A Novel TTC7A Deficiency Presenting with Combined Immunodeficiency

Practitioner's Corner 358

6. Armentia A, Martín S, Barrio J, Martín B, García JC, Vega JM, et al. Value of microarray allergen assay in the management A Novel TTC7A Deficiency Presenting With of eosinophilic oesophagitis. Allergol Immunopathol (Madr); Combined Immunodeficiency and Chronic 2015;43(1):73-80. Gastrointestinal Problems 7. Belver MT, Caballero MT, Contreras J, Cabañas R, Sierra E, Madero R, et al. Associations among pollen sensitizations Sharafian 1S , Alimadadi H2, Shahrooei M3,4, Gharagozlou M1, from different botanical species in patients living in the Aghamohammadi A1,5, Parvaneh N1,5 northern area of Madrid. J Investig Allergol Clin Immunol. 1Division of Allergy and Clinical Immunology, Department of 2007;17(3):157-9. Pediatrics, Tehran University of Medical Sciences, Tehran, Iran 8. Rodríguez del Río P, Díaz-Perales A, Sánchez-García S, Escudero 2Division of Gastroenterology, Department of Pediatrics, Tehran C, Ibáñez M, Méndez-Brea P, et al. Profilin, a change in the University of Medical Sciences, Tehran, Iran paradigm. J Investig Allergol Clin Immunol. 2017;28(1):1-12. 3Department of Microbiology and Immunology, Laboratory of 9. Domínguez Ortega J, Pérez-Bedmar J, Rodríguez Jiménez B, Clinical Bacteriology and Mycology, KU Leuven, Leuven, Belgium Butrón M, Kindelan C, Ledesma A. Eosinophilic esophagitis 4Specialized Immunology Laboratory of Dr. Shahrooei, Ahvaz, due to profilin allergy. J Invest Allergol Clin Immunol. Iran 2008;19(4):321-39. 5Research Center for Immunodeficiencies, Tehran University of Medical Sciences, Tehran, Iran

J Investig Allergol Clin Immunol 2018; Vol. 28(5): 358-360 doi: 10.18176/jiaci.0290

Manuscript received October 1, 2017; accepted for publication Key words: Tetratricopeptide repeat domain 7A (TTC7A). Combined on June 25, 2018. Immunodeficiency. Gastrointestinal. Marina Lluncor-Salazar Palabras clave: Dominio de Repeticiones de Tetratricopeptides 7A Allergy Department (TTC7A). Inmunodeficiencia combinada. Gastrointestinal. Hospital Universitario La Paz Paseo de la Castellana, 261 28046 Madrid, Spain E-mail: [email protected] Tetratricopeptide repeat domain 7A (TTC7A) deficiency is a very rare and severe hereditary disorder [1,2]. Only a few cases have been reported to date. TTC7A, which is expressed in various cells, plays an important role in cellular processes such as cell polarity, gut and lymphocyte homeostasis, and development of T and B lymphocytes [3]. Mutations in this gene usually result in gastrointestinal defects and immunodeficiency. Variations in clinical manifestations have been observed in patients with TTC7A mutations. The most widely reported are combined immunodeficiency (CID) and gastrointestinal defects such as multiple intestinal atresia (MIA), diarrhea, and extensive enteropathy [2]. We report the case of a patient with gastrointestinal problems and immunodeficiency syndrome. A 4-year-old girl born to consanguineous Iranian parents presented with recurrent pneumonia and chronic diarrhea. Her birth weight was 3 kg. She was the first of 2 children, her junior being a healthy 2.5-year-old brother. During the second year of life, she was hospitalized several times owing to recurrent pneumonia. She also experienced nonbloody and nongreasy diarrhea, which gradually worsened. At 39 months of age, she was admitted to hospital with pneumonia and severe diarrhea (10-12 times a day) that had led to a 4-kg weight loss. She was discharged after a 2-week stay in hospital with a prescription for elemental formula, since the diarrhea had not completely ceased. In February 2017, her eyes and skin turned yellow. Therefore, she was hospitalized in the gastrointestinal department because of liver and gallbladder involvement, as well as persistent diarrhea. Liver biopsy showed cholestatic

liver disease with significantly reduced bile ducts in portal variable immunodeficiency accompanying enteropathy was areas. Consequently, she was diagnosed with vanishing bile reported in the third. Therefore, a missense mutation was duct syndrome and became a candidate for liver transplantation. identified in 2 patients and skipping of exon 17 in theTTC7A In July 2017, she was hospitalized because of lethargy gene in 1 patient [1]. and anorexia. Intravenous immunoglobulin (IVIG) was Phenotypic variation of TTC7A mutations complicates administered monthly because of hypogammaglobulinemia timely diagnosis, with the result that different therapeutic (IgG, 146 mg/dL; IgM, 12 mg/dL; IgA, 3 mg/dL). She was procedures are required [5]. As stated in the literature review, hospitalized owing to diarrhea and anorexia once again in up to three-quarters of patients with TTC7A mutations September 2017. developed a CID phenotype. This abnormality stems from Endoscopy and biopsy of the duodenum and stomach thymus failure and, consequently, defective lymphocyte revealed erythema in the distal third of the esophagus, a large development [5]. Despite the CD4 and CD8 deficiency in the bleeding ulcer in the cardia, erosive gastritis, and moderate patient we report, the T-cell count (CD3+) was normal. This chronic gastritis with focal activity. Pathological findings in the discrepancy could be attributed to the presence of a double- biopsy specimens from the duodenum and antrum suggested negative T-cell population (CD3+CD4–CD8–). It has been autoimmune enteropathy and chronic erosive gastritis, suggested that these double-negative T cells are involved in respectively. Histopathology also revealed Helicobacter pylori. regulation of T-cell activation [6]. Furthermore, high-resolution computed tomography of Recurrent diarrhea and enteropathy were major the lung revealed hyperaeration, mosaic attenuation, diffuse gastrointestinal problems in the present case. However, unlike bronchiectasis, and peribronchial thickening. Additionally, some patients with TTC7A deficiency, this case indicated no atelectasis and consolidation were observed in the right middle evidence of intestinal atresia. It has been suggested that the lobe segment. Pleural effusion was not detected. A chest CT absence of TTC7A protein could augment Rho kinase activity, scan indicated right parahilar and left upper lobe alveolar and thereby growth, cell polarity, differentiation of intestinal consolidation, along with bronchiectasis in the right middle cells, and cell homeostasis [3]. lobe. The main pulmonary artery was dilated, and pulmonary Even though most patients with TTC7A mutations die in hypertension was suspected. the early months of their lives [7], the initial symptoms of Magnetic resonance imaging revealed normal findings for the present patient manifested in the second year of life. As the liver, spleen, pancreas, gallbladder, and kidney, although reported by Fernandez et al [7], in addition to gastrointestinal fluid dilation caused by ileus was observed in the small bowel effects and immunodeficiency, patients withTTC7A mutation and colon. could also show dysfunctions of other organs such as the The lymphocyte and immunoglobulin profiles (normal thymus, liver, and lungs. We identified pulmonary and liver range adapted from reference [4]) were as follows: T-cell involvement in the case we report. subsets, CD3, 1780 (1400-3700) cells/μL; CD4, 593 (700- Syndromic diarrhea (tricho-hepato-enteric syndrome) 2200) cells/μL; CD8, 333.7 (490-1300) cells/μL; B-cell is another autosomal recessive disease that shares clinical subsets, CD19, 185.5 (390-1400) cells/μL; IgM, 84 mg/dL; manifestations—diarrhea and immunodeficiency—with MIA- IgG, 933 mg/dL; IgA, 8 mg/dL. These findings indicated CID. This rare syndrome is the result of a defect in the TTC37 T-cell lymphopenia (CD4 and CD8 deficiency) and B-cell and SKIVL2 genes. Patients with the syndrome manifest other lymphopenia. Despite the low levels of immunoglobulins, the symptoms such as facial dysmorphism and hair, skin, and liver evaluation of the antibody response to diphtheria and tetanus abnormalities [8]. was normal. A delayed-type hypersensitivity test with tetanus In conclusion, patients with gastrointestinal manifestations toxoid and a PPD test were performed to evaluate the function and immunodeficiency should be evaluated for mutations of cell-mediated immunity. The results of these tests indicated in TTC7A, TTC37, and SKIVL2 [8,9]. The severity of this dysfunction of cellular immunity. abnormality, its variable phenotypes, and overlapping Whole exome sequencing revealed a novel homozygous syndromes require advanced diagnostic measures such as mutation in the TTC7A gene (NM_001288951: exon17: whole exome sequencing to differentiate between alternatives c.1955delA). This took the form of a frameshift deletion and make a timely diagnosis. mutation (p.Q652fs) that is likely pathogenic based on most predictors. Sanger sequencing confirmed that the patient Funding was homozygous and her parents were heterozygous for this The authors declare that no funding was received for the mutation. present study. The clinical manifestations, laboratory findings, and genetic study revealed gastrointestinal defects and immunodeficiency syndrome. Unfortunately, at the age of 4 years, the patient Conflicts of Interest died of hepatic encephalopathy when she was admitted for The authors declare that they have no conflicts of interest. liver transplantation. We report the case of a patient with a novel TTC7A mutation. To the best of our knowledge, there have been References no previous reports of a frameshift deletion mutation in exon 17. Lawless et al [1] reported mutations of exon 17 1. Lawless D, Mistry A, Wood PM, Stahlschmidt J, Arumugakani in 3 patients, 2 of whom had MIA-CID, while common G, Hull M, et al. Bialellic Mutations in Tetratricopeptide

Repeat Domain 7A (TTC7A) Cause Common Variable Immunodeficiency-Like Phenotype with Enteropathy. J Clin Thermolability of Soybean Allergen Gly m bd 30K: Immunol. 2017;37(7):617-22. Report of a Case of Anaphylaxis 2. Yang W, Lee PP, Thong MK, Ramanujam TM, Shanmugam A, Koh MT, et al. Compound heterozygous mutations in TTC7A Ojeda P1, Pineda F2, Mourelle R1, Rubio G1, Yago A1, Baquero D1, cause familial multiple intestinal atresias and severe combined Ojeda I1 immunodeficiency. Clin Genet. 2015;88(6):542-9. 1Clinica de Asma y Alergia Dres. Ojeda, Madrid, Spain 3. Bigorgne AE, Farin HF, Lemoine R, Mahlaoui N, Lambert N, 2Diater Laboratories, Madrid, Spain Gil M, et al. TTC7A mutations disrupt intestinal epithelial apicobasal polarity. J Clin Invest. 2014;124(1):328-37. J Investig Allergol Clin Immunol 2018; Vol. 28(5): 360-362 4. Shearer WT, Rosenblatt HM, Gelman RS, Oyomopito R, doi: 10.18176/jiaci.0291 Plaeger S, Stiehm ER, et al. Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Key words: Soybean. Food allergy. Gly m bd30K. Thermolability. Clinical Trials Group P1009 study. J Allergy Clin Immunol. Anaphylaxis. 2003 Nov;112(5):973-80. Palabras clave: Soja. Alergia alimentaria. Gly m bd30K. Termolabilidad. 5. Lien R, Lin YF, Lai MW, Weng HY, Wu RC, Jaing TH, et al. Anafilaxia. Novel Mutations of the Tetratricopeptide Repeat Domain 7A Gene and Phenotype/Genotype Comparison. Front Immunol. 2017;8:1066. 6. Bhatnagar N, Girard PM, Lopez-Gonzalez M, Didier C, Collias L, Jung C, Bollens D, et al. Potential Role of Vδ2+ γδ T Cells Soybean is a legume from the oilseed family that is widely in Regulation of Immune Activation in Primary HIV Infection. consumed by humans and animals owing to its high content Front Immunol. 2017;8:1189. in proteins, carbohydrates, and fiber [1]. 7. Fernandez I, Patey N, Marchand V, Birlea M, Maranda B, A Spanish study carried out in children revealed a Haddad E, et al. Multiple intestinal atresia with combined positive result in 45%-85% of skin prick tests and specific immune deficiency related to TTC7A defect is a multiorgan IgE >0.7 kU/L against soybean, although fewer than 5% pathology: study of a French-Canadian-based cohort. presented symptoms after consumption [2]. Heat treatment, Medicine (Baltimore). 2014;93(29):e327. fermentation, and high-pressure processing may affect the 8. Neves JF, Afonso I, Borrego L, Martins C, Cordeiro AI, Neves allergenic potential of soy products [3]. C, et al. Missense mutation of TTC7A mimicking tricho- We report the case of a 38-year-old man who experienced hepato-enteric (SD/THE) syndrome in a patient with very-early skin itching, facial angioedema, progressive dyspnea, onset inflammatory bowel disease. Eur J Med Genet. 2018 low blood pressure, and loss of consciousness requiring Apr;61(4):185-8. hospitalization at an intensive care unit for 24 hours. The 9. Guana R, Garofano S, Teruzzi E, Vinardi S, Carbonaro G, symptoms appeared 5-10 minutes after eating a premade Cerrina A, et al. The complex surgical management of the white chocolate drink with almonds during the summer. At first case of severe combined immunodeficiency and multiple the time, he was being treated with finasteride, ibuprofen intestinal atresias surviving after the fourth year of life. Pediatr 600 mg (for joint pain, last dose 3-4 hours before onset of Gastroenterol Hepatol Nutr. 2014;17(4):257-62. symptoms), omeprazole, and hemorrhoid cream. He reported no previous effort and had eaten steak and pasta for lunch (both tolerated after the episode). Tryptase levels during the episode were 4.2 µg/dL. Previous allergy studies reported negative skin prick test results. Specific IgE against respiratory and food allergens Manuscript received April 28, 2018; accepted for publication (ISAC Microarray, Thermo Fisher) was negative to the whole June 28, 2018. panel, and challenge tests with ibuprofen and omeprazole were also negative. The patient had been advised to avoid nuts Nima Parvaneh Division of Allergy and Clinical Immunology, Department of before coming to our clinic and tolerated chocolate without Pediatrics symptoms. Children's Medical Centre, No 62 Gharib St Skin prick tests were repeated with Dermatophagoides 14194 Tehran, Iran. pteronyssinus, Alternaria species, dog and cat dander, grass E-mail: [email protected] pollen, olive tree pollen, Taraxacum species, milk, egg, wheat, gluten, gliadin, cashew, lupin bean, white fish, blue fish, shrimp, peanut, walnut, sunflower seed, peach LTP, latex, Anisakis species, cocoa, and sesame). Once again, the results were negative. As the results of tests with the beverage components had all been negative and chocolate was unlikely to be the cause of the anaphylactic reaction, a challenge test was scheduled with the same white chocolate he had consumed