Document Type : case report
- Amirsaeed Sabeti Aghabozorgi 1
- Najmeh Ahangari 2
- Moein Mobini 3
- Rahim Vakili 4
- Mohammad Doosti 5
- Saba Vakili 3
- Ehsan Ghayoor Karimiani 6
1 Medical Genetics Research Center, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran
2 Innovative Medical Research Center, Islamic Azad University, Mashhad, Iran. Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran.
3 General Paediatrics, Evelina London Children’s Hospital, Guy’s and St. Thomas’ National Health Service Foundation Trust, London, United Kingdom
4 Department of Pediatric Endocrinology and Metabolism, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
5 Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran
6 Innovative Medical Research Center, Islamic Azad University, Mashhad, Iran. Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran. Molecular and Clinical Sciences Institute, St. George’s, University of London, London, United Kingdom.
Background: Short stature is estimated to account for half of the new visits to pediatric endocrine practices. Therefore, evaluating its underlying causes seems essential in order to choose the best treatment. Recently, some studies revealed the impact of ACAN, which encodes for aggrecan, mutations on growth ranging from mild idiopathic short stature to severe skeletal dysplasia.
Methods: Here, we describe clinical and molecular characteristics of an Iranian family with short stature using exome sequencing and co-segregation analysis through Sanger sequencing.
Results: A novel variant of ACAN mutation c.1604delG (p.Arg535fs) was identified in the heterozygote pattern which was confirmed through co-segregation analysis in family members.
Conclusion: We have found a novel variant within the ACAN gene in association with insignificant bone abnormality without a high incidence of familiar bone malformation. In order to achieve better clinical outcomes, we suggest genetic testing at an earlier age and also long-term GH treatment for children who are at risk of ACAN mutations. Children who are born small considering their gestational age, or who have persistent short stature, advanced bone age, midfacial hypoplasia, joint problems, or broad toes, can be candidates for ACAN sequencing.
- Stavber L, Hovnik T, Kotnik P, Lovrečić L, Kovač J, Tesovnik T, Bertok S, Dovč K, Debeljak M, Battelino T, Avbelj Stefanija M. High frequency of pathogenic ACAN variants including an intragenic deletion in selected individuals with short stature. European journal of endocrinology. 2020; 182(3):243-53.
- Wit JM, Clayton P, Rogol A, Savage M, Saenger P, Cohen P. Idiopathic short stature: definition, epidemiology, and diagnostic evaluation. Growth Hormone & IGF Research. 2008; 18(2):89-110.
- Murray PG, Clayton PE, Chernausek SD. A genetic approach to evaluation of short stature of undetermined cause. The Lancet Diabetes & Endocrinology. 2018; 6(7):564-74.
- Xu D, Sun C, Zhou Z, Wu B, Yang L, Chang Z, Zhang M, Xi L, Cheng R, Ni J, Luo F. Novel aggrecan variant, p. Gln2364Pro, causes severe familial nonsyndromic adult short stature and poor growth hormone response in Chinese children. BMC medical genetics. 2018; 19(1):1-8.
- Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, 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(5):405-24.
- Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, 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. Genetics in medicine. 2015; 17(5):405-23.
- Thompson SW, Merriman B, Funari VA, Fresquet M, Lachman RS, Rimoin DL, Nelson SF, Briggs MD, Cohn DH, Krakow D. A recessive skeletal dysplasia, SEMD aggrecan type, results from a missense mutation affecting the C-type lectin domain of aggrecan. The American Journal of Human Genetics. 2009; 84(1):72-9.
- Hu X, Gui B, Su J, Li H, Li N, Yu T, Zhang Q, Xu Y, Li G, Chen Y, Qing Y, Chinese Genetic Short Stature Consortium; Li C, Luo J, Fan X, Ding Y, Li J, Wang J, Wang X, Chen S, Shen Y. Novel pathogenic ACAN variants in non-syndromic short stature patients. Clinica Chimica Acta. 2017; 469:126-9.
- van der Steen M, Pfundt R, Maas SJ, Bakker-van Waarde WM, Odink RJ, Hokken-Koelega AC. ACAN gene mutations in short children born SGA and response to growth hormone treatment. The Journal of Clinical Endocrinology & Metabolism. 2017; 102(5):1458-67.
- Nilsson O, Guo MH, Dunbar N, Popovic J, Flynn D, Jacobsen C, Flynn D, Jacobsen C, Lui JC, Hirschhorn JN, Baron J, Dauber A. Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations. The Journal of Clinical Endocrinology & Metabolism. 2014; 99(8):E1510-E8.
- Quintos JB, Guo MH, Dauber A. Idiopathic short stature due to novel heterozygous mutation of the aggrecan gene. Journal of Pediatric Endocrinology and Metabolism. 2015; 28(7-8):927-32.
- Kang MJ. Novel genetic cause of idiopathic short stature. Annals of pediatric endocrinology & metabolism. 2017; 22(3):153.
- Sentchordi-Montané L, Aza-Carmona M, Benito-Sanz S, Barreda-Bonis AC, Sánchez-Garre C, Prieto-Matos P, Ruiz-Ocaña P, Lechuga-Sancho A, Carcavilla-Urquí A, Mulero-Collantes I, Martos-Moreno GA, Pozo AD, Vallespín E, Offiah A, Parrón-Pajares M, Dinis I, Sousa SB, Ros-Pérez P, González-Casado I, Heath KE. Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature. Clinical endocrinology. 2018; 88(6):820-9.
- Florio A, Papa R, Caorsi R, Consolaro A, Gastaldi R, Gattorno M, Picco P. A child with a novel ACAN missense variant mimicking septic arthritis. Italian Journal of Pediatrics. 2019; 45(1):148.