ESPE Abstracts (2014) 82 FC4.4

Short Stature, Accelerated Bone Maturation, and Early Growth Cessation due to Heterozygous Aggrecan Mutations

Ola Nilssona,b, Michael Guoc,f, Nancy Dunbard, Jadranka Popovice, Daniel Flynne, Christina Jacobsenc, Julian Luia, Joel Hirschhornf,g, Jeffrey Barona & Andrew Dauberc,g

aProgram in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA; bPediatric Endocrinology Unit, Department of Women’s and Children’s Health, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; cDivision of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA; dConnecticut Children’s Medical Center, Hartford, Connecticut, USA; eChildren’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; fDepartment of Genetics, Harvard Medical School, Boston, Massachusetts, USA; gProgram in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA

Background: Most children with idiopathic short stature (ISS) have a delayed bone age (BA). ISS with advanced BA is far less common. We studied three families with autosomal dominant short stature, unexplained BA acceleration, and premature growth cessation.

Objective and hypotheses: To identify the genetic cause of this condition and describe its clinical spectrum.

Method: Whole exome sequencing was performed in selected individuals from the three families.

Results: Family 1 included two brothers with short stature (−3.5, −1.9 SDS) and advanced BAs (3.5, 3.0 years over chronological age (CA)). Their mother was a normal height until her linear growth stopped at age 10 years (2 years prior to menarche) with an adult height of 145.9 cm (−2.7 SDS). Similarly, in families 2 and 3, all affected children had short stature (−2.1 to −2.9 SDS), advanced BA (1.5–4.0 years over CA). All affected adults reported early linear growth cessation (age 12–13 years) despite normal puberty, yielding decreased adult heights (−4.0 to −2.4 SDS). No endocrine explanation for short stature or advanced BA was detected in any affected individual. Less consistent features included macrocephaly, midface hypoplasia, brachydactyly, exaggerated lumbar lordosis, and early onset knee osteoarthritis. In each family, whole exome sequencing identified a novel, heterozygous variant in aggrecan (ACAN), a proteoglycan component of the extracellular matrix in growth plate and other cartilage structures. The mutations were present in all affected subjects, but in no unaffected family members. Two of the variants were predicted to be complete loss-of-function variants, one frameshift and one canonical splice site mutation, and the third variant was a missense variant leading to loss of a highly evolutionarily conserved residue in the C-type lectin domain of ACAN.

Conclusion: Our findings indicate that aggrecan mutations can present as autosomal dominant short stature with advanced BA and early growth cessation. Our findings expand the spectrum of aggrecan defects and provide a molecular genetic etiology for the unusual child with short stature and accelerated skeletal maturation.