ABSTRACT
Deficiency of ubiquitin-specific peptidase 18 (USP18) is a severe type I interferonopathy. USP18 down-regulates type I interferon signaling by blocking the access of Janus-associated kinase 1 (JAK1) to the type I interferon receptor. The absence of USP18 results in unmitigated interferon-mediated inflammation and is lethal during the perinatal period. We describe a neonate who presented with hydrocephalus, necrotizing cellulitis, systemic inflammation, and respiratory failure. Exome sequencing identified a homozygous mutation at an essential splice site on USP18. The encoded protein was expressed but devoid of negative regulatory ability. Treatment with ruxolitinib was followed by a prompt and sustained recovery. (Funded by King Saud University and others.).
Subject(s)
Hereditary Autoinflammatory Diseases/drug therapy , Interferons/metabolism , Interleukins/metabolism , Janus Kinase 1/antagonists & inhibitors , Janus Kinase Inhibitors/therapeutic use , Loss of Function Mutation , Pyrazoles/therapeutic use , Ubiquitin Thiolesterase/deficiency , Homozygote , Humans , Hydrocephalus/genetics , Infant, Newborn , Male , Nitriles , Pyrimidines , Receptors, Interferon/metabolism , Remission Induction , Shock, Septic/genetics , Signal Transduction/genetics , Ubiquitin Thiolesterase/genetics , Exome SequencingABSTRACT
PURPOSE: Combined immunodeficiency (CID), due to mutations in TFRC gene that encodes the transferrin receptors (TfR1), is a rare monogenic disorder. In this study, we further characterize the clinical and immunological phenotypes in a cohort of eight patients. METHODS: A retrospective review of clinical and immunological features of patients diagnosed with a TFRC gene mutation between 2015 and 2019 in three tertiary centers. RESULTS: Eight patients from six unrelated families were enrolled. The patients had a median age of 7 years (4-32 years). All patients presented with recurrent sinopulmonary infections, chronic diarrhea, and failure to thrive in early life. Less common features were skin abscesses, conjunctivitis, global developmental delay, optic nerve atrophy, vitiligo, multinodular goiter, and hemophagocytic lymphohistiocytosis-like symptoms. All patients had intermittent neutropenia and 87% of the patients had recurrent thrombocytopenia. Anemia was found in 62%. All patients had hypogammaglobinemia and one had a persistent high IgM level. All patients had impaired function of T cells. The same homozygous missense mutation c.58T>C:p.Y20H, in the TFRC gene, was detected in all patients. Stem cell transplantation from matched donors was successful in two patients. Five patients did not receive stem cell transplantation, and they are on prophylactic treatment. One patient died due to severe sepsis and neurological complications. CONCLUSION: This report provides a large cohort with a long follow up of patients with this disease. Our cohort showed variable disease severity.
Subject(s)
Antigens, CD/genetics , Mutation , Phenotype , Primary Immunodeficiency Diseases/diagnosis , Primary Immunodeficiency Diseases/genetics , Receptors, Transferrin/genetics , Severe Combined Immunodeficiency/diagnosis , Severe Combined Immunodeficiency/genetics , Adolescent , Adult , Biomarkers , Child , Child, Preschool , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Magnetic Resonance Imaging , Male , Neuroimaging , Retrospective Studies , Young AdultABSTRACT
Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3-47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.
Subject(s)
Genetic Association Studies , Guanine Nucleotide Exchange Factors/deficiency , Guanine Nucleotide Exchange Factors/genetics , Adolescent , Adult , Child , Child, Preschool , Cohort Studies , Female , Follow-Up Studies , Humans , Immunoglobulin E/blood , Immunoglobulin E/immunology , Incidence , Infant , Infections/diagnosis , Infections/epidemiology , Infections/etiology , Job Syndrome/complications , Job Syndrome/diagnosis , Job Syndrome/genetics , Job Syndrome/immunology , Job Syndrome/mortality , Job Syndrome/therapy , Lymphocyte Count , Lymphocyte Subsets/immunology , Lymphocyte Subsets/metabolism , Male , Middle Aged , Mutation , Neoplasms/epidemiology , Neoplasms/etiology , Phenotype , Young AdultABSTRACT
Deficiency of the purine salvage enzyme adenosine deaminase leads to SCID (ADA-SCID). Hematopoietic cell transplantation (HCT) can lead to a permanent cure of SCID; however, little data are available on outcome of HCT for ADA-SCID in particular. In this multicenter retrospective study, we analyzed outcome of HCT in 106 patients with ADA-SCID who received a total of 119 transplants. HCT from matched sibling and family donors (MSDs, MFDs) had significantly better overall survival (86% and 81%) in comparison with HCT from matched unrelated (66%; P < .05) and haploidentical donors (43%; P < .001). Superior overall survival was also seen in patients who received unconditioned transplants in comparison with myeloablative procedures (81% vs 54%; P < .003), although in unconditioned haploidentical donor HCT, nonengraftment was a major problem. Long-term immune recovery showed that regardless of transplant type, overall T-cell numbers were similar, although a faster rate of T-cell recovery was observed after MSD/MFD HCT. Humoral immunity and donor B-cell engraftment was achieved in nearly all evaluable surviving patients and was seen even after unconditioned HCT. These data detail for the first time the outcomes of HCT for ADA-SCID and show that, if patients survive HCT, long-term cellular and humoral immune recovery is achieved.
Subject(s)
Agammaglobulinemia/drug therapy , Hematopoietic Stem Cell Transplantation , Severe Combined Immunodeficiency/drug therapy , Transplantation Conditioning , Adenosine Deaminase/deficiency , Adenosine Deaminase/immunology , Agammaglobulinemia/immunology , Agammaglobulinemia/mortality , Agammaglobulinemia/pathology , Child , Child, Preschool , Female , Graft Survival , Histocompatibility Testing , Humans , Immunity, Cellular , Immunity, Humoral , Infant , Infant, Newborn , Kaplan-Meier Estimate , Lymphocyte Count , Male , Myeloablative Agonists/therapeutic use , Retrospective Studies , Severe Combined Immunodeficiency/immunology , Severe Combined Immunodeficiency/mortality , Severe Combined Immunodeficiency/pathology , Siblings , T-Lymphocytes/immunology , Treatment Outcome , Unrelated DonorsABSTRACT
PURPOSE: Autosomal recessive hyper-IgE syndrome is a rare combined immunodeficiency characterized by susceptibility to viral infections, atopic eczema, high serum IgE and defective T cell activation. The genetic etiologies are diverse. Null mutations in DOCK8 and TYK2 are responsible for many cases. This study aims to provide a detailed clinical and immunological characterization of the disease and explore the underlying genetic defects among a large series of patients followed by a single center. The available data might improve our understanding of the disease pathogenesis and prognosis. METHODS: Clinical data of twenty-five patients diagnosed with AR-HIES were collected. Seventeen patients screened for STAT3, TYK2 and DOCK8 mutations. RESULTS: Sinopulmonary infections, dermatitis, hepatic disorders, cutaneous and systemic bacterial, fungal and viral infections were the most common clinical features. The rate of hepatic disorders and systemic infections were high. Twelve patients died with a median age of 10 years. CMV infection was the only statistically significant predicting factor for poor prognosis (early death). Three novel DOCK8 mutations and two large deletions were found in thirteen patients. No mutations found in STAT3 or TYK2 genes. CONCLUSION: Autosomal recessive hyper-IgE syndrome is a combined immunodeficiency disease characterized by high morbidity and mortality rate. The different genetic background and environmental factors may explain the more severe phenotypes seen in our series. DOCK8 defect is the most common identified genetic cause. Patients with no identified genetic etiology are likely to carry mutations in the regulatory elements of genes tested or in novel genes that are yet to be discovered.
Subject(s)
Gene Deletion , Guanine Nucleotide Exchange Factors/chemistry , Guanine Nucleotide Exchange Factors/deficiency , Hospitals, Special , Job Syndrome/genetics , Job Syndrome/immunology , Adolescent , Child , Child, Preschool , Codon, Nonsense/genetics , Female , Genes, Recessive/immunology , Guanine Nucleotide Exchange Factors/genetics , Humans , Immunoglobulin E/adverse effects , Immunoglobulin E/blood , Incidence , Job Syndrome/epidemiology , Male , Saudi Arabia/epidemiology , Secondary PreventionABSTRACT
Background: Inhibitor of kappa kinase 2 (IKK2) deficiency is a recently described combined immunodeficiency. It undermines the nuclear factor-kappa B (NF-κB) activation pathway. Methods: The clinical and immunological data of four patients diagnosed with combined immunodeficiency (CID) from two related Saudi families were collected. Autozygosity mapping of all available members and whole exome sequencing of the index case were performed to define the genetic etiology. Results: The patients had early onset (2-4 months of age) severe infections caused by viruses, bacteria, mycobacteria, and fungi. They all had hypogammaglobulinemia and low absolute lymphocyte count. Their lymphocytes failed to respond to PHA mitogen stimulation. A novel homozygous non-sense mutation in the IKBKB gene, c.850C>T (p. Arg284*) was identified in the index patient and segregated with the disease in the rest of the family. He underwent hematopoietic stem cell transplantation (HSCT) from a fully matched sibling with no conditioning. The other three patients succumbed to their disease. Interestingly, all patients had delayed umbilical cord separation. Conclusion: IKK2 deficiency causes CID with high mortality. Immune reconstitution with HSCT should be considered as early as possible. Delayed umbilical cord separation in CID patients may be a clue to IKK2 deficiency.
Subject(s)
Guanine Nucleotide Exchange Factors/deficiency , Hematopoietic Stem Cell Transplantation , Severe Combined Immunodeficiency/therapy , Child , Fatal Outcome , Guanine Nucleotide Exchange Factors/genetics , Guanine Nucleotide Exchange Factors/immunology , HLA Antigens/genetics , HLA Antigens/immunology , Histocompatibility Testing , Humans , Male , Severe Combined Immunodeficiency/genetics , Severe Combined Immunodeficiency/immunology , Severe Combined Immunodeficiency/pathology , Transplantation Chimera , Transplantation ConditioningABSTRACT
Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is typically sporadic. Inborn errors of TLR3- and DBR1-mediated central nervous system cell-intrinsic immunity can account for forebrain and brainstem HSE, respectively. We report five unrelated patients with forebrain HSE, each heterozygous for one of four rare variants of SNORA31, encoding a small nucleolar RNA of the H/ACA class that are predicted to direct the isomerization of uridine residues to pseudouridine in small nuclear RNA and ribosomal RNA. We show that CRISPR/Cas9-introduced bi- and monoallelic SNORA31 deletions render human pluripotent stem cell (hPSC)-derived cortical neurons susceptible to HSV-1. Accordingly, SNORA31-mutated patient hPSC-derived cortical neurons are susceptible to HSV-1, like those from TLR3- or STAT1-deficient patients. Exogenous interferon (IFN)-ß renders SNORA31- and TLR3- but not STAT1-mutated neurons resistant to HSV-1. Finally, transcriptome analysis of SNORA31-mutated neurons revealed normal responses to TLR3 and IFN-α/ß stimulation but abnormal responses to HSV-1. Human SNORA31 thus controls central nervous system neuron-intrinsic immunity to HSV-1 by a distinctive mechanism.
Subject(s)
Encephalitis, Herpes Simplex/genetics , Herpesvirus 1, Human/genetics , Neurons/immunology , RNA, Small Nucleolar/genetics , Adult , Central Nervous System/immunology , Central Nervous System/virology , Child, Preschool , Encephalitis, Herpes Simplex/immunology , Encephalitis, Herpes Simplex/pathology , Encephalitis, Herpes Simplex/virology , Female , Genetic Predisposition to Disease , Herpesvirus 1, Human/immunology , Herpesvirus 1, Human/pathogenicity , Humans , Immunity/genetics , Infant , Male , Metagenome/genetics , Metagenome/immunology , Middle Aged , Neurons/virology , RNA, Small Nucleolar/immunologyABSTRACT
Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ). The clinical features are characterized by childhood onset of bacille Calmette-Guérin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor ß1 (IL-12Rß1) deficiency. In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.
Subject(s)
Interleukin-12 Subunit p40/deficiency , Interleukin-12 Subunit p40/genetics , Mycobacterium Infections, Nontuberculous/genetics , Salmonella Infections/genetics , Adolescent , Adult , Age of Onset , Asia, Western/epidemiology , Child , Child, Preschool , Cohort Studies , DNA Mutational Analysis , Female , Founder Effect , Genetic Predisposition to Disease , Humans , Infant , Male , Mycobacterium Infections, Nontuberculous/immunology , Mycobacterium Infections, Nontuberculous/mortality , Penetrance , Survival Analysis , Tunisia/epidemiology , Young AdultABSTRACT
Reports on primary immunodeficiency diseases (PIDs) have clearly shown wide geographic and ethnic variations. Understanding these variations is expected to play a major role in improving the diagnosis and management of such diseases, and will also affect research on PIDs. In this short review, we explore the unique aspects of primary immunodeficiencies in the Middle East.
Subject(s)
Immunologic Deficiency Syndromes/diagnosis , Immunologic Deficiency Syndromes/epidemiology , Immunologic Deficiency Syndromes/therapy , Humans , Immunologic Deficiency Syndromes/ethnology , Middle East/epidemiology , Middle East/ethnologyABSTRACT
Disseminated cryptococcal infection is the second most common cause of death after tuberculosis in acquired immune deficiency syndrome patients. Surprisingly, it has been reported only in few patients with primary immunodeficiency diseases. Herein, we report the clinical presentation and outcome of a 23-month-old boy with novel JAK3 mutation severe combined immunodeficiency disease complicated by severe disseminated cryptococcal infection.
Subject(s)
Cryptococcosis/diagnosis , Cryptococcosis/pathology , Janus Kinase 3/deficiency , Severe Combined Immunodeficiency/complications , Stem Cell Transplantation , Humans , Infant , Janus Kinase 3/genetics , Male , Severe Combined Immunodeficiency/genetics , Treatment OutcomeABSTRACT
Herpes simplex encephalitis (HSE) is the most common sporadic viral encephalitis of childhood. Autosomal recessive (AR) UNC-93B and TLR3 deficiencies and autosomal dominant (AD) TLR3 and TRAF3 deficiencies underlie HSE in some children. We report here unrelated HSE children with AR or AD TRIF deficiency. The AR form of the disease was found to be due to a homozygous nonsense mutation that resulted in a complete absence of the TRIF protein. Both the TLR3- and the TRIF-dependent TLR4 signaling pathways were abolished. The AD form of disease was found to be due to a heterozygous missense mutation, resulting in a dysfunctional protein. In this form of the disease, the TLR3 signaling pathway was impaired, whereas the TRIF-dependent TLR4 pathway was unaffected. Both patients, however, showed reduced capacity to respond to stimulation of the DExD/H-box helicases pathway. To date, the TRIF-deficient patients with HSE described herein have suffered from no other infections. Moreover, as observed in patients with other genetic etiologies of HSE, clinical penetrance was found to be incomplete, as some HSV-1-infected TRIF-deficient relatives have not developed HSE. Our results provide what we believe to be the first description of human TRIF deficiency and a new genetic etiology for HSE. They suggest that the TRIF-dependent TLR4 and DExD/H-box helicase pathways are largely redundant in host defense. They further demonstrate the importance of TRIF for the TLR3-dependent production of antiviral IFNs in the CNS during primary infection with HSV-1 in childhood.
Subject(s)
Adaptor Proteins, Vesicular Transport/deficiency , Encephalitis, Herpes Simplex/genetics , Herpesvirus 1, Human , Adaptor Proteins, Vesicular Transport/genetics , Adaptor Proteins, Vesicular Transport/physiology , Amino Acid Sequence , Child, Preschool , Codon, Nonsense , Consanguinity , DEAD-box RNA Helicases/physiology , Female , Genes, Dominant , Genes, Recessive , Genetic Heterogeneity , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotype , Humans , Infant , Interferon-alpha/biosynthesis , Interferon-alpha/genetics , Male , Molecular Sequence Data , Mutation, Missense , Pedigree , Saudi Arabia , Sequence Alignment , Sequence Homology, Amino Acid , Signal Transduction/physiology , Toll-Like Receptor 3/physiology , Toll-Like Receptor 4/physiologyABSTRACT
Pseudohypoparathyroidism type 1b (PHP1b) is a rare metabolic bone disorder characterized by isolated renal parathyroid hormone resistance. The disorder is almost always associated with an imprinting defect or deletions in the differentially methylated region of the GNAS locus located on chromosome 20q13. In addition to the epigenetic and genetic aberrations of the differentially methylated region, PHP1b can also result from a deletion of STX16, a long-range control element of methylation at the GNAS locus located centromeric of GNAS. This report describes the utilization of a recently described methylation-specific multiplex-ligation-dependent probe amplification assay for high-throughput molecular analysis of a patient with the clinical diagnosis of PHP1b. Although more patients will need to be tested to confirm this, methylation-specific multiplex-ligation-dependent probe amplification in our hands proved to be a rapid, sensitive, and fairly easy-to-interpret assay that can be used in lieu of Southern blot analysis to diagnose PHP1b.
Subject(s)
DNA Methylation , Nucleic Acid Amplification Techniques/methods , Pseudohypoparathyroidism/diagnosis , Pseudohypoparathyroidism/genetics , Adolescent , Bone Diseases, Metabolic/diagnostic imaging , Bone Diseases, Metabolic/genetics , Chromogranins , Chromosomes, Human, Pair 20/genetics , Female , GTP-Binding Protein alpha Subunits, Gs/genetics , Genomic Imprinting , Haplotypes , Humans , Ligase Chain Reaction/methods , Male , Microsatellite Repeats , Molecular Probe Techniques , Pedigree , Pseudohypoparathyroidism/classification , Radiography , Syntaxin 16/geneticsABSTRACT
Interleukin-12 receptor ß1 (IL-12Rß1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infections were diagnosed in 40 cases, with combined mycobacteriosis and salmonellosis in 36 individuals. BCG disease strongly protected against subsequent EM disease (p = 0.00008). Various other infectious diseases occurred, albeit each rarely, yet candidiasis was reported in 33 of the patients (23%). Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7 years ± 9.8 years (range, 0.5-46.4 yr). IL-12Rß1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis, rare recurrences of mycobacterial disease, and more frequent recurrence of salmonellosis. The condition has higher clinical penetrance, broader susceptibility to infections, and less favorable outcome than previously thought.