Congenital Athymia: Genetic Etiologies, Clinical Manifestations, Diagnosis, and Treatment

Cathleen Collins, Emily Sharpe, Abigail Silber, Sarah Kulke, Elena W Y Hsieh, Cathleen Collins, Emily Sharpe, Abigail Silber, Sarah Kulke, Elena W Y Hsieh

Abstract

Congenital athymia is an ultra-rare disease characterized by the absence of a functioning thymus. It is associated with several genetic and syndromic disorders including FOXN1 deficiency, 22q11.2 deletion, CHARGE Syndrome (Coloboma, Heart defects, Atresia of the nasal choanae, Retardation of growth and development, Genitourinary anomalies, and Ear anomalies), and Complete DiGeorge Syndrome. Congenital athymia can result from defects in genes that impact thymic organ development such as FOXN1 and PAX1 or from genes that are involved in development of the entire midline region, such as TBX1 within the 22q11.2 region, CHD7, and FOXI3. Patients with congenital athymia have profound immunodeficiency, increased susceptibility to infections, and frequently, autologous graft-versus-host disease (GVHD). Athymic patients often present with absent T cells but normal numbers of B cells and Natural Killer cells (T-B+NK+), similar to a phenotype of severe combined immunodeficiency (SCID); these patients may require additional steps to confirm the diagnosis if no known genetic cause of athymia is identified. However, distinguishing athymia from SCID is crucial, as treatments differ for these conditions. Cultured thymus tissue is being investigated as a treatment for congenital athymia. Here, we review what is known about the epidemiology, underlying etiologies, clinical manifestations, and treatments for congenital athymia.

Keywords: Congenital athymia; DiGeorge; T cells; immunodeficiency; midline defects.

Conflict of interest statement

Cathleen Collins, Emily Sharpe, Abigail Silber and Elena Hsieh receive consulting fees from Enzyvant Therapeutics. Sarah Kulke is Vice President of Medical Affairs at Enzyvant Therapeutics (since May 2020) and therefore receives salary, annual performance bonus, and cash based long term incentive program.

Figures

Fig. 1
Fig. 1
Genetic etiologies of congenital athymia and impact on embryogenesis. Artistic rendering of the different etiologies associated with congenital athymia and how they impact the developing embryo. Genetic etiologies can be categorized by whether the impacted gene is involved in development of the entire midline region or more directly in thymic organ development
Fig. 2
Fig. 2
Normal thymus embryogenesis. Artistic rendering of the development of the thymus and parathyroid from the third pharyngeal pouch. Spatial and functional separation occurs early, with the thymus in the ventral posterior region and the parathyroid more anterior. During development, the thymus migrates caudally and medially to its final position in the anterior part of the thorax and fuses with the developing thymus from the contralateral side
Fig. 3
Fig. 3
Congenital athymia diagnostic pathway. Schematic of the diagnostic pathway for congenital athymia from initial identification through newborn screening to final diagnosis, including steps for how to accurately differentiate athymia from T−B+NK+ SCID

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