ABSTRACT
Kabuki Syndrome (KS) is a multisystemic genetic disorder. A portion of patients has immunological manifestations characterized by increased susceptibility to infections and autoimmunity. Aiming to describe the clinical and laboratory immunological aspects of KS, we conducted a retrospective multicenter observational study on patients with KS treated in centers affiliated to the Italian Primary Immunodeficiency Network.Thirty-nine patients were enrolled, with a median age at evaluation of 10 years (range: 3 m-21y). All individuals had organ malformations of variable severity. Congenital heart defect (CHD) was present in 19/39 patients (49%) and required surgical correction in 9/39 (23%), with associated thymectomy in 7/39 (18%). Autoimmune cytopenia occurred in 6/39 patients (15%) and was significantly correlated with thymectomy (p < 0.002), but not CHD. Individuals with cytopenia treated with mycophenolate as long-term immunomodulatory treatment (n = 4) showed complete response. Increased susceptibility to infections was observed in 22/32 patients (69%). IgG, IgA, and IgM were low in 13/29 (45%), 13/30 (43%) and 4/29 (14%) patients, respectively. Immunoglobulin substitution was required in three patients. Lymphocyte subsets were normal in all patients except for reduced naïve T-cells in 3/15 patients (20%) and reduced memory switched B-cells in 3/17 patients (18%). Elevated CD3 + TCRαß + CD4-CD8-T-cells were present in 5/17 individuals (23%) and were correlated with hematological and overall autoimmunity (p < 0.05).In conclusion, immunological manifestations of KS in our cohort include susceptibility to infections, antibody deficiency, and autoimmunity. Autoimmune cytopenia is correlated with thymectomy and elevated CD3 + TCRαß + CD4-CD8-T-cells, and benefits from treatment with mycophenolate.
Subject(s)
Abnormalities, Multiple , Face/abnormalities , Hematologic Diseases , Vestibular Diseases , Humans , Female , Retrospective Studies , Male , Child , Hematologic Diseases/immunology , Hematologic Diseases/therapy , Adolescent , Italy , Vestibular Diseases/immunology , Child, Preschool , Young Adult , Abnormalities, Multiple/immunology , Infant , Autoimmunity , AdultABSTRACT
Koolen-de Vries syndrome (KdVS) is a rare disorder caused by haploinsufficiency of KAT8 regulatory NSL complex subunit 1 (KANSL1), which is characterized by intellectual disability, heart failure, hypotonia, and congenital malformations. To date, no effective treatment has been found for KdVS, largely due to its unknown pathogenesis. Using siRNA screening, we identified KANSL1 as an essential gene for autophagy. Mechanistic study shows that KANSL1 modulates autophagosome-lysosome fusion for cargo degradation via transcriptional regulation of autophagosomal gene, STX17. Kansl1+/- mice exhibit impairment in the autophagic clearance of damaged mitochondria and accumulation of reactive oxygen species, thereby resulting in defective neuronal and cardiac functions. Moreover, we discovered that the FDA-approved drug 13-cis retinoic acid can reverse these mitophagic defects and neurobehavioral abnormalities in Kansl1+/- mice by promoting autophagosome-lysosome fusion. Hence, these findings demonstrate a critical role for KANSL1 in autophagy and indicate a potentially viable therapeutic strategy for KdVS.
Subject(s)
Abnormalities, Multiple/genetics , Intellectual Disability/genetics , Mitophagy/genetics , Nuclear Proteins/genetics , Abnormalities, Multiple/drug therapy , Abnormalities, Multiple/immunology , Abnormalities, Multiple/pathology , Animals , Autophagosomes/drug effects , Autophagosomes/metabolism , Autophagosomes/pathology , Cerebral Cortex/cytology , Cerebral Cortex/pathology , Chromosome Deletion , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 17/immunology , Disease Models, Animal , Female , Haploinsufficiency/immunology , HeLa Cells , Humans , Intellectual Disability/drug therapy , Intellectual Disability/immunology , Intellectual Disability/pathology , Isotretinoin/pharmacology , Isotretinoin/therapeutic use , Lysosomes/drug effects , Lysosomes/metabolism , Lysosomes/pathology , Mice , Mice, Transgenic , Mitophagy/drug effects , Mitophagy/immunology , Neurons , Nuclear Proteins/metabolism , Primary Cell CultureABSTRACT
INTRODUCTION AND OBJECTIVES: The purpose of this study was to evaluate patients diagnosed with 22q11.2 deletion syndrome and determine the clues directing to diagnosis and evaluation of immunological findings for excellent management of the disease. MATERIAL AND METHODS: Thirty-three pediatric patients with 22q11.2 deletion syndrome diagnosed between 1998 and 2019 at Pediatric Immunology Division of Ege University Faculty of Medicine and SBU Izmir Dr Behcet Uz Children's Education and Research Hospital were evaluated. RESULTS: This study includes the largest case series reported from Turkey. Congenital cardiac anomalies were the most common pathology associated with the syndrome (90.9%). Hypocalcemic symptoms were observed in 13 patients (40%). Twenty-two of the 33 (66.6%) patients were diagnosed before two years of age. Autoimmune diseases, dysmorphic facial findings, recurrent infections, growth retardation, and speech impairment were other clues for diagnosis in older patients. Clinical spectrum and immunological abnormalities of this syndrome are quite variable. All T-cell subset counts were less than 5th percentile below median by age in one patient (3%) and 10 patients had normal all T-cell subset counts (30.3%). Overall, 69.6% of the patients had normal IgG, IgA, and IgM levels and two patients had panhypogammaglobulinemia. Recurrent infections were revealed in 75.7% of the patients during follow-up. CONCLUSIONS: Presence of cardiac anomaly is more helpful in the diagnosis, especially under two years of age. Patients with immunologically high or standard risk did not show any difference in terms of numbers and severity of infections and autoimmunity.
Subject(s)
DiGeorge Syndrome/diagnosis , DiGeorge Syndrome/therapy , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/immunology , Abnormalities, Multiple/therapy , Child , Child, Preschool , DiGeorge Syndrome/immunology , Disease Management , Female , Heart Defects, Congenital/diagnosis , Heart Defects, Congenital/immunology , Heart Defects, Congenital/therapy , Humans , Hypocalcemia/diagnosis , Hypocalcemia/immunology , Hypocalcemia/therapy , Immunoglobulin Isotypes/blood , Infant , Infant, Newborn , Lymphocyte Subsets/cytology , Male , TurkeyABSTRACT
Inborn errors of immunity (IEI) are genetic disorders characterized by a wide spectrum of clinical manifestations, ranging from increased susceptibility to infections to significant immune dysregulation. Among these, primary immune regulatory disorders (PIRDs) are mainly presenting with autoimmune manifestations, and autoimmune cytopenias (AICs) can be the first clinical sign. Significantly, AICs in patients with IEI often fail to respond to first-line therapy. In pediatric patients, autoimmune cytopenias can be red flags for IEI. However, for these cases precise indicators or parameters useful to suspect and screen for a hidden congenital immune defect are lacking. Therefore, we focused on chronic/refractory AIC patients to perform an extensive clinical evaluation and multiparametric flow cytometry analysis to select patients in whom PIRD was strongly suspected as candidates for genetic analysis. Key IEI-associated alterations causative of STAT3 GOF disease, IKAROS haploinsufficiency, activated PI3Kδ syndrome (APDS), Kabuki syndrome and autoimmune lymphoproliferative syndrome (ALPS) were identified. In this scenario, a dysregulated immunophenotype acted as a potential screening tool for an early IEI diagnosis, pivotal for appropriate clinical management and for the identification of new therapeutic targets.
Subject(s)
Abnormalities, Multiple , Autoimmune Lymphoproliferative Syndrome , Face/abnormalities , Hematologic Diseases , Primary Immunodeficiency Diseases , Vestibular Diseases , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Abnormalities, Multiple/immunology , Adolescent , Adult , Autoimmune Lymphoproliferative Syndrome/diagnosis , Autoimmune Lymphoproliferative Syndrome/genetics , Autoimmune Lymphoproliferative Syndrome/immunology , Child , Child, Preschool , Class I Phosphatidylinositol 3-Kinases/genetics , Class I Phosphatidylinositol 3-Kinases/immunology , Female , Hematologic Diseases/diagnosis , Hematologic Diseases/genetics , Hematologic Diseases/immunology , Humans , Infant , Male , Primary Immunodeficiency Diseases/diagnosis , Primary Immunodeficiency Diseases/genetics , Primary Immunodeficiency Diseases/immunology , Prospective Studies , Vestibular Diseases/diagnosis , Vestibular Diseases/genetics , Vestibular Diseases/immunologyABSTRACT
BACKGROUND: Kabuki syndrome (KS) is commonly caused by mutations in the histone-modifying enzyme lysine methyltransferase 2D (KMT2D). Immune dysfunction is frequently observed in individuals with KS, but the role of KMT2D in immune system function has not been identified. OBJECTIVE: We sought to understand the mechanisms driving KS-associated immune deficiency (hypogammaglobulinemia [low IgA], splenomegaly, and diminished immunization responses). METHODS: We performed a comprehensive evaluation of humoral immunity and secondary lymphoid tissues in an established KS (Kmt2d+/ßGeo) mouse model and validated select findings in a patient with KS. RESULTS: Compared with wild-type littermates, Kmt2d+/ßGeo mice demonstrated deficiencies in multiple B-cell lineages and reduced serum IgA and elevated IgM levels across multiple ages. The bone marrow, spleen, and intestine of Kmt2d+/ßGeo mice contained diminished numbers of IgA-secreting cells, while elevated germinal center B cells were found in the mesenteric lymph node and Peyer patches. Kmt2d+/ßGeo mice have decreased size and numbers of Peyer patches, a finding confirmed in human samples. We identified deficiency of Itgb7 RNA and protein expression, a gene encoding an adhesion protein that mediates intestinal homing, and we demonstrated KMT2D-dependent control of ITGB7 expression in a human cell line. CONCLUSIONS: Kmt2d haploinsufficiency has broad deleterious effects on B-cell differentiation, specifically hampering gut lymphocyte homing and IgA+ plasma cell differentiation. Intestinal lymphoid defects caused by ITGB7 deficiency have not previously been recognized in KS, and these results provide new mechanistic insights into the pathogenesis of KS-associated immune deficiency.
Subject(s)
Abnormalities, Multiple/immunology , Abnormalities, Multiple/pathology , B-Lymphocytes/pathology , Face/abnormalities , Hematologic Diseases/immunology , Hematologic Diseases/pathology , Peyer's Patches/pathology , Vestibular Diseases/immunology , Vestibular Diseases/pathology , Animals , B-Lymphocytes/immunology , Cell Differentiation/immunology , Cell Movement/immunology , DNA-Binding Proteins/genetics , Face/pathology , Histone-Lysine N-Methyltransferase/genetics , Humans , IgA Deficiency/genetics , IgA Deficiency/immunology , Integrin beta Chains/metabolism , Intestines/immunology , Mice , Mutation , Myeloid-Lymphoid Leukemia Protein/genetics , Neoplasm Proteins/genetics , Peyer's Patches/immunologyABSTRACT
PURPOSE: Kabuki syndrome (KS) (OMIM 147920 and 300867) is a rare genetic disorder characterized by specific facial features, intellectual disability, and various malformations. Immunopathological manifestations seem prevalent and increase the morbimortality. To assess the frequency and severity of the manifestations, we measured the prevalence of immunopathological manifestations as well as genotype-phenotype correlations in KS individuals from a registry. METHODS: Data were for 177 KS individuals with KDM6A or KMT2D pathogenic variants. Questionnaires to clinicians were used to assess the presence of immunodeficiency and autoimmune diseases both on a clinical and biological basis. RESULTS: Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; 13.6% (24/177) had autoimmune disease (AID; 25.6% [11/43] in adults), 5.6% (10/177) with ≥2 AID manifestations. The most frequent AID manifestations were immune thrombocytopenic purpura (7.3% [13/177]) and autoimmune hemolytic anemia (4.0% [7/177]). Among nonhematological manifestations, vitiligo was frequent. Immune thrombocytopenic purpura was frequent with missense versus other types of variants (p = 0.027). CONCLUSION: The high prevalence of immunopathological manifestations in KS demonstrates the importance of systematic screening and efficient preventive management of these treatable and sometimes life-threatening conditions.
Subject(s)
Autoimmune Diseases/epidemiology , DNA-Binding Proteins/genetics , Face/abnormalities , Hematologic Diseases/complications , Histone Demethylases/genetics , Neoplasm Proteins/genetics , Primary Immunodeficiency Diseases/epidemiology , Vestibular Diseases/complications , Abnormalities, Multiple/genetics , Abnormalities, Multiple/immunology , Adolescent , Adult , Aged , Child , Child, Preschool , Female , Genetic Association Studies , Hematologic Diseases/genetics , Hematologic Diseases/immunology , Humans , Infant , Infant, Newborn , Male , Middle Aged , Mutation , Prevalence , Registries , Severity of Illness Index , Vestibular Diseases/genetics , Vestibular Diseases/immunology , Young AdultABSTRACT
The term congenital hypopigmentary disorders refers to a wide group of heterogeneous hereditary diseases, clinically characterized by inborn pigmentary defects of the iris, hair, and/or skin. They include Gray Hair Syndromes (GHSs), a rare group of autosomal recessive genodermatosis hallmarked by inborn silvery gray hair. GHSs encompass Griscelli, Chediakâ»Higashi, Elejalde, and Cross syndromes, which are all characterized by a broad spectrum of severe multisystem disorders, including neurological, ocular, skeletal, and immune system impairment. In this manuscript, we describe in detail the clinical, trichoscopic, and genetic features of a rare case of Griscelli syndrome; moreover, we provide an overview of all the GHSs known to date. Our report highlights how an accurate clinical examination with noninvasive methods, like trichoscopy, may play a crucial rule in diagnosis of rare and potentially lethal genetic syndromes such as Griscelli syndrome, in which timely diagnosis and therapy may modify the clinical course, quality of life, and likelihood of survival.
Subject(s)
Pigmentation Disorders/diagnosis , Pigmentation Disorders/genetics , Rare Diseases/diagnosis , Rare Diseases/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Abnormalities, Multiple/immunology , Abnormalities, Multiple/pathology , Adult , Chediak-Higashi Syndrome/diagnosis , Chediak-Higashi Syndrome/genetics , Chediak-Higashi Syndrome/immunology , Chediak-Higashi Syndrome/pathology , Child, Preschool , Craniofacial Abnormalities/diagnosis , Craniofacial Abnormalities/genetics , Craniofacial Abnormalities/immunology , Craniofacial Abnormalities/pathology , Diagnosis, Differential , Female , Hair/abnormalities , Hearing Loss, Sensorineural/diagnosis , Hearing Loss, Sensorineural/genetics , Hearing Loss, Sensorineural/immunology , Hearing Loss, Sensorineural/pathology , Humans , Hypertrichosis/chemically induced , Iris/abnormalities , Male , Mutation , Neurocutaneous Syndromes/diagnosis , Neurocutaneous Syndromes/genetics , Neurocutaneous Syndromes/immunology , Neurocutaneous Syndromes/pathology , Piebaldism/diagnosis , Piebaldism/genetics , Piebaldism/immunology , Piebaldism/pathology , Pigmentation Disorders/immunology , Pigmentation Disorders/pathology , Quality of Life , Rare Diseases/immunology , Rare Diseases/pathology , Skin Abnormalities , rab27 GTP-Binding Proteins/geneticsABSTRACT
Posner-Schlossman-Syndrome (PSS) is clinically characterized by acute, recurrent, mild, unilateral uveitis anterior accompanied by elevated intraocular pressure (IOP). Fuchs´ Uveitis (FU) is a chronic, low-grade-inflammatory disorder, involving anterior uvea and vitreous. The clinical findings show remarkable similarities as well as differences. In our study, we determine the composition of immune mediators in aqueous humor of patients with PSS and FU and evaluate if immune mediators play a crucial role in specific viral intraocular inflammation and IOP rises. Aqueous humor samples from 81 uveitis patients (= eyes) presenting with either PSS or FU were collected at one time point. Local intraocular antibody synthesis to rubella virus was confirmed in 65 patients, whereas 16 were tested positively for human cytomegalovirus. Thirteen patients with PSS and 10 patients with FU were treated with glaucoma medications. Additionally, 11 cataract patients acted as control group. Immune mediator concentrations were measured by Bio-Plex Pro assay. We observed in both PSS (IFN-γ: 174.9 pg/mL; TNF-α: 25.1 pg/mL) and FU (IFN-γ: 25.4 pg/mL; TNF-α: 27.2 pg/mL) groups a significantly increased level of T-helper 1 immune mediators compared to controls (IFN-γ, TNF-α: 0 pg/mL) [median]. Notably, PSS patients (IL-1RA: 73.4 pg/mL; IL-8: 199.4 pg/mL; IL-10: 33.4 pg/mL; IP-10: 126350 pg/mL) showed a stronger and more active ocular inflammatory response, than FU patients (IL-1RA: 4.3 pg/mL; IL-8: 72.4 pg/mL; IL-10: 1.6 pg/mL; IP-10: 57400 pg/mL). Furthermore, a negative correlation between mediators and IOP was seen in the PSS group, potentially caused by acetazolamide-treatment. Our findings show that immune mediators play a crucial role in specific viral intraocular inflammation and influence IOP levels. Remarkable similarities but also significant differences of immune mediator concentrations are apparent in PSS compared to FU. High concentrations of IL-1RA, IL-8, IL-10, and IP-10 correlate with active inflammation in PSS, while FU may trigger chronic inflammation. Our data also substantiated a very similar composition of cytokines in those patients from the PSS group suffering from ocular hypertension and thus offers a potential explanation model for a negative correlation between mediators and IOP.
Subject(s)
Abnormalities, Multiple/immunology , Eye/immunology , Eye/pathology , Uveitis/immunology , Abnormalities, Multiple/physiopathology , Abnormalities, Multiple/virology , Adult , Aged , Aged, 80 and over , Aqueous Humor/metabolism , Cluster Analysis , Cytokines/metabolism , Eye/physiopathology , Eye/virology , Female , Humans , Inflammation Mediators/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Intraocular Pressure , Male , Middle Aged , Statistics, Nonparametric , Syndrome , Th1 Cells/immunology , Th2 Cells/metabolism , Uveitis/pathology , Uveitis/physiopathology , Uveitis/virology , Young AdultSubject(s)
Abnormalities, Multiple/immunology , Chromosome Deletion , Chromosomes, Human, Pair 1/chemistry , Intellectual Disability/immunology , Lymphopenia/immunology , Severe Combined Immunodeficiency/immunology , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Female , Humans , Infant, Newborn , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Intellectual Disability/pathology , Lymphopenia/diagnosis , Lymphopenia/genetics , Lymphopenia/pathology , Neonatal Screening , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Severe Combined Immunodeficiency/diagnosis , Severe Combined Immunodeficiency/genetics , Severe Combined Immunodeficiency/pathology , T-Lymphocytes/immunology , T-Lymphocytes/pathologyABSTRACT
BACKGROUND: One of the most frequent non-infectious complications of humoral immunodeficiencies with a CVID-like pattern is a particular form of inflammatory lung disease which is called granulomatous-lymphocytic interstitial lung disease (GLILD). Its development worsens patient prognosis, with a significant decrease in survival. Currently, there are no unified guidelines regarding its management, and different combinations of immunosuppressants have been used with variable success. METHODS: Clinical and radiological data were collected from patient's medical charts. Flow cytometry was performed to characterize the immunological features with special focus in regulatory T cells (Tregs). RESULTS: A 16-year-old girl with Kabuki syndrome and a 12-year-old boy, both with a CVID-like humoral immunodeficiency on immunoglobulin replacement treatment, developed during follow-up an inflammatory complication radiologically, clinically, and histologically compatible with GLILD. They required treatment, and sirolimus was started, with very good response and no serious side effects. CONCLUSIONS: These 2 cases provide insight into the underlying local and systemic immune anomalies involved in the development of GLILD, including the possible role of Tregs. Combined chemotherapy is commonly used as treatment for GLILD when steroids fail, but there have been some reports of successful monotherapy. As far as we know, these are the first 2 GLILD patients treated successfully with sirolimus, suggesting the advisability of further study of mTOR inhibitors as a more targeted treatment for GLILD, if impairment in Tregs is demonstrated.
Subject(s)
Immunologic Deficiency Syndromes/complications , Immunosuppressive Agents/therapeutic use , Lung Diseases, Interstitial/drug therapy , Sirolimus/therapeutic use , T-Lymphocytes, Regulatory/metabolism , Abnormalities, Multiple/immunology , Adolescent , Biomarkers/metabolism , Child , Face/abnormalities , Female , Hematologic Diseases/complications , Hematologic Diseases/immunology , Humans , Immunologic Deficiency Syndromes/immunology , Lung Diseases, Interstitial/diagnosis , Lung Diseases, Interstitial/immunology , Male , Vestibular Diseases/complications , Vestibular Diseases/immunologySubject(s)
Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Mutation , Nucleotidyltransferases/genetics , Abnormalities, Multiple/immunology , Agammaglobulinemia/diagnosis , Anemia, Sideroblastic/diagnosis , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Cardiomyopathy, Hypertrophic/diagnosis , Developmental Disabilities/diagnosis , Homozygote , Humans , Infant , Infections/diagnosis , Male , Pedigree , Recurrence , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Exome Sequencing/methodsSubject(s)
Abnormalities, Multiple/genetics , DNA Ligase ATP/deficiency , Hematopoietic Stem Cell Transplantation , Heterozygote , Severe Combined Immunodeficiency/genetics , Abnormalities, Multiple/immunology , Abnormalities, Multiple/pathology , Abnormalities, Multiple/therapy , DNA Ligase ATP/genetics , DNA Ligase ATP/immunology , Facies , Fatal Outcome , Female , Humans , Immunoglobulins, Intravenous/therapeutic use , Infant , Mutation , Severe Combined Immunodeficiency/immunology , Severe Combined Immunodeficiency/pathology , Severe Combined Immunodeficiency/therapy , Syndrome , Treatment FailureABSTRACT
Patients who present with unique immunological phenotypes provide an opportunity to better understand defect-driving mutations. In this issue of the JCI, Cottineau and colleagues characterize 5 individuals who exhibited growth restriction, facial deformities, and a history of bacterial and viral infection. Further characterization revealed that these patients were neutropenic and NK cell deficient. These phenotypes were unexpectedly linked to mutations in the gene encoding a subunit of the Go-Ichi-Ni-San (GINS) complex, which is essential for DNA replication prior to cell division. Together, the results of this study lay the groundwork for future studies to explore the role of DNA replication in immune cell generation and function.
Subject(s)
Abnormalities, Multiple , Bacterial Infections , DNA Replication , Killer Cells, Natural/immunology , Mutation , Neutropenia , Neutrophils/immunology , Virus Diseases , Abnormalities, Multiple/genetics , Abnormalities, Multiple/immunology , Abnormalities, Multiple/pathology , Animals , Bacterial Infections/genetics , Bacterial Infections/immunology , Bacterial Infections/pathology , Cell Division/genetics , Cell Division/immunology , DNA Replication/genetics , DNA Replication/immunology , DNA-Binding Proteins/immunology , Humans , Killer Cells, Natural/pathology , Neutropenia/genetics , Neutropenia/immunology , Neutropenia/pathology , Neutrophils/pathology , Virus Diseases/genetics , Virus Diseases/immunology , Virus Diseases/pathologyABSTRACT
BACKGROUND: Primary immunodeficiencies (PID) represent a heterogeneous group of genetic disorders characterised by poor or absent function in one or more components of the immune system. Humoral or antibody immunodeficiencies are the most common form of PID, of which common variable immunodeficiency (CVID) is the most frequent symptomatic form. CVID is usually characterised by hypogammaglobulinaemia with poor antibody specificity, and an increased susceptibility to infections, autoimmunity and lymphoproliferation. Fewer than 10% of CVID patients have a known monogenic basis. Several chromosomal abnormalities (chromosome 18q-syndrome, monosomy 22, trisomy 8 and trisomy 21) are currently identified as causes of hypogammaglobulinaemia, and can manifest with recurrent infections and mimic CVID. METHODS: Review of clinical charts and laboratory results of paediatric patients followed in the outpatient clinic of PID with a diagnosis of genetic disease and humoral immunodeficiency. RESULTS: Three patients with different genetic diseases (19p13.3 deletion, a ring 18 chromosome and Kabuki syndrome), were identified. During follow-up, they developed signs and symptoms suggestive of humoral deficiency mimicking CVID, despite which immunoglobulin levels were quantified with considerable delay with respect to symptoms onset, and specific management was subsequently delayed. CONCLUSIONS: Patients with genetic abnormalities and recurrent infections should be evaluated for hypogammaglobulinaemia. An early diagnosis of humoral deficiency can allow treatment optimisation to prevent complications and sequelae.
Subject(s)
Abnormalities, Multiple/immunology , Chromosome Deletion , Chromosomes, Human, Pair 19/genetics , Face/abnormalities , Hematologic Diseases/immunology , Immunity, Humoral/genetics , Vestibular Diseases/immunology , Adolescent , Agammaglobulinemia/diagnosis , Agammaglobulinemia/genetics , Autoimmunity/genetics , Child , Chromosomes, Human, Pair 18/immunology , Chromosomes, Human, Pair 19/immunology , Common Variable Immunodeficiency/diagnosis , Diagnosis, Differential , Female , Humans , Immunoglobulins, Intravenous , Male , Ring Chromosomes , SpainSubject(s)
DNA-Binding Proteins/genetics , Face/abnormalities , Hematologic Diseases/complications , Mutation/genetics , Neoplasm Proteins/genetics , Thyroiditis, Autoimmune/complications , Vestibular Diseases/complications , Abnormalities, Multiple/genetics , Abnormalities, Multiple/immunology , Child , Female , Hematologic Diseases/genetics , Hematologic Diseases/immunology , Humans , Prognosis , Thyroiditis, Autoimmune/genetics , Thyroiditis, Autoimmune/immunology , Vestibular Diseases/genetics , Vestibular Diseases/immunologyABSTRACT
Kabuki syndrome (KS) is a rare multi-systemic disorder characterized by a distinct face, postnatal growth deficiency, mild-to-moderate intellectual disability, skeletal and visceral (mainly cardiovascular, renal, and skeletal) malformations, dermatoglyphic abnormalities. Its cause is related to mutations of two genes: KMT2D (histone-lysine N-methyltransferase 2D) and KDM6A (lysine-specific demethylase 6A), both functioning as epigenetic modulators through histone modifications in the course of embryogenesis and in several biological processes. Epigenetic regulation is defined as the complex of hereditable modifications to DNA and histone proteins that modulates gene expression in the absence of DNA nucleotide sequence changes. Different human disorders are caused by mutations of genes involved in the epigenetic regulation, and not surprisingly, all these share developmental defects, disturbed growth (in excess or defect), multiple congenital organ malformations, and also hematological and immunological defects. In particular, most KS patients show increased susceptibility to infections and have reduced serum immunoglobulin levels, while some suffer also from autoimmune manifestations, such as idiopathic thrombocytopenic purpura, hemolytic anemia, autoimmune thyroiditis, and vitiligo. Herein we review the immunological aspects of KS and propose a novel model to account for the immune dysfunction observed in this condition.
Subject(s)
Epigenesis, Genetic , Gene Expression Regulation , Immune System/immunology , Immune System/metabolism , Abnormalities, Multiple/genetics , Abnormalities, Multiple/immunology , Autoimmunity , Face/abnormalities , Genetic Association Studies , Hematologic Diseases/complications , Hematologic Diseases/genetics , Hematologic Diseases/immunology , Histones/metabolism , Humans , Infections/etiology , Methylation , Mutation , Vestibular Diseases/complications , Vestibular Diseases/genetics , Vestibular Diseases/immunologyABSTRACT
BACKGROUND: Kabuki syndrome (KS) is a complex multisystem developmental disorder associated with mutation of genes encoding histone-modifying proteins. In addition to craniofacial, intellectual, and cardiac defects, KS is also characterized by humoral immune deficiency and autoimmune disease, yet no detailed molecular characterization of the KS-associated immune phenotype has been reported. OBJECTIVE: We sought to characterize the humoral immune defects found in patients with KS with lysine methyltransferase 2D (KMT2D) mutations. METHODS: We comprehensively characterized B-cell function in a cohort (n = 13) of patients with KS (age, 4 months to 27 years). RESULTS: Three quarters (77%) of the cohort had a detectable heterozygous KMT2D mutation (50% nonsense, 20% splice site, and 30% missense mutations), and 70% of the reported mutations are novel. Among the patients with KMT2D mutations (KMT2D(Mut/+)), hypogammaglobulinemia was detected in all but 1 patient, with IgA deficiency affecting 90% of patients and a deficiency in at least 1 other isoform seen in 40% of patients. Numbers of total memory (CD27(+)) and class-switched memory B cells (IgM(-)) were significantly reduced in patients with KMT2D(Mut/+) mutations compared with numbers in control subjects (P < .001). Patients with KMT2D(Mut/+) mutations also had significantly reduced rates of somatic hypermutation in IgG (P = .003) but not IgA or IgM heavy chain sequences. Impaired terminal differentiation was noted in primary B cells from patients with KMT2D(Mut/+) mutations. Autoimmune pathology was observed in patients with missense mutations affecting the SET domain and its adjacent domains. CONCLUSIONS: In patients with KS, autosomal dominant KMT2D mutations are associated with dysregulation of terminal B-cell differentiation, leading to humoral immune deficiency and, in some cases, autoimmunity. All patients with KS should undergo serial clinical immune evaluations.
Subject(s)
Abnormalities, Multiple/genetics , Abnormalities, Multiple/immunology , B-Lymphocytes/cytology , DNA-Binding Proteins/genetics , Face/abnormalities , Hematologic Diseases/genetics , Hematologic Diseases/immunology , Neoplasm Proteins/genetics , Vestibular Diseases/genetics , Vestibular Diseases/immunology , Adolescent , Adult , Agammaglobulinemia/genetics , Agammaglobulinemia/immunology , B-Lymphocytes/immunology , Cell Differentiation , Child , Child, Preschool , Humans , Infant , Mutation , Young AdultSubject(s)
Abnormalities, Multiple/genetics , Abnormalities, Multiple/immunology , Face/abnormalities , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/immunology , Hematologic Diseases/genetics , Hematologic Diseases/immunology , Immunity, Humoral , Vestibular Diseases/genetics , Vestibular Diseases/immunology , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/drug therapy , Alleles , Complement System Proteins/immunology , Gene Frequency , Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/drug therapy , Hematologic Diseases/diagnosis , Hematologic Diseases/drug therapy , Hemizygote , Histone Demethylases/genetics , Humans , Immunoglobulin Isotypes/blood , Immunoglobulin Isotypes/immunology , Infant , Lymphocyte Activation/immunology , Lymphocyte Subsets/immunology , Lymphocyte Subsets/metabolism , Male , Mutation , Nuclear Proteins/genetics , Transmembrane Activator and CAML Interactor Protein/genetics , Vestibular Diseases/diagnosis , Vestibular Diseases/drug therapyABSTRACT
Kabuki or Niikawa-Kuroki syndrome (KS) is a rare disorder with multiple malformations and recurrent infections, especially otitis media. This study aimed to investigate the genetic defects in Kabuki syndrome and determine if immune status is related to recurrent otitis media. Fourteen patients from 12 unrelated families were enrolled in the 9-year study period (2005-2013). All had Kabuki faces, cleft palate, developmental delay, mental retardation, and the short fifth finger. Recurrent otitis media (12/14) and hearing impairment (8/14) were also more common features. Immunologic analysis revealed lower memory CD19+ cells (11/13), lower memory CD4+ cells (8/13), undetectable anti-HBs antibodies (7/13), and antibody deficiency (7/13), including lower IgA (4), IgG (2), and IgG2 (1). Naïve emigrant lymphocytes, lymphocyte proliferation function, complement activity, and superoxide production in polymorphonuclear cells were all normal. All the patients had KMT2D mutations and 10 novel mutations of R1252X, R1757X,Y1998C, P2550R fs2604X, Q4013X, G5379X, E5425K, R5432X, R5432W, and R5500W. Resembling the phenotype of common variable immunodeficiency, KS patients with antibody deficiency, decreased memory cells, and poor vaccine response increased susceptibility to recurrent otitis media. Large-scale prospective studies are warranted to determine if regular immunoglobulin supplementation decreases the frequency of otitis media and severity of hearing impairment.