Natural history and clinical characteristics of 50 patients with Wolfram syndrome



To describe clinical characteristics of diabetes mellitus (DM) in a group of patients with Wolfram Syndrome (WS).


Descriptive, cross-sectional observational design. The sample consisted of 50 patients diagnosed with WS. Clinical criteria contributing to WS diagnosis were analyzed: diabetes mellitus (DM), optic nerve atrophy (OA), sensorineural deafness, urological and neurological dysfunction, among others. These parameters were assessed according to their presence/absence, age of onset, and various clinical-analytical parameters.


All the patients studied presented DM and OA, with a mean age of onset of 5.4 ± .9 (1–14) years and 9 ± .9 (1–16) years, respectively. The remaining criteria were present with a variable frequency: 77% had diabetes insipidus, 66.7% auditory alterations, 77.8% neurogenic bladder, 61.1% neurological involvement, and 27.8% hypogonadism. A 16.7% of the patients had positive albuminuria (urinary albumin/creatinine ratio > 30 mg/g) and 72.2% had hyporreflexia. There were no significant differences in the age of diagnosis nor of the presence of different pathologies according to sex.


The early presence of a non-autoimmune insulin dependent DM, should alert us of an “infrequent” diabetes syndrome. Wolfram’s presumptive diagnosis could be established if juvenile-onset DM occurs concomitantly with OA, and this visual impairment is not attributable to diabetic retinopathy. Despite the long period of evolution of DM and altered values of HbA1c, the prevalence of microvascular complications in the sample are low.

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Fig. 1


  1. 1.

    F. Khanim, J. Kirk, F. Latif, T.G. Barrett, WFS1/wolframin mutations, Wolfram syndrome, and associated diseases. Hum. Mutat. 17, 357–67 (2001).

    Article  PubMed  CAS  Google Scholar 

  2. 2.

    T. Barrett, S. Bundey, A. Macleod, Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet 346, 1458–63 (1995).

    Article  PubMed  CAS  Google Scholar 

  3. 3.

    S. Amr, C. Heisey, M. Zhang et al. A homozygous mutation in a novel zinc-finger protein, ERIS, is responsible for Wolfram syndrome 2. Am. J. Hum. Genet. 81, 673–83 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. 4.

    F. Urano, Wolfram syndrome: diagnosis, management, and treatment. Curr. Diabetes Rep. 16, 6 (2016).

    Article  Google Scholar 

  5. 5.

    S. Kumar, Wolfram syndrome: important implications for pediatricians and pediatric endocrinologists. Pediatr. Diabetes 11, 28–37 (2010)

    Article  PubMed  CAS  Google Scholar 

  6. 6.

    P. Garcia, A. Leal, F. Villamil et al. Síndrome de DIDMOADUA (DIDMOAD). Estudio de tres familias con 5 nuevos casos. Diferencias con la diabetes mellitus insulindependiente clásica. Med. Clin. 85, 486–90 (1985)

    Google Scholar 

  7. 7.

    K. Homa, A. Stefański, A. Zmysłowska, P. Molęda, M. Bryśkiewicz, L. Majkowska, False diagnosis of type 1 diabetes mellitus and its complications in Wolfram syndrome–is it the reason for the low number of reported cases of this abnormality?. Endokrynol. Pol. 65, 398–400 (2014).

    Article  PubMed  CAS  Google Scholar 

  8. 8.

    G. Boutzios, S. Livadas, E. Marinakis, N. Opie, F. Economou, E. Diamanti-Kandarakis, Endocrine and metabolic aspects of the Wolfram syndrome. Endocrine 40, 10–13 (2011).

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    L. Paris, Y. Usui, J. Serino, J. Sá, M. Friedlander, A challenging form of non-autoimmune insulin-dependent diabetes in a wolfram syndrome patient with a novel sequence variant. J. Diabetes Metab. 6, 1–5 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    G. Esteban, F. Gómez, Manifestaciones clínicas y retraso diagnóstico en el síndrome de Wolfram. Rev. Clínica Esp. 206, 332–335 (2006).

    Article  Google Scholar 

  11. 11.

    G. Esteban, M. Ruano, I. Motero, M. Soler, I. Balaguer, in Las enfermedades raras. Desde una perspectiva bio-psico-social, ed. by (ASUNIVEP)EAU de E y P (Acercamiento Multidisciplinar a La Salud En El Envejecimiento, 2013), pp. 199–204.

  12. 12.

    G. Esteban, M. Ruano, S. Durán, Analizan la calidad de vida de los padres de enfermos con síndrome de Wolfram. Salud Cienc. 17, 444–8 (2010)

    Google Scholar 

  13. 13.

    G. Esteban, Aproximación al tratamiento integral del Síndrome de Wolfram. Aspectos biopsicosociales. (2015)

  14. 14.

    L. Rigoli, G. DʼAnnunzio, in Diabetes in Wolfram Syndrome: Update of Clinical and Genetic Aspects, ed. by F. Barbetti, L. Ghizzoni, F. Guaraldi (Karger Publishers, 2017) pp. 69–77

  15. 15.

    A. Karasik, C. O’Hara, S. Srikanta, et al. Genetically Programmed Selective Islet β-Cell Loss in Diabetic Subjects With Wolfram’s Syndrome. Diabetes Care 12, (1989).

  16. 16.

    C.W.R.J. Cremers, P.G.A.B. Wijdeveld, A.J.L.G. Pinckers, Juvenile diabetes mellitus, optic atrophy, hearing loss, diabetes insipidus, atonia of the urinary tract and bladder, and other abnormalities (WOLFRAM SYNDROME). Acta Paediatr. 66(s264), 1–16 (1977).

    Article  Google Scholar 

  17. 17.

    I. Bernabeu, R. Cámara, R. Araujo et al. Descripción del síndrome de Wolfram (DIDMOAD) a partir de un nuevo caso. Rev. Clin. Esp. 184, 418–20 (1989)

    Google Scholar 

  18. 18.

    B. Kinsley, M. Swift, R. Dumont, R. Swift, Morbidity and mortality in the wolfram syndrome. Diabetes Care 18, (1995).

  19. 19.

    A. Cano, L. Molines, R. Valéro, G. Simonin, V. Paquis-Flucklinger, B. Vialettes, Microvascular diabetes complications in wolfram syndrome (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness [DIDMOAD]). Diabetes Care 30, (2007).

  20. 20.

    M. Dreyer, H. Rüdiger, K. Bujara et al. The syndrome of diabetes insipidus, diabetes mellitus, optic atrophy, deafness, and other abnormalities (DIDMOAD-Syndrome). Klin. Wochenschr. 60, 471–5 (1982)

    Article  PubMed  CAS  Google Scholar 

  21. 21.

    Project E-W. Management of Wolfram Syndrome a Clinical Guideline. Wolfram Syndrome Guideline Development Group. (2014). 28_04_2014.pdf

  22. 22.

    J. Rohayem, C. Ehlers, B. Wiedemann et al. Diabetes and neurodegeneration in Wolfram syndrome A multicenter study of phenotype and genotype. Diabetes Care 34, 1503–10 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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We sincerely thank the patients and families of the Association for Research and Help for Wolfram Syndrome who have agreed to participate in this study. To Dr. Timothy G. Barrett for his invaluable contributions in the present manuscript, to the professionals that make up the Multidisciplinary Team of Wolfram Syndrome (Mónica Ruano Garcia (MF y C), Luisa M. Botella Cubells (Inv. genética), Luz María Martín Egea (psicóloga), Fernando Sánchez García (pediatría) Maria Alharilla Montilla Ibáñez. (ORL), Nicolas Fernandez Fernandez. (ORL), Jose Ignacio Abad Vivas-Pérez (urologia), Belén Gomez Navarro (OFT.), M. Teresa Belmonte García (DUE)).

Authors contribution

All authors contributed towards preparation of this manuscript.


This study was funded by the Consejería de Salud de la Junta de Andalucía, Spain. (Ref. PI-0410-2016).

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Correspondence to Gema Esteban Bueno.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Bueno, G.E., Ruiz-Castañeda, D., Martínez, J.R. et al. Natural history and clinical characteristics of 50 patients with Wolfram syndrome. Endocrine 61, 440–446 (2018).

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  • Wolfram syndrome
  • Diabetes mellitus
  • Optic atrophy
  • Sensorineural deafness
  • Neurodegeneration