LTBP2-related "Marfan-like" phenotype in two Roma/Gypsy subjects with the LTBP2 homozygous p.R299X variant

Am J Med Genet A. 2019 Jan;179(1):104-112. doi: 10.1002/ajmg.a.10. Epub 2018 Dec 18.


Recessive variants in LTBP2 are associated with eye-restricted phenotypes including (a) primary congenital glaucoma and (b) microspherophakia/megalocornea and ectopia lentis with/without secondary glaucoma. Nosology of LTBP2 pathology in humans is apparently in contrast with the consolidated evidence of a wide expression of this gene in the developing embryo. Accordingly, in previously published patients with LTBP2-related eye disease, additional extraocular findings have been occasionally reported and include, among others, high-arched palate, tall stature, and variable cardiac involvement. Anyway, no emphasis was put on such systemic manifestations. Here, we report two unrelated Roma/Gypsy patients first ascertained for a multisystem disorder mainly characterized by primary congenital glaucoma, complex congenital heart defect, tall stature, long fingers, skin striae and dystrophic scarring, and resembling Marfan syndrome. Heart involvement was severe with polyvalvular heart dysplasia in one, and transposition of great arteries, thoracic arterial tortuosity, polyvalvular heart dysplasia, and neo-aortic root dilatation in the other. Both patients were homozygous for the recurrent c.895C>T[p.(R299X)] variant, typically found in individuals of Roma/Gypsy descent with an eye-restricted phenotype. Our findings point out LTBP2 as responsible of a systemic phenotype coherent with the community of syndromes related to anomalies in genes involved in the TGFβ-pathway. Among these disorders, LTBP2-related systemic disease emerges as a distinct condition with expanding prognostic implications and autosomal recessive inheritance.

Keywords: LTBP2; Marfan syndrome; congenital heart defect; connective tissue; polyvalvular heart dysplasia.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Corneal Diseases / genetics
  • Corneal Diseases / physiopathology
  • Ectopia Lentis / genetics
  • Ectopia Lentis / physiopathology
  • Eye Diseases, Hereditary / genetics
  • Eye Diseases, Hereditary / physiopathology
  • Female
  • Genetic Diseases, X-Linked / genetics
  • Genetic Diseases, X-Linked / physiopathology
  • Glaucoma / diagnostic imaging
  • Glaucoma / genetics*
  • Glaucoma / physiopathology
  • Heart / diagnostic imaging
  • Heart / physiopathology
  • Heart Defects, Congenital / diagnostic imaging
  • Heart Defects, Congenital / genetics*
  • Heart Defects, Congenital / physiopathology
  • Homozygote
  • Humans
  • Iris / abnormalities
  • Iris / physiopathology
  • Latent TGF-beta Binding Proteins / genetics*
  • Male
  • Marfan Syndrome / genetics*
  • Marfan Syndrome / physiopathology
  • Phenotype
  • Roma / genetics
  • Transforming Growth Factor beta / genetics


  • LTBP2 protein, human
  • Latent TGF-beta Binding Proteins
  • Transforming Growth Factor beta

Supplementary concepts

  • Megalocornea
  • Microspherophakia