Endocrine Abstracts

JOINT1079

Aim: To assess the identification of genetic causes in children with short stature (SS) and to identify diagnostic patterns and inheritance in the real world.

Methods: A real world cohort referred for SS (n = 150; 91 males, height <-2 SD or short for parents) was grouped as: atypical Growth Hormone deficiency (GHD, n = 8), no genetic diagnosis (non-SGA, n = 49; SGA, n = 33), genetic diagnoses (GH-axis-related, n = 4; bone-related, n = 20; non-GH/bone-related, n = 14; possibly SS-related/VUS (variant-of-unknown-significance), n = 10), and pre-referral genetic diagnosis (n = 12). Typical GHD, Turner syndrome, and Constitutional Delay of Growth and Puberty were excluded.

Results: Boys’ mean referral age was 6. 13±4. 34 years and girls’ 7. 10±4. 2 years. Boys’ mean referral height was -3. 03±1. 29 SD and girls’ -3. 19±1. 37 SD. Genetic diagnosis was made in 33% of patients, plus 7% showed VUS. Missense variants prevailed in GH-axis- and bone-related gene variants, and copy-number-variations (CNVs) in the VUS-group. Predominant pathogenic gene variants were CUL7 (4x, 2 siblings), NPR2 (3x, 2 siblings), chromosome 14 hypomethylation (3x, 2 siblings), SMAD4 (3x), ATM (2x, siblings), DYRK1A (2x), CDC45 (2x, siblings), H19 hypomethylation (2x). GH-axis-related genes included PTPN11, BRAF, SOS1 and IGF1R variants. VUS included SHOX (3x), ACAN, KMT2A, FGFR1, FGFR2, MNX, 21q22. 2 duplication, 10q22. 2-23-3 duplication. Inherited variants prevailed in bone-related gene variants, de novo in non-GH/bone variants. Eleven boys and one girl had pre-referral diagnoses. Excluding those, gender did not affect genetic diagnosis likelihood (p>0. 05), nor did being SGA or having microcephaly (HC <-2SD). Genetic diagnosis likelihood was higher if height ≤-2. 5 SD vs height >-2. 5 SD (30% vs 23%). Patients with bone-related genetic variants had most severe SS (height SDS -3. 89±2. 15 vs others -2. 97±1. 11; P = 0. 0035), and higher BMI SDS (0. 27±2. 03). Patients with GH-axis-related variants had the lowest BMI SDS (-2. 45±0. 36; ANOVA P = 0. 035). Dividing IGF1 into quintiles, elevated IGF1 prevailed in GH-axis (25%) and bone-related (29%) diagnoses, while atypical GHD had most frequent low IGF1 (38%). Non-GH/bone diagnoses were more prevalent in those with microcephaly (17% of genetic diagnoses if HC ≤ 2 SDS), while bone-related diagnoses were more frequent if HC > 2 SDS (20% of the genetic diagnoses).

Conclusions: Genetic testing is crucial for SS, including for mild SS (-2 to -2. 5 SD), enabling personalised care and potentially improving clinical outcomes. Bone-related gene variants are the leading cause for short stature, and affected patients are shorter, often with high IGF1, which requires further research.