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

Abstract

ContextClinical genetic evaluation has been demonstrated as an important tool to elucidate the causes of growth disorders. Genetic defects of collagen formation (the collagenopathies) have been reported to be associated with short stature and skeletal dysplasias. Etiological diagnosis of skeletal abnormality-related short stature is challenging, and less is known about recombinant human growth hormone (rhGH) therapy.ObjectiveThis is a single-center cohort study which aims at exploring the genetic architecture of short-stature children with skeletal abnormalities and evaluating the frequency of collagenopathies to determine their phenotype, including the rhGH treatment response.Patients and MethodsOne hundred and six children with short stature and skeletal abnormalities were enrolled who were evaluated by next-generation sequencing (NGS) to detect variants in the skeletal collagen genes including COL1A1, COL1A2, COL2A1, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1, and COL11A2. The results were evaluated using American College of Medical Genetics and Genomics (ACMG) guidelines. Clinical characteristics and rhGH treatment response were summarized.ResultsTwenty-four pathogenic or likely pathogenic variants of collagen genes were found in 26 of 106 (24.5%) short-stature patients with skeletal abnormalities, of which COL2A1 mutations were the most common, accounting for about 57.7%. Other frequent mutations associated with skeletal development include FGFR3, ACAN, NPR2, COMP, and FBN1 in 12.2%, 0.9%, 0.8%, 0.4%, and 0.4%, respectively, resulting in significantly different degrees of short stature. An overview of clinical features of collagenopathies showed growth retardation, skeletal abnormalities, and heterogeneous syndromic abnormalities involving facial, eye, hearing, and cardiac abnormalities. The average height of 9 patients who received rhGH treatment improved from a median of -3.2 ± 0.9 SDS to -2.2 ± 1.3 SDS after 2.8 ± 2.1 years. The most significant height improvement of 2.3 SDS and 1.7 SDS was also seen in two patients who had been treated for more than 6 years.ConclusionsA proband-based NGS revealed that distinct genetic architecture underlies short stature in varying degrees and clinical features. Skeletal abnormality-related short stature involving multiple systems should be tested for skeletal collagen gene mutation. Limited rhGH treatment data indicate an improved growth rate and height, and close monitoring of adverse reactions such as scoliosis is required.

Exploring the Genetic Causes for Postnatal Growth Failure in Children Born Non-Small for Gestational Age

“…The genes for growth plate dysfunction have been identified in ISS or FSS group (Table 3). Collagen gene mutations were detected in FSS patients (10/87, 11.5%) and of unknown origin in SS patients (18/232, 7.8%) [55,56]. Importantly, our study highlighted the effectiveness of GH therapy in patients with growth failure.…”

“…Although the identified genetic defects involving the ECM may limit the response to GH treatment, most patients in this study displayed height gain after GH treatment. There have been several efforts to assess the efficacy of GH treatment on the genotype of growth plate dysfunction, despite the small numbers of patients [30,33,[55][56][57]. One study of nine patients with a collagen gene defect showed a change in height SDS of 1.0 for 2.8 years of GH treatment [55].…”

Clinical and molecular characterization of a patient with MBTPS1 related spondyloepiphyseal dysplasia: Evidence of pathogenicity for a synonymous variant

“…Growth hormone stimulation tests suggested our patient had growth hormone deficiency, but according to the study of Kondo et al, the patient received growth hormone therapy for 1 year appeared limited response ( 1 ). In addition, S1P-deficient short stature might be compared with other skeletal disorders which tend to respond inefficiently to rGH ( 22 , 23 ). Altogether, the efficiency of rGH to the SEDKF remains doubtful.…”

“…One study described an adult proband with a novel heterozygous de novo mutation in MBTPS1 showed episodic hyperCKemia and focal myoedema (20). Another research introduced two unrelated and ethnically diverse children probands presented a new entity named cataract, alopecia, oral mucosal disorder, and psoriasis-like (CAOP) syndrome and WES and Sanger sequencing of both patients identified compound heterozygous variants in the MBTPS1 gene (21). Two phenotypes markedly different from our proband could be due to gain-of-function or the different involved organelles.…”

Análise genética prospectiva de uma coorte de pacientes classificados como tendo baixa estatura idiopática

“…o colágeno tipo II o principal colágeno sintetizado pelos condrócitos. Esse tipo COL2A1, COL11A1 e COL11A2, algumas mutações nos genes do colágeno já foram relatadas em coortes de BEI29,71,80,130,131 . Em um estudo recente, Plachy e col. OMIM 617180) e Craniossinostose tipo 4 (OMIM 600775) com heranças autossômico dominante136 .…”