ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 4.14 | DOI: 10.1530/ey.18.4.14

Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, 150 06 Prague 5, Czech Republic.

J Clin Endocrinol Metab. 2021;106:1742–1749. doi: 10.1210/clinem/dgab084. PMID: 33570564

This study aimed to assess the frequency of genetic collagenopathies in children with familial short stature (FSS), describing the phenotype and reporting the response to rhGH treatment after 1 and 3 years and at adult height.

Collagen types II, IX, X, and XI are synthesized by chondrocytes and represent the main collagen types in the extracellular matrix of the growth plate (1). Defects in collagen genes cause different disorders affecting growth plate and are frequently associated with short stature (1,2). Phenotypes include syndromic and non-syndromic short stature with mild clinical signs (3,4).

The authors studied 87 children affected by FSS, defined as height ≤ –2 S.D. in both the patient and the shorter parent, and treated with rhGH. Next-generation sequencing (NGS) for variants in the COL2A1, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1, and COL11A2 genes was used and results were confirmed by Sanger sequencing. For all children with pathogenic variants, response to rhGH treatment after 1 and 3 years was evaluated retrospectively. In 4 children, adult height was compared with pretreatment height SDS and height of the untreated parent with the same genetic variant.

A likely pathogenic variant was found in 10/87 children (11.5%). The pathogenic variants were in COL2A1 (5 patients), COL11A1 (4 patients) and COL11A2 (1 patient). Eight of 10 children were born small for gestational age (SGA) with birth length more severely affected than birth weight. Clinical features included proportional short stature in 8/10 affected children; the remaining 2 had mildly shorter limbs. Four of 10 children had mild signs of bone dysplasia such as scoliosis, pronounced lumbar lordosis, genua valga or limited elbow extension. rhGH treatment increased growth velocity during the first year. Height increased from a median of –3.1 SDS (range: –2.4 to –4.3 SDS) at start of GH treatment to –2.2 SDS (–0.8 to –2.9 SDS) after 3 years of therapy. Adult height, reached in only 4 patients, did not show a significant improvement compared to the untreated parent with the same causative genetic variant.

This study shows that mildly symptomatic collagenopathies are relatively frequent in children with FSS. GH treatment seems to improve stature in the short-term.

Reference: 1. Ricard-Blum S. The collagen family. Cold Spring Harb Perspect Biol. 2011;3(1):a004978.2. Shen G. The role of type X collagen in facilitating and regulating endochondral ossification of articular cartilage. Orthod Craniofac Res. 2005;8(1):11–7.3. Plachy L, Dusatkova P, Maratova K, Petruzelkova L, Elblova L, Kolouskova S, et al. Familial Short Stature-A Novel Phenotype of Growth Plate Collagenopathies. J Clin Endocrinol Metab. 2021;106(6):1742–9.4. Plachy L, Strakova V, Elblova L, Obermannova B, Kolouskova S, Snajderova M, et al. High Prevalence of Growth Plate Gene Variants in Children With Familial Short Stature Treated With GH. J Clin Endocrinol Metab. 2019;104(10):4273–81.

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