A rare case of skeletal dysplasia: biallelic variant in ACAN gene
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Gülçin Arslan
,
Filiz Hazan
,
Gülin Tabanlı
,
Tarık Kırkgöz
and
Behzat Özkan
Abstract
Objectives
Spondylo-epimetaphyseal dysplasia-aggregan (SEMD-ACAN) is a rare form of osteo-chondrodysplasia that includes vertebral, epiphyseal and metaphyseal dysplasia. It occurs as a result of loss-of-function mutations in the ACAN gene, which encodes aggregan protein, which is the basic component of the extracellular matrix in cartilage. It results in disproportionately short stature and skeletal abnormalities. Here, we aimed to present the fourth SEMD-ACAN report in the literature.
Case presentation
A 9-year-old girl was admitted to our clinic with growth retardation. She was born from a first-degree cousin marriage with severe short stature (41 cm; −3.54 SDS). Her mother also had severe short stature. Her height was 110 cm (−4.6 SDS); she had midface hypoplasia, low-set ears, short neck, short limbs, and central obesity. Biochemical and hormonal tests were normal. Skeletal survey showed moderate platyspondylia, thoracolumbar scoliosis, lumbar lordosis, bilateral femoro-acetabular narrowing, and advanced bone age (10 years). The patient’s brother was 100 cm (−3.97 SDS). He had similar but milder clinical findings. Biallelic ACAN variation (c.512C>T; p. Ala171Val) was detected in two siblings by next-generation sequencing. The parents were heterozygous carriers. Before, the heterozygous form of this variant has been reported in a 15-year-old boy with short stature, advanced bone age, and dysmorphic features.
Conclusions
SEMD-ACAN is a rare genetic condition that affects bone growth and development and can cause physical and developmental abnormalities. This article highlights the importance of considering genetic testing in characteristic symptoms associated with SEMD-ACAN, such as severe growth retardation and skeletal abnormalities.
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Research ethics: The local Institutional Review Board deemed the study exempt from review.
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Informed consent: Informed consent was obtained from all individuals included in this study.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Use of Large Language Models, AI and Machine Learning Tools: None declared.
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Conflict of interest: Authors state no conflict of interest.
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Research funding: None declared.
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Data availability: Not applicable.
References
1. Tompson, SW, Merriman, B, Funari, VA, Fresquet, M, Lachman, RS, Rimoin, DL, et al.. A recessive skeletal dysplasia, SEMD aggrecan type, results from a missense variation affecting the c-type lectin domain of aggrecan. Am J Hum Genet 2009;84:72–9. https://doi.org/10.1016/j.ajhg.2008.12.001.Search in Google Scholar PubMed PubMed Central
2. Cormier-Daire, V. Spondylo-epi-metaphyseal dysplasia. Best Pract Res Clin Rheumatol 2008;22:33–44. https://doi.org/10.1016/j.berh.2007.12.009.Search in Google Scholar PubMed
3. Aspberg, A. The different roles of aggrecan interaction domains. J Histochem Cytochem 2012;60:987–96. https://doi.org/10.1369/0022155412464376.Search in Google Scholar PubMed PubMed Central
4. Gleghorn, L, Ramesar, R, Beighton, P, Wallis, G. A variation in the variable repeat region of the aggrecan gene (AGC1) causes a form of spondyloepiphyseal dysplasia associ ated with severe, premature osteoarthritis. Am J Hum Genet 2005;77:484–90. https://doi.org/10.1086/444401.Search in Google Scholar PubMed PubMed Central
5. Fukuhara, Y, Cho, SY, Miyazaki, O, Hattori, A, Seo, JH, Mashima, R, et al.. The second report on spondyloepimetaphyseal dysplasia, aggrecan type: a milder phenotype than originally reported. Clin Dysmorphol 2019;28:26–9. https://doi.org/10.1097/mcd.0000000000000241.Search in Google Scholar PubMed PubMed Central
6. Masunaga, Y, Ohkubo, Y, Nishimura, G, Ueno, T, Fujisawa, Y, Fukami, M, et al.. ACAN biallelic variants in a girl with severe idiopathic short stature. J Hum Genet 2022;67:481–6. https://doi.org/10.1038/s10038-022-01030-3.Search in Google Scholar PubMed
7. Li, H, Schwartz, NB, Vertel, BM. cDNA cloning of chick cartilage chondroitin sulfate (aggrecan) core protein and identification of a stop codon in the aggrecan gene associated with the chondrodystrophy, nanomelia. J Biol Chem 1993;268:23504–11. https://doi.org/10.1016/s0021-9258(19)49491-x.Search in Google Scholar
8. Watanabe, H, Kimata, K, Line, S, Strong, D, Gao, LY, Kozak, CA, et al.. Mouse cartilage matrix deficiency (cmd) caused by a 7 bp deletion in the aggrecan gene. Nat Genet 1994;7:154–7. https://doi.org/10.1038/ng0694-154.Search in Google Scholar PubMed
9. Krueger, RCJr, Kurima, K, Schwartz, NB. Completion of the mouse aggrecan gene structure and identification of the defect in the cmd-Bc mouse as a near complete deletion of the murine aggrecan gene. Mamm Genome 1999;10:1119–25. https://doi.org/10.1007/s003359901176.Search in Google Scholar PubMed
10. Stattin, EL, Wiklund, F, Lindblom, K, Onnerfjord, P, Jonsson, BA, Tegner, Y, et al.. A missense variation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans. Am J Hum Genet 2010;86:126–37. https://doi.org/10.1016/j.ajhg.2009.12.018.Search in Google Scholar PubMed PubMed Central
11. Greulich, WW, Pyle, SI. Radiographic atlas of skeletal development of the hand and wrist, 2nd ed. California: Stanford University Press; 1959.10.1097/00000441-195909000-00030Search in Google Scholar
12. ACMG Laboratory Quality Assurance Committee, Richards, S, Aziz, N, Bale, S, Das, S, Gastier-Foster, J, Grody, WW, et al.. ACMG laboratory quality assurance committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405–24. https://doi.org/10.1038/gim.2015.30.Search in Google Scholar PubMed PubMed Central
13. Baron, J, Sävendahl, L, De Luca, F, Dauber, A, Phillip, M, Wit, JM, et al.. Short and tall stature: a new paradigm emerges. Nat Rev Endocrinol 2015;11:735–46. https://doi.org/10.1038/nrendo.2015.165.Search in Google Scholar PubMed PubMed Central
14. Wit, JM, Oostdijk, W, Losekoot, M, van Duyvenvoorde, HA, Ruivenkamp, CA, Kant, SG. Mechanisms in endocrinology: novel genetic causes of short stature. Eur J Endocrinol 2016;174:R145–73. https://doi.org/10.1530/eje-15-0937.Search in Google Scholar PubMed
15. Nilsson, O. Aggrecanopathies highlight the need for genetic evaluation of ISS children. Eur J Endocrinol 2020;183:C9–10. https://doi.org/10.1530/eje-20-0420.Search in Google Scholar
16. Stavber, L, Hovnik, T, Kotnik, P, Lovrečić, L, Kovač, J, Tesovnik, T, et al.. High frequency of pathogenic ACAN variants including an intragenic deletion in selected individuals with short stature. Eur J Endocrinol 2020;182:243–53. https://doi.org/10.1530/eje-19-0771.Search in Google Scholar PubMed PubMed Central
17. Lin, L, Li, M, Luo, J, Li, P, Zhou, S, Yang, Y, et al.. A high proportion of novel ACAN variations and their prevalence in a large Cohort of Chinese short stature children. J Clin Endocrinol Metab 2021;106:e2711–19. https://doi.org/10.1210/clinem/dgab088.Search in Google Scholar PubMed PubMed Central
18. Nilsson, O, Guo, MH, Dunbar, N, Popovic, J, Flynn, D, Jacobsen, C, et al.. Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan variations. J Clin Endocrinol Metab 2014;99:E1510–8. https://doi.org/10.1210/jc.2014-1332.Search in Google Scholar PubMed PubMed Central
19. Sentchordi-Montané, L, Aza-Carmona, M, Benito-Sanz, S, Barreda-Bonis, AC, Sánchez-Garre, C, Prieto-Matos, P, et al.. Heterozygous aggrecan variants are associated with short stature and brachydactyly: description of 16 probands and a review of the literature. Clin Endocrinol 2018;88:820–9. https://doi.org/10.1111/cen.13581.Search in Google Scholar PubMed
20. Kang, MJ. Novel genetic cause of idiopathic short stature. Ann Pediatr Endocrinol Metab 2017;22:153–7. https://doi.org/10.6065/apem.2017.22.3.153. Epub 2017 Sep 28.Search in Google Scholar PubMed PubMed Central
21. Tatsi, C, Gkourogianni, A, Mohnike, K, DeArment, D, Witchel, S, Andrade, AC, et al.. Aggrecan variations in nonfamilial short stature and short stature without accelerated skeletal maturation. J Endocr Soc 2017;1:1006–11. https://doi.org/10.1210/js.2017-00229.Search in Google Scholar PubMed PubMed Central
22. Liang, H, Miao, H, Pan, H, Yang, H, Gong, F, Duan, L, et al.. Growth-promoting therapies may be useful in short stature patients with nonspecific skeletal abnormalities caused by acan heterozygous variations: six Chinese cases and literature review. Endocr Pract 2020;26:1255–68. https://doi.org/10.4158/ep-2019-0518.Search in Google Scholar
23. Deng, S, Hou, L, Xia, D, Li, X, Peng, X, Xiao, X, et al.. Description of the molecular and phenotypic spectrum in Chinese patients with aggrecan deficiency: novel ACAN heterozygous variants in eight Chinese children and a review of the literature. Front Endocrinol 2022;13:1015954. https://doi.org/10.3389/fendo.2022.1015954.Search in Google Scholar PubMed PubMed Central
24. Dateki, S. ACAN variations as a cause of familial short stature. Clin Pediatr Endocrinol 2017;26:119–25. https://doi.org/10.1297/cpe.26.119.Search in Google Scholar PubMed PubMed Central
25. Quintos, JB, Guo, MH, Dauber, A. Idiopathic short stature due to novel heterozygous variation of the aggrecan gene. J Pediatr Endocrinol Metab 2015;28:927–32. https://doi.org/10.1515/jpem-2014-0450.Search in Google Scholar PubMed PubMed Central
26. Fenwick, SA, Gregg, PJ, Kumar, S, Smith, J, Rooney, P. Intrinsic control of vascularization in developing cartilage rudiments. Int J Exp Pathol 1997;78:187–96. https://doi.org/10.1046/j.1365-2613.1997.210355.x.Search in Google Scholar PubMed PubMed Central
27. Hu, X, Gui, B, Su, J, Li, H, Li, N, Yu, T, et al.. Novel pathogenic ACAN variants in non-syndromic short stature patients. Clin Chim Acta 2017;469:126–9. https://doi.org/10.1016/j.cca.2017.04.004.Search in Google Scholar PubMed
28. Kim, TY, Jang, KM, Keum, CW, Oh, SH, Chung, WY. Identification of a heterozygous ACAN variation in a 15-year-old boy with short stature who presented with advanced bone age: a case report and review of the literature. Ann Pediatr Endocrinol Metab 2020;25:272–6. https://doi.org/10.6065/apem.1938198.099.Search in Google Scholar PubMed PubMed Central
29. Xu, D, Sun, C, Zhou, Z, Wu, B, Yang, L, Chang, Z, et al.. Novel aggrecan variant, p. Gln2364Pro, causes severe familial nonsyndromic adult short stature and poor growth hormone response in Chinese children. BMC Med Genet 2018;19:79. https://doi.org/10.1186/s12881-018-0591-z.Search in Google Scholar PubMed PubMed Central
30. Wu, H, Wang, C, Yu, S, Ye, X, Jiang, Y, He, P, et al.. Downregulation of ACAN is Associated with the Growth hormone pathway and Induces short stature. J Clin Lab Anal 2023;37:e24830. https://doi.org/10.1002/jcla.24830.Search in Google Scholar PubMed PubMed Central
31. Van der Steen, M, Pfundt, R, Maas, S, Bakker-van Waarde, WM, Odink, RJ, Hokken Koelega, ACS. ACAN gene variations in short children born SGA and response to growth hormone treatment. J Clin Endocrinol Metab 2017;102:1458–67. https://doi.org/10.1210/jc.2016-2941.Search in Google Scholar PubMed
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- Through the eyes of the parents: a transdiagnostic psychiatric perspective for children with differences of sexual development
- Experiences and psychological issues affecting parents of children born with atypical genitalia in India
- Case Reports
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- Novel PIK3R1 gene mutation associated with SHORT syndrome: a case report of a 15-year-old female
- Mineralocorticoid receptor antagonist monotherapy in pediatric non-classical 11β-hydroxylase deficiency
- A rare case of skeletal dysplasia: biallelic variant in ACAN gene
- Letter to the Editor
- Another look at the necessity of polysomnography for infants with Prader-Willi syndrome prior to initiation of growth hormone therapy
- Annual Reviewer Acknowledgment
- Reviewer Acknowledgment
Articles in the same Issue
- Frontmatter
- Review
- Effect and safety of aromatase inhibitors for the treatment of short stature in male children and adolescents: a meta-analysis of randomized controlled trials
- Original Articles
- Do hybrid closed loop insulin pump systems improve glycemic control and reduce hospitalizations in poorly controlled type 1 diabetes?
- Long-term effectiveness and safety of long-acting growth hormone preparation in children with growth hormone deficiency
- Gonadal changes in children and adolescents with congenital adrenal hyperplasia
- Hsa_circ_0002473 inhibits GH3 cell proliferation and GH secretion as a competitive endogenous RNA for has-miR-4645-3p
- Through the eyes of the parents: a transdiagnostic psychiatric perspective for children with differences of sexual development
- Experiences and psychological issues affecting parents of children born with atypical genitalia in India
- Case Reports
- A rare case of central precocious puberty in a male infant with adrenal hypoplasia congenita
- Gly183Ser homozygous mutation of the steroid 5-a reductase type 2 (SRD5A2) gene in a Brazilian patient: case report
- Novel PIK3R1 gene mutation associated with SHORT syndrome: a case report of a 15-year-old female
- Mineralocorticoid receptor antagonist monotherapy in pediatric non-classical 11β-hydroxylase deficiency
- A rare case of skeletal dysplasia: biallelic variant in ACAN gene
- Letter to the Editor
- Another look at the necessity of polysomnography for infants with Prader-Willi syndrome prior to initiation of growth hormone therapy
- Annual Reviewer Acknowledgment
- Reviewer Acknowledgment
