Familial Short Stature - a Novel Phenotype of Growth Plate Collagenopathies

Backround: Collagens are the most abundant proteins in the human body. In a growth plate, collagen types II, IX, X and XI are present. Defects in collagen genes cause heterogeneous syndromic disorders frequently associated with asymmetric short stature (e.g. Kniest dysplasia, spondyloepiphyseal dysplasia). Less is known about nonsyndromic collagenopathies - data about their frequency and subtle phenotypic signs are sparse, the information about their response to growth hormone (GH) treatment is lacking completely. Aim: To evaluate the frequency of collagenopathies in familial short stature (FSS) children and to describe their phenotype, including growth hormone (GH) treatment response. Methods: Out of 522 individuals treated in our center with GH from the indication of primary GH deficiency (GHD) or small for gestational age short stature (SGA-SS), 87 children with FSS fulfilled the inclusion criteria (pre-treatment height ≤-2 SD in both patient/their shorter parent, signed written informed consent) and were enrolled to the study. Next-generation sequencing was performed to search for variants in COL2A1, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1 and COL11A2 genes. The results were evaluated using ACMG guidelines. The phenotype of children with (likely) pathogenic variants was described including the short-term GH treatment response (growth velocity and body-height SDS increase over three years of treatment). For statistical evaluation, parametric tests were used, p-values <0.05 were considered significant. Results: A (likely) pathogenic variant in one of the collagen genes was found in 10/87 (11.5%) children. Their age was 12.5 years (median, range 6-17 years), their pre-treatment height was -3.1 SD (-2.4 to -4.3 SD). Their birth length (median -2.8 SD; range -0.7 to -4.1 SD) was more severely affected than birth weight (median -2.1 SD; range -1.0 to -2.7 SD). Eight children were treated with GH from SGA-SS indication, the remaining 2 were classified as mild GHD (maximal stimulated GH concentration 8.0 and 9.7 ug/l, normal brain MRI and examination of other pituitary hormones). Detailed anthropometric examination described mild asymmetry with shorter limbs and mild bone dysplasia signs (scoliosis, more pronounced lumbar lordosis, genua valga, limited elbow extension) in 2/10 and 4/10 affected children, respectively. Growth velocity improved from a median of 5.3 cm/year to 8.7 cm/year after one year of treatment (p<0.001, paired-sample T-test), height improved from a median of -3.1 SD to -2.2 SD after three years of therapy (p=0.001, ANOVA repeated measures analysis of variants). Conclusion: Nonsyndromic collagenopathies are a frequent cause of FSS. The short-term response to GH treatment is promising. Supported by the Ministry of Health, Czech Republic, grant number NV18- 07-00283 and by the research project of the Grant Agency of Charles University of Prague, GAUK 976718.