Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations

Abstract

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.

Identification of a novel heterozygous mutation of the Aggrecan gene in a family with idiopathic short stature and multiple intervertebral disc herniation

“…As such, it is noteworthy that several patients with ACAN mutations have been recently reported to have back pain and intervertebral disc disease, although the details have not yet been described. 9 As seen in our patients, individuals with ACAN haploinsufficiency have mild short stature with advanced bone age at the pre-pubertal stage; however, premature growth cessation after the start of puberty results in severe short stature in adulthood. Premature hypertrophic chondrocyte maturation followed by the decreased expression of aggrecan in the extra-chondrocyte matrix and early invasion of blood vessels and osteoblasts into the growth plates have been proposed as the mechanisms for the advanced bone age, early epiphyseal fusion, and premature growth cessation.…”

“…13 To date, at least 25 pathological ACAN mutations including our case have been reported. [5][6][7][8][9][10][11][12] The autosomal recessive condition in a single family was characterized by extreme short stature (66-71 cm final height) with short necks, barrel chests and craniofacial abnormalities, including macrocephaly, brachydactyly, and mid-face hypoplasia, referred as SEMD aggrecan type. 5 On the other hand, the heterozygous mutations exhibit a broad phenotypic spectrum of short stature associated with advanced bone maturation, early-onset osteoarthritis, and mild dysmorphic features including mid-facial hypoplasia, brachydactyly, broad great toes, and lumbar lordosis, with no apparent genotype-phenotype correlations.…”

“…16,17 Recently, the effectiveness of combined GH and GnRH analog treatment for adult height has been reported in several cases of ACAN mutations. 6,8,9 Van der Steen et al reported that patients with ACAN mutation who had received GH treatment in combination with GnRH analog treatment for 2 years from the onset of puberty achieved 5 to 8 cm greater adult height than their family members of the same sex with an ACAN mutation. 8 In our study, the estimated final height of the elder brother (158.5 cm), who has received combined GH and GnRH analog treatment, is higher than that of the younger brother (145.6 cm), who has received GnRH analog only.…”

“…4 To date, at least 24 pathological ACAN mutations have been identified in patients with highly variable phenotypes, such as spondyloepimetaphyseal dysplasia (SEMD) aggrecan type, spondyloepiphyseal dysplasia Kimberley type, familial osteochondritis dissecans, early-onset osteoarthritis, and short stature with advanced bone maturation. [5][6][7][8][9][10][11][12] We herein report a Japanese family with ISS with a novel heterozygous frameshift mutation in the ACAN gene (c.1744delT; p.Phe582fs*69), providing further evidence that ACAN haploinsufficiency causes short stature with advanced bone maturation. Furthermore, we advocate multiple lumbar disc herniation as a novel phenotype associated with ACAN haploinsufficiency.…”

Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature

“…For example, SHOX abnormalities account for 1-17% of ISS cases [4,5]. Mutations in ACAN, a gene encoding an essential component of cartilage extracellular matrix aggrecan, lead to autosomal dominant ISS accompanied by advanced bone age, midface hypoplasia, and joint problems [6][7][8].…”