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.
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).
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.
GD and AD are progressive multisystemic disorders with life-threatening complications associated with specific genotype. A careful multidisciplinary follow-up is needed.
Subscribe to Journal
Get full journal access for 1 year
only $41.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Le Goff C, Cormier-Daire V. Genetic and molecular aspects of acromelic dysplasia. Pediatr Endocrinol Rev PER. 2009;6:418–423.
Marzin P, Cormier-Daire V. Geleophysic dysplasia. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. Seattle: University of Washington; 1993. Accessed 4 December 2018. http://www.ncbi.nlm.nih.gov/books/NBK11168/.
Allali S, Le Goff C, Pressac-Diebold I, et al. Molecular screening of ADAMTSL2 gene in 33 patients reveals the genetic heterogeneity of geleophysic dysplasia. J Med Genet. 2011;48:417–421.
Maroteaux P, Stanescu R, Stanescu V, Rappaport R. Acromicric dysplasia. Am J Med Genet. 1986;24:447–459.
Faivre L. Acromicric dysplasia: long term outcome and evidence of autosomal dominant inheritance. J Med Genet. 2001;38:745–749.
Le Goff C, Mahaut C, Wang LW, et al. Mutations in the TGFβ binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias. Am J Hum Genet. 2011;89:7–14.
McInerney-Leo AM, Le Goff C, Leo PJ, et al. Mutations in LTBP3 cause acromicric dysplasia and geleophysic dysplasia. J Med Genet. 2016;53:457–464.
Le Goff C, Morice-Picard F, Dagoneau N, et al. ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-beta bioavailability regulation. Nat Genet. 2008;40:1119–1123.
Le Goff C, Cormier-Daire V. Chondrodysplasias and TGFβ signaling. Bonekey Rep. 2015;4:642.
Delhon L, Mahaut C, Goudin N, et al. Impairment of chondrogenesis and microfibrillar network in Adamtsl2 deficiency. FASEB J. 2019;33:2707–2718.
Liu W, Xie Y, Ma J, et al. IBS: an illustrator for the presentation and visualization of biological sequences: Fig. 1. Bioinformatics. 2015;31:3359–3361.
Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJE. The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc. 2015;10:845.
Lee SSJ, Knott V, Jovanović J, et al. Structure of the integrin binding fragment from fibrillin-1 gives new insights into microfibril organization. Structure. 2004;12:717–729.
Robert X, Gouet P. Deciphering key features in protein structures with the new ENDscript server. Nucleic Acids Res. 2014;42(W1):W320–W324.
Janson G, Zhang C, Prado MG, Paiardini A. PyMod 2.0: improvements in protein sequence-structure analysis and homology modeling within PyMOL. Bioinformatics. 2017;33:444–446.
Klein C, Goff CL, Topouchian V, et al. Orthopedics management of acromicric dysplasia: follow up of nine patients. Am J Med Genet A. 2014;164:331–337.
Moey LH, Flaherty M, Zankl A. Optic disc swelling in acromicric and geleophysic dysplasia. Am J Med Genet A. 2019;179:1898–1901.
Lin AE, Michot C, Cormier-Daire V, et al. Gain-of-function mutations in SMAD4 cause a distinctive repertoire of cardiovascular phenotypes in patients with Myhre syndrome. Am J Med Genet A. 2016;170:2617–2631.
Elhoury ME, Faqeih E, Almoukirish AS, Galal MO. Cardiac involvement in geleophysic dysplasia in three siblings of a Saudi family. Cardiol Young. 2015;25:81–86.
Rama G, Chung WK, Cunniff CM, Krishnan U. Rapidly progressive mitral valve stenosis in patients with acromelic dysplasia. Cardiol Young. 2017;27:797–800.
Scott A, Yeung S, Dickinson DF, Karbani G, Crow YJ. Natural history of cardiac involvement in geleophysic dysplasia. Am J Med Genet A. 2005;132A:320–323.
Globa E, Zelinska N, Dauber A. The clinical cases of geleophysic dysplasia: one gene, different phenotypes. Case Rep Endocrinol. 2018;2018:8212417.
Legare JM, Modaff P, Strom SP, Pauli RM, Bartlett HL. Geleophysic dysplasia: 48 year clinical update with emphasis on cardiac care. Am J Med Genet A. 2018;176:2237–2242.
Goumans M-J, ten Dijke P. TGF-β signaling in control of cardiovascular function. Cold Spring Harb Perspect Biol. 2018;10:a022210.
Gore B, Izikki M, Mercier O, et al. Key role of the endothelial TGF-β/ALK1/endoglin signaling pathway in humans and rodents pulmonary hypertension. PLoS ONE. 2014;9:e100310.
Saito A, Horie M, Nagase T. TGF-β signaling in lung health and disease. Int J Mol Sci. 2018;19:2460
Michot C, Le Goff C, Mahaut C, et al. Myhre and LAPS syndromes: clinical and molecular review of 32 patients. Eur J Hum Genet. 2014;22:1272–1277.
Oldenburg MS, Frisch CD, Lindor NM, Edell ES, Kasperbauer JL, O’Brien EK. Myhre-LAPs syndrome and intubation related airway stenosis: keys to diagnosis and critical therapeutic interventions. Am J Otolaryngol. 2015;36:636–641.
Meng X-M, Nikolic-Paterson DJ, Lan HY. TGF-β: the master regulator of fibrosis. Nat Rev Nephrol. 2016;12:325–338.
Karagiannidis C, Hense G, Martin C, et al. Activin A is an acute allergen-responsive cytokine and provides a link to TGF-beta-mediated airway remodeling in asthma. J Allergy Clin Immunol. 2006;117:111–118.
Kochhar A, Kirmani S, Cetta F, Younge B, Hyland JC, Michels V. Similarity of geleophysic dysplasia and Weill–Marchesani syndrome. Am J Med Genet A. 2013;161A:3130–3132.
Cain SA, McGovern A, Baldwin AK, Baldock C, Kielty CM. Fibrillin-1 mutations causing Weill–Marchesani syndrome and acromicric and geleophysic dysplasias disrupt heparan sulfate interactions. PLoS ONE. 2012;7:e48634.
Richardson JS, Richardson DC. Natural β-sheet proteins use negative design to avoid edge-to-edge aggregation. Proc Natl Acad Sci USA. 2002;99:2754–2759.
Faivre L, Collod-Beroud G, Callewaert B, et al. Clinical and mutation-type analysis from an international series of 198 probands with a pathogenic FBN1 exons 24–32 mutation. Eur J Hum Genet. 2009;17:491–501.
Seo GH, Kim Y-M, Kang E, et al. The phenotypic heterogeneity of patients with Marfan-related disorders and their variant spectrums. Medicine (Baltimore). 2018;97:e10767.
The authors declare no conflicts of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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
- acromelic dysplasia