Early-onset diabetes mellitus as a presenting feature of Werner's syndrome in an Indian family.
WRN
Werner's syndrome
diabetes mellitus
lipodystrophy
myxoid malignant peripheral nerve sheath tumor
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
10 Oct 2023
10 Oct 2023
Historique:
revised:
20
09
2023
received:
07
06
2023
accepted:
29
09
2023
medline:
10
10
2023
pubmed:
10
10
2023
entrez:
10
10
2023
Statut:
aheadofprint
Résumé
Diabetes mellitus (DM) in children and adolescents is typically caused by type 1 DM, followed by type 2 DM and maturity-onset diabetes of the young (MODY). We report an unusual Asian Indian family in which three members presented with DM at ages 15, 20, and 30, but not fitting the typical clinical picture of type 1 DM, type 2 DM, or MODY. The primary objective was to elucidate the molecular genetic basis of DM in this family. The proband, a 22-year-old man, had short stature, gray hair, osteoporosis, and markedly reduced subcutaneous fat on the body, especially on the extremities along with acanthosis nigricans, and developed myxoid malignant peripheral nerve sheath tumor. Detailed family history revealed multiple loops of consanguinity. The proband underwent whole-genome sequencing, and seven relatives underwent whole-exome sequencing. The proband and three additional family members were found to have the homozygous c.561A>G nucleotide variant of WRN RecQ-like helicase (WRN) gene consistent with the diagnosis of Werner's syndrome. The c.561A>G variant induces a new splicing site on exon 6 resulting in a truncated WRN protein, p.Lys187Trpfs*13. Our report brings to attention the onset of DM during childhood or early adulthood in patients with Werner's syndrome who typically develop type 2 DM around the age of 30-40 years. Presence of consanguinity among parents, dysmorphic features, and malignancy should prompt consideration of diagnosis of Werner's syndrome.
Sections du résumé
BACKGROUND
BACKGROUND
Diabetes mellitus (DM) in children and adolescents is typically caused by type 1 DM, followed by type 2 DM and maturity-onset diabetes of the young (MODY). We report an unusual Asian Indian family in which three members presented with DM at ages 15, 20, and 30, but not fitting the typical clinical picture of type 1 DM, type 2 DM, or MODY. The primary objective was to elucidate the molecular genetic basis of DM in this family.
METHODS
METHODS
The proband, a 22-year-old man, had short stature, gray hair, osteoporosis, and markedly reduced subcutaneous fat on the body, especially on the extremities along with acanthosis nigricans, and developed myxoid malignant peripheral nerve sheath tumor. Detailed family history revealed multiple loops of consanguinity. The proband underwent whole-genome sequencing, and seven relatives underwent whole-exome sequencing.
RESULTS
RESULTS
The proband and three additional family members were found to have the homozygous c.561A>G nucleotide variant of WRN RecQ-like helicase (WRN) gene consistent with the diagnosis of Werner's syndrome. The c.561A>G variant induces a new splicing site on exon 6 resulting in a truncated WRN protein, p.Lys187Trpfs*13.
CONCLUSION
CONCLUSIONS
Our report brings to attention the onset of DM during childhood or early adulthood in patients with Werner's syndrome who typically develop type 2 DM around the age of 30-40 years. Presence of consanguinity among parents, dysmorphic features, and malignancy should prompt consideration of diagnosis of Werner's syndrome.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2299Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK105448
Pays : United States
Organisme : NIH HHS
ID : R01-DK105448
Pays : United States
Informations de copyright
© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.
Références
Atallah, I., McCormick, D., Good, J., Barigou, M., Fraga, M., Sempoux, C., Superti-Furga, A., Semple, R. K., & Tran, C. (2022). Partial lipodystrophy, severe dyslipidaemia and insulin resistant diabetes as early signs of Werner syndrome. Journal of Clinical Lipidology, 16(5), 583-590.
Cingolani, P., Platts, A., Wang, L. L., Coon, M., Nguyen, T., Wang, L., Land, S. J., Lu, X., & Ruden, D. M. (2012). A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff. Fly (Austin), 6(2), 80-92.
Davydov, E. V., Goode, D. L., Sirota, M., Cooper, G. M., Sidow, A., & Batzoglou, S. (2010). Identifying a high fraction of the human genome to be under selective constraint using GERP. PLoS Computational Biology, 6(12), e1001025.
Ducatman, B. S., Scheithauer, B. W., Piepgras, D. G., Reiman, H. M., & Ilstrup, D. M. (1986). Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer, 57(10), 2006-2021.
Epstein, C. J., Martin, G. M., Schultz, A. L., & Motulsky, A. G. (1966). Werner's syndrome a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process. Medicine, 45(3), 177-221.
Froguel, P., Zouali, H., Vionnet, N., Velho, G., Vaxillaire, M., Sun, F., Lesage, S., Stoffel, M., Takeda, J., Passa, P., Permutt, M. A., Beckmann, J. S., Bell, G. I., & Cohen, D. (1993). Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. The New England Journal of Medicine, 328(10), 697-702.
Garg, A. (2004). Acquired and inherited lipodystrophies. The New England Journal of Medicine, 350(12), 1220-1234.
Goto, M., Miller, R. W., Ishikawa, Y., & Sugano, H. (1996). Excess of rare cancers in Werner syndrome (adult progeria). Cancer Epidemiology, Biomarkers & Prevention, 5(4), 239-246.
Greulich, W. W., & Pyle, S. I. (1950). Radiographic atlas of skeletal development of the hand and wrist. Stanford University Press.
Hattersley, A. T., Murphy, R., & Ellard, S. (2008). Clinical implications of a molecular genetic classification of monogenic β-cell diabetes. Nature Clinical Practice. Endocrinology & Metabolism, 4(4), 200-213.
Huang, S., Lee, L., Hanson, N. B., Lenaerts, C., Hoehn, H., Poot, M., Rubin, C. D., Chen, D., Yang, C., Juch, H., Dorn, T., Spiegel, R., Oral, E. A., Abid, M., Battisti, C., Lucci-Cordisco, E., Neri, G., Steed, E. H., Kidd, A., … Oshima, J. (2006). The spectrum of WRN mutations in Werner syndrome patients. Human Mutation, 27(6), 558-567.
Ishii, T. (1976). Progeria: Autopsy report of one case, with a review of pathologic findings reported in the literature. Journal of the American Geriatrics Society, 24(5), 193-202.
Ishii, T., Hosodal, Y., Hamada, Y., Nakagawa, S., Asian, G., & Horrible, Y. (1985). Pathology of the Werner syndrome. Advances in Experimental Medicine and Biology, 190, 187-214.
Jaganathan, K., Kyriazopoulou Panagiotopoulou, S., McRae, J. F., Darbandi, S. F., Knowles, D., Li, Y. I., Kosmicki, J. A., Arbelaez, J., Cui, W., Schwartz, G. B., Chow, E. D., Kanterakis, E., Gao, H., Kia, A., Batzoglou, S., Sanders, S. J., & Farh, K. K. (2019). Predicting splicing from primary sequence with deep learning. Cell, 176(3), 535-548.e24.
Lauper, J. M., Krause, A., Vaughan, T. L., Monnat, J., & Raymond, J. (2013). Spectrum and risk of neoplasia in Werner syndrome: A systematic review. PLoS One, 8(4), e59709.
Lawrence, J. M., Divers, J., Isom, S., Saydah, S., Imperatore, G., Pihoker, C., Marcovina, S. M., Mayer-Davis, E. J., Hamman, R. F., Dolan, L., Dabelea, D., Pettitt, D. J., & Liese, A. D. (2021). Trends in prevalence of type 1 and type 2 diabetes in children and adolescents in the US, 2001-2017. Journal of the American Medical Association, 326(8), 717-727.
Macfarlane, W. M., Frayling, T. M., Ellard, S., Evans, J. C., Allen, L. I., Bulman, M. P., Ayres, S., Shepherd, M., Clark, P., Millward, A., Demaine, A., Wilkin, T., Docherty, K., & Hattersley, A. T. (1999). Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes. The Journal of Clinical Investigation, 104(9), R33-R39.
McKenna, A., Hanna, M., Banks, E., Sivachenko, A., Cibulskis, K., Kernytsky, A., Garimella, K., Altshuler, D., Gabriel, S., Daly, M., & DePristo, M. A. (2010). The genome analysis toolkit: A mapreduce framework for analyzing next-generation DNA sequencing data. Genome Research, 20(9), 1297-1303.
Narasimhan, V., Danecek, P., Scally, A., Xue, Y., Tyler-Smith, C., & Durbin, R. (2016). BCFtools/RoH: A hidden Markov model approach for detecting autozygosity from next-generation sequencing data. Bioinformatics, 32(11), 1749-1751.
Okabe, E., Takemoto, M., Onishi, S., Ishikawa, T., Ishibashi, R., He, P., Kobayashi, K., Fujimoto, M., Kawamura, H., & Yokote, K. (2012). Incidence and characteristics of metabolic disorders and vascular complications in individuals with Werner syndrome in Japan. Journal of the American Geriatrics Society, 60(5), 997-998.
Oshima, J., Sidorova, J. M., & Monnat, R. J. (2016). Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions. Ageing Research Reviews, 33, 105-114.
Oshima, J., Yu, C., Piussan, C., Klein, G., Jabkowski, J., Balci, S., Miki, T., Nakura, J., Ogihara, T., Ells, J., Smith, M. A. C., Melaragno, M. I., Fraccaro, M., Scappaticci, S., Matthews, J., Ouais, S., Jarzebowicz, A., Schellenberg, G. D., & Martin, G. M. (1996). Homozygous and compound heterozygous mutations at the Werner syndrome locus. Human Molecular Genetics, 5(12), 1909-1913.
Rosa, M. A., Falcone, G., De Santis, V., & Azzaro, O. (2003). Malignant peripheral nerve sheath tumor in a patient with Werner's syndrome. Journal of Orthopaedics and Traumatology, 4, 95-99.
Saha, B., Lessel, D., Nampoothiri, S., Rao, A. S., Hisama, F. M., Peter, D., Bennett, C., Nürnberg, G., Nürnberg, P., Martin, G. M., Kubisch, C., & Oshima, J. (2013). Ethnic-specific WRN mutations in south Asian Werner syndrome patients: Potential founder effect in patients with Indian or Pakistani ancestry. Molecular Genetics & Genomic Medicine, 1(1), 7-14.
Sharma, R., Lewis, S., & Wlodarski, M. W. (2020). DNA repair syndromes and cancer: Insights into genetics and phenotype patterns. Frontiers in Pediatrics, 8, 570084.
Stucky, C. H., Johnson, K. N., Gray, R. J., Pockaj, B. A., Ocal, I. T., Rose, P. S., & Wasif, N. (2011). Malignant peripheral nerve sheath tumors (MPNST): The mayo clinic experience. Annals of Surgical Oncology, 19(3), 878-885.
Takemoto, M., Kubota, Y., Taniguchi, T., Motegi, S., Taniguchi, A., Nakagami, H., Maezawa, Y., Koshizaka, M., Kato, H., Tsukamoto, K., Mori, S., Kuzuya, M., & Yokote, K. (2021). Management guideline for Werner syndrome 2020. 3. Diabetes associated with Werner syndrome. Geriatrics & Gerontology International, 21(2), 142-145.
Takemoto, M., Mori, S., Kuzuya, M., Yoshimoto, S., Shimamoto, A., Igarashi, M., Tanaka, Y., Miki, T., & Yokote, K. (2013). Diagnostic criteria for Werner syndrome based on Japanese nationwide epidemiological survey. Geriatrics & Gerontology International, 13(12), 475-481.
Tuomi, T., Santoro, N., Caprio, S., Cai, M., Weng, J., & Groop, L. (2014). The many faces of diabetes: A disease with increasing heterogeneity. Lancet, 383(9922), 1084-1094.
Wang, X., Liu, S., Qin, F., Liu, Q., & Wang, Q. (2022). Werner syndrome presenting as early-onset diabetes: A case report. Journal of Diabetes Investigation, 13(3), 592-598.
Werner, O. (1985). On cataract in conjunction with scleroderma. Otto Werner, doctoral dissertation, 1904, royal ophthalmology clinic, Royal Christian Albrecht University of Kiel. Advances in Experimental Medicine and Biology, 190, 1-14.
Yamagata, K., Oda, N., Kaisaki, P. J., Menzel, S., Furuta, H., Vaxillaire, M., Southam, L., Cox, R. D., Lathrop, G. M., Boriraj, V. V., Chen, X., Cox, N. J., Oda, Y., Yano, H., Le Beau, M. M., Yamada, S., Nishigori, H., Takeda, J., Fajans, S. S., … Bell, G. I. (1996). Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature, 384(6608), 455-458.
Yu, C., Oshima, J., Fu, Y., Wijsman, E. M., Hisama, F., Alisch, R., Matthews, S., Nakura, J., Miki, T., Ouais, S., Martin, G. M., Mulligan, J., & Schellenberg, G. D. (1996). Positional cloning of the Werner's syndrome gene. Science, 272(5259), 258-262.
Zemel, B. S., Kalkwarf, H. J., Gilsanz, V., Lappe, J. M., Oberfield, S., Shepherd, J. A., Frederick, M. M., Huang, X., Lu, M., Mahboubi, S., Hangartner, T., & Winer, K. K. (2011). Revised reference curves for bone mineral content and areal bone mineral density according to age and sex for black and non-black children: Results of the bone mineral density in childhood study. The Journal of Clinical Endocrinology and Metabolism, 96(10), 3160-3169.