Intraoral and maxillofacial abnormalities in patients with autosomal dominant hyper-IgE syndrome.

Autosomal dominant hyper-IgE syndrome (AD-HIES) is an inborn error of immunity (IEI) caused by a dominant-negative mutation in the signal transducer and activator of transcription 3 (STAT 3). This disease is characterized by chronic eczematoid dermatitis, recurrent staphylococcal skin abscesses, pneumonia, pneumatoceles, and extremely high serum IgE levels. Loss-of-function STAT3 mutations may also result in distinct non-immunologic features such as dental, facial, skeletal, and vascular abnormalities, central nervous system malformations and an increased risk for bone fractures. Prophylactic treatment of Candida infections and prophylactic antimicrobial therapy for staphylococcal skin infections and sinopulmonary infections are essential. An awareness of the oral and maxillofacial features of HIES may facilitate early diagnosis with genetic counselling and may improve future patient care. This study describes oral, dental, and maxillofacial manifestations in 14 patients with genetically defined AD-HIES. We also review the literature and propose recommendations for the complex care of patients with this rare primary immunodeficiency.

Case report: The spectrum of SMPD1 pathogenic variants in Hungary.

Acid sphingomyelinase deficiency (ASMD) is an autosomal recessive disease caused by biallelic pathogenic variants in the sphingomyelin phosphodiesterase-1 (SMPD1) gene. Acid sphingomyelinase deficiency is characterized by a spectrum of disease and is broadly divided into three types (ASMD type A, ASMD type A/B, and ASMD type B). More than 220 disease-associated SMPD1 variants have been reported, and genotype/phenotype correlations are limited. Here we report the first description of all six diagnosed acid sphingomyelinase deficiency cases in Hungary. Nine SMPD1 variants are present in this cohort, including 3 SMPD1 variants (G247D, M384R, and F572L), which have only been described in Hungarian patients. All described variants are deemed to be pathogenic. Eight of the variants are missense, and one is a frameshift variant. The treatment of an ASMD type A/B patient in this cohort using hematopoietic stem cell transplantation is also detailed. This study may help to support diagnosis, patient genetic counseling, and management of acid sphingomyelinase deficiency.

Case Report: Association between cyclic neutropenia and SRP54 deficiency.

Autosomal dominant mutations in the signal recognition particle (SRP) 54 gene were recently described in patients with severe congenital neutropenia (SCN). SRP54 deficiency cause a chronic and profound neutropenia with maturation arrest at the promyelocyte stage, occurring in the first months of life. Nearly all reported patients with SRP54 mutations had neutropenia without a cyclic pattern and showed a poor or no response to granulocyte colony-stimulating factor (G-CSF) therapy. We report here an 11-year-old female patient with cyclic neutropenia and recurrent heterozygous p.T117del (c.349_351del) in-frame deletion mutation in SRP54, who showed remarkable therapeutic response to G-CSF treatment. The diagnosis of cyclic pattern of neutropenia was established by acceptable standards. ELANE gene mutation was excluded by using various genetic approaches. The patient described here also had dolichocolon which has not been described before in association with SCN.

Chronic mucocutaneous candidiasis. / Krónikus mucocutan candidiasis.

Összefoglaló. A krónikus mucocutan candidiasis genetikailag heterogén betegségcsoport, amelyre a bor, a körmök és a nyálkahártyák Candida okozta tartós vagy visszatéro, nem invazív fertozése jellemzo. A Candida-fertozések iránti fokozott fogékonyság oka a Th17-sejtes immunitás defektusa, amelynek hátterében különbözo gének mutációja állhat. A betegség izolált formájában, amelyet más néven krónikus mucocutan candidiasis betegségnek is nevezünk, a mucocutan candidiasis a betegség egyetlen vagy elsodleges tünete. Ezzel szemben a betegség ún. szindrómás formáira a nem invazív Candida-fertozések mellett autoimmun betegség társulása is jellemzo, amely a leggyakrabban az endokrin rendszert érinti. A diagnózis megerosítésében fontos a genetikai vizsgálat, amely az érintett családokban lehetoséget teremt praenatalis genetikai vizsgálatok végzésére is. A szerzok bemutatják a krónikus mucocutan candidiasis fobb típusait, klinikumát, és elemzik a diagnosztikus, illetve terápiás lehetoségeket. A szerzok összefoglalják továbbá a betegség molekuláris genetikai hátterét és a patomechanizmus jelenleg ismert folyamatait. Orv Hetil. 2022; 163(5): 171-180. Summary. Chronic mucocutaneous candidiasis is a genetically heterogeneous group of disorders, which are characterised by chronic or recurrent non-invasive skin, nail and mucous membrane infections caused by Candida. The increased susceptibility to Candida infections is due to a Th17-cell mediated immune defect with different gene mutations in the background. The isolated form of the disorder, referred to as chronic mucocutaneous candidiasis, presents primarily or only with mucocutaneous candidiasis. In contrast, the syndromic form of the disorder is characterised, besides the non-invasive Candida infections, by autoimmune disorders, which most commonly affect the endocrine system. Genetic tests are important in confirming the diagnosis, which in affected families would provide the opportunity for prenatal genetic testing. The authors present the main types of chronic mucocutaneous candidiasis, exploring the clinical aspects, diagnostic methods, and available therapies. Furthermore, the authors conclude the molecular genetic background and the currently known pathomechanism of the disorder. Orv Hetil 2022; 163(5): 171-180.

Care of patients with inborn errors of immunity in thirty J Project countries between 2004 and 2021.

Introduction: The J Project (JP) physician education and clinical research collaboration program was started in 2004 and includes by now 32 countries mostly in Eastern and Central Europe (ECE). Until the end of 2021, 344 inborn errors of immunity (IEI)-focused meetings were organized by the JP to raise awareness and facilitate the diagnosis and treatment of patients with IEI. Results: In this study, meeting profiles and major diagnostic and treatment parameters were studied. JP center leaders reported patients' data from 30 countries representing a total population of 506 567 565. Two countries reported patients from JP centers (Konya, Turkey and Cairo University, Egypt). Diagnostic criteria were based on the 2020 update of classification by the IUIS Expert Committee on IEI. The number of JP meetings increased from 6 per year in 2004 and 2005 to 44 and 63 in 2020 and 2021, respectively. The cumulative number of meetings per country varied from 1 to 59 in various countries reflecting partly but not entirely the population of the respective countries. Altogether, 24,879 patients were reported giving an average prevalence of 4.9. Most of the patients had predominantly antibody deficiency (46,32%) followed by patients with combined immunodeficiencies (14.3%). The percentages of patients with bone marrow failure and phenocopies of IEI were less than 1 each. The number of patients was remarkably higher that those reported to the ESID Registry in 13 countries. Immunoglobulin (IgG) substitution was provided to 7,572 patients (5,693 intravenously) and 1,480 patients received hematopoietic stem cell therapy (HSCT). Searching for basic diagnostic parameters revealed the availability of immunochemistry and flow cytometry in 27 and 28 countries, respectively, and targeted gene sequencing and new generation sequencing was available in 21 and 18 countries. The number of IEI centers and experts in the field were 260 and 690, respectively. We found high correlation between the number of IEI centers and patients treated with intravenous IgG (IVIG) (correlation coefficient, cc, 0,916) and with those who were treated with HSCT (cc, 0,905). Similar correlation was found when the number of experts was compared with those treated with HSCT. However, the number of patients treated with subcutaneous Ig (SCIG) only slightly correlated with the number of experts (cc, 0,489) and no correlation was found between the number of centers and patients on SCIG (cc, 0,174). Conclusions: 1) this is the first study describing major diagnostic and treatment parameters of IEI care in countries of the JP; 2) the data suggest that the JP had tremendous impact on the development of IEI care in ECE; 3) our data help to define major future targets of JP activity in various countries; 4) we suggest that the number of IEI centers and IEI experts closely correlate to the most important treatment parameters; 5) we propose that specialist education among medical professionals plays pivotal role in increasing levels of diagnostics and adequate care of this vulnerable and still highly neglected patient population; 6) this study also provides the basis for further analysis of more specific aspects of IEI care including genetic diagnostics, disease specific prevalence, newborn screening and professional collaboration in JP countries.

Novel STAT-3 gain-of-function variant with hypogammaglobulinemia and recurrent infection phenotype.

Signal transducer and activator of transcription 3 (STAT-3) gain-of-function (GOF) syndrome is an early-onset monogenic inborn error of immunity characterized by multi-organ autoimmune disorders, growth failure and lymphoproliferation. We describe that STAT-3 GOF syndrome may be presented with hypogammaglobulinemia and recurrent severe upper and lower respiratory tract infections. In addition, the patient had lymphoproliferation, short stature and interstitial lung disease. Chest computerized tomography examinations showed mild bronchiectasis with areas of non-fibrosing alveolar-interstitial disease and maldevelopment of bilateral first ribs. Using Sanger sequencing, we revealed a novel c.508G>C, p.D170H STAT-3 variant affecting the coiled coil domain of STAT-3. Functional studies confirmed that p.D170H was a GOF variant, as shown by increased phosphorylated STAT-3 (pSTAT-3) and STAT-3 transcriptional activity. Our observation suggests that STAT-3 GOF syndrome can manifest in early childhood with hypogammaglobulinemia and recurrent severe respiratory tract infections. We suggest that patients with lymphoproliferation, hypogammaglobulinemia and severe recurrent infections should be screened for STAT-3 variants, even if autoimmune manifestations are missing.

Niemann­Pick disease: own observations and new therapeutic options / Niemann-Pick-betegség: saját megfigyelések és új terápiás lehetoségek.

Összefoglaló. A Niemann-Pick-betegség autoszomális recesszíven öröklodo lizoszomális tárolási betegség, amelynek hátterében a savi szfingomielináz enzim hiánya vagy csökkent aktivitása (A-, A/B- és B-típus), illetve a Niemann-Pick C intracelluláris koleszterintranszporter fehérje deficientiája (C- és D-típus) állhat. A defektus következtében szfingomielin és koleszterin halmozódik fel a sejtek lizoszómáiban. A betegség leggyakoribb prezentációs tünete a hepatosplenomegalia miatt elodomborodó nagy has. A legsúlyosabb tünetek a progresszív neurodegeneráció következményei. A diagnózis megerosítésében elengedhetetlen a genetikai vizsgálat, amely az érintett családokban lehetoséget teremt praenatalis genetikai vizsgálatok végzésére is. A betegség idejekorán történo felismerése rendkívül fontos, hiszen napjainkban a terápiás lehetoségek egyre bovülnek. A szubsztrátredukciós, illetve enzimpótló kezeléseknek köszönhetoen a hepatosplenomegalia mérsékelheto, és lassítható vagy visszafordítható a neurológiai tünetek progressziója. A szerzo két esetismertetésen keresztül mutatja be a Niemann-Pick-betegség fobb típusait, klinikumát, molekuláris genetikai hátterét, és elemzi a diagnosztikus, illetve terápiás lehetoségeket. Orv Hetil. 2021; 162(2): 74-80. Summary. The Niemann-Pick disease is an autosomal recessive lysosomal storage disorder caused by the lack or decreased activity of the acid sphingomyelinase enzyme or a deficiency of the Niemann-Pick C intracellular cholesterol transporter protein. As a result of the defect, sphingomyelin and cholesterol accumulate in the lysosomes of the cells. The most common presentation symptom of the disease is abdominal protrusion due to hepatosplenomegaly. The most severe symptoms are the consequences of progressive neurodegeneration. Genetic testing is essential to confirm the diagnosis, which also allows for prenatal genetic testing in the affected families. Early detection of the disease is extremely important as therapeutic options are expanding. Thanks to substrate reduction and enzyme replacement therapies, hepatosplenomegaly can be reduced, and progression of neurological symptoms can be reversed. Through two case reports, the author presents the main types, clinical manifestations, and molecular genetic background of this rare metabolic disorder. The author describes the diagnostic and therapeutic approaches to Niemann-Pick disease. Orv Hetil. 2021; 162(2): 74-80.

Recurrent, Severe Aphthous Stomatitis and Mucosal Ulcers as Primary Manifestations of a Novel STAT1 Gain-of-Function Mutation.

Chronic mucocutaneous candidiasis (CMC) characterized by persistent and recurrent Candida infection of the skin, nails, and the mucosa membranes has been proposed as the major infectious phenotype in patients with gain-of-function mutation of signal transducer and activator of transcription 1 (STAT1) 1. However, viral infections caused mostly by herpesviruses, and a broad range of autoimmune disorders may also be part of the clinical phenotype. We report here on a 31 years old female patient suffering from severe mucosal aphthous mucositis and ulcers and recurrent herpes simplex for decades. We found a previously unknown heterozygous sequence variant in STAT1 (c.1219C>G; L407V) affecting the DNA-binding domain of the protein in the patient and her 4 years old daughter. We found this mutation gain-of-function (GOF) by using immunoblot and luciferase assays. We detected low proportion of IL-17A-producing CD4+ T cell lymphocytes by using intracellular staining and flow cytometry. Candida-induced secretion of IL-17A and IL-22 by mononuclear cells from the patient was markedly decreased compared to controls. These data suggest that the novel mutant allele may result in impaired differentiation of CD4+ T cells to CD4+/IL-17+ cells. The clinical phenotype of the disease in this patient was unique as it was dominated primarily by severe aphthous stomatitis and ulcerative esophagitis and only partly by typical CMC resulting in diagnostic delay. We suggest that patients with severe recurrent aphthous stomatitis and esophagitis should be evaluated for STAT1 GOF mutation. Based on the broad clinical spectrum of the disease, we also suggest that CMC and CMC disease may not be an appropriate term to define clinically STAT1 GOF mutation.

[Oral manifestations in patients with primary immunodeficiencies]. / Szájüregi manifesztációk primer immundeficientiákban.

Characteristic lesions of the oral cavity in primary immunodeficiencies are commonly found in the form of periodontal disease, tooth decay and disorders of the oral mucosa. Humoral immunodeficiencies may cause tooth decay, while severe forms of plaque-induced periodontal disease are common in phagocytic deficiencies. The structural abnormalities of the teeth can occur in immunodeficiencies associated with apoptosis defect. Oral squamous cell carcinoma is a possible complication of immunodeficiencies associated with DNA repair defects. Orv Hetil. 2018; 159(49): 2079-2086.

[Molecular genetic studies in primary immunodeficiencies]. / Molekuláris genetikai vizsgálatok primer immundefektusokban.

Next generation sequencing methods represent the latest era of molecular genetic diagnostics. After a general introduction on primary immunodeficiencies, the author summarizes the importance of molecular genetic studies, especially next generation sequencing in the diagnosis of primary immunodeficiencies. Another purpose of the manuscript is to give a brief summary on the methodological basis of next generation sequencing. The author analyzes the advantages and disadvantages of primary immunodeficiency gene-panel sequencing and whole-exome and whole-genome sequencing. Primary immunodeficiency genes and diseases recognized by next generation sequencing is also summarized. Finally, the author emphasizes the indispensability of gene level diagnostics in primary immunodeficiencies and presents the results achieved in this field in Hungary. Orv Hetil. 2018; 159(49): 2095-2112.

[Neonatal screening of severe combined immunodeficiencies]. / A súlyos kombinált immundefektusok újszülöttkori szurovizsgálata.

Severe combined immunodeficiency is the first immune deficiency disorder which was included in the newborn screening program in the United States in 2010. In Hungary, newborn screening for severe combined immunodeficiencies is crucial because of the routine BCG vaccination, as in the case of an affected newborn with negative family history, the vaccine may lead to fatal BCG-itis. This paper analyzes the possibilities of introducing newborn screening for severe combined immunodeficiencies and summarizes current experiences and results. Orv Hetil. 2018; 159(23): 948-956.

The Evolving View of IL-17-Mediated Immunity in Defense Against Mucocutaneous Candidiasis in Humans.

The discovery of interleukin (IL)-17-mediated immunity has provided a robust framework upon which our current understanding of the mechanism involved in host defense against mucocutaneous candidiasis (CMC) has been built. Studies have shed light on how pattern recognition receptors expressed by innate immune cells recognize various components of Candida cell wall. Inborn errors of immunity affecting IL-17+ T cell differentiation have recently been defined, such as deficiencies of signal transducer and activator of transcription (STAT)3, STAT1, IL-12Rß1 and IL-12p40, and caspase recruitment domain 9. Impaired receptor-ligand coupling was identified in patients with IL-17F and IL-17 receptor A (IL17RA) deficiency and autoimmune polyendocrine syndrome (APS) type 1. Mutation in the nuclear factor kappa B activator (ACT) 1 was described as a cause of impaired IL-17R-mediated signaling. CMC may be part of a complex clinical phenotype like in patients with deficiencies of STAT3, IL-12Rß1/IL-12p40 and APS-1 or may be the only or dominant phenotypic manifestation of disease which is referred to as CMC disease. CMCD may result from deficiencies of STAT1, IL-17F, IL-17RA and ACT1. In this review we discuss how recent research on IL-17-mediated immunity shed light on host defense against mucocutaneous infection by Candida and how the discovery of various germ-line mutations and the characterization of associated clinical phenotypes have provided insights into the role of CD4+IL-17+ lymphocytes in the regulation of anticandidal defense of body surfaces.

Autoantibodies to IL-17A may be correlated with the severity of mucocutaneous candidiasis in APECED patients.

The relative roles of various autoantibodies against IL-17-type cytokines in susceptibility to chronic mucocutaneous candidiasis (CMC) in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) remain poorly defined. The purpose of this longitudinal study was to analyze the relationship between the occurrence of mucocutaneous candidiasis and levels of anti-IL-17A, anti-IL-17F and anti-IL-22 autoantibodies. We studied six APECED patients from four families with various disease manifestations. Clinical data were collected during regular follow-up. Anti-endocrine organ antibody levels and clinical chemistry and immunology parameters were determined in routine laboratory assays on freshly isolated serum. Levels of autoantibodies against IL-17A, IL-17F, IL-22, IFN-α, IFN-ω and TNF-α, and cytokine release by Candida-exposed blood cells were determined by ELISA. Mutations were analyzed by sequencing genomic DNA. Four patients carried the germline c.769C > T homozygous nonsense mutation, which results in R257X truncation of the AIRE protein, and two patients from the same family were compound heterozygous for the c.769C > T/c.1344delC mutation. We found persistently high levels of antibodies against IL-17A in the serum samples of one patient presenting CMC since infancy and low or undetectable anti-IL-17A antibody levels in the sera of five patients with no candidiasis or without severe candidiasis. By contrast, levels of autoantibodies against IL-17F and IL-22 were higher in all patients than in healthy controls. Release of IL-17-type cytokines by Candida-exposed blood mononuclear cells was low or negligible in all patients tested. We suggest that anti-IL-17A antibodies may play an important role in the predisposition to candidiasis of APECED patients. However, the lack of severe CMC in APECED patients with high levels of IL-17F and anti-IL-22 autoantibodies clearly calls into question the role of these antibodies as the principal cause of cutaneous and mucosal candidiasis in at least some APECED patients. These data also suggest that the impaired release of IL-17-type cytokines by blood cells may be an element of the immunopathology of CMC in APECED patients.

Novel dedicator of cytokinesis 8 mutations identified by multiplex ligation-dependent probe amplification.

Dedicator of cytokinesis 8 (DOCK8) deficiency is an innate error of adaptive immunity characterized by recurrent infections with viruses, bacteria and fungi, very high serum IgE concentrations, and a progressive deterioration of T- and B-cell-mediated immunity. We studied the genetic and immunological features of two sisters (aged 11 and 6 yr). Mutational analysis of genomic DNA and cDNA from the patients and their parents, by a combination of PCR and bidirectional targeted sequencing, failed to localize the mutation site. However, a multiplex ligation-dependent probe amplification (MLPA) assay revealed two novel large deletions, del1-14 exons and del8-18 exons, of DOCK8 in both patients. Immunoblot analysis demonstrated that DOCK8 protein was absent from the peripheral blood lymphocytes of both patients. These data suggest that compound heterozygous del1-14 exons and del8-18 exons mutations result in a loss of function of DOCK8 protein and a typical DOCK8 deficiency phenotype.

[Enzyme replacement therapy for Gaucher disease introduced in late adulthood]. / Idoskorban kezdett enzimszubsztitúciós terápia Gaucher-kórban.

Gaucher disease is the most prevalent lysosomal storage disorder caused by recessive mutation of the beta-glucocerebrosidase gene, which leads to massive lysosomal accumulation of glucocerebrosids especially in macrophages of bone marrow, liver and spleen. The most common presenting signs and symptoms are hepatosplenomegaly, bone pain, pathologic fractures, fatigue, bleeding tendency and recurrent infections. Regular enzyme replacement therapy which is available since 1992 in Hungary successfully reverses the symptoms of the disorder, including hematological abnormalities, bone infiltration and hepatosplenomegaly. Authors present here two cases diagnosed in late adulthood to emphasize the importance of early diagnosis and treatment.

Molecular genetic characterization of novel sphingomyelin phosphodiesterase 1 mutations causing niemann-pick disease.

Niemann-Pick disease (NPD) types A and B are autosomal recessive disorders caused by acid sphingomyelinase (ASM) deficiency due to mutation in the sphingomyelin phosphodiesterase 1 gene (SMPD1). Although a number of SMPD1 mutations were reported, expression studies were performed for only a small number of missense mutations. We evaluated three unrelated patients with clinical manifestations of NPD. Sequence analysis revealed two previously described (S248R and W391G) and two novel (G247D and F572L) missense mutations. To analyze the effects of the novel mutations on ASM function, cDNA was generated by site-directed mutagenesis and expressed in COS-7 cells. In vitro biochemical assays revealed marked deficiency of ASM activity consistent with the disease phenotype in cells homoallelic for each mutation. We show that each mutation dramatically reduced half-life and catalytic activity of ASM with more pronounced decrease by the G247D mutation. These data suggest that impaired protein stability and decreased enzyme activity are responsible for the disease in sphingomyelinase-deficient patients carrying the G247D and F572L mutations.