Prenatal diagnosis of a novel pathogenic variation in the <i>ACAN</i> gene presenting with isolated shortening of fetal long bones in the second trimester of gestation: a case report

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Abstract

Background

Heterozygous mutations of the ACAN gene are a major cause of different evolutive growth defects in the pediatric population, but were never described as a cause of fetal skeletal dysplasia.

Case presentation

A G1 at 21w + 3d came to our institution for the second-trimester ultrasound and a skeletal dysplasia with prevalent involvement of limb’s rhizomelic tracts was suspected. Amniocentesis followed by CGH-array was performed, with normal results. An examination by NGS of some genes associated with skeletal dysplasias showed a novel pathogenic variant of the ACAN gene: c.2677delG.

Conclusion

Sequence variations of ACAN were never described as a possible cause of fetal skeletal anomalies to date. In this case report, we describe the first prenatal diagnosis of skeletal dysplasia associated with a pathogenic variant of ACAN.

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Most cited references 4

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The role of aggrecan in normal and osteoarthritic cartilage

Peter J. Roughley, John Mort (2014)

Aggrecan is a large proteoglycan bearing numerous chondroitin sulfate and keratan sulfate chains that endow articular cartilage with its ability to withstand compressive loads. It is present in the extracellular matrix in the form of proteoglycan aggregates, in which many aggrecan molecules interact with hyaluronan and a link protein stabilizes each interaction. Aggrecan structure is not constant throughout life, but changes due to both synthetic and degradative events. Changes due to synthesis alter the structure of the chondroitin sulfate and keratan sulfate chains, whereas those due to degradation cause cleavage of all components of the aggregate. These latter changes can be viewed as being detrimental to cartilage function and are enhanced in osteoarthritic cartilage, resulting in aggrecan depletion and predisposing to cartilage erosion. Matrix metalloproteinases and aggrecanases play a major role in aggrecan degradation and their production is upregulated by mediators associated with joint inflammation and overloading. The presence of increased levels of aggrecan fragments in synovial fluid has been used as a marker of ongoing cartilage destruction in osteoarthritis. During the early stages of osteoarthritis it may be possible to retard the destructive process by enhancing the production of aggrecan and inhibiting its degradation. Aggrecan production also plays a central role in cartilage repair techniques involving stem cell or chondrocyte implantation into lesions. Thus aggrecan participates in both the demise and survival of articular cartilage.

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Genetic screening confirms heterozygous mutations in ACAN as a major cause of idiopathic short stature

Nadine Hauer, Heinrich Sticht, Sangamitra Boppudi … (2017)

Short stature is a common pediatric disorder affecting 3% of the population. However, the clinical variability and genetic heterogeneity prevents the identification of the underlying cause in about 80% of the patients. Recently, heterozygous mutations in the ACAN gene coding for the proteoglycan aggrecan, a main component of the cartilage matrix, were associated with idiopathic short stature. To ascertain the prevalence of ACAN mutations and broaden the phenotypic spectrum in patients with idiopathic short stature we performed sequence analyses in 428 families. We identified heterozygous nonsense mutations in four and potentially disease-causing missense variants in two families (1.4%). These patients presented with a mean of −3.2 SDS and some suggestive clinical characteristics. The results suggest heterozygous mutations in ACAN as a common cause of isolated as well as inherited idiopathic short stature.

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The aggrecanopathies; an evolving phenotypic spectrum of human genetic skeletal diseases

Beth Gibson, MICHAEL D. BRIGGS (2016)

The large chondroitin sulphated proteoglycan aggrecan (ACAN) is the most abundant non-collagenous protein in cartilage and is essential for its structure and function. Mutations in ACAN result in a broad phenotypic spectrum of non-lethal skeletal dysplasias including spondyloepimetaphyseal dysplasia, spondyloepiphyseal dysplasia, familial osteochondritis dissecans and various undefined short stature syndromes associated with accelerated bone maturation. However, very little is currently known about the disease pathways that underlie these aggrecanopathies, although they are likely to be a combination of haploinsufficiency and dominant-negative (neomorphic) mechanisms. This review discusses the known human and animal aggrecanopathies in the context of clinical presentation and potential disease mechanisms.

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Author and article information

Contributors

Lavinia Di Meglio:

ORCID: http://orcid.org/0000-0003-0759-4545

laviniadimeglio@gmail.com

Journal

Journal ID (nlm-ta): BMC Pregnancy Childbirth

Journal ID (iso-abbrev): BMC Pregnancy Childbirth

Title: BMC Pregnancy and Childbirth

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2393

Publication date (Electronic): 29 June 2021

Publication date PMC-release: 29 June 2021

Publication date Collection: 2021

Volume: 21

Electronic Location Identifier: 459

Affiliations

[1 ]GRID grid.4691.a, ISNI 0000 0001 0790 385X, Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine and Surgery Federico II of Naples, , University of Naples Federico II, ; Naples, Italy

[2 ]Diagnostica Ecografica e Prenatale di A. Di Meglio, Via dei Fiorentini n.21, Naples, Italy

[3 ]GRID grid.4708.b, ISNI 0000 0004 1757 2822, Department of Obstetrics and Gynecology, H. Buzzi, , University of Milan, ; Milan, Italy

[4 ]Department of Medical Genetics, A.O.R.N. “San Pio”, Benevento, Italy

Author information

Lavinia Di Meglio http://orcid.org/0000-0003-0759-4545

Article

Publisher ID: 3952

DOI: 10.1186/s12884-021-03952-w

PMC ID: 8243643

PubMed ID: 34187405

SO-VID: 3bbccde8-391e-48a3-aa95-33729d8a0acc

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 23 March 2021

Date accepted : 10 June 2021

Custom metadata

ScienceOpen disciplines: Obstetrics & Gynecology

Keywords: prenatal diagnosis,skeletal dysplasia,acan,aggrecan,case report

Data availability:

ScienceOpen disciplines: Obstetrics & Gynecology

Keywords: prenatal diagnosis, skeletal dysplasia, acan, aggrecan, case report

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Prenatal diagnosis of a novel pathogenic variation in the ACAN gene presenting with isolated shortening of fetal long bones in the second trimester of gestation: a case report

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Abstract

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Most cited references 4

The role of aggrecan in normal and osteoarthritic cartilage

Genetic screening confirms heterozygous mutations in ACAN as a major cause of idiopathic short stature

The aggrecanopathies; an evolving phenotypic spectrum of human genetic skeletal diseases

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