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Congenital athymia
Congenital athymia
	Human thymus, posterior view.
Specialty	Immunology, Medical genetics

Congenital athymia is an extremely rare disorder marked by the absence of the thymus at birth.^[1] T cell maturation and selection depend on the thymus, and newborns born without a thymus experience severe immunodeficiency.^[2] A significant T cell deficiency, recurrent infections, susceptibility to opportunistic infections, and a tendency to develop autologous graft-versus-host disease (GVHD) or, in the case of complete DiGeorge syndrome, a "atypical" phenotype are characteristics of congenital athymia.^[3]^[4]

Signs and symptoms

Congenital athymia's clinical symptoms are directly related to the thymus's absence and its incapacity to generate T cells with the necessary immune capabilities. An increased vulnerability to bacterial, viral, and fungal infections results from T-cell immunodeficiency.^[1]

These patients have an especially high incidence of pneumonias. M. bovis and the respiratory syncytial virus have been linked to additional cases of severe pulmonary infections. This group is also prone to gastrointestinal infections, such as those caused by the rotavirus, norovirus, enterovirus, M. bovis, and C. difficile viruses. Diarrhea, malabsorption, and failure to thrive can result from these infections. Although gastrointestinal and lung infections are the most frequently reported infection types, congenital athymia patients can present with a wide range of other infection types. There have been reports of infections of the head, ears, nose, and throat, including meningitis, sinusitis, mastoiditis, and thrush, as well as infections of the urinary tract caused by K. pnuemoniae, E. faecium, and echovirus.^[5]^[6]^[7]

T cells may expand extrathymic oligoclonally in congenital athymia. These cells can infiltrate organs and result in autologous graft-versus-host disease, but they confer little to no protective immunity. Individuals who have an expansion of oligoclonal T cells usually have an eczematous rash and accompanying lymphadenopathy. T cell infiltration can result in enteropathy and transaminitis in the gastrointestinal tract.^[8]

Congenital athymia patients also have other autoimmune-mediated manifestations, such as autoimmune thyroiditis, hypothyroidism, and Coombs-positive hemolytic anemia.^[7]^[6]^[5]

Causes

Congenital athymia is linked to a number of genetic disorders, congenital syndromes, and environmental variables. Genetic abnormalities that are either (1) specific to thymic development or (2) related to the development of the midline region as a whole can cause congenital athymia.^[1]

Risk factors

Congenital athymia is linked to multiple environmental etiologies. Affected fetal thymus size and other congenital anomalies like renal agenesis and butterfly vertebrae are linked to diabetic embryopathy.^[9] It has been shown that babies of diabetic mothers have thymic aplasia.^[10] Retinoic acid exposure during fetal development is also linked to phenotypes associated with DiGeorge syndrome, such as hypoplasia and thymic developmental abnormalities such as aplasia and ectopia.^[11]

Genetics

The most well-known gene associated with thymic development is Forkhead Box N1 (FOXN1). As a member of the transcription factor family known as the forkhead box gene family, FOXN1 plays a role in the growth and differentiation of skin epithelial cells as well as the development, differentiation, and maintenance of thymic epithelial cells during embryonic and postnatal life.^[12]^[13]^[14]

The transcription factors known as the paired box family, which control tissue differentiation, includes Paired Box 1 (PAX1).^[15] Numerous studies have reported on patients with autosomal recessive otofaciocervical syndrome type 2 (OTFCS2) and mutations in PAX1. Because of altered thymus development, OTFCS2 is associated with a syndromic form of SCID.^[16]^[17]

The two most common genetic syndromes linked to thymus development defects are 22q11.2 deletion syndrome and CHARGE syndrome. Patients with these syndromes exhibit a variety of symptoms because the genes TBX1 and CHD7, associated with these disorders, play a role in the development of the entire midline region.^[1] Additional genes that may be involved in healthy thymus development are FOXI3 and TBX2.^[18]^[19]

Treatment

In October 2021, the thymus tissue product Rethymic was approved by U.S. Food and Drug Administration (FDA) as a medical therapy for the treatment of children with congenital athymia.^[20] It takes six months or longer to reconstitute the immune function in treated children.^[20]

References

^ ^a ^b ^c ^d Collins, Cathleen; Sharpe, Emily; Silber, Abigail; Kulke, Sarah; Hsieh, Elena W. Y. (13 May 2021). "Congenital Athymia: Genetic Etiologies, Clinical Manifestations, Diagnosis, and Treatment". Journal of Clinical Immunology. 41 (5). Springer Science and Business Media LLC: 881–895. doi:10.1007/s10875-021-01059-7. ISSN 0271-9142. PMC 8249278.
^ Markert, M.Louise; Hummell, Donna S.; Rosenblatt, Howard M.; Schiff, Sherrie E.; Harville, Terry O.; Williams, Larry W.; Schiff, Richard I.; Buckley, Rebecca H. (1998). "Complete DiGeorge syndrome: Persistence of profound immunodeficiency". The Journal of Pediatrics. 132 (1). Elsevier BV: 15–21. doi:10.1016/s0022-3476(98)70478-0. ISSN 0022-3476. PMID 9469994.
^ Markert, M. Louise; Devlin, Blythe H.; Alexieff, Marilyn J.; Li, Jie; McCarthy, Elizabeth A.; Gupton, Stephanie E.; Chinn, Ivan K.; Hale, Laura P.; Kepler, Thomas B.; He, Min; Sarzotti, Marcella; Skinner, Michael A.; Rice, Henry E.; Hoehner, Jeffrey C. (6 February 2007). "Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants". Blood. 109 (10). American Society of Hematology: 4539–4547. doi:10.1182/blood-2006-10-048652. ISSN 0006-4971. PMC 1885498. PMID 17284531.
^ Markert, M. Louise; Marques, José G.; Neven, Bénédicte; Devlin, Blythe H.; McCarthy, Elizabeth A.; Chinn, Ivan K.; Albuquerque, Adriana S.; Silva, Susana L.; Pignata, Claudio; de Saint Basile, Geneviève; Victorino, Rui M.; Picard, Capucine; Debre, Marianne; Mahlaoui, Nizar; Fischer, Alain; Sousa, Ana E. (13 January 2011). "First use of thymus transplantation therapy for FOXN1 deficiency (nude/SCID): a report of 2 cases". Blood. 117 (2). American Society of Hematology: 688–696. doi:10.1182/blood-2010-06-292490. ISSN 0006-4971. PMC 3031487.
^ ^a ^b Janda, Ales; Sedlacek, Petr; Hönig, Manfred; Friedrich, Wilhelm; Champagne, Martin; Matsumoto, Tadashi; Fischer, Alain; Neven, Benedicte; Contet, Audrey; Bensoussan, Danielle; Bordigoni, Pierre; Loeb, David; Savage, William; Jabado, Nada; Bonilla, Francisco A.; Slatter, Mary A.; Davies, E. Graham; Gennery, Andrew R. (30 September 2010). "Multicenter survey on the outcome of transplantation of hematopoietic cells in patients with the complete form of DiGeorge anomaly". Blood. 116 (13). American Society of Hematology: 2229–2236. doi:10.1182/blood-2010-03-275966. ISSN 0006-4971. PMC 4425440. PMID 20530285.
^ ^a ^b Markert, M. Louise; Alexieff, Marilyn J.; Li, Jie; Sarzotti, Marcella; Ozaki, Daniel A.; Devlin, Blythe H.; Sedlak, Debra A.; Sempowski, Gregory D.; Hale, Laura P.; Rice, Henry E.; Mahaffey, Samuel M.; Skinner, Michael A. (15 October 2004). "Postnatal thymus transplantation with immunosuppression as treatment for DiGeorge syndrome". Blood. 104 (8). American Society of Hematology: 2574–2581. doi:10.1182/blood-2003-08-2984. ISSN 0006-4971. PMID 15100156.
^ ^a ^b Davies, E. Graham; Cheung, Melissa; Gilmour, Kimberly; Maimaris, Jesmeen; Curry, Joe; Furmanski, Anna; Sebire, Neil; Halliday, Neil; Mengrelis, Konstantinos; Adams, Stuart; Bernatoniene, Jolanta; Bremner, Ronald; Browning, Michael; Devlin, Blythe; Erichsen, Hans Christian; Gaspar, H. Bobby; Hutchison, Lizzie; Ip, Winnie; Ifversen, Marianne; Leahy, T. Ronan; McCarthy, Elizabeth; Moshous, Despina; Neuling, Kim; Pac, Malgorzata; Papadopol, Alina; Parsley, Kathryn L.; Poliani, Luigi; Ricciardelli, Ida; Sansom, David M.; Voor, Tiia; Worth, Austen; Crompton, Tessa; Markert, M. Louise; Thrasher, Adrian J. (2017). "Thymus transplantation for complete DiGeorge syndrome: European experience". Journal of Allergy and Clinical Immunology. 140 (6). Elsevier BV: 1660–1670.e16. doi:10.1016/j.jaci.2017.03.020. hdl:10547/622087. ISSN 0091-6749. PMID 28400115.
^ Markert, M. Louise; Devlin, Blythe H.; Chinn, Ivan K.; McCarthy, Elizabeth A. (9 December 2008). "Thymus transplantation in complete DiGeorge anomaly". Immunologic Research. 44 (1–3). Springer Science and Business Media LLC: 61–70. doi:10.1007/s12026-008-8082-5. ISSN 0257-277X. PMC 4951183. PMID 19066739.
^ Dörnemann, Ria; Koch, Raphael; Möllmann, Ute; Falkenberg, Maria Karina; Möllers, Mareike; Klockenbusch, Walter; Schmitz, Ralf (1 January 2017). "Fetal thymus size in pregnant women with diabetic diseases". Journal of Perinatal Medicine. 45 (5). Walter de Gruyter GmbH: 595–601. doi:10.1515/jpm-2016-0400. ISSN 1619-3997. PMID 28195554. S2CID 4920690.
^ Wang, Raymond; Martínez-Frías, Maria Luísa; Graham, John M. (2002). "Infants of diabetic mothers are at increased risk for the oculo-auriculo-vertebral sequence: A case-based and case-control approach". The Journal of Pediatrics. 141 (5). Elsevier BV: 611–617. doi:10.1067/mpd.2002.128891. ISSN 0022-3476. PMID 12410187.
^ Coberly, S; Lammer, E; Alashari, M (1996). "Retinoic acid embryopathy: case report and review of literature". Pediatric Pathology & Laboratory Medicine. 16 (5): 823–836. PMID 9025880.
^ Blackburn, C C; Augustine, C L; Li, R; Harvey, R P; Malin, M A; Boyd, R L; Miller, J F; Morahan, G (11 June 1996). "The nu gene acts cell-autonomously and is required for differentiation of thymic epithelial progenitors". Proceedings of the National Academy of Sciences. 93 (12): 5742–5746. Bibcode:1996PNAS...93.5742B. doi:10.1073/pnas.93.12.5742. ISSN 0027-8424. PMC 39131. PMID 8650163.
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^ Paganini, I.; Sestini, R.; Capone, G.L.; Putignano, A.L.; Contini, E.; Giotti, I.; Gensini, F.; Marozza, A.; Barilaro, A.; Porfirio, B.; Papi, L. (24 October 2017). "A novel <scp>PAX1</scp> null homozygous mutation in autosomal recessive otofaciocervical syndrome associated with severe combined immunodeficiency". Clinical Genetics. 92 (6). Wiley: 664–668. doi:10.1111/cge.13085. ISSN 0009-9163. PMID 28657137. S2CID 33417887.
^ Yamazaki, Yasuhiro; Urrutia, Raul; Franco, Luis M.; Giliani, Silvia; Zhang, Kejian; Alazami, Anas M.; Dobbs, A. Kerry; Masneri, Stefania; Joshi, Avni; Otaizo-Carrasquero, Francisco; Myers, Timothy G.; Ganesan, Sundar; Bondioni, Maria Pia; Ho, Mai Lan; Marks, Catherine; Alajlan, Huda; Mohammed, Reem W.; Zou, Fanggeng; Valencia, C. Alexander; Filipovich, Alexandra H.; Facchetti, Fabio; Boisson, Bertrand; Azzari, Chiara; Al-Saud, Bander K.; Al-Mousa, Hamoud; Casanova, Jean Laurent; Abraham, Roshini S.; Notarangelo, Luigi D. (14 February 2020). "PAX1 is essential for development and function of the human thymus". Science Immunology. 5 (44). American Association for the Advancement of Science (AAAS). doi:10.1126/sciimmunol.aax1036. ISSN 2470-9468. PMC 7189207. PMID 32111619.
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^ ^a ^b "FDA Approves Innovative Treatment for Pediatric Patients with Congenital Athymia". U.S. Food and Drug Administration (FDA) (Press release). 8 October 2021. Retrieved 8 October 2021. This article incorporates text from this source, which is in the public domain.