Endocrine Abstracts

Introduction: De novo truncating heterozygous mutations in the additional sex combs-like 3 (ASXL3) gene have been implicated to cause Bainbridge-Ropers syndrome (BRPS) characterised by severe developmental delay, feeding problems, short stature and characteristic facial features. We describe, for the first time, a patient with severe short stature secondary to IGF1 deficiency, severe learning difficulties and dysmorphic features due to novel compound heterozygous mutation in ASXL3.

Patient and methods: A 7-year-old boy had severe short stature (−3.5 SDS, MPH: −1.1 SDS), dysmorphic features, severe learning difficulties, and speech delay. He had downward slanting of eyes, low set ears, short neck, hypoplastic toe nails, shortening of metacarpals and ring finger, previous surgically repaired sagittal craniosynostosis and bilateral undescended testes. Peak growth hormone (GH) was 11.7 μg/l to arginine stimulation and bone age was delayed by 3 years. The rest of the pituitary function was normal. IGF1 was persistently low at 4.9 nmol/l (−3.1 SDS) with no increase on IGF1 generation test. A trial of high dose GH (50 μg/kg/day) was ineffective in improving height velocity. Subsequently, recombinant IGF1 therapy was commenced. CGH microarray did not reveal any copy number changes. Whole exome sequencing was performed on genomic DNA from patient’s blood and both biological parents. Exons were captured by SureSelect XT Human All Exon V5 capture library. A Sequence library was constructed using the SureSelect XT Target Enrichment System and sequencing performed using the Illumina HiSDefault 4000.

Results: Two novel heterozygous ASXL3 mutations [p.(Arg989Gly), p.(Lys1026Asn)] were found in the patient, inherited from his unaffected mother and his unaffected father respectively. The missense mutations affect highly conserved amino acid residues across several species and in silico analysis predict the changes to be deleterious (SIFT), disease causing and probably damaging (MutationTaster, PolyPhen) on protein function.

Conclusion: We report, for the first time, a novel compound heterozygous mutation in ASXL3 causing BRPS along with IGF1 deficiency. ASXL3 is a putative Polycomb group (PcG) protein that is required to maintain the transcriptionally repressive state of homeotic genes throughout development. Further functional studies are undertaken to evaluate the mechanism(s) underlying the molecular interaction between ASXL3 and IGF1 pathways.