Expanding the Nude SCID/CID Phenotype Associated with FOXN1 Homozygous, Compound Heterozygous, or Heterozygous Mutations

Abstract

Human nude SCID is a rare autosomal recessive inborn error of immunity (IEI) characterized by congenital athymia, alopecia, and nail dystrophy. Few cases have been reported to date. However, the recent introduction of newborn screening for IEIs and high-throughput sequencing has led to the identification of novel and atypical cases. Moreover, immunological alterations have been recently described in patients carrying heterozygous mutations. The aim of this paper is to describe the extended phenotype associated with FOXN1 homozygous, compound heterozygous, or heterozygous mutations. We collected clinical and laboratory information of a cohort of 11 homozygous, 2 compound heterozygous, and 5 heterozygous patients with recurrent severe infections. All, except one heterozygous patient, had signs of CID or SCID. Nail dystrophy and alopecia, that represent the hallmarks of the syndrome, were not always present, while almost 50% of the patients developed Omenn syndrome. One patient with hypomorphic compound heterozygous mutations had a late-onset atypical phenotype. A SCID-like phenotype was observed in 4 heterozygous patients coming from the same family. A spectrum of clinical manifestations may be associated with different mutations. The severity of the clinical phenotype likely depends on the amount of residual activity of the gene product, as previously observed for other SCID-related genes. The severity of the manifestations in this heterozygous family may suggest a mechanism of negative dominance of the specific mutation or the presence of additional mutations in noncoding regions.

Current and Future Therapeutic Approaches for Thymic Stromal Cell Defects

“…The long term follow up of the other patient showed sustained immune recovery, despite decreased thymic output over time (68), similar to what has been observed in transplanted cDGS patients. More recently, we have transplanted three further cases with homozygous or compound heterozygous FOXN1 mutations (67). Two had allograft biopsies confirming the establishment of thymopoeisis of whom, one has done well and one died as a consequence of severe inflammatory complications.…”

“…Yet 1 in 8 of the reported cases with FOXN1 heterozygosity suffered a more severe degree of immune deficiency. An additional recent report highlights that a spectrum of clinical manifestations may be associated with different mutations (67). Disease severity likely depends on the residual FOXN1 protein activity.…”

“…This is an autosomal recessive (AR) disorder due to bi-allelic loss-offunction (LOF) mutations in FOXN1, a critically important transcription factor expressed in epithelial cells of the thymus, skin and nail matrix (113). Nude SCID has been reported in a small number of patients in whom FOXN1 deficiency underlies an impaired development of the thymic epithelial stroma with subsequent impaired T-cell differentiation (66,67,(114)(115)(116). Their profound T-cell lymphopenia is marked by very low counts of naïve T-cells and recent thymic emigrants, as well as impaired T-cell proliferation responses.…”

“…Their profound T-cell lymphopenia is marked by very low counts of naïve T-cells and recent thymic emigrants, as well as impaired T-cell proliferation responses. A handful of Nude SCID patients have been treated by HSCT, of which three, receiving transplantation from a matched sibling donor, have been reported (67,(116)(117)(118). Only one patient survived, but without regeneration of CD4 + naïve T-cells (117).…”

“…In the mouse model, a gene dosage effect was documented for Foxn1 expression in TECs for all of the heterozygote variants. Three patients with compound heterozygosity for LOF mutations also displayed more severe clinical phenotype (67,133). While most FOXN1 +/patients can be successfully managed conservatively, a better understanding of the mechanisms of action of these mutations and of their impact on FOXN1 function is necessary to be able to predict which cases should at least be considered for potentially corrective treatment.…”