Dataset Information

Novel aggrecan variant, p. Gln2364Pro, causes severe familial nonsyndromic adult short stature and poor growth hormone response in Chinese children.

ABSTRACT: BACKGROUND:Mutations in the aggrecan (ACAN) gene can cause short stature (with heterogeneous clinical phenotypes), impaired bone maturation, and large variations in response to growth hormone (GH) treatment. For such cases, long-term longitudinal therapy data from China are still scarce. We report that a previously unknown ACAN gene variant reduces adult height and we analyze the GH response in children from an affected large Chinese family. METHODS:Two children initially diagnosed with idiopathic short stature (ISS) and a third mildly short child from a large Chinese family presented with poor GH response. Genetic etiology was identified by whole exome sequencing and confirmed via Sanger sequencing. Adult heights were analyzed, and the responses to GH treatment of the proband and two affected relatives are summarized and compared to other cases reported in the literature. RESULTS:A novel ACAN gene variant c.7465 T?>?C (p. Gln2364Pro), predicted to be disease causing, was discovered in the children, without evident syndromic short stature; mild bone abnormity was present in these children, including cervical-vertebral clefts and apophyses in the upper and lower thoracic vertebrae. Among the variant carriers, the average adult male and female heights were reduced by -?5.2 and?-?3.9 standard deviation scores (SDS), respectively. After GH treatment of the three children, first-year heights increased from 0.23 to 0.33 SDS (cases in the literature: -?0.5 to 0.8 SDS), and the average yearly height improvement was 0.0 to 0.26 SDS (cases in the literature: -?0.5 to 0.9 SDS). CONCLUSIONS:We report a novel pathogenic ACAN variant in a large Chinese family which can cause severe adult nonsyndromic short stature without evident family history of bone disease. The evaluated cases and the reports from the literature reveal a general trend of gradually diminishing yearly height growth (measured in SDS) over the course of GH treatment in variant-carrying children, highlighting the need to develop novel management regimens.

SUBMITTER: Xu D

PROVIDER: S-EPMC5956957 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Novel aggrecan variant, p. Gln2364Pro, causes severe familial nonsyndromic adult short stature and poor growth hormone response in Chinese children.

Xu Dandan D Sun Chengjun C Zhou Zeyi Z Wu Bingbing B Yang Lin L Chang Zhuo Z Zhang Miaoying M Xi Li L Cheng Ruoqian R Ni Jinwen J Luo Feihong F

BMC medical genetics 20180516 1

<h4>Background</h4>Mutations in the aggrecan (ACAN) gene can cause short stature (with heterogeneous clinical phenotypes), impaired bone maturation, and large variations in response to growth hormone (GH) treatment. For such cases, long-term longitudinal therapy data from China are still scarce. We report that a previously unknown ACAN gene variant reduces adult height and we analyze the GH response in children from an affected large Chinese family.<h4>Methods</h4>Two children initially diagnose ...[more]

PMID: 29769040

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Project description:ObjectiveACAN gene variants are an important cause of familial short stature (FSS). Appropriate growth-promoting therapies effectively improve the patient height. Here, we report a therapeutic assessment of cases of seven families of FSS patients with heterozygous ACAN variants. Our findings provide a valuable theoretical basis for the clinical diagnosis and treatment of this disease.MethodsFrom December 2020 to June 2021, 32 FSS patients were examined in Tianjin Medical University General Hospital (Tianjin, China) by whole-exome sequencing to determine whether ACAN variants were present. Their clinical data were summarized and scrupulously analyzed.ResultsWe found seven novel heterozygous ACAN variants: c.1051 + 2T > A, c.313T > C (p.S105P), c.2660C > G (p.S887X), c.2153C > A (p. T718K), c.7243delG (p.D2415Tfs*4), c.2911G > T (p.G971X), c.758-7T > C. All seven patients had proportionate short stature and mild skeletal dysplasia. Endocrine examination results were normal. Only one of the patients had an advanced bone age (1.1 years older than chronological age), whereas the other patients had normal bone ages. All of them had a family history of short stature, with or without osteoarthritis or intervertebral disc disease. All seven patients accepted treatment with recombinant human growth hormone (rhGH) and were regularly followed up. One patient did not come at the follow-up visit. The height of the remaining six patients before and after the treatment was -2.89 ± 0.68 SDS, -1.91 ± 0.93 SDS, respectively, with a treatment course of 1.85 ± 1.91 years. A good therapeutic response was observed in all of them.ConclusionsIn this study, seven novel heterozygous variants in ACAN were discovered, which expanded the spectrum of the already established ACAN pathogenic variants. In FSS cohort, the proportion of ACAN variants accounted was large. The treatment with rhGH effectively increased the patient height, but further studies with longer follow-up periods and more extensive observations are required to elucidate the long-term effect.

Dataset Information

Novel aggrecan variant, p. Gln2364Pro, causes severe familial nonsyndromic adult short stature and poor growth hormone response in Chinese children.

Publications

Novel aggrecan variant, p. Gln2364Pro, causes severe familial nonsyndromic adult short stature and poor growth hormone response in Chinese children.

Similar Datasets

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