M Crippa1, S Giangiobbe2, R Villa2, I Bestetti1, T De Filippis3, L Fatti3, J Taurino2, L Larizza1, L Persani3,4, F Bellini5, P Finelli1,6, M T Bonati7. 1. Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano, via Ariosto 13, 20145, Milan, Italy. 2. Clinic of Medical Genetics, IRCCS Istituto Auxologico Italiano, Piazzale Brescia 20, 20149, Milan, Italy. 3. Laboratory of Endocrine and Metabolic Research and Division of Endocrine and Metabolic Diseases, IRCSS Istituto Auxologico Italiano, Piazzale Brescia 20, 20149, Milan, Italy. 4. Department of Clinic Sciences and Community Health, Università degli Studi, Milan, via Sforza 35, 20122, Milan, Italy. 5. Department of Radiology, IRCCS Istituto Auxologico Italiano, Casa di Cura Capitanio, via Giuseppe Mercalli 28, 20122, Milan, Italy. 6. Department of Medical Biotechnology and Translational Medicine, Università degli Studi, Milan, via Fratelli Cervi 93, Segrate, 20090, Milan, Italy. 7. Clinic of Medical Genetics, IRCCS Istituto Auxologico Italiano, Piazzale Brescia 20, 20149, Milan, Italy. mt.bonati@auxologico.it.
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.
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.
Entities:
Keywords:
Aggrecanopathies; Bone age advancement; Chromosome translocation; Decreased growth spurt; Proportionate short stature
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