Prurigo-like atopic dermatitis in a child with CARD11-associated severe combined immunodeficiency successfully treated with dupilumab.

A 12-year-old boy affected by severe combined immunodeficiency due to a heterozygous variant in the CARD domain of CARD11, c.169G>A; p.Glu57Lys, developed severe atopic dermatitis and alopecia areata. After failure of conventional systemic therapy, dupilumab was administered at a dose of 400 mg subcutaneously, followed by 200 mg every 14 days. The patient had an excellent clinical response after 1 month and complete remission after a year, with the absence of side effects, demonstrating good efficacy and safety profile.

ORAI1 defect in a patient with disseminated CMV infection and severe hypotonia.

BACKGROUND: A clinical presentation similar to severe combined immunodeficiency (SCID) with defective T cell activation but normal lymphocyte development occurs due to certain molecule defects including ORAI1- and STIM1. CASE: A four-month-old girl sufferd from fever, restlessness, diarrhea, and poor weight gain following the neonatal period. There was consanguinity and a positive family history. She had hypotonia and spontaneous opisthotonic posture. Refractory and extensive CMV infections were detected; immunological investigations revealed normal quantitative immunoglobulins and low numbers of CD3+, CD4+, and CD8+ cells. The next generation sequencing analysis revealed a mutation in the ORAI1 gene. CONCLUSIONS: The present patient`s history of refractory and widespread CMV infections shows a clinically substantial reduction in resistance against opportunistic microorganisms. This case emphasizes the importance of considering STIM1 and ORAI1 defects in patients with SCID phenotype and neurologic involvement, such as hypotonia.

Proposal of Slovenian guidelines for the diagnosis of neonatal erythroderma with a case report of Omenn syndrome.

Diagnosing and treating neonatal and infantile erythroderma can be challenging due to the wide variety of potential causes. Neonatal erythroderma is rare and is associated with a high mortality rate due to complications of erythroderma itself and potential life-threatening underlying diseases. Prolonged erythroderma should always be a warning sign and an indication for referral to a hospital where a multidisciplinary team approach is possible. The role of a pediatric dermatologist is to keep in mind the wide spectrum of differential diagnoses that could be causing the condition and the determination of the final diagnosis. To avert a delay in establishing the correct diagnosis, we suggest adhering to specific guidelines. We reviewed available guidelines and adapted a step-by-step approach for use in Slovenia. We also discuss a case of a neonate with erythroderma to illustrate the applicability of the proposed guidelines. Our patient presented with persistent erythroderma, pustules on the trunk and limbs, and intertriginous dermatitis. Despite local corticosteroid treatment, the skin redness persisted. After the exclusion of a systemic infection and additional tests, Omenn syndrome was diagnosed as the underlying cause.

Hepatocellular Carcinoma in ADA-SCID Patient After Hematopoietic Stem Cell Transplantation.

Adenosine deaminase (ADA) deficiency is one of the most prevalent forms of severe combined immunodeficiency and results in the accumulation of toxic substrates which creates a systemic metabolic disease. It predisposes patients to the development of malignancies, most commonly lymphoma. We report an 8-month-old infant with ADA deficient severe combined immunodeficiency who developed progressive liver dysfunction and hepatocellular carcinoma after successful hematopoietic stem cell transplantation. This is the first case report of an ADA-deficient patient who presented with hepatocellular carcinoma and gives an insight into the complex etiology that can lie behind liver dysfunction in these patients.

Use of Monoclonal Antibodies in a Pediatric Patient With Severe Combined Immunodeficiency and Persistent SARS-CoV-2 Infection.

We describe the use of monoclonal antibodies for the treatment of persistent SARS-CoV-2 infection in a pediatric patient with severe combined immunodeficiency who required urgent stem cell transplantation to cure his disease.

POLD3 deficiency is associated with severe combined immunodeficiency, neurodevelopmental delay, and hearing impairment.

Combined immunodeficiency diseases (CID) represent the most severe forms of inborn errors of immunity. Defective T cell development and/or function, leading to an impairment in adaptive immunity are responsible for these diseases. The DNA polymerase δ complex is important for genome duplication and maintenance and consists of the catalytic subunit POLD1, and the accessory subunits POLD2 and POLD3 which stabilizes the complex. Mutations in POLD1 and POLD2 have been recently shown to be associated with a syndromic CID characterized by T cell lymphopenia with or without intellectual deficiency and sensorineural hearing loss. Here we report a homozygous POLD3 variant (NM_006591.3; p.Ile10Thr) in a Lebanese patient, the product of a consanguineous family, presenting with a syndromic severe combined immunodeficiency (SCID) with neurodevelopmental delay and hearing loss. The homozygous POLD3Ile10Thr variant abolishes POLD3 as well as POLD1 and POLD2 expression. Our findings implicate POLD3 deficiency as a novel cause of syndromic SCID.

Successful Hematopoietic Stem Cell Transplant in a Patient with Omenn Syndrome: A Case Report.

Omenn syndrome is a rare subtype of severe combined immunodeficiency. Affected patients present recurrent infections, lymphadenopathy, skin eruptions, eosinophilia, hepatosplenomegaly, failure to thrive, and gastrointestinal complications with variable severity. A 3-month-old female infant, born to consanguineous healthy parents, presented with splenomegaly, erythroderma, failure to thrive, and history of recurrent otitis media, hypothyroidism, and Bacille Calmette-Guérin lymphadenitis following Bacille Calmette-Guérin vaccination.The immunologic workup showed lymphopenia; low levels of CD3+ T cells, CD4+ T cells, and CD8+ T cells; normal levels of CD19+ B cells and CD16+/CD56+ natural killer cells; hypogammaglobulinemia; and a high level of serum immunoglobulin E. She was clinically diagnosed with T-B+NK+ severe combined immunodeficiency. Genetic study revealed a missense homozygous alteration (c.617G>A, p.Arg206Gln) in exon 5 of the IL7R gene in the patient, as well as carrier states for the same variant in both parents. The patient received a peripheral blood stem cell transplant from a matched unrelated donor. A reduced intensity conditioning regimen was applied, including fludarabine, melphalan, rabbit antithymocyte globulin, and graft- versus-host disease prophylaxis by cyclosporine and mycophenolate mofetil. She clinically improved, and after engraftment the donor chimerism was 100% at 1 year after transplant. Hematopoietic stem cell transplantis a curative therapeutic option for patients with Omenn syndrome and, when combined with an early diagnosis, can prevent complications and improve patient survival.

A variant of RAG1 gene identified in severe combined immunodeficiency: a case report.

BACKGROUND: The recombination-activating gene 1 (RAG1) protein is essential for the V (variable)-D (diversity)-J (joining) recombination process. Mutations in RAG1 have been reported to be associated with several types of immune disorders. Typical clinical features driven by RAG1 variants include persistent infections, severe lymphopenia, and decreased immunoglobulin levels . CASE PRESENTATION: In this study, a 2-month-24-days-old infant with recurrent fever was admitted to our hospital with multiple infections and absence of T and B lymphocytes. The infant was diagnosed with severe combined immunodeficiency (SCID). A homozygous variation c.2147G>A (NM_000448.2: exonme2: c.2147G>A (p.Arg716Gln)) was identified in the RAG1 gene using whole-exome sequencing and Sanger sequencing. The predicted 3D structure of variant RAG1 indicated altered protein stability. Additionally, decreased expression of variant RAG1 gene was detected at both the mRNA and protein levels. CONCLUSIONS: Our study identified a novel homozygous variant in RAG1 gene that causes SCID. This finding expands the variant spectrum of RAG1 in SCID and provides further evidence for the clinical diagnosis of SCID.

Concomitant Langerhans and Interdigitating Reticulum Cell Hyperplasia in a Reactive Lymph Node of an Infant with Omenn Syndrome: A Diagnostic Pitfall for Langerhans Cell Histiocytosis.

Omenn syndrome, a rare form of combined immunodeficiency in infants, presenting with recurrent infections, erythroderma, lymphadenopathy, hepatosplenomegaly, eosinophilia, and increased serum IgE levels. It is a fatal condition unless treated by hematopoietic stem cell transplant. Hence, an early diagnosis and a prompt treatment can lead to better outcome in these unfortunate babies afflicted with Omenn syndrome. Here, we present an 8-week-old infant with typical features of Omenn syndrome, both clinically as well as on laboratory analysis, but surprising immunohistochemical findings on lymph node biopsy.

Effect of Early Bacillus Calmette-Guerin Vaccination of Pediatric Severe Combined Immunodeficiency Patients on the Outcome of Hematopoietic Stem Cell Transplantation Using a Reduced-Intensity Conditioning Regimen.

The eminence of Bacillus Calmette-Guerin (BCG) vaccine in newborn vaccination programs has been conspicuous throughout the years, especially in low-income developing countries where tuberculosis is prevalent; however, application of the BCG vaccine is not without constraints, especially in patients afflicted with immunodeficiency diseases, such as severe combined immunodeficiency (SCID). The present study aimed to evaluate whether the administration of BCG vaccine at birth could improve the outcomes of hematopoietic stem cell transplantation (HSCT) in pediatric patients with SCID. In this study, 30 SCID patients who underwent HSCT using a reduced-intensity conditioning regimen (RIC) were followed-up for 2 years post-HSCT. The outcomes of HSCT were evaluated in both non-BCG-vaccinated patients (n = 12) and BCG-vaccinated patients (n = 18). Our results show a higher incidence of acute graft-versus-host disease (aGVHD), but not of chronic GVHD, in the BCG-vaccinated patients, and a similar overall survival (OS) rate in the 2 groups. We speculate that the similar OS rate in the 2 groups, despite the risk of BGC vaccination, was because this group received an RIC conditioning regimen. There was no other difference between the 2 groups. Considering the effect of the BCG vaccine on HSCT outcome, we suggest that the administration of BCG vaccine be deferred until age 3 months so that APT testing without the interference of maternal antibodies can be performed. However, this study could benefit from a larger cohort to further validate our findings, as the possible reason for some factors not being statistically significant was our small sample size.

Case Report: Mutations in JAK3 causing severe combined immunodeficiency complicated by disseminated Bacille Calmette-Guérin disease and Pneumocystis pneumonia.

Background: As a form of severe combined immunodeficiency (SCID), Janus kinase 3 (JAK3) deficiency can be fatal during severe infections in children, especially after inoculation of live-attenuated vaccines. We report a unique case of JAK3 deficiency with two compound heterozygous JAK3 mutations complicated by disseminated Bacille Calmette-Guérin (BCG) disease and Pneumocystis pneumonia. Case description: A 5-month-old Chinese girl presented with recurring fever and productive cough after BCG vaccination and ineffective antibiotic treatment. Chest CT demonstrated bilateral infiltrations, enlarged mediastinal and axillary lymph nodes, and hypoplasia of the thymus. Mycobacterium tuberculosis and Pneumocystis jirovecii were detected from blood samples by sequencing. Acid-fast bacilli were also found from the sputum aspirate and gastric aspirate. Lymphocyte subset analyses indicated T-B+NK- immunodeficiency, and gene sequencing identified two heterozygous missense mutations (one unreported globally) in the Janus homology 7 (JH7) domain of JAK3. The patient received rifampicin, isoniazid, ethambutol, and trimethoprim/sulfamethoxazole and was discharged after improvements but against advice. Outcome: The patient died at 13 months of age due to severe infections and hepatic damage. Discussion: SCID should be recognized before inoculation of live-attenuated vaccines in children. Newborn screening for SCID is advocated. Further investigations are needed to better understand the pathogenicity of the variants and molecular mechanism of the JH7 domain of JAK3.

Features of Hemophagocytic Lymphohistiocytosis in Infants With Severe Combined Immunodeficiency: Our Experience From Chandigarh, North India.

Background: Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled and excessive inflammation leading to high mortality. Aetiology of HLH can be primarily due to genetic causes or secondarily due to infections or rheumatological illness. However, rarely T-cell deficiencies like severe combined immunodeficiency (SCID) can develop HLH. Objective: To describe clinical and laboratory features of SCID cases who developed HLH. Methods: We collected clinical, laboratory, and molecular details of patients with SCID who developed HLH at our center at Chandigarh, North India. Results: Of the 94 cases with SCID, 6 were noted to have developed HLH-like manifestations. Male-female ratio was 5:1. Median (inter-quartile range) age of onset of clinical symptoms was 4.25 months (2-5 months). Median (inter-quartile range) delay in diagnosis was 1 month (1-3.5 months). Family history of deaths was seen in 4 cases. Molecular defects in IL2RG were seen in 5 out of 6 cases. Documented infections include disseminated bacillus calmette-guerin (BCG) infection (n=2), blood stream infections (n=3) with Staphylococcal aureus (n=1), Klebsiella pneumonia (n=1), and Pseudomonas aeruginosa (n=1), pneumonia (influenza H1N1 strain, and K. pneumoniae (n=1). Conclusion: Children with SCID can present with HLH-like manifestations secondary to fulminant infections. A high index of suspicion of SCID is needed in infants who present with HLH who have an associated infection or a suggestive family history. Occurrence of HLH-like manifestations in SCID suggests that T-lymphocytes may not have a significant role in immunopathogenesis of HLH.

[Adenosine deaminase 2 deficiency: a disease with multiple presentations]. / Déficit en adénosine désaminase 2 : une maladie aux présentations multiples.

Adenosine deaminase 2 deficiency (DADA2) is a genetic auto- inflammatory disease that most often presents in childhood, but that can also have a late onset in adulthood. It is characterized by vasculitis, mainly of the skin and nervous system most often in the form of a stroke, associated to immunodeficiency and cytopenias. The diagnosis is made by measuring adenosine deaminase 2 (ADA2) enzymatic activity and confirming the presence of mutations in the ADA2 gene by genetic testing. The treatment of choice for the inflammatory phenotype is the early administration of anti-TNFa to avoid the risk of major neurological disabilities. In the case of severe hematological involvement, hematopoietic stem cell transplantation is the only curative treatment currently available.

Le déficit en adénosine désaminase 2 (DADA2) est une maladie génétique auto-inflammatoire qui se manifeste le plus souvent à l'âge pédiatrique mais qui peut également débuter à l'âge adulte. Il se caractérise par une atteinte vasculitique responsable d'altérations cutanées et d'AVC associée à une immunodéficience et des cytopénies. Le diagnostic de DADA2 est posé par le dosage de l'activité de l'adénosine désaminase 2 (ADA2) et la confirmation par un test génétique d'une mutation dans le gène ADA2. Le traitement de choix du phénotype inflammatoire repose sur l'administration précoce d'anti-TNFα pour éviter la survenue d'un handicap neurologique majeur. En cas d'atteinte hématologique sévère, la greffe de cellules souches hématopoïétiques est le seul traitement curatif actuellement disponible.

Proposal for a 6-step approach for differential diagnosis of neonatal erythroderma.

The broad differential diagnosis of neonatal erythroderma often poses a diagnostic challenge. Mortality of neonatal erythroderma is high due to complications of the erythroderma itself and the occasionally severe and life-threatening underlying disease. Early correct recognition of the underlying cause leads to better treatment and prognosis. Currently, neonatal erythroderma is approached on a case-by-case basis. The purpose of this scoping review was to develop a diagnostic approach in neonatal erythroderma. After a systematic literature search in Embase (January 1990 - May 2020, 74 cases of neonatal erythroderma were identified, and 50+ diagnoses could be extracted. Main causes were the ichthyoses (40%) and primary immunodeficiencies (35%). Congenital erythroderma was present in 64% (47/74) of the cases, predominantly with congenital ichthyosis (11/11; 100%), Netherton syndrome (12/14, 86%) and Omenn syndrome (11/23, 48%). Time until diagnosis ranged from 102 days to 116 days for cases of non-congenital erythroderma and congenital erythroderma respectively. Among the 74 identified cases a total of 17 patients (23%) died within a mean of 158 days and were related to Omenn syndrome (35%), graft-versus-host disease (67%) and Netherton syndrome (18%). Disease history and physical examination are summarized in this paper. Age of onset and a collodion membrane can help to narrow the differential diagnoses. Investigations of blood, histology, hair analysis, genetic analysis and clinical imaging are summarized and discussed. A standard blood investigation is proposed, and the need for skin biopsies with lympho-epithelial Kazal-type related Inhibitor staining is highlighted. Overall, this review shows that diagnostic procedures narrow the differential diagnosis in neonatal erythroderma. A 6-step flowchart for the diagnostic approach for neonatal erythroderma during the first month of life is proposed. The approach was made with the support of expert leaders from international multidisciplinary collaborations in the European Reference Network Skin-subthematic group Ichthyosis.

Omenn Syndrome due to RAG1 Mutation Presenting With Nonimmune Hydrops Fetalis in Two Siblings.

Omenn syndrome (OS) is a rare variant of severe combined immunodeficiency characterized by susceptibility to severe opportunistic infections and peculiar manifestations, such as protein-losing erythroderma, alopecia, hepatosplenomegaly, lymphadenopathies, and severe diarrhea. The typical form of the disease is caused by hypomorphic mutation of the recombination-activating genes (RAG1 and RAG2), which are critical in initiating the molecular processes leading to lymphocyte and immunoglobulin receptor formation. Affected patients lack B cells, whereas autoreactive oligoclonal T cells infiltrate the skin, gut, spleen, and liver. In the absence of hematopoietic stem cell transplantation, patients with OS usually succumb early in life because of opportunistic infections. The incidence of OS is estimated to be <1 per 1 000 000; however, the actual frequency is difficult to ascertain. We report 2 siblings affected by OS due to a homozygous frameshift mutation (NM_000448.3:c.519delT, p.E174Sfs*26) in the RAG1 gene presenting with nonimmune hydrops fetalis (NIHF). To the best of our knowledge, this is the first reported association between OS and NIHF. NIHF specifically refers to the presence of ≥2 abnormal fluid collections in the fetus, without red blood cell alloimmunization. A broad spectrum of pathologies is associated with NIHF; however, in ∼20% of the cases, the primary cause remains unclear. Understanding the etiology of NIHF is essential for guiding clinical management, determining prognosis, and informing parents regarding recurrence risk. Our case contributes to expanding the spectrum of OS presentation and highlights the importance of a complete immunologic and genetic workup in otherwise unexplained cases of NIHF.

Isolation and characterization of a Sabin 3/Sabin 1 recombinant vaccine-derived poliovirus from a child with severe combined immunodeficiency.

An 8-month-old child diagnosed with severe combined immunodeficiency (SCID) was found to be excreting vaccine-derived poliovirus (VDPVs). Five stool samples from the child and stool samples from 24 contacts were collected during the following 7 months. Complete genome sequence by next generation sequencing (NGS) identified 0.7 to 1.4% nucleotide substitutions in the capsid P1 region of the first and the last isolates compared with Sabin 3 strain. Simplot analysis revealed that all isolates were Sabin 3/Sabin 1 recombinants, sharing a single recombination breakpoint in the 2C region. Multiple nucleotide variants were identified in the 5'UTR (T472→C and G395→A); amino acid mutations were identified in residues at VP1-6 (Thr to Ile), VP1-105 (Met to Thr), VP1-286 (Arg to Lys), VP2-155 (Lys to Glu), VP3-59 (Ser to Asn) and VP3-91 (Phe to Ser). These variants were commonly observed in other PV strains, which may contribute to attenuation and temperature sensitivity. None of the 24 tested contacts of the patient and related transmits was found to be infected with poliovirus. Our study provides a rapid and reliable method for the characterization of VDPV research in Poliovirus infection. In post-OPV era, immunodeficient people with persistent and chronic infection remain a major challenge for polio eradication in China.