Familial Short Stature—A Novel Phenotype of Growth Plate Collagenopathies

Abstract

Context :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 short stature. Less is known about oligosymptomatic collagenopathies. Objectives :To evaluate the frequency of collagenopathies in familial short stature (FSS) children and to describe their phenotype, including growth hormone (GH) treatment response. Design, Settings and Patients Eighty-seven FSS children (pretreatment height ≤-2 SD in both patient/their shorter parent) treated with GH were included in 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 GH treatment response of affected children was retrospectively evaluated. Results A likely pathogenic variant in the collagen gene was found in 10/87 (11.5%) children. Detailed examination described mild asymmetry with shorter limbs and mild bone dysplasia signs in 2/10 and 4/10 affected children, respectively. Their growth velocity improved from a median of 5.3 cm/year to 8.7 cm/year after one year of treatment. Their height improved from a median of -3.1 SD to -2.6 SD and to -2.2 SD after one and three years of therapy, respectively. The final height reached by 4/10 children differed by -0.67 to +1.0 SD and -0.45 to +0.5 SD compared to their pretreatment height and their affected untreated parent’s height, respectively. Conclusion Oligosymptomatic collagenopathies are a frequent cause of FSS. The short-term response to GH treatment is promising.

Clinical Characteristics of Short-Stature Patients With Collagen Gene Mutation and the Therapeutic Response to rhGH

“…Recently, we demonstrated a good effect of rhGH treatment in patients with NPR2 heterozygous mutation, and the efficacy was negatively correlated with the initial age of treatment and was associated with gender and the gene positions of mutation ( 15 ). A study evaluating the efficiency of rhGH treatment with collagenopathy in a cohort also demonstrated a height Z score improvement from a median of –3.1 to –2.6 and to –2.2 after 1 and 3 years of therapy, respectively ( 17 ). Our study provides new evidence for the evaluation of rhGH therapy for skeletal collagenopathies.…”

“…COL2A1 mutations were detected in 15 patients (14%), which was slightly higher than that of a recent NGS study on 82 short Chinese patients with clear signs of bone dysplasia (positive rate = 11%) ( 16 ). A recent study evaluating oligosymptomatic collagenopathies yielded a lower molecular diagnostic rate of 11.5% in 87 FSS patients treated with rhGH ( 17 ). Meanwhile, our study revealed the genetic architecture of short stature with skeletal abnormalities and proposed that mutations of collagen genes (especially COL2A1 ), FGFR3 , ACAN , NPR2 , COMP , and FBN1 are common for short stature due to skeletal abnormalities in outpatient clinics in pediatric endocrinology.…”

Response to Letter to the Editor from Youn Hee Jee: “Familial Short Stature - A Novel Phenotype of Growth Plate Collagenopathies”

“…The ClinVar classification of the variant as benign was based solely on a single article evaluating genetic variants relating only to hearing loss but not to short stature or clinical signs of bone dysplasia ( 8 ); therefore, it is ranked with only the lowest score of one star in the ClinVar reliability classification. Similarly, we believe that all other variants mentioned in the Letter to the Editor have been classified correctly, and the proof of their causality is well documented in the original article and its supplementary materials ( 2 ).…”

“…In the Letter to the Editor ( 1 ) commenting on our article entitled “Familial Short Stature - A Novel Phenotype of Growth Plate Collagenopathies” ( 2 ) by Youn Hee Jee, the results of the interpretation of genetic variants have been questioned based on the different variant classification in the ClinVar database.…”

Novel Insights Into the Genetic Causes of Short Stature in Children

“…Indeed, recent studies have focused on collagen diseases as a possible cause of growth failure. 60 In the growth plate, collagen types II, IX, X and XI are present; among them type II collagen represents the most abundant component. Collagenopathies type II are related to COL2A1 variants and are associated with short stature and skeletal dysplasia, although there is not a clear genotype–phenotype correlation.…”