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Title: | Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations |
Authors: | GKOUROGIANNI, Alexandra; ANDREW, Melissa; TYZINSKI, Leah; CROCKER, Melissa; DOUGLAS, Jessica; DUNBAR, Nancy; FAIRCHILD, Jan; FUNARI, Mariana F. A.; HEATH, Karen E.; JORGE, Alexander A. L.; KURTZMAN, Tracey; LAFRANCHI, Stephen; LALANI, Seema; LEBL, Jan; LIN, Yuezhen; LOS, Evan; NEWBERN, Dorothee; NOWAK, Catherine; OLSON, Micah; POPOVIC, Jadranka; PRUHOVA, Stepanka; ELBLOVA, Lenka; QUINTOS, Jose Bernardo; SEGERLUND, Emma; SENTCHORDI, Lucia; SHINAWI, Marwan; STATTIN, Eva-Lena; SWARTZ, Jonathan; ANGEL, Ariadna Gonzalez del; CUELLAR, Sinhue Diaz; HOSONO, Hidekazu; SANCHEZ-LARA, Pedro A.; HWA, Vivian; BARON, Jeffrey; NILSSON, Ola; DAUBER, Andrew |
Citation: | JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, v.102, n.2, p.460-469, 2017 |
Abstract: | 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, -2.8 standard deviation score (SDS); range, -5.9 to -0.9] 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, -2.0 SDS; range, -4.2 to -0.6). Most children with ACAN mutations had advanced bone age (bone age - 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. |
Appears in Collections: | Artigos e Materiais de Revistas Científicas - FM/MCM Artigos e Materiais de Revistas Científicas - HC/ICHC Artigos e Materiais de Revistas Científicas - LIM/25 Artigos e Materiais de Revistas Científicas - LIM/42 |
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