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A Case of Common Variable Immunodeficiency with CREBP Gene Mutation without Rubinstein Taybi Syndrome Features

A Case of Common Variable Immunodeficiency with CREBP Gene Mutation without Rubinstein Taybi... Hindawi Case Reports in Immunology Volume 2022, Article ID 4970973, 5 pages https://doi.org/10.1155/2022/4970973 Case Report A Case of Common Variable Immunodeficiency with CREBP Gene Mutation without Rubinstein Taybi Syndrome Features 1 2 1 3 Ugur Musabak , Serdar Ceylaner , Tuba Erdogan , and Ebru Sebnem Ayva Division of Immunology and Allergy, Baskent University, Faculty of Medicine, Ankara, Turkey Department of Medical Genetics, Lokman Hekim University, Ankara, Turkey Department of Pathology, Baskent University, Faculty of Medicine, Ankara, Turkey Correspondence should be addressed to Ugur Musabak; umusabak@hotmail.com Received 12 April 2022; Accepted 27 May 2022; Published 4 July 2022 Academic Editor: Necil Ku¨t¨ukç¨uler Copyright © 2022 Ugur Musabak et al. �is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hypogammaglobulinemias, based on inborn errors of immunity, are primary immunode„ciencies (PIDs) that can also be diagnosed for the „rst time in adulthood. Common variable immunode„ciency (CVID) is a multifactorial disease often symptomatic due to antibody de„ciency. In addition, some PIDs are classi„ed into the category of immunode„ciencies with syndromic features due to their accompanying clinical „ndings unrelated to immunity. In this article, a patient with CVID who was diagnosed in adulthood and who was revealed to have a mutation speci„c to Rubinstein–Taybi syndrome and clinical features reminiscent of this syndrome only after molecular tests was presented. detected in the upper gastrointestinal tract examination 1. Introduction performed for chronic diarrhea. In the patient’s history, it Primary immunode„ciencies (PIDs), a group of rare diseases, was learned that after the age of „fteen, she had „ve or six are caused by defects or dysfunction of the human immune sinusitis attacks per year and had pneumonia twice in total. system [1]. �e characteristic manifestations of PIDs are In addition, she also had frequent and prolonged watery chronic, serious, or life-threatening infections. �ese disor- diarrhea in the last two years and was treated for long-term ders, also called as inborn errors of immunity (IEI), are mainly vaginitis. �e patient was born at term by normal delivery. divided into 10 subgroups according to the a•ected com- �ere was no mental or developmental retardation in her ponent/components of immunity [2]. Predominantly anti- childhood compared to her peers. �e patient’s school body de„ciencies (PADs) are the most prevalent PIDs among success was consistently high. �e patient, who is a phar- these subgroups. In addition, the patients with PIDs who have macist, has a 10-year-old boy. �e patient’s parents are not some congenital anomalies are classi„ed into a subgroup of relatives. �e patient, the only child in the family, did not PIDs with syndromic features. �e frequency of PIDs in this have a history of recurrent infections or a dysmorphic subgroup is less than those of PADs. Common variable disease in her parents or close relatives. On physical ex- immunode„ciency (CVID) is one of the PADs in which a amination, the patient’s height was 160 cm, her weight was heterogeneous clinical manifestation is presented. Herein, we 46 kg, and the body mass index was 17.9. On physical ex- report a rare case with CVID who had some clinical features amination, she did not have the clinical features of of Rubinstein–Taybi syndrome (RTS). Rubinstein–Taybi syndrome-like mental retardation, post- natal growth de„ciency, microcephaly, and dysmorphic facial features. But she had a high arched palate and slightly 2. Case Presentation wide big toes [Figure 1]. Twenty years ago, the patient underwent orthodontic treatment due to crooked and A 38-year-old female patient was admitted to our immu- nology outpatient clinic due to nodular lymphoid aggregates misplaced teeth. �erefore, the tooth arrangement was seen 2 Case Reports in Immunology (a) (b) (c) (d) Figure 1: (e patient with high arched palate, missing teeth, and wide big toes. as normal. However, her teeth were missing due to tooth liver. In addition, no abnormal findings were seen in direct extraction during dental treatment. Other systemic exami- anterior-posterior and lateral chest radiographs. nation findings were normal. All routine biochemical pa- In the endoscopic examination of the upper gastroin- rameters measured in venous blood were within normal testinal tract, the findings were consistent with pangastritis limits except for the total protein level [5.1 g/L (6.2–8.3)]. A and nodular bulbitis. (e rectum, cecum, and ascending complete blood count (CBC) with differential was respec- colon mucosa were observed as mottled, hyperemic, and tively found as white blood cell: 10.8·103/mm (4.5–11.103), partially pale in the colonoscopic examination. Multiple neutrophil: 4.6·103/mm (2–7.8·103), lymphocyte: 2.7·103/ millimeter-sized nodules along 20–25 cm were detected in 3 3 the terminal ileum. In the histopathological examination of mm (1–4·103), monocyte: 0.5·103/mm (0–1·103), eosino- 3 3 phil: 2.7·103/mm (0–1·103), basophil: 0.1·103/mm the biopsies, while chronic erosive gastritis accompanied by intestinal metaplasia was observed in the stomach, Heli- (0–0.2·103), haemoglobin: 14.7 gr/dL (12.5–16), haematocrit: 43.2% (37–47), and platelet count: 156·103/mm cobacter pylori was observed in abundance. Multiple nodular (150–400·10 ). Acute phase reactants were slightly increased lymphoid hyperplasia (NLH) with prominent germinal than their reference values, such as C-reactive protein centers were detected in the mucosa of the stomach, duo- (CRP): 12 mg/L (0–5) and erythrocyte sedimentation rate denum, terminal ileum, and colon, while an inflammatory (ESR) 22 mm/hour. Serum tissue transglutaminase antibody reaction characterized by an increase in eosinophils was levels in IgA (tTg-IgA) and IgG (tTg-IgG) isotypes were observed in the mucosa of the duodenum, terminal ileum, lower than 2 RU/mL (<20: negative). Although anti- and colon (>50, >50, >100 per HPF (high-power field), microsomal antibodies and antithyroglobulin antibodies respectively) (Figure 2). When the previous biochemical tests of the patient were were found to be increased as, respectively, 52.6 IU/mL (<5, 6) and 94.1 IU/mL (<4), the patient’s thyroid-stimulating examined retrospectively, it was determined that the total hormone (TSH) was at a normal level of 1.4 mU/L (0.3–4.9). protein levels were consistently low. As the patient had Serum levels of all major immunoglobulin isotypes were profound hypogammaglobulinemia, serum immunoglobu- low at the time of diagnosis. Respectively, IgG: 0.27 g/L lins were measured to confirm once again before treatment. (6.5–16.3), IgA: 0.02 g/L (0.6–4.2), IgM: 0.12 g/L (0.3–2.9), (e patient’s previous low protein levels were interpreted as and total IgE: 11 IU/mL (<87). While the patient’s blood the result of low immunoglobulin levels. (e patient was group was A Rh +, the anti-B antibody titer was lower than 1: diagnosed as CVID in accordance with the European Society 8. (e anti-HB antibody level of the patient, who was for Immunodeficiencies (ESID) criteria [3]. vaccinated 5 years ago with hepatitis B, was 750 U/L (<10). Whole exome sequencing (WES) was performed using (e percentages of lymphocyte subsets were found within next-generation sequencing (NGS) technology for the molecular diagnosis of the patient. A heterozygous patho- reference ranges as CD3: 74.8%, CD4: 28.1%, CD8: 33.4%, CD19: 17.9%, CD45:100%, CD3-CD16+CD56+: 6,8%, genic variant was detected in exon 31 of the CREBBP gene respectively. [NM_004380.3; c.5552G> A (p. Argl851His)], which is Sixty-seven leukocytes (0–5) were detected in each field specific for Rubinstein–Taybi 1. In addition, HLA alleles in the complete urinalysis. (e stool of the patient was have been identified in the patient, which increase the watery in appearance. However, no parasites, parasite eggs, likelihood of gluten enteropathy (HLA-DQ2 : DQA1 ∗ 05 : or bleeding were observed in the microscopic examination 05 : 01 and -DQB1 ∗ 02 : 02 : 01). Our patient is married and of the stool. (e patient’s fecal calprotectin level was has a 10-year-old boy. Molecular tests were also applied to >1800 mcg/g of stool (>50). other family members so that we could guide their future plans. It was seen that her son also had the same pathogenic No splenomegaly or LAP was detected in the whole abdominal ultrasonography, except for the slightly enlarged variant in one allele of the CREBBP gene. (ere is just one Case Reports in Immunology 3 500 μm 5.09x (a) 500 μm 4.70x (b) 500 μm 5.09x (c) Figure 2: Hyperplastic lymphoid follicles with prominent germinal centers, in keeping with nodular lymphoid hyperplasia. Stomach (a), small intestine (b), and colon (c) biopsies with haematoxylin-eosin staining. case with this in the Genome Aggregation Database pathogenic in Clinvar Database. (at’s why, we classified (GnomAD) and Genomes database. (e UniProt database this variant as a “likely pathogenic variant” due to ACMG showed that this variant was 63% pathogenic for the criteria. CBP_HUMAN region of interest. Pathogenicity prediction In direction with the recommendations of international was conducted based on 9 different computational methods. drug agencies, immunoglobulin (IVIG) treatment was ini- A different variant in the same codon was classified as tiated at the dose of 600 mg/kg every three weeks due to 4 Case Reports in Immunology hypogammaglobulinemia [4]. In addition, oral budesonide, Although recurrent infections are seen in a significant a topically acting synthetic steroid, at three daily doses of portion of the patients, there has been no comprehensive study investigating the immune system in patients with RTS 3 mg and oral methylprednisolone (MP) at a single daily dose of 0.5 mg/kg, were used for the treatment of NLH [5]. to date. In a recently published meta-analysis, previously (e dose titrations of these drugs were adjusted according to published articles on RTS in the literature were reviewed by the patient’s clinical response. Vitamin D and Calcium Saettini et al., and clinical and immunological data of a large supplements were also given to prevent the adverse effect of cohort of 97 patients with RTS were analyzed in detail [8]. In glucocorticoid therapy on bone metabolism. result, one in five patients with RTS were found to have hypogammaglobulinemia having clinical manifestations consistent with CVID or ALPS. As in the patient we pre- 3. Discussion sented, it was shown that the diagnosis of hypogamma- globulinemia was delayed until adulthood in all 3 patients in CVID is a heterogeneous PID that develops autoimmunity, this cohort. malignancy, and granuloma formation in the course of the It is well known that orofacial dysmorphism, growth disease, except for recurrent infections [5, 6]. Although retardation, and intellectual disability are characteristic recurrent infection is the hallmark of the CVID, nonin- clinical features in RTS. However, not all of these findings fectious manifestations may appear before the infection. (is may typically be found in all cases, and each patient may disease, with an incidence of between 1/25,000 and 1/50,000, present with a different clinical phenotype. In a cohort with occurs after the age of 4 or in adulthood. Immune cytopenia RTS consisting of 11 individuals described by Menke et al., is the most common autoimmune complication developing some patients had a few signs compatible with RTS, such as in CVID. (e autoimmune diseases that mainly affect the growth retardation and less characteristic low-set ears or joints, skin, and gastrointestinal tract can also develop in this micrognathia [9]. Nine patients had apparent intellectual disease (e.g., rheumatoid arthritis, systemic lupus eryth- disability (82%), while none of them had the classical facial ematosus, psoriasis, vitiligo, and immune enteropathies). RSTS features, the truly broad or angulated thumbs, and (e most common malignancies developing based on CVID halluces, or the broad distal phalanges of the fingers. Ten are gastric cancer and lymphomas. distinct missense mutations in exon 30 or 31 of the CREBBP Noninfectious inflammatory enteropathies like those of gene had been found in these patients who had incomplete ulcerative colitis, Crohn’s disease, and celiac disease occur in signs for RTS. 10 to 12% of patients with CVID [6, 7]. In patients with In a recent article published by Banka et al., similar gastrointestinal complications, the clinical course is rela- results were reported that three individuals with missense tively severe, and the prognosis is poor due to malabsorption mutations in exon 30 or 31 of the CREBBP gene but not have and weight loss. Accordingly, in the previous report, the characteristic dysmorphic features of RTS [10]. When all the common gastrointestinal tract conditions were gastritis/ cases published in the literature are evaluated together with duodenitis (73.1%), NLH (30.8%), and chronic diarrhea ours, it can be concluded that different variants in the (19.2%) in our cohort with CVID [6]. In addition, chronic CREBP gene are responsible for different clinical pheno- diarrhea and NLH were significantly more common in the types. However, in order to reach a more definite conclusion patients with a low body weight than in those patients with on this issue, more comprehensive studies in larger patient an ideal body weight (83.3% vs. 0%, p� not applicable: 83.3% series are required. vs. 15%, p � 0.001, respectively). As a result, the clinical features of PADs and some Herein, we present a patient with CVID who had genetic diseases, which are mostly diagnosed in childhood, noninfectious inflammatory complications throughout the may appear in adulthood, and therefore, their diagnoses and gastrointestinal tract. (e patient’s endoscopic and histo- treatments may be delayed. Although the case we presented pathological findings supported the presence of an obvious herein had strong signs of immunodeficiency, the diagnosis inflammatory process in the mucosa. Alleviation of symp- was delayed, and its dysmorphic features could only be toms with a gluten-free diet showed that the patient had a revealed by reexamination according to the results of mo- disease similar to celiac disease. Compatible with clinico- lecular analysis. (erefore, in cases with suspected immu- pathologic findings, HLA-DQ2 alleles showing the likeli- nodeficiency, more careful evaluation should be made to hood of gluten enteropathy were detected in the case. reduce both mortality and morbidity and the economic Interestingly, instead of variants identified in immu- burden due to late diagnosis. On the other hand, it seems nodeficiencies, a heterozygous pathogenic variant in the imperative to raise awareness of rare diseases in all segments CREBBP gene which is specific for RTS was detected in WES of society. analyses performed to define the genetic aetiology. Because of this, the patient was reexamined by the medical geneticist Data Availability with respect to showing the clinical features specific to RTS. As a result of a careful examination, mild dysmorphic No data were used to support this study. features consistent with this syndrome were found in the patient. She did not have mental retardation, which is a Consent characteristic feature of RTS. Even the case was a graduate of the faculty of pharmacy. Written consent was obtained from the patient. Case Reports in Immunology 5 Conflicts of Interest (e authors declare no conflicts of interest. Authors’ Contributions (is article has been read and approved by all the authors. References [1] N. Mahlaoui, K. Warnatz, A. Jones, S. Workman, and A. Cant, “Advances in the care of primary immunodeficiencies (PIDs): from birth to adulthood,” Journal of Clinical Immunology, vol. 37, no. 5, pp. 452–460, 2017. [2] A. Bousfiha, L. Jeddane, C. Picard et al., “Human inborn errors of immunity: 2019 update of the IUIS phenotypical classification,” Journal of Clinical Immunology, vol. 40, no. 1, pp. 66–81, 2020. [3] R. Ameratunga, M. Brewerton, C. Slade et al., “Comparison of diagnostic criteria for common variable immunodeficiency disorder,” Frontiers in Immunology, vol. 5, p. 415, 2014. [4] I. Mahmood, M. A. Tegenge, and B. Golding, “Considerations for optimizing dosing of immunoglobulins based on phar- macokinetic evidence,” Antibodies, vol. 9, no. 2, p. 24, 2020. [5] F. S. Rizvi, H. Zainaldain, H. Rafiemanesh et al., “Autoim- munity in common variable immunodeficiency: a systematic review and meta-analysis,” Expert Review of Clinical Immu- nology, vol. 16, no. 12, pp. 1227–1235, 2020. [6] U. Mu¸abak s and T. Erdogan, ˘ “Clinical features and immu- noglobulin replacement therapy outcomes of adults with common variable immunodeficiency: a single centre experi- ence,” Turkish Journal of Medical Sciences, vol. 51, no. 5, pp. 2427–2436, 2021. [7] M. Uzzan, H. M. Ko, S. Mehandru, and C. Cunningham- Rundles, “Gastrointestinal disorders associated with common variable immune deficiency (CVID) and chronic granulo- matous disease (CGD),” Current Gastroenterology Reports, vol. 18, no. 4, p. 17, 2016. [8] F. Saettini, R. Herriot, E. Prada et al., “Prevalence of im- munological defects in a cohort of 97 rubinstein-taybi syn- drome patients,” Journal of Clinical Immunology, vol. 40, no. 6, pp. 851–860, 2020. [9] L. A. Menke, M. J. Van Belzen, M. Alders et al., “CREBBP- mutations in individuals without rubinstein-taybi syndrome phenotype,” American Journal of Medical Genetics, Part A, vol. 170, no. 10, pp. 2681–2693, 2016. [10] S. Banka, R. Sayer, C. Breen et al., “Genotype-phenotype specificity in Menke-Hennekam syndrome caused by mis- sense variants in exon 30 or 31 of CREBBP,” American Journal of Medical Genetics, Part A, vol. 179, no. 6, pp. 1058–1062, http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Immunology Hindawi Publishing Corporation

A Case of Common Variable Immunodeficiency with CREBP Gene Mutation without Rubinstein Taybi Syndrome Features

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Abstract

Hindawi Case Reports in Immunology Volume 2022, Article ID 4970973, 5 pages https://doi.org/10.1155/2022/4970973 Case Report A Case of Common Variable Immunodeficiency with CREBP Gene Mutation without Rubinstein Taybi Syndrome Features 1 2 1 3 Ugur Musabak , Serdar Ceylaner , Tuba Erdogan , and Ebru Sebnem Ayva Division of Immunology and Allergy, Baskent University, Faculty of Medicine, Ankara, Turkey Department of Medical Genetics, Lokman Hekim University, Ankara, Turkey Department of Pathology, Baskent University, Faculty of Medicine, Ankara, Turkey Correspondence should be addressed to Ugur Musabak; umusabak@hotmail.com Received 12 April 2022; Accepted 27 May 2022; Published 4 July 2022 Academic Editor: Necil Ku¨t¨ukç¨uler Copyright © 2022 Ugur Musabak et al. �is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hypogammaglobulinemias, based on inborn errors of immunity, are primary immunode„ciencies (PIDs) that can also be diagnosed for the „rst time in adulthood. Common variable immunode„ciency (CVID) is a multifactorial disease often symptomatic due to antibody de„ciency. In addition, some PIDs are classi„ed into the category of immunode„ciencies with syndromic features due to their accompanying clinical „ndings unrelated to immunity. In this article, a patient with CVID who was diagnosed in adulthood and who was revealed to have a mutation speci„c to Rubinstein–Taybi syndrome and clinical features reminiscent of this syndrome only after molecular tests was presented. detected in the upper gastrointestinal tract examination 1. Introduction performed for chronic diarrhea. In the patient’s history, it Primary immunode„ciencies (PIDs), a group of rare diseases, was learned that after the age of „fteen, she had „ve or six are caused by defects or dysfunction of the human immune sinusitis attacks per year and had pneumonia twice in total. system [1]. �e characteristic manifestations of PIDs are In addition, she also had frequent and prolonged watery chronic, serious, or life-threatening infections. �ese disor- diarrhea in the last two years and was treated for long-term ders, also called as inborn errors of immunity (IEI), are mainly vaginitis. �e patient was born at term by normal delivery. divided into 10 subgroups according to the a•ected com- �ere was no mental or developmental retardation in her ponent/components of immunity [2]. Predominantly anti- childhood compared to her peers. �e patient’s school body de„ciencies (PADs) are the most prevalent PIDs among success was consistently high. �e patient, who is a phar- these subgroups. In addition, the patients with PIDs who have macist, has a 10-year-old boy. �e patient’s parents are not some congenital anomalies are classi„ed into a subgroup of relatives. �e patient, the only child in the family, did not PIDs with syndromic features. �e frequency of PIDs in this have a history of recurrent infections or a dysmorphic subgroup is less than those of PADs. Common variable disease in her parents or close relatives. On physical ex- immunode„ciency (CVID) is one of the PADs in which a amination, the patient’s height was 160 cm, her weight was heterogeneous clinical manifestation is presented. Herein, we 46 kg, and the body mass index was 17.9. On physical ex- report a rare case with CVID who had some clinical features amination, she did not have the clinical features of of Rubinstein–Taybi syndrome (RTS). Rubinstein–Taybi syndrome-like mental retardation, post- natal growth de„ciency, microcephaly, and dysmorphic facial features. But she had a high arched palate and slightly 2. Case Presentation wide big toes [Figure 1]. Twenty years ago, the patient underwent orthodontic treatment due to crooked and A 38-year-old female patient was admitted to our immu- nology outpatient clinic due to nodular lymphoid aggregates misplaced teeth. �erefore, the tooth arrangement was seen 2 Case Reports in Immunology (a) (b) (c) (d) Figure 1: (e patient with high arched palate, missing teeth, and wide big toes. as normal. However, her teeth were missing due to tooth liver. In addition, no abnormal findings were seen in direct extraction during dental treatment. Other systemic exami- anterior-posterior and lateral chest radiographs. nation findings were normal. All routine biochemical pa- In the endoscopic examination of the upper gastroin- rameters measured in venous blood were within normal testinal tract, the findings were consistent with pangastritis limits except for the total protein level [5.1 g/L (6.2–8.3)]. A and nodular bulbitis. (e rectum, cecum, and ascending complete blood count (CBC) with differential was respec- colon mucosa were observed as mottled, hyperemic, and tively found as white blood cell: 10.8·103/mm (4.5–11.103), partially pale in the colonoscopic examination. Multiple neutrophil: 4.6·103/mm (2–7.8·103), lymphocyte: 2.7·103/ millimeter-sized nodules along 20–25 cm were detected in 3 3 the terminal ileum. In the histopathological examination of mm (1–4·103), monocyte: 0.5·103/mm (0–1·103), eosino- 3 3 phil: 2.7·103/mm (0–1·103), basophil: 0.1·103/mm the biopsies, while chronic erosive gastritis accompanied by intestinal metaplasia was observed in the stomach, Heli- (0–0.2·103), haemoglobin: 14.7 gr/dL (12.5–16), haematocrit: 43.2% (37–47), and platelet count: 156·103/mm cobacter pylori was observed in abundance. Multiple nodular (150–400·10 ). Acute phase reactants were slightly increased lymphoid hyperplasia (NLH) with prominent germinal than their reference values, such as C-reactive protein centers were detected in the mucosa of the stomach, duo- (CRP): 12 mg/L (0–5) and erythrocyte sedimentation rate denum, terminal ileum, and colon, while an inflammatory (ESR) 22 mm/hour. Serum tissue transglutaminase antibody reaction characterized by an increase in eosinophils was levels in IgA (tTg-IgA) and IgG (tTg-IgG) isotypes were observed in the mucosa of the duodenum, terminal ileum, lower than 2 RU/mL (<20: negative). Although anti- and colon (>50, >50, >100 per HPF (high-power field), microsomal antibodies and antithyroglobulin antibodies respectively) (Figure 2). When the previous biochemical tests of the patient were were found to be increased as, respectively, 52.6 IU/mL (<5, 6) and 94.1 IU/mL (<4), the patient’s thyroid-stimulating examined retrospectively, it was determined that the total hormone (TSH) was at a normal level of 1.4 mU/L (0.3–4.9). protein levels were consistently low. As the patient had Serum levels of all major immunoglobulin isotypes were profound hypogammaglobulinemia, serum immunoglobu- low at the time of diagnosis. Respectively, IgG: 0.27 g/L lins were measured to confirm once again before treatment. (6.5–16.3), IgA: 0.02 g/L (0.6–4.2), IgM: 0.12 g/L (0.3–2.9), (e patient’s previous low protein levels were interpreted as and total IgE: 11 IU/mL (<87). While the patient’s blood the result of low immunoglobulin levels. (e patient was group was A Rh +, the anti-B antibody titer was lower than 1: diagnosed as CVID in accordance with the European Society 8. (e anti-HB antibody level of the patient, who was for Immunodeficiencies (ESID) criteria [3]. vaccinated 5 years ago with hepatitis B, was 750 U/L (<10). Whole exome sequencing (WES) was performed using (e percentages of lymphocyte subsets were found within next-generation sequencing (NGS) technology for the molecular diagnosis of the patient. A heterozygous patho- reference ranges as CD3: 74.8%, CD4: 28.1%, CD8: 33.4%, CD19: 17.9%, CD45:100%, CD3-CD16+CD56+: 6,8%, genic variant was detected in exon 31 of the CREBBP gene respectively. [NM_004380.3; c.5552G> A (p. Argl851His)], which is Sixty-seven leukocytes (0–5) were detected in each field specific for Rubinstein–Taybi 1. In addition, HLA alleles in the complete urinalysis. (e stool of the patient was have been identified in the patient, which increase the watery in appearance. However, no parasites, parasite eggs, likelihood of gluten enteropathy (HLA-DQ2 : DQA1 ∗ 05 : or bleeding were observed in the microscopic examination 05 : 01 and -DQB1 ∗ 02 : 02 : 01). Our patient is married and of the stool. (e patient’s fecal calprotectin level was has a 10-year-old boy. Molecular tests were also applied to >1800 mcg/g of stool (>50). other family members so that we could guide their future plans. It was seen that her son also had the same pathogenic No splenomegaly or LAP was detected in the whole abdominal ultrasonography, except for the slightly enlarged variant in one allele of the CREBBP gene. (ere is just one Case Reports in Immunology 3 500 μm 5.09x (a) 500 μm 4.70x (b) 500 μm 5.09x (c) Figure 2: Hyperplastic lymphoid follicles with prominent germinal centers, in keeping with nodular lymphoid hyperplasia. Stomach (a), small intestine (b), and colon (c) biopsies with haematoxylin-eosin staining. case with this in the Genome Aggregation Database pathogenic in Clinvar Database. (at’s why, we classified (GnomAD) and Genomes database. (e UniProt database this variant as a “likely pathogenic variant” due to ACMG showed that this variant was 63% pathogenic for the criteria. CBP_HUMAN region of interest. Pathogenicity prediction In direction with the recommendations of international was conducted based on 9 different computational methods. drug agencies, immunoglobulin (IVIG) treatment was ini- A different variant in the same codon was classified as tiated at the dose of 600 mg/kg every three weeks due to 4 Case Reports in Immunology hypogammaglobulinemia [4]. In addition, oral budesonide, Although recurrent infections are seen in a significant a topically acting synthetic steroid, at three daily doses of portion of the patients, there has been no comprehensive study investigating the immune system in patients with RTS 3 mg and oral methylprednisolone (MP) at a single daily dose of 0.5 mg/kg, were used for the treatment of NLH [5]. to date. In a recently published meta-analysis, previously (e dose titrations of these drugs were adjusted according to published articles on RTS in the literature were reviewed by the patient’s clinical response. Vitamin D and Calcium Saettini et al., and clinical and immunological data of a large supplements were also given to prevent the adverse effect of cohort of 97 patients with RTS were analyzed in detail [8]. In glucocorticoid therapy on bone metabolism. result, one in five patients with RTS were found to have hypogammaglobulinemia having clinical manifestations consistent with CVID or ALPS. As in the patient we pre- 3. Discussion sented, it was shown that the diagnosis of hypogamma- globulinemia was delayed until adulthood in all 3 patients in CVID is a heterogeneous PID that develops autoimmunity, this cohort. malignancy, and granuloma formation in the course of the It is well known that orofacial dysmorphism, growth disease, except for recurrent infections [5, 6]. Although retardation, and intellectual disability are characteristic recurrent infection is the hallmark of the CVID, nonin- clinical features in RTS. However, not all of these findings fectious manifestations may appear before the infection. (is may typically be found in all cases, and each patient may disease, with an incidence of between 1/25,000 and 1/50,000, present with a different clinical phenotype. In a cohort with occurs after the age of 4 or in adulthood. Immune cytopenia RTS consisting of 11 individuals described by Menke et al., is the most common autoimmune complication developing some patients had a few signs compatible with RTS, such as in CVID. (e autoimmune diseases that mainly affect the growth retardation and less characteristic low-set ears or joints, skin, and gastrointestinal tract can also develop in this micrognathia [9]. Nine patients had apparent intellectual disease (e.g., rheumatoid arthritis, systemic lupus eryth- disability (82%), while none of them had the classical facial ematosus, psoriasis, vitiligo, and immune enteropathies). RSTS features, the truly broad or angulated thumbs, and (e most common malignancies developing based on CVID halluces, or the broad distal phalanges of the fingers. Ten are gastric cancer and lymphomas. distinct missense mutations in exon 30 or 31 of the CREBBP Noninfectious inflammatory enteropathies like those of gene had been found in these patients who had incomplete ulcerative colitis, Crohn’s disease, and celiac disease occur in signs for RTS. 10 to 12% of patients with CVID [6, 7]. In patients with In a recent article published by Banka et al., similar gastrointestinal complications, the clinical course is rela- results were reported that three individuals with missense tively severe, and the prognosis is poor due to malabsorption mutations in exon 30 or 31 of the CREBBP gene but not have and weight loss. Accordingly, in the previous report, the characteristic dysmorphic features of RTS [10]. When all the common gastrointestinal tract conditions were gastritis/ cases published in the literature are evaluated together with duodenitis (73.1%), NLH (30.8%), and chronic diarrhea ours, it can be concluded that different variants in the (19.2%) in our cohort with CVID [6]. In addition, chronic CREBP gene are responsible for different clinical pheno- diarrhea and NLH were significantly more common in the types. However, in order to reach a more definite conclusion patients with a low body weight than in those patients with on this issue, more comprehensive studies in larger patient an ideal body weight (83.3% vs. 0%, p� not applicable: 83.3% series are required. vs. 15%, p � 0.001, respectively). As a result, the clinical features of PADs and some Herein, we present a patient with CVID who had genetic diseases, which are mostly diagnosed in childhood, noninfectious inflammatory complications throughout the may appear in adulthood, and therefore, their diagnoses and gastrointestinal tract. (e patient’s endoscopic and histo- treatments may be delayed. Although the case we presented pathological findings supported the presence of an obvious herein had strong signs of immunodeficiency, the diagnosis inflammatory process in the mucosa. Alleviation of symp- was delayed, and its dysmorphic features could only be toms with a gluten-free diet showed that the patient had a revealed by reexamination according to the results of mo- disease similar to celiac disease. Compatible with clinico- lecular analysis. (erefore, in cases with suspected immu- pathologic findings, HLA-DQ2 alleles showing the likeli- nodeficiency, more careful evaluation should be made to hood of gluten enteropathy were detected in the case. reduce both mortality and morbidity and the economic Interestingly, instead of variants identified in immu- burden due to late diagnosis. On the other hand, it seems nodeficiencies, a heterozygous pathogenic variant in the imperative to raise awareness of rare diseases in all segments CREBBP gene which is specific for RTS was detected in WES of society. analyses performed to define the genetic aetiology. Because of this, the patient was reexamined by the medical geneticist Data Availability with respect to showing the clinical features specific to RTS. As a result of a careful examination, mild dysmorphic No data were used to support this study. features consistent with this syndrome were found in the patient. She did not have mental retardation, which is a Consent characteristic feature of RTS. Even the case was a graduate of the faculty of pharmacy. Written consent was obtained from the patient. Case Reports in Immunology 5 Conflicts of Interest (e authors declare no conflicts of interest. Authors’ Contributions (is article has been read and approved by all the authors. References [1] N. Mahlaoui, K. Warnatz, A. Jones, S. Workman, and A. Cant, “Advances in the care of primary immunodeficiencies (PIDs): from birth to adulthood,” Journal of Clinical Immunology, vol. 37, no. 5, pp. 452–460, 2017. [2] A. Bousfiha, L. Jeddane, C. Picard et al., “Human inborn errors of immunity: 2019 update of the IUIS phenotypical classification,” Journal of Clinical Immunology, vol. 40, no. 1, pp. 66–81, 2020. [3] R. Ameratunga, M. Brewerton, C. Slade et al., “Comparison of diagnostic criteria for common variable immunodeficiency disorder,” Frontiers in Immunology, vol. 5, p. 415, 2014. [4] I. Mahmood, M. A. Tegenge, and B. Golding, “Considerations for optimizing dosing of immunoglobulins based on phar- macokinetic evidence,” Antibodies, vol. 9, no. 2, p. 24, 2020. [5] F. S. Rizvi, H. Zainaldain, H. Rafiemanesh et al., “Autoim- munity in common variable immunodeficiency: a systematic review and meta-analysis,” Expert Review of Clinical Immu- nology, vol. 16, no. 12, pp. 1227–1235, 2020. [6] U. Mu¸abak s and T. Erdogan, ˘ “Clinical features and immu- noglobulin replacement therapy outcomes of adults with common variable immunodeficiency: a single centre experi- ence,” Turkish Journal of Medical Sciences, vol. 51, no. 5, pp. 2427–2436, 2021. [7] M. Uzzan, H. M. Ko, S. Mehandru, and C. Cunningham- Rundles, “Gastrointestinal disorders associated with common variable immune deficiency (CVID) and chronic granulo- matous disease (CGD),” Current Gastroenterology Reports, vol. 18, no. 4, p. 17, 2016. [8] F. Saettini, R. Herriot, E. Prada et al., “Prevalence of im- munological defects in a cohort of 97 rubinstein-taybi syn- drome patients,” Journal of Clinical Immunology, vol. 40, no. 6, pp. 851–860, 2020. [9] L. A. Menke, M. J. Van Belzen, M. Alders et al., “CREBBP- mutations in individuals without rubinstein-taybi syndrome phenotype,” American Journal of Medical Genetics, Part A, vol. 170, no. 10, pp. 2681–2693, 2016. [10] S. Banka, R. Sayer, C. Breen et al., “Genotype-phenotype specificity in Menke-Hennekam syndrome caused by mis- sense variants in exon 30 or 31 of CREBBP,” American Journal of Medical Genetics, Part A, vol. 179, no. 6, pp. 1058–1062,

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Case Reports in ImmunologyHindawi Publishing Corporation

Published: Jul 4, 2022

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