Fatih Çelmeli

Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

Significance Chronic mucocutaneous candidiasis (CMC) is defined as persistent or recurrent infections of the skin and/or mucosae by commensal fungi of the Candida genus. It is often seen in patients with T-cell deficiencies, whether inherited or acquired, who typically suffer from multiple infectious diseases. Rare patients are otherwise healthy and display isolated CMC, which often segregates as a Mendelian trait. In 2011, we described the first genetic cause of isolated CMC, with autosomal recessive (AR), complete IL-17 receptor A (IL-17RA) deficiency, in a single patient. We report here 21 patients from 12 unrelated kindreds, homozygous for 12 different mutant alleles that underlie AR IL-17RA deficiency. All patients have isolated CMC and their cells do not respond to IL-17A, -17F, and -17E/IL-25. Chronic mucocutaneous candidiasis (CMC) is defined as recurrent or persistent infection of the skin, nails, and/or mucosae with commensal Candida species. The first genetic etiology of isolated CMC—autosomal recessive (AR) IL-17 receptor A (IL-17RA) deficiency—was reported in 2011, in a single patient. We report here 21 patients with complete AR IL-17RA deficiency, including this first patient. Each patient is homozygous for 1 of 12 different IL-17RA alleles, 8 of which create a premature stop codon upstream from the transmembrane domain and have been predicted and/or shown to prevent expression of the receptor on the surface of circulating leukocytes and dermal fibroblasts. Three other mutant alleles create a premature stop codon downstream from the transmembrane domain, one of which encodes a surface-expressed receptor. Finally, the only known missense allele (p.D387N) also encodes a surface-expressed receptor. All of the alleles tested abolish cellular responses to IL-17A and -17F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes. The patients are currently aged from 2 to 35 y and originate from 12 unrelated kindreds. All had their first CMC episode by 6 mo of age. Fourteen patients presented various forms of staphylococcal skin disease. Eight were also prone to various bacterial infections of the respiratory tract. Human IL-17RA is, thus, essential for mucocutaneous immunity to Candida and Staphylococcus, but otherwise largely redundant. A diagnosis of AR IL-17RA deficiency should be considered in children or adults with CMC, cutaneous staphylococcal disease, or both, even if IL-17RA is detected on the cell surface.

CTLA-4 (+49A/G) Polymorphism and Type-1 Diabetes in Turkish Children

Objective: To evaluate the contribution of cytotoxic T-Iymphocyte antigen-4 (CTLA-4)+49A/G polymorphism to the susceptibility to type-1 diabetes (T1D) in Turkish children. Methods: A case-control study was designed to include 91 Turkish children with T1D and 99 healthy controls. CTLA-4 (+99A/G) gene polymorphism typing was done by PCR amplification followed by restriction fragment length polymorphism method. Results: The genotype and allele frequencies of the CTLA-4 (+99A/G) polymorphism in patients with T1D were not different from those in the controls (p>0.05). The allele frequency of G was 36.2% in patients with T1D, and 31.8% in controls (p>0.05). Additionally, this polymorphism was not associated with the clinical and laboratory characteristics of the patients with T1D (p>0.05). Conclusions: Our case-control study suggests that the CTLA-4 (+99A/G) gene polymorphism is not associated with T1D in the Turkish population. Conflict of interest:None declared.

Successful Granulocyte Colony-stimulating Factor Treatment of Relapsing Candida albicans Meningoencephalitis Caused by CARD9 Deficiency.

Caspase-associated recruitment domain-9 (CARD9) deficiency is an autosomal-recessive primary immunodeficiency with genetic defects in Th17 immunity marked by susceptibility to recurrent and invasive Candida infections. We present a case of relapsing Candida albicans meningoencephalitis over 1-year period despite appropriate antifungal therapy. We detected a homozygous p.Q295X mutation in CARD9 as well as a defective interleukin-17 and interferon gamma synthesis in Enzyme-Linked ImmunoSpot tests. We achieved complete clinical remission, and improvement of interleukin-17 secretion with subcutaneous granulocyte colony-stimulating factor) treatment.

A successful unrelated peripheral blood stem cell transplantation with reduced intensity-conditioning regimen in a patient with late-onset purine nucleoside phosphorylase deficiency

PNP deficiency is a rare combined immunodeficiency with autosomal recessive mode of inheritance. The immunodeficiency is progressive with normal immune functions at birth, but then, T‐cell deficiency with variable B‐cell functions usually presents by the age of two yr. The only curative treatment for PNP deficiency is hematopoietic stem cell transplantation. Here, we present a 13‐yr‐old girl with late‐onset PNP deficiency. Despite many complications of infections, she was successfully transplanted with a reduced intensity‐conditioning regimen from an HLA‐identical unrelated donor.

Unexplained cyanosis caused by hepatopulmonary syndrome in a girl with APECED syndrome.

Abstract Autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED) is a rare but devastating primary immunodeficiency disease caused by loss-of-function mutations in autoimmune regulator (AIRE) gene on chromosome 21q22.3. The clinical spectrum of the disease is characterized by a wide heterogeneity because of autoimmune reactions toward different endocrine and non-endocrine organs. Here, we report a 17-year-old Turkish girl diagnosed with APECED at 9 years in whom a novel homozygote mutation in AIRE gene p.R15H (c.44G>A) was found. In the clinical course of the patient, chronic liver disease due to autoimmune hepatitis has evolved resulting in hepatopulmonary syndrome (HPS) which has not been reported before in patients with APECED.

Late-Onset Congenital Diaphragmatic Hernia; Report of Three Cases

105 Ya z›fl ma Ad re si/Ad dress for Cor res pon den ce Dr. Fatih Çelmeli, Antalya Eğitim ve Araştırma Hastanesi, Çocuk Aleji ve İmmünoloji Kliniği, Antalya, Türkiye Tel.: +90 532 262 69 98 E-posta: fcelmeli@hotmail.com Ge liş ta ri hi/Re cei ved: 23.10.2014 Ka bul ta ri hi/ Ac cep ted: 23.02.2015 ÖZET ABS TRACT Konjenital diyafragma hernisi (KDH) intrauterin dönemde diyafragmanın yapısal defekti ile karakterize doğumsal bir anomalidir. İlk bir aydan sonra tanı alan olgular geç başlangıçlı KDH olarak adlandırılır. Bu olgu sunumunda, farklı klinik bulgularla kliniğimize başvuran ve geç başlangıçlı KDH tanısı alıp cerrahi müdahale ile başarılı bir şekilde tedavi edilen üç olguyu sunuyoruz. The Journal of Pediatric Research 2015;2(2):105-8 Anahtar kelimeler: Geç başlangıç, konjenital diyafragma hernisi, çocuklar