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



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.

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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.


  1. 1.

    Le Goff C, Cormier-Daire V. Genetic and molecular aspects of acromelic dysplasia. Pediatr Endocrinol Rev PER. 2009;6:418–423.

    PubMed  Google Scholar 

  2. 2.

    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.

  3. 3.

    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.

    CAS  Article  Google Scholar 

  4. 4.

    Maroteaux P, Stanescu R, Stanescu V, Rappaport R. Acromicric dysplasia. Am J Med Genet. 1986;24:447–459.

    CAS  Article  Google Scholar 

  5. 5.

    Faivre L. Acromicric dysplasia: long term outcome and evidence of autosomal dominant inheritance. J Med Genet. 2001;38:745–749.

    CAS  Article  Google Scholar 

  6. 6.

    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.

    Article  Google Scholar 

  7. 7.

    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.

    Article  Google Scholar 

  8. 8.

    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.

    Article  Google Scholar 

  9. 9.

    Le Goff C, Cormier-Daire V. Chondrodysplasias and TGFβ signaling. Bonekey Rep. 2015;4:642.

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Delhon L, Mahaut C, Goudin N, et al. Impairment of chondrogenesis and microfibrillar network in Adamtsl2 deficiency. FASEB J. 2019;33:2707–2718.

    CAS  Article  Google Scholar 

  11. 11.

    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.

    CAS  Article  Google Scholar 

  12. 12.

    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.

    CAS  Article  Google Scholar 

  13. 13.

    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.

    CAS  Article  Google Scholar 

  14. 14.

    Robert X, Gouet P. Deciphering key features in protein structures with the new ENDscript server. Nucleic Acids Res. 2014;42(W1):W320–W324.

    CAS  Article  Google Scholar 

  15. 15.

    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.

    CAS  Google Scholar 

  16. 16.

    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.

    Article  Google Scholar 

  17. 17.

    Moey LH, Flaherty M, Zankl A. Optic disc swelling in acromicric and geleophysic dysplasia. Am J Med Genet A. 2019;179:1898–1901.

    Article  Google Scholar 

  18. 18.

    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.

    CAS  Article  Google Scholar 

  19. 19.

    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.

    Article  Google Scholar 

  20. 20.

    Rama G, Chung WK, Cunniff CM, Krishnan U. Rapidly progressive mitral valve stenosis in patients with acromelic dysplasia. Cardiol Young. 2017;27:797–800.

    Article  Google Scholar 

  21. 21.

    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.

    CAS  Article  Google Scholar 

  22. 22.

    Globa E, Zelinska N, Dauber A. The clinical cases of geleophysic dysplasia: one gene, different phenotypes. Case Rep Endocrinol. 2018;2018:8212417.

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    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.

    CAS  Article  Google Scholar 

  24. 24.

    Goumans M-J, ten Dijke P. TGF-β signaling in control of cardiovascular function. Cold Spring Harb Perspect Biol. 2018;10:a022210.

    Article  Google Scholar 

  25. 25.

    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.

    Article  Google Scholar 

  26. 26.

    Saito A, Horie M, Nagase T. TGF-β signaling in lung health and disease. Int J Mol Sci. 2018;19:2460

    Article  Google Scholar 

  27. 27.

    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.

    CAS  Article  Google Scholar 

  28. 28.

    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.

    Article  Google Scholar 

  29. 29.

    Meng X-M, Nikolic-Paterson DJ, Lan HY. TGF-β: the master regulator of fibrosis. Nat Rev Nephrol. 2016;12:325–338.

    CAS  Article  Google Scholar 

  30. 30.

    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.

    CAS  Article  Google Scholar 

  31. 31.

    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.

    Article  Google Scholar 

  32. 32.

    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.

    CAS  Article  Google Scholar 

  33. 33.

    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.

    CAS  Article  Google Scholar 

  34. 34.

    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.

    CAS  Article  Google Scholar 

  35. 35.

    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.

    Article  Google Scholar 

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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).

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  • acromelic dysplasia
  • TGF-β
  • FBN1
  • LTBP3