TY - JOUR
T1 - Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations
AU - Gkourogianni, Alexandra
AU - Andrew, Melissa
AU - Tyzinski, Leah
AU - Crocker, Melissa
AU - Douglas, Jessica
AU - Dunbar, Nancy
AU - Fairchild, Jan
AU - Funari, Mariana F.A.
AU - Heath, Karen E.
AU - Jorge, Alexander A.L.
AU - Kurtzman, Tracey
AU - LaFranchi, Stephen
AU - Lalani, Seema
AU - Lebl, Jan
AU - Lin, Yuezhen
AU - Los, Evan
AU - Newbern, Dorothee
AU - Nowak, Catherine
AU - Olson, Micah
AU - Popovic, Jadranka
AU - Pruhova, Stepanka
AU - Elblova, Lenka
AU - Quintos, Jose Bernardo
AU - Segerlund, Emma
AU - Sentchordi, Lucia
AU - Shinawi, Marwan
AU - Stattin, Eva Lena
AU - Swartz, Jonathan
AU - Del Angel, Ariadna Gonzalez
AU - Cuellar, Sinhue Diaz
AU - Hosono, Hidekazu
AU - Sanchez-Lara, Pedro A.
AU - Hwa, Vivian
AU - Baron, Jeffrey
AU - Nilsson, Ola
AU - Dauber, Andrew
N1 - Publisher Copyright:
© 2017 by the Endocrine Society.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - Context: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation. Objective: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies. Patients and Methods: One hundred three individuals (57 females, 46 males) from 20 families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next-generation sequencing, and/or Sanger sequencing. Clinical information was collected from the medical records. Results: Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, 22.8 standard deviation score (SDS); range, 25.9 to 20.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype-phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, 22.0 SDS; range, 24.2 to 20.6). Most children with ACAN mutations had advanced bone age (bone age 2 chronologic age; median, +1.3 years; range, +0.0 to +3.7 years). Nineteen individuals had received growth hormone therapy with some evidence of increased growth velocity. Conclusions: Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.
AB - Context: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation. Objective: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies. Patients and Methods: One hundred three individuals (57 females, 46 males) from 20 families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next-generation sequencing, and/or Sanger sequencing. Clinical information was collected from the medical records. Results: Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, 22.8 standard deviation score (SDS); range, 25.9 to 20.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype-phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, 22.0 SDS; range, 24.2 to 20.6). Most children with ACAN mutations had advanced bone age (bone age 2 chronologic age; median, +1.3 years; range, +0.0 to +3.7 years). Nineteen individuals had received growth hormone therapy with some evidence of increased growth velocity. Conclusions: Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.
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U2 - 10.1210/jc.2016-3313
DO - 10.1210/jc.2016-3313
M3 - Article
C2 - 27870580
AN - SCOPUS:85012081706
SN - 0021-972X
VL - 102
SP - 460
EP - 469
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 2
ER -