Heterogeneity in RAG1 and RAG2 deficiency: 35 cases from a single-centre.

Recombination activating genes (RAG)1 and RAG2 deficiency leads to combined T/B-cell deficiency with varying clinical presentations. This study aimed to define the clinical/laboratory spectrum of RAG1 and RAG2 deficiency. We retrospectively reviewed the clinical/laboratory data of 35 patients, grouped them as severe combined immunodeficiency (SCID), Omenn syndrome (OS), and delayed-onset combined immunodeficiency (CID) and reported nine novel mutations. The male/female ratio was 23/12. Median age of clinical manifestations was 1 months (mo) (0.5-2), 2 mo (1.25-5), and 14 mo (3.63-27), age at diagnosis was 4 mo (3-6), 4.5 mo (2.5-9.75), and 27 mo (14.5-70) in SCID (n = 25; 71.4%), OS (n = 5; 14.3%), and CID (n = 5; 14.3%) patients, respectively. Common clinical manifestations were recurrent sinopulmonary infections 82.9%, oral moniliasis 62.9%, diarrhea 51.4%, and eczema/dermatitis 42.9%. Autoimmune features were present in 31.4% of the patients; 80% were in CID patients. Lymphopenia was present in 92% of SCID, 80% of OS, and 80% of CID patients. All SCID and CID patients had low T (CD3, CD4, and CD8), low B, and increased NK cell numbers. Twenty-eight patients underwent hematopoietic stem cell transplantation (HSCT), whereas seven patients died before HSCT. Median age at HSCT was 7 mo (4-13.5). Survival differed in groups; maximum in SCID patients who had an HLA-matched family donor, minimum in OS. Totally 19 (54.3%) patients survived. Early molecular genetic studies will give both individualized therapy options, and a survival advantage because of timely diagnosis and treatment. Further improvement in therapeutic outcomes will be possible if clinicians gain time for HSCT.

Long Term Follow-Up of the Patients with Severe Combined Immunodeficiency After Hematopoietic Stem Cell Transplantation: A Single-Center Study.

BACKGROUND: We aimed to evaluate hematopoietic stem cell transplantation (HSCT) related outcomes of patients with severe combined immunodeficiency (SCID). METHODS: We retrospectively collected data from SCID patients who were diagnosed, followed up and survived at least 2 years after HSCT. RESULTS: Forty four SCID patients were included in the study. Median age of HSCT and follow-up period after HSCT were 7.1 months and 8.7 years, respectively. Human leukocyte antigen (HLA) identical donors were used in 77.3% (n = 34) of the patients (23 siblings, six fathers, two mothers, three extended family donors), HLA 1-2 mismatched family donors in 11.3% (n = 5), and haploidentical family donors in 11.3% (n = 5). CD3 and CD19 counts were normal in more than 90% and in 45.4% at last follow-up, respectively. Intravenous immunoglobulin (IVIG) could be stopped in 72.7% (n = 32) after HSCT. B+ SCID patients had better CD19 counts than B- (p < .001). T cell numbers, lymphocyte proliferation, IVIG need, immunoglobulin levels, antibody responses did not differ among B- and B+ immunophenotypes. Acute graft-versus-host disease (GVHD) was less in bone marrow transplanted patients (19.4%) than peripheral stem cell (58.3%) transplanted ones (p = .024). There was no correlation between age at transplantation and immune reconstitution. At the last follow-up, 70.2% and 78.3% of the patients had body weight and height above 3rd percentile, respectively. CONCLUSION: The immune reconstitution and the growth were normal in the majority of SCID patients after HSCT. It may be rational to use bone marrow instead of peripheral stem cell, as acute GVHD was less in bone marrow transplanted patients.

Genetic Analysis of a Cohort of 275 Patients with Hyper-IgE Syndromes and/or Chronic Mucocutaneous Candidiasis.

Hyper-IgE syndromes and chronic mucocutaneous candidiasis constitute rare primary immunodeficiency syndromes with an overlapping clinical phenotype. In recent years, a growing number of underlying genetic defects have been identified. To characterize the underlying genetic defects in a large international cohort of 275 patients, of whom 211 had been clinically diagnosed with hyper-IgE syndrome and 64 with chronic mucocutaneous candidiasis, targeted panel sequencing was performed, relying on Agilent HaloPlex and Illumina MiSeq technologies. The targeted panel sequencing approach allowed us to identify 87 (32 novel and 55 previously described) mutations in 78 patients, which generated a diagnostic success rate of 28.4%. Specifically, mutations in DOCK8 (26 patients), STAT3 (21), STAT1 (15), CARD9 (6), AIRE (3), IL17RA (2), SPINK5 (3), ZNF341 (2), CARMIL2/RLTPR (1), IL12RB1 (1), and WAS (1) have been detected. The most common clinical findings in this cohort were elevated IgE (81.5%), eczema (71.7%), and eosinophilia (62.9%). Regarding infections, 54.7% of patients had a history of radiologically proven pneumonia, and 28.3% have had other serious infections. History of fungal infection was noted in 53% of cases and skin abscesses in 52.9%. Skeletal or dental abnormalities were observed in 46.2% of patients with a characteristic face being the most commonly reported feature (23.1%), followed by retained primary teeth in 18.9% of patients. Targeted panel sequencing provides a cost-effective first-line genetic screening method which allows for the identification of mutations also in patients with atypical clinical presentations and should be routinely implemented in referral centers.

Mutations of the gene FNIP1 associated with a syndromic autosomal recessive immunodeficiency with cardiomyopathy and pre-excitation syndrome.

AMPK (adenosine monophosphate-activated protein kinase) is phosphorylated (AMPK-P) in response to low energy through allosteric activation by Adenosine mono- or diphosphate (AMP/ADP). Folliculin (FLCN) and the FLCN-interacting proteins 1 and 2 (FNIP1, 2) modulate AMPK. FNIP1 deficiency patients have a AMPK-P gain of function phenotype with hypertrophic cardiomyopathy, Wolff-Parkinson-White pre-excitation syndrome, myopathy of skeletal muscles and combined immunodeficiency.

ADA Deficiency: Evaluation of the Clinical and Laboratory Features and the Outcome.

INTRODUCTION: Adenosine deaminase (ADA) deficiency is an autosomal recessive primary immunodeficiency. It results in the intracellular accumulation of toxic metabolites which have effects particularly on lymphocytes and the brain. The aim of this study was to evaluate the outcome of 13 ADA-deficient patients. We planned to evaluate their clinical and laboratory findings before and after enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (aHSCT), and hematopoietic stem cell gene therapy (HSCGT). METHODS: Measurement of ADA enzyme activity and metabolites and sequencing of the ADA gene were performed in most of the patients with ADA deficiency. One of the patients with late-onset ADA deficiency was diagnosed by the help of primary immunodeficiency panel screening. RESULTS: Ten out of 13 patients were diagnosed as SCID, while 3 out of 13 were diagnosed as delayed-/late-onset ADA deficiency. Late-onset ADA deficiency patients had clinical and laboratory findings of combined immunodeficiency (CID). Eight patients with ADA-SCID were found to have higher levels of ADA metabolite (dAXP%) (62.1% (34.6-71.9)) than 3 patients with delayed-/late-onset ADA deficiency (6.9% (2.1-8.9). All but one patient with SCID had T-B-NK- phenotype, one had T-B-NK+ phenotype. Genetic defect was documented in 11 patients. Four out of 11 patients had compound heterozygous defects. Three out of 4 patients with compound heterozygous defects had delayed-onset/late-onset ADA deficiency. Seven out of 11 patients with SCID had homozygous defects. Five out of 7 had the same homozygous indel frameshift mutation (c.955-959delGAAGA) showing a founder effect. There were two novel splice site defects: one (IVS10+2T>C) was heterozygous in a patient with late-onset ADA deficiency, and the other was homozygous (IVS2delT+2) in a SCID patient. Other defects were missense defects. Nine out of 13 patients were put on pegylated ADA ERT. Four out of six patients were transplanted without using a conditioning regimen. HSCGT was performed to one of the patients. CONCLUSION: The genetic diagnosis of SCID is utmost important. There is a chance to give ERT before the definitive therapy if the patient with SCID/CID has ADA deficiency. Although ERT was insufficient to restore a normal immune function in ADA-SCID patients, it was useful to improve and stabilize the clinical status before curative therapy (aHSCT/HSCGT). Enzyme replacement therapy was successful in patients with late-/delayed-onset ADA deficiency who presented with the features of combined immunodeficiency. Gastrointestinal polyposis in a patient with late-onset ADA deficiency may be an association or a coincidental finding. Intermittent neurodevelopmental evaluation especially for hearing impairment should be performed in most of the ADA-deficient patients. This may alleviate the speech delay and cognitive abnormalities which may be observed in the follow-up.

B lymphocyte subsets and outcomes in patients with an initial diagnosis of transient hypogammaglobulinemia of infancy.

PURPOSE: Transient hypogammaglobulinemia of infancy (THI) is a common immunodeficiency, but definitive diagnosis can only be made retrospectively. While the pathogenesis is still unknown, abnormalities have been reported in the B cell compartment. In this study, we analysed the B cell subsets of patients with an initial THI diagnosis (n = 20) and compared them with those of healthy age-matched Turkish children (n = 72). METHODS: Flow cytometric analyses of the B subsets were performed by staining with anti-CD27-PE, anti-CD19-PerCP, anti-IgD-FITC and anti-IgM-APC antibodies. RESULTS: During a median follow-up of 6.6 years, 13 patients whose IgG levels had normalized before they reached four years of age were diagnosed with definitive THI. The memory subsets of these patients were lower but not statistically different from the healthy controls (HC). The remaining seven patients had prolonged hypogammaglobulinemia after the age of four and had significantly lower memory B cell subsets compared to the HC. On follow-up, these patients had not experienced recurrent infections or autoimmunity. Re-evaluation of patients' B cell subsets six years later showed that the memory B cell ratios had increased to levels comparable to HC, despite the patients still having mildly low IgG levels. CONCLUSION: Patients with prolonged hypogammaglobulinemia had lower levels of memory B cells despite having a similar clinical course to patients who had been diagnosed with definitive THI. This subgroup of putative THI patients poses a diagnostic and classification dilemma. Our results suggested that these patients' memory B cells and IgG levels may recover over time.

A novel mutation in TAP1 gene leading to MHC class I deficiency: Report of two cases and review of the literature.

Major histocompatibility complex (MHC) class I deficiency syndrome is a rare primary immunodeficiency caused by mutations in the peptide transporter complex associated with antigen presentation (TAP) gene which plays a crucial role in intracellular peptide antigen presentation. A few cases have been reported to date. Recurrent sinopulmonary infections and skin ulcers are the main characteristics of the syndrome. Here we report two siblings diagnosed with TAP1 deficiency syndrome associated only with recurrent sinopulmonary infections with the description of a novel mutation leading to a premature stop codon in TAP1 gene and review of the relevant literature. Both of the siblings had recurrent sinopulmonary infections since childhood, responded to antibiotherapy well, neither of them had hospitalization history because of infections. One had chronic hepatitis B infection which may possibly be related to TAP1 gene defect.

Hematopoietic stem cell transplantation in children with Griscelli syndrome: A single-center experience.

GS2 is a rare autosomal recessive disease characterized by hypopigmentation, variable immunodeficiency with HLH. HSCT is the only curative treatment for GS2. We analyzed the outcome of 10 children with GS2 who underwent HSCT at our center between October 1997 and September 2013. The median age of the patients at transplant was 13.5 months (range, 6-58 months). All of the patients developed HLH before HSCT and received HLH 94 or HLH 2004 protocols. Donors were HLA-identical relatives in 8 patients, HLA-mismatched relatives in 2 patients. Engraftment was achieved in all except one patient. None of the patients developed acute GVHD. Chronic GVHD occurred in one and veno-occlusive disease occurred in four patients. Eight of the patients are under remission without any neurologic sequelae-median time of disease-free survival is 92.4 months. The present study shows successful transplant outcome without long-term neurologic sequelae in patients with GS2 who underwent HSCT from HLA-related donors.

Progressive neurodegenerative syndrome in a patient with X-linked agammaglobulinemia receiving intravenous immunoglobulin therapy.

A progressive encephalopathy of unknown etiology has been described in patients with primary immunodeficiency disorders. In this report, we characterize the clinical features of this progressive neurodegenerative dementing disorder in a young man with Bruton agammaglobulinemia, through neuropsychological tests and a video sequence. The clinical course of the encephalopathy seems rather uniform: Cognition, especially frontal lobe function, is affected in the early stages, and some patients develop movement disorders. The syndrome causes severe cognitive and physical disability, and can eventually be fatal. The autoimmunity results from dysregulated immune responses, but the underlying mechanism has not yet been fully explained.

Additional diverse findings expand the clinical presentation of DOCK8 deficiency.

We describe seven Turkish children with DOCK8 deficiency who have not been previously reported. Three patients presented with typical features of recurrent or severe cutaneous viral infections, atopic dermatitis, and recurrent respiratory or gastrointestinal tract infections. However, four patients presented with other features. Patient 1-1 featured sclerosing cholangitis and colitis; patient 2-1, granulomatous soft tissue lesion and central nervous system involvement, with primary central nervous system lymphoma found on follow-up; patient 3-1, a fatal metastatic leiomyosarcoma; and patient 4-2 showed no other symptoms initially besides atopic dermatitis. Similar to other previously reported Turkish patients, but in contrast to patients of non-Turkish ethnicity, the patients' lymphopenia was primarily restricted to CD4(+) T cells. Patients had homozygous mutations in DOCK8 that altered splicing, introduced premature terminations, destabilized protein, or involved large deletions within the gene. Genotyping of remaining family members showed that DOCK8 deficiency is a fully penetrant, autosomal recessive disease. In our patients, bone marrow transplantation resulted in rapid improvement followed by disappearance of viral skin lesions, including lesions resembling epidermodysplasia verruciformis, atopic dermatitis, and recurrent infections. Particularly for patients who feature unusual clinical manifestations, immunological testing, in conjunction with genetic testing, can prove invaluable in diagnosing DOCK8 deficiency and providing potentially curative treatment.

Two SCID cases with Cernunnos-XLF deficiency successfully treated by hematopoietic stem cell transplantation.

SCID affects T and B cell differentiation and functions, presenting with severe opportunistic infections in the early postnatal period. It is fatal unless stem cell transplantation is performed. RS SCID forms are caused by defects in the NHEJ pathway, the enzymatic process required for the repair of DNA double-strand breaks. Cernunnos-XLF defect is one of the defects in this pathway. Here, we present two patients with Cernunnos-XLF defect, both having microcephaly, prominent growth retardation, and T-B-NK+SCID, one of whom had AHA. These patients received hematopoietic stem cells from HLA identical related donor without conditioning regimen and recovered without any complication. Now, both of the patients are well and alive seven and one yr after transplantation, respectively. A remarkable observation was the severe diarrhea that occurred in both patients soon after transplantation.

Griscelli syndrome types 1 and 3: analysis of four new cases and long-term evaluation of previously diagnosed patients.

Griscelli syndrome (GS) is a rare autosomal recessive disorder characterized by partial albinism. Three different types are caused by defects in three different genes. Patients with GS type 1 have primary central nervous system dysfunction, type 2 patients commonly develop hemophagocytic lymphohistiocytosis, and type 3 patients have only partial albinism. While hematopoietic stem cell transplantation is life saving in type 2, no specific therapy is required for types 1 and 3. Patients with GS types 1 and 3 are very rare. To date, only 2 patients with type 3 and about 20 GS type 1 patients, including the patients described as Elejalde syndrome, have been reported. The neurological deficits in Elejalde syndrome were reported as severe neurodevelopmental delay, seizures, hypotonia, and ophthalmological problems including nystagmus, diplopia, and retinal problems. However, none of these patients' clinical progresses were reported. We described here our two new type 1 and two type 3 patients along with the progresses of our previously diagnosed patients with GS types 1 and 3. Our previous patient with GS type I is alive at age 21 without any other problems except severe mental and motor retardation, patients with type 3 are healthy at ages 21 and 24 years having only pigmentary dilution; silvery gray hair, eye brows, and eyelashes. Since prognosis, treatment options, and genetic counseling markedly differ among different types, molecular characterization has utmost importance in GS.

Increased availability of family donors for hematopoietic stem cell transplantation in a population with increased incidence of consanguinity.

The study was planned to determine the frequency of parental and non-sibling family donor transplants in our center and to investigate the rate of familial donor availability at two HLA-typing laboratories in Turkey. Among 203 patients who underwent hematopoietic stem cell transplantation (HSCT), 151 (74.4%) received stem cells from siblings, 48 (23.6%) from non-sibling family donors, two (1.0%) from unrelated cord blood, and two (1.0%) autologous transplantation. Of these 48 patients received stem cells from non-sibling family donors; donors were mothers for 26 (12.8%), fathers for 20 (9.9%), and aunts for two (1.0%). The rate of transplants from parental donors was 22.6% in this patient population with increased frequency of inherited diseases (58.1%). Among these 203 patients, there was consanguinity between parents in 60.6% of the patients. Of 833 subjects applying as donor candidates to HLA-typing laboratories, 527 (63.3%) had HLA 6/6 identical family donors. Among 527 full-matched donors, 479 (90.9%) were sibling, 21 (4.0%) were fathers, and 17 (3.2%) were mothers. The remaining 10 (1.9%) were other relatives. The results have shown that the unfavorable factor of consanguinity marriage may increase the availability of family donors for HSCT in particularly developing countries where large donor registries are lacking.

Hereditary C1q deficiency: a new family with C1qA deficiency.

Hereditary deficiency of complement component C1q is a rare genetic disorder with susceptibility to recurrent infections with polysaccharide-containing encapsulated microorganisms and a high prevalence of autoimmune diseases, most often systemic lupus erythematosus (SLE). Here, we report a 29-month-old boy who presented with facial rash and history of early death of a sibling with infections, who was found to have a selective deficiency of C1q. The facial rash was composed of patchy erythematous plaques and centrally hypopigmented macules and desquamation. Two siblings had died of severe bacterial infections and his uncle had died of meningitis. Molecular study disclosed a homozygous point mutation in the C1qA chain gene. Five members of the family, including the parents and three healthy siblings, were heterozygous for this mutation.

Clinical features of chronic granulomatous disease: a series of 26 patients from a single center.

Chronic granulomatous disease is a genetically determined immunodeficiency disorder affecting phagocytic cells rendering them unable to kill certain bacteria and fungi. The present study is a single-center retrospective study that aimed to document the clinical course of 26 children, with a median age of 2.5 years, from 21 families diagnosed as chronic granulomatous disease from 1989-2008. A median delay of 39 months was observed between the onset of infections and age at diagnosis. Pneumonia was the most common initial manifestation of the disease followed by lymphadenitis, skin abscess and diarrhea. An AR inheritance was predominant in the study group. All patients received antibacterial and antifungal prophylaxis, resulting in a marked decrease in the incidence of infections. Overall mortality was 19.2%. These results showed that all features in our group (clinical, progression and outcome) were similar to the literature except for the predominance of autosomal recessive form.

Mild clinical phenotype and subtle radiographic findings in an infant with cartilage-hair hypoplasia.

Cartilage-hair hypoplasia (CHH) is one of the well-known immuno-osseous dysplasias (IOD), which are a combination of skeletal dysplasia and immunodeficiency. It is characterized by disproportionate short stature, fine sparse hair, ligamentous laxity, hematological abnormalities with anemia, a predisposition to malignant tumors, and recurrent infections usually due to cellular and/or humoral immunodeficiency. However, there is a significant overlap of clinical findings among the other IODS such as Schimke's IOD. Here, we present a case of CHH with mild skeletal changes and immunological findings associated with recurrent otitis media, neutropenia, and lymphopenia. With this report, we once more emphasize the difficulty in assessing young individuals with CHH presenting with mild ectodermal findings and subtle radiographic changes.

The Efficacy and Evidence-Based Use of Biologics in Children and Adolescents: Using Monoclonal Antibodies and Fusion Proteins as Treatments.

BACKGROUND: Monoclonal antibodies (mAb) and fusion proteins (FP) are increasingly being used in children and adolescents. In this review, we analyze the evidence for their safety and efficacy in the treatment of the most common chronic inflammatory diseases. METHODS: We systematically searched PubMed, AWMF.org, and other databases for high-quality trials (i.e., randomized controlled trials with clinical primary endpoints) and guidelines published at any time up to 10 December 2018 that dealt with mAb and FP that are approved for pediatric use. The search term was "monoclonal anti- body/fusion protein [e. g. adalimumab] AND children." RESULTS: The 620 hits included 25 high-quality trials (20 of them manufacturer- sponsored) on 9 mAb/FP (omalizumab, adalimumab, etanercept, ustekinumab, infliximab, golimumab, anakinra, canakinumab, tocilizumab, and abatacept), as well as 6 guidelines (3 each of levels S3 and S2k) on the treatment of bronchial asthma, psoriasis, juvenile idopathic arthritis, and chronic inflammatory bowel diseases. For none of these conditions are mAb and FP the drugs of first choice. Adverse drug effects are rare but sometimes severe (infection, immune dysregulation, tumors). CONCLUSION: The retrieved trials have deficiencies that make it difficult to reliably evaluate the efficacy, safety, and utility of mAb/FP for children and adolescents with chronic inflammatory diseases. mAb/FP nonetheless represent a treatment option to be considered in case conventional immune-modulating drugs are ineffective. Researcher-initiated, high-quality trials and manufacturer-independent, systematic long-term evaluations of adverse effects (e.g., tumors) are sorely needed.

Hematopoietic stem cell transplantation in a CD3 gamma-deficient infant with inflammatory bowel disease.

Partial or total CD3 chain expression defects including CD3 gamma, epsilon, delta, and zeta chain are among the autosomally inherited SCID presenting with T-B+NK+ phenotype with lymphopenia. The clinical findings are generally severe in all except for CD3 gamma deficiency. Here we present a 10-month-old CD3 gamma deficient boy with IBD. The patient had suffered from intractable diarrhea, recurrent pulmonary infections and oral moniliasis since two months of age. Following the first allogeneic HSCT from his HLA-identical (6/6) sister after a reduced intensity regimen, a second transplantation was performed five months later. On day +19 after second transplantation, the CD3 TCR alpha/beta chain expression increased to 66% with development of full donor chimerism (98.6%). A significant improvement in diarrhea, perianal lesions, and rectal fistula was observed suggesting an improvement in inflammatory bowel disease. The patient died at home on day +50 with a sudden respiratory failure secondary to an undetermined infection. The case was interesting being the first reported case with SCID and inflammatory bowel disease who responded very well to HSCT by full recovery of intractable diarrhea, failure to thrive, laboratory findings, and improvement of fistula formation.

Infectious diseases, autoimmunity and midline defect in a patient with a novel bi-allelic mutation in IL12RB1 gene.

Clinical disease caused by weakly pathogenic mycobacterial species, which is known as Mendelian susceptibility to mycobacterial disease (MSMD), is a rare entity. IFN-γ and IL-17 production are defective due to insufficient response to IL-2 and IL-23 in IL-12Rß1 deficiency; so this also causes tendency to intracellular microorganisms and candidal diseases. Here, we present a patient who suffers IL-12Rß1 deficiency caused by a novel bi-allelic mutation with recurrent salmonellosis, mycobacterial, fungal infections and remained asymptomatic during 13 months of follow-up after hIFN-γ treatment. In addition she had hemolytic anemia and midline defects like cleft lip and palate which have not been reported in a patient with MSMD in the literature prior to this case report. In conclusion, diagnosis of MSMD should be kept in mind in patients with recurrent salmonellosis, mycobacterial and fungal infections especially in countries with a high consanguinity rate.

Atypical combined immunodeficiency due to Artemis defect: a case presenting as hyperimmunoglobulin M syndrome and with LGLL.

SCID can be caused by various genetic mutations leading to distinctive phenotypes according to the presence of T, B and NK cells. Artemis is a gene encoded on chromosome 10p. The deficiency of this molecule causes an inability to repair DNA double strand breaks and is one of the causes of radiosensitive T-B-NK+ SCID. The syndrome usually presents with opportunistic infections in the first years of life that leads to death if not treated with stem cell transplantation. The spectrum of the disease can be wide because of the heterogeneity of the mutations. Herein we present an atypical SCID (CID) patient with Artemis defect mimicking hyper IgM syndrome. Our patient had high serum IgM with low IgG and IgA levels, lymphocytosis and recurrent infections, intractable diarrhea, growth retardation, systemic CMV infection and sclerosing cholangitis. He also developed large granular lymphocytic leukemia and survived until the age of 6.5 years.