J Clin Immunol (2016) 36:103–106 DOI 10.1007/s10875-015-0229-2
LETTER TO EDITOR
An infant with ZAP-70 deficiency with disseminated mycobacterial disease Saliha Esenboga 1 & Deniz Cagdas Ayvaz 1 & Pinar Gur Cetinkaya 1 & Mirjam van der Burg 2 & İlhan Tezcan 1
Received: 15 June 2015 / Accepted: 18 December 2015 / Published online: 28 December 2015 # Springer Science+Business Media New York 2015
To the Editor: Combined immunodeficiency (CID) is a genetic disorder characterized by defects in the development of T and B lymphocytes. A variety of mechanisms affecting antigen presentation, cytokine signaling, recombination events, T cell receptor signal transduction or other basic cellular processes play role in the pathogenesis of CID. Regardless of the underlying genetic defect, patients with CID classically present with recurrent and severe infections such as oral candidiasis, CMV pneumonia or chronic diarrhea resulting in failure to thrive in the early years of life [1]. Zeta chain associated protein kinase 70 (ZAP-70), a cytoplasmic tyrosine kinase involved in T-cell receptor(TCR) signalling, play a critical role in T cell differentiation and function. Its deficiency which is caused by autosomal recessive mutations in ZAP-70 gene, can lead to a rare form of CID. CD8 T cell lymphopenia and presence of anergic CD4+ T cells unresponsive to mitogens are usually the hallmark findings of ZAP-70 deficiency, however the clinical presentation can be variable, Similar to other forms of CID, hematopoietic stem cell transplantation is usually considered as a definite therapy for ZAP-70 deficiency. Here, we present a case of male patient with ZAP-70 deficiency and bronchial hyperreactivity who presented with disseminated mycobacterial infection. Invagination developed
* Saliha Esenboga
[email protected] 1
Department of Pediatrics, Division of Immunology, Hacettepe University Faculty of Medicine, 06100 Sıhhiye, Ankara, Turkey
2
Department of Immunology, Erasmus University, Rotterdam, Netherlands
due to enlarged intraabdominal lymph nodes led to the diagnosis of mycobacterial infection. A thirteen-month old boy presented to our emergency department with three week history of fever and more recent onset of vomiting and abdominal distention. He was born at term with a normal birth weight to non-consanguineous parents originating from the same territory of a city in Turkey. The family reported history of recurrent wheezing episodes and hospitalizations starting around 8 months of age. His physical examination revealed weight of 9100 g (3rd - 10th percentiles), height of 74 cm (10th - 25th percentiles), head circumference of 43 cm (10th - 25th percentiles), distended abdomen and hepatomegaly (liver palpable 2 cm below the costal margin). Abdominal ultrasound showed multiple conglomerated mesenteric lymphadenopathies (the largest 30 mm in diameter), minimal dilatation of intestinal loops with invagination of a short segment in the left upper quadrant. Initial differential diagnosis was broad and included infections, malignancy and hemophagocytosis. The laboratory analysis and a normal bone marrow aspiration smear ruled out hemophagocytic lymphohistiocytosis (HLH). A ppd. test was performedand it was found to be anergic despite BCG vaccination at 2 months of age as a part of the vaccination schedule in Turkey. It was found out from the medical records that he had no local complications after BCG vaccination. Smears of gastric lavage collected in 3 consecutive days were negative for acid-fast bacilli. Thorax and abdominal computed tomography showed mediastinal, hilar, axillary and extensive intraabdominal (mesenteric and paraaortic) lymphadenopathy,with lymph node diameter as large 13 mm in the abdomen and 25 mm in the thorax (Fig. 1). The patient underwent abdominal surgery for invagination which was thought to be due to enlarged intraabdominal lymph nodes. Excisional mesenteric lymph node biopsy was positive with Ziehl-Neelsen dye and tissue PCR revealed M. tuberculosis complex. The patient was started
104
J Clin Immunol (2016) 36:103–106
on isoniazid, rifampicin, streptomycin and pyrazinamide with the suspicion of disseminated mycrobacterial disese. Skin prick test revealed fish and nut allergy. Furhter workup for disseminated mycobacterial disease revealed a borderline lymphopenia (ALC: 2500/mm3), mildly low levels of IgA and IgG and significant CD8 lymphopenia (Table 1). Lymphocyte proliferation test showed normal response to phorbol myristrate
acetate (PMA) and ionomycin, however there was inadequate response to phytohemagglutinin (PHA) and concanavalin-A (ConA) when compared to healthy control (Table 1). These results were suggestive of ZAP-70 defeciency and the diagnosis was confirmed with sequence analysis. The sequence analysis showed homozygous mutation (c. 1520C > T) in exon 12 of the ZAP-70 gene which resulted in alanine to valine replacement at aminoacid position 507 (p. Ala507Val). The parents were found to be heterozygous cariers of the same mutation. Firstly matched family and then matched unrelated donor screening was performed and intravenous immunoglobulin (IVIG) treatment was started. At 14 months of age the patient developed acute ataxia, nystagmoid eye movements, loss of consciousness all of which were thought to be due to viral cerebellitis or mycobacterial involvement of brain. However, cerebrospinal fluid was negative for acid-fast bacilli. And brain MRI did not demonstrate any findings suggestive of mycobacterial disease or infarct. The patient unfortunately died at 15 months of age due to acute respiratory distress syndrome. CID is characterized by deficiency of cellular and humoral immune response due to T and B cell dysfunction. ZAP-70 deficiency may present with a variety of clinical entities
Table 1 Immunological test results of the patient
Results
Fig. 1 Intraabdominal multiple lymphadenopathies
Immunological tests Complete blood count Hb(g/dL) WBC (/mm3) Plt (/mm3) ALC (/mm3) ANC (/mm3) AEC (/mm3) Immunoglobulins IgA (g/dL)
9.0(10.5–14.0) 6800(6000–14,000) 289.000(150,000–400,000) 2500 (2600–10,400) 2600 200 28.4(30–107)
IgG (g/dL) 558(605–1430) IgM (g/dL) 92.5(66–228) Total IgE (IU/mL) 6.28 Lymphocyte subsets [% and absolute numbers (/mm3)] CD3 68 %(54–76)/1800(1600–6700) CD4 60 % (31–54)/1590(1000–4600) CD8 CD16 + 56 CD19 NBT IL12-IFNγ expression Lymphocyte transformation
4 % (12–28)/104(400–2100) 5 % (3–17)/133(200–1200) 22 % (15–39)/585(600–2700) 100 % Patient 100 % patient PHA 5155/902:5.71 ConA 4239/902:4.69 PMA/Iyn 97.083/902:107.63
Control 100 % control 352.964/21.902:16.11 283.358/21.902:12.93 259.364/21.902:11.84
Hb hemoglobin, WBC white blood cell, Plt platelet, ALC absolute lymphocyte count, ANC absolute neutrophil count, AEC absolute eosinophil count, Ig immunoglobulin, CD cluster of differentiation, NBT nitro-blue-tetrazolium, IL interleukin, PMA phorbol-myristrate-acetate, PHA phytohemagglutinin, conA Concanavalin-A
J Clin Immunol (2016) 36:103–106
including classical form of SCID, atypical SCID (Omenn syndrome), lymphoma, silent brain infarcts, BCG infection, congenital nephrotic syndrome or allergic symptoms [2–5]. The patient’s symptoms began with recurrent wheezing episodes due to food allergy at 8 months of age and he lastly presented to our emergency department with abdominal distention and enlarged lymph nodes at13 months of age. A case of ZAP-70 deficiency presenting with recurrent wheezing episodes was previously reported by Turul et al. [2]. Interestingly, our patient and the patient reported by Turul et al. carried the same homozygous mutation in ZAP-70 gene (Exon 12, 1520C > T) resulting in alanine to valine replacement at aminoacid position 507 (p. Ala507Val). Although we did not identify any consanguinity between these two patients, they were from same geographical region (Black Sea region) of Turkey. It has been reported that the heterogenity of clinical symptoms in ZAP70 deficiency usually leads to diagnostic delays [2]. The patient initially presented with non-specific symptoms therefore our initial differential diagnosis was broad. He was initially evaluated for lymphoma because of prolonged fever and disseminated lymphadenopathy. However, bone marrow aspiration and lymph node biopsies ruled out lymphoma or other hematologic malignancies. It should always be kept in mind that patients with ZAP-70 deficiency and other forms of CID are at risk of developing lymphoma. For instance, Newell et al. reported a 11-month old patient with ZAP-70 deficiency and EBV–associated lymphoma [3]. It has been proposed that near complete absence of CD8+ T cell lineage, absence or diminished numbers of cytotoxic and supressor T cells in ZAP-70 deficiency affects the development and function of B cells and this may lead to uncontrolled lymphoproliferation due to EBV infection [3]. The diagnostic clue for an an underlying immunodeficiency in the patient was disseminated mycobacterial infection and associated invagination. The possible sources of disseminated mycobacterial infection in the patient was either BCG vaccination or primary Mycobacterium tuberculosis infection. However, we think the latter was unlikely because family screening for tuberculosis was negative. BCG, which is a live vaccine, is absolutely contraindicated in patients with SCID [5]. It is one of the pitfalls of nationwide BCG vaccination programs that, unless there is a family history of immunodeficiency, this vaccine is administered to retrospective multicenter study showed that BCG vaccination caused localized or disseminated complications 17 % or 34 % of patient with SCID patients, respectively [5]. Most commonly affected organs were extraregional lymph nodes, skin and lungs. Similar to the findings of the study, the patient had disseminated mycobacterium infection primarily in lymph nodes and lungs. Antituberculosis therapy was initiated once the diagnosis was made, but this was not sufficient to slow down the clinical progression of the disease likely because of the underlying CID.
105
Newborn screening programs(NBS) play a critical role in early diagnosis and effective treatment of most forms of SCID such as RAG1/2, ADA, CD3D, JAK3, IL2RA, LIGASE deficiencies. However NBS using T cell receptor excision circle (TREC) levels have litations and may miss some forms of SCID at birth. For instance, Junker et al. reported a 7 month old ZAP-70 deficient patient with ARDS due to rhinovirus pneumonia whose TREC level was found to be normal at birth but was undetectable at the age of 9 months after the onset of symptoms [6]. In recent years, survival rates of patients with SCID have improved significantly mainly with appropriate use of hematopoietic stem cell transplantation (HSCT) [6]. For the patient, antimicrobial prophylaxis and IVIG replacement therapy were initiated and donor screening for HSCT was performed as soon as CID diagnosis was made. However, matched family or unrelated donor was not found. In conclusion, ZAP-70 deficiency is a rare form of CID and its clinical presentation may vary from allergic symptoms to more severe complications such as lymphoma or disseminated mycobacterial infection following BCG vaccination. Its diagnosis is challenging because these patients may have normal lymphocyte count on routine laboratory analysis and accurate diagnosis usualy requires lymphocyte subset and transformation tests or genetic testing. Early diagnosis can improve the chance of effective treatment in patients with ZAP-70 deficiency, as in other forms of CID. Acknowledgments This work was not supported by any funding organization or person. Compliance with ethical standards This report was prepared with complaince to ethical standards. Informed consent This report was prepared after the death of our patient and informed consent was obtained from the parents.
References 1.
2.
3.
4.
Van der Burg M. Gennery A.R. Educational paper. The expanding clinical and immunological spectrum of severe combined immunodeficiency. Eur J Pediatr. 2011;170(5):561–71. doi:10.1007/s00431011-1452-3. Turul T, Tezcan I, Artac H, de Bruin-Versteeg S, Barendregt BH, Reisli I, Sanal O, van Dongen JJ, van der Burg M. Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency. Eur J Pediatr. 2009;168(1):87–93. doi:10.1007/s00431-008-0718-x. Newell A, Dadi H, Goldberg R, Ngan BY, Grunebaum E, Roifman CM. Diffuse large B-cell lymphoma as presenting feature of zap-70 deficiency. J Allergy Clin Immunol. 2011;127(2):517–20. doi:10. 1016/j.jaci.2010.09.016. Haluk Akar H, Patiroglu T, Akyildiz BN, Tekerek NU, Sait Doğan M, Doğanay S, van der Burg M, Dusunsel R. Silent brain infarcts in two patients with zeta chain-associated protein 70 kDa (ZAP70)
106
5.
J Clin Immunol (2016) 36:103–106 deficiency. Clin Immunol. 2015;158(1):88–91. doi:10.1016/j.clim. 2015.03.014. Marciano BE, Huang CY, Joshi G, Rezaei N, Carvalho BC, Allwood Z, Ikinciogullari A, Reda SM, Gennery A, Thon V, Espinosa-Rosales F, Al-Herz W, Porras O, Shcherbina A, Szaflarska A, Kiliç Ş, Franco JL, Gómez Raccio AC, Roxo P Jr, Esteves I, Galal N, Grumach AS, AlTamemi S, Yildiran A, Orellana JC, Yamada M, Morio T, Liberatore D, Ohtsuka Y, Lau YL, Nishikomori R, Torres-Lozano C, Mazzucchelli JT, Vilela MM, Tavares FS, Cunha L, Pinto JA, Espinosa-Padilla SE, Hernandez-Nieto L, Elfeky RA, Ariga T, Toshio H, Dogu F, Cipe F, Formankova R, Nuñez-Nuñez ME, Bezrodnik L, Marques JG, Pereira
6.
MI, Listello V, Slatter MA, Nademi Z, Kowalczyk D, Fleisher TA, Davies G, Neven B, Rosenzweig SD. BCG vaccination in patients with severe combined immunodeficiency: Complications, risks and vaccination policies. J Allergy Clin Immunol 2014;133(4):1134–1141. doi: 10.1016/j.jaci.2014.02.028. Erratum in: J Allergy Clin Immunol. 2014 Jul;134(1):244. Ak J, Turvey SE, Grazioli S, Bennett M, Hildebrand KJ, Vallance H. Limitation of TREC-based newborn screening for ZAP70 severe combined immunodeficiency. Clin Immunol. 2014 Jul;153(1):209– 10. doi:10.1016/j.clim.2014.04.015.
