Endocrine Abstracts

Introduction: B3GAT3, encoding β-1,3-glucuronyltransferase 3, has an important role in proteoglycan biosynthesis. Homozygous B3GAT3 mutations have been associated with short stature, skeletal deformities and congenital heart defects. We describe for the first time, a novel heterozygous splice site mutation in B3GAT3 contributing to severe short stature, growth hormone (GH) deficiency, recurrent ketotic hypoglycaemia, facial dysmorphism and congenital heart defects.

Patient and methods: A female infant, born at 34 weeks gestation to non-consanguineous Caucasian parents with a birth weight of 1.9kg was noted to have cloacal abnormality, ventricular septal defect, pulmonary stenosis and congenital sensorineural deafness. She had multiple dysmorphic features: anteverted nares, small upturned nose, hypertelorism, slight frontal bossing, short proximal bones, hypermobile joints and down slanting palpebral fissures. She also had recurrent hypoglycaemic episodes and the results were consistent with severe ketotic hypoglycaemia. At 4 years of age, she was diagnosed with GH deficiency due to her short stature (height<2.5SD) and commenced on GH therapy. MRI of the pituitary gland revealed small anterior pituitary. There was a history of short stature and dysmorphism in father and a stillborn previous sibling with multiple dysmorphic features, congenital heart defects and short bones. Targeted exome sequencing of genes associated with ketogenesis, ketolysis, carbohydrate metabolism and fatty acid oxidation was negative for pathogenic mutations. Whole exome sequencing (WES) was performed on the genomic DNA from the patient but the DNA samples from biological parents were unavailable.

Results: A heterozygous B3GAT3 mutation (c.888+262T>G) in the invariant “GT” splice donor site was identified. This variant is considered to be pathogenic as it decreases the splicing efficiency in the mRNA as predicted by a MaxEntScan score decrease of 100% (from 11.01 to −0.14) thereby creating an alternative splice site resulting in a frame shift and truncation through protein misfolding.

Conclusion: B3GAT3 is involved in glycosaminoglycan (GAG) biosynthesis, which provides structural support within the extracellular matrix surrounding the cells. Genetic defects can thus lead to multi-system disorders. We report a novel splice site mutation in B3GAT3 associated with short stature, GH deficiency and multiple congenital anomalies.