Letter to the Editor
Ann Lab Med 2022; 42(3): 373-375
Published online May 1, 2022 https://doi.org/10.3343/alm.2022.42.3.373
Copyright © Korean Society for Laboratory Medicine.
Skewed X-Chromosome Inactivation in a Korean Girl with Severe Mucopolysaccharidosis Type II
Departments of 1Pediatrics, 2Laboratory Medicine, and 3Rare Disease Center, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
Correspondence to: Jung Min Ko, M.D., Ph.D.
Department of Pediatrics, Seoul National University Children’s Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
Tel: +82-2-2072-7592, Fax: +82-2-743-3455
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Mucopolysaccharidosis type II (MPS II, Hunter syndrome, OMIM 309900) is a multisystem disorder caused by deficient production or activity of the lysosomal hydrolase iduronate 2-sulfatase, encoded by the
A 41-month-old girl was referred to the genetics clinic of SNUH for investigation of dysostosis multiplex. The patient was the first-born child of healthy non-consanguineous parents. At the time of visit, the patient showed delayed speech development and was noted to have coarse facies, multiple persistent Mongolian spots, a mild umbilical hernia, multiple joint contractures, and hepatosplenomegaly. Echocardiography revealed mild mitral regurgitation with anterior mitral leaflet thickening and prolapse. A magnetic resonance imaging brain scan revealed an enlarged perivascular space in both the genu of the corpus callosum and periventricular white matter. The urine glycosaminoglycan analysis result was positive, and plasma iduronate 2-sulfatase activity was very low (1.8 nmol/4 hours/mg protein; age matched control: 496.3±165.7 nmol/4 hours/mg protein). Enzyme test results for α-iduronidase, α-N-acetylglucosaminidase, β-galactosidase, arylsulfatase B, and β-glucuronidase excluded MPS I, MPS IIIB, MPS IV, MPS VI, and MPS VII, respectively.
The chromosome microarray analysis results revealed that the karyotype is normal. Sequence analysis of
Figure 1. Genetic analysis of
IDS-IDS2recombination and X-chromosome inactivation. (A) PCR amplification of the inversion junctions shows recombinant fragments containing the proximal (2.8 kb) and distal (1.7 kb) junctions. Lanes 1 and 2: PCR amplification from a normal female [1: proximal region (2.0 kb), 2: distal region (1.0 kb)]. Lanes 3 and 4: PCR amplification of the current patient (3: proximal recombination, 4: distal recombination). (B) X-chromosome inactivation analysis shows extremely skewed X-inactivation. Before HpaII: undigested DNA; After HpaII: HpaII-digested DNA.
At the age of 3 years and 7 months, the patient started ERT that continued for 6 years and 7 months. The treatment was well-tolerated and resulted in disease stabilization at follow-up. At the age of 10 years and 2 months, the hepatosplenomegaly was resolved, and physical endurance was maintained with improvement of the joint contractures. However, the patient exhibited growth retardation, mild left ventricular systolic dysfunction requiring medication, and persistent intellectual disability.
There have been few reports regarding female patients with MPS II, most of which have been caused by preferential XCI of the non-mutant allele. High genetic heterogeneity is observed in females with MPS II, including intragenic sequence variants, inversion variants, indels, and chromosomal translocation [3, 5, 8]. The
In conclusion, we report a case in Korea of a female patient with MPS II and a severe phenotype caused by skewed XCI. This report highlights the importance of considering a diagnosis of MPS II and the early initiation of treatment in any female presenting with the related clinical symptoms. Further studies are needed to elucidate the molecular pathogenesis of preferred inactivation of the non-mutant allele in female patients with MPS II.
We express our gratitude to the patient and her parents for their participation in the study.
Kim HY and Ko JM conceptualized the study and collected the data. Kim HY wrote the manuscript. Kim MJ and Seong MW contributed to the data analysis and interpretation. All authors have read and consented to the final manuscript.
CONFLICTS OF INTEREST
This work was supported by the Seoul National University Hospital Research Fund (grant number 800-20210295).
- D'Avanzo F, Rigon L, Zanetti A, Tomanin R. Mucopolysaccharidosis type II: one hundred years of research, diagnosis, and treatment. Int J Mol Sci 2020;21:1258.
- Manara R, Rampazzo A, Cananzi M, Salviati L, Mardari R, Drigo P, et al. Hunter syndrome in an 11‐year old girl on enzyme replacement therapy with idursulfase: brain magnetic resonance imaging features and evolution. J Inherit Metab Dis 2010;33(S3):S67-72.
- Jurecka A, Krumina Z, Żuber Z, Różdżyńska‐Świątkowska A, Kłoska A, Czartoryska B, et al. Mucopolysaccharidosis type II in females and response to enzyme replacement therapy. Am J Med Genet A 2012;158A:450-4.
- Julien DC, Woolgar K, Pollard L, Miller H, Desai A, Lindstrom K, et al. Immune modulation for enzyme replacement therapy in a female patient with Hunter syndrome. Front Immunol 2020;11:1000.
- Piña-Aguilar RE, Zaragoza-Arévalo GR, Rau I, Gal A, Alcántara-Ortigoza MA, López-Martínez MS, et al. Mucopolysaccharidosis type II in a female carrying a heterozygous stop mutation of the iduronate-2-sulfatase gene and showing a skewed X chromosome inactivation. Eur J Med Genet 2013;56:159-62.
- Lagerstedt K, Karsten SL, Carlberg BM, Kleijer WJ, Tönnesen T, Pettersson U, et al. Double-strand breaks may initiate the inversion mutation causing the Hunter syndrome. Hum Mol Genet 1997;6:627-33.
- Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet 1992;51:1229-39.
- Sohn YB, Kim SJ, Park SW, Park HD, Ki CS, Kim CH, et al. A mother and daughter with the p. R443X mutation of mucopolysaccharidosis type II: genotype and phenotype analysis. Am J Med Genet A 2010;152A:3129-32.
- Sohn YB, Ki CS, Kim CH, Ko AR, Yook YJ, Lee SJ, et al. Identification of 11 novel mutations in 49 Korean patients with mucopolysaccharidosis type II. Clin Genet 2012;81:185-90.
- Stapleton M, Kubaski F, Mason RW, Yabe H, Suzuki Y, Orii KE, et al. Presentation and treatments for mucopolysaccharidosis type II (MPS II; Hunter syndrome). Expert Opin Orphan Drugs 2017;5:295-307.