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

Genetics in Medicine (2020)Cite this article

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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Author information

Affiliations

  1. Fédération de Génétique médicale, Centre de référence pour les maladies osseuses constitutionnelles AP-HP, Hôpital Necker-Enfants malades, Paris, France

    Pauline Marzin MD, Andrea Dancasius MD, Anne Cavau MD, Caroline Michot MD, PhD, Sophie Rondeau MD, Geneviève Baujat MD & Valérie Cormier-Daire MD, PhD

  2. Université de Paris, UMR1163, INSERM, Institut Imagine, Paris, France

    Pauline Marzin MD, Andrea Dancasius MD, Caroline Michot MD, PhD, Sophie Rondeau MD, Geneviève Baujat MD & Valérie Cormier-Daire MD, PhD

  3. ENT pediatric department, AP-HP, Necker Children Hospital, Paris, France

    Briac Thierry MD

  4. Université de Paris UMR976, INSERM, Paris, France

    Briac Thierry MD

  5. Université de Paris, UMR8038, CNRS, Faculté de Pharmacie, Paris, France

    Gilles Phan PhD

  6. Service de fœtopathologie, AP-HP, Hôpital Necker-Enfants malades, Paris, France

    Maryse Bonnière MD

  7. Service de Pneumologie et Allergologie Pédiatriques, AP-HP, Hôpital Necker-Enfants malades, Paris, France

    Muriel Le Bourgeois MD & Christophe Delacourt MD, PhD

  8. M3C-Necker, Cardiologie Congénitale et Pédiatrique, AP-HP, Hôpital Necker-Enfants malades, Paris, France

    Diala Khraiche MD & Damien Bonnet MD, PhD

  9. Service de chirurgie orthopédique pédiatrique, hôpital Necker-Enfants-Malades, Paris, France

    Zagorka Pejin MD

  10. Université de Paris, Sorbonne Paris Cité, Paris, France

    Damien Bonnet MD, PhD

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  1. Pauline Marzin MD
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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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