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

Pauline Marzin; Briac Thierry; Andrea Dancasius; Anne Cavau; Caroline Michot; Sophie Rondeau; Geneviève Baujat; Gilles Phan; Maryse Bonnière; Muriel Le Bourgeois; Diala Khraiche; Zagorka Pejin; Damien Bonnet; Christophe Delacourt; Valérie Cormier-Daire

doi:10.1038/s41436-020-00994-x

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

Genet Med. 2021 Feb;23(2):331-340. doi: 10.1038/s41436-020-00994-x. Epub 2020 Oct 21.

Authors

Pauline Marzin^{1

2}, Briac Thierry^{3

4}, Andrea Dancasius^{1

2}, Anne Cavau¹, Caroline Michot^{1

2}, Sophie Rondeau^{1

2}, Geneviève Baujat^{1

2}, Gilles Phan⁵, Maryse Bonnière⁶, Muriel Le Bourgeois⁷, Diala Khraiche⁸, Zagorka Pejin⁹, Damien Bonnet^{8

10}, Christophe Delacourt⁷, Valérie Cormier-Daire^{11

12}

Affiliations

¹ Fédération de Génétique médicale, Centre de référence pour les maladies osseuses constitutionnelles AP-HP, Hôpital Necker-Enfants malades, Paris, France.
² Université de Paris, UMR1163, INSERM, Institut Imagine, Paris, France.
³ ENT pediatric department, AP-HP, Necker Children Hospital, Paris, France.
⁴ Université de Paris UMR976, INSERM, Paris, France.
⁵ Université de Paris, UMR8038, CNRS, Faculté de Pharmacie, Paris, France.
⁶ Service de fœtopathologie, AP-HP, Hôpital Necker-Enfants malades, Paris, France.
⁷ Service de Pneumologie et Allergologie Pédiatriques, AP-HP, Hôpital Necker-Enfants malades, Paris, France.
⁸ M3C-Necker, Cardiologie Congénitale et Pédiatrique, AP-HP, Hôpital Necker-Enfants malades, Paris, France.
⁹ Service de chirurgie orthopédique pédiatrique, hôpital Necker-Enfants-Malades, Paris, France.
¹⁰ Université de Paris, Sorbonne Paris Cité, Paris, France.
¹¹ Fédération de Génétique médicale, Centre de référence pour les maladies osseuses constitutionnelles AP-HP, Hôpital Necker-Enfants malades, Paris, France. valerie.cormier-daire@inserm.fr.
¹² Université de Paris, UMR1163, INSERM, Institut Imagine, Paris, France. valerie.cormier-daire@inserm.fr.

PMID: 33082559
DOI: 10.1038/s41436-020-00994-x

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.

Keywords: ADAMTSL2; FBN1; LTBP3; TGF-β; acromelic dysplasia.

MeSH terms

ADAMTS Proteins* / genetics
Bone Diseases, Developmental
Child
Fibrillin-1 / genetics
Fibrillins
Genetic Association Studies
Humans
Limb Deformities, Congenital
Microfilament Proteins* / genetics
Mutation
Retrospective Studies

Substances

Fibrillin-1
Fibrillins
Microfilament Proteins
ADAMTS Proteins
ADAMTSL2 protein, human

Supplementary concepts

Acromicric dysplasia