Prevalence of Immunological Defects in a Cohort of 97 Rubinstein–Taybi Syndrome Patients


Although recurrent infections in Rubinstein–Taybi syndrome (RSTS) are common, and probably multifactorial, immunological abnormalities have not been extensively described with only isolated cases or small case series of immune deficiency and dysregulation having been reported. The objective of this study was to investigate primary immunodeficiency (PID) and immune dysregulation in an international cohort of patients with RSTS. All published cases of RSTS were identified. The corresponding authors and researchers involved in the diagnosis of inborn errors of immunity or genetic syndromes were contacted to obtain up-to-date clinical and immunological information. Ninety-seven RSTS patients were identified. For 45 patients, we retrieved data from the published reports while for 52 patients, a clinical update was provided. Recurrent or severe infections, autoimmune/autoinflammatory complications, and lymphoproliferation were observed in 72.1%, 12.3%, and 8.2% of patients. Syndromic immunodeficiency was diagnosed in 46.4% of individuals. Despite the broad heterogeneity of immunodeficiency disorders, antibody defects were observed in 11.3% of subjects. In particular, these patients presented hypogammaglobulinemia associated with low B cell counts and reduction of switched memory B cell numbers. Immunoglobulin replacement therapy, antibiotic prophylaxis, and immunosuppressive treatment were employed in 16.4%, 8.2%, and 9.8% of patients, respectively. Manifestations of immune dysfunctions, affecting mostly B cells, are more common than previously recognized in patients with RSTS. Full immunological assessment is warranted in these patients, who may require detailed investigation and specific supportive treatment.

Graphical Abstract

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3



Autoimmune lymphoproliferative syndrome


Combined immunodeficiency


Common variable immunodeficiency


European Society for Immunodeficiencies


Familial Mediterranean fever


Hematopoietic stem cell transplantation


Primary immunodeficiency


Rubinstein–Taybi syndrome


Selective IgA deficiency


Unclassified syndromic immunodeficiency


  1. 1.

    Negri G, Milani D, Colapietro P, Forzano F, Della Monica M, Rusconi D, et al. Clinical and molecular characterization of Rubinstein-Taybi syndrome patients carrying distinct novel mutations of the EP300 gene. Clin Genet. 2015;87:148–54.

    CAS  PubMed  Google Scholar 

  2. 2.

    Fergelot P, Van Belzen M, Van Gils J, Afenjar A, Armour CM, Arveiler B, et al. Phenotype and genotype in 52 patients with Rubinstein–Taybi syndrome caused by EP300 mutations. Am J Med Genet Part A. 2016;170A:3069–82.

    Google Scholar 

  3. 3.

    Stevens CA, Pouncey J, Knowles D. Adults with Rubinstein-Taybi syndrome. Am J Med Genet Part A. 2011;155:1680–4.

    Google Scholar 

  4. 4.

    Naimi DR, Munoz J, Rubinstein J, Hostoffer RW. Rubinstein-Taybi syndrome: an immune deficiency as a cause for recurrent infections. Allergy Asthma Proc. 2006;27(3):281–4.

    PubMed  Google Scholar 

  5. 5.

    Kimura H, Ito Y, Koda Y, Hase Y. Rubinstein-Taybi syndrome with thymic hypoplasia. Am J Med Genet. 1993;46(3):293–6.

    CAS  PubMed  Google Scholar 

  6. 6.

    Villella A, Bialostocky D, Lori E, Meyerson H, Hostoffer RW. Rubinstein-Taybi syndrome with humoral and cellular defects: a case report. Arch Dis Child. 2000;83(4):360–1.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Freitas NM, Imbronito AV, La Scala CSK, Lotufo RFM, Pustiglioni FE. Periodontal disease in a Rubinstein-Taybi syndrome patient: case report. Int J Paediatr Dent. 2006;16(4):292–6.

    CAS  PubMed  Google Scholar 

  8. 8.

    Rivas F, Fragoso R, Ramos-Zepeda R, Vaca G, Hernandez A, Gonzalez-Quiroga G, et al. Deficient cell immunity and mild intermittent hyperaminoacidemia in a patient with the Rubinstein-Taybi syndrome. Acta Paediatr. 1980;69(1):123–5.

    CAS  Google Scholar 

  9. 9.

    Hamilton MJ, Newbury-Ecob R, Holder-Espinasse M, Yau S, Lillis S, Hurst JA, et al. Rubinstein-Taybi syndrome type 2: report of nine new cases that extend the phenotypic and genotypic spectrum. Clin Dysmorphol. 2016;25:135–45.

    PubMed  Google Scholar 

  10. 10.

    Pasic S. Rubinstein-Taybi syndrome associated with humoral immunodeficiency. J Investig Allergol Clin Immunol. 2015;25(2):137–8.

    CAS  PubMed  Google Scholar 

  11. 11.

    Rivalta B, Zama D, Pancaldi G, Facchini E, Cantarini ME, Miniaci A, et al. Evans syndrome in childhood: long term follow-up and the evolution in primary immunodeficiency or rheumatological disease. Front Pediatr. 2019;23;7:304.

  12. 12.

    Saettini F, Moratto D, Grioni A, Maitz S, Iascone M, Rizzari C, et al. A novel EP300 mutation associated with Rubinstein-Taybi syndrome type 2 presenting as combined immunodeficiency. Pediatr Allergy Immunol. 2018;29(7):776–81.

    PubMed  Google Scholar 

  13. 13.

    Lougaris V, Facchini E, Baronio M, Lorenzini T, Moratto D, Specchia F, et al. Progressive severe B cell deficiency in pediatric Rubinstein-Taybi syndrome. Clin Immunol. 2016;173:181–3.

    CAS  PubMed  Google Scholar 

  14. 14.

    Herriot R, Miedzybrodzka Z. Antibody deficiency in Rubinstein-Taybi syndrome. Clin Genet. 2016;89(3):355–8.

    CAS  PubMed  Google Scholar 

  15. 15.

    Shearer WT, Rosenblatt HM, Gelman RS, Oyomopito R, Plaeger S, Stiehm ER, et al. Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 Study. J Allergy Clin Immunol. 2003 Nov;112(5):973–80.

    PubMed  Google Scholar 

  16. 16.

    Sheffield protein reference unit. Available at: Accessed October 31, 2019. doi: Epub 2015 Oct 6.

  17. 17.

    Farruggia P, Fioredda F, Puccio G, Porretti L, Lanza T, Ramenghi U, et al. Autoimmune neutropenia of infancy: data from the Italian Neutropenia Registry. Am J Hematol. 2015 Dec;90(12):E221–2.

    PubMed  Google Scholar 

  18. 18.

    Romaniouk I, Romero A, Runza P, Nieto C, Mouzo R, Simal F. Management of neuroendocrine tumor in a patient with Rubinstein-Taybi syndrome in chronic hemodialysis. Nefrologia. 2018;38(4):446–8.

    PubMed  Google Scholar 

  19. 19.

    Mar N, Digiuseppe JA, Dailey ME. Rubinstein–Taybi syndrome – a window into follicular lymphoma biology. Leuk Lymphoma. 2016;57(12):2908–10.

    PubMed  Google Scholar 

  20. 20.

    Kamenarova K, Simeonov E, Tzveova R, Dacheva D, Penkov M, Kremensky I, et al. Identification of a novel de novo mutation of CREBBP in a patient with Rubinstein-Taybi syndrome by targeted next-generation sequencing: a case report. Hum Pathol. 2016;47(1):144–9.

    CAS  PubMed  Google Scholar 

  21. 21.

    Torres LC, De LL CM, Delboni TP, Okay TS, Carneiro-Sampaio M, Sugayama S. Rubinstein-Taybi syndrome: a female patient with a de novo reciprocal translocation T(2; 16)(Q36.3; P13.3) and dysgranulopoiesis. Clinics. 2010;65(1):107–9.

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Torres LC, Sugayama SMM, Arslanian C, Sales MM, Carneiro-Sampaio M. Evaluation of the immune humoral response of Brazilian patients with Rubinstein-Taybi syndrome. Brazilian J Med Biol Res. 2010;43(12):1215–24.

    CAS  Google Scholar 

  23. 23.

    Kosaki R, Kikuchi S, Koinuma G, Higuchi M, Torii C, Kawasaki K, et al. Two patients with Rubinstein-Taybi syndrome and severe pulmonary interstitial involvement. Am J Med Genet A. 2010;152A(7):1844–6.

    PubMed  Google Scholar 

  24. 24.

    Kalyoncu U, Tufan A, Karadag O, Kisacik B, Akdogan A, Calguneri M. Rubinstein-Taybi syndrome and familial Mediterranean fever in a single patient: two distinct genetic diseases located on chromosome 16p13.3. J Natl Med Assoc. 2006;98(10):1692–3.

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Kim CJ, Nam JH, Chung HY, Kook JH, Kim SY, Woo YJ. Kimura disease in a patient with Rubinstein-Taybi syndrome. Pediatr Int. 2004;46(5):609–11.

    PubMed  Google Scholar 

  26. 26.

    Bayle P, Bazex J, Lamant L, Lauque D, Durieu C, Albes B. Multiple perforating and non perforating pilomatricomas in a patient with Churg-Strauss syndrome and Rubinstein-Taybi syndrome. J Eur Acad Dermatology Venereol. 2004;18(5):607–10.

    CAS  Google Scholar 

  27. 27.

    Altintas F, Cakmakkaya S. Anesthetic management of a child with Rubinstein-Taybi syndrome. Paediatr Anaesth. 2004;14(7):610–1.

    PubMed  Google Scholar 

  28. 28.

    Çaksen H, Bartsch O, Okur M, Temel H, Açikgöz M, Yilmaz C. Rubinstein-Taybi syndrome and CREBBP c.201-202delTA mutation: a case presenting with varicella meningoencephalitis. Genet Couns. 2009;20(3):255–60.

    PubMed  Google Scholar 

  29. 29.

    Shashi V, Fryburg JS. Vascular ring leading to tracheoesophageal compression in a patient with Rubinstein-Taybi syndrome. Clin Genet. 1995;48:324–7.

    CAS  PubMed  Google Scholar 

  30. 30.

    Jonas DM, Heilbron DC, Ablin AR. Rubinstein-Taybi syndrome and acute leukemia. J Pediatr. 1978;92(5):851–2.

    CAS  PubMed  Google Scholar 

  31. 31.

    Levinson ED, Spencer RP. Bone scan-demonstrated urinary tract abnormalities in a patient with Rubinstein-Taybi syndrome. Clin Nucl Med. 1980;5(10):454–6.

    CAS  PubMed  Google Scholar 

  32. 32.

    Rohlfing B, Lewis K, Singleton EB. Rubinstein-Taybi syndrome: report of an unusual case. Am J Dis Child. 1971;121(1):71–4.

    CAS  PubMed  Google Scholar 

  33. 33.

    Sinnette C, Odeku EL. Rubinstein-Taybi syndrome: the first case in an African child and the first case recognized at birth. Clin Pediatr (Phila). 1968;7:488–92.

  34. 34.

    Berkhout A, Prociv P, Anthony H, Anthony LT, Clare N. Two cases of neuroangiostrongyliasis: a rare disease because rarely considered or rarely diagnosed? J Paediatr Child Health. 2019;55(12):1463–9.

    PubMed  Google Scholar 

  35. 35.

    Noble A, Drouin E, Faure C. Eosinophilic esophagitis and gastritis in Rubinstein-Taybi syndrome. J Pediatr Gastroenterol Nutr. 2007;44(4):498–500.

    CAS  PubMed  Google Scholar 

  36. 36.

    Shaheed MM, Khamaheh R, Rifai SZ, Abomelha AM. Rubinstein Taybi syndrome and lymphoblastic leukemia. Saudi Med J. 1999;20(10):800–2.

    CAS  PubMed  Google Scholar 

  37. 37.

    ESID Registry Working Party. ESID Registry - Working definitions for clinical diagnosis of IEI 2019;1–33. Available from:

  38. 38.

    Pieper K, Rizzi M, Speletas M, Smulski CR, Sic H, Kraus H, et al. A common single nucleotide polymorphism impairs B-cell activating factor receptor’s multimerization, contributing to common variable immunodeficiency. J Allergy Clin Immunol. 2014;133:1222–1225.e10.

  39. 39.

    Ming J.E., Stiehm E.R. Syndromic immunodeficiencies. In: Rezaei N., Aghamohammadi A., Notarangelo L. (eds) Primary immunodeficiency diseases. 2017; Springer, Berlin, Heidelberg.

  40. 40.

    Oliveira JB, Bleesing JJ, Dianzani U, Fleisher TA, Jaffe ES, Lenardo MJ, et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood. 2010;116(14):e35–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Wehr C, Kivioja T, Schmitt C, Ferry B, Witte T, Eren E, et al. The EUROclass Trial: defining subgroups in common variable immunodeficiency. Blood. 2008;111(1):77–85.

    CAS  PubMed  Google Scholar 

  42. 42.

    Posey JE, Harel T, Liu P, Rosenfeld JA, James RA, Coban Akdemir ZH, et al. Resolution of disease phenotypes resulting from multilocus genomic variation. N Engl J Med. 2017;376(1):21–31.

    CAS  PubMed  Google Scholar 

  43. 43.

    Stray-Pedersen A, Sorte HS, Samarakoon P, Gambin T, Chinn IK, Coban Akdemir ZH, et al. Primary immunodeficiency diseases: genomic approaches delineate heterogeneous Mendelian disorders. J Allergy Clin Immunol. 2017 Jan;139(1):232–45.

    PubMed  Google Scholar 

  44. 44.

    Notarangelo LD. PIDs and cancer: an evolving story. Blood. 2010;116(8):1189–90.

    CAS  PubMed  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Francesco Saettini.

Ethics declarations

The study conformed to the Declaration of Helsinki and was approved by the institutional review boards/ethic committee of Comitato Etico Brianza (Monza, Italy; PID-GENMET).

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material


(DOCX 206 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Saettini, F., Herriot, R., Prada, E. et al. Prevalence of Immunological Defects in a Cohort of 97 Rubinstein–Taybi Syndrome Patients. J Clin Immunol 40, 851–860 (2020).

Download citation


  • Rubinstein–Taybi syndrome
  • EP300
  • hypogammaglobulinemia
  • antibody deficiency
  • syndromic immunodeficiency
  • humoral defects
  • lymphoproliferation
  • B cells