medwireNews: A study reports the characteristics of a series of patients with heterozygous mutations in the gene encoding aggrecan (ACAN).
Fourteen of the 16 reported cases had short stature, with a median height standard deviation score (SDS) of –2.9, and mild skeletal dysplasia, and the other two cases had spondyloepiphyseal dysplasia, Kimberley type (SEDK).
Six of the variants of ACAN – the protein product of which is an important component of the cartilage growth plate – were classified as pathogenic and 10 were variants of unknown significance (VUS). All but one of the mutations were inherited, identified in a total of 20 family members who all had short stature and/or mild skeletal defects or SEDK.
Researcher Karen Heath (Institute of Medical & Molecular Genetics, Madrid, Spain) and colleagues note that all 14 patients without SEDK had brachydactyly, in contrast to previous reports, and they suggest this finding could prompt clinicians to request analysis of ACAN. They also highlight that 38% of patients had mild hip abnormalities, which they say is previously unreported.
In other aspects, the patients varied, with three having advanced bone age, two of three who had reached their adult height having had a poor pubertal growth spurt, and the severity of short stature being “very variable”. A fairly common presentation, seen in seven (53%) patients was frontal bossing and depressed nasal bridge and/or mid-facial dysplasia.
Phenotype varied according to the type of ACAN variant; those with pathogenic mutations were shorter than those with VUS, with a height SDS of –3.33 versus –2.7, coxa valga was present in 37% versus 0%, and 60% versus 0% had advanced bone age.
The researchers note that, based on reported findings to date, although advanced bone age “is a good indicator for the presence of mutations in ACAN, it cannot be the principal selection criteria.”
Clinical features also varied between members of the same family with the same variant, leading the researchers to suggest that the manifestations of the mutations can vary with age.
Writing in Clinical Endocrinology, the team stresses the importance of the correct diagnosis of ACAN-related dysplasias.
“Individuals with ACAN mutations are at risk of short stature, early growth cessation and poor pubertal spurt, and other health related problems such as obesity and orthopaedic problems should be prevented or their effects reduced”, they say.
Clin Endocrinol 2018; Advance online publication
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