Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations.
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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, Pruhová Štepánka, Elblova Lenka, Quintos Jose Bernardo, Segerlund Emma, Sentchordi Lucia, Shinawi Marwan, Stattin Eva-Lena, Swartz Jonathan, Angel Ariadna González Del, Cuéllar Sinhué Diaz, Hosono Hidekazu, Sanchez-Lara Pedro A, Hwa Vivian, Baron Jeffrey, Nilsson Ola, Dauber Andrew
Аннотация
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.