Identification of a heterozygous ACAN mutation in a 15-year-old boy with short stature who presented with advanced bone age: a case report and review of the literature
2
조회
0
다운로드
1
인용
0
참고문헌
키워드
초록
Longitudinal bone growth is primarily mediated by the growth plate, which is a specialized cartilaginous structure. Aggrecan, encoded by ACAN, is a primary proteoglycan component of the extracellular matrix in both the growth plate and articular cartilage. Aggrecanopathies have emerged as a phenotype of genetic skeletal disease in humans. A heterozygous ACAN mutation causes short stature, premature growth cessation, and accelerated bone age maturation. We report the case of a 15-year-old boy with familial short stature, with height of 149 cm (Korean standard deviation score [SDS] of -3.6) and weight of 50.5 kg (-1.48 SDS). He presented with mild midfacial hypoplasia, frontal bossing, a broad chest, and a short neck. The father's and mother's heights were 150 cm (-4.8 SDS) and 153 cm (-1.69 SDS), respectively. The patient's bone age was 2–3 years more advanced than his chronological age, and no endocrine abnormalities were detected. Whole-exome sequencing followed by Sanger sequencing revealed a heterozygous ACAN mutation, c.512C>T (p.Ala171Val), in both the proband and his father. Short stature is generally associated with a delayed bone age, and this case suggests that ACAN mutations may be the most likely etiology among patients with short stature and an advanced bone age and should warrant early treatment.
Abstract
Longitudinal bone growth is primarily mediated by the growth plate, which is a specialized cartilaginous structure. Aggrecan, encoded by ACAN, is a primary proteoglycan component of the extracellular matrix in both the growth plate and articular cartilage. Aggrecanopathies have emerged as a phenotype of genetic skeletal disease in humans. A heterozygous ACAN mutation causes short stature, premature growth cessation, and accelerated bone age maturation. We report the case of a 15-year-old boy with familial short stature, with height of 149 cm (Korean standard deviation score [SDS] of -3.6) and weight of 50.5 kg (-1.48 SDS). He presented with mild midfacial hypoplasia, frontal bossing, a broad chest, and a short neck. The father's and mother's heights were 150 cm (-4.8 SDS) and 153 cm (-1.69 SDS), respectively. The patient's bone age was 2–3 years more advanced than his chronological age, and no endocrine abnormalities were detected. Whole-exome sequencing followed by Sanger sequencing revealed a heterozygous ACAN mutation, c.512C>T (p.Ala171Val), in both the proband and his father. Short stature is generally associated with a delayed bone age, and this case suggests that ACAN mutations may be the most likely etiology among patients with short stature and an advanced bone age and should warrant early treatment.
참고문헌 (18)
- Savendahl L, "Hormonal regulation of growth plate cartilage", Horm Res, 64(2 Suppl), pp.94~97 (2005)
- Baron J, "Short and tall stature : a new paradigm emerges", Nat Rev Endocrinol, 11, pp.735~746 (2015)
- Anderson IJ, "Spondyloepiphyseal dysplasia, mild autosomal dominant type is not due to primary defects of type II collagen", Am J Med Genet, 37, pp.272~276 (1990)
- Tompson SW, "A recessive skeletal dysplasia, SEMD aggrecan type, results from a missense mutation affecting the C-type lectin domain of aggrecan", Am J Hum Genet, 84, pp.72~79 (2009)
- 김유미, "Identification of a novel heterozygous mutation of ACAN in a Korean family with proportionate short stature", Journal of Genetic Medicine, 15(2), pp.102~106 (2018), 대한의학유전학회[DOI]
- Valhmu WB, "Structure of the human aggrecan gene : exon-intron organization and association with the protein domains", Biochem J, 309, pp.535~542 (1995)
- Dateki S, "ACAN mutations as a cause of familial short stature", Clin Pediatr Endocrinol, 26, pp.119~125 (2017)
- Roughley PJ, "The role of aggrecan in normal and osteoarthritic cartilage", J Exp Orthop, 1, pp.8~ (2014)
- Nilsson O, "Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations", J Clin Endocrinol Metab, 99, pp.1510~1518 (2014)
- Gkourogianni A, "Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations", J Clin Endocrinol Metab, 102, pp.460~469 (2017)
- Domowicz MS, "Aggrecan modulation of growth plate morphogenesis", Dev Biol, 329, pp.242~257 (2009)
- Lauing KL, "Aggrecan is required for growth plate cytoarchitecture and differentiation", Dev Biol, 396, pp.224~236 (2014)
- Dateki S, "Identification of a novel heterozygous mutation of the Aggrecan gene in a family with idiopathic short stature and multiple intervertebral disc herniation", J Hum Genet, 62, pp.717~721 (2017)
- Watanabe H, "Dwarfism and age-associated spinal degeneration of heterozygote cmd mice defective in aggrecan", Proc Natl Acad Sci U S A, 94, pp.6943~6947 (1997)
- van der Steen M, "ACAN gene mutations in short children born SGA and response to growth hormone treatment", J Clin Endocrinol Metab, 102, pp.1458~1467 (2017)
- Hattori A, "Next generation sequencingbased mutation screening of 86 patients with idiopathic short stature", Endocr J, 64, pp.947~954 (2017)
- Hauer NN, "Genetic screening confirms heterozygous mutations in ACAN as a major cause of idiopathic short stature", Sci Rep, 7, pp.12225~ (2017)
- Hu X, "Novel pathogenic ACAN variants in non-syndromic short stature patients", Clin Chim Acta, 469, pp.126~129 (2017)