Geleophysic and acromicric dysplasias: natural history, genotype–phenotype correlations, and management guidelines from 38 cases

Abstract

Purpose

Geleophysic dysplasia (GD) and acromicric dysplasia (AD) are characterized by short stature, short extremities, and progressive joint limitation. In GD, cardiorespiratory involvement can result in poor prognosis. Dominant variants in the FBN1 and LTBP3 genes are responsible for AD or GD, whereas recessive variants in the ADAMTSL2 gene are responsible for GD only. The aim of this study was to define the natural history of these disorders and to establish genotype–phenotype correlations.

Methods

This monocentric retrospective study was conducted between January 2008 and December 2018 in a pediatric tertiary care center and included patients with AD or GD with identified variants (FBN1, LTBP3, or ADAMTSL2).

Results

Twenty-two patients with GD (12 ADAMTSL2, 8 FBN1, 2 LTBP3) and 16 patients with AD (15 FBN1, 1 LTBP3) were included. Early death occurred in eight GD and one AD. Among GD patients, 68% presented with heart valve disease and 25% developed upper airway obstruction. No AD patient developed life-threatening cardiorespiratory issues. A greater proportion of patients with either a FBN1 cysteine variant or ADAMTSL2 variants had a poor outcome.

Conclusion

GD and AD are progressive multisystemic disorders with life-threatening complications associated with specific genotype. A careful multidisciplinary follow-up is needed.

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Fig. 1: Postsurgery mitral valve of patient 15 and control with Masson trichrome stain.
Fig. 2: Structure analyses of missense pathogenic variants involving a cysteine in the TB5 domain of the FBN1 protein.
Fig. 3: Two-dimensional representations of ADAMTSL2 and LTB3 proteins.

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Correspondence to Valérie Cormier-Daire MD, PhD.

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Marzin, P., Thierry, B., Dancasius, A. et al. Geleophysic and acromicric dysplasias: natural history, genotype–phenotype correlations, and management guidelines from 38 cases. Genet Med (2020). https://doi.org/10.1038/s41436-020-00994-x

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Keywords

  • acromelic dysplasia
  • TGF-β
  • FBN1
  • ADAMTSL2
  • LTBP3

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