Phenotypic and genetic characterization of heterozygous FOXN1 variants: a case series of mild immunodeficiency

Background: FOXN1 belongs to the Foxhead-box (FOX) family of transcription factors and is fundamental for the successful development of T cells in the thymus. Homozygous pathogenic variants in the FOXN1 gene are associated with a severe combined immunodeficiency (SCID) phenotype. In contrast, individuals carrying a heterozygous single pathogenic variant in FOXN1 demonstrate a less severe phenotype. Patients described thus far can present with frequent mild respiratory infections and associated T cell lymphopenia that has been shown to improve with age. We present three patients with heterozygous variants in FOXN1 presenting with a mild clinical phenotype. Methods: Informed consent was obtained from patients and families. Case data was compiled retrospectively from the patients’ medical charts. Genetic testing used an augmented exome slice of 251 genes implicated in inborn errors of immunity, with Sanger backfill of select genes. Case presentation: Probands P1 and P2 are two unrelated pediatric patients identified by a positive newborn screen for SCID. P3 is the father of P2. All were found to have heterozygous pathogenic variants in FOXN1. In P1 and P2, laboratory investigations revealed T cell lymphopenia on initial bloodwork. Lymphopenia improved with age. A surveillance approach was taken to manage both pediatric patients, based on local experience with similar presentations, and both have done well thus far. Aside from a typical number of minor infections including common upper respiratory tract illnesses and otitis media, neither child had infections requiring hospitalizations or IV antibiotics. Additionally, P1 and P2 tolerated live viral vaccines. P3 had a history of 1 severe dental infection but had otherwise been well prior to diagnosis, and since. Conclusion: With the increasing implementation of newborn screening, patients with heterozygous pathogenic variants in FOXN1 are increasingly identified. No clear care pathway has been established. Our cases add to the growing body of literature in presenting a cohort of patients with heterozygous pathogenic FOXN1 variants whose phenotype indicates mild, self-resolving infections despite T cell lymphopenia. It will be important to identify and follow these patients longitudinally to consider recommendation of a surveillance approach if appropriate, and to provide guidance to affected families regarding the trajectory of this condition. Statement of novelty: Heterozygous FOXN1 deficiency is currently an insufficiently understood condition, and its optimal management continues to be unclear. We present 2 case reports of children for whom a surveillance approach was taken successfully. Additionally, we describe a healthy adult who was found to have a heterozygous variant later in life.