Abstract
Purpose
Few examples of the involvement of a single gene in idiopathic short stature have been described until now. Our aim was to identify the causative gene of proportionate short stature in a large family showing co-segregation of the phenotype with the reciprocal translocation t(10;15)(q22;q24).
Methods
FISH mapping was carried out with BACs and long-range PCR probes to identify the smallest genomic regions harboring the translocation breakpoints. Real-Time RT-PCR was performed in blood after pre-amplification of target genes cDNA.
Result
The affected family members presented with a final height of between − 2.41 and − 4.18 SDS and very mild skeletal dysmorphisms. Growth rates of the proband and of her cousin, whose childhood and pre-pubertal bone age corresponded to the chronological age, showed a poor growth spurt during treatment with rhGH. However, their adult height was greater than that of their untreated mothers, suggesting efficacy of GH therapy. Breakpoint mapping revealed that the translocation t(10;15)(q22.3;q26.1) disrupts, on 15q, the ACAN gene at intron 1, decreasing its transcriptional expression.
Conclusions
This is the first description of a chromosome rearrangement disrupting ACAN and leading to its haploinsufficiency. ACAN loss of function should be considered a potential underpinning of short patients who display a poor growth spurt and belong to families with autosomal dominant segregation of proportionate short stature. Besides this core phenotype, literature review suggests that advanced bone age, early onset osteochondritis dissecans, osteoarthritis, intervertebral disc disease as well as craniofacial dysmorphisms can be important suggestive phenotypes in affected families.
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References
Andrade AC, Jee YH, Nilsson O (2017) New genetic diagnoses of short stature provide insights into local regulation of childhood growth. Horm Res Paediatr 88:22–37. https://doi.org/10.1159/000455850
Bonafe L, Cormier-Daire V, Hall C, Lachman R, Mortier G, Mundlos S, Nishimura G, Sangiorgi L, Savarirayan R, Sillence D, Spranger J, Superti-Furga A, Warman M, Unger S (2015) Nosology and classification of genetic skeletal disorders: 2015 revision. Am J Med Genet Part A 167(12):2869–2892. https://doi.org/10.1002/ajmg.a.37365
Nilsson O, Guo MH, Dunbar N, Popovic J, Flynn D, Jacobsen C, Lui JC, Hirschhorn JN, Baron J, Dauber A (2014) Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations. J Clin Endocrinol Metab 99(8):E1510–E1518. https://doi.org/10.1210/jc.2014-1332
Quintos JB, Guo MH, Dauber A (2015) Idiopathic short stature due to novel heterozygous mutation of the aggrecan gene. J Pediatr Endocrinol Metab 28(7–8):927–932. https://doi.org/10.1515/jpem-2014-0450
Gkourogianni A, Andrew M, Tyzinski L, Crocker M, Douglas J, Dunbar N, Fairchild J, Funari MF, Heath KE, Jorge AA, Kurtzman T, LaFranchi S, Lalani S, Lebl J, Lin Y, Los E, Newbern D, Nowak C, Olson M, Popovic J, Pruhová Š, Elblova L, Quintos JB, Segerlund E, Sentchordi L, Shinawi M, Stattin EL, Swartz J, Angel AG, Cuéllar SD, Hosono H, Sanchez-Lara PA, Hwa V, Baron J, Nilsson O, Dauber A (2017) Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations. J Clin Endocrinol Metab 102(2):460–469. https://doi.org/10.1210/jc.2016-3313
van der Steen M, Pfundt R, Maas SJWH, Bakker-van Waarde WM, Odink RJ, Hokken-Koelega ACS (2017) ACAN gene mutations in short children born SGA and response to growth hormone treatment. J Clin Endocrinol Metab 102(5):1458–1467. https://doi.org/10.1210/jc.2016-2941
Dateki S, Nakatomi A, Watanabe S, Shimizu H, Inoue Y, Baba H, Yoshiura KI, Moriuchi H (2017) 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(7):717–721. https://doi.org/10.1038/jhg.2017.33
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 (2017) Novel pathogenic ACAN variants in non-syndromic short stature patients. Clin Chim Acta 469:126–129. https://doi.org/10.1016/j.cca.2017.04.004
Hattori A, Katoh-Fukui Y, Nakamura A, Matsubara K, Kamimaki T, Tanaka H, Dateki S, Adachi M, Muroya K, Yoshida S, Ida S, Mitani M, Nagasaki K, Ogata T, Suzuki E, Hata K, Nakabayashi K, Matsubara Y, Narumi S, Tanaka T, Fukami M (2017) Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature. Endocr J 64(10):947–954. https://doi.org/10.1507/endocrj.EJ17-0150
Hauer NN, Sticht H, Boppudi S, Büttner C, Kraus C, Trautmann U, Zenker M, Zweier C, Wiesener A, Jamra RA, Wieczorek D, Kelkel J, Jung AM, Uebe S, Ekici AB, Rohrer T, Reis A, Dörr HG, Thiel CT (2017) Genetic screening confirms heterozygous mutations in ACAN as a major cause of idiopathic short stature. Sci Rep 7(1):12225. https://doi.org/10.1038/s41598-017-12465-6
Gleghorn L, Ramesar R, Beighton P, Wallis G (2005) A mutation in the variable repeat region of the aggrecan gene (AGC1) causes a form of spondyloepiphyseal dysplasia associated with severe, premature osteoarthritis. Am J Hum Genet 77(3):484–490. https://doi.org/10.1086/444401
Stattin EL, Tegner Y, Domellöf M, Dahl N (2008) Familial osteochondritis dissecans associated with early osteoarthritis and disproportionate short stature. Osteoarthritis Cartilage 16(8):890–896. https://doi.org/10.1016/j.joca.2007.11.009
Stattin EL, Wiklund F, Lindblom K, Onnerfjord P, Jonsson BA, Tegner Y, Sasaki T, Struglics A, Lohmander S, Dahl N, Heinegård D, Aspberg A (2010) A missense mutation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans. Am J Hum Genet 86(2):126–137. https://doi.org/10.1016/j.ajhg.2009.12.018
Tompson SW, Merriman B, Funari VA, Fresquet M, Lachman RS, Rimoin DL, Nelson SF, Briggs MD, Cohn DH, Krakow D (2009) 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(1):72–79. https://doi.org/10.1016/j.ajhg.2008.12.001
Crippa M, Bestetti I, Perotti M, Castronovo C, Tabano S, Picinelli C, Grassi G, Larizza L, Pincelli AI, Finelli P (2014) New case of trichorinophalangeal syndrome-like phenotype with a de novo t(2;8)(p16.1;q23.3) translocation which does not disrupt the TRPS1 gene. BMC Med Genet 15:52. https://doi.org/10.1186/1471-2350-15-52
Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, Hilhorst-Hofstee Y, Jondeau G, Faivre L, Milewicz DM, Pyeritz RE, Sponseller PD, Wordsworth P, De Paepe AM (2010) The revised Ghent nosology for the Marfan syndrome. J Med Genet 47(7):476–485. https://doi.org/10.1136/jmg.2009.072785
Fredriks AM, van Buuren S, van Heel WJ, Dijkman-Neerincx RH, Verloove-Vanhorick SP, Wit JM (2005) Nationwide age references for sitting height, leg length, and sitting height/height ratio, and their diagnostic value for disproportionate growth disorders. Arch Dis Child 90(8):807–812
Lauing KL, Cortes M, Domowicz MS, Henry JG, Baria AT, Schwartz NB (2014) Aggrecan is required for growth plate cytoarchitecture and differentiation. Dev Biol 396(2):224–236. https://doi.org/10.1016/j.ydbio.2014.10.005
Acknowledgements
The authors would like to thank the family members for their collaboration. We also thank Dr. Mirella Moro (Division of Endocrine and Metabolic Diseases, IRCSS Istituto Auxologico Italiano, Milan) as well as Dr. Maria Francesca Bedeschi (Clinical Genetics Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan) for contributing to the clinical review.
Funding
This study was funded by the Ministry of Health ‘Ricerca Corrente’, Grant number 08C622_2016, to IRCCS Istituto Auxologico Italiano (Prof. PF).
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The authors declare that they have no conflict of interests.
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This study was approved by the Ethics Review Board of Istituto Auxologico Italiano.
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All participants gave informed consent to the genetic tests.
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40618_2017_819_MOESM1_ESM.tif
Supplementary material 1 (TIFF 5650 kb) Supplementary Fig. S1 Skeletal survey of t(10;15) carriers. Radiographs of the proband (IV-6) (A) and of her mother (III-2) (B-C) at 54 years, showing thin ribs, mild scoliosis, and stocky and ovoid femoral necks; an abnormal lateral protrusion of the tibia epiphysis in the index case IV-6 (D) and in III-2 (E). (F-G) Triangular shape of thumbs’ distal phalanges, enlargement of distal portion of the remnant distal phalanges, and (H-I) similar findings in the feet of the proband IV-6 (F, H), III-2 (G) and III-1 (I) at 54 years
40618_2017_819_MOESM2_ESM.tif
Supplementary material 2 (TIFF 2849 kb) Supplementary Fig. S2 Physical maps of the genomic regions containing the 10q22.3 bkp, which includes the BAC clones used for the FISH analysis. The probe which shows hybridization signal on der(10) is indicated in gray, that hybridizing on der(15) is in black, and those giving a smaller signal on both derivative chromosomes are indicated by striped rectangles. The known UCSC genes are shown in blue, and the segmental duplications are shown in different shades of gray (human genome assembly GRCh37/hg19)
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Crippa, M., Giangiobbe, S., Villa, R. et al. A balanced reciprocal translocation t(10;15)(q22.3;q26.1) interrupting ACAN gene in a family with proportionate short stature. J Endocrinol Invest 41, 929–936 (2018). https://doi.org/10.1007/s40618-017-0819-3
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DOI: https://doi.org/10.1007/s40618-017-0819-3