Deniz Cagdas Ayvaz

Additional Diverse Findings Expand the Clinical Presentation of DOCK8 Deficiency

We describe seven Turkish children with DOCK8 deficiency who have not been previously reported. Three patients presented with typical features of recurrent or severe cutaneous viral infections, atopic dermatitis, and recurrent respiratory or gastrointestinal tract infections. However, four patients presented with other features. Patient 1–1 featured sclerosing cholangitis and colitis; patient 2–1, granulomatous soft tissue lesion and central nervous system involvement, with primary central nervous system lymphoma found on follow-up; patient 3–1, a fatal metastatic leiomyosarcoma; and patient 4–2 showed no other symptoms initially besides atopic dermatitis. Similar to other previously reported Turkish patients, but in contrast to patients of non-Turkish ethnicity, the patients’ lymphopenia was primarily restricted to CD4+ T cells. Patients had homozygous mutations in DOCK8 that altered splicing, introduced premature terminations, destabilized protein, or involved large deletions within the gene. Genotyping of remaining family members showed that DOCK8 deficiency is a fully penetrant, autosomal recessive disease. In our patients, bone marrow transplantation resulted in rapid improvement followed by disappearance of viral skin lesions, including lesions resembling epidermodysplasia verruciformis, atopic dermatitis, and recurrent infections. Particularly for patients who feature unusual clinical manifestations, immunological testing, in conjunction with genetic testing, can prove invaluable in diagnosing DOCK8 deficiency and providing potentially curative treatment.

Atypical combined immunodeficiency due to Artemis defect: A case presenting as hyperimmunoglobulin M syndrome and with LGLL

SCID can be caused by various genetic mutations leading to distinctive phenotypes according to the presence of T, B and NK cells. Artemis is a gene encoded on chromosome 10p. The deficiency of this molecule causes an inability to repair DNA double strand breaks and is one of the causes of radiosensitive T-B-NK+ SCID. The syndrome usually presents with opportunistic infections in the first years of life that leads to death if not treated with stem cell transplantation. The spectrum of the disease can be wide because of the heterogeneity of the mutations. Herein we present an atypical SCID (CID) patient with Artemis defect mimicking hyper IgM syndrome. Our patient had high serum IgM with low IgG and IgA levels, lymphocytosis and recurrent infections, intractable diarrhea, growth retardation, systemic CMV infection and sclerosing cholangitis. He also developed large granular lymphocytic leukemia and survived until the age of 6.5 years.

Patients with Primary Immunodeficiencies Are a Reservoir of Poliovirus and a Risk to Polio Eradication

Immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) have been isolated from primary immunodeficiency (PID) patients exposed to oral poliovirus vaccine (OPV). Patients may excrete poliovirus strains for months or years; the excreted viruses are frequently highly divergent from the parental OPV and have been shown to be as neurovirulent as wild virus. Thus, these patients represent a potential reservoir for transmission of neurovirulent polioviruses in the post-eradication era. In support of WHO recommendations to better estimate the prevalence of poliovirus excreters among PIDs and characterize genetic evolution of these strains, 635 patients including 570 with primary antibody deficiencies and 65 combined immunodeficiencies were studied from 13 OPV-using countries. Two stool samples were collected over 4 days, tested for enterovirus, and the poliovirus positive samples were sequenced. Thirteen patients (2%) excreted polioviruses, most for less than 2 months following identification of infection. Five (0.8%) were classified as iVDPVs (only in combined immunodeficiencies and mostly poliovirus serotype 2). Non-polio enteroviruses were detected in 30 patients (4.7%). Patients with combined immunodeficiencies had increased risk of delayed poliovirus clearance compared to primary antibody deficiencies. Usually, iVDPV was detected in subjects with combined immunodeficiencies in a short period of time after OPV exposure, most for less than 6 months. Surveillance for poliovirus excretion among PID patients should be reinforced until polio eradication is certified and the use of OPV is stopped. Survival rates among PID patients are improving in lower and middle income countries, and iVDPV excreters are identified more frequently. Antivirals or enhanced immunotherapies presently in development represent the only potential means to manage the treatment of prolonged excreters and the risk they present to the polio endgame.

Successful treatment of severe myasthenia gravis developed after allogeneic hematopoietic stem cell transplantation with plasma exchange and rituximab

Myasthenia gravis is among the rare complications after allogeneic hematopoietic stem cell transplantation and is usually associated with chronic GVHD. Herein, we report a 2‐year and 10 months of age female with Griscelli syndrome, who developed severe myasthenia gravis at post‐transplant +22nd month and required respiratory support with mechanical ventilation. She was unresponsive to cyclosporine A, methylprednisolone, intravenous immunoglobulin, and mycophenolate mofetil and the symptoms could only be controlled after plasma exchange and subsequent use of rituximab, in addition to cyclosporine A and mycophenolate mofetil maintenance. She is currently asymptomatic on the 6th month of follow‐up. Pediatr Blood Cancer 2014;61:928–930.

A novel mutation in TAP1 gene leading to MHC class I deficiency: Report of two cases and review of the literature

Major histocompatibility complex (MHC) class I deficiency syndrome is a rare primary immunodeficiency caused by mutations in the peptide transporter complex associated with antigen presentation (TAP) gene which plays a crucial role in intracellular peptide antigen presentation. A few cases have been reported to date. Recurrent sinopulmonary infections and skin ulcers are the main characteristics of the syndrome. Here we report two siblings diagnosed with TAP1 deficiency syndrome associated only with recurrent sinopulmonary infections with the description of a novel mutation leading to a premature stop codon in TAP1 gene and review of the relevant literature. Both of the siblings had recurrent sinopulmonary infections since childhood, responded to antibiotherapy well, neither of them had hospitalization history because of infections. One had chronic hepatitis B infection which may possibly be related to TAP1 gene defect.

An infant with ZAP-70 deficiency with disseminated mycobacterial disease

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 Tcell lymphopenia and presence of anergic CD4+ Tcells 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 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 revealedweight 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 revealedM. tuberculosis complex. The patient was started * Saliha Esenboga salihaeren@yahoo.com

A young girl with severe cerebral fungal infection due to card 9 deficiency

Pattern recognition receptors (PRRs), receptors of the innate immune system, are important in interaction with pathogens. Caspase Recruitment Domain-containing protein 9 (CARD9), a member of PRRs, is an intracellular adaptor protein important in fungal defense. CARD9 deficiency causes a rare primary immunodeficiency (PID) characterized by superficial and deep fungal infections. We report a 17year-old female with a homozygous nonsense mutation in CARD9, who presented with severe cerebral fungal infection of the central nervous system. She was also found to have an heterozygous NLRP12 mutation, which may have had add-on effect on the severity of the infection.

Progressive neurodegenerative syndrome in a patient with X-linked agammaglobulinemia receiving intravenous immunoglobulin therapy.

A progressive encephalopathy of unknown etiology has been described in patients with primary immunodeficiency disorders. In this report, we characterize the clinical features of this progressive neurodegenerative dementing disorder in a young man with Bruton agammaglobulinemia, through neuropsychological tests and a video sequence. The clinical course of the encephalopathy seems rather uniform: Cognition, especially frontal lobe function, is affected in the early stages, and some patients develop movement disorders. The syndrome causes severe cognitive and physical disability, and can eventually be fatal. The autoimmunity results from dysregulated immune responses, but the underlying mechanism has not yet been fully explained.

Metamizole-Induced Bicytopenia Reversed by G-CSF and IVIG Treatment in a Child

Metamizole is an effective antipyretic and analgesic drug, whereas it has a risk of hematological toxicity including agranulocytosis, neutropenia, thrombocytopenia, pancytopenia, and aplastic anemia. The observed reactions are idiosyncratic and are not dose-dependent. Basak et al. from Poland reported that crude estimates of the rate of agranulocytosis and aplastic anemia associated with metamizole were 0.16 and 0.08 cases/million person-days of use, respectively. While metamizole is prohibited in the USA, UK, Denmark, and Sweden, it is available in Turkey, Spain, Poland, Bulgaria, Russia, India, Latin and South America, and Africa [1]. Here, a 9-year-old-girl developed bicytopenia possibly related to metamizole sodium; successfully treated with granulocyte colony stimulating factor (G-CSF) and intravenous immunoglobulin (IVIG) treatments has been presented. A 9-year-old girl was admitted to our hospital with fever lasting for 1 month. She was diagnosed as Brucella infection and secondary hemophagocytic lymphohistiocytosis (HLH) 4 months ago in another center. She had doxiciclina and rifampicin treatments for Brucella infection and pulse methyl prednisolone and IVIG treatment for secondary HLH. She was in good health for more than 3 months, whereas she had again fever for the last 1 month. Her parents are not consanguineous and she has one healthy brother. At admission to our hospital, she had cervical lymphadenopathies not bigger than 1-cm in diameter and no hepatosplenomegaly on her physical examination. On her laboratory studies, her hemoglobin was 6.9 g/dL; hematocrite, 20.9%; mean corpuscular volume, 75 fL; total leukocyte count, 2800/mm3; and platelet count, 387,000/mm3. Her peripheral blood smear revealed 96% lymphocytes and 4% monocytes. Her erythrocyte sedimentation rate and C-reactive protein were 120 mm/h and 13 mg/dL (0–0.8), respectively. Brucella agglutination test was negative. Her bone marrow aspiration smears revealed hypocellularity in erythroid and myeloid series and a lot of plasma cells were observed with differential count of 1% neutrophil, 79%

Hypomorphic RAG1 defect in a child presented with pulmonary hemorrhage and digital necrosis

• In the patients with atypical presentations of vasculitis, suspicion of monogenic disorders may avoid delays in diagnosis and treatment.