phenotypic spectrum, analyze genotype-phenotype correlations and assess the response and safety of growth hormone (GH) treatment in children with a heterozygous pathogenic NPR2 variant.

Patients: Twenty-seven (18 boys, 9 girls) short-statured children with pathogenic NPR2 variants and treated for ≥1 year with GH (1.4 mg/m²/day) were identified in the Dutch National Registry of GH treatment in children.

Results: In our cohort of 27 children, we identified 18 different pathogenic NPR2 variants. Most variants (10/18) were located in the ligand binding domain. Seven subjects had a truncating variant, 18 subjects a non-truncating variant and 2 subjects a splice site variant. Median (IQR) baseline height SDS was -2.9 (-3.3 to -2.4). Fifteen subjects were prepubertal, 12 subjects pubertal. In ~30% of children no specific clinical or dysmorphic features were reported, however, the majority of patients did show minor features suggestive of a skeletal dysplasia. Dysmorphic features of the hands were most frequently described (14/27) including brachydactyly and cone-shaped epiphysis. Sitting height to height ratio was ≥1.0 SDS in 13 subjects. Subjects with a truncating NPR2 variant had a shorter height SDS compared to subjects with a non-truncating variant (-3.3 and -2.5 respectively, P = 0.019). After 2 years of GH treatment, gain in height SDS in prepubertal children was 1.2 (0.9 to 1.4, P = 0.003). In pubertal children height SDS remained stable, which is in contrast to the loss in height SDS that is reported in untreated, pubertal NPR2 subjects. Six children reached adult height (AH): 3 subjects reached an AH ≥-2 SDS, in 2 subjects AH SDS had improved in comparison to the untreated affected parent and in 1 subject AH was comparable with the untreated affected parent. GH treatment was well-tolerated without the report of severe adverse events.

Conclusion: The majority of patients with a heterozygous pathogenic NPR2 variant have some features suggestive of skeletal dysplasia. Careful examination, especially of the hand, is helpful in identifying which children to test for a NPR2 variant. We furthermore show that the majority of NPR2 patients have a significant response to GH during 2 years of treatment.