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.
| Original language | English |
|---|---|
| Pages (from-to) | 929-936 |
| Number of pages | 8 |
| Journal | Journal of Endocrinological Investigation |
| Volume | 41 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - Aug 1 2018 |
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Keywords
- Aggrecanopathies
- Bone age advancement
- Chromosome translocation
- Decreased growth spurt
- Proportionate short stature
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Endocrinology
Cite this
A balanced reciprocal translocation t(10;15)(q22.3;q26.1) interrupting ACAN gene in a family with proportionate short stature. / Crippa, M.; Giangiobbe, S.; Villa, R.; Bestetti, I.; De Filippis, T.; Fatti, L.; Taurino, J.; Larizza, L.; Persani, L.; Bellini, F.; Finelli, P.; Bonati, M. T.
In: Journal of Endocrinological Investigation, Vol. 41, No. 8, 01.08.2018, p. 929-936.Research output: Contribution to journal › Article
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TY - JOUR
T1 - A balanced reciprocal translocation t(10;15)(q22.3;q26.1) interrupting ACAN gene in a family with proportionate short stature
AU - Crippa, M.
AU - Giangiobbe, S.
AU - Villa, R.
AU - Bestetti, I.
AU - De Filippis, T.
AU - Fatti, L.
AU - Taurino, J.
AU - Larizza, L.
AU - Persani, L.
AU - Bellini, F.
AU - Finelli, P.
AU - Bonati, M. T.
PY - 2018/8/1
Y1 - 2018/8/1
N2 - 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.
AB - 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.
KW - Aggrecanopathies
KW - Bone age advancement
KW - Chromosome translocation
KW - Decreased growth spurt
KW - Proportionate short stature
UR - http://www.scopus.com/inward/record.url?scp=85040034782&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85040034782&partnerID=8YFLogxK
U2 - 10.1007/s40618-017-0819-3
DO - 10.1007/s40618-017-0819-3
M3 - Article
C2 - 29302920
AN - SCOPUS:85040034782
VL - 41
SP - 929
EP - 936
JO - Journal of Endocrinological Investigation
JF - Journal of Endocrinological Investigation
SN - 0391-4097
IS - 8
ER -