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Clin Endocrinol (Oxf). 2018 Jun;88(6):820-829. doi: 10.1111/cen.13581. Epub 2018 Mar 24.

Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature.

Author information

1
Department of Pediatrics, Hospital Universitario Infanta Leonor, Madrid, Spain.
2
Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autonóma de Madrid, IdiPAZ, Madrid, Spain.
3
Skeletal dysplasia Multidisciplinary Unit (UMDE), Hospital Universitario La Paz, Madrid, Spain.
4
CIBERER, ISCIII, Madrid, Spain.
5
Department of Pediatric Endocrinology, Hospital Universitario La Paz, Madrid, Spain.
6
Department of Pediatric Endocrinology, Hospital de Terrassa, Terrassa, Spain.
7
Department of Pediatrics, Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario Salamanca, Salamanca, Spain.
8
Department of Pediatrics, Hospital Universitario Puerta del Mar, Cádiz, Spain.
9
Department of Pediatrics, Hospital Virgen de la Salud, Toledo, Spain.
10
Department of Pediatrics, Hospital Universitario Río Hortega, Valladolid, Spain.
11
Department of Endocrinology, Instituto de Investigación Sanitaria La Princesa, Hospital Infantil Universitario Niño Jesús, Universidad Autonóma de Madrid, Madrid, Spain.
12
Department of Pediatrics, Universidad Autónoma de Madrid and CIBEROBN, ISCIII, Madrid, Spain.
13
Department of Oncology and Metabolism, Academic Unit of Child Health, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
14
Department of Pediatric Radiology, Hospital Universitario La Paz, Madrid, Spain.
15
Department of Pediatric Endocrinology, Diabetes and Growth Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
16
Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar de Coimbra, Coimbra, Portugal.
17
Department of Pediatrics, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.

Abstract

OBJECTIVE:

Mutations in the aggrecan gene (ACAN) have been identified in two autosomal dominant skeletal dysplasias, spondyloepiphyseal dysplasia, Kimberley type (SEDK), and osteochondritis dissecans, as well as in a severe recessive dysplasia, spondyloepimetaphyseal dysplasia, aggrecan type. Next-generation sequencing (NGS) has aided the identification of heterozygous ACAN mutations in individuals with short stature, minor skeletal defects and mild facial dysmorphisms, some of whom have advanced bone age (BA), poor pubertal spurt and early growth cessation as well as precocious osteoarthritis.

DESIGN AND METHODS:

This study involves clinical and genetic characterization of 16 probands with heterozygous ACAN variants, 14 with short stature and mild skeletal defects (group 1) and two with SEDK (group 2). Subsequently, we reviewed the literature to determine the frequency of the different clinical characteristics in ACAN-positive individuals.

RESULTS:

A total of 16 ACAN variants were located throughout the gene, six pathogenic mutations and 10 variants of unknown significance (VUS). Interestingly, brachydactyly was observed in all probands. Probands from group 1 with a pathogenic mutation tended to be shorter, and 60% had an advanced BA compared to 0% in those with a VUS. A higher incidence of coxa valga was observed in individuals with a VUS (37% vs 0%). Nevertheless, other features were present at similar frequencies.

CONCLUSIONS:

ACAN should be considered as a candidate gene in patients with short stature and minor skeletal defects, particularly those with brachydactyly, and in patients with spondyloepiphyseal dysplasia. It is also important to note that advanced BA and osteoarticular complications are not obligatory conditions for aggrecanopathies/aggrecan-associated dysplasias.

KEYWORDS:

ACAN; aggrecan; brachydactyly; short stature; skeletal dysplasia

PMID:
29464738
DOI:
10.1111/cen.13581
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