Name: T-cell lymphopenia with or without nail dystrophy, AD | Acronym: TLIND
Alt. names: FOXN1 haploinsufficiency

Gene: FOXN1 | MOI: Autosomal dominant | Mechanism of action: Haploinsufficiency

No. of cases in DB: 71 | First reported in: 2005

Last updated on: 2023-04-01 03:28:58 by Xiao P. Peng

OMIM: 618806

Orphanet: 169095

MONDO: 0032928

DOID: -

ClinGen:

To date, 61 patients from 58 families have been described with heterozygous loss-of-function FOXN1 variants resulting in FOXN1 haploinsufficiency associated with low TREC levels and T cell lymphopenia at birth that progressively improves with age (PMID: 15897400, 31566583, 31447097). Nail dystrophy, recurrent sinorespiratory tract infections (predominantly viral), evidence of thymic hypoplasia or aplasia on imaging, dental caries, dermatitis and skin rashes, and hair abnormalities were the most common findings. A minority of patients also suffered from recurrent GI infections and mucocutaneous candidiasis. Immunophenotyping was notable for persistent lymphopenia during infancy affecting predominantly CD8+ T cells, decreased lymphocyte proliferative responses to mitogens, and abnormal numbers of B and NK cells in a minority of patients. One or few patients additionally had intellectual disability, failure-to-thrive, variable inflammatory findings, and congenital anomalies such as ventricular septal defects, polydactyly, Arnold-Chiari malformation, and tracheoesophageal fistula. Most adults showed normal CD4+ T cell counts but a lower than normal proportion of naive CD4+ T cells, suggesting that normalization of total CD4+ T cell count with age is contributed by homeostatic proliferation.

Anti-microbial prophylaxis and early and aggressive treatment of infections may be beneficial. HSCT is unlikely to be a curative treatment given the thymus-intrinsic defect. Indeed, of the three patients receiving HSCT before molecular diagnosis, two remained T cell lymphopenic after transplant despite successful engraftment and a third died of transplant-related complications 2 years post-HSCT. Given the normalization of T cell lymphopenia over time, it remains to be seen whether thymic transplant may be needed in severe cases.