Geleophysic dysplasia

Geleophysial dysplasia (GD) is a rare skeletal dysplasia characterized by short stature, prominent malformations of the hands and feet, progressive, limited joint mobility, characteristic facial features, thickened skin, and progressive heart valve involvement. Most manifestations, resembling a lysosomal storage disease, occur in the first year of life.

GD is genetically heterogeneous. In half of the cases, there is autosomal dominant or autosomal recessive inheritance. The autosomal dominant form (GPHYSD2) is caused by heterozygous variants in the FBN1 gene. To date, all pathogenic variants described in GPHYSD2 cluster in a specific region of the FBN1 gene (exon 41-42), which codes for the TGFß binding protein-like 5 (TB5) domain of fibrillin-1. The autosomal recessive form (GPHYSD1) is caused by homozygous or combined heterozygous variants in the ADAMTSL2 gene. In this case, the pathogenic variants are distributed across the entire gene.

Clinically, GD patients with variants in the FBN1 gene cannot be distinguished from those with variants in the ADAMTSL2 gene. The hypothesis for the molecular pathogenesis of GD is a specific interaction between fibrillin-1 and the glycoprotein encoded by ADAMTSL2 (disintegrin and metalloproteinase with thrombospondin repeats-like 2), which leads to dysregulation of the FBN1/ADAMTSL2/TGFß signalling pathway. In addition, heterozygous variants in the LTBP3 gene were identified in 2016 in two patients with GD and severe lung involvement. In the fibroblasts of these patients, a disorganization of the microfibril network was seen that is similar to patients with FBN1 or ADAMTSL2 variants.