Mucopolysaccharidosis II with diverse genetic origins in a single family: a case series and literature review

To highlight the mutations of the iduronate-2-sulfatase (IDS) gene in one family with different origins. The proband (case 1) was a 4-year and 7-month-old boy who presented for "inability to fully extend his fingers for over 2 years". His developmental milestones were unremarkable. However, his fingers could not be extended straight when he was about 2 years old. Snoring was also reported. Physical examination showed dense eyebrows and hair, macrocephaly, coarse facial features, a collapsed nose bridge, hypertelorism, big ears, full lips, a short neck, a lot of Mongolian spots, hypertrichosis, short fingers, and joint contracture in fingers. X-ray showed dysostosis multiplex and brain magnetic resonance showed enlarged ventricles and widened sulci. A high ratio of urea glycosaminoglycans and creatinine (GAGs/Cr) and decreased activity of iduronate-2-sulfatase (IDS) were found. Whole exome sequencing (WES) revealed a hemizygous c.593 A > C (p.D198A) variant of the IDS gene originated from his mother. Furthermore, high urea GAGs/Cr, decreased activity of IDS, and a similar mutation were also noted in his younger brother (case 2, 1.5 years old), who had slight coarse facies and a lot of Mongolian spots. Moreover, the MPS II screen found that a distantly related cousin of case 1 (case 3, 7-month-old) had high urea GAGs/Cr and decreased activity of IDS. It was notable that WES analysis revealed a novel hemizygous c.1403G > A (p.Arg468Gln) variant in the IDS gene, which was de novo and distinct from cases 1 and 2. In children with coarse faces, joint contracture, Mongolian spots, or hirsute, MPS should be considered in the differential diagnosis. Two completely different mutations may independently exist in a family. Hence, only the known mutation verified in family members may result in a missed diagnosis, urea GAGs and IDS activity measurement may reduce this condition.