European Journal of Clinical Investigation, Oct 1, 2009
One of the rarest forms of autosomal recessive chronic granulomatous disease (AR-CGD) is attribut... more One of the rarest forms of autosomal recessive chronic granulomatous disease (AR-CGD) is attributable to mutations in the NCF2 gene, which encodes the polypeptide p67(phox), a key cytoplasmic protein in the phagocyte NADPH oxidase system. NCF2 is localized on chromosome 1q25, encompasses 40 kb and contains 16 exons. We report here the clinical and molecular characterization of six patients with CGD from six consanguineous Turkish families. The ages of the five female patients were between 3 and 22 years and a male patient was 2 years old; all patients showed clear clinical symptoms of CGD. The mothers of the patients did not show a bimodal histogram pattern specific for X-CGD in the dihydrorhodamine-1,2,3 (DHR) assay. Moreover, p67(phox) protein expression was not detectable using flow cytometric analysis of the patients' neutrophils except in those from patient 6, which had a diminished expression. Mutation analysis of NCF2 revealed four different homozygous mutations: a novel nonsense mutation in exon 3 c.229C>T, p.Arg77X; a novel missense mutation in exon 4 c.279C>G, p.Asp93Glu; a nonsense mutation in exon 4 c.304C>T, p.Arg102X; and a novel missense mutation in exon 6 c.605C>T, p.Ala202Val. The parents were found to be heterozygotes for these mutations. The prevalence of NCF2 mutant families is approximately 15% in our series of 40 CGD families. This high incidence of A67 CGD in Turkey is undoubtedly caused by the high incidence of consanguineous marriages. We found three new mutations in NCF2 and one previously described. These are presented together with an overview of all NCF2 mutations now known.
Page 1. Published by Maney Publishing (c) WS Maney & Son Ltd Familial haemophagocytic lymphoh... more Page 1. Published by Maney Publishing (c) WS Maney & Son Ltd Familial haemophagocytic lymphohistiocytosis in two newborn siblings: a good mimicker of newborn sepsis AHMET YAGMUR BAS, NIHAL DEMIREL, AYS¸EGUL ZENCIROGLU, NESE YARALI* & AYSE METIN{ ...
Innate lymphoid cell (ILC) subsets ILC1, ILC2 and ILC3 mirror image the functions helper CD4+ T c... more Innate lymphoid cell (ILC) subsets ILC1, ILC2 and ILC3 mirror image the functions helper CD4+ T cell subsets, Th1, Th2 and Th17, respectively; rely on similar transcription factors for their development, and produce similar effector cytokines. Thus, they have recently been shown to be crucial for protective immunity in mice. More importantly, in several chronic inflammatory diseases activated or increased frequency of ILCs have been reported in the circulation or affected tissues of patients. Our previous work with Dock8-defective Dock8pri/pri mice revealed that Dock8 is required for the development/function and survival of murine ILC3s. Thus Dock8pri/pri mice lacked ILC3s and was susceptible to Citrobacter rodentium infections. However to date, whether DOCK8 regulates ILC3 development or functions in humans has not been addressed. In the current study, using 11 DOCK8 mutant patients from across Turkey, we show, for the first time, that humans with DOKC8 deficiency lack peripheral I...
Spinal Muscular Atrophy (SMA) is a fatal neuromuscular disease characterized by motor neuron loss... more Spinal Muscular Atrophy (SMA) is a fatal neuromuscular disease characterized by motor neuron loss and advanced muscle weakness, which occurs in functional SMN (Survival Motor Neuron) protein deficiency with SMN1 gene-induced deletions and mutations. The incidence of SMA, which is an autosomal recessive disease, is 1/10,000 in the world. The SMN protein acts as a molecular chaperone in the formation of the spliceosome complex, which catalyzes the splicing of pre-mRNA, enabling mRNAs and non-coding RNAs to mature. Since the current SMN1-encoding Adeno-associated virus (AAV) or SMN2 gene targeting antisense oligonucleotide-based strategies cannot provide long-term stable SMN expression in neuron cells, more effective methods need to be developed. CRISPR technology, which adds a new dimension to genetic engineering and gene therapies, makes it possible to treat many genetic diseases. In terms of SMA, some previous studies in the literature prove that it is possible to treat SMA with the...
Mendelian susceptibility to mycobacterial disease is a rare syndrome that predisposes to poor vir... more Mendelian susceptibility to mycobacterial disease is a rare syndrome that predisposes to poor virulent mycobacteria and environmental nontuberculous mycobacteria. Also, severe infection with salmonella nontifoid are seen in this syndrome. Th e most common complaints of these patients are widespread lymphadenopathy. Our four cases are common features of lymphadenopathy. Four month old cases are twin brothers. Both were admitted with generalized lymphadenopathy and persistent symptoms of oral moniliazis. Ten years old man who is the third case of salmonella infection, was admitted with complaints of bloody diarrhea and generalized lymphadenopathy. Our fourth eleven years old male patient with salmonella infection, was admitted with persistent oral moniliazis and lymphadenitis due to a history of appendectomy. IL-12Rβ1 defect should be kept in mind in the diff erential diagnosis of patients with chronic lymphadenopathy.
The most common symptoms of COVID-19 infection are fever and cough; but may cause respiratory, en... more The most common symptoms of COVID-19 infection are fever and cough; but may cause respiratory, enteric, hepatic, nephrotic, neurological, and skin involvement. Onychomadesis is the proximal separation of the nail plate from the nail matrix due to a temporary cessation of nail growth. Numerous studies about cutaneous manifestations of COVID-19 were reported; however findings of nails were limited. This paper reported a case of onychomadesis which appeared on the nails after a severe COVID-19 infection (MIS-C).
Background/aim: Ig level assessment is frequently used in the diagnosis and follow-up of immunode... more Background/aim: Ig level assessment is frequently used in the diagnosis and follow-up of immunodeficiency, as well as in studies investigating the prevalence of low serum Ig level in specific diseases. Material and methods: Patients who underwent Ig testing in the inpatient and outpatient clinics of our hospital in the years 2010-2016 were included. The Ig levels of the patients were assessed separately according to two reference systems commonly used in Turkey and another reference system used in the USA. Results: A total of 20,138 patients (57.6% male) were included in the study. The median age of the patients was 55.7 months (interquartile range: 23.1-96.7). According to the reference intervals determined by Tezcan et al., 30.6% of the patients were deficient in one or more Ig values. This rate was 4 times higher than those based on the reference intervals determined by Aksu et al. (7.7%) and those in the Nelson Textbook of Pediatrics (6.8%). We also determined that the frequency of low Ig levels with three reference systems. Conclusion: In this study, we found that the rates of low Ig level in a group of pediatric patients differed significantly when evaluated using three different reference systems for age-related serum Ig levels
Défaut de commutation et anomalie de réparation Human PMS2 deficiency is associated with impaired... more Défaut de commutation et anomalie de réparation Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination (ESID Parallel Session IVa : New insights in B-cell development) A. Durandy HyperIgM syndrome complicated with colorectal carcinoma in a patient with neurofibromatosis-like skin lesions-Poster A. Metin
The Journal of Allergy and Clinical Immunology: In Practice, Mar 1, 2019
BACKGROUND: Biallelic variations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined ... more BACKGROUND: Biallelic variations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease. OBJECTIVE: To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables. METHODS: We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8-deficient patients. RESULTS: We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range, 0.7-27.2 years) between 1995 and 2015. After median follow-up of 26 months (range, 3-135 months), 68 (84%) patients are alive. Severe acute (III-IV) or chronic graft versus host disease occurred in 11% and 10%, respectively. Causes of death were infections (n = 5), graft versus host disease (5), multiorgan failure (2), and preexistent lymphoma (1). Survival after matched related (n = 40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced-toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared with fully myeloablative busulfan-based regimens (97% vs 78%; P = .049). Ninety-six percent of patients younger than 8 years at HSCT survived, compared with 78% of those 8 years and older (P = .06). Of the 73 patients with chimerism data available, 65 (89%) had more than 90% donor Tcell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections, and mollusca resolved quicker than food allergies or failure to thrive. CONCLUSIONS: HSCT is curative in most DOCK8-deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced-toxicity regimen may offer the best chance for survival. Aydin et al.
IL-12Rβ1 deficiency is an autosomal recessive disorder characterized by predisposition to recurre... more IL-12Rβ1 deficiency is an autosomal recessive disorder characterized by predisposition to recurrent and/or severe infections caused by otherwise poorly pathogenic mycobacteria and salmonella. IL-12Rβ1 is a receptor chain of both the IL-12 and the IL-23 receptor and deficiency of IL-12Rβ1 thus abolishes both IL-12 and IL-23 signaling. IL-12Rβ1 deficiency is caused by biallelic mutations in the IL12RB1 gene. Mutations resulting in premature stop codons, such as nonsense, frame shift, and splice site mutations, represent the majority of IL-12Rβ1 deficiency causing mutations (66%; 46/70). Also every other morbid mutation completely inactivates the IL-12Rβ1 protein. In addition to disease-causing mutations, rare and common variations with
Mutations in any of four known NADPH-oxidase components lead to CGD. X-linked CGD (X-CGD) is caus... more Mutations in any of four known NADPH-oxidase components lead to CGD. X-linked CGD (X-CGD) is caused by defects in CYBB, the gene that encodes gp91-phox. Autosomal recessive (AR) CGD is caused by defects in the genes for p47 phox, p22-phox or p67-phox. The aim of this study was to screen the molecular defect in the fetus of an X-CGD carrier mother and postnatal confirmation of the results. In a family whose first-born child died from X-CGD, fetal DNA was obtained from an ongoing pregnancy by chorionic villus sampling (CVS). Direct sequencing was used to detect the previously identified CYBB gene mutation. The NADPH oxidase activity in the neutrophils from the carrier mother and from the newborn was analyzed by the DHR assay. Our studies predicted that the fetus in question was not affected by chronic granulomatous disease, which was demonstrated to be correct at birth. For prenatal screening in a pregnant X-CGD carrier, direct sequencing is a good method for detecting the mutation in the fetal DNA. Postnatal confirmation of results with the DHR assay is more practical than mutation screening to show whether the newborn have normal NADPH oxidase activity or does not.
Abstract A study was conducted to investigate the association of lymphocyte subgroups and disease... more Abstract A study was conducted to investigate the association of lymphocyte subgroups and diseases severity in children with Crimean Congo haemorrhagic fever (CCHF). 16 patients who had clinical and laboratory findings with malaise, fever, petechiae, headache, nausea ...
European Journal of Clinical Investigation, Oct 1, 2009
One of the rarest forms of autosomal recessive chronic granulomatous disease (AR-CGD) is attribut... more One of the rarest forms of autosomal recessive chronic granulomatous disease (AR-CGD) is attributable to mutations in the NCF2 gene, which encodes the polypeptide p67(phox), a key cytoplasmic protein in the phagocyte NADPH oxidase system. NCF2 is localized on chromosome 1q25, encompasses 40 kb and contains 16 exons. We report here the clinical and molecular characterization of six patients with CGD from six consanguineous Turkish families. The ages of the five female patients were between 3 and 22 years and a male patient was 2 years old; all patients showed clear clinical symptoms of CGD. The mothers of the patients did not show a bimodal histogram pattern specific for X-CGD in the dihydrorhodamine-1,2,3 (DHR) assay. Moreover, p67(phox) protein expression was not detectable using flow cytometric analysis of the patients' neutrophils except in those from patient 6, which had a diminished expression. Mutation analysis of NCF2 revealed four different homozygous mutations: a novel nonsense mutation in exon 3 c.229C>T, p.Arg77X; a novel missense mutation in exon 4 c.279C>G, p.Asp93Glu; a nonsense mutation in exon 4 c.304C>T, p.Arg102X; and a novel missense mutation in exon 6 c.605C>T, p.Ala202Val. The parents were found to be heterozygotes for these mutations. The prevalence of NCF2 mutant families is approximately 15% in our series of 40 CGD families. This high incidence of A67 CGD in Turkey is undoubtedly caused by the high incidence of consanguineous marriages. We found three new mutations in NCF2 and one previously described. These are presented together with an overview of all NCF2 mutations now known.
Page 1. Published by Maney Publishing (c) WS Maney & Son Ltd Familial haemophagocytic lymphoh... more Page 1. Published by Maney Publishing (c) WS Maney & Son Ltd Familial haemophagocytic lymphohistiocytosis in two newborn siblings: a good mimicker of newborn sepsis AHMET YAGMUR BAS, NIHAL DEMIREL, AYS¸EGUL ZENCIROGLU, NESE YARALI* & AYSE METIN{ ...
Innate lymphoid cell (ILC) subsets ILC1, ILC2 and ILC3 mirror image the functions helper CD4+ T c... more Innate lymphoid cell (ILC) subsets ILC1, ILC2 and ILC3 mirror image the functions helper CD4+ T cell subsets, Th1, Th2 and Th17, respectively; rely on similar transcription factors for their development, and produce similar effector cytokines. Thus, they have recently been shown to be crucial for protective immunity in mice. More importantly, in several chronic inflammatory diseases activated or increased frequency of ILCs have been reported in the circulation or affected tissues of patients. Our previous work with Dock8-defective Dock8pri/pri mice revealed that Dock8 is required for the development/function and survival of murine ILC3s. Thus Dock8pri/pri mice lacked ILC3s and was susceptible to Citrobacter rodentium infections. However to date, whether DOCK8 regulates ILC3 development or functions in humans has not been addressed. In the current study, using 11 DOCK8 mutant patients from across Turkey, we show, for the first time, that humans with DOKC8 deficiency lack peripheral I...
Spinal Muscular Atrophy (SMA) is a fatal neuromuscular disease characterized by motor neuron loss... more Spinal Muscular Atrophy (SMA) is a fatal neuromuscular disease characterized by motor neuron loss and advanced muscle weakness, which occurs in functional SMN (Survival Motor Neuron) protein deficiency with SMN1 gene-induced deletions and mutations. The incidence of SMA, which is an autosomal recessive disease, is 1/10,000 in the world. The SMN protein acts as a molecular chaperone in the formation of the spliceosome complex, which catalyzes the splicing of pre-mRNA, enabling mRNAs and non-coding RNAs to mature. Since the current SMN1-encoding Adeno-associated virus (AAV) or SMN2 gene targeting antisense oligonucleotide-based strategies cannot provide long-term stable SMN expression in neuron cells, more effective methods need to be developed. CRISPR technology, which adds a new dimension to genetic engineering and gene therapies, makes it possible to treat many genetic diseases. In terms of SMA, some previous studies in the literature prove that it is possible to treat SMA with the...
Mendelian susceptibility to mycobacterial disease is a rare syndrome that predisposes to poor vir... more Mendelian susceptibility to mycobacterial disease is a rare syndrome that predisposes to poor virulent mycobacteria and environmental nontuberculous mycobacteria. Also, severe infection with salmonella nontifoid are seen in this syndrome. Th e most common complaints of these patients are widespread lymphadenopathy. Our four cases are common features of lymphadenopathy. Four month old cases are twin brothers. Both were admitted with generalized lymphadenopathy and persistent symptoms of oral moniliazis. Ten years old man who is the third case of salmonella infection, was admitted with complaints of bloody diarrhea and generalized lymphadenopathy. Our fourth eleven years old male patient with salmonella infection, was admitted with persistent oral moniliazis and lymphadenitis due to a history of appendectomy. IL-12Rβ1 defect should be kept in mind in the diff erential diagnosis of patients with chronic lymphadenopathy.
The most common symptoms of COVID-19 infection are fever and cough; but may cause respiratory, en... more The most common symptoms of COVID-19 infection are fever and cough; but may cause respiratory, enteric, hepatic, nephrotic, neurological, and skin involvement. Onychomadesis is the proximal separation of the nail plate from the nail matrix due to a temporary cessation of nail growth. Numerous studies about cutaneous manifestations of COVID-19 were reported; however findings of nails were limited. This paper reported a case of onychomadesis which appeared on the nails after a severe COVID-19 infection (MIS-C).
Background/aim: Ig level assessment is frequently used in the diagnosis and follow-up of immunode... more Background/aim: Ig level assessment is frequently used in the diagnosis and follow-up of immunodeficiency, as well as in studies investigating the prevalence of low serum Ig level in specific diseases. Material and methods: Patients who underwent Ig testing in the inpatient and outpatient clinics of our hospital in the years 2010-2016 were included. The Ig levels of the patients were assessed separately according to two reference systems commonly used in Turkey and another reference system used in the USA. Results: A total of 20,138 patients (57.6% male) were included in the study. The median age of the patients was 55.7 months (interquartile range: 23.1-96.7). According to the reference intervals determined by Tezcan et al., 30.6% of the patients were deficient in one or more Ig values. This rate was 4 times higher than those based on the reference intervals determined by Aksu et al. (7.7%) and those in the Nelson Textbook of Pediatrics (6.8%). We also determined that the frequency of low Ig levels with three reference systems. Conclusion: In this study, we found that the rates of low Ig level in a group of pediatric patients differed significantly when evaluated using three different reference systems for age-related serum Ig levels
Défaut de commutation et anomalie de réparation Human PMS2 deficiency is associated with impaired... more Défaut de commutation et anomalie de réparation Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination (ESID Parallel Session IVa : New insights in B-cell development) A. Durandy HyperIgM syndrome complicated with colorectal carcinoma in a patient with neurofibromatosis-like skin lesions-Poster A. Metin
The Journal of Allergy and Clinical Immunology: In Practice, Mar 1, 2019
BACKGROUND: Biallelic variations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined ... more BACKGROUND: Biallelic variations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease. OBJECTIVE: To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables. METHODS: We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8-deficient patients. RESULTS: We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range, 0.7-27.2 years) between 1995 and 2015. After median follow-up of 26 months (range, 3-135 months), 68 (84%) patients are alive. Severe acute (III-IV) or chronic graft versus host disease occurred in 11% and 10%, respectively. Causes of death were infections (n = 5), graft versus host disease (5), multiorgan failure (2), and preexistent lymphoma (1). Survival after matched related (n = 40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced-toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared with fully myeloablative busulfan-based regimens (97% vs 78%; P = .049). Ninety-six percent of patients younger than 8 years at HSCT survived, compared with 78% of those 8 years and older (P = .06). Of the 73 patients with chimerism data available, 65 (89%) had more than 90% donor Tcell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections, and mollusca resolved quicker than food allergies or failure to thrive. CONCLUSIONS: HSCT is curative in most DOCK8-deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced-toxicity regimen may offer the best chance for survival. Aydin et al.
IL-12Rβ1 deficiency is an autosomal recessive disorder characterized by predisposition to recurre... more IL-12Rβ1 deficiency is an autosomal recessive disorder characterized by predisposition to recurrent and/or severe infections caused by otherwise poorly pathogenic mycobacteria and salmonella. IL-12Rβ1 is a receptor chain of both the IL-12 and the IL-23 receptor and deficiency of IL-12Rβ1 thus abolishes both IL-12 and IL-23 signaling. IL-12Rβ1 deficiency is caused by biallelic mutations in the IL12RB1 gene. Mutations resulting in premature stop codons, such as nonsense, frame shift, and splice site mutations, represent the majority of IL-12Rβ1 deficiency causing mutations (66%; 46/70). Also every other morbid mutation completely inactivates the IL-12Rβ1 protein. In addition to disease-causing mutations, rare and common variations with
Mutations in any of four known NADPH-oxidase components lead to CGD. X-linked CGD (X-CGD) is caus... more Mutations in any of four known NADPH-oxidase components lead to CGD. X-linked CGD (X-CGD) is caused by defects in CYBB, the gene that encodes gp91-phox. Autosomal recessive (AR) CGD is caused by defects in the genes for p47 phox, p22-phox or p67-phox. The aim of this study was to screen the molecular defect in the fetus of an X-CGD carrier mother and postnatal confirmation of the results. In a family whose first-born child died from X-CGD, fetal DNA was obtained from an ongoing pregnancy by chorionic villus sampling (CVS). Direct sequencing was used to detect the previously identified CYBB gene mutation. The NADPH oxidase activity in the neutrophils from the carrier mother and from the newborn was analyzed by the DHR assay. Our studies predicted that the fetus in question was not affected by chronic granulomatous disease, which was demonstrated to be correct at birth. For prenatal screening in a pregnant X-CGD carrier, direct sequencing is a good method for detecting the mutation in the fetal DNA. Postnatal confirmation of results with the DHR assay is more practical than mutation screening to show whether the newborn have normal NADPH oxidase activity or does not.
Abstract A study was conducted to investigate the association of lymphocyte subgroups and disease... more Abstract A study was conducted to investigate the association of lymphocyte subgroups and diseases severity in children with Crimean Congo haemorrhagic fever (CCHF). 16 patients who had clinical and laboratory findings with malaise, fever, petechiae, headache, nausea ...
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