Understanding the phenotypic spectrum of ASXL-related disease: Ten cases and a review of the literature

Abstract

Over the past decade, pathogenic variants in all members of the ASXL family of genes, ASXL1, ASXL2, and ASXL3, have been found to lead to clinically distinct but overlapping syndromes. Bohring-Opitz syndrome (BOPS) was first described as a clinical syndrome and later found to be associated with pathogenic variants in ASXL1. This syndrome is characterized by developmental delay, microcephaly, characteristic facies, hypotonia, and feeding difficulties. Subsequently, pathogenic variants in ASXL2 were found to lead to Shashi-Pena syndrome (SHAPNS) and in ASXL3 to lead to Bainbridge-Ropers syndrome (BRPS). While SHAPNS and BRPS share many core features with BOPS, there also seem to be emerging clear differences. Here, we present five cases of BOPS, one case of SHAPNS, and four cases of BRPS. By adding our cohort to the limited number of previously published patients, we review the overlapping features of ASXL-related diseases that bind them together, while focusing on the characteristics that make each neurodevelopmental syndrome unique. This will assist in diagnosis of these overlapping conditions and allow clinicians to more comprehensively counsel affected families.

Keywords: ASXL1; ASXL2; ASXL3; Bainbridge-Ropers syndrome; Bohring-Opitz syndrome; Shashi-Pena syndrome.

Figure 1.

Representative images of individuals with ASXL1, ASXL2, and ASXL3 pathogenic variants. (a-b) Individual 4 with pathogenic variant in ASXL1 demonstrating frontal prominence, glabellar nevus flammeus, upslanted eyes, hypertelorism, clenched hands with upper extremity hypertonia, and with tracheostomy. (c-e) Individual 6 with pathogenic variant in ASXL2 demonstrating long face with narrow biparietal diameter, fullness of the superior eyelids, upslanted palpebral fissures, hypertelorism, squared superior portion helix with large lower earlobes, and low columella at 3.5 years of age (c) and 6.5 years of age (d-e). (f-h) Individual 7 with pathogenic variant in ASXL3 demonstrating ptosis and downslanted palpebral fissures.

Figure 2.

Bohring-Opitz Syndrome, Shashi-Pena Syndrome, and Bainbridge-Ropers Syndrome have an overlapping phenotype but can also be distinguished by unique features.