TY - JOUR
AU1 - Schreiner,, Felix
AU2 - Plamper,, Michaela
AU3 - Dueker,, Gesche
AU4 - Schoenberger,, Stefan
AU5 - Gámez-Díaz,, Laura
AU6 - Grimbacher,, Bodo
AU7 - Hilger, Alina, C.
AU8 - Gohlke,, Bettina
AU9 - Reutter,, Heiko
AU1 - Woelfle,, Joachim
AB - Abstract Context: Type 1 diabetes mellitus (T1DM) is caused by autoimmunity against pancreatic β-cells. Although a significant number of T1DM patients have or will develop further autoimmune disorders during their lifetime, coexisting severe immunodysregulation is rare. Objective: Presuming autosomal-recessive inheritance in a complex immunodysregulation disorder including T1DM and short stature in two siblings, we performed whole-exome sequencing. Case Presentation: Two Libyan siblings born to consanguineous parents were presented to our diabetology department at ages 12 and 5 years, respectively. Apart from T1DM diagnosed at age 2 years, patient 1 suffered from chronic restrictive lung disease, mild enteropathy, hypogammaglobulinemia, and GH deficiency. Fluorescence-activated cell sorting analysis revealed B-cell deficiency. In addition, CD4+/CD25+ and CD25high/FoxP3+ cells were diminished, whereas an unusual CD25−/FoxP3+ population was detectable. The younger brother, patient 2, also developed T1DM during infancy. Although his enteropathy was more severe and electrolyte derangements repeatedly led to hospitalization, he did not have significant pulmonary problems. IgG levels and B-lymphocytes were within normal ranges. Results: By whole-exome sequencing we identified a homozygous truncating mutation (c.2445_2447del(C)3ins(C)2, p.P816Lfs*4) in the lipopolysaccharide-responsive beige-like anchor (LRBA) gene in both siblings. The diagnosis of LRBA deficiency was confirmed by a fluorescence-activated cell sorting-based immunoassay showing the absence of LRBA protein in phytohemagglutinin-stimulated peripheral blood mononuclear cells. Conclusion: We identified a novel truncating LRBA mutation in two siblings with T1DM, short stature, and severe immunodysregulation. LRBA mutations have previously been reported to cause multiorgan autoimmunity and immunodysfunction. In light of the variable phenotypes reported so far in LRBA-mutant individuals, LRBA deficiency should be considered in all patients presenting with T1DM and signs of severe immunodysregulation. Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disorder caused by antibody-mediated destruction of pancreatic β-cells. Besides genetic factors including both major histocompatibility complex (MHC) and non-MHC genetic loci, environmental factors are supposed to play a significant role in the pathogenesis of T1DM, especially in view of the increasing disease incidence observed in many countries worldwide (1, 2). Up to 30% of patients with T1DM have or will develop further autoimmune disorders during their lifetime, including autoimmune thyroid diseases, celiac disease, or Addison disease (3). On the other hand, coexisting severe immunodysregulation is rarely seen in T1DM patients. Prompted by advances in immunological and molecular genetic technologies, a significant number of novel monogenic conditions with severe autoimmunity and immunodysfunction that become clinically symptomatic already in early infancy have been described during the last decade. For example, mutations in about 50 genes have been identified in patients presenting immunodysfunction with chronic inflammatory bowel disease (4). Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome caused by mutations in the FOXP3 gene can be considered as the prototype of immunodysfunction disorder, including early-onset autoimmune diabetes mellitus and inflammatory bowel disease. IPEX-like phenotypes have also been reported in patients with mutations in CD25, Stat1, Stat3, or CTLA4 (5–8). In addition, Biason-Lauber et al (9) recently reported a family carrying a SIRT1 mutation, in which all affected members suffered from autoimmune disorders: four had T1DM, and one had ulcerative colitis. However, many T1DM patients with coexisting severe immunodysfunction do not have a definite molecular diagnosis yet. Here, we report a consanguineous Libyan kindred with two siblings suffering from T1DM and severe immunodysfunction disorder, in whom whole-exome sequencing (WES) in both affected siblings identified a novel homozygous truncating mutation in the lipopolysaccharide-responsive beige-like anchor (LRBA) gene. Case Presentation After immigrating to Europe, two siblings born to consanguineous Libyan parents presented at our diabetes outpatient department at the ages of 12 and 5 years, respectively. Patient 1 was diagnosed to have T1DM at age 2 years (autoantibody-positive for islet cell antibody, >40 Juvenile Diabetes Foundation units [JDF-U], normal range, 0 JDF-U; glutamic acid decarboxylase antibody, 1.46 U/mL, normal range, <0.9 U/mL; insulin autoantibody, 0.1 U/m, normal range, <0.1 U/mL; and C-peptide, undetectable at age 12 years). From early infancy, the girl suffered from recurrent chest infections, leading to severe chronic restrictive lung disease, resembling lymphocytic interstitial pneumonia. In addition, stool frequency was increased, and loose stools together with histological signs of chronic duodenitis and colitis indicated the presence of autoimmune enteropathy. Serological analyses for celiac disease were unremarkable (transglutaminase IgA and IgG negative; low total IgA levels). She also had low IgG serum levels and received regular IgG substitutions for several years. Apart from B cell deficiency, fluorescence-activated cell sorting analysis revealed diminished CD4+/CD25+ and CD25high/FoxP3+ cells, whereas an unusual CD25−/FoxP3+ population was detectable. Coexisting hepatosplenomegaly, several sonographically hypodense spleen lesions, and generalized lymphadenopathy led to the suspicion of an autoimmune lymphoproliferative syndrome-like disorder. Erythrocyte and thrombocyte counts were mostly within normal ranges. There was no history of severe invasive bacterial infections. However, PCR analyses in lung biopsy specimens revealed reactivations of human herpesvirus 6 and cytomegalovirus infections. Pharmacological treatment with valganciclovir and cidofovir, combined with an immunosuppressive treatment (mycophenolatmofetil), led to improvement of respiratory function, although vital capacity tended to decline between periods of antiviral treatment (current vital capacity ranging between 40 and 60%) and during recurrent episodes of suboptimal therapy compliance evidenced by low mycophenolate plasma levels. A significant variability in insulin dose requirements, presumably resulting from varying degrees of chronic inflammation and systemic steroid treatment but, on the other hand, recurrent hypoglycemia, warranted suboptimal blood glucose control with glycosylated hemoglobin levels around 8.0% or higher. Between 2011 and 2015, her daily insulin requirement ranged from 0.7 to 2.1 U/kg/d (treatment with insulin analog aspart via continuous sc insulin injection), with high doses above 1.5 U/kg/d temporarily being necessary even during periods without systemic steroid treatment. Despite several factors adversely affecting metabolic control (chronic inflammation, systemic steroid treatment), she did not develop significant ketoacidosis (pH <7.25), either at the time of diabetes manifestation or in the following years. Furthermore, the girl suffered from severe short stature (height <−4 SDS) (Supplemental Figure 1) and GH deficiency (GHD), diagnosed by severely diminished IGF-1 and IGF binding protein-3 serum levels and two GH stimulation tests showing insufficient GH secretion (GH maximum, 6.3 ng/mL; cutoff, 8.0 ng/mL). Her younger brother (patient 2) also suffered from infancy-onset T1DM (autoantibody-positive for islet cell antibody, >40 JDF-U, normal range, 0 JDF-U; insulin autoantibody, 20.6 U/mL, normal range, <0.1 U/mL; glutamic acid decarboxylase antibody, negative; C-peptide, undetectable). Except for an increased frequency of upper airway infections, he had no history of severe respiratory problems. He suffered from severe chronic diarrhea (>10–15 stools daily) since infancy, accompanied by severe electrolyte disturbances and difficulties in glucose control that repeatedly led to hospitalization. Under immunosuppressive treatment using sirolimus combined with azathioprine and a low glucocorticoid maintenance dose, stool frequency significantly decreased to less than five to eight stools daily. B-lymphocyte function appeared to be less affected, and IgG serum levels ranged around the lower normal limit. A single episode of a thrombocytopenic purpura and anemia (age, 5 years) responded well to systemic glucocorticoid treatment after leukemic disease was ruled out by bone marrow biopsy. Compared to his sister, body growth initially appeared to be less severely affected (height, −2.5 SDS), and growth velocity during the first 12 months after immigration was within the normal range (Supplemental Figure 1). Thereafter, subnormal growth velocity in combination with low serum IGF-1 and retarded bone age led to suspicion of GHD. However, a GH stimulation test revealed a normal GH response (9.3 ng/mL). Blood glucose control was also complicated by recurrent severe hypoglycemia and significantly varying insulin dose requirements, so that glycosylated hemoglobin levels rarely were below 8.0%. Compared to his sister, daily insulin requirement was comparatively lower. Although amounts of up to 1.8 U/kg/d were required during periods of high inflammatory activity and systemic steroid treatment, treatment with only 0.45 to 0.7 U/kg/d turned out to be appropriate (and reasonably safe). Like his sister, he has not developed significant ketoacidosis (pH <7.25) so far. Another sibling, who was diagnosed to have T-cell deficiency and Evans-syndrome, died at age 7 years, before the family immigrated to Europe. A fourth child of the family is currently 7 years old and did not present symptoms of immunodysfunction and/or autoimmunity. Patients and Methods For WES of patients 1 and 2, exonic and adjacent intronic sequences were enriched from genomic DNA using the NimbleGen SeqCap EZ Human Exome Library version 2.0 enrichment kit. WES was performed using a 100-bp paired-end read protocol according to the manufacturer's recommendations on an Illumina HiSeq2000 sequencer by the Cologne Center for Genomics (CCG), Cologne, Germany. WES data analysis and filtering of mapped target sequences were performed with the Varbank exome and genome analysis pipeline version 2.1 (CCG). We obtained a mean coverage of 75 reads, and 96% of targets were covered more than 10×. We applied the following criteria for filtering of the WES variants: coverage of more than six reads, a minimum quality score of 10, an allele frequency ≥75%, a minor allele frequency <1% in the 1000 Genomes database (http://www.1000genomes.org/) and the Exome Variant Server (NHLBI Exome Sequencing Project, www.evs.gs.washington.edu/EVS/), and not annotated in the in-house WES data sets of the CCG. Using these filter criteria, we identified a total of five homozygous variants (Table 1). These homozygous variants included four missense variants and one frameshift in the LRBA gene [c.2445_2447del(C)3ins(C)2; p.P816Lfs*4], which leads to a protein-terminating stop codon. LRBA yielded a residual variation intolerance score of 2.51 (percentile, 0.93). Table 1. List of Homozygous Variants Fulfilling the Filter Criteria and Present in Both Affected Siblings Gene . Nucleotide . Amino Acid . Chromosome . RefSeq . Gene Function . ARAP2 c.348C>G p.S116R 4 NM_015230.3 Focal adhesions (cytoskeleton) N4BP2 c.4165A>G p.N1389D 4 NM_018177.4 ATP hydrolysis (putatively 5'-polynucleotide kinase activity, DNA repair) AK8 c.506C>A p.T169K 9 NM_152572.2 Adenylate-kinase LRBA c.2445_2447del(C) 3ins(C)2 p.P816Lfs*4 4 NM_006726.4 B-cell activation, Treg-cell function FAM160A1 c.2363G>A p.G788E 4 NM_001109977.1 Unknown Gene . Nucleotide . Amino Acid . Chromosome . RefSeq . Gene Function . ARAP2 c.348C>G p.S116R 4 NM_015230.3 Focal adhesions (cytoskeleton) N4BP2 c.4165A>G p.N1389D 4 NM_018177.4 ATP hydrolysis (putatively 5'-polynucleotide kinase activity, DNA repair) AK8 c.506C>A p.T169K 9 NM_152572.2 Adenylate-kinase LRBA c.2445_2447del(C) 3ins(C)2 p.P816Lfs*4 4 NM_006726.4 B-cell activation, Treg-cell function FAM160A1 c.2363G>A p.G788E 4 NM_001109977.1 Unknown Open in new tab Table 1. List of Homozygous Variants Fulfilling the Filter Criteria and Present in Both Affected Siblings Gene . Nucleotide . Amino Acid . Chromosome . RefSeq . Gene Function . ARAP2 c.348C>G p.S116R 4 NM_015230.3 Focal adhesions (cytoskeleton) N4BP2 c.4165A>G p.N1389D 4 NM_018177.4 ATP hydrolysis (putatively 5'-polynucleotide kinase activity, DNA repair) AK8 c.506C>A p.T169K 9 NM_152572.2 Adenylate-kinase LRBA c.2445_2447del(C) 3ins(C)2 p.P816Lfs*4 4 NM_006726.4 B-cell activation, Treg-cell function FAM160A1 c.2363G>A p.G788E 4 NM_001109977.1 Unknown Gene . Nucleotide . Amino Acid . Chromosome . RefSeq . Gene Function . ARAP2 c.348C>G p.S116R 4 NM_015230.3 Focal adhesions (cytoskeleton) N4BP2 c.4165A>G p.N1389D 4 NM_018177.4 ATP hydrolysis (putatively 5'-polynucleotide kinase activity, DNA repair) AK8 c.506C>A p.T169K 9 NM_152572.2 Adenylate-kinase LRBA c.2445_2447del(C) 3ins(C)2 p.P816Lfs*4 4 NM_006726.4 B-cell activation, Treg-cell function FAM160A1 c.2363G>A p.G788E 4 NM_001109977.1 Unknown Open in new tab Sanger sequencing was used to confirm the LRBA sequence variation identified by WES and to analyze LRBA genotypes of the clinically unaffected family members. LRBA protein expression was analyzed by flow cytometry after isolating peripheral blood mononuclear cells (PBMCs) and stimulating them with phytohemagglutinin (PHA) (10 ng/μL) for 72 hours. We used PHA because, from our experience, PHA stimulation in individuals with LRBA deficiency discriminates better than many other stimuli (B. Grimbacher, unpublished data). Further technical details are described in Ref. 10. Results After mutations in genes linked to classical IPEX-syndrome (FOXP3) or complex autoimmunity disorder including T1DM (AIRE, Stat3) were excluded by means of Sanger sequencing, WES was considered the appropriate diagnostic tool to screen for autosomal-recessive mutations, which were presumed because of the parents' consanguinity. In particular, WES was performed in both affected siblings to significantly reduce the number of potential candidate variants. Five variants matched the selection criteria and were homozygous in both siblings (Table 1). Of these, one variant was located in a gene recently linked to a complex autoimmune dysregulation phenotype, including B- and Treg-cell dysfunction, enteropathy, lymphocytic interstitial pneumonitis, and very recently, T1DM as present in the two siblings reported in here. Sanger sequencing with DNA samples of the two patients, the unaffected brother, and their parents confirmed the assumed pattern of autosomal-recessive inheritance (Figure 1). By generating a premature stop codon at codon 820 of 2852, LRBA p.P816Lfs*4 is likely to abolish LRBA function. Figure 1. Open in new tabDownload slide Both patients (filled symbols) are homozygous for the deletion at nucleotide 2445 (c.2445_2447del(C)3ins(C)2). Considering previous reports on LRBA-deficient patients with autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura, the lethal phenotype of the deceased sibling may be caused by LRBA deficiency due to homozygosity for c.2445_2447del(C)3ins(C)2, too. Figure 1. Open in new tabDownload slide Both patients (filled symbols) are homozygous for the deletion at nucleotide 2445 (c.2445_2447del(C)3ins(C)2). Considering previous reports on LRBA-deficient patients with autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura, the lethal phenotype of the deceased sibling may be caused by LRBA deficiency due to homozygosity for c.2445_2447del(C)3ins(C)2, too. The absence of inducible LRBA-positive PBMCs biochemically confirmed the diagnosis of LRBA deficiency in both patients (Figure 2). Accordingly, a significantly reduced LRBA expression (∼50%) was detected in PBMCs of the clinically unaffected heterozygous brother. Figure 2. Open in new tabDownload slide LRBA protein expression in PBMC after phytohemagglutinin (PHA) stimulation analyzed by flow cytometry. Figure 2. Open in new tabDownload slide LRBA protein expression in PBMC after phytohemagglutinin (PHA) stimulation analyzed by flow cytometry. Discussion Here we report two siblings with severe immunodysregulation phenotypes due to a homozygous LRBA mutation identified by WES. LRBA mutations were first described in 2012 in five index patients presenting with hypogammaglobulinemia and variable features of autoimmunity, including autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, chronic lung disease, and autoimmune enteropathy (11). Since then, more than a dozen other individuals with LRBA mutations have been identified by WES (10–16) or whole-genome sequencing approaches (17). The LRBA gene contains 57 exons and encodes an approximately 2800 amino acid protein, which is expressed in various tissues, including lymphocytes (18, 19). LRBA protein function is not fully understood yet. It is involved in endocytosis and polarized cytosolic trafficking during activation of B lymphocytes (18), and autoimmunity in LRBA deficiency has been functionally linked to impaired development and reduced suppressive function of Treg cells (14). Very recently, Lo et al (20) reported that patients with LRBA deficiency showed sustained clinical improvement in response to abatacept, an IgG-CTLA4 fusion protein drug currently used for the immunosuppressive treatment of rheumatoid arthritis. The authors speculated that LRBA is implicated in the regulation of cytotoxic T lymphocyte antigen-4 (CTLA4), which is known to be expressed on activated T cells and FoxP3+ Treg cells and to be implicated in the inhibitory regulation of immune responses. They found not only LRBA colocalizing with CTLA4 in endosomal vesicles, but also the absence of LRBA leading to an increased turnover and reduced levels of CTLA4 protein. Further in vitro experiments using chloroquine, which inhibits lysosomal degradation, and a selective knockdown of clathrin-associated adaptor protein complex, which is implicated in CTLA4 trafficking to lysosomes, confirmed their hypothesis of LRBA to play a major immunomodulatory role by protecting CTLA4 from being sorted to and degraded within lysosomes (20). Similar to the phenotypes of our two patients, substantial variability of the clinical presentation can be observed even within single families. Notably, only five very recently reported LRBA-deficient patients suffered from T1DM (14, 16, 20). However, it can be speculated that a significant number of patients with FoxP3 mutation-negative IPEX-like syndromes actually might suffer from LRBA deficiency. Especially for patients with T1DM, sufficient and temporally constant control of inflammatory processes is essential to achieve acceptable glucose control. Along with descriptions of the variable clinical presentation of LRBA-mutant patients, various pharmacological immunosuppressive treatment strategies used to attenuate autoimmune symptoms have been reported (eg, steroids, azathioprine, infliximab, mycophenolatmofetil, rituximab, and sirolimus). In addition, many patients had hypogammaglobulinemia and received regular IgG substitutions. A very promising therapeutic approach is the aforementioned CTLA4 modulation by abatacept, for which a dramatic and sustained clinical improvement has been reported in LRBA-deficient patients with life-threatening chronic organ manifestations such as severe restrictive lung disease or enteropathy (20). Clinical studies with abatacept in patients with rheumatoid arthritis have confirmed its long-term safety (21, 22). Nonetheless, an increased susceptibility to infections and hypothetical concerns about potential blunting of antitumor responses may require special considerations in patients with LRBA deficiency (20). To date, no causal treatment option for LRBA deficiency is available. Out of more than 20 reported patients with LRBA deficiency, three received hematopoietic stem cell transplantation (HSCT) (10, 15, 20). Seidel et al (10) reported a patient in whom HSCT had been performed because of autoimmune lymphoproliferative syndrome going along with profound immunodeficiency and life-threatening infections before the molecular diagnosis of LRBA deficiency was made. Interestingly, mild symptoms of autoimmunity (vitiligo, immune thrombocytopenia with good response to high-dose Ig treatment) relapsed 4 years after HSCT despite full donor chimerism. Although the authors speculate that a reduced LRBA expression in the donor cells of the clinically healthy human leukocyte antigen-identical mother might be responsible for this phenomenon, the long-term remission without recurrence of severe immunodysfunction warrants further consideration of this treatment option for patients with LRBA deficiency (10). During the last two decades, a large number of innovative immunomodulatory treatment approaches for T1DM have been reported by basic scientists and clinicians, most of them, however, were either not successful in achieving insulin independence or not applicable because of disproportionate adverse effects (23–25). Interestingly, promising results in newly diagnosed T1DM patients were achieved by autologous nonmyeloablative HSCT (26–28). One may speculate that future HCST-based treatment approaches for primary immunodysfunction conditions using either allogeneic or autologous cells, eg, after genome editing through TALENs- or CRISPR/Cas9-based techniques (29), may be particularly beneficial for patients with coexisting and newly diagnosed T1DM. Short stature and/or failure to thrive were reported in more than 50% of LRBA-deficient patients (Supplemental Table 1) and probably reflect a heterogeneous spectrum of growth impairment related to chronic inflammation, systemic steroid treatment, and/or malabsorption in individuals suffering from enteropathy. Of 17 patients with reported short stature and/or failure to thrive, 13 had enteropathy (10–16, 20). GHD was diagnosed in only one previous LRBA-deficient individual (12). In the family reported here, both patients exhibited severe short stature and were tested for GHD by two GH stimulation tests each, but only patient 1 had subnormal GH peaks consistent with the diagnosis of GHD. Growth velocity of this girl, however, remained subnormal after initiation of GH replacement, presumably reflecting coexistence of the aforementioned reasons for growth retardation such as chronic pulmonary inflammation and enteropathy, which can lead to secondary GH insensitivity. It is currently not clear whether autoimmune GHD might be an additional symptom of LRBA deficiency. GHD generally does not seem to represent a common finding in patients with autoimmune polyendocrine syndromes. To our knowledge, there are only a few documented cases of GHD in autoimmune polyendocrine syndrome-1 (30–33). Antipituitary autoantibodies as parameters of organ-specific autoimmunity, which could help to discriminate between patients with coexisting GHD and those with short stature due to other reasons, can be generally found in up to one-third of pediatric patients with isolated GHD (34). However, they can also be detected in many healthy individuals and may only have diagnostic specificity at high titers or in coincidence with distinct pituitary pathologies such as lymphocytic hypophysitis (34–36). In patient 1, who presented subnormal GH peaks in two GH stimulation tests, magnetic resonance imaging did not reveal any pituitary abnormalities. Considering that the girl received regular IgG substitutions, which may significantly increase the probability of false-positive antibody screening results, we did not analyze antipituitary autoantibodies. Furthermore, correct diagnostic testing for GHD in patients with short stature and accompanying chronic inflammatory disorders is challenging. Proinflammatory cytokines including TNF-α and IL-6 have been implicated as potential mediators of acquired GH resistance (37) and may distort the GH response in routinely used stimulation tests, too. Taken together, optimization of treatment strategies to control inflammation and symptoms of multiorgan autoimmunity will also be important in order to improve somatic growth in patients with LRBA deficiency. In summary, we report a novel LRBA mutation identified in two siblings with T1DM, short stature, and severe immunodysregulation phenotypes. A substantial variability of the clinical presentation can be observed even within families. Although T1DM was reported in only a few patients with LRBA mutations so far, LRBA deficiency should be considered in all patients presenting with T1DM and signs of severe autoimmunity or immunodysfunction. Acknowledgments This work was supported by Federal Ministry of Education and Research Grants 01EO1303 and E:med_SysInflame_012 × 1306F. 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TI - Infancy-Onset T1DM, Short Stature, and Severe Immunodysregulation in Two Siblings With a Homozygous LRBA Mutation
JF - Journal of Clinical Endocrinology and Metabolism
DO - 10.1210/jc.2015-3382
DA - 2016-03-01
UR - https://www.deepdyve.com/lp/oxford-university-press/infancy-onset-t1dm-short-stature-and-severe-immunodysregulation-in-two-n9ch0qoiuH
SP - 898
VL - 101
IS - 3
DP - DeepDyve
ER -