Display options
Share it on

Am J Med Genet A. 2021 Oct;185(10):3170-3175. doi: 10.1002/ajmg.a.62395. Epub 2021 Jun 30.

Singleton-Merten syndrome: A rare cause of femoral head necrosis.

American journal of medical genetics. Part A

Elio Assaf, Mohamad Bdeir, Elisabeth Mohs, Franz-Joseph Dally, Sascha Gravius, Cleo-Aron Weis, Ali Darwich, Smith, Akiva


  1. Department of Orthopedics and Trauma Surgery, University Medical Centre, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany.
  2. Institute of Pathology, University Medical Centre, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany.

PMID: 34189824 DOI: 10.1002/ajmg.a.62395


Singleton-Merten syndrome (SMS) is a type I interferonopathy. In this report, we disclose the first-to the best of our knowledge-direct association of SMS with femoral head necrosis (FHN). The following case report presents the condition of a 38-year-old male suffering from SMS with FHN, characterized by acute symptoms and rapid disease progression. As per the recommendations of the Association Research Circulation Osseous (ARCO) and the S3-guidelines, we successfully treated the FHN with core decompression. Our histological results correlate with the changes described in medical literature in patients with SMS and MDA5-knockout in vivo experiments such as osteopenia, widened medullary cavity, and thin cortical bone. Moreover, the conducted immunohistochemistry shows strong CD56 positivity of the osteoblasts and osteocytes, as well as significant CD68 and CD163 positivity of the middle-sized osteoclasts. Collectively, these findings suggest an underlying syndrome in the FHN. A six-month post-operative follow-up revealed complete recovery with the absence of the initial symptoms and ability to resume normal daily activities. Taken together, our findings suggest that SMS is an additional cause of FHN in young adults. Early detection and adequate treatment using well-established joint-preserving techniques demonstrate a favorable improvement of the patient's clinical condition.

© 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.

Keywords: MDA5; Singleton-Merten syndrome; core decompression; femoral head necrosis; rare disease


  1. Bohndorf, K., Beckmann, J., Jäger, M., Kenn, W., Maus, U., Nöth, U., Peters, K. M., Rader, C., Reppenhagen, S., Roth, A., & Deutsche Gesellschaft für Orthopädie und Orthopädische Chirurgie. (2015). S3 guideline. Part 1: Diagnosis and differential diagnosis of non-traumatic adult femoral head necrosis. Zeitschrift für Orthopädie und Unfallchirurgie, 153(4), 375-386. https://doi.org/10.1055/s-0035-1545901 - PubMed
  2. Bursztejn, A. C., Briggs, T. A., del Toro Duany, Y., Anderson, B. H., O'Sullivan, J., Williams, S. G., Bodemer, C., Fraitag, S., Gebhard, F., Leheup, B., Lemelle, I., Oojageer, A., Raffo, E., Schmitt, E., Rice, G. I., Hur, S., & Crow, Y. J. (2015). Unusual cutaneous features associated with a heterozygous gain-of-function mutation in IFIH1: Overlap between Aicardi-Goutieres and Singleton-Merten syndromes. The British Journal of Dermatology, 173(6), 1505-1513. https://doi.org/10.1111/bjd.14073 - PubMed
  3. Eytan, O., Morice-Picard, F., Sarig, O., Ezzedine, K., Isakov, O., Li, Q., Ishida-Yamamoto, A., Shomron, N., Goldsmith, T., Fuchs-Telem, D., Adir, N., Uitto, J., Orlow, S. J., Taieb, A., & Sprecher, E. (2013). Cole disease results from mutations in ENPP1. American Journal of Human Genetics, 93(4), 752-757. https://doi.org/10.1016/j.ajhg.2013.08.007 - PubMed
  4. Feigenbaum, A., Müller, C., Yale, C., Kleinheinz, J., Jezewski, P., Kehl, H. G., MacDougall, M., Rutsch, F., & Hennekam, R. C. (2013). Singleton-Merten syndrome: An autosomal dominant disorder with variable expression. American Journal of Medical Genetics. Part A, 161A(2), 360-370. https://doi.org/10.1002/ajmg.a.35732 - PubMed
  5. Jang, M. A., Kim, E. K., Now, H., Nguyen, N. T., Kim, W. J., Yoo, J. Y., Lee, J., Jeong, Y. M., Kim, C. H., Kim, O. H., Sohn, S., Nam, S. H., Hong, Y., Lee, Y. S., Chang, S. A., Jang, S. Y., Kim, J. W., Lee, M. S., Lim, S. Y., … Ki, C. S. (2015). Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome. American Journal of Human Genetics, 96(2), 266-274. https://doi.org/10.1016/j.ajhg.2014.11.019 - PubMed
  6. Kamal, K. C., Alexandru, D. O., Rogoveanu, O. C., Panus, C., Kamal, D., Maria, D. T., & Traistaru, M. R. (2018). Immunohistochemical analysis of bone metabolism in osteonecrosis of the femoral head. Romanian Journal of Morphology and Embryology, 59(3), 819-824. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30534821. - PubMed
  7. Kohn, M. D., Sassoon, A. A., & Fernando, N. D. (2016). Classifications in brief: Kellgren-Lawrence classification of osteoarthritis. Clinical Orthopaedics and Related Research, 474(8), 1886-1893. https://doi.org/10.1007/s11999-016-4732-4 - PubMed
  8. Ozyuksel, A., Ersoy, C., Canturk, E., & Akcevin, A. (2014). Progressive supra-aortic stenosis in a young adult with the findings of singleton Merten syndrome. BML Case Reports, 2014. https://doi.org/10.1136/bcr-2014-205985 - PubMed
  9. Pettersson, M., Bergendal, B., Norderyd, J., Nilsson, D., Anderlid, B. M., Nordgren, A., & Lindstrand, A. (2017). Further evidence for specific IFIH1 mutation as a cause of singleton-Merten syndrome with phenotypic heterogeneity. American Journal of Medical Genetics. Part A, 173(5), 1396-1399. https://doi.org/10.1002/ajmg.a.38214 - PubMed
  10. Rice, G. I., del Toro Duany, Y., Jenkinson, E. M., Forte, G. M., Anderson, B. H., Ariaudo, G., Bader-Meunier, B., Baildam, E. M., Battini, R., Beresford, M. W., Casarano, M., Chouchane, M., Cimaz, R., Collins, A. E., Cordeiro, N. J., Dale, R. C., Davidson, J. E., de Waele, L., Desguerre, I., … Crow, Y. J. (2014). Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nature Genetics, 46(5), 503-509. https://doi.org/10.1038/ng.2933 - PubMed
  11. Rice, G. I., Park, S., Gavazzi, F., Adang, L. A., Ayuk, L. A., van Eyck, L., Seabra, L., Barrea, C., Battini, R., Belot, A., Berg, S., Billette de Villemeur, T., Bley, A. E., Blumkin, L., Boespflug-Tanguy, O., Briggs, T. A., Brimble, E., Dale, R. C., Darin, N., … Crow, Y. J. (2020). Genetic and phenotypic spectrum associated with IFIH1 gain-of-function. Human Mutation, 41(4), 837-849. https://doi.org/10.1002/humu.23975 - PubMed
  12. Roth, A., Beckmann, J., Bohndorf, K., Fischer, A., Heiß, C., Kenn, W., Jäger, M., Maus, U., Nöth, U., Peters, K. M., Rader, C., Reppenhagen, S., Smolenski, U., Tingart, M., Kopp, I., Sirotin, I., & Breusch, S. J. (2016). S3-guideline non-traumatic adult femoral head necrosis. Archives of Orthopaedic and Trauma Surgery, 136(2), 165-174. https://doi.org/10.1007/s00402-015-2375-7 - PubMed
  13. Rutsch, F., MacDougall, M., Lu, C., Buers, I., Mamaeva, O., Nitschke, Y., Rice, G. I., Erlandsen, H., Kehl, H. G., Thiele, H., Nürnberg, P., Höhne, W., Crow, Y. J., Feigenbaum, A., & Hennekam, R. C. (2015). A specific IFIH1 gain-of-function mutation causes singleton-Merten syndrome. American Journal of Human Genetics, 96(2), 275-282. https://doi.org/10.1016/j.ajhg.2014.12.014 - PubMed
  14. Rutsch, F., Ruf, N., Vaingankar, S., Toliat, M. R., Suk, A., Höhne, W., Schauer, G., Lehmann, M., Roscioli, T., Schnabel, D., Epplen, J. T., Knisely, A., Superti-Furga, A., McGill, J., Filippone, M., Sinaiko, A. R., Vallance, H., Hinrichs, B., Smith, W., … Nürnberg, P. (2003). Mutations in ENPP1 are associated with ‘idiopathic’ infantile arterial calcification. Nature Genetics, 34(4), 379-381. https://doi.org/10.1038/ng1221 - PubMed
  15. Schmitt-Sody, M., Kirchhoff, C., Mayer, W., Goebel, M., & Jansson, V. (2008). Avascular necrosis of the femoral head: Inter- and intraobserver variations of Ficat and ARCO classifications. International Orthopaedics, 32(3), 283-287. https://doi.org/10.1007/s00264-007-0320-2 - PubMed
  16. Soda, N., Sakai, N., Kato, H., Takami, M., & Fujita, T. (2019). Singleton-Merten syndrome-like skeletal abnormalities in mice with constitutively activated MDA5. Journal of Immunology, 203(5), 1356-1368. https://doi.org/10.4049/jimmunol.1900354 - PubMed
  17. Van Campenhout, A., & Golledge, J. (2009). Osteoprotegerin, vascular calcification and atherosclerosis. Atherosclerosis, 204(2), 321-329. https://doi.org/10.1016/j.atherosclerosis.2008.09.033 - PubMed
  18. Zhang, Q. Y., Li, Z. R., Gao, F. Q., & Sun, W. (2018). Pericollapse stage of osteonecrosis of the femoral head: A last chance for joint preservation. Chinese Medical Journal, 131(21), 2589-2598. https://doi.org/10.4103/0366-6999.244111 - PubMed
  19. Zhao, M. M., Xu, M. J., Cai, Y., Zhao, G., Guan, Y., Kong, W., Tang, C., & Wang, X. (2011). Mitochondrial reactive oxygen species promote p65 nuclear translocation mediating high-phosphate-induced vascular calcification in vitro and in vivo. Kidney International, 79(10), 1071-1079. https://doi.org/10.1038/ki.2011.18 - PubMed

Publication Types